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NATIONAL INSTITUTES OF HEALTH
NIH LIBRARY

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BLDG 10, 10 CENTER DR
BETHESDA,MD 20892-1150

DIVISION OF COMPUTER RESEARCH AND TECHNOLOGY

FISCAL

YEAR

1981

ANNUAL
REPORT

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DIVISION OF COMPUTER RESEARCH AND TECHNOLOGY

FISCAL ANNUAL VOLUME 1

YEAR REPORT

1981

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Foreword

The work of the Division of Computer Research and
Technology covers a large spectrum of activities. It
ranges from doing research in biology, statistics,
mathematics, and computer science to providing
computer facilities and services for the NIH.

The several DCRT laboratories and branches
embody and integrate this variety of talents. Each
has a major functional focus. But the success of the
Division's work arises from the interaction of
members of each group with others across
organizational and disciplinary lines. Many projects in
the Division require the expertise of people from
several segments of the spectrum.

DCRT's collaborative projects link its staff to
professionals both inside and outside NIH. The result
is a balance in emphasis to provide the work done
by DCRT at NIH with the benefits of collaborations
outside of NIH.

While DCRT does not have money for grants, it does
provide occasional support for meetings on scientific
topics related to its work.

This year's annual report is presented in two
volumes:

Volume 1 gives a summary overview of the

work of each group and highlights its

accomplishments.

Volume 2 includes detailed projects and

activities of each group.
If you have comments on the report or suggestions
for improving future annual reports, please send
them to:

DCRT Information Office

Building 12A, Room 3027

Division of Computer Research

and Technology
National Institutes of Health

Bethesda, Maryland 20205

Dr. Arnold Pratt, DCRT Director, is internationally known for
his research in computational linguistics.

From the Director

The Division of Computer Research and Technology
(DCRT) was established in 1964 to make computers
useful at NIH. Over the years, the work of the
Division has become an integral part of the conduct
and management of NIH research programs.

It is a pleasure to report once again the
accomplishments of the people in an exceptionally
competent and productive group of laboratories,
branches, and offices. All parts of the DCRT
program are important for that balance of science
and technology that has made the Division and
computing throughout NIH so successful.

Three brief glimpses into the stream of fiscal year
1981 history, help to show that computing thrives and
supports progress in all the NIH programs.
• NIH biomedical scientists got wide recognition
for using computers. A single June issue of the
NIH Record carried three examples.
One article told of a young NIH staff physician
becoming professor of radiology at an academic
medical center. He first came to NIH in 1973 as
a medical student for our course on computers
in medicine; after graduating, he returned to
work in DCRT and in the NIH Nuclear fvledicine
Department, creating and using new computing
techniques.

Another reported an award by the Endocrine
Society to an NIH medical scientist for
outstanding leadership and service. The award
was for his development of a series of computer
programs that are used in laboratories
throughout the world as well as widely at NIH.
The third story told of a prestigious European
prize for distinction in advancement of
knowledge about diabetes mellitus. The picture
in the Record showed the recipient working at
a computer terminal, using one of the several
advanced DCRT systems he exploited
successfully while he was a Visiting Scientist at
NIH.

• NIH can pay its suppliers promptly. A computer
system can now process vouchers for goods
and services as soon as they come to the NIH
Accounts Payable Section. In the past, manual
processing labored under week- or month-long
backlogs. The administrative data base system
created by DCRT staff cuts out most of the
paper work in voucher payment, and it also
automatically records obligations and accruals in
the central accounting record.

• The NIH Computer Center obtained contracts
for new equipment. This feat came after
seemingly endless years of preparation and
negotiation. Over the next five or more years,
the 8,000 users of the central NIH systems will
benefit in a timely way from proven advances in
computing technology.

DCRT looks forward with enthusiasm to the coming
year as an opportunity to work with NIH scientists
and administrators in creating still more powerful and
useful systems. The challenge lies in building strong
intellectual links from computers, mathematics, and
engineering to the substance of science and the art
of administration. After 17 years the frontiers of
computing remain open for new advances in all NIH
programs. Research and development programs
within DCRT will continue to help lead the way.

InA*^'

Arnold W. Pratt, M.D.

Director

Division of Computer Research
and Technology

Contents

Division of Computer Research
and Technology

Laboratory of Statistical and Mathematical
Methodology 8

Provides statistical and mathematical help in the
computer analysis of biomedical data; offers
statistical and mathematical packages for users;
develops methodology in multivariate analysis, curve
fitting, biological shape and pattern theory.

Computer Systems Laboratory 14

Provides consultation and collaboration in the design
and implementation of specialized computer systems
for laboratory and clinical applications.

Laboratory of Applied Studies 20

Relates mathematics, statistics, and computer
science to such biomedical problems as ECG
analysis, evaluation of physiological systems in
health and disease, modeling of the microcirculation,
and estimation problems in laboratory medicine.

Physical Sciences Laboratory 24

Conducts research in mathematical theory and
practical instrumentation to explain biological
phenomena in terms of chemistry and physics at the
subcellular molecular levels.

Data Management Branch 28

Serves as a central resource of systems analysis,
design, and programming for data processing
projects relating to scientific, technical, management,
and administrative data.

Computer Center Branch 32

Designs, implements, and operates the NIH
Computer Center; provides assistance, training and
technical communications to the more than 8,000
users of the Central Utility.

Office of ADP Policy Coordination 39

Coordinates the complex Federal policies and
procedures that govern getting and using computers
at NIH.

Office of Administrative Management 41

Provides general administrative management support
for the Division's w^ork.

Office of Scientific and Technical 42
Communications

Serves as a central source of information about
DCRT activities and about computer-related
disciplines.

LSM combines research in mathematical statistics,
mathematics, and computer and information science.

Research projects in LSM vary from studies of natural
language processing for medical information systems to
studies in statistical methodologies for biomedical
applications.

Laboratory of Statistical and
i\/lathematical l\/lethodology

James E. Mosimann, Chief

Function

In addition to the position of chief, the laboratory has
fifteen full-time professional positions distributed
among four sections:

• The Statistical Software Section (SSS)
provides consultation to and collaboration with
NIH researchers and administrators in all
computational aspects of biomedical data
analysis, including selection and support of large
systems/packages. Three specialists in scientific
programming are led by a computer systems
analyst whose specialty is statistics.

• The Biomatiiematics and Computer Science
Section (BCS), directed by a mathematician,
performs independent research and provides
consultation and collaboration in the specialties
of its five computer and mathematical scientists.

• The Statistical Methodology Section (SMS)
works closely with the Statistical Software
Section. Two professionals in mathematical
statistics provide biostatistical consultation and
do independent research.

• The Medical Information Science Section
(MIS) investigates and develops methods for
application of information and computer science
to medical language data processing. Two
computer specialists work under the direction of
a computer systems analyst who is an expert in
computational linguistics.

Scope of Work

LSM staff interact with all NIH institutes, with other
Federal agencies outside HHS, and with biomedical
researchers worldwide. FY81 was LSM's seventh
year as a separate entity within DCRT. The volume
of its computational and consultative services
continued to expand; its research activities
maintained about the same level as the preceding
year.

A major part of LSM activity is the offering of
statistical and mathematical systems/ packages to
the NIH user community. LSM accepts responsibility

for evaluation of new systems/packages and their
suitability for NIH. When it offers a system/package
to the NIH community, LSM makes three basic
commitments:

1. Maintenance of the package, with adequate
documentation, through NIH computer system
changes, system/package updates, and corrections.

2. Rapid response to queries concerning user
access to a system/package program, including job
control language and program parameters.

3. Assistance in interpretation of results.
During this year, as in the past year, the Statistical
Software Section of LSM maintained the following
systems/packages and programs on the IBM 370
system of the DCRT Computer Center:

BMD (BMDP, Biomedical Computer Programs,
UCLA)

SPSS (Statistical Package for the Social Sciences,
SPSS, Inc.)

SAS (Statistical Analysis System, SAS Institute,
Inc.)

P-STAT (Statistical Package, P-STAT, Inc.)

IMSL (International Mathematical and Statistical
Libraries, IMSL, Inc.)

MSTAT1 (Collection of Mathematical and
Statistical Programs, DCRT)
There is a major commitment to maintain these
systems/packages and respond to queries about
their use. In FY81 alone the SSS staff responded to
over 4,500 calls. Also during this year, every system/
package went through at least one major update.

The Biomathematics and Computer Science Section
maintains several systems/packages and specialized
systems on the DECsystem-10 of the Computer
Center. Foremost in use is the interpretive system
MLAB, designed (by LSM scientists) for
biomathematical modeling. BCS supports the
PROLOG system (for non-numerical data
processing) and also a DECsystem-10 version of
IMSL whose S/370 version is supported by SSS. C-
LAB, a system on the DEC-10 for pattern recognition
and clustering (written by an LSM scientist) is
supported by SMS. The Unified Generator Package,
written and maintained by a BCS staff member, is on
DCRT's IBM System 370.

As a result of LSM's policy of not only supporting the
use of these systems/packages but also aiding in

42000 -T

37800 -

33600 -

29400 -

25200 -

21000 -

16800 -

12600 -

8400 -

4200 -

1000 -

Uses per month of

Statistical paclcages supported by LSIVi*

JUN'75 JUN'76 JUN 77 JUN '78 JUN '79 JUN '80 JUN '81

'Packages supported by the Statistical Software Section only. Does not include
packages supported by the Biomathematics and Computer Sciences Section.

the interpretation of their output, the statisticians of
the Statistical Methodology Section provide
consultation over a wide range of scientific fields.
Some very brief consultations are very successful
because there is a known answer to the question at
hand. Other consultations involve extensive time and
statistical/mathematical/computer science research
as well.

Research projects in LSM vary widely from studies
of natural language processing for medical
information systems and studies of efficient
algorithms for information retrieval to studies in
mathematics and statistical methodologies for
biomedical applications.

Highlights of the Year's Activities

Computation

In FY81 LSM continued to expand teaching and
documentation for supported systems/packages.
LSM taught four introductory courses for SAS, two
for BMDP, two for SPSS, and one for IMSL. In
addition, two introductory courses and one advanced
course for MLAB, and one introductory course for C-
LAB were taught. Five articles on MLAB techniques
and one article on mathematical modeling of
chemical kinetics systems appeared in INTERFACE.
A new edition of the MLAB Applications Manual was
released, with additional sections on bivariate density
analysis (including 3-dimensional graphics and
contour mapping methods in MLAB) and on delta
modulation encoding of signals.

Two new systems/packages were offered on an
experimental basis to the NIH computer user
community. SCSS, an interactive version of SPSS,
and SAS/GRAPH, a graphics package from the SAS
Institute, were installed and tested at DCRT.

A DECsystem-10 utility program for interactive
computer generation of an index to a user's
document was completed. It is being production-
tested on new editions of the MLAB Reference
Manual and the MLAB Beginner's Guide, now in
preparation.

MLAB was enhanced by technical improvements to
increase speed and reduce memory requirements
and by the addition of Fourier transform and inverse
transform operators.

Consultation, Collaboration, and Research

As in FY80, LSM consultation and research in FY81
was closely tied to the use of the computer. Most
consultations (55 percent) involved statistical advice
combined with considerable computer use. Others
(40 percent) involved computer use alone and a
small fraction (5 percent) involved mathematical or
statistical advice with only limited computer use.

In FY81, LSM research, collaborative, and
consultative efforts merged more closely and were
less distinguishable among themselves. In a number
of studies, statistical methodologies were developed
for, or modified to suit, specific biomedical problems.
For example, in a collaboration with A. DeBlas,
NHLBI, discrete distribution models were used to

analyze data from monoclonal hybridoma
experiments. In a collaboration with A. Grimes, CC,
an unordered paired-data method was modified to
study monaural versus binaural amplification in
hearing-impaired children. In a third example, a
collaboration of several years duration (with Drs. G.
Hirschman, R. Wineman, and M. Wolfson, NIADDK)
on complications of dialysis for patients with end
stage kidney disease was completed, using a special
method for adjusting hospitalization rate by the
patient's length of time at risk. Results from all three
collaborations have been published or accepted for
publication.

Other areas in which LSM consultation led to
productive collaborative efforts include studies on
schistosomiasis with Dr. A. Cheever, NIAID, with
three papers published, as well as studies on the
pain syndrome Causalgia with Dr. A. Tahmoush,
NINCDS. In the latter case a paper, using linear
model methods, for unbalanced data, has been
prepared on measurements of sympathetic nervous
system activity in patients versus controls.

Statistical research on simultaneous confidence
intervals for ratios continued in FY81. The results, of
wide applicability, are accepted for publication. Other
research included a study of the connection between
statistical and algebraic independence. These results
are applicable to the sample covariance matrix of
multivariate data. This latter is important in statistical
discriminant analyses, which is a subject of LSM
research in collaboration with Drs. J. Darroch,
Flinders University, South Australia, and H. Hoffman,
DRS. Discriminant methods adapted for size and
shape variables are being used to study genetic
variation in laboratory mice. A separate study of
independence of size and shape variables before
and after scale change is in press, along with other
LSM studies of statistical distributions.

In computer science, research on computer
generation of scientific manuscripts led to
development of an interactive software system. This
system has the capability of generating complex
displays of mathematical formulas and MLAB
graphics on a high-resolution printer-plotter. Recent
research on procedures for managing extendible
array files was completed and published. Research
also continued on the 'symmetric axis' method for

Staff members teach courses on the use of various program
packages that LSM supports.

The Statistical Software Section (SSS) provides consultation
to and collaboration with NIH researchers and
administrators.

describing biological shapes. This included
augmentation of software, publication of a paper or
the geometry of the three-dimensional case, and
collaboration with Dr. R. Webber, NIDR, in the
analysis of human mandible images. Mathematical
studies of equivalence of theories of modules over
ring, and also of convex homogeneous cones in
finite-dimensional vector spaces over the real field
were completed. The latter studies have potential
application in a variety of areas, including size and
shape variables. In linguistic analysis an extensive
set of IBM 370 assembly language programs was
developed for the automatic identification of prefixe
and suffixes in French medical terminology. In
collaboration with Drs. J. Costa and D. Henson, NC
studies of the automatic processing of natural
language surgical pathology reports continued.

Future Plans

No major shift in laboratory service or research is
anticipated in the coming year. Current levels of
statistical and mathematical systems/packages
support, consultation, and user assistance will be
maintained. Research projects will be continuations
of those already initiated and reported here.

Publications

Blum. H : 3-D Symmetric Axis Coordinates: An Overview and Prospectus In
Badler. N . Bajcsy. R and Otto. G. (Eds.): Three Dimensional Ob/ecl
Representation New YorK. London, and Heidelberg. Spnnger-Veriag,
1981

Carlson. R , and Malley, J D.: Job Satisfaction of Staff RN'S in Primary and
Team Nursing Delivery Systems Research in Nursing and Health,

Cheever, A. W.. Duvall, R. H.. Minker, R. G,: Extrahepatic Pathology in
Rabbits Infected with Japanese and Philippine Strains of Schistosoma
Japonicum and the Relation of Intestinal Lesions to Passage of Eggs in
the Feces The American Journal of Tropical Medicine and Hygiene 29:
1316-1326. 1980

Cheever, A W. Duvall. R H , Minker. R. G . and Nash T E.: Hepatic
Fibrosis in Rabbits Infected with Japanese and Philippine Strains of
Schistosoma Japonicum The American Journal of Tropical Medicine
and Hygiene 29: 1327-1339. 1980.

Cheever. A, W , Duvall R H,. and Minker. R. G.: Quantitative Parasitologic
Findings in Rabbits Infected with Japanese and Philippine Strains of
Schistosoma Japonicum The American Journal of Tropical Medicine
and Hygiene 29: 1307-1315. 1980.

DeBlas. A, L,. Ratnaparkhi. M. V.. Mosimann, J. E.: Estimation of the
number of monoclonal hybridomas in a cell fusion expenment. Journal
of Immunological Methods (in press)

Garcia-Hidalgo. I , and Dunham, G.: An experiment in English-Spanish auto-
mated translation of medical language data Methods of Information in
Medicine 2^: 38-46. 1981,

Gnmes. A. M.. Mueller, H G. and Malley. J, D.: Examination of binaural
amplification in children. Ear and Hearing (in press).

Hirschman. G. H,. Wolfson, M., Mosimann, J. E,. Clark, C B.. Dante. M. L.,
and Wineman. R. J.: Complications of dialysis. Clinical Nephrology
15:66, 1981

Hutchinson. G : A complete logic for n-permutable congruence lattices.
Algebra Universalis (in press).

Knott. G. D.: Procedures for managing extendible array files Software
Practice and Experience 11: 63-84, 1981.

Malley. J. D.: Simultaneous confidence intervals for ratios of normal means.
Journal of The American Statistical Association (in press),

Minker. J., and Minker. R. G.: Optimization of Boolean Expressions-Histori-
cal Developments, Annals of the History of Computing 2: 227-238.
1980

Mosimann. J. E.. and Malley, J. D,: The Independence of Size and Shape
Before and After Scale Change, In Taillie. C. Patil. G P . and Baldes-
sari. B. (Eds): Statistical Distributions in Scientific Work, Vol 4. Models,
Structures and Characterizations Dordrecht, Holland. D Reidel Pub-
lishing Co (in press).

Norton. L M : A note about Laplace transform tables for computer use.
SIGSAM Bulletin 14: 30-31. 1980.

O'Connor. M A : Invariant metrics on cones. Proc of the Conference on
Invariant Metrics and Holomorphic Maps. Rome. Italy. Istituto di Alta
Matematica F. Seven di CNR, (in press)

Ratnaparkhi. M V : Some bivanate distributions of (X.Y) where the condi-
tional distnbution of Y. given X is either beta or unit-gamma In Taillie,
C. Patil. G. P . and Baldessari. B (Eds ). Statistical Distributions in
Scientific Work. Vol 4. Models. Structures and Characterizations. Dor-
drecht, Holland. D Reidel Publishing Co (in press).

Roux. J. J J . and Ratnaparkhi. M V On matnxvanate beta type I distribu-
tion and related charactenzation of Wishart distribution. In Tail'ie. C,
Patil. G, P., and Baldessari. B. (Eds ) Statistical Distributions in Scientif-
ic Work. Vol. 4. Models. Structures and Charactenzations. Dordrecht,
Holland. D, Reidel Publishing Co. (in press).

Harold Ostrow, a CSL engineer, contributed to tine
development of the heart probe, which allows non- invasive
study of cardiac function.

Dr. Benes Trus (CSL) and Dr. Alasdair C. Steven (NIADDK)
collaborated to study the molecular organization of beet
necrotic yellow vein virus (Virology, in press). Left: original
electron micrograph; middle: computer reconstruction; right:
computer model.

Computer Systems Laboratory

Alan M. Demmerle, Chief

Function and Scope of Work

The Computer Systems Laboratory, a group of about
30 professionals representing the disciplines of
engineering, computer science, medicine, and
chemistry, is the major source of expertise at NIH for
minicomputer and microcomputer technology. CSL
engineers and scientists, in collaboration with NIH
laboratory and clinical investigators, apply this
technology in the areas of laboratory automation and
patient care. Most work supports intramural research
programs, although some projects have been
undertaken with extramural programs and, more
rarely, with other Federal agencies. In addition to
supporting ongoing research, CSL also investigates
new applications of computers to biomedical
research and identifies appropriate technology for
use in these applications.

Small computers that can be used in the laboratory
or at the patient's bedside are increasingly important
to biomedical and clinical research because of more
complex research methods and instrumentation.
Laboratory automation, data acquisition from
analytical instruments, and patient monitoring are
examples of functions to which CSL has applied
small computers at NIH. Computers may be used
only in an adjunctive manner, for example, as a more
convenient means to acquire laboratory data; or they
may be integral parts of an elaborate instrumentation
system such as the computer-controlled mass
spectrometer.

Recent technological advances are contributing to
changes in the nature of CSL's work. Foremost
among these advances are developments in large
scale circuit integration (LSI)--the microprocessor
revolution--that have brought about the
miniaturization of computer components and a
dramatic decline in their prices and power
requirements. One result has been a greater
availability of computers for biomedical research.
Thus, CSL engineers are now able to use
microprocessors to solve problems that once were
avoided because of cost, size, or manpower
constraints.

The Laboratory brings together professionals with
diverse backgrounds to apply computer technology
effectively to NIH programs and to offer research
and development capabilitites responsive to NIH
needs. Engineers, computer scientists, and

mathematicians evaluate and apply new electronics
and computer technology to solve biomedical
problems. Personnel with backgrounds in medicine,
biology, and chemistry communicate effectively with
biomedical investigators and clinicians and identify
potential computer applications. This multidisciplinary
approach aids the recognition of problem areas that
will benefit from automation and the interpretation of
research needs in terms of computer methods.

This year, CSL engineers and scientists worked on
approximately 28 projects, representing collaboration
with almost all of the Institutes. Many of these
projects were continued from previous years; 9
projects were begun this year and there were
significant changes in scope in four others. Projects
range in size from consulting activities of a few days
or weeks duration to large scale efforts taking a
number of man-years. Because much work involves
the development of new methods or technology, or
is influenced strongly by the changing needs of
research, it is often difficult to predict the long term
scope of a project.

Fiscal Year 1981 Highlights

During the past year the scope of CSL computing
has broadened considerably. Modest computing
requirements posed by individual scientists, or local
groups of investigators, are being met increasingly
through the use of microcomputers, while at the
other end of the computational spectrum CSL is
involved in the design, development, and
management of large minicomputer systems,
including, for example, those directed toward
providing general image processing services to a
significant segment of the NIH community.

Two projects that typify the exploitation of
microcomputer technology in clinical and laboratory
settings are, respectively, the Automated Pulmonary
Physiology Testing Project and the Molecular
Interaction Laboratory Data System. The Automated
Pulmonary Physiology Testing Project utilizes a
Digital Equipment Corporation DECLAB MINC 11/03
microcomputer system in support of pulmonary
dysfunction diagnostic testing. Analog signals are
rapidly acquired, digitized, and analyzed, providing
the physician with intermediate results that can be

used to determine the course of further testing.
Reports suitable for the medical record are produced
locally and, together with any raw data desired,
archived in machine readable form for retrospective
analysis. These data will eventually be incorporated
into the Pulmonary Branch data base being
developed by DCRT's Data Management Branch on
the NIH IBM 370 computers. Telephone data
transmission to either the IBM 370 or the
DECsystem-10 computers of the NIH Central Facility
will then afford the Pulmonary Laboratory offline
access to a full array of scientific, mathematical, and
database manipulation functions. Specific procedures
already implemented include static compliance and
inspiratory muscle strength. Treadmill stress testing,
dynamic compliance, and work of breathing are
currently being added to the system repertoire.
Future plans anticipate the establishment of breath-
by-breath studies and closed-loop exercise
procedures where such parameters as patient heart
rate may be held constant by varying treadmill speed
and grade. Use of this system has resulted in
decreased time and increased accuracy and quality
of the procedures performed, thus benefitting patient
and physician alike

CSL collaborative efforts put minicomputers and
microcomputers to work for a variety of scientific needs
throughout NIH.

The recently completed Molecular Interaction
Laboratory Data System features a Digital Equipment
Corporation PDP-1 1 /03 microcomputer system
interfaced to a Beckman Model E analytical
ultracentrifuge and a Gary Model 61 circular dichroic
spectropolarimeter owned by the Molecular Disease
Branch, NHLBI. Ultracentrifuge data are conditioned,
converted, formatted, and graphically displayed on a

video display terminal. A system operator selects
data for further processing and creates a file from
these data, and from data required for analysis
functions that have been previously entered into a
log file. This file of preprocessed data is then
transferred to the NIH DECsystem-10 where
preestablished command sequences, invoked under
the modeling laboratory program MLAB, are used to
compute molecular weights and to assess molecular
interactions. Circular dichroism spectra generated by
the Cary 61 spectropolarimeter are digitized and high
frequency noise is removed by digital filtering
techniques. Spectra may be added, subtracted or
averaged prior to transfer to the NIH DECsystem-10
for further analysis. Typically the samples analyzed
by this technique are proteins that the investigator
wishes to characterize with respect to their three-
dimensional conformations under various conditions.
Using recently published data on the relationship
between circular dichroism spectra and conformation
in terms of the contributions to its structure by the
four basic types of tertiary structure: helix, beta
sheet, beta turn, and random coil.

A significant increase in computational complexity
over that represented by microcomputer projects is
found in long-term CSL support for the flow
microfluorimetry/cell sorter users at NIH. This work
started as a minicomputer-based project to acquire,
display, and analyze data from a Becton-Dickinson
flow microfluorimeter (FMF) and a Los Alamos
Scientific Laboratory FMF. Successful system
development and operation has led to reproduction
of the system for a number of new users and to
incorporation of microcomputer technology to meet
expanded requirements. The basic minicomputer
system is implemented on a Digital Equipment
Corporation (DEC) PDP-1 1/34 computer and
features CSL instrument interfaces and an extensive
software package that runs under DEC's single user
RT-1 1 operating system. During the past year a
system was installed for NHLBI and two were
installed for NCI, thus bringing to five the number of
systems supported by CSL. Copies of the CSL
design are also being used by several organizations
outside of NIH.

To facilitate the simultaneous acquisition and
processing of FMF/cell sorter data in a high
workload environment, development is underway to
replace the DEC RT-1 1 operating system with the

DEC RSX-11M multiuser operating system. An LSI-
11 microcomputer is being introduced into the
system to remove the data acquisition task from the
PDP-11/34 computer. Besides providing independent
operator interaction during parameter entry and
acquisition phases, the microcomputer will produce a
permanent hardcopy of the 'laboratory notebook.' It
is planned that only completed data files will be
transferred across the direct memory access link
between the LSI-11 microcomputer and PDP-11 /34
computer.

An increasing number of scientific projects at NIH
produce visually-based experimental data such as
electron micrographs, stained tissue sections, gel
electrophoresis, autoradiographs, etc., which require
objective, accurate, quantitative analysis. Utilizing
DCRT's powerful DEC PDP-11/70 -driven Evans and
Sutherland Image Processing System as the key
resource, CSL has, for the past three years,
collaborated with scientists of several Institutes in a
variety of image processing projects. Although these
projects were directed toward specific goals, an
important supplementary aim was the creation of
general purpose software easily adaptable to a wide
range of image processing needs. This latter role
has expanded significantly during FY81 as CSL was
assigned a major role in managing the Evans and
Sutherland Image Processing System.

Current CSL involvement with the Evans and
Sutherland Image Processing System is focused
primarily on the development of biomedically-
oriented image processing software, complemented
by the support necessary to make such packages
usable to NIH scientists. Typical programs included
PIC, CINT, and (VIONKEY. The PIC software package
facilitates examination of collagen structure from
electron micrographs, performs quantitative analysis
of one-dimensional gels, and elucidates virus
structures. CINT automatically locates and integrates
up to 1200 spots on a two-dimensional gel picture
and provides limited analysis of autoradiographs.
MONKEY is a general image enhancement package
that can be used to evaluate all or part of an image
and includes operations such as smoothing,
sharpening, statistics, and linear combinations. The
Evans and Sutherland System supports both
molecular graphics and image processing users.
Demand upon the system has escalated to such a
degree that severe scheduling problems exist not

only during prime time but throughout most of the
evening period as well. Many image processing
problems, moreover, are not amenable to solution on
the powerful but relatively dated Evans and
Sutherland System. CSL is therefore in the process
of designing and procuring a new image processing
system. This system will consist of a powerful 32-bit
computer with a mixture of medium and high
resolution video displays. The microdensitometer
associated with the Evans and Sutherland System
will not be required by molecular graphics users and
will be used to provide precise digitization of x-rays,
micrographs and other images. The computer and its
peripherals have been purchased and delivery is
anticipated in FY82. Procurement of the display
subsystem is being held up pending the availability of
funds.

Continuing in its more traditional role CSL has
pursued a number of collaborative image processing
projects. A new project, undertaken with scientists
from the NEI and Harvard Medical School, is
track cataract disease history. Images produced by
split-lens lamp photography are digitized by means
of microdensitometry and entered into the computer

CSL engineers and scientists evaluate and apply electronics
and computer technology to solve biomedical problems.

concerned with measurement of opacity of the
human eye lens along the visual axis in order to
for analysis. Present work is oriented to determine
the effects of variables-such as camera type,
photographer, photographic processing, and
microdensitometry factors-on expenmental
accuracy.

Another project new this year focuses the combined
power of Computer Assisted Tomography (CAT) and
Positron Emission Tomography (PET) upon a study
of brain cell metabolism and its relationship to
disease associated with aging. Conducted in
conjunction with NIA scientists, the project's initial
goal is to delineate brain substructures represented
in sequential CAT scan images and to determine
metabolic activity in these substructures from
corresponding sequential PET scan images.

Ongoing image analysis work with the NHLBI
includes topographic analysis of arterial
atherosclerosis formation and graphical
representation of myocardial blood flow. Further
refinement of the block model used by NINCDS
scientists to provide three-dimensional graphic
representation of the neuronal structure of the cat
brain stem now make it useful for arbitrary plane
viewing of other spatially-sequenced images.

Good R&D programs require good tools. For many
years CSL has had an electronics laboratory. More
recently, a computer laboratory has been added. The
computer laboratory facilities include 'development
systems'-minicomputer and microcomputer
systems--that are used to investigate and implement
new software and hardware for eventual use in
target computer systems, i.e., systems intended for
use in specific projects. These development systems
permit work to begin on a project long before the
target system ordered for that project is delivered,
thus improving productivity and reducing the time
until project completion. Development systems are
indispensable to microprocessor projects, because
software development work is often not possible on
the microprocessor hardware itself. The computer
laboratory facilities were expanded again this year so
that more people can use the development systems
at the same time. Virtually all minicomputer and
microcomputer work can now be done using
development systems.

CSL is called upon for consultative assistance in its
areas of expertise by both the intramural and
extramural programs. Usually such assistance in
limited to providing expert advice--the conventional
definition of consulting. Occasionally however, a
consulting role may lead to engineering or software
work, or even to an extensive project. During the

past year consultation activities with the
Rehabilitation Medicine Department of the Clinical
Center led to a survey of the state-of-the-art in gait
laboratory automation. Subsequent to this survey,
requirements, possible design approaches, and costs
for automating the NIH Gait Laboratory were studied.
A collaborative project culminating in the
computerization of NIH Gait Laboratory activities
appears imminent.

The Computer Systems Laboratory continued its
support of the annual international conference,
Computers in Cardiology. This conference provides a
forum for direct interaction and exchange among
physicians, computer scientists, and engineers who
use computers to assist research or clinical care in
the field of cardiology.

Future Plans/Trends

In common with many organizations, CSL can expect
FY82 and beyond to be clouded by many of the
uncertainties that were encountered this year
concerning resources. Technological developments
in large scale circuit integration promise an increase
in the number of biomedical applications for which
microcomputers and minicomputers can be useful
and affordable; however, anticipated budget
reductions combined with an unpredictable rate of
inflation may well offset these advances. The
proposed new Image Processing System poses a
striking example of the potential conflict. Hailed just
one year ago as a project that owed its feasibility to
technological progress and declining costs, it has
remained virtually dormant during the past year, a
hostage to the unavailability of funds.

An expected continuation of stringent personnel
restrictions serves to further obscure a precise
forecast of future directions. Limitations in staffing
tend to encourage an escalation in demands for
automation; however, all new NIH computer
initiatives will have to be reconciled with uncertain
funding and uncertain CSL support. Moreover, CSL
has for many years required Institutes to provide
some limited computer expertise as a condition for
assistance. At a time when CSL is fully extended,
the commitment of Institute personnel assumes
greater than usual significance; participation by the
Institutes will prove difficult as so many computer

projects permit increasingly complex research
activities rather than conserve manpower. An
excellent illustration of staffing problems can be
seen in the NIH Library Project. Automation of the
Library has become imperative if an exploding
volume of literature is to be managed by a fixed or
shrinking Library staff. Nevertheless, after
languishing for one year in a CSL project queue
awaiting the availability of appropriate personnel, the
project has suffered another equally lengthy delay
due to the existence of a similar staffing plight in the
NIH Contracts Department.

The substantial uncertainties and delays that have
plagued many recent projects make effective use of
a limited CSL staff an imposing challenge. A number
of actions adopted to confront the resource
problems appear to hold promise and may become
trends for the future.

A contract to provide software support has been
established and already two projects are expected to
benefit from this type of support. Provided that
adequate funding can be maintained, the contract
mechanism offers an attractive supplement to CSL
programming capability, particularly for well defined
projects.

As was the case during the past year, continued
heavy involvement in providing consultation services
can be expected for the future. During the past year,
for example, substantial specialized advice was
given to the National Toxicology Program, NHLBI
Framingham Longitudinal Study, Clinical Center
Department of Critical Care Medicine, Clinical Center
Nuclear Medicine Department, NHLBI Surgery
Branch, NHLBI Cardiology Branch, Clinical Center
Department of Rehabilitation Medicine, and NCI
Surgery Branch. Although some consultations have
been, and undoubtedly will continue to be,
substitutes for actual work on indefinitely delayed
projects, consultation services can offer, in
appropriate circumstances, substantial rewards
relative to I'mited personnel investment.

Finally CSL will continue to deploy staff on those
projects promising maximum impact to the NIH
Community. Current examples of this policy are the
Flow Microfluorimetry Project with its duplicated
systems and the Image Processing Project with its
general purpose developments.

Publications and Presentations

Allen, S.. Songco, D.. Plexico. P.. and Mortord. R : A Voice Output Module
Developed tor a Blind Programmer. Journal ol Visual Impairment and
Blindness. New York, American Foundation lor the Blind, April 1981.
pp. 157-161

Bacharach, S , Green, M , Bonow. R . Findley, S , Ostrow, H., and Johnston.
G Measurement ol Ventricular Function by ECG Gating During Atrial
Fibrillation. J. Nuclear Med 22226-23 1,1 981,

Bacharach, S,, Green. M , Ostrow. H . and Johnston. G.: Developments in
Nuclear Medicine's Computer System-Applications to Cardiology IEEE
Transactions in Nuclear Science 22:1095-1 101.1980,

Barrett, W.: An Interactive Algorithm lor Multiple Threshold Detection. IEEE
Proceedings. Pattern Recognition and Image Processing (in press)

Barrett, W,, DeLeo, J.. Cornhill, J , and Fry, D.: A System lor Automated
Analysis ol Plaque Formation in Expenmental Atherosclerosis 53rd
Scientilic Sessions ol the American Heart Association, November 19,
1980

Computer Systems Laboratory of the National Institutes of Health. NIH
Publication No, 81-1926, June 1981, 12pp.

Green, M,, Ostrow, H.. Bacharach, S.. Allen, S., Bonow, R., and Johnston.
G.: Real-time Scintillation Probe Measurement ol Lett Ventncular Func-
tion. Proceedings ol the Meeting in Freiburg (in press).

Hauser, S , and Almeida, A.: A Control and Data Processing instrument lor
Kidney Tubule Research Biomedical Sciences Instrumentation 1713-
19, 1981.

Marlino. R., Kempner, K., McClellan. J., and McLees. B.: Automation ol a
Medical Intensive Care Environment with a Flexible Conliguration ol
Computer Systems. In O'Neill, J,T {E6.):Proceedings ol the Fourth
Annual Symposium on Computer Applications in Medical Care. New
York, IEEE, 1980, pp. 1562-1568.

Nadel, L.: Automated Pulmonary Analysis by an On-line Microcomputer In
Nair, S (Ed): Proceedings of the Conference on Computers in Cntical
Care and Pulmonary Medicine (in press).

Nikodem, V., Trus. B.. and Rail. J.: Two-dimensional Gel Analysis ol Rat
Liver Nuclear Proteins alter Thyroidectomy and Thyroid Hormone
Treatment Proc. Natl. Acad Sci USA (in press),

Padikal, R., Lichter, A., Tepper, J,. Gladstein. E.. Schwade. Jr.. Fredrickson,
H.. Risso, W., Roberson, L, Van de Geijn, J , and Kinsella, T.: Expen-
ence with a CT Based Treatment Planning System. In O'Neill. J.T.
(Ed.): Proceedings ol the Fourth Annual Symposium on Computer Ap-
plications in Medical Care. 1980, pp. 83-88,

Plexico, P.: Microcomputer Application in Biomedical Research, Association
lor the Advancement of Medical Instrumentation 14:307-310.1980,

Powell, J,, Fico. R-, Jennings. W., O'Bryan, E , and Schultz. Jr.. A.: A Local
Network lor Distributed Laboratory Microcomputer Proceedings ol the
Twenty-first IEEE Computer Society International Conference. 1980, pp.
185-190.

Steven, A., Trus. B.. Putz. C, and Wurtz, M.: The Molecular Organization ol
Beet Necrotic Yellow Vein Virus, Virology (in press).

Trus, B., and Steven, A,: Digital Image Processing ol Electron Micrographs-
The PIC System. Journal of Ultramicroscopy (in press).

In collaboration with the NIH Nuclear Medicine Department
LAS researcher Margaret Douglas is producing diagnostic '
images (see insert) that allow scientists to detect motion ,
defects in the walls of the heart. i

Special Achievement Awards were earned by Martha
Norton and Margaret Douglas for their contributions toward
developing a text- and command-entry technique for
computerized typesetting printing systems. The awards
were presented by Dr. Eugene Harris, Chief, LAS

Laboratory of Applied Studies

Eugene K. Harris, Chief

Functions

The Laboratory of Applied Studies (LAS) has three
main purposes:

1. in collaboration with biomedical scientists, to
apply mathematical theory and computing science to
the construction, testing, and improvement of
mathematical models of physiological processes--
particularly reaction-diffusion kinetics, transport of
substrate to tissues, and the control of metabolism
within cells and tissues;

2. In collaboration with clinicians, to develop and
apply mathematical or statistical theory and special-
purpose computing procedures (analog or digital as
required) to facilitate research projects aimed at
improving the diagnosis of disease and assessment
of treatment;

3. to engage in independent research in applied
mathematics, statistics, and computer systems
necessary to provide a sound theoretical basis for
collaborative studies, and to insure that state-of-the-
art mathematical and computational methods are
available as research tools at NIH.

Two sections carry out these primary LAS functions:

Applied Mathematics Section-AMS-CJohn E.
Fletcher, Ph.D., Chief). This staff of five includes
specialists in applied mathematics, computer
science, biomathematics, and medicine.

Medical Applications Section -MAS-(James J.
Bailey, M.D., Chief). This five-member staff includes
physician-scientists, electronic engineers, and
computer systems analysts.
The Chief, LAS, is a biostatistician with training in
public health and the basic medical sciences.

Scope of Work

The Laboratory of Applied Studies works on projects
in basic and clinical biomedical science. Largely,
these involve collaboration with other groups at NIH,
elsewhere in the U.S.A., and abroad. The
collaborating investigators this year included:

• biochemists and pharmacologists at NIH, at the
Medical College of Virginia, and at other
universities in the U.S.A. and in France working
on models for receptors of drugs or other
ligands, on the kinetics of enzymes in
membranes and on other problems in tissue
metabolism

• physiologists and chemical engineers in the
U.S. A and Europe studying the transport of
substrate within the microcirculation and the
regulation of tissue perfusion

• clinicians in the cardiology, pulmonary, and
hematology branches of the NHLBI; in the
arthritis and rheumatism branch of the NIADDK;
and in the medical intensive care unit and the
departments of diagnostic radiology and
diagnostic imaging of the Clinical Center

• clinical chemists and pathologists at NIH
(Clinical Pathology Department, Clinical Center)
and elsewhere in the U.S.A., in Europe, and in
Japan engaged in the collection and study of
reference values in laboratory medicine

• electrocardiologists and biomedical engineers in
the U.S.A., Canada, and Europe concerned with
improved algorithms for computer-based
interpretation of ECG's and evaluation of ECG
interpretative programs.

During FY81 LAS staff members participated in
various teaching and consulting, or advisory,
activities.

J. Fletcher continues to serve as Chairman of the
fvlathematics and Computer Science Departments,
Foundation for Advanced Education in the Sciences.

J. Bailey continues as a member of an NHLBI site-
visiting team concerned with computer analysis of
exercise ECG's. He also serves as consultant on
common standards for quantitative
electrocardiography for an EEC-sponsored program
in medicine and public health.
E. Harris continues to be a consultant in applied
statistics to the Food and Drug Administration's
Division of Medical Devices and Diagnostic Products.
Dr. Harris also serves as consultant statistician to
the College of American Pathologists and to the
International Federation of Clinical Chemistry (Expert
Panel on the Theory of Reference Values), and is a
member of the Board of Editors of Clinical
Chemistry.

During this reporting year, Dr. Adelin Albert, a
mathematical statistician from the University of
Liege, Belgium, joined the laboratory as a Fogarty
International Research Fellow under Dr. Harris'

ALKALINE PHOSPHATASE

Charts like this one, which illustrates blood chemistry
differences in healthy individuals, aid Dr. Harris in his
collaborative studies.

preceptorship. Dr. Albert is developing and testing
appropriate statistical techniques to utilize
multivariate, serial data for optimal prediction of
patient outcomes.

Highlights of Year's Activities

This year has seen substantial progress in all active
LAS collaborative research projects, based in many
cases on the technical advances reported last year
in developing and implementing various computer
systems. Some major accomplishments this year
include:

• A joint project with the Pulmonary Branch and
the Clinical Hematology Branch, NHLBI on the
computerized analysis of pulmonary gas

exchange in normal volunteers and selected
patient groups has been accelerated through the
efforts of R. Burgess and E. Pottala of the
Applied Mathematics and Medical Applications
Sections. Complete redesign of analog circuitry
has produced a reliable gas analysis system.
The computer and computer-controlled exercise
testing equipment has been specified, ordered,
and, in large part, received. Dr. Burgess has
also substantially increased the precision and
sample size of the renal scintigraphy study on
dogs, initiated during the prior reporting year.

• A major advance in the mathematical analysis of
blood and substrate supply to tissue has been
initiated by J. Fletcher (Chief, AMS). Incorrect
solutions found in the existing literature for
mathematical models of perfused tissue
experiments have been corrected. The correct
solutions to these and more general models are
now being explored and will be used to predict
distributed substrate levels for comparison with
experimentally obtained microelectrode
measurements.

• A comparative study of two ECG computer
programs, based on ECG-independent clinical
documentation of the presence or absence of
various forms of heart disease in 284 patients
has been completed and published by J. Bailey
(Chief, MAS), M. Horton (MAS), and
cardiologists at the Royal Infirmary in Glasgow.
This study should provide a model for future
evaluations of widely-used ECG programs
because of the careful clinical documentation
and the methods used to categorize ECG
diagnostic output statements, allowing
recognition of semantic equivalents despite
differences in the terms used in different
programs. The LAS investigators have extended
their studies to the evaluation of serial
computer-based ECG interpretations in a joint
project initiated this year with Dr. D. Savage of
the Framingham Heart Study, NHLBI.

• The PICTUR image processing computer
package, developed and implemented last
reporting year by M. Douglas (MAS) has been
extensively applied, in collaboration with Dr. J.
Costa (NIMH), to determination of the spatial
distribution of fluorine within the dense bodies of

blood platelets. If continuing work proves
successful, this fluorine-dense body system
could become a reliable model for intracellular
monitoring of therapeutic drugs in patients.
• M. Douglas and M. Horton (MAS) shared a
DHHS special service award for their work with
N. Crawford and V. A. Parsegian (Physical
Sciences Laboratory) on computerized
typesetting of scientific papers.

Future Plans

Installation of the computer-based gas analysis/
exercise system will be completed and testing of
normal volunteers will begin in cooperation with the
pulmonary and clinical hematology branches of
NHLBI. The scintigraphic studies of renal
hypertension in dogs will be completed and the
results will be prepared for publication. Expected
progress in other active projects will include:

--application of generalized mathematical models
to experimental data on organ perfusion with the
goal of identifying the ranges of critical parameters
controlling organ response to physiologic challenge,

-expanded collaboration with NIH laboratory
scientists on application of network simulation
programs to improving the understanding of
molecular transport across membranes,

"development of appropriate physical and
statistical theory to support the continued study of
intracellular distributions of physiologically important
molecules through electron beam analysis, and

-completion of comparative statistical analysis of
multivariate and univariate time series applied to
clinical laboratory data, using both real and simulated
results of patient monitoring.

Publications and Presentations List

Bailey, J J : The future ol gold standards and computenzed electrocardio-
graphy In Tolan, GD, and Pryor. T A (Eds): Computerized Interpreta-
tion of the ECG. V. New York, Engineering Foundation, 1980, pp. 229-
233.

Bailey J J.. Berson, AS., Jackson, L.K., Milliken, J.A., Stevens, J.M., Tolan,
GO. and Wolf, H.K.: Evaluation Methodologies for ECG diagnostic
systems In Bonner. RE, and Pryor, T A (Eds ): Computerized Inter-
pretation of the ECG. VI (in press).

Bailey, J J , and Harris, E,K ; Evaluation of ECG interprelalionTrulh versus
beauty. In Tolan, GD., and Pryor, T,A. (Eds): Computerized Interpreta-
tion ol the ECG. V New York, Engineering Foundation, 1980, pp. 179-
182

Bailey, J J , and Norton, MR: Type A electrocardiogram data bases: Pur-
pose and development In Wolf. H K , and Macfarlane, P.W. (Eds):
Optimization ol Computer-ECG Processing. New York, Norlh-Holland
Publishing Company, 1980, pp. 189-195.

Berk, P.D., Blaschke, T.F., Shrager, R.I,, and Waggoner, J.G.: Phenobarbitol
does not increase hepalichema turnover in man. Gastroenterology
79:1004, 1980.

Bunow, B : Cellular Enzymology: Effect of compartmentation on steady
stale kinetics J. Theor Biol 84: 611-628, 1980

Bunow, B.: Turing and the physico-chemical basis of biological patterns. In
Prewitt, J (Ed): IEEE Turing Memorial (in press).

Bunow, B., Kernevez. J.P , Duban, MC, Jolly, G,, and Thomas, D,: Pattern
formation by reaction-diffusion instabilities: Application to morphogene-
sis in Drosophila, J. Theor Biol 84 629-649, 1980,

Bunow, B,, and Mikulecky, DC : On the feasibility of using flux meas-
urements to distinguish among active transport models. Polish Winter
School of fi/lembrane Transport (in press).

Douglas, M.A., Hui, S,W,, Costa, J,L,, and Bailey. J, J,: Computerized proc-
essing and subtraction of energy-filtered electron images as an aid to
elemental analysis. In Bailey, G,W (Ed): Proceedings of the Thirty-
eighth Meeting EMSA. Baton Rouge, Claitor's Publishing Division.
1980, pp 128-129,

Fletcher, J,E , and Jolly, M,: The Compulation of Substrate Levels in Per-
fused Tissues, Proceedings of the Annual SIAM Meeting (in press),

Fletcher, J,E,. and Schubert, R.W,: The Theoretical Prediction ol Substrate
Levels and Their Histograms in Cell Free Perlused Tissues. Proceed-
ings of the International Meeting of the Society of Oxygen Transport to
Tissue (ISOTT) (in press),

Harris, E,K,: Further applications of lime series analysis to short series of
biochemical measurements. Proceedings of Workshop on Reference
Values in Clinical Pathology (m press),

Harris, E,K,: Regression, least squares and correlation. In Seligson, D., M.D.
(Ed): Handbook ol Clinical Chemistry (in press)

Harris. E.K.: Statistical aspects ol relerence values in clinical pathology. In
Stefanini, M.. and Benson, E. (Eds.): Progress in Clinical Pathology.
New York, Grune & SIralton. Inc., 1981, Vol VIII, pp. 45-66.

Harns. E.K,: Use ol statistical models to detect subject-specific changes.
Proceedings of International Conference on Automated Multiphasic
Health Testing & Services (in press).

Kernevez. J.P,, Jolly, G,, Thomas, D,, and Bunow, B,: Pattern formation and
wave propagation in the S-A system In Bardos, C. Lasry, J,M . and
Schatzman, M. (Eds.): Lecture Notes in Mathematics 782: 201-221,
Spnnger-Verlag, 1980.

Macfarlane, P.W., Chen, C.Y., and Bailey, J. J.: A comparison of point
scoring techniques for the diagnosis of LVH. In Macfarlane, P.W. (Ed.):
New Frontiers in Eleclrocardiology (in press).

Macfarlane. P.W., Melville, D,l . Horton. MR., and Bailey, J. J.: Comparative
evaluation of the IBM (12 lead) and Glasgow Royal Infirmary (3 ortho-
gonal lead) ECG computer programs. Circulation 63 354-359. 1981.

Sharan, M.. Kernevez. J.P,, and Bunow, B,: On numerical exploration of
bifurcating branches of solutions in reaction diffusion equations model-
ing enzymatically active artificial membranes Research report of the
Department of Applied Mathematics. Compiegne, France, University of
Technology of Compiegne, 50 pp.

%'n.-. t

Nancy Crawford shared an award with LAS members for
her work with Dr. Adrian Parsegian on the computerized
typesetting of scientific papers.

PSL carries out research to understand biological
phenomena in terms of physics and chemistry.

lI^I

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^ 1

Physical Sciences laboratory

George H. Weiss, Chief

Function

The Physical Sciences Laboratory has three principal
functions:

• to carry out research in the physical sciences in
order to understand biological phenomena in
terms of physics and chemistry

• to develop theory and practical instrumentation
for biomedical experiments, and in particular to
relate these to the capabilities of modern
computer technology

• to provide consulting services to other scientists
at NIH in physics, theoretical chemistry, and
several fields in applied mathematics.

The staff of the Physical Sciences Laboratory
consists of seven professionals who work in the
areas of general biophysics, nuclear magnetic
resonance, applications of light scattering techniques
in biomedical experiments, the physical chemistry of
polyelectrolytes, and problems in applied
mathematics.

Scope of Work

The Physical Sciences Laboratory has a combined
program of research projects internal to the
laboratory and collaborative projects with scientists
at NIH and at other institutions. The collaborative
projects, done jointly with approximately twenty-five
other investigators, include two major projects with
data being generated by off-campus scientists.

Highlights of the Year's Activities

Although a large amount of time was devoted to
getting bugs out of the 360 MHz spectrometer,
useful experimental information is now becoming
available. The advantages of being able to do pulsed
and two-dimensional Fourier transform spectrometry
are being exploited by Dr. James Ferretti in several
ongoing investigations. He is investigating cross
relaxation pathways in rigid organic molecules. Dr.
Ferretti is also developing both theoretical and
experimental aspects of Fourier transform
spectroscopy allowing the deduction of internuclear
distances and rotational correlation times by the use
of cross relaxation. He has also concluded an
investigation of the relation between errors in
chemical shifts due to random and digitization errors.
Specifically Dr. Ferretti has contrasted several

strategies for filtering and smoothing resulting data,
finding optimal strategies for many cases of practical
interest.

Dr. Adrian Parsegian and his collaborators have
made several significant advances in the
understanding of intermolecular forces in proteins
and nucleic acids. Methods similar to those
developed earlier by Dr. Parsegian to measure
membrane-membrane forces are now being applied
to the study of the aggregation, gelation, and
crystallization of proteins, and to the packing of
parallel double helical strands of DNA. This project
will continue with the development of theory and
experiments to systematically collect thermodynamic
data on gelation and crystallization.

Dr. Ralph Nossal and his collaborators have
performed experiments on experimental analogues
of the flow of blood cells confirming an earlier
theoretical development that allows one to interpret
light scattering experiments in vivo. The combination
of theory and experimental verification sets the stage
for clinical applications of light scattering and in
particular for the measurement of blood flow in
capillaries, which has heretofore been impossible.

A theory has been developed by Dr. Nahum
Gershon of the PSL and Dr. B. Aizenbud of MIT for
diffusion on curved surfaces, with particular
reference to fluorescent photobleaching recovery
experiments. The major result of this investigation is
that curvature does not affect estimated diffusion
constants to any significant degree.

Dr. Parsegian was appointed Editor of the
Discussions of the Biophysical Society and Dr. Weiss
was appointed Mathematics Editor of the Journal of
the Washington Academy of Sciences.

PSL develops theory and practical instrumentation for
biomedical experiments.

Future Plans

With few exceptions, plans for the future involve
building on scientific insights that have been gained
in the course of PSL current research. Now that
nnost of the bugs have been eliminated from the 360
MHz spectrometer, the next hope is both to develop
methodology for two dimensional Fourier transform
spectroscopy and to apply this technique to specific
structure and configuration problems for biologically
interesting molecules.

Studies of forces in membranes will continue with
further analyses of the properties of sickle cell
hemoglobin. Another project coming to fruition in the
coming year will be a study of protein and nucleic
acid contact using the molecular graphics crystal
structures. These will enable investigators to vary
configuration parameters to elucidate the contacts
stabilizing protein dimers and tetramers.

Publications

Aizenbud, B. M., and Gershon. N.D.: Hydrodynamic equations and VH light
scattenng from viscoelaslic (solid-like and tluid-like) systems. Pheno-
menological approach. Physica A (in press).

Bonner, R., and Nossal, R.: A model (or laser Doppler measurements of
blood flow in tissues. Applied Optics 20:2097-2108. 1981

Brenner. S. L.. and Korn, E D.: Stimulation of actin ATPase activity by
cytochalasins provides evidence for a new species of monomeric aclin.
J. Biol. Chem. (in press).

Ciarkowski, J. E., Ferretti. J. A., and Marshall, G. R.; Comparative conforma-
tional studies of angiotensin II and two stencally constrained analogs
by 600 MHz proton spectroscopy. J. Am. Chem. Soc. (in press).

Egan. W.. Ferretti. J. A., and Marshall, G. R.: Relaxation parameters and
motional properties in biological macromolecules. Bull Magnet. Reso-
nance 2.\bA7 . 1981.

Gershon, N.D., Smith, R. M., and Jarett, L.: Computer assisted analysis of
ferritin-insulin receptor sites on adipocytes and the effect of cytochala-
sin B on groups of insulin receptor sites. J. Membr. Biol. 58:155-160,
1981

Gupta, R. K., Ferretti, J, A., Becker, E. D., and Weiss, G. H.: A modified fast
inversion recovery technique for spin-lattice relaxation measurements.
J. Magnet. Resonance 38:447-452, 1981.

Kiefer, J. E., and Weiss, G. H.: A comparison of tvro methods for accelerat-
ing the convergence of Fourier series. Computers and Mathematics (in
press).

Lindenberg, K., Seshadri, V. E.. Shuler, K. E.. and Weiss. G. H.: Lattice
random walks for sets of random walkers. J. Statistical Physics 23:11-
25, 1980

Us, L. J., Parsegian, V. A., and Rand, R. P.: Binding of divalent cations to
dipalmitoylphosphatidylcholine bilayers and its effect on bilayer interac-
tion. Biochemistry 20.M&\-\770. 1981.

Lis, L. J., Lis, W. T., Parsegian, V. A., and Rand, R. P.: Adsorption of
divalent cations to a variety of phosphatidylcholine bilayers. Biochemis-
try 20:MT\-M77. 1981.

Lis, L. J., McAlister, M., Fuller. N,. Rand, R. P., and Parsegian, V. A.:
Interactions between neutral phospholipid bilayer membranes. Biophys.
J. (in press).

Lis, L. J., McAlister, M.. Fuller, N., Rand, R. P., and Parsegian, V.A.:
Measurement of the lateral compressibility of several phospholipid bi-
layers. Biophys. J. (in press).

Mohr, J. P., Weiss, G. H., Caveness, W. F., Dillon, J, D., Meirowsky, A, M.,
and Rish, B. L.: Language and motor deficits following penetrating head
iniunes in Vietnam. Neurology 30:1273-1279, 1980.

Meirowsky, A. M., Caveness, W. F., Rish, 8. L., Dillon, J. D., Mohr, J. P.,
Kistler, J. P., and Weiss, G. H.: Cerebrospinal fluid complicating missile
wounds of the brain. J. Neurosurgery Si:ii-i7 , 1981.

Nossal, R.: Mathematical theories of topotaxis. In Jager, W., Post, H,, and
Tautu, P. (Eds): Biological Growth and Spread. Mathematical Theories
and Applications. Heidelberg, Spnnger-Verlag, 1980, pp. 410-440.

Nossal, R.: Quasielastic light scattenng from polymer gels. In Chen, S. H..
Chu, 8., and Nossal, R. (Eds): Scattering Techniques Applied to Supra-
molecular and Nonequilibrium Systems. Plenum Publ. Corp., New York
(in press).

Nossal, R., and Jolly, M.: Shear waves in cylindrical gels. J. Appl. Phys. (in
press).

Oppenheim, I.. Shuler, K. E.. and Weiss, G. H.: Stochastic processes. In
Lerner, R. G., and Tngg, G. L. (Eds): Encyclopedia o1 Physics. New
York, Addison-Wesley, 1980, pp. 964-967.

Parsegian, V. A.: Forces between membranes approaching contact. Scandi-
navian J. of Clinical Investigation 41:156, 39-47, 1981.

Parsegian, V. A., Rand, R. P., and Slamatoff, J.: Perturbation of membrane
structure by uranyl acetate labeling. Biophys. J. 33:475-478. 1981.

Parsegian. V. A., and Weiss, G. H.: Spectroscopic parameters for computa-
tion of van der Waals forces. J. Colloid Interface Sci. 81:285-289. 1981.

Rish, B. L.. Dillon. J. D.. Caveness. W. F . Mohr. J. P.. Kistler. J. P.. and
Weiss, G. H.: The evolution of craniotomy as a debridement technique
for penetrating craniocerebral injunes. J. Neurosurgery 53:772-775.
1980.

Weiss. G. H.: Asymptotic form for random walk survival probabilities on 3-D
lattices with traps Proc. Natl Acad Sci USA 77:1273-1274. 1980.

Weiss. G. H,: Can one measure rate constants using chromatographic
methods? Separation Sci 16 75-80. 1981

Weiss, G- H.: First passage time problems for one dimensional random
walks. J. Statistical Physics 24581-589, 1981.

Weiss, G. H.: Note on lattice random walks with an excluded point. J.
Mathematical Physics 22:562-563, 1981.

Weiss, G. H.. and Darvey. I. G.: A note on the choice of substrate concen-
tration in enzyme kinetics. J. Theoretical Biology 90:437-439. 1981

Weiss. G. H.. Ferretti. J A., and Kiefer. J E : A study of precision in the
measurement of chemical shifts. J. Magnet Resonance (in press).

Weiss. G. H., and Shiesinger. M F.: On the expected number of distinct
points in a subset visited by an N-step random walk. J. Statistical
Physics (in press).

Data base management technology provides both online
and batch processing to meet various operational
accounting and management control needs of NIH.

The Branch creates and maintains user-oriented tools, like
RMAG, to speed building of programs and to improve
operation of applications systems.

DMB supports the NIH data base management system,
which, when complete, will handle nearly all NIH materiel
and financial transactions.

Data Management Branch

J. Emmett Ward, Chief

Functions

The Data Management Branch (DMB) provides
advice and assistance to research investigators,
progrann officials, and administrators throughout NIH
In planning for and obtaining computer data
processing services. In this role the branch is a
central NIH resource for systems analysis, design,
and programming. There are currently 47 permanent
full time employees whose disciplines include
computer science, mathematics, and statistics.

Scope of Work

DMB staff design and create computer-based data
management systems that provide practical solutions
to the unique mix of administrative, scientific and
management data processing problems encountered
at the NIH. Each new computer system user is
provided comprehensive training in all system
facilities and functions. In addition DMB staff teach
courses about data management and DMB
programming tools; they provide advice on data
management techniques to NIH programmers; they
serve as consultants to the B/I/D's for obtaining and
monitoring contracting services for computer
systems development; and they create and maintain
general purpose, user-oriented programming tools to
speed building and improve operation of applications
systems.

The DMB comprises five sections. The Applied
Systems Programming Section (ASPS) and the
Scientific Applications Section (SAS) provide
general computer systems analysis and programming
services for all of the B/I/D's. The ASPS supports
general data management, and the SAS handles
those projects which require scientific data analysis.

The Data Base Applications Section and the Data
Base Enhancement and Control Section develop
and maintain the central administrative data base for
NIH materiel and financial management. The Clinical
Support Section develops and maintains the
Clinical Information Utility as a data base for
research and patient care in the Clinical Center.

FY81 Accomplishments

In the NIH Administrative Data Base system, during
the first quarter, the demands for ad-hoc reporting
and the significant increase in maintenance of the
backup and general reporting functions for data base
management required another shift of Branch
personnel. The Software Support Section was
abolished and its primary function was transferred to
the Office of the Chief. Two people were transferred
to the Data Base Applications Section to assume the
maintenance and reporting functions.
As a result of this transfer, major progress is being
made to streamline the backup and maintenance
functions and to standardize software for both ad-
hoc and recurring reports. A commitment source
data system, which:

1. controls telephone charge agreements, basic
purchase agreements, and indefinite delivery
contracts

2. monitors records of call and telephone charge
orders against these agreements and contracts

3. validates and summarizes fund and
accounting information

4. enables automatic generation of vendor
identification and address on purchase documents,

has also been installed on the administrative data
base. This provides managers, purchasing
personnel, and financial clerks with fully
synchronized information on the status of all source
commitment documents.

A delegated procurement and receiving entry system
was completed during the year and is now in the
process of being installed on site in the B/I/D's.
When it is completely installed, the movement of ail
paper actions relating to delegated purchasing and
receiving will end, and the computer data base will
be the source for all information except the locally
signed, legally required hard copy documents.

In the accounts payable area, DMB has provided a
full invoice inventory procedure which ties the
invoice process to the purchase order. When orders
are eligible to be paid, invoices are automatically
displayed to the voucher examiner, preliminary
payment schedules are electronically prepared and
presented for review, and final schedules to Treasury
are released through the computer system. The
experience gained in working with staff of the
Division of Financial Management (DFM) has also

led to the streamlining of manual and machine
procedures which optimize the entire payment
process.

In the NIH Clinical Information Utility (CIU),
development this year has concentrated on
implementing the weekly cumulative laboratory
summary and on reducing the size of the hard copy
medical record. It became clear that producing
complete retrospective summaries each week not
only required an unacceptable level of elapsed
computer time to produce, but also literally inundated
the medical records staff with weekly volumes of old
and new paper. To eliminate both problems, it was
agreed that only permanent medical record
replacements would be provided every six months. A
sophisticated computer system was developed to
provide this capability. This new system balances the
volume of the permanent replacement paper flow
and collates the permanent and weekly summaries
in a way that assures ease of handling by medical
records personnel.

Further reduction of the medical record is now in the
requirements analysis stage. Specific consideration
is being given to: identification of information
required legally and medically in the record,
requirements for access and display of high and low
use medical records data, and methods and modes
of electronic, hard copy, and other alternative forms
of storing medical records data. The final design of
either a system or systems to accomplish a
reduction in the bulk and optimization of access and
display of medical records data is hoped to be
completed by January 1982.

Another clinically-oriented project, which eventually
will require an interface with the CIU, is the
extension and enhancement of the BRIGHT system
to provide Clinical Center investigators the ability to
perform online analysis of their own clinical data. A t-
test module and a plotting module have been added
recently to BRIGHT. Other modules--to provide
descriptive statistics, chi-square test, linear
regression, ANOVA, normality test, non-parametric
tests, and life table analysis-are planned. Modules
will be added as new requests are received from
investigators.

In addition to this work on central NIH administrative
and medical data management facilities, the

significance and breadth of DMB's involvement in
the NIH mission is evident in many computer
systems it has developed to support individual
scientific, administrative, and management projects
during the past year. Virtually every B/l/D has
benefitted from services provided by the DMB. Each
of these systems has served a vital segment of NIH
and, when viewed together, they illustrate DMB's
very reason for existence as a central resource for
all of NIH.

In the area of general support for NIH activities,
DMB continued to maintain and teach courses on
the Inquiry and Reporting System (IRS) and MARK
IV; to support NIH use of Chemical Biological
Activities (CBAC) and Biosciences Information
System (BIOSIS) awareness searches on a biweekly
and semimonthly basis, respectively; to maintain and
distribute the NCI Survival System; and to consult
with and assist NIH programmers and contractors,
enabling facile use of DCRT computer facilities.

The Scientific Applications Section (SAS) is developing a
computer system that will enable Clinical Center
investigators to analyze their own data.

Future Plans

Publications

The Clinical Support Section will begin, by January
1982, software development for the system or
systems to reduce the size and optimize the use of
medical records data. As a by-product of this effort,
it is anticipated also that requirements for an
integrated CIU data base will be defined and the
software development for this effort can begin
shortly afterwards. As each new benefit becomes
available, it will be phased into the day-to-day
functions of the Clinical Center.

New functions anticipated to be added to the NIH
Administrative Data Base system include: stock
requisitioning, central and self-service stores
inventory, open market requisitioning, accounts
receivable, and vendor credits. The requirements
study for an upgraded financial management system
should be completed by the end of this calendar
year; a system should begin shortly after that.

In addition DMB will continue its primary role as a
central resource for computer applications
development to all components of NIH that need this
service.

Hams, E.K., Yasaka, T,, Horton. MR., and Shakarji, G.; Comparing Multivar-
iate and Univariate Subject-specific Reference Regions for Blood Con-
stituents in Healttiy Persons (in press)

Hirscfiman, G H . Wolfson, M., Mosimann. J.E.. Clark, C.B., Dante, ML, and
Wineman, R J : Complications of Dialysis. Clinical Nephrology 15:66,
1981

Rodbard, D, Cole. B.. and Munson, P.J.: The Need for innovative Ap-
proaches to Radioimmunoassay Quality Control. In Wilson. D. W. (Ed.):
Quality Control ol Radioimmunoassays (in press).

Bill Jones, Carol Kahl, Jennifer Fajman, and Roger Fajman
were some of the computer professionals involved in
designing the new version of WYLBUR.

The NIH Computer Utility provides services to over 8,000
users and processes about 21,000 job sessions each day.

Computer Center Branch

Joseph D. Naughton, Chief

Function

The Computer Center Branch (CCB), the largest
connponent of DCRT, designs and operates the NIH
Central Computer Utility and its associated online
telecommunications facilities, in support of scientific
and administrative programs throughout NIH.

Two large multi-computer facilities, the IBM System
370 and the DECsystem-10, form the nucleus of the
Computer Utility. These are linked by
communications facilities and connected by
telephone lines to hundreds of remote interactive
terminals located in research laboratories and
administrative offices throughout NIH.
Complementing this array of systems hardware is a
complex set of software, either designed and
implemented by Center personnel or acquired from
other sources and adapted to meet the unique
requirements of the NIH biomedical research
program.

Approximately 140 professional, technical, and
administrative personnel ensure the smooth
functioning of the NIH Computer Utility 24 hours a
day. The computer specialists, programmers, and
systems analysts design, implement and maintain
the complex computer systems software that
monitors and controls the flow of work through the
system. They also design and conduct extensive
training courses, write and publish technical
documentation on the use of the Utility, assist users
in problem diagnosis, and maintain and schedule
recurring production applications. Experienced
technicians operate the computer systems and
auxiliary equipment and provide data entry services.
The remainder of the staff provides the necessary
administrative support for this complex work.

Research and development projects are active in the
areas of scientific image processing, computer
networking and communications, text editing, display
of biomedical objects, and utilization of mass storage
devices.

To augment the function of the Central Computer
Utility, the Computer Center provides systems
programming support, consultation, documentation,
and training.

Scope of Work

The NIH Computer Utility provides services to over
8,000 authorized users. These include research
scientists and program managers from every area of
NIH. The IBM System 370 facility is used as a
Federal Data Processing Center for biomedical and
statistical computation by authorized staff in 24 other
Federal agencies. All services are provided on a
cost-recovery, fee-for-service basis through the NIH
Service and Supply Fund.

A variety of programming languages-including
FORTRAN, COBOL, PASCAL, BASIC, SPEAKEASY,
PL/I, and SAIL-are available, as well as a data
base/data management system (IMS) and a
comprehensive library of utility programs. Direct
interactive computing and batch job services are
available through WYLBUR, TSO, and through
similar interactive systems on the DECsystem-10.
The Center provides several facilities for job output
on paper and microfiche and has programs for
creating two- or three-dimensional graphic displays
for advanced projects such as those involving
macromolecular structures.

The work load of the Computer Utility has grown
steadily since it opened in 1968, and FY81 has been
no exception. The Computer Utility processed an
average of 21,000 job-sessions per day during the
past year. Workload on the IBM System 370
exceeded half a million job-sessions per month for
the first time in October 1980 and in March 1981
reached 544,248. The DECsystem-10 timesharing
facility, utilizing new equipment acquired late last
year, continued to expand its services and workload.

Highlights of the Year's
Accomplishments

The past year has been an especially important one,
with major achievements being made in a number of
areas.

--The long-awaited new and greatly enhanced NIH
version of WYLBUR became operational on January
8, 1981 for all users of the Utility. An 11 -week
transition period, during which both old and new
versions were available, proved to be exceptionally
smooth; user reaction to the new features of this
interactive, terminal-oriented facility was enthusiastic.
The improved document formatting and new
command procedures facilities proved to be
especially popular. The document formatting
capability facilitates the production of all types of
documents. Command procedures can prompt for
and validate data and can automate repetitive work
within WYLBUR, providing improved productivity in
many types of computing applications.

-One of the largest procurements ever conducted
by NIH was brought to a close this year as a ten-
year, 'total system' contract was formally signed with
IBM Corporation. IBM agreed to provide hardware,
software, maintenance, and support services to the
NIH Computer Center throughout the 1980's,
enabling the Center to meet NIH's information
processing needs efficiently without the lengthy
procurement delays that occurred frequently in the
past. The contract allows rapid utilization of new
technologies as they are developed by industry and
provides the flexibility to adapt to changes in
workload, thus permitting improved cost
effectiveness.

"Advances were made in the renovation of
Buildings 12 and 12A. The plotter and the bursting
equipment were moved closer to the computer room
on the first floor of Building 12A, resulting in
improved turnaround for these services. Construction
of modern classrooms and a new graphics systems
area began in the basement of Building 12A. A new,
enlarged user terminal area and the new classroom
facilities are expected to be completed in early 1982.
"Major work was accomplished with the molecular
graphics system this year. Activities included
determination of structures by crystallographic
methods, display of known structures, and modeling
of hypothetical structures. The coordinates for two
virus structures were determined during the year.

Techniques for extending known protein structures
to other members of the same family were also
developed. This enabled modeling of hypothetical
structures of immunoglobulins, myoglobins, and the
clotting factor proteins. The most exciting experiment
involved trying to predict the correct architecture for
proteins where only the primary structure is known.
The first result at this level is a model for the
structure of the human leucocyte interferon.

--In FY81 as in previous years, the Computer
Center evaluated available hardware and software
compoments. It selected and installed those that
serve best to help the Center meet computing needs
of NIH. This year additions include:

• A PASCAL/VS compiler for the IBM 370 to
make PASCAL, a language used widely by
computer scientists, available on both systems
of the Computer Utility

• SPEAKEASY, a language designed at the
Argonne National Laboratory for scientific and
mathematical problem solving

• DISSPLA and TELL-A-GRAF, commercial
systems that provide extensive facilities for
creating graphic output and make these facilities
available to users having graphic display
terminals.

NIH COMPUTER UTILITY

SYSTEM 370 SERVICES

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CALENDAR YEAR

Future Plans

Completing the installation and integration of the
new IBM equipment and developing the full
operating capacity of both the DECsystem-10 and
the IBM System 370 will remain important goals of
the coming years. Installation of new IBM equipment
will continue into the coming year as old equipment
is gradually phased out and replaced with newer,
faster, and more reliable technology. For instance,
the 3380 disk drive, IBM's newest disk drive, will be
installed toward the end of 1981. The new disk drive,
which will provide both local disk workspace and
shared permanent storage, will triple the storage
capacity of the system and provide greatly enhanced
operating speeds as well as increased reliability.

Improving the reliability, availability, and performance
of the Computer Utility is a continuing goal of the
Center. However, the Computer Center faces a
major challenge as it endeavors to continue
improving services while responding to the current
need to reduce operating expenses and limit staff
size. To meet this challenge, the Computer Center
has established a special support level for non-
critical software. While essential software will
continue to receive full support service, less widely-
used products will be designated to receive limited
support. This lower level of support will exclude
consulting and assistance with problem diagnosis
and will provide only limited maintenance service.
The new policy will allow the Computer Center to
continue expanding software offerings without
jeopardizing quality of service and responsiveness.

The coming year will also see completion of the
building program, installation of security facilities to
improve data security, and development of simpler
capabilities for output processing on the JES2
facilities. Several new training courses will help users
take maximum advantage of new features of
VVYLBUR; these include an introductory WYLBUR
course for programmers, courses on document
formatting and command procedures, and a series of
seminars on advanced topics in WYLBUR.

I I I I I I I

Two-dimensional computer graphics like this one, which
shows the nucleic acid sequence for an RNA fragment help
scientists in their investigative work throughout NIH

Publications

Feldmann, R. J., and BIng, D H.: Teaching Aids for Macromolecular Struc-
ture. New York, The Taylor-Merchant Corp.. 1980, 98 pp.

The three DCRT Offices complement the work of the
six Laboratories and Branches by:
• coordinating the complex Federal policies and

procedures that govern getting and using

computers at NIH

providing general administrative management

support for the Division's work

serving as a central source of information about

DCRT activities and about computer-related

disciplines.

The DCRT Library maintains a collection of about 6,000
books and technical reports on computer science,
mathematics, statistics, engineering, management, and
Information science.

Gloria Crawford, the DCRT Administrative Officer,
supervises all travel, training, forms management. Privacy
Act, and business functions of the Division.

Mike Reed and Julia Neel of the Financial Management
Section oversee the financial operation of DCRT.

Office of ADP Policy Coordination

Functions

The Office of ADP Policy Coordination, under the
direction of the Assistant Director of the Division, has
three closely related functions:

1. it is a focus for NIH-wide coordination of
automatic data processing (ADP) policy matters.

2. It serves as a central NIH point of contact on
policy and regulatory questions with the Public
Health Service, the Department of Health and
Human Services, other HHS Agencies, and the
General Service Administration.

3. It provides advice and assistance concerning
the internal operations of DCRT in matters of ADP
policies and regarding interagency sharing
agreements with other Federal agencies.

Scope

The role of the office includes:

• advising the Director of DCRT and through him
the Director of NIH on ADP policy matters

• reviewing and evaluating proposals from NIH B/
l/D's for procurements and contracts related to
computing and ADP

• directing the development of the annual NIH
ADP Plan

• assisting the NIH Division of Management Policy
on questions relating to its responsibility for
administrative and management computer
applications

• representing NIH in PHS and DHHS policy
formulation efforts

• working with GSA staff to obtain necessary
approvals for NIH on procurements and
contracts

• coordinating interagency agreements with other
Federal agencies that use DCRT facilities, and

• answering inquiries from scientists and
administrators who are confused by the whole
process.

This office has grown over the years in the breadth
of its activities but not in its size or cost. This fact is
strikingly analogous to the growth of the ADP
technology itself over the last decade and a half.
The functions of the office have evolved to solve
problems as new problems arose, to adapt to
change as changes occurred and to fill gaps as they

Henry J. Juenemann, Chief

became obvious. This is strikingly similar to the
parallel changes in computer technology itself, where
every year has been marked by increased capacity
and capabilities applicable to a wider range of
problem areas but still attainable with resource
expenditures of similar or smaller magnitude as
those of the older technologies being replaced.

Highlights of FY81 Activities

A major highlight of the year was completion of the
complex reprocurements of both systems comprising
the NIH central computing facility. After a protracted
five year process and in spite of a GAO protest,
award of a contract was made representing a full
reprocurement of the general purpose IBM 370
system. The resulting contract provides NIH
computer users with a long penod of stability while
also permitting flexibility to respond promptly to
technological and workload changes. Likewise,
reprocurement of the DECsystem-10 scientific time
sharing system was completed to provide a
combination of a period of stability with the same
flexibility to adjust to change. Both reprocurements
were accomplished in a way that had no adverse
impact on their user communities.

During the year this office reviewed nearly 600
proposals for acquisition of ADP equipment and/or
services. Each was reviewed to ensure that it was
justified and was in conformance with PHS, HHS,
GSA, and 0MB guidelines. Suggestions and
assistance were provided to the NIH Procurement
Branch and to contracting officers in Research
Contract Branches as to the most expeditious
procurement route to follow. In many cases one or
more of the Laboratories and Branches of DCRT
assisted by providing expertise to help in the review
of technical aspects of the proposals.

The office arranged the transfer of a computer
system from DCRT to the National Library of
Medicine, for relocation in a computer room in the
Lister Hill Center building. This action resulted in a
significant increase in NLM capacity to support its
information retrieval activities and made possible
savings estimated to be nine million dollars over the
next three years.

Arrangements were also made for the system thus
discontinued by NLM to become the primary support
system for the NIH Clinical Center Medical
Information System. It replaced a much older and
more limited contractor-operated system for meeting
day-to-day patient care information needs of the NIH
Clinical Center. The transfer included arrangements
for the Clinical Center to make use of the computer
room facilities formerly used for the NLM system.
The transfer satisfied for the first time the vital need
for backup redundancy in a system which-24 hours
a day, 7 days a week-serves all of the wards and
clinical services in a patient care environment. This
relocation resulted in an anticipated saving of 1.5
million dollars over a 28-month period.

During the year a number of cell sorter and image
processing computer system procurements were
expedited as well as procurements of a variety of
other automated equipment including, this year,
many microcomputers. An RFP was issued for the
automation of the NIH Library; a contract award is
expected in the last few months of the year so that
implementation of the initial phases of the project
can begin.

At year end the most time-consuming undertaking of
this office was the effort to extend DCRT's program
to supply users with several varieties of 'NIH
Standard' terminals. Having standard terminals
maximizes efficiency of the Center and of the users
who access the NIH central computing facilities.
Extension of contracts for the three existing types of
standard terminals was being sought as was
expansion of the program to cover those needed for
the new NIH Administrative Data Base System.

The Annual ADP Plan-which combines projections
of new ADP initiatives and required ADP
expenditures for all bureaus, institutes, divisions, and
offices of NIH-was completed. It details an NIH ADP
program projected to be 62 million dollars and 783
work years in FY82 growing to 88 million dollars and
833 work years by FY87. Although the accuracy of
the out-year projections must be regarded with
caution, the trend of ADP and computing
involvement in the scientific and managerial life of
NIH is unmistakable.

Future Plans ^M

FY82 will be marked by major changes in the
structure, staffing, and focus of NIH's overall ADP
Policy Coordination functions. These changes, the
nature of which are not predictable at this writing,
will be accomplished during FY82.

Office of Administrative
iVIanagement

L. Lee Manuel, Chief

Function and Scope of Work

The Office of Administrative IVlanagement, under the
direction of the Executive Officer, consists of 15
people, organized functionally into three sections:
finance, personnel, and general administration. The
office serves as liaison between these functions and
the NIH Office of Administration, Office of Research
Services and with other NIH, PHS, and DHHS
offices. It handles a broad range of administrative
managerial functions for an NIH research division of
almost 300 people.

Fiscal Year 1981 Accomplishments

The Administrative Office processed a vast number
of administrative actions and acquired approximately
30 million do^lars in supplies and equipment during
FY8I. Day-to-day management activities conducted
by this staff included: procurement purchases and
contracts; travel; training; the administration of
property, space, and communications; payroll; and
mail/messenger services. As a result of new and
pending delegations, the position descriptions of the
staff were reviewed and restructured as necessary to
better take advantage of these authorities. An
automated system was developed to track and
report travel plans and obligations.

During FY81 the Project Control Office conducted a
major update of its files of information on 8,000
users under some 2,000 project accounts. The
Project Control Officer also was appointed Assistant
Systems Security Coordinator for the Division and
was charged with operational responsibility for
meeting departmental guidelines and reporting
requirements relating to ADP systems security.

The Budget Office spent most of the year coping
with a continually decreasing Management Fund
budget and increasing reporting requirements to NIH
program officials on various detailed levels, such as
travel and consultant services. The office studied the
impact of estimated 1981 operating expenses in the
fee-for-service areas along with workload/income
projections. Division cost center managers
negotiated rates for various services with the
Division of Financial Management.

DCRT acquired its own personnel staff as a result of
the Division of Personnel Management
decentralization. As a result a DCRT Personnel

Officer was appointed for the first time and several
delegated authorities, such as position classification,
were acquired. The Personnel Office provided DCRT
with advice and assistance in several areas.

During FY81, approximately 400 personnel actions
that included promotions, reassignments, temporary
appointments, excepted appointments, and transfers
were processed. In February 1981, hiring outside the
Department was restricted to hardship appointments
and clinical case positions only; DCRT was not
affected. Recruitment efforts have been solely
departmental for vacancies we have been able to fill.
The hiring freeze and Reduction In Force within PHS
increased the supply of applicants for the computer
specializations, but have made it difficult to retain our
computer operators, an area in which we have
experienced a large number of losses.

DCRT is serving as the NIH-wide focal point in the
development of Performance Elements and
Standards for the Computer Specialist, Technician,
Mathematics, and Statistics occupational groups.
This effort is being carried out for implementation of
the Performance Management System (PMS) to be
instituted October 1981. The Personnel Officer also
took the leadership role in implementing the Factor
Evaluation System for the 334 (computer specialist)
series and for the PMS.

Future Plans/Trends

Contracting, procurement, travel, and consultant
service requirements as mandated by PHS and
Office of the Secretary, DHHS involve intensive
monthly and quarterly reporting of financial
procurement plans vs. the actual commitment and
numerous other reporting requirements for
consultant sen/ices, travel, budget reductions in
equipment, and other items. To meet this need, we
plan to cross-train existing staff and to decentralize
the entering of procurement actions into the NIH
Materiel Management System.

The Financial Management/ Project Control Section
will develop budgets at the laboratory level within the
Division and will implement a system reporting to the
lab chiefs on expenditures. A revised Project Control
Office form is being developed to ease the annual
process of updating files.

Office of Scientific and
Technical Communications

William C. Mohler, M.D., Chief

Functions

The DCRT Office of Scientific and Technical
Communications (OSTC), under the direction of the
Associate Director, DCRT, includes:

• The DCRT Library, which maintains a collection
in computer science and mathematics, statistics,
engineering, information science, and
management

• The DCRT Information Office, which serves as
the focus for providing the NIH community and
the general public with information about
DCRT's activities and their relationship to
biomedical research

• Scientists assigned to this office, working in
related areas of pattern recognition,
multidimensional information processing, and
applications to medical decision making.

Scope of Activities

The DCRT Library is a small, independent, special
library, staffed by the Librarian and a library
technician. The staff members provide a full range of
library activities and have access to a wide variety of
online information services and data bases. The
collection of monographs, periodicals, and other
documents covers subjects related to the work of
DCRT. These include computer science,
mathematics, statistics, electronic engineering,
information science, and management.

The Library supports the work of the DCRT staff and
serves as a resource for employees in the rest of
NIH. It is an integral part of the Washington area
network of special libraries and cooperates with
libraries outside the area to share resources. It does
this through organizations such as the Interlibrary
Users Association of the Washington/Baltimore
Area, the Metropolitan Washington Library Council,
FEDLINK (a Federal library consortium), and--at the
national level-the OCLC (Online Computer Library
Center) network.

The DCRT Information Office, too, is small and
handles the full range of activities of an NIH
Information Office. The Information Officer, assisted
by a Public Information Specialist, answers inquiries,
produces and distributes print and audiovisual
materials, and arranges briefings for visitors. They
coordinate special events, work with members of the

■

media and provide advice, assistance, and
educational resources on communications for the
DCRT staff. The office is responsible for all Freedom
of Information requests coming to DCRT.

A significant part of the Information Office program is
directed toward improving within NIH an ^H

understanding of the Division's work and the ^|
application of computing to biomedical research. But
the scope of its communications includes Federal
agencies, schools, libraries, private industry, medical
organizations, and a wide variety of individual
scientists and lay persons. The Information Officer is
active in the NIH information community and in
Washington area associations of communication
professionals.

The other professional activities of OSTC derive from
the interests of its scientific professionals. They work
with other professionals at NIH and with medical and
technical groups, government and private, outside of
NIH. They have research and development projects
on image processing and decision analysis.

Highlights of FY81

The DCRT Library maintained its excellent services
to users during FY81 in spite of transient vacancy in
its library technician position and a period of
extended sick leave for the Librarian. Indeed the
number of books circulated and online bibliographic
searches made surpassed those of the previous
year. The new Library Technician, Anita Florentino,
came to DCRT with six years experience from the
Technical Services Branch of the NIH Library. She
and the Librarian, Mrs. Chu, cleaned up the
accumulated backlog in processing library materials
by closing the Library to users one afternoon a week
during the early spring. Preliminary design and
drafting is complete on a new Library user's
brochure to replace the old (1971) version.

The computer-based Circulation System and ^M

Document Indexing Systems installed in previous ^"
years by the Library with the help of DCRT staff
continued to function well and to assure timely
availability of books and documents to DCRT staff
and to other Library users. The Librarian was a guest
speaker on the realities of library automation at a
meeting of the Special Libraries Association in

Washington, D.C., and served with other DCRT staff
on the Advisory Task Force on Automation for the
NIH Library. She completed her year as Chairperson
of the delegation from FEDLINK (the Federal Library
Network) to the Users Council of (OCLC Online
Computer Library Center), a national cooperative
library network. She was elected a Director and
member of the Executive Board of the District of
Columbia Library Association.

With the assistance of the DCRT Library Advisory
Committee, the Librarian completed a review of
journal holdings, made major revisions to the list of
journals for subscription in FY82, and set new criteria
for holdings of back year copies as hard copy or
microform. The Librarian participated with other
DCRT and NIH staff at meetings to advise on
collection policies for books in mathematics,
statistics, engineering, and physics at the NIH
Library. The consensus held that the NIH Library
should have an up-to-date, if limited, set of books in
these areas for all NIH. The DCRT Library assumed
responsibility for the collection of highly theoretical
and advanced works.

The DCRT Information Office had a busy and
productive year.

The office produced a 22-minute videotape program
documenting two DCRT projects dealing with
computer voice technology. The first of these two
systems dealt with a computer voice output system
developed by CSL and now in use by a blind
computer programmer. The tape also dealt with an
existing computer voice input system being used by
a quadriplegic programmer employed by DMB.
During the International Year of Disabled Persons
(1981), the videotape was distributed nationwide to
100 organizations serving the handicapped, to
several other Federal agencies, and to a local media
outlet. The tape was made available to
approximately 180 public television stations
throughout the United States and its territories. PBS
member station WETA-TV in Washington, D.C. aired
the program in March, 1981.

A short sound/slide show describing DCRT and the
work of its laboratories and branches was also
created.

The Information Office prepared new brochures for

LSM, DMB, and the DCRT Library, and assisted in
the production of the CSL brochure. The office
reprinted Computers at NIH: Tools for the
Advancement of tvledicine and issued an update of
Computing Resources, the compendium of who does
what in DCRT, designed to help NIH staff
understand how DCRT can aid NIH scientists and
administrators.

Coordinating and producing the FY81 DCRT Annual
Report was another major job. The FY80 version
received an Award of Achievement from the Society
for Technical Communication, Washington Chapter.

A third communications course, 'Effective Listening,'
was organized. Thirty-five Division staff members
received this training. This course complements the
'Effective Speaking' and 'Effective Writing' courses
given in previous years.

Both public inquiries and publication distribution
remained at levels similar to those of last year. The
Information Office handled approximately 30 special
inquiries and distributed about 300 publications each
month. The general public and other B/I/D's made
up the majority of the DCRT audience, but a
significant number of students and schools also
received materials. Several groups received a DCRT
briefing and tour, including scientists from China and
Japan. Information Office staff members also visited
several nearby colleges to discuss DCRT's role at
NIH and the application of computers to biomedical
research.

The Information Officer continued independent
research work on preparing text in magnetic format
for direct typesetting by GPO; this may result in a
system ready for NIH-wide use by the end of the
calendar year. She was appointed Chair of the NIH
Printing Committee. In addition, she was also active
in outside professional organizations, heading a
panel on evolving technologies in editing for the
annual conference of the National Association of
Government Communicators. She also served as
president of the 350-member Washington chapter of
Women in Communications, Inc., a national
organization for public relations, journalism,
broadcasting, and communications professionals.

Work of the scientists assigned to the office
continued along lines it has followed in previous

years. The areas covered are best seen in the list of
publications and presentations. Dr. Judith M. S.
Prewitt, research mathematician in the Office of the
Director, was elected Fellow of the Institute of
Electrical and Electronics Engineers (IEEE). She is
also an officer of several scientific societies and an
editorial board member of four scholarly journals:
IEEE Transactions on Pattern Analysis and Machine
Intelligence, Computer Graphics and Image
Processing, Medical Decision Making, and Analytical
and Quantitative Cytology. She is a National Visiting
Lecturer of the Society for Industrial and Applied
Mathematics as well as its representative to the
American Association for the Advancement of
Science, Mathematics and Statistics Sections. She
has just been appointed first Chairman of the new
IEEE Computer Society Technical Committee on
Computational Medicine.

Plans

The Library and the Information Office will support
the needs of DCRT and NIH within the limits set by
available staff and funds. The Library will continue to
work on changing catalog records to conform to the
new forms of the revised Anglo-American Cataloging
Rules (AA CR 2). It will explore the applicability of
computer systems to support this task and to keep
up with the effects of automation by the Library of
Congress on its catalog. As a first step, the Librarian
and DCRT volunteers reviewed older monographs to
weed the collection. The retrospective conversion on
the OCLC system will begin during the summer of
1981. Catalog records for items added to the library
prior to 1976 will be tagged for inclusion on the
DCRT holdings tape. The DCRT Library will use
computer programs written by the Computer
Systems Laboratory for preliminary processing of the
OCLC tapes.

The Information Office will continue to develop and
improve materials to tell people what DCRT does
and how computers are used in biomedical research.
This may include some new materials for use at NIH
and perhaps for export in response to requests from
outside NIH. The Information Office will survey both
DCRT and NIH to bring up to date the list of needs
for communications about computers at NIH.

Publications and Presentations

Computers at NIH: Tools for the Advancement of Ivledlcine. NIH Publication

No. 81-1039, reprinted 1981, 24 pp.
Computing Resources of the Division of Computer Research and Technol-
ogy. NIH Publication No. 81-1698, reprinted April 1981, 28 pp.
Data Management Branch. NIH Publication No. 81-1927 (in press).

Dwyer, A., Prewitt, J. M. S., Ecker, J., and Plunkett, J.: The Use of the
Hazard Rate to Allay the Peril of Inappropriate Followup: An Optimiz-
ation Approach. Third Annual Meeting of Society for Medical Decision
Making, Philadelphia, PA, October 19-21, 1981.

Herron, R., Dwyer, S. J., and Prewitt, J. M. S.: Computer Graphics for
Medical Imaging. NCGA '81 Tutorial T-11: Summary (in press).

Laboratory of Statistical and Mathematical Methodology. NIH Publication
No. 81-1930, July 1981, 12 pp.

Miller, P. O.: Text-to-tape Copy Preparation. Communication in the 80's:
Meeting the Challenge (in press).

Prewitt, J. M. S.: Computerized Cell Classification and Counting: The Auto-
mation of Obsolescence and Uncertainty? Washington Bioengineering
Group, American Red Cross, Bethesda, MD, December 11, 1980.

Prewitt, J. M. S.: Mathematical Methods Applied to Image Processing in
Medicine. In Cardus, D., and Vallbona, C. (Eds.): First Conference on
Mathematics at the Service of Man. Berlin, Springer-Verlag, 1981, pp.
24-97.

Prewitt, J. M. S.: Operations Guide for the IEEE Computer Society Techni-
cal Committee on Computational Medicine or Computer Science and
Engineering in Medicine. New York, IEEE Computer Society Press,
1981, 18 pp.

Prewitt, J. M. S.: The Diagnostic Performance of Leukocyte Counters. Ninth
Northeast Bioengineering Conference. New Brunswick, NJ, March 20,
1981.

Prewitt, J. M. S., Lander, B., and Roelofs, L: Computer Graphics for the
Intelligent Microscope. National Computer Graphics Association, Inc.
Second Annual Conference and Exposition, Baltimore, MD, June 15-18,
1981.

Prewitt, J. M. S., Plantholt, M., Simpson, M., Edberg, T., and Sanfeliu, A.:
The Graph-Theoretic Characterization of Tissue Textures. Eighth Con-
ference on Analytical Cytology and Cytometry, Society for Analytical
Cytology, Portsmouth, NH, May 19-25, 1981.

Prewitt, J. M. S., Ranade, S., and Kohler, M. S.: Segmentation of Cell
Images: Art or Science? Eighth Conference on Analytical Cytology and
Cytometry, Society for Analytical Cytology, Portsmouth, NH, May 19-25,
1981.

* U.S. GOVERNMENT PRINTING OFFICE: 1981-720-020/6581 REGION 3-1

DIVISION OF COMPUTER RESEARCTTTCND TECHNOLOGY

FISCAL

YEAR

1981

ANNUAL
REPORT

VOLUME 2

DaXRTK

U !AJ

f
DIVISION OF COMPUTER RESEARCH AND TECHNOLOGY

FISCAL ANNUAL VOLUME 2

YEAR REPORT

1981

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DCDCKTKr

Foreword

While DCRT does not have money for grants, it does
provide occasional support for meetings on scientific
topics related to its work.

This year's annual report is presented in two
volumes:

• Volume 1 gives a summary overview of the
work of each group and highlights its
accomplishments.

• Volume 2 includes detailed projects and
activities of each group.

If you have comments on the report or suggestions
for improving future annual reports, please send
them to:

DCRT Information Office

Building 12A, Room 3027

Division of Computer Research

and Technology
National Institutes of Health
Bethesda, Maryland 20205

Contents

Laboratory of Statistical and Mathematical
Methodology

Summary of Activities 7
Computation 7
Consultation 8

Research Projects 10
Automated Data Processing of Medical Language 10
Cluster Analysis 1 1

Research Topics in Computer Science 12
Discrete Mathematics and Applications 13
Biological and Visual Shape 14
Multivariate Statistical Analysis 14
Linear Methods in Statistics 15
Non-numerical Programming Techniques and

Applications 16
Topics in Geometry and Analysis 1 7

Computer Systems Laboratory

Summary of Activities 19

Research Projects 24
Computer Support for Flow Microfluorimetry 'Cell Sorters

(FMF) 24
Distributed Laboratory Data Acquisition and Control

System 25
Molecular Interactions Laboratory Data System 27
Californium-252 Plasma DesorptJon Mass Spectrometer

Data System 27
Combined EDS-WDS X-ray Analysis Scanning Electron

Microscope System 28
Cardiac Scintillation Probe 28
Medical Intensive Care Unit Patient Monitoring Computer

System 29
Cardiac Intensive Care Unit Patient Monitoring Computer

System 31
Computerized Radiation Therapy 32
Image Processing Facility 33

Digital Imaging Applications in Cardiovascular Research 34
Cerebral Metabolic Imaging 35
Computer Analysis of Gel Electrophoresis 36
Automated Analysis of Plaque Formation in Experimental

Atherosclerosis 37
Computerized Three-Dimensional Model of the Cat's

Brain Stem 38
Rehabilitation Medicine Department Computer System 39
Image Processing of Electron Micrographs 40
Positron Emission Tomography (PET) Scan Image

Analysis in Aging Studies 41
Computer Analysis of Autoradiographic Images of

Recombinant DNA Colonies 42
Cataract Grading via Computenzed Slit-lamp Image

Analysis 43

Image Analysis in Computerized Tomography (CT)

Contrast Material Evaluation 44
Image Analysis in Automated Radiotherapy Treatment

Planning 45
Automated Pulmonary Physiology Testing 45
Measurement of Transepithelial Resistance of Kidney

Tubule 47
Electron Microanalysis Facility 48
Computer Assistance for Blind Computer Users 49
Metabolic Energy Measurements 50
Medical Information Technology Project 51

Laboratory of Applied Studies

Summary of Activities 53

Research Projects 55
Statistical Research in Clinical Pathology 55
Mathematical Models of Binding Equilibria 57
Mathematical Modeling of Substrate Transport in

Physiological Environments 57
Analysis of Coupled Transport and Biochemical Kinetics 59
Nonlinear Equations 62
Numencal Approximation Techniques for the Solution of

Reaction-Diffusion Systems in Biology 63
Computer-based Studies in Pulmonary Pathophysiology

and Respiratory Disease 65
Investigation of Hybrid Computing for the Construction of

Simulation Models and for the Analysis of Physiologic

Signals 66
Computer Systems for Nuclear Medicine 67
Computer-Aided Analysis of Electrocardiograms 69
Computer-based studies in Ultrasonography 70
Computer Based Analysis and Image Processing in

Electron Microscopy and X-ray and Electron-Loss

Spectroscopy 71

Physical Sciences Laboratory

Summary of Activities 75

Research Projects 77
Consulting Sen/ices 77

Theory of Biochemical Separation Techniques 77
Actin in Nonmuscle Cells— Biophysical and Biochemical

Studies 78
Theory and Application of Nuclear Magnetic Resonance

Spectroscopy 79
Correlation Function Spectroscopy/Laser Light Scattering 81
Cell IVIotility and Chemotaxis 81
Theory and Ivleasurement of Intermolecular Forces 82
Studies in tvlathematics and Statistics 83
Quantitative Analysis of the Electronmicroscopy of Cells

and their Plasma Ivlembrane 84
Diffusion of r\/lolecules on Cell Surfaces and Light

Scattenng from Fluids 85
Computerized Typesetting of Scientific Papers 87

Data Management Branch

Summary of Activities 89

Computer Center Branch

Summary of Activities 95

Research Projects 97
Nucleic Acid Structure Synthesis and Display 97

Office of the Director

Summary of Activities 98

Research Projects 99
Text-to-tape Copy Preparation 99

Laboratory of Statistical and
Mathematical Methodology

James E. Mosimann, Chief

Summary of Activities

LSM activities can be divided into three areas:
computation, consultation, and research.

Computation
A major part of LSM activity is the offering of
statistical and mathematical systems/packages to
the NIH user community. LSM accepts responsibility
for evaluation of new program packages and their
suitability for NIH. When LSM does support a
system/package for the NIH community, it provides
maintenance, documentation, instruction, and
assistance for users to interpret the results.

Statistical Systems/Packages Support. Dunng
this year, as in the past year, the Statistical Software
Section of LSM maintained the following program
packages and programs:

BMD, BMDP: Biomedical Computer Programs,
UCLA.

SPSS: Statistical Package for the Social Sciences,
SPSS, Inc.

SAS: Statistical Analysis System, SAS Institute,
Inc.

P-STAT: Statistical Package, P-STAT, Inc.

IMSL: International Mathematical and Statistical
Libraries, IMSL, Inc.

MSTAT1: Collection of Mathematical and
Statistical Programs, DCRT.

Dunng the year every system/package went through
at least one major update. The SSS staff answered
over 4,500 calls for assistance, and taught a total of
eight courses on these systems/packages; two each
on the SPSS and BMDP packages and four courses
on the SAS system.

The use of program packages continues to increase.
The average accesses per month of all the statistical
packages rose from around 23,000 during FY80 to
over 33,000 in FY81. For the fifth year in a row SAS
experienced the largest increase of any of the
packages. SAS averages over 24,000 accesses per
month, up from 15,000 per month in FY81. The
average number of accesses per month for SPSS
increased from 5,500 to 6,000. The average

combined accesses of the BMDP and BMD
packages rose from 1,700 accesses per month in
FY80 to around 2,600 this year. As an example of a
package used for specialized purposes, PSTAT
averaged 60 accesses per month, down from 70
average accesses per month in FY80. The mam
programs and subroutines in MSTAT1 averaged 650
accesses per month, in contrast with 450 in FY80.
Accesses to the IMSL package cannot be counted,
but it is estimated that usage increased during FY81.

In addition, two new systems/packages were offered
on an expenmental basis to the NIH computer user
community. SCSS, an interactive version of SPSS,
and SAS/GRAPH, a graphics package from SAS
Institute, were installed and tested at DCRT.

MLAB Support. The Biomathematics and Computer
Science Section maintains the DECsystem-10
interpretive program MLAB for biomathematical
modeling at NIH. This package, designed and
implemented by BCS staff, is used by several
hundred NIH researchers each year for various
modeling and graphical display tasks. It has been
sent to many universities and research centers at
their request. It is part of the NIH-funded Prophet
system, SUMEX-AIM at Stanford University, and the
NIH-EPA Chemical Information System.

During FY81, a revision (Third Edition) of the MLAB
Applications Manual was prepared and distributed. A
series of tutorial articles on MLAB in INTERFACE
continued this year, and six more articles have
appeared. Two beginning MLAB courses and one
advanced course were taught during FY81. MLAB
was enhanced by improvements making it more
efficient and by the addition of Fourier transform and
inverse transform operations.

Support of C-LAB. SMS has assumed support of
C-LAB, a computer system/package for pattern
recognition and cluster analysis. A course on C-LAB
was taught during the fiscal year. C-LAB techniques
were modified to follow the latest published
methods, and compatibility with MLAB was
maintained.

Support for the Unified Generator Pacloge. This
package, developed by a BCS staff member,
generates IBM S/370 assembly language programs.
The compatibility of the package with new WYLBUR
was maintained. As before, assistance was provided
for users on request.

Support for REDUCE and PROLOG. BCS has

continued support for the REDUCE system (obtained
from the University of Utah) for manipulation of
algebraic formulas.

The PROLOG software system (obtained from the
University of Edinburgh) is used for non-numerical
data processing. PROLOG has been applied in LSM
research in linguistic analysis.

Indexing Program. An interactive DECsystem-10
program for generating the index of a document file
was completed. It is undergoing production testing
on MLAB documentation now in preparation.

Consultation
As in previous years there was considerable
variation in the amount of time required for an LSM
consultation. Some very brief consultations are
successful, and are brief precisely because there is a
known answer to the question posed. Other
consultations involve extensive time and statistical/
mathematical/computer science research as well.

LSM consultations in FY81 were of the following
types:

• Mathematical, statistical and computer science
advice with limited computer use (5%).

• Mathematical or statistical advice with
considerable computer use (55%).

• Computational advice alone (40%).

The large computer use in these figures results from
the continued availability and use of general purpose
statistical and mathematical packages like SAS and
MLAB.

The diverse nature of LSM consulting is indicated by
the projects and activities listed below.

Hemodynamic and Plasma Catecholamine
Responses to Hyperthermic Cancer Therapy in
Humans. Y. Kim (CC/ANES). Cancer patients
treated by induction of hyperthermia under thiopental
and fentanyl anesthesia, respond with attenuated
hemodynamic changes compared with those
reported on normal volunteers. Measured plasma
catecholamine at hyperthermic condition showed
evidence of sympathetic nerve response to
hyperthermia. Statistical procedures used include
multiple regression analysis, anova, and descriptive
statistics.

Sleep Analysis. W. Duncan (NIMH/BDP). The
analysis focuses on examining the relationship
between mental illness and sleep disorders.
Discriminant analysis was employed to evaluate
possible contribution of sleep variables in
distinguishing between groups of normal subjects
and depressed (unipolar or bipolar) or insomniac
patients.

Non-parametric Tests. W. Schniderwind (CC). This
study involves use of the non-parametric median and
Mann-Whitney tests for comparing the effect of staff
education on medical and patient care encounters. ^,

Spectral Analysis of Mood Cycles. F. Putnam ^
(NIMH). A frequency-domain spectral analysis study
was done of possible connections between mood
cycles and physiological measurements in disturbed ,
patients.

Automatic Processing of Natural Language
Pathology Reports. D. Henson (NCI/BCPC). A
data base for the Clinical Center surgical pathology
data is being created using automatic encoding of
natural language reports. An initial updating of the
systematized Nomenclature of Pathology (dubbed
SNOP-NIH) has been completed.

Automatic Encoding of Surgical Pathology
Reports. E. Jaffe (NCI/LP). In connection with the
automatic encoding of surgical pathology reports, the
new malignant lymphoma classification currently
used at NIH was incorporated into SNOP.

Atlanta Autopsy Data Base . T. O'Leary (NCI/LP).
The data and lexicographic changes consistent with
SNOP were incorporated into the current Atlanta
autopsy data base. Test runs were conducted.

Metal Ion Protein Binding. C. Chatterji (NIAID/
LC). Optical absorbance experiments measured
metal ion binding to a protein constituent of snake
venom. LSM designed MLAB procedures to curve-fit
mathematical models to the data.

Analysis of Simultaneous Binding Reactions. L.

Jacobson (NICHD/LCP). Simultaneous binding
reactions were studied by obtaining NMR scanner
absorbances at specific frequencies. LSM assisted in
mathematical modeling.

Ultracentrifuge Analysis. M. Lewis (DRS/BEI). A
mathematical model was developed for studying the
distribution of molecules in an organic solvent during
ultracentrifugation. LSM assisted in model
modifications to represent compressibility effects.

Compartmental Analysis of Drug Action. R.

Burns (NIMH/LCS). Effects of drugs with radioactive
tracers were studied in experimental animals. LSM

assisted in modeling drug action by developing a
three-compartment differential equation system.

Interferon Measurements. M. Morin (DRS/VR).
Groups of monkeys were injected with various
compounds, and the yield of interferon was
determined by measuring viral inhibition. Sample
sizes required to produce significant differences
between groups of compounds were calculated.

Potency Analysis. G. Krishna (NHLBI/IR CP).
Maximum likelihood estimates of relative potencies
of groups of compounds administered to a strain of
mice were calculated. Log potency probit analysis
techniques were applied.

Mapping Enzyme Cutting Sites on Circular
Plasmid DNA. M. Huberman (NHLBI/MH).
Specimen circular plasmid DNA is subjected to
enzymes that cut the DNA at specific sites.
Fragment lengths from one- and two-enzyme
complete digest experiments are measured by
electrophoresis. LSM designed and tested a pilot
MLAB procedure to generate DNA maps consistent
with the fragment data. An assessment of a Stanford
computer program for constructing DNA maps from
fragment data is scheduled for this fiscal year.

Continuous, Constant-Volume Diafiltration
Methods. K. Roy (NIADDK/LMB). A laboratory
technique for continuous, constant volume
diafiltration measurements of binding parameters
was designed and tested on several nucleic acid
monomer-polymer systems. LSM assisted in
modeling, designing, and testing of MLAB
procedures. These procedures perform such
functions as automatic elimination of bad data,
curve-fitting of models to data, and generation of
graphical displays of raw data, selected good data,
and curve-fitted models.

K-means Clustering. J. Wunderlich (NCI). K-means
clustenng in CLAB was used to study the genetic
control of immune response in mice, to identify high
and low responders.

Depletion of Lymphocytes in Circulation. J E.

French (FDA/DBBP). Analysis of covariance was
done for data pertaining to the depletion of
circulating lymphocytes by leukapheresis in dogs.

Cell Microfilament Networks. N. Gershon (DCRT/
PSL). Three-dimensional graphical displays of cell
microfilament networks were prepared and
presented at a scientific conferenceiposter session.
LSM assisted in using MLAB facilitie^ for computer
generation of three-dimensional graphical displays.

Free Run Cycling of Firefly Pacemaker. John
Buck (NIADDK/LPB). The interflash duration of

fireflies was used as a measure of endogenous
pacemaker timing behavior. Since Student's t-test,
needed in analyzing free run pacemaking, requires
that interflash durations have a Gaussian distribution,
chi-square analyses of truncated samples were used
to ascertain whether this requirement was fulfilled.

Protein Frequency Profiles. H. Saroff (NIADDK/
LBP). Chi-square goodness-of-fit tests of the
Gaussian, binomial, and Poisson distributions were
applied to distnbutions of the number of random
matches for amino acid sequences obtained from
Monte Carlo experiments.

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Research Projects

Automated Data Processing of Medical
Language

The major objective of the project is the
development of methods for the automatic
processing of natural medical language. A major
application is the program for information storage
and retrieval of pathology data for the Laboratory of
Pathology, NCI. The entire corpus of surgical
pathology will be encoded.
The continued collaboration with the Laboratory of
Pathology, NCI, to create a data base for the Clinical
Center surgical pathology data indexed by automatic
encoding has reached the following stage.

With Dr. Donald E. Henson (NCI/BCPC), the initial
updating of the Systematized Nomenclature of
Pathology (dubbed SNOP-NIH) was completed. This
now permits indexing of almost all SNOP
topographic descriptions found in the surgical
pathology reports. The SNOP category of
morphological diagnoses has been similarly updated
for surgical pathology data. With Dr. Elaine S. Jaffe
(NCI/LP), the new malignant lymphoma classification
currently in use at NIH has been incorporated into
SNOP-NIH.

The current surgical pathology data base has been
automatically encoded, and some changes have
been made in the automatic encoding program to
reduce redundant and erroneous encoding.

This year, the Atlanta autopsy data base project was
revived under the leadership of Dr. T. J. O'Leary,
(NCI/LP) . On the basis of test runs of these data,
some lexicographic changes consistent with SNOP
were incorporated into the current dictionary.

Work continued on the study of morphosemantic
structuring of medical Greek-Latin derived forms.
The goal is development of a generalized system for
automatic morphosemantic analysis of medical
compound words.

Work was elaborated on a project to determine
automatically the productive morphemes (prefixes,
infixes, suffixes) used in the formation of the terms
appearing in the French translation of SNOP. The
morphemes were isolated by procedures involving
pairwise and setwise comparisons of terms. Nearly
17,000 terms were segmented.

An English-to-Spanish translation procedure and its
associated dictionaries were developed and
implemented for 1,426 terms of the morphology
section of the International Classification of Diseases

for Oncology. Morphological substitutions and
respelling rules permit translation of the ICD-0 terms
derived from Greek and Latin, which are cognate in
the source and target languages, without
construction of a large lexicon. This work was
accomplished in cooperation with a guest worker,
Isabel Garcia-Hidalgo.

The stem dictionary for the 'hepatitis' data base for
NLM was completed.

A list of semantically productive terminal morphemes
in medical language was prepared for the MEDLINE
system at NLM.

Page copies of computer oriented medical
dictionaries (SNOP, ICD) were made available to
three medical institutions.

Future efforts:

a. Continuation of research studies in medical
language at present level (morphology, syntax,
semantics).

b. Creation of a lexicographic data base to be
used for merging of medical dictionaries and
extraction of microglossaries.

c. Continuation of collaboration in the encoding of
surgical pathology data with the Laboratory of
Pathology, NCI, to refine the medical dictionary and
study the language of diagnoses.

Publications:

Garcia-Hidalgo. I , and Dunham. G.; An experiment in English-Spanish auto-
mated translation of medical language data. Methods of Intormalion in
Medicine 20: 38-46, 1981.

the distribution of cones is non-random, tending
towards regularity.

Statistical methods, based on nearest neighbor
distances between cones, were used to determine
which type of regular pattern, with known error, is
matched most closely. Voronoi regions (convex
polygons surrounding each point) were computed
and are being used as another approach to
measuring regularity.

Proposed Course: Earlier work on measuring the
effectiveness of cluster tendency algorithms will be
completed.

More retinal cone data will be collected, and spatial
distributions modeled, based on a statistical analysis
of the data. A wider range of cluster analysis
algorithms will continue to be developed and applied.

Publications: None

Cluster Analysis

Cluster analysis algorithms based on the latest
published research and extensions to it were
developed and tested.

Algorithms for analyzing spatial point patterns were
developed for testing patterns of retinal cones for
regularity.

Background and Objectives: The main objective is
the development of computer programs and
methods for cluster analysis and related problem
areas for use by NIH researchers.

Progress in FY81: New algorithms for representing
multivariate data graphically have been programmed
and will be added to the C-LAB cluster analysis
package. These include Andrews plots, biplots, and
probability plots. Recent work in the analysis of point
patterns is being applied to the distribution pattern of
cones from monkey retinas to determine if there is
an underlying regularity and to measure the degree
of regularity. Standard statistical tests indicate that

, 1980 through Scptcnbor 31. 19S1

> Topks In Corputer Scl(

Computer Spcctallsl

Laboratory of Stflt)stic«l and Hatheratlcal Hethodology

and Conputer Scier

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Currently, a study or Che hashing storage and retr

Research Topics in Computer Science

Various storage and retrieval algorithms have been
studied. The development of flexible and efficient
storage and retrieval algorithms is very useful; such
algorithms are used in almost all computer programs.
Thus biomedical computation in particular can
benefit from improved storage and retrieval methods.

Currently, a study of the hashing storage and
retrieval methods is underway. This has resulted in
the analysis of the performance of the hashing
method that resolves collisions using direct-chaining
with coalescing lists.

Project Description: The object of this project is to
develop theoretical bases for new computer
methods which will expand and improve the use of
computing in biomedical computation. The methods
used are the application of known algorithms and the
development of new pertinent theorems involving
combinatoric and other related mathematics.
Research work in storage and retrieval algorithms
and their efficiency has been the primary topic of
concern.

Concurrently, an exhaustive survey of storage and
retrieval methods is underway. This includes the
recently-introduced k-d tree method. Various
improvements and refinements in both the
algorithms and their analysis are being studied.

Much effort has gone into studying the B-Tree data
structure for large files and developing a deletion
algorithm to efficiently remove items from B-Trees.

Routines to store, retrieve, and delete items in a
hash table that employs direct-chaining with and
without coalescing lists have been prepared. The
analysis of these algorithms is an active area of
study.

Publications:

Knott, G. D.: Procedures for managing extendible array files. Software
Practice and Experience 1 1 : 63-84, 1 981 .

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BlomathwMttci and Computer Science Section

DCRT. NIH, Sethetda. Ilaryland 20?0&

1.3 1 0.8 1 O.S

Inclutton r«1atlont between vector ipaees and related problcas concerning
•nodwies over rings were itodled.

Preparation of utenltflc nanuscriptt by conputer graphics nethods using
printer-plotters on nJnicowputeri MS Investigated.

Discrete Mathematics and Applications

Inclusion relations between vector spaces and
related problems concerning modules over rings
were studied.

Preparation of scientific manuscripts by computer
graphics methods using printer-plotters on
minicomputers was investigated.

Project Description: The project objective is to
develop mathematical theory and computational
techniques using discrete mathematics (algebra,
combinatorics and graph theory), and to apply such
methods to appropriate problems of biomedical
research and computer science.

Methiods Employed and Major Findings: Studies of
inclusion relations between modules over a ring (a
mathematical concept generalizing vector spaces
and commutative groups) continued. A study giving
five characterizations of the case that two rings have
the same module inclusion theories (plus three more
characterizations for finite nngs) was completed and
submitted for publication.

In computer science, previously developed
minicomputer software for generating graphical
displays of scientific and mathematical text was
augmented. New facilities include: high-resolution
hard copy output of scientific and mathematical text
obtained using a Varian 9211 printer/plotter, direct
incorporation of figures and graphs generated on the
DECsystem-10 using MLAB or OMNIGRAPH into
pages of scientific text, and many new notations and
character fonts implemented. It is expected that the
first complete version of this system will be available
duhng this fiscal year. Parallel with this work, the
computer program TEX developed at Stanford
University for computer generation of mathematical
text was adapted for NIH by the Laboratory Systems
Unit. Experimental trials have used TEX to generate
mathematical text on the printer/plotter.

Proposed Course: Study of the equivalence of
different approaches to module theory will be
continued. The most important unsolved problem is
the classification of nngs that lead to the same
restricted theory of modules.

Research on computer generation of scientific
manuscripts will continue, with most work
concentrated on improvement of computer input
methods so that mathematical notations can be
described without placing heavy burdens on the
users. Experimental work involving the TEX system
will continue.

Publications:

Hutchinson. G A complete logic (or n-permulable congruence lattices
Algebra UniversalisXm press).

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Research Cen. Phys. Sefentlsl LSH DCRT

Chief, Clinical InveiHgations

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SioMthtiMtlcs and Comiuter Science Section |

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: V.H1. NIH. eethesda, Maryland 2O20S

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Biological and Visual Shape

The overall objective is to develop a formal
descriptive language natural to biological shapes and
apply this language to a number of problems arising
in main areas of medicine and biology. This would
allow for the automation of many shape processes
now done by humans and permit better modeling
and understanding of shape and shape development
for biological and medical purposes.

Progress in FY81: A general program for extracting
symmetric axis descriptions is now available at
DCRT. The mathematics for extending this geometry
to three-dimensional data, such as will be coming
from a variety of new scanners, is continuing. In
addition, the development of mathematics for
extracting these descriptions from gray scale data
(for example, tissue sections and x-rays) is
continuing.

This geometry is being applied to the study of growth
and development of the human mandible. Some
shape invariants have been found and are being
studied. This work will possibly be continued in two
directions. The first is a continued examination of
individual human mandibles. The second is the study
of genetic and environmental influences of shape
development in the mandibles of laboratory mice.

Proposed Course:
mandibles.

Finish worl< on human

Publications:

Blum, H.: 3-D Symmetric Axis Coordinates: An Overview and Prospectus. In
Badler, N., Bajcsy, R. and Otto. G. (Eds.): Three Dimensional Object
Representation. New York, London, and Heidelberg, Springer-Verlag,
1981.

Multivariate Statistical Analysis

The overall objective of this project is the study of
multivariate statistical methods for the analysis of
data that take the form of ratios or proportions.

Study continues on multivariate statistical methods
(size-shape methods) for analyzing ratios following a
multivariate lognormal distribution. Studies also
continue on ratios which follow an Inverted Dirichlet
distribution. Studies of discriminant analyses for size
and shape variables (with J. N. Darroch) continue.
The Principal Investigator presented a review of his
work along with a tutorial seminar for biologists at
the Florida State University, Tallahassee. A study on
bivariate distributions where the conditional
distribution of Y given X is a Beta distribution (by M.
V. Ratnaparkhi) is in press.

A study of complications of dialysis (with G.
Hirschman, et al.) was published during this year.
This study used methods for analyzing proportions of

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•Miytcs durlnq the year. Nhtch (re of Midespread use 4t HUi.

patients hospitalized in relation to time at risk.

Statistically similar methods were also applied to the
design of experiments for the production of
hybridomas (A. DeBlas).

Publications:

DeBlas. A L . Ralnaparkhi. M V. Mosimann. J. E.: Estimation ol the
number o( monoclonal hybridomas in a cell fusion expenment Journal
ol Immunological Methods (in press)

Hirschman. G H . Woltson. M , Mosimann, J E.. Clark, C. B.. Dante. M L ,
and Wineman. R. J : Complications of dialysis. Clinical Nephrology
1566. 1981.

Mosimann. J. E.. and Malley. J D The Independence of Size and Shape
Before and After Scale Change In Taillie. C . Patil, G P . and Baldes-
sari. B (Eds): Statistical Distributions in Saeniilic Work. Vol 4, Models.
Structures and Characterizations Dordrecht. Holland. D Reidel Pub-
lishing Co (in press)

Ralnaparkhi. M V Some bivariale distnbutions of (X.Y) where the condi-
tional distribution of Y. given X is either beta or unit-gamma In Taillie.
C. Patil. G P . and Baldessari. B (Eds ) Statistical Distributions m
Scienti/ic Work. Vol 4. Models. Structures and Characterizations Dor-
drecht. Holland. D, Reidel Publishing Co (m press)

Roux. J J J . and Ralnaparkhi. M V On matnx-variate beta type I distnbu-
tion and related charactenzation of Wishart distnbution In Taillie. C .
Patil. G P . and Baldessari. B (Eds); Statistical Distributions m Scientil-
ic Work. Vol 4. Models. Structures and Characterizations Dordrecht.
Holland. D Reidel Publishing Co (in press)

Linear Methods in Statistics

The overall objective of this project is the study of
linear methods in analyses during the year, which
are of widespread use at NIH.

Progress in FY81: Linear methods in statistics
continue to be studied. Theoretical results on
algebraic independence and statistical independence
were obtained. These are of the sample covariance
matrix of multivariate measurements. Previous
research on Simultaneous Confidence limits for
ratios was refined and consolidated into a single
report for publication. These latter methods are of
broad application, for example, with multiple
regression and discriminant analyses.

New research into studies of conditional probability
were undertaken and are in progress. Studies of the
application of linear model with unbalanced data (a
common type of data at NIH) continued. Some
stress was put on repeated measures anaylses using
the new versions of the statistical systems SAS and
SPSS.

Publications:

Carlson. H . and Malley. J D Job Satisfaction of Staff RNS in Primary and
Team Nursing Delivery Systems Research in Nursing and Health.
1981

Gnmes. A. M . Mueller. H G and Malley. J D : Examination of binaural
amplification in children Ear and Hearing (in press)

Malley. J D : Simultaneous confidence intervals for ratios of normal means
Journal ol The American Statistical Association (in press)

Mosimann. J E . and Malley. J D The Independence of Size and Shape
Before and After Scale Change In Taillie. C . Patil. G P . and Baldes-
sari. B (Eds ) Statistical Distnbutions m Scientitic Work. Vol 4. Models.
Structures and Characterizations Dordrecht. Holland. D Reidel Pub-
lishing Co (in press)

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F Statistical and Mathematical Methodology

DCfiT. HIH. Bethesda. Maryland 20205

Non-numerical Programming Techniques and
Applications

The special-purpose computer language PROLOG is
being used to explore a potential research project in
computational linguistics and artificial intelligence.
The ultimate goal of this project is to develop a
methodology for automatically transforming the
information presented in a textbook into a form
which may be used in an appropriate manner by a
computer.

A textbook on BASIC programming has been chosen
and a heavily edited version of its first chapter has
been used to avoid numerous problems of
computational linguistics not directly relevant to the
specific task of manipulating knowledge
representations. To date, a PROLOG program has
been developed that can analyze an input of three
paragraphs in English that describe how to write
expressions in the BASIC language. As a result of
analyzing these paragraphs, the PROLOG program
automatically synthesizes a program that could
determine whether or not strings of characters form
legal BASIC expressions. The use of PROLOG is
essential to this project. It is appropriate for tasks in
computational linguistics and artificial intelligence,
and for the representation of knowledge (particularly
procedural knowledge) as well.

A paper has been prepared which discusses the
aims, methods, and initial progress of this project.

Publications:

Norton, L M.: A note about Laplace transform tables for computer use.
SIGSAM Bulletin 14: 30-31, 1980.

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Topics in Geometry and Analysis

Metrics for convex homogeneous cones were
studied. A mathematical formalism for the symmetric
axis transform is under development.

Progress in FY81: Four invanant (under the group
of linear automorphisms) metrics on convex
homogeneous cones have been studied. Bounds on
those have been obtained, and an equivalent
expression for each has been found, which allows its
explicit calculation in a simple closed form involving
generalized 'eigenvalues' of the cone's Vinberg
algebra representation. A parametrization of an
interesting family of cones has been obtained, which
offers the possibility of applications to the
generalized symmetric spaces, and further study of
this has been initiated.

A mathematical formalism for the symmetric axis
transform is being developed. The techniques
involved allow generalizations from open sets in two-
dimensional Euclidean space to open sets in n-
dimensional Euclidean space and the study of
convergence properties of symmetric axis
transforms. By methods analogous to those used in
cut sets of Riemannian manifolds, topological
invariants of the manifold have been shown to be
inherited by its symmetric axis. A study of local
differential geometric properties of the axis has been
initiated.

Publications:

O'Connor. MA Invariant metrics on cones. Proc. ol the Conference on
Invanant Melncs and Holomorphic Maps. Rome, Italy, Istitulo di Alta
Matematica F Seven di CNR (in press)

Computer Systems
Laboratory

Alan M. Demmerle, Chief

Summary of Activities

Computer Support for Flow Microfluorimetry/Cell

Sorters[FMF] (NCI, NHLBI). This project provides
support for acquisition and processing for four
Becton-Dickinson FACS II and one Coulter
instrument. Of these, three were new in FY81. FACS
ll/PDP-11/34 systems were installed for IR, EA,
NHLBI and EEB, NCI. A Coulter PDP-11/34 system
was installed for VA MOB, NCI. All CSL systems are
currently using DEC'S RT-11 single user operating
system. CSL is developing an RSX-11M multi-user
system to replace RT in some high volume
applications. This system will feature an LSI-1 1
microcomputer that will independently interact with
the FMF operator dunng parameter entry and will
acquire data. Benchmark testing and design of the
LSI-1 1 buffer was accomplished in FY81. Both the
RT and RSX systems use DEC'S VT-1 1 graphics
terminal, which is no longer available for purchase
and on which guarantee maintenance is scheduled
to be eliminated. After a thorough evaluation, a
Tektronix T4025 was selected as a replacement.
CSL IS pursuing a contract to develop software to
respond to the existing VT-1 1 graphic calls and drive
the T4025.

Cardiac Scintillation Probe(NM, NHLBI). CSL has
continued the development of its Cardiac Scintillation
Probe System begun in 1977. This non-imaging
ECG-Gated scintillation probe, when used in
conjuction with left ventricular (LV) catheterization,
permits simultaneous quantification of the variation
of LV volume and pressure. Derived parameters
such as LV compliance can also be monitored, in
addition to such measurements as ejection fraction,
filling and ejection rates, and temporal relationships.
This year realtime pressure-volume measurements
were used to study the effects of nephidipine and
verapermil on patients with asymmetric septal
hypertrophy. New hardware and software have been
developed to allow online calculation of new
parameters and permit the system to be easily used
on a routine basis by the Clinical Center personnel.
Development is continuing to increase the detection
efficiency of the probe and to quantify the limitations
of the technique.

Nuclear Medicine Computer Systems(CC). CSL

has continued consultation and support for the
imaging systems located in the Nuclear fvledicine
Department. This involved working with Nuclear
IVIedicine to assess their clinical computing
requirements in regard to their changing needs and
anticipated growth with the new Ambulatory Care
Research Facility. This year, due to the increased
demand for routine clinical cardiac studies, the
Nuclear Medicine Department has doubled the
capabilities in this area by purchasing an additional
camera system and expanding its computer system.
CSL helped specify a camera system that, in
addition to performing present cardiac studies, would
permit the investigation into high efficiency camera
systems and their potential applications.

Computerized Radiation Therapy(NCI). CSL has
developed a computer system, now in clinical
operation in the Radiation Oncology Branch, NCI, to
use the detailed contour and density information
available from computer assisted tomography to
improve radiation treatment planning. This system for
external beam treatment planning is based on a
generalized 3-D dose field model that covers photon,
electron, and neutron beams.

The computer program and most of its clinical
implementation has been completed for the photon
and electron fields available from the local 6 MV and
12 MV linear accelerators. The current capabilities
include interactive simulation of most irradiation
techniques, including the effect of most beam
modifying devices. The system enables the display
of dose distributions computed in several transverse
contours and overlaid on corresponding CT scans.

Cardiac Intensive Care Unit Patient Monitoring
Computer System(NHLBI). The Surgery Branch of
NHLBI has collaborated with CSL on a continuing
basis in the development of automated techniques
for monitoring patients in a post-operative cardiac
intensive care environment. Previous annual reports
describe the details of the system's functional goals
and project milestones. The system was maintained
in continuous operation until the end of December
when the computer was removed from sen^ice, in

anticipation of the Surgery Branch's pending
relocation to new facilities in the Clinical Center. The
new Intensive Care Unit, constructed this year, had
been planned with the design features necessary to
support computerization. The decision as to which of
several approaches to online patient monitoring is to
be implemented will be deferred until next year.

Medical Intensive Care Unit Patient Monitoring
Computer System(CC). Automation of the Medical
Intensive Care Unit required the development of a
multiple-computer system configuration to provide for
the measurement, analysis, control, and
recordkeeping functions that are dictated by the role
of the unit. The departure of the unit's senior staff at
the end of last year resulted in the temporary
cessation of hardware/software development,
although the system was maintained in continuous
operation. With the arrival of a new Department
Chief, a reconsideration of system goals was
undertaken. Particular emphasis was placed on
upgrading the system's cardiac catheterization
capabilities. Data collection and retrieval functions of
the primary patient data management system are
being reconfigured to support anticipated research
protocols.

The Biomedical Image Analysis Project(NHLBI,
NEI, NCI, NIDR, NIADDK). This project is oriented
toward the development of general-purpose
algorithms and techniques for image digitization,
contrast enhancement, edge detection, contour
extraction, contour following, contour coordinate data
compression, and three-dimensional representation.
The resultant general-purpose capability is being
accomplished through work with a number of NIH
researchers who encounter relatively similar classes
of problems in unique individual settings.

Automated Electrocardiogram Processing

System(CC). A computer system for the online
collection, analysis, storage, and retrieval of
diagnostic electrocardiograms was procured this year
to automate the Clinical Center's Heart Station. The
system was installed in refurbished facilities at the
site of the dismantled cardiac intensive care unit
patient monitoring computer system, and acceptance
testing was rapidly completed. The delivery and
installation of special NIH-specified software
paralleled the training of the operational staff and
the education of all clinical center physicians
regarding the switchover to the automated
electrocardiogram system.

Molecular Graphics(NIDR). Three projects use the
Evans and Sutherland Picture System for modeling
of protein structures.

1. From the amino acid sequence of collagen,
detailed structures can be analyzed and compared
with x-ray diffraction and electron microscopy data.

2. As the amino acid sequence of the helical |
portion of myosin is obtained from cyanogen i
bromide fragments, these pieces can be modeled as
double stranded alpha helices. When the complete
sequence is known, more sophisticated models
including groups of molecules can be designed.

3. A study of the structure and possible models of
streptococcal M proteins is also underway in
collaboration with the Rockefeller University. These
models are based on a double stranded alpha helix.

Rehabilitation Medicine Department Computer
System(CC). This project involves the development
of computer techniques in rehabilitation medicine in
collaboration with the Rehabilitation Medicine
Department of the NIH Clinical Center. CSL has
recommended computer techniques that can be
used to automatically acquire anatomical and
physiological information from patients, perform
calculations on the data obtained, and display the
necessary results to the medical staff. The
automated techniques include the measurement of
body forces (hand and ground reaction forces),
muscle activity (monitoring the electromyogram of
muscles), and body kinematics (the position and
angles of the limbs and joints in space and time).
The system will also allow the medical staff to
access a data base with computer generated forms
displayed on a terminal screen, and to perform
inquiries and generate reports using the accumulated
data. In FY82 CSL will continue the work begun in
FY81 including the specification of the computer
system, the evaluation of methods to perform the
desired measurements, the selection of the
necessary transducers and instrumentation, and the
specification of the required software.

Automated Pulmonary Physiology

Testing(NHLBI). Lung compliance and inspiratory
muscle strength procedures performed in the
pulmonary physiology/exercise laboratory of the
Pulmonary Branch have been automated using a
MINC 11/03 computer system. Data is acquired and
analyzed in realtime, with graphical and textual
reports being produced at the completion of each
procedure. An exercise testing procedure has been
partially automated. Data from the test is entered
into the computer manually. Analysis and report
generation are then completed automatically by the
computer. Work is in progress to enable automatic
realtime acquisition of exercise data. A scheme has
been developed to locally store patient results from
the above tests on disk for retrospective reference.

Eventually, this data will be transmitted to the central
PB data base scheduled for development by the
Data Management Branch.

Pulmonary Branch Support(NHLBI). This project
involves assisting the Pulmonary Branch to meet its
computer and data processing needs. CSL has
helped to maintain the computer portion of the two
automated pulmonary function analyzers installed
last year. Cooperation with DMB resulted in a
proposal accepted by PB for DMB to develop a
clinical data base. During FY82, we expect the data
base system to be completed. We will interface both
the automated pulmonary function analyzers and the
pulmonary physiology computer (reported separately)
to it.

Computer Interfaces for Clinical Laboratory
Instruments(CC). Efforts were continued this year to
improve the acquisition and reporting of clinical
laboratory test results. A second Coulter Model S-
Plus cell counter was connected to the Clinical
Laboratory Computer System using the method
designed in FY80. Development of a multistation
microcomputer system for white cell differential
counting, started in FY80, was also continued this
year. The system will support up to eight stations
and will be connected directly to the Clinical
Laboratory Computer System. In addition to
differential counting, technologists will be able to use
the system to access and review Coulter results.
Testing of a single station prototype system is
complete; the full system should be operational early
in FY82.

Distributed Laboratory Data Acquisition and
Control System(NIADDK). A Distributed Laboratory
Data Acquisition and Control System (DLDACS) has
been implemented for NIADDK, in Building 2, as a
replacement to the Laboratory Computer System
developed by CSL ten years ago. The new system
consists of a network of remote microcomputers
connected in a star configuration through a
communications processor to a central data
processing computer. The remote microcomputers
handle all of the realtime data acquisition
requirements and provide instrument control
functions when required. The collected data is
normalized, buffered, and transmitted at a
convenient time to the communications processor as
files over a serial line, using a standard block
communications protocol. The communications
processor serves as a store and forward front end
for the central computer. Currently there are seven
satellites connected to the system supporting ten
instruments which includes four added this year.
Presently the system is configured with two host

processors, a Honeywell-516 and a DEC PDP-11/70,
connected to the communications processor allowing
a staged transition of processing programs from the
H-516 to the PDP-11/70.

Molecular Interactions Laboratory Data

System(NHLBI). This microcomputer (PDP-11/03)
data system supervises the acquisition and
processing of information from an ultracentrifuge and
a circular dichroic spectropolanmeter used in MDB,
NHLBI to investigate the interactions between
human lipoprotein subunits. Current capabilities
include acquisiton, display, and preprocessing of
data from the ultracentrifuge and transfer of
preprocessed data files to the DECsystem-10 for
further analysis. The characterization of interacting
systems is then carried out under MLAB on the
DECsystem-10. Computation of molecular weights
for both associating and non-associating systems are
also performed under MLAB. An interface to the
GARY 61 spectropolarimeter was designed,
fabricated and tested in FY81. Software support
includes the ability to add, subtract, and average CD
spectra and to transfer files to the PDP-10 for further
analysis.

Californium-252 Plasma Desorption Mass
Spectrometer Data System(NHLBI). The
Californium-252 plasma desorption mass
spectrometer puts unusual and stnngent demands
on the data system that controls the spectrometer
and acquires and processes its data output.
Realtime performance and the ability to access very
large data arrays in main memory are key
considerations. A data system design modeled after
one in use at Texas A & M University has been
purchased and will be operational soon. Special
interface electronics and stepping motor controllers
for automatic tuning are under construction in CSL.

Combined EDS-WDS X-Ray Analysis Scanning
Electron Microscope System(NIADDK). This
Project entailed the development of a scanning
electron microscope system capable of
simultaneously analyzing the x-ray emissions of a
sample under observation by both energy-dispersive
and wavelength-dispersive detectors. The system
permits localization and quantitation of both light and
heavy elements in the sample, storage of raw and
reduced data within the data system, processing of
data, and transmission of data to a remote
DECsystem-10 computer system at DCRT. This
system is complete and no further development is
anticipated.

Radiation Counter Data Recorder. A six-month
extension was negotiated for the contract awarded in

FY80 for the manufacture of Radiation Counter Data
Loggers. Under this extension NIH investigators
could purchase Data Recorders using a Record of
Call. NIH purchased 18 Data Recorders under this
extension. Since the response was small, a new
contract will not be sought. NIH laboratories can
continue to order Data Recorders using a standard
requisition (NIH-402). CSL continues to assist
laboratories in converting their liquid scintillation and
gamma counter data outputs to Data Recorder
systems, and in overcoming related data
communications problems.

Measurements of Transepithelial Resistance of
Kidney Tubules(NHLBI). A microprocessor-based
instrument was developed in FY80 to facilitate the
determination of the transepithelial resistance of an
in vitro preparation of kidney tubule. The instrument
was upgraded this year to include the online
calculation of the tubule resistances and other
parameters of interest using a complex set of
equations derived from a transmission line model.
Floating-point hardware was added to the instrument
along with the software to utilize it. This new function
provides the investigator with immediate feedback
about the course of the experiment.

Electron Microanalysis Facility{DRS). CSL in
collaboration with DRS/BEIB is developing an
automated electron microanalysis facility consisting
of two electron microscopes interfaced to a PDP-11/
60 computer system. The facility will be used for
research into the elemental composition of biological
specimens, and for the development of new
techniques in electron microscopy. CSL is designing
and implementing the computer system, which will
acquire and display the spectra and images resulting
from Electron Energy Loss and x-ray spectrometry.
This year, software was developed for defining
specimen target areas, for acquiring EELS and EDS
spectra and electron current signals while scanning
the target, and for acquiring, calibrating, monitoring,
and displaying 'housekeeping' parameters. Work was
begun on software for the DeAnza Color Display
System and for retrieving empirical x-ray information.

Metabolic Energy Measurements(NHLBI). This
project is directed toward the development of new
and improved instrumentation and techniques for the
study of energy transfer at the cellular level. In FY80
a microprocessor based system was designed to
study energy parameters of respiring membranes
and this year the system was made operational.
Electrodes are used to measure concentrations of
specific ions as well as those of protons and of
oxygen. The membrane potentials measured by
these new techniques agree with those determined

by traditional methods.

Bioassay Information System(NCI/NTP, NCTR/
FDA). Through an interagency agreement, the
National Center for Toxicological Research (NCTR)
of the Food and Drug Administration is developing a
computerized data base system for the NCI Bioassay
Program using the NCTR Toxicology Data
Management System (TDMS). The NCI Bioassay
Program involves the testing of chemicals with
animals for the detection of carcinogens by contract
laboratories located at many sites around the
country. A goal of this project is to automate the
acquisition of the animal data at the laboratory sites
and to transmit this data to a central computer so
the data can be used to monitor the progress of all
tests and to evaluate test results. Since FY77 CSL
has served as a consultant to NCI specifying and
evaluating hardware and software components of
this system.

During FY81, the terminal contractor delivered thirty
of the microcomputer-based programmable data
acquisition terminals to NCTR in Arkansas for final
testing before being shipped to the laboratory sites.
Five of these terminals were shipped to Southern
Research Institute, Birmingham, Alabama, the first
bioassay laboratory location chosen for automation.
CSL has monitored the contractor performance on
providing the hardware and software components of
the terminal. Another terminal was shipped to NCI,
Bethesda, Maryland and was used by CSL to
establish and test a high speed (4800 baud)
synchronous communications link with the NCTR
IBM computer facility in Arkansas using a
communications protocol emulator software package
provided by the contractor. This link will be used by
the bioassay laboratories in the future to transfer
files with NCTR. CSL also reviewed a report written
by three outside consultants evaluating the entire
TDMS. CSL expects to continue its consulting role
which includes the evaluation of possible new
configurations for this computer network.

Small Animal Section Data Base Management

System(DRS). The Small Animal Section of the
Veterinary Resources Branch requires a data base
system to facilitate the data entry, record keeping,
and report generation associated with animal
breeding and distribution. CSL has concluded an in-
depth study of the Small Animal Section operations
and has composed the functional specifications for a
system that will satisfy the needs of the SAS. From
these specifications we anticipate releasing one or
more Requests for Proposals early in FY82 to cover
requirements for a total system to manage the data
associated with breeding, ordering/inventory control.

quality control, and genetic resources. No known
system currently exists that will meet all of these
requirements.

Voice Output Terminal for the Blind The voice
output terminal design was first made operational in
FY79 and has proved to be a valuable asset to the
blind computer professional. Voice output terminals
are now available from several vendors. Two of
these are based on original CSL work. We are
collaborating with our blind users to develop ways of
presenting complex text formats-tables, forms, etc-
in audible form. This should make voice output
devices useful to a wider segment of the blind
community.

Library Automation Project(DRS). This project is
directed toward automating the major functions of
the NIH Library. In response to the CSL study
reported on in FY79, the NIH Library has decided to
purchase the available elements of an automated
total Library system. As no currently procurable
system is expected to meet all NIH Library
specifications, CSL plans to adapt a purchased
system to unique Library requirements. CSL
exhaustively studied Library needs and generated a
comprehensive 'Request tor Proposals' covehng
hardware, software, and conversion of Library
holdings to machine readable form in FY80. The
Library system procurement was delayed one year
for administrative reasons. During the last year, CSL
developed a cost-benefit analysis for the Library
system and updated the RFP to reflect the
improvements in the available systems. System
installation is anticipated for late Summer 1982, at
which time CSL's development effort should be
underway.

Image Processing Facility. This project is intended
to provide a utility to display and analyze digital
images. The system will consist of a powerful 32-bit
computer with a mixture of medium and high
resolution video displays. Also, the system will
include a microdensitometer to allow precise
digitization of x-rays, micrographs, and other images.
The computer and peripherals have been purchased,
with delivery expected duhng the next fiscal year,
and the design for physical space to house the
system is complete. Construction will begin soon,
with completion expected during the next eight
months. The display subsystem specifications are
complete, and procurement is expected during the
next year.

Medical Information Technology Project. This
project is concerned with developing improved man-
machine interface methods such that modern
microprocessor technology can better serve the

needs of physicians and the practice of medicine.

This year we have started to field test some of the
concepts developed in previous years. We have
created a friendly assistive environment, which
allows a dermatologist to create and retrieve the full
spectrum of data contained in a patient record. With
a minimum of keystrokes the examining physician
can select and simultaneously record from a set of
choices for diagnosis, symptoms, signs, procedures,
tests, and prescriptions. We have chosen the most
frequent dermatologic disorders, encompassing over
half of all patient visits, as a basis for this pilot study.
Advantageous techniques that result from this study
will be applied to other clinical and research
recording situations.

Computers in Cardiology Conference. CSL has

continued its support of the annual International
Conference on Computers in Cardiology. The
conference provides a forum for direct interaction
and exchange between physicians, computer
scientists, and engineers who are involved in various
aspects of clinical systems in the field of cardiology.
CSL was responsible for planning and organizing the
1980 Conference in Williamsburg, VA, and helped
edit the Proceedings. This year, six pre-conference
tutorials were organized. Each tutorial is designed to
introduce its subject area to those who are unfamiliar
with it. Participants who need an introduction to the
computer aspects of a subject area or those with
computer experience who need an introduction to
the medical aspects of a subject area are
encouraged to attend. This year's Conference was
attended by 300 people from 14 countries.

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.«««!i^«iuKN'^r*«

ZOl CT00050-02 CSL

October 1, 1980 to September 30, 1981

Computer Support for Flow Mlcrofluorimetry/Cell Sorters (FHF)

PI: Robert J. Romanoff Computer Specialist CSL

OTHER: Ronald Fico Electronics Engineer CSL
Irving Levy Electronics Engineer CSL
Lee w. Freeman Computer Prograimer CSL
Eric S. Loiederman Computer Aid CSL
Arthur R. Schultz, Jr. Chief. Processor Design Section CSL

DCRT

DCRT
DCRT

't:;:v;:";c.:.b.hc. «»B.«:„.™.,

Computer Systems Labordtory

""'processor Design Section

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^'•'-~' °" ""'" *'■'-»"

arious levels for four

hroughput is the principle
T-11 operating syste-.i is
system in order to allow

ies are being added during

This project provides PDP-11 computer support at
Becton-Dickinson FACS II Flow Microfluorimeter (FHF)/C

WADS FHF. Data displav and analysis for hiqh samole
system feature. Software currently running under the

more sophisticated recordkeeping and more effective su
cipated workloads. New hardware and software capabili
the conversion effort.

Research Projects

■

siSEifiSBiE'gssiS'SH*!;?: iT^ai"

,1'ifsiiif'™!,

"ZZ

0056-02 CSL

'"octo^r™. 1980 to September 3D. 19B1 |

Distributed Laboratory Data Acquisiti

n and Control System

PI: John Powell Elect

OTHER: Milliam Jennings Physi
Ronald Fico Elect

Eugene O'Bryan Elect
Arthur fi. Schult;. Jr. Chief

onics Engineer

ronics Engineer
°^jcsjngjneer_ ^ ^^^^_^

LCP, NIAOOK

LCP and LMB. NIAOOK

Computer Systems Laboratory

|OIH»i

:(.) MWNMjEm dWhi»«iiss

« p U) .E.IHER

A local computer networ
Building Z at the National I
laboratory data acquisition

n5""oces

as part 0

an integrated

crocompu

and control over an mstrument/experirr
Storage medium. The hub of the netwo

ent. Although

storage device to the satell

■"

age rriedium to appear as a

Computer Support for Flow Microfluorimetry/Cell
Sorters (FMF)

This project provides PDP-1 1 computer support at
various levels for four Becton-Dickinson FACS II
Flow Microfluorimeter (FMF)/Cell Sorters and one
Coulter MDADS FMF. Data display and analysis for
high sample throughput is the principle system
feature. Software currently running under the RT-1 1
operating system is being converted to function
under the RSX-11M operating system in order to
allow more sophisticated recordkeeping and more
effective support of current and anticipated
workloads. New hardware and software capabilities
are being added during the conversion effort.

Background and Objectives: Since FY75, CSL has
provided engineering, system integration, and
software support necessary to meet the data
acquisition, data display, and analysis needs of
several investigators using Flow Microfluorimeters
(FMF's) at NIH.

In FY81, CSL continued to support a FACS-II/PDP-
11/34 FMF system for I, NCI and a similar system
for LP, NCI. LP, NCI replaced their Los Alamos
Scientific Laboratory FMF with a FACS-II in FY80.
Two new FACS-ll/PDP-11/34 systems were installed
in FY81 with CSL assistance. These are located in
EA, H and EEB, NCI. CSL also assisted in installing
and making software modifications for a Coulter
MDADS/PDP-11/34 system located at the VA
Hospital in Washington, D.C. for VA MOB, NIC. All
CSL supported systems are currently using the RT-
1 1 single-user operating system.

Progress in FY81: The major software effort in FY81
was continuing the conversion of RT-1 1 programs to
run under the RSX-11M multi-user operating system
as well as adding functionality to these programs.
The RSX-1 1 M system is being developed to replace
RT-1 1 in selected CSL-supported systems in order to
provide more effective support of current and
anticipated workloads and more sophisticated data
acquisition and record keeping functions. In FY81, a
multi-level report generation program for FMF data
file information was developed, as was a more
efficient driver program for ZETA 1 553 incremental
plotters. Improvements were also made to the data
display and analysis programs.

Currently, both the RT-11 and RSX-1 1M systems use
the Digital Equipment Corporation (DEC) VT-1 1 as
the graphics display device. The VT-1 1 is no longer
available for purchase and DEC will not provide
guaranteed maintenance after three additional years.

After a thorough evaluation of available devices, CSL
selected a new graphics terminal, a Tektronix T4025,
initially for RSX-1 1 M use and eventually for RT-1 1
use. During the third quarter of FY81, CSL was
pursuing a contract to develop software packages
that will respond to the existing VT-1 1 graphics calls
and drive the T4025 under both RT-1 1 and RSX-
11M.

In order to deal with the degradation of data
acquisition speed under RSX-11M, it was decided to
develop an LSI-11 microconnputer-based data
acquisition system that will independently interact
with the FMF operator during parameter entry and
send the acquired data to the host PDP-11/34 RSX-
11M system over an interprocessor link. An
important feature of the LSI-1 1 will be the ability to
create a 'laboratory notebook' as a permanent hard
copy rather than continuing this as a manual task.
Considerable benchmark testing and design of this
system was accomplished in FY81 and appropriate
hardware was ordered.

Several minor improvements to the RT-11 display
and analysis programs were made in FY81 in order
to accommodate immediate needs of our users.

Also, an efficient program to interface RT-11 to the
ZETA 1553 incremental plotter was written and
installed. The ZETA 1553 plotter replaced the
Houston Instruments plotter on all CSL-supported
systems in FY81.

During FY80, a contract was negotiated to provide
four FMF hardware interfaces. These were delivered,
tested, and installed during the third quarter of FY81.

CSL has also responded to many external requests
and has provided copies of the interface hardware
schematics, software, and documentation to FMF
sites in the U.S., Europe, and Australia.

Proposed Course: In the forthcoming year, CSL
plans to complete the first RSX-1 IM-based FMF
system and LSI-11 -based data acquisition system
and put them into operation at the I, NCI facility. If
resources permit, the RT-11 software will be
rewritten to use the T4025 graphics terminal as a
replacement for the VT-1 1.

Distributed Laboratory Data Acquisition and
Control System

A local computer network has been developed for
LCP and LMB, NIADDK, in Building 2 at the National
Institutes of Health (NIH) as part of an integrated
laboratory data acquisition and processing system.
This network is configured with satellites connected
in a star configuration to a host processor. At each
satellite a dedicated microcomputer system performs

data acquisition from and control over an
instrument/experiment. Although acquired data files
may be stored locally, they are normally transferred
via the network to a host storage medium. The hub
of the network, the concentrator, utilizes DMA
hardware on all communicating links and performs a
file store and fonward function. The local network
allows the host storage medium to appear as a
'virtual' storage device to the satellites.

Background and Objectives: A system of
microcomputers capable of independently controlling
and acquiring data from an instrument/experiment
was proposed in December 1976 as the best system
architecture of upgrading laboratory data processing.
A prototype laboratory data acquisition and control
(LDACS) computer and the essential elements of the
communication system were developed.

Satellites perform the realtime data acquisition and
instrument control functions. Their configuration
includes a Digital Equipment Corporation (DEC) LSI-
1 1 microcomputer, 28K words memory, low density
random access storage, graphics terminal, and all
the necessary I/O hardware to interface the
instrument/experiment. Satellite software runs under
DEC'S RT-11 realtime operating system. A hardwired
serial link connects a satellite to the concentrator.
Although each satellite is capable of stand-alone
operation, the immediate transfer of the files allows
data processing to proceed on the host system
simultaneously with data acquisition on the satellite
system. The host processor, a DEC PDP11/70, is
configured with: 128K words of memory, a high
speed printer/plotter, a 9-track magnetic tape drive,
and two large capacity disc drives. DEC's multiuser,
multitasking operating system, RSX-1 1M, is used to
service the processing needs of the users. User
access to the host is provided by hardwired links
between terminals and host timesharing ports.
Instruments previously reported as being connected
to the network include: Spectrophotometers; CARY
118, Perkin Elmer 580B, CARY 14;
Spectropolarimeter, CARY 60; Electron spin
resonance spectrometer; Varian; and a stimulus
response retina experiment.

Progress in FY81: Seven satellites supporting ten
instruments are currently connected to the system.
Four instruments added this year include a CARY
219 spectrophotometer, a microspectrophotometer
designed by NIADDK, a Jasco J500A
spectropolarimeter, and a I.S. Co. Model 1440 liquid
chromatograph.

Presently, the system is configured with two host
processors, a Honeywell-516 and a DEC PDP-11/70.

The H516 is the data acquisition and processing
computer from a 1 0-year old centralized system in
NIADDK. Having both host processors available
allows a gradual transition of processing functions
from the H-516 to the PDP-11 /70.

In addition, a multipurpose counter/timer module
was developed for use with LDACS and software
was provided for the GARY 1 1 8 LADACS to
accommodate a new experimental technique for
measuring absorbance versus concentration.

CSL had the first part of a two-part users manual
written under contract. This 60-page document is
intended as a guide to introduce scientists to the
system and the LDACS functions and utilities that
are common to all instruments. The second part of
the manual will be specific for each LDACS and will
describe unique instrument related functions.

Proposed Course: Support for the system will
continue. Additional software to further utilize
systems capabilities will be provided for the Jasco
J500A, the Perkin Elmer 580B, the CARY 219, and
the microspectrophotometer. Earlier LDACS software
will be modified as necessary to incorporate the
software libraries and modules that have now been
standardized for LDACS. Documentation of the
system will be given a higher priority, with the
objective of completing an LDACS users guide for
each LDACS and of documenting the common
software libraries developed for LDACS.

Publications:

Powell, J. I., Fico, R., Jennings, W. H., O'Bryan, E. R., Sohultz, Jr., A. R.: A
Local Network for Distributed Laboratory Microcomputer. Proceedings
of the Twenty-first iEEE Computer Society International Conference.
September 1980, pp. 185-190.

:is:cTi£.s'iS"w - lis :sT'

Z01 CT00057-OZ CSL

) SepmKxr 30. I?81_

I Ho1ecu1«r Interactions Laboratory Oat^ Systcs

Conputer Systems Laboratory
Processor Design Section

, MRT, HIA. fietheiila^ MD _2Q2QS_

rtiH. luirMj. TmgiisuWM,.

This microcomputer [PQP-llVojf <lVta system supervises the acquisition it
icesstng of Information from an analytical ul tracentrlfuge and a circular

itlng iys

I by a few simple coinnanas. ai
•clropolarlmeler signals, clMi
■s tne ability to add. subtrac
;o the POP-10 for further anal.

Ointly developed by CSL an(
lie perfonned under MLAB usi

ng predefined pi
ivelength. Softi

_Octobcr 1, 1980 to Septewfter 30. 19B1

C«1iromtum-2S2 Plasma Oesorptlon Mass Spectrometer Data Systea

OTHER: Henry Fait

CSL. OCRT
LC. NHLBI

CoBputer Systems Laboratory

Processor Design Section

DCRT, NIH. Sethesda, W 2020S

3 to «

The CaHfomljB-35g plasma, desorptlon mass spectrgTCSpr [
stringent demands on the data system that controls the spectre
acquires and processes its data output. Real-time performance
to access very large data arrays in main memory are key consK
evaluated alternatives to meet trie data processing needs of tt

Molecular Interactions Laboratory Data System

This microcomputer (PDP-11/03) data system
supervises the acquisition and processing of
information from an analytical ultracentrifuge and a
circular dichroic spectropolarimter used in MDB,
NHLBI to investigate the interactions between
human lipoprotein subunits. Current capabilities
include acquisition, display, and preprocessing of
data from the ultracentrifuge and transfer of
preprocessed data files to the DECsystem-10 for
further analysis. The nonlinear analyses necessary
for the characterization of interacting systems are
then carried out under MLAB on the DECsystem-10.
CLINK, the PDP-1 1/PDP-10 communications
software package jointly developed by CSL and
CCB, is used to perform the data transfers.
Computation of molecular weights for both
associating and non-associating systems can be
performed under MLAB using predefined procedures
invoked by a few simple commands. An interface
has been constructed to acquire the
spectropolarimeter signals, ellipticity, and
wavelength. Software support includes the ability to
add, subtract, and average CD spectra and to
transfer files to the PDP-1 0 for further analysis.

Californium-252 Plasma Desorption Mass
Spectrometer Data System

The Californium-252 plasma desorption mass
spectrometer puts unusual and stringent demands
on the data system that controls the spectrometer
and acquires and processes its data output.
Realtime performance and the ability to access very
large data arrays in main memory are key
considerations. CSL evaluated alternatives to meet
the data processing needs of the instrument and
recommended a more recent model of the computer
used for this purpose at Texas A&M University. This
data system has been purchased and will be
operational soon. Special interface electronics and
stepping motor controllers for automatic tuning are
under construction in CSL.

siii;iris«JSTaS'»ifrii?:js?.T'

.l^iHiii^ffil

PflDJECr hlWBEH

ZOl CT00059-02 CSL

"Octoberi. 1980 to September 30. 1981

Combined EDS-WDS X-ray Analysis Scanning Electron Microscope System

PI: Ramon L. Tate. Ph.D. Computer Specialist CSL, DCRT

OTHER: Htlliam A. Hagins. M.D.. Ph.D. Chief. Meinbrane Biophysics

Section LCP, N!ADOl

Computer Systems Laboratory

Processor Design Section

'""oCRrTNIHV'e'ethesda. HD 20205

,ouL-«u.iiL. ^^ |™c.(ss.w.L. ^_^ |omB.

In 1979. following the reconmendations of CSL. Dr

and heavy elements in the sample, storage of raw and r

computer at DCRT. This system is complete and no furt
pa ted.

ntitation of both light
ed>jced data within the dat;
0 a remote DECsystem-lO
her development is antici-

ZOl CT00051-02 CSL

October 1. 1980 to September 30. 1981

Harold OstroH

Scott Allen
Steve Bacharach

Robert Bonow

I Research Analyst

■ Medicine, CC, Cardiology Branch, NHLBI

'"Dt^'f,"l3lWt*ye*thesda. HD

'tit TiSs 'con£rSJe?f tKe deve'TopSenToT'its Carxliac Scintillation Probe Sysi
begun in_1977. This non-imaging ECG-gated scintillatton'probe. when used in

Implemented capability for
itudy the effects of nephi<
;epta1 hypertrophy. The pr

T"Z

sly

on frac

inn

sjimetr

c'°

; effect;

I Center personnel. Development 1

Combined EDS-WDS X-ray Analysis Scanning
Electron Microscope System

In 1979, following the recommendations of CSL, Dr.
Hagins procured a combined energy dispersive
(EDS) and wavelength-dispersive (WDS) X-ray
analysis system for his scanning electron
miscroscope. A single vendor did not market a
combined EDS-WDS system. CSL arranged for the
EDS vendor to integrate a WDS into their system.
The system permits: localization and quantitation of
both light and heavy elements in the sample, storage
of raw and reduced data within the data system,
processing of data, and transmission of data to a
remote DECsystem-10 computer at DCRT. This
system is complete and no further development is
anticipated.

Cardiac Scintillation Probe

CSL has continued the development of its Cardiac
Scintillation Probe System begun in 1977. This non-
imaging ECG-gated scintillation probe, when used in
conjunction with left ventricular (LV) catheterization,
permits simultaneous quantification of the variation
of LV volume and pressure. By simultaneously
measuring LV volume and LV pressure, parameters
such as LV compliance can be continuously
monitored, in addition to such measurements as
ejection fraction, filling and ejection rates, and
temporal relationships. This year the previously
implemented capability for realtime pressure-volume
measurements were used to study the effects of
nephidipine and verapermil on patients with
asymmetric septal hypertrophy. The pressure-volume
relationships produced by the probe system allowed
the effects of drugs to be quantitated in a manner
not possible before. New hardware and software
have been developed to allow online calculation of
new parameters and to permit the system to be
easily used on a routine basis by the Clinical Center
personnel. Development is continuing on increasing
the detection efficiency of the probe and in
quantifying the limitation of the technique.

.,;iswrxsissr'^,^pyij^

im CTIKKIS4-U Ol

October 1. 1980 te SeptcMber 30. 1981 [

Hedlcal Intensive Care Unit Patient Honltorfng Ctwputtr Systm

Ssn.^s:*ss^>':::^;;vz':;;:;; - -"•' •"•■•■"'-■ - ■" •■-

PI: Kenneth H. Keitipner Electrvnlct Engineer
Robert L. Hdrttno Clectronlcs Engineer

est. K«t
est. OC«I

CrUkal Care Hedlclne OipartMnt. CHnlcal Center

CfiuuUr-

Syitawt >sl9n Sectloi

PCWT. NIM. B«th>«d. HP gPgOS

system for IM

utoiuted patient ronlt

orlna

ch subsystem,
er subsystem
etopnent of n

ord keeping functions
re already operallona

ms, compoter-

ontroUed drug infuse

«t^ra^e

f the patient informa
for retrospective slu

Medical Intensive Care Unit Patient Monitoring
Computer System

This project involves the development of an
automated patient monitoring system for
measurement, analysis, control, and recordkeeping
functions in a nine-bed medical intensive care unit. A
minicomputer-based patient data management
system, a cardiovascular research subsystem, a
software development subsystem, and a medical
mass spectrometer subsystem are already
operational. Future project goals involve the
development of noninvasive measurements of the
cardiovascular and respiratory systems, computer-
controlled drug infusion, and automated unne output
measurement. A data base of the patient information
obtained with the systems will be created and used
for retrospective studies by the medical staff.

Background and Ob/ectives: The IVIedical Instensive
Care Unit (MICU), which is administered by the
Department of Cntical Care ivledicine in the NIH
Clinical Center, receives critically ill patients from
clinical programs of NIH. The MICU comprises a five-
bed ward area, a two-bed special study area, a pair
of isolation beds, and a vascular research laboratory.
The research goals of this unit include the
development of techniques for automated patient
monitoring and noninvasive measurements of the
cardiovascular and respiratory systems. In addition,
the medical staff is performing complete cardiac
cathetehzation studies.

Over the past four years, CSL has invested six man-
years in this project. Working with clinical center
staff, CSL contributed to the engineering design of
the intensive care unit. CSL also undertook the
specification, procurement, and installation of the
bedside patient monitoring equipment and four
computer systems:

1 . a Patient Data Management System used for
automaticaly monitoring patient variables, manually
entering patient data, retrieving information online,
and keeping medical records;

2. a Cardiovascular Research Subsystem used for
acquiring and processing cardiovascular pressure
waveforms, measuring cardiac output, displaying
measured results online, and generating a cardiac
catheterization report;

3. a Software Development Subsystem used for
developing software for the above described
systems; and

4. a Medical Mass Spectrometer Subsystem used
for monitoring both the patient airway gases and the
gases delivered by the patient's respirator at all nine
beds. Featuring the same minicomputer, the first

three systems were purchased from the Hewlett-
Packard Corporation. The Chemetron Corporation
manufactures the microprocessor-based mass
spectrometer system.

Major Findings: The automation of the MICU has
aided the medical staff by: managing the large
amount of data needed for the care of the critically ill
patient, performing desired calculations, and allowing
measurments that would not otherwise be possible.

Progress in FY81: The four computer systems have
been in operation for over two years. The departure
of the unit's senior staff at the end of the last
reporting year resulted in the temporary cessation of
hardware/software development. With the arrival of
a new department chief, a reconsideration of system
goals was undertaken. Particular emphasis was
placed on upgrading the system's cardiac
catheterization capabilities. Data collection and
retrieval functions of the primary patient data
management system are being reconfigured to
support anticipated research protocols.

Significance to Biomedical Researcii: Many
hospitals around the world are automating various
functions in their intensive care units. In particular,
the Hewlett-Packard computerized patient monitoring
system purchased for this project has been installed
in many private, university, and government
hospitals. Therefore, any new developments made
on this project will benefit many users of automated
systems, as well as patient care and clinical
research within the MICU at NIH.

Proposed Course: Depending on the research
goals of the new medical staff, possible
modifications to the primary patient data
management system include the addition of urine
output measurement hardware and the
computerization of fluid infusion therapy with
microprocessor-controlled infusion pumps. In
addition, software modifications to the patient data
management and vascular research computers can
tailor their functional capabilities to the unit's
developing research interests.

Publications:

Marlino, R. L., Kempner, K. M., McClellan, J. R., and McLees, B. C:
Automation of a Medical Intensive Care Environment with a Flexible
Configuration of Computer Systems. Proceedings of the Fourth Annual
Symposium on Computer Applications in Medical Care. New York,
Institute of Electrical and Electronics Engineers, Inc., 1980, pp. 1562-
1658.

5Sij?inaa!S'r"irrji?:.^S2i!i"

;2fw»;«;"

ZOl CT00053-0^ CSL

"octobeM, 1980 to September 30, 1981

Cardiac Intensive Care Unit Patient Monitoring Computer System

PI: Kenneth M. Kempner Electronics Engineer CSL, OCRT
Andrew G. Morrow, H.D. Chief, Sfi SB, NHLBI

OTHER: William L. Risso Electronics Engineer CSL, OCRT
Robert L. Hartino Electronics Engineer CSL. OCRT
Lee Freenan Computer Prograniner CSL, OCRT

Surgery Branch, NHLBI

Systems Design Section

The computerized patient monitoring system developed in conjunction with
Surgery Branch. NHLBI, provides realtime, beat-to-beat analysis of physiologic

a Xerox Sigma-3 Computer, the system monitors the electrocardiogram, arterial
and venous blood pressures, body temperature, urine output, and blood loss, as
well as thermal and dye-dilution cardiac output.

A Morphology Analysis of tne electrocardiogram and arterial blood pressure
waveforms is performed to detect fiducial markers. The application of cross-
correlation techniques to the electrocardiogram allows the detection of pre-

sand electrocardiographic complexes may be recalled at any time in the form of

minute electrocardiogram memo

arrhythmias. Vital si

nrire retrievab"%r''"'

eight-hour nursing shift surmianes in tabular form.

r as 12-, 24-, or 72-hour

vital siqns graphs.

Cardiac Intensive Care Unit Patient Monitoring
Computer System

The computerized patient monitoring system
developed in conjunction with Surgery Branch,
NHLBI, provides realtime, beat-to-beat analyis of
physiologic waveforms from patients within a four-
bed intensive care unit. Based around a Xerox
Sigma-3 Computer, the system monitors the
elctrocardiogram, arterial and venous blood
pressures, body temperature, urine output, and blood
loss, as well as thermal and dye-dilution cardiac
output.

A Morphology Analysis of the electrocardiogram and
arterial blood pressure waveforms is performed to
detect fiducial markers. The application of cross-
correlation techniques to the electrocardiogram
allows the detection of premature ventricular
contractions. Beat-to-beat data from the most recent
thousand electrocardiographic complexes may be
recalled at any time in the form of Joint Interval
Histograms and Correlation Coefficient Scatter
Diagrams. A five-minute electrocardiogram memory
is maintained in realtime for use in the detection of
transient ventricular arrhythmias. Vital signs are
retrievable as eight-hour nursing shift summaries in
tabular form, or as 12-, 24-, or 72-hour vital signs
graphs.

Background and Objectives: The principle objective
of this long-term project was to investigate new
approaches to the problem of providing an
automated patient monitoring environment. More
specifically, project goals include: the release of the
nursing staff from routine clerical tasks, the uniform
collection of all vital signs at high frequency, the
automated detection of potentially life-threatening
ventricular arrhythmias, and the development of an
online tool for the evaluation of signal processing
algorithms.

Methods Employed: A general-purpose process-
control computer system was chosen as the central
element of the interactive patient monitoring system.
The Xerox Sigma-3 computer was interfaced to a
high-speed 16-channel video generator system.
Commercially available bedside electronic modules
were chosen to provide for the monitoring of all
relevant physiologic parameters. Transducers were
developed to monitor urine output and blood loss
(chest drainage). Active analog and digital
transmission lines were fabricated to connect the
intensive care unit with the computer room.

The operating system provided with the Xerox
Sigma-3 was extensively modified to provide a more
suitable environment for realtime, beat-to-beat

patient monitoring tasks. Many signal analysis
programs, and a sophisticated graphics package,
were written to accomplish the functional
specifications selected for this system.

Major Findings in FY81: No major findings occurred
during FY81. The system was maintained in
continuous operation without additional hardware/
software development or evaluation. The use of this
system was terminated at the end of December in
anticipation of the relocation of the Surgery Branch
to new facilities within the Clinical Center. This
system had been in place for ten years, but because
the mainframe hardware was no longer in
production, replacement parts and maintenance
became an increasing burden. Design of the new
five-bed intensive care unit was carefully planned to
incorporate all utilities, conduits, and structural
accommodations necessary for the computerization
of the unit.

Significance to Biomedical Research: The
computerized patient monitoring system can be
practically applied to the continuous collection of
data for research protocols.

The novel approach to the monitoring of cardiac
arrhythmias implemented on this system is easily
adaptable to other computer systems with waveform
capture capability. These arrhythmia monitoring
techniques should prove useful in many clinical and
experimental animal protocols, such as drug
evaluation studies.

Proposed Course: A final decision must be reached
concerning the desired approach for replacement of
the previously developed ICU Monitoring Computer
System. Some factors to be considered are: medical
utility of computerization, trade-offs of alternative
systems, time for implementation, staffing for
design/implementation, and operational personnel
required. The selected approach would then be
carried through the final design phase, including a
detailed cost estimate.

SiSJflS.iS'r.W^rKK

'S!fl"

'31if:r'

"zoiTl^-O. CSL

or Ui>)

Image Processing Faci

ity

MOFESSIOHH. PtHSOHNEL EM.OtD

M IH£ «OJ£CI

PI- H Risso

Electronics Engineer

CSL, DCRT

D. Syed

Chief, Systems Design Sect

on CSL. DCRT

OTHER: D. Foxvog

Computer Specialist

CSL. DCRT

A. Pashayan

Computer Specialist

B. Trus

Research Chemist

Computer Systems Laboratory

Systems Oesiqn Sectf

DCRT. NIH. Bethesda,

HO 20Z05

10UL«Mt«S. ^^ pCftSSIONAL. ^^ lOIHER. 1

Tut 'ZTZ'xzT'^

(d «E,mR

a(><) H'NMS Q(.IJ .NIEOyiE

•s

UMUr » M*i> (100 rtr^. ,r I

.. - W.rli«. l..,,.ort.)

This project Is t

tended to provide a utility t

lal imaqes. The syste

win consist of a powerful 3

ture of medtun- and high-resolution video displays.

Also, the system will

tion of "-rays, micrographs

delivery expected durt

g the next fiscal year, and t

isplay subsystem specffi-

cations are complete.

nd procurement is expected du

Computerized Radiation Tlierapy

CSL has developed a computer system, now in
clinical operation in the Radiation Oncology Branch,
NCI, to use the detailed contour and density
information available from computer assisted
tomography to improve radiation treatment planning.
This system for external beam treatment planning is
based on a generalized 3-D dose field model that
covers photon, electron, and neutron beams.

Background and Objectives: During the past five
years, CSL has maintained an active collaborative
relationship with staff of the Radiation Oncology
Branch, NCI. The goal of this effort is to develop and
implement a generalized system for computer
assisted radiation treatment planning. Initially aimed
at utilizing CT scans during planning, the scope of
the project has now broadened.

Methods Employed: The dose field model
developed by Jan van de Geijn was implemented in
RSX-11M FORTRAN and experimentally tested for
the local radiation facilities. The theoretical model
was extended to cover irregularly-shaped beams as
well as irregularly-shaped shielding blocks. Emphasis
has been placed on optimization of interactive
operational facilities and accommodations of input
and hard copy techniques to clinical demands.

Major Findings: The system is now in routine use
for clinical treatment planning. It offers high speed
computation and display of complete dose
distributions in multiple slices, superimposed on CT
images, including effects of wedge filters, shielding
blocks, and diaphragm rotation.

Significance to Biomedicai Researcti: The
convenient interactive manipulation of key beam
parameters in combination with fast response is
highly valuable in complicated dosimetry problems
encountered in special protocol studies.

Proposed Course:

• Implement the Dose Field Model for regular and
irregular electron fields.

• Establish multiple treatment planning stations to
allow simultaneous use of the computer display
equipment.

• Extend the capabilities to compute and display
dose distributions in sagittal and coronal
sections of the patient.

Publications:

Padikal. T . Lichter, A., Tepper, J,. Glatstein. E-. Schwade. J , Frednckson,
H., Risso. W,, Roberson, P., Her. v., Van de Gei|n. J., and Kinsella. T ,
Experience with a CT Based Treatment Planning System In O'Neill. J
T. (Ed ): Proceedings of the Fourth Annual Symposium on Computer
Applications in Medical Care New York. Institute of Electrical and
Electronics Engineers, 1980. pp 83-88

Image Processing Facility

This project is intended to provide a utility to display
and analyze digital innages. The system will consist
of a powerful 32-bit computer with a mixture of
medium- and high-resolution video displays. Also, the
system will include a microdensitometer to allow
precise digitization of x-rays, micrographs and other
images. The computer and peripherals have been
purchased, with delivery expected during the next
fiscal year, and the design for physical space to
house the system is complete. Construction will
begin soon, with completion expected during the
next eight months. The display subsystem
specifications are complete, and procurement is
expected during the next year.

Background and Objectives: This project arose in
response to a critically overcrowded situation that
exists on the present DCRT Evans and Sutherland
Graphics computer. As image processing
applications at NIH have increased, the limited
resources of that graphics system have been
saturated. During FY80, CSL, in collaboration with
present and potential users designed a new general-
purpose computer facility to aid the acquisition,
display, and analysis of images such as electron
micrographs, CAT scans, and radiographs. This
facility will be available for use by the NIH
community.

Progress in FY81: The system will be based on a
32-bit, one megabyte computer, with a smaller 16-bit
processor to handle image acquisition. A multidisplay
raster scan frame buffer will provide several users
concurrent access to the central processor. Images
will be digitized when necessary through a
microdensitometer or a vidicon camera. Hard copy
will be provided by a camera system.

The computers and several related peripherals have
been purchased, with delivery expected toward the
middle of next year. A formal 'Request for Proposals'
for the display sub-systems has been prepared and
is awaiting funding for purchase next year. The
design for the physical space of this facility is
complete, and a contract for the construction should

be awarded early in FY82.

Significance to Biomedical Research: Study of
images obtained in the biomedical laboratory is
proving more and more fruitful as technology is able
to supply the proper tools at a reasonable cost.
Biomedical scientists are employing image analysis
for a wide variety of research goals, and the use of
such techniques is expected to grow very rapidly in
the near future.

Proposed Course: Pending the availability of funds,
the outstanding system components will be
purchased, the physical site will be prepared, and
the development work to assemble the various parts
into a working system will begin.

iluSiiii^'i!!.

PflOJEOt ««.BER

ZOl CT00075-02

CSL

"TlobeM. 1980 to September 30, 19B1 |

IITL. » WJtei 1«0 =^.r.c..r, .r I,,.)

Digital Imaging Applications tn Cardiovascular Research

«»^.i'C'noNTa'«S'oN*''.lt «i*cJ *'" """ " """'"' '•"""""'" ""' *'' """

PI: Douglas Foxvog Computer Specialist CSL,

Michael Jones Senior Surgeon H Ifi SU,

NHLBI

OTHER: Wfl Ham Barrett Staff Feltow CSL,
James M. DeLeo Computer Systems Analyst CSL,

°c"t

Joseph Zulschenberger Clinical Associate H IR SU,

GOOPIHIIIKC UNITS (if •'.,)

Clinic of Surgery. NHLBI

Computer Systems Laboratory

Systems Desiqn Section

o.t« iPWOPHuiE eo<U;)

j(.| mHu.iMXCi'. [j)(»)h.N»«r.sigts a{'=) -timB

G (.1) KisDOS u (.J) iMCHvliys

a1 topics in myocard

jl am

Digital image analysis has been applied to seve
valvular research. This project has been renamed fro

-Morphoraetric analysis of myoc

ardial hypertrophy. Software has been devel
of samples of hypertrophied myocardium from
These packages allow determination of cell

ped

to enable interactive analysis
and from experintental aniinals

-Bioprosthetic heart valve studies. To investigate t

e cause of stenosis
jgraphy. Analysis c

imaged radlographlcally, and a

'ter sectiol^nq'! by°pho

-Reqional myocardial blood flo

w Quantitative data from experimental anim

displayed as a map of the hear
atlons in intensity or color.

Comparison of epicardia

'-""°"""'""°"''

'So?Sit'6F"

ZOl CT00O73-O2 CSL

1980 to Septerrber 30. I9B1

Cerebral Metabolic InE

Laboratory of Cerebral Metabolism (LCH), NIMH

CnnpiitPr <;y;tfm<L laboratory

flTRT WIH Bethesda Maryland 20205

-flJ I [LJ_

showing cerebral metabolic activity in micro tornei
-^ntal animal brains has been developed to facili

aligned paralled Inages. Use of the algorithm, which is based on minimizing

ilgorlthm development on the i

i NIHH De Anza Imaging

Digital Imaging Applications in Cardiovascular
Research

Digital image analysis has been applied to several
topics in myocardial and valvular research. This
project has been renamed from last year to reflect a
somewhat broader scope.

• Morphometric analysis of myocardial
hypertrophy. Software has been developed to
enable interactive analysis of samples of
hypertrophied myocardium from humans and
from experimental animals. These packages
allow determination of cell diameter, nuclei
densities, capillary densities, and percent
interstitium.

• Bioprosthetic heart valve studies. To investigate
the cause of stenosis of prosthetic valves,
diseased valves are removed from experimental
animals and imaged radiographically, and after
sectioning, by photography. Analysis can
quantify sites of calcifications and the amounts
of fibrous sheath and normal tissue.

• Regional myocardial blood flow. Quantitative
data from experimental animals are displayed as
a map of the heart, with increases in blood flow
indicated by variations in intensity or color.
Comparison of epicardial-endocardial flows and
control vs. test data will be studied.

Background and Objectives: This project applies
computer assisted digital imaging techniques to
areas of interest in cardiovascular research. The
project began last year with the morphological
analysis of cardiac tissue, and this year includes a
preliminary study of bioprosthetic heart valves and
development of a system to examine regional
myocardial blood flow.

Methods Employed:

• Morphometric Analysis. Specimens are
microtomed, mounted, stained, and
photographed under a light microscope.
Resultant negatives are then digitized by
microdensitometry, and entered into the Evans
and Sutherland display computer. The programs
calculate myocyte cross-sectional areas,
myocyte diameter and perimeter, capillary and
nuclei count, and statistics on one or more than
one sample.

• Bioprosthetic heart valves. Transverse
microtome sections taken from the valve leaflets
and radiographs of the valve are scanned for
computer input. The amount of calcification,
fibrous sheath, and normal leaflet tissue can be
determined quickly and efficiently using an
interactive contouring and thresholding algorithm.

• Regional blood flow. Data are obtained from the
injection and tracking of tagged microspheres.
The epicardial and endocardial wall of the right
and left ventricle as well as both sides of the
septal wall are examined. Numerical data
consisting of regional blood flow measurements
are represented graphically as varying shades of
intensity or color. Values between adjacent
regions can be interpolated to form a more
continuous surface, with high to low flow
variations repsented by a rainbow color
spectrum. This should provide an effective
means for the visualization of flow patterns in a
single animal and of the distribution of flow
patterns over the entire experimental population.

Progress in FY81: An interactive computer program
MORPH has been used to study the left ventricular
mid-anterior wall of adult foxhounds as part of a
preliminary study of the effectiveness, accuracy, and
utility of computer-assisted morphometric analysis. In
addition to inherent reproducibility, the variance per
sample analyzed decreases tenfold when compared
to manual point counting techniques. There is also a
ten percent reduction in the standard error of the
estimate for the mean interstitial fraction of a tissue
evaluated from five separate microscope fields. The
primary benefit of this method is in facilitating the
analysis of multiple fields and multiple slides per
tissue sample. Increasing the number of samples
decreases the overall variance proportionally.
Programs that display regional blood flow and
provide ratio comparisons of endocardial and
epicardial flow have been completed.

Significance to Biomedica/ Researcti: These digital
image analysis techniques provide scientists with
accurate, reproducible, and efficient tools,
superceding alternate manual approaches such as
planimetry or point counting.

Proposed Course: This project will continue to
refine the morphometric analysis now in use, and
extend the techniques to three-dimensional
examination of cardiac muscle cells by
reconstruction from thin slices of human and animal
cells. The prosthetic valve study will resume after
leaflets are resectioned, to produce a more
anatomically consistent data base than was
previously obtained. Regional blood flow studies will
continue. Methods are to be devised to meaningfully
compare myocardial blood flow during different tests
on one animal, as well as to compare different
animals. Correlation of endocardial with epicardial
flows will also be provided.

Cerebral Metabolic Imaging

An algorithm to align spatially sequential, parallel
images of autoradiographs showing cerebral
metabolic activity in microtomed sliced sections of
experimental animal brains has been developed to
facilitate arbitrary plane viewing in the three-
dimensional image space resulting from the stacking
of aligned parallel images. Use of the algorithm,
which is based on minimizing non-overlapping areas,
demonstrates the need for fixed fiducial reference
points in specimen images. Preliminary attempts in
prepanng specimens to provide fiducial points
illustrate the difficulty of this task. LCM will continue
algorithm development on the newly installed NIMH
DeAnza Imaging System. CSL will remain available
for consultation.

Bacl<ground and Objectives: The Laboratory of
Cerebral Metabolism, NIMH has been engaged in
computer-assisted image processing of
autoradiographs that illustrate cerebral metabolic
activity in microtome-sliced sections of experimental
animal brains since 1977. In 1979, the Computer
Systems Laboratory was asked to collaborate in the
development of a methodology to enhance and align
spatially sequential microtome brain slice images for
the purpose of reconstructing alternate views
through this three-dimensional image data.
Algorithms developed by CSL on the DCRT Evans
and Sutherland Image Processing System were to be
transportable to a DeAnza image processing system
on order by NIMH.

Methods Employed: CSL has implemented software
to align sequential images by an algorithm which
minimizes overlapping areas. The limitations of this
approach are especially evident when aligning
images in which brain segments are physically
detached. It was, therefore, agreed to investigate
new methods of specimen preparation that would
provide fixed fiducial marker points to enhance
automated alignment.

Major Findings: To assure quality three-dimensional
imaging of cerebral metabolic activity, it is essential
to have sufficient internal and/or external fixed
fiducial marker points to facilitate automated
alignment. Unsuccessful early attempts in specimen
preparation to provide fiducial points illustrate the
complexity of this problem.

Proposed Course: Procedures and algorithms
developed by CSL have been given to LCM. Now
that the new NIMH DeAnza image processing
system has arnved, LCM staff members will continue
algorithm development on that system. CSL staff will
continue to be available for consultation in this work.

'^-^^---^'

,.3i"!s!»i'I.

ZOl CT00080-01

CSL

""'octobe"l. 1980 to Septenber 30. 1981 1

(tiki » FHOJtei (BO <h,r.cl.r* or 1...)

Computer Analysis of Gel Electrophoresis

itwir HiwrwT .NO ihsllTuu ifniTiTiwisr^soTrru'. o< pfliNcipiL f

PI: B. L. Trus Rese.rch Chemist

est. DCBT _

OTHER: ». iHoOe. Staff Fellov.

CE. NIAODK

NIADOK

tea. NIAOOK

Program

1
searci,

k../...«.

^^ p»,i.,».L, u^ """■ }

cici «»onii.ii .o.(tsl

:l.) »».«!..jttl! Q|.).™ili:nl! -J

(.) ,n«.

al.il ...•.! D(.i) i.u...e-s

sm.i.Y tr g»>. III. ..™. ., 1.. .,„i., ..,-..1 )

r^r'the coTOuter'a

alysls

qated.

Dqraphs are beinq i

1 gels

«ijEC?'NSBM'f3"lio"«rIhlt JJf?^"

'ZsiSlilir

TcToI^-oa CSL

Automated Analysis of Plaque Formation in Experimental Atherosclerosis

PI: HilHam Barrett Staff Fellow CSL. OCRT

OTHER: James H. OeLeo Computer Systems Analyst CSL. XRT

Donald Fry H.O. Ohio State University
J. F. Cornhill M.D. Ohio State University

COOMRHIhC UNITS (it ..,)

None

Conputer Systems Laboratory

Systems Design Section

'DCRT'."NTH.''Bet'h"esda, Maryland 20205

lOMi «mEMs, |Pfl<irtssiw*L,^ joiner.

:(.) .iw..N iuB^cii u(t)w«'".iiiw£s aic)NEimR

Computer programs have been developed and package
quantitatinq atherosclerotic disease formation and its

d for detecting and

Ifet. and vessel wall permeabi

ity. Permeability is indicated with Evans" Blue
^TSudan IV Red dye. Colors are separated using

dinate system. An iterative edqe-findinq

algorithm searches the image f

coincidence of disease at a gl
longroent distribution of the

it^tologlc. physical, blochemi

te diseased areas. Topographic naps, formed bv
from different animals, show the incidence and
ven location. The raps describe the extrenely
disease in a concise and quantitative manner and
tool for correlation of disease patterns with local

Computer Analysis of Gel Electrophoresis

This project, which was transferred frorri NIDR during
this reporting period, is intended to design hardware
and software mechanisms for the computer analysis
of one- and two-dimensional gel electrophoresis.
Image processing is being used to evaluate and
compare differences in protein composition. Only
computer analysis can make such comparisons
strictly quantitative. Analysis of two-dimensional gels
is completely automatic, while analysis of one-
dimensional gels is interactive. Additional
applications with autoradiographs are being
Investigated.

Background and Objectives: The objective of this
project is to develop computer software that can
automatically analyze photographs of two-
dimensional gels or autoradiographs, and to
optimally utilize available hardware for accuracy and
reliability. In addition, two-dimensional photographs
of one-dimensional gels, using the PIC system can
be easily converted into one-dimensional
representations for quantitative comparison or
integration.

Significance to Biomedical Research: Use of gel
electrophoresis or autoradiographs is commonplace
in chemical, biochemical, and biomedical analysis.
However, the quantization or comparison of such
gels is tedious, qualitative, and difficult. Use of the
Evans and Sutherland system to evaluate such
samples permits scientists greater information with
increased reliability and simplicity of operation.

Progress in FY81: This project, which was begun in
1 980, has produced many successful results.
However, as new projects contain slightly differing
needs, there is an ongoing expansion and
generalization of software to satisfy these needs. In
addition, the number of laboratories that use the
methods developed in this project is increasing
rapidly. Some new laboratories will be using the
methods collaboratively, while others will be
independent.

Metiiods Employed: Samples are scanned on the
Perkin-Elmer microdensitometer and stored on
magnetic tape for later processing. Two-dimensional
gels are processed by a program, CI NT (Computer
Integration), which corrects for background,
automatically locates peaks, automatically integrates
all peaks, and provides a printed summary of results.
In addition, an image can be obtained either from the
video frame buffer or from a Calcomp plotter. Two or
more gels can be compared graphically by means of
a program OVERLP which correlates two gels and
provides data to generate overlapping Calcomp plots

with each gel as a different color.

Proposed Course: Computer software will be
expanded to encompass new types of data. A prime
consideration of software development has been
machine independence, and the software can thus
be easily transported to other private facilities. With
the acquisition of the image processing laboratory
hardware, the present programs will be converted to
execute more quickly and efficiently.

Publications:

Nikodem. V M., Trus, B. L., and Rail, J. E.: Two.-Dimensional Gel Analysis
of Rat Liver Nuclear Proteins alter Thyroidectomy and Thyroid Hor-
mone Treatment. Proceedings of the National Academy of Sciences
(in press).

Automated Analysis of Plaque Formation in
Experimental Atherosclerosis

Computer programs have been developed and
packaged for detecting and quantitating
atherosclerotic disease formation and its location
along the entire arterial tree, and and for statistical
correlation of disease patterns with anatomy, diet,
and vessel wall permeability. Permeability is
indicated with Evans' Blue dye and disease is
indicated with Sudan IV Red dye. Colors are
separated using appropriate filters in the scanning
process and the resulting digital images are
transformed to a standard coordinate system. An
iterative edge-finding algorithm searches the image
for an optimal threshold of maximum optical intensity
to identify and isolate diseased areas. Topographic
maps, formed by overlaying the disease patterns
from different animals, show the incidence and
coincidence of disease at a given location. The
maps describe the extremely congruent distribution
of the disease in a concise and quantitative manner
and provide the researcher with a tool for correlation
of disease patterns with local histologic, physical,
and biomedical events.

Background and Objectives: Atherosclerosis was
produced experimentally in 41 animals by feeding
them high-calorie, cholesterol-rich diets. Eleven
control animals were also included in the population
for comparison with the experimental group. Pnor to
sachfice, animals were injected with Evans' Blue
dye, an indicator of vessel wall permeability. A
systematized necropsy procedure and standardized
format were developed for arranging and fastening
the opened arterial tree to reflective panels, after
which the vessel segments were stained with Sudan
IV Red dye to indicate areas of disease.

Although atherosclerosis is a multifaceted disease,
experimental studies indicate that this disease is very
discrete and local in occurrence. Moreover, the
patterns of distribution of sudanophilic lesions tend

to have a characteristic common topography in a
given species. Thus, it is important to define the
spatial occurrence statistically to facilitate correlation
of disease patterns with local structural, chemical,
histological, and fluid mechanical events.

Methods Employed: Thirty-five millimeter slides of
the preparations are scanned at a resolution of 50
microns using neutral density, red, and blue filters.
Digitized images are displayed and analyzed on an
Evans and Sutherland Video Frame Buffer. Images
are transformed to a common coordinate system
through the use of local anatomical landmarks, the
coordinates of which are identified by a technician
familiar with the anatomy, using a graph pen and a
tablet that is interfaced to the computer (PDP-1 1/70)
driving the display. An iterative edge-finding
algorithm outlines the image at an initial intensity
value, and then performs an orthogonal search of
the outlines to identify an optimal threshold, which is
used to segment the image into areas of disease
and non-disease.

Thresholded images corresponding to a given
arterial segment are added together to produce a
topographic map representing the location and
relative frequency (probability) of lesion occurrence
in a given population of animals. The map is
displayed on a video screen by using various
intensity values or colors to represent levels of
incidence and coincidence of the disease. The
intersection of two different maps provides a
quantitative measure of the correlation between
disease patterns as they occur in different groups of
animals, or between different variables within the
same group.

Major Findings: Programs for image processing and
analysis, file management, storage, retrieval, and
review of results, have all been efficiently integrated
into a system. Close to 1000 images have now been
processed, producing topographic maps showing the
statistical distribution of the disease along major
arterial pathways. The eight hours previously
required to manually identify landmarks and
transform images has been reduced to
approximately three minutes, making this objective
and statistical approach practical. In addition,
automated thresholding of disease patterns
compares favorably with manual methods, while
reducing the time involved and assuring
reproducibility.

The probability maps illustrate the consistent
distribution of disease patterns and show a strong
relationship between these patterns and the
anatomical detail in the vessel wall. This is striking

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Computerized Three-Dimensional Hodel of the Cat's Brain Stem

PI: Douglas A. Foxvog Computer Specialist CSL, DCRT
James H. DeLeo Coinputer Systems Analyst CSL, DCRT
Joe Adams Senior Staff Fellow LND, NINCDS

Laboratory of Neuro-otolarngology. LND, NINCDS

Systems Design Section

A ihree-dirwnsional. colo

red. 50^ volume element
allows rapid selection

al animals. InvestT^^

block model representing

the neuronal structure of the

data from different e;(oeriment

f a viewing surface com-
ical and physiological

MrilSng'EhrpIaneTlcribed

by various electrode penetrations in the experi-

been developed and used successfully on the Evans
ation-quality output has been produced. An atlas

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ZOl CT 00081-01 CSL

- 1, 19B0 to September 30. 19B1

1 Medicine Department Conputer System

1 Medicine Department,

Systems Design Secti

; the development of c

H\ti Clinical Center.

<. begun in Frei ■

■»nl\/ ^B

evidence that the formation of lesions is strongly
influenced by local factors such as hemodynamic
forces acting on the surrounding anatomy. Areas of
coincidence or 'hot spots' indicated a high statistical
occurrence of sudanophilic lesions and may point to
key locations in the genesis of the disease. Maps
have also been created as a function of diet, and
show a dramatic difference in the propagation of
disease patterns when factors such as cholesterol
and thyroid inhibitor are added to the diet.
Preliminary results show a high correlation (r=.92)
between maps created from the red and blue stained
images, indicating a striking relationship between
sites of lesion formation and vessel wall permeability.
However, this relationship appears to be most
pronounced near the periphery of a lesion when
studied on an individual basis.

Proposed Course: The present study will culminate
with the processing of the coronary arteries, a site of
vital clinical interest. Correlation between Evans'
Blue and Sudan IV images will be completed in an
effort to further quantitate the relation between
vessel wall permeability and disease. It is hoped that
results of this study will not only help to characterize
the pattern and distribution of atheromatous plaque
formation, but will provide the researcher with a tool
for further investigation into the cause and
mechanism of the disease.

Publications:

Barrett, W. A., DeLeo, J, M., Cornhill, J. F., and Fry, D. L.: A system for
Automated Analysis of Plaque Formation in Experimental Atherosclero-
sis. 53rd Scientific Sessions of the Americal Heart Association, Novem-
ber 19, 1980.

Barrett, W. A.: An Iterative Algorithm for l^^ultiple Threshold Detection. IEEE
Conference on Pattern Recognition and Image Processing, August,
1981.

Computerized Three-dimensional lUlodel of the
Cat's Brain Stem

A three-dimensional, colored, volume element (60-
cubed) block model representing the neuronal
structure of the superior olivary complex of a cat's
brain stem has been developed. The model allows
rapid selection of a viewing surface computed for
any selected cutting plane through the model
volume. The model provides a common frame of
reference for comparing anatomical and
physiological data from different experimental
animals. Investigators should be able to view a
section of the 'normal' cat on the same plane M

described by various electrode penetrations in the \
experimental animal. The model has been developed
and used successfully on the Evans and Sutherland
System. Publication-quality output has been
produced. An atlas of over 1 50 views is being
submitted for publication.

I
I

Background and Objectives: The objectives of this
project were:

1. To develop and implement a three-dimensional
block model of a cat's brain stem for laboratory-
collected data specifying cell types and their spatial
relationships.

2. To provide a method for producing publication-
quality colored and black-and-white two-dimensional
graphics that illustrate the three-dimensional
graphics block model.

Methods Employed: Consecutive 80-micron-thick
microtomed slices for the superior olivary complex of
the cat's brain stem were stained and examined by a
neuroanatomist by means of a Zeiss microscope.
The stage of the microscope was attached to a
computer, as was a function box, thus enabling the
neuroanatomist to log spatial coordinates and cell
types in a computer data file. This data was
transferred to the Evans and Sutherland System and
used as input to the volume element (60-cubed)
block model program specifically developed for this
project. The block model software allows the
investigator to view the surface of any selected
cutting plane through the model volume.

Progress in FY81 Publication-quality output has
been produced. The software developed for this
project has shown itself to be applicable to several
other biomedical imaging applications.

Proposed Course: This project has been
completed. It is expected that the block model
software will be extended to other applications.

Rehabilitation Medicine Department Computer
System

This project involves the development of computer
techniques in rehabilitation medicine in collaboration
with the Rehabilitation Medicine Department of the
NIH Clinical Center. CSL has recommended
computer techniques that can be used to
automatically acquire anatomical and physiological
information from patients, perform the required
calculations on the data obtained, and display the
necessary results to the medical staff. The
automated techniques include: the measurement of
body forces (hand and ground reaction forces),
muscle activity (monitoring the electromyogram of
muscles), and body kinematics (the position and
angles of the limbs and joints in space and time).
The system will allow the medical staff to easily
enter patient and staff data into a data base with
computer-generated forms displayed on a terminal
screen, and to perform inquiries and generate
reports using the accumulated data. In FY82 CSL will

continue the work begun in FY81 including the
specification of the computer system, the evaluation
of methods to perform the desired measurements,
the selection of the necessary transducers and
instrumentation, and the specification of the required
software.

Bac/<ground and Objectives: The Rehabilitation
Medicine Department provides psychiatric evaluation
and treatment, physical therapy, occupational
therapy, and speech therapy for NIH Clinical Center
patients referred by Institute physicians. In addition, it
develops various indices to evaluate these services.
The department supports the efforts of and
collaborates with Institute physicians engaged in
research relevant to physical rehabilitation medicine.
It also initiates both clinical and basic research
independent of the Institutes in the rehabilitation of
mentally and physically handicapped individuals.

In support of these goals, CSL is specifying a
computer system for the Rehabilitation Medicine
Department. Initially, the department will use the
system for the following three projects:

1. The Physical Therapy Quality Assurance
System-a data base system that will be used to:
assess medical staff effectiveness in providing the
types of patient care needed, determine staff
workload and scheduling, and identify areas for
clinical research for the Physical Therapy Service;

2. The Hand Dynamometer Instrument-a device
that will be used to measure the magnitude and
direction of the forces in the hand and to develop
clinical tests to diagnose the mechanical and
functional status of the hand, arm, and shoulder;

3. The Automated Biomechanics Laboratory-a
system that will be used to automatically measure:
the position of the limb segments in space, the
forces in the lower limbs, and the electromyographic
signals from the muscles in the limbs. The computer
will perform measurement, analysis, display, and
recordkeeping functions in these and future
applications.

Significance to Biomedical Research: The computer
system will be used with arthritic, orthopedic, and
neurological patients, and with amputees in order to
evaluate drug therapy, orthopedic and prosthetic
devices, and medical interventions. It also will be
used as a teaching tool to help these patients learn
to function with their disability in an efficient manner.
Many hospitals in the United States are presently
establishing automated biomechanics and gait
analysis laboratories. Therefore, any new
developments made on this project will benefit users
of these automated systems, as well as patient care

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Z01 CT00082-01 CSL

Image Processing of Electron Micrographs

PI; 8. L. Trus Research Chemist CSL. DCRT

OTHER: A. C. Steven Visiting Associate LPB. NIADDK
K. A. Piei Chief LB, NIDR

™:;r™.r;';;:«™

Computer Systems Laboratory

""system Design Section

DCRT. NIH. Bethesda. HO 20205

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i<L infpnrlpd to dpsian hardware and software mechanisms for the image processinq
and imaqe reconstruction of electron micrographs. Computer software that has
been developed is used by a number ot NIH research groups and programs have been
exported to outside facilities. Under investigation at tliis time as part of
this project are virus structures and collagen structures; other groups are look-

ing at numerous other biological specimens such as keratin, membrane structure.

October 1, 1960 Co September 30, 1981

1 Tomography (PET) Scan Image Analysis in Aging Studif

Computer Systems t

i Design Sectioi

and clinical research within the Rehabilitation
Medicine Department at NIH.

Progress in FY81: CSL's collaboration with the
Clinical Center's Rehabilitation Medicine Department
began this year. Areas that could benefit from
computer support were identified and specifications
for the required computer hardware and software
components were developed. CSL established the
preliminary requirements for the department's
computer system.

A large amount of specialized instrumentation is
needed to perform the required automated
measurements. The Biomedical Engineering and
Instrumentation Branch of NIH's Division of
Research Services built the hand dynamometer. CSL
acquired information on commercially available force
plates that are used to measure ground reaction
forces and portable electromyogram telemetry units
that transmit the muscle signals from the patient to
the computer without any impeding cables. CSL also
evaluated camera systems that can automatically
measure body kinematics including the United S

Technologies Research Center infrared system, the^
Oxford Medical Systems strobe light system, and the
Selcom Light Emitting Diode system.

Proposed Course: CSL will continue to offer advice
regarding computer hardware and software,
transducers, and instrumentation. Rehabilitation
Medicine expects to purchase these components
during the coming year.

Image Processing of Electron Micrographs

This project, which was transferred from NIDR during
this reporting period, is intended to design hardware
and software mechanisms for the image processing
and image reconstruction of electron micrographs.
Computer software that has been developed is used
by a number of NIH research groups, and programs
have been exported to outside facilities. Under
investigation at this time as part of this project are
virus structures and collagen structure; other groups
are looking at numerous biological specimens such
as keratin, membrane structure, immunoglobulin
structure, and muscle structure.

Background and Objectives: The objective of this
project is to develop a general-purpose software
package for the analysis of electron micrographs. In
addition, the computer analysis requires optimal
utilization of the available hardware. These
techniques and software have been used in
independent applications by some researchers, and
in collaborative projects by others.

Significance to Biomedical Researcii: Computer

analysis of electron micrographs is a relatively recent
addition to the tools available for structural analysis.
It is an extrennely powerful technique when applied
to two-dimensional crystalline structures, and can be
used to correlate and align similar particles that are
not crystalline. In addition, images can be corrected
for a number of artifacts and experimental problems.

Progress in FY81: This project, which was begun in
NIDR, has involved some growth in software and
hardware methods, but primarily has grown in the
utilization of programs and in the number of people
who are using the software system PIC. In addition,
use of Brookhaven STEM data is markedly
increased. PIC has been expanded to interact with
much of the general purpose image processing
software in the image processing computer system.

Computer analysis of electron micrographs of beet
necrotic yellow vein virus (BNYVV) has been
completed. The structure is similar to that of tobacco
mosaic virus (TMV), but important differences exist.
The spatial arrangement of BYNVV RNA (49
residues per helical turn, pitch = 2.6nm) is virtually
identical to that of TMV (49 residues per turn,
pitch = 2.3nm). However, the helical packing of the
protein cost is significantly different. The BNYVV
protein has a helical packing of 49/4 subunits per
turn and 4 bases per subunit while TMV has 49/3
subunits per turn and 3 boxes per subunit.

Proposed Course: This project will continue
software development as needed, and will be
converted to utilize the new image processing facility
when it is available. In addition, because new
biological structures are regularly available, these will
be examined.

Publications:

Steven, A. C, Trus, B. L.. Putz. C, and Wurtz. M.: The Molecular Organiza-
tion of Beet Necrotic Yellow Vein Virus. Virology (in press)

Trus. B. L. and Steven, A. C: Digital Image Processing of Electron li^icro-
graphs-The PIC System. Ullramicroscopy (in press).

Positron Emission Tomography (PET) Scan
Images Analysis in Aging Studies

Exploration of the use of the combined power of
Computer Assisted Tomography (CAT) scanning and
Positron Emission Tomography (PET) scanning to
study brain cell metabolism in disease associated
with aging is the purpose of this project. The initial
goal is to provide a computerized image analysis
procedure to delineate brain substructures
represented in spatially, sequenced CAT scan
images and to determine metabolic activity in these
substructures from corresponding sequenced PET
scan images.

Bacl<ground and Objectives: Positron Emission
Tomography (PET) scanning performed in the
Nuclear Medicine Department of the NIH Clinical
Center pi^ovides a spatially sequenced series of
images of regional cerebral glucose metabolism in
man. The Laboratory of Neurosciences of the
National Institute of Aging wishes to incorporate PET
scanning technology in the study of disease
associated with aging. The initial goal of this project
is to delineate brain substructures represented in
spatially sequenced Computer Assisted Tomography
(CAT) scan images and to determine metabolic
activity in these substructures from corresponding
spatially sequenced PET scan images.

Met/iods Employed: Methods for establishing
external coordinates to align corresponding PET and
CAT scans are being investigated. Equations for
converting radiation units to glucose utilization units
are being finalized. Procedures for transporting PET
scan and CAT scan images from the NIH Clinical
Center to the DCRT Image Processing Facility have
been established. Software is being written to
determine statistical characteristics of PET scan
regions of interest as delineated manually on
corresponding CAT scan images.

Significance to Biomedical Research: It is
anticipated that this work will provide a basis for
evaluating the utility of PET scanning in studying
diseases associated with aging. Successful
implementation of an external coordinate system
should provide for accurate anatomical region
designation via higher resolution CAT scan images
to measure physiological processes from
corresponding lower resolution PET scan images.

Proposed Course: Upon implementation of an
external coordinate device and finalization of
radiation-to-glucose conversion equations, analysis
will commence.

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ZOl CT00084-0, CSL

nut Of WJICI (80 ch>r>ctT> «r Utt)

Computer Analysis of Autoradiographic Images of Recombinant ONA Colonies

PI: James M. DeLeo Computer Systems Analyst CSL. DCRT
Floyd Taub Research Associate LB, C

OTHER: Brad Thompson Section Chief LB, C

Laboratory of Biology (LB), C

* Computer Systems Laboratory

Systems Design Laboratory

L «..»«., ^^ pOftSSIWAL, ^^ |OTH£H.

A computerized methodology for analyzing autoradiographic spot images asso-
:iated with recombinant UNA bacterial colonies has been developed in collaboratio i
<ith scientists in Nil. Ihis system represents a unique refinement in a method

ievelopmentally or homonally induced. Spot density measurements are computed
from dipitized images produced via microdensitometry. These measurements are
:orrected for variability in exposure and local background, calibrated to
lybridization standards, and normalized for comparison purposes. The system
irovides a variety of graphical and tabulation output that effectively sunwarizes

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ZOl CT00085-01

CSL

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Cataract Grading via Computerize

d Slit-lamp Image Analysis

PI: James M. DeLeo

Robert D. Sperduto
Leo T. Chylack, Jr.

Computer Systems Analyst

Chief, Division of Ophthalmolrtgy

Office of Biometry & Epidemiology (BE), NEI
Division of Ophthalmology, Harvard Medical School

Computer Systems Laboratory

Systems Design Section

OCRT. NIH^'se'thesda. HD 20Z05 |

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The aim of this project is t

sch«e-

SjeTCped

aj(ls for purposes of comparing
Early results demonstrate the

ducted to further detomiine th

for improved quali
the methodology. Ex

en lens ha; been d
f this approach.

Computer Analysis of Autoradiographic Images
of Recombinant DNA Colonies

A computerized methodology for analyzing
autoradiographic spot images associated with
recombinant DNA bacterial colonies has been
developed in collaboration with scientists in NCI.
This system represents a unique refinement in a
method to directly identify cloned seqences
complementary to messenger RNA that are
developmentally or hormonally induced.

Spot density measurements are computed from
digitized images produced via microdensitometry.
These measurments are corrected for variability in
exposure and local background, calibrated to
hybridization standards, and normalized for
comparison purposes. The system provides a variety
of graphical and tabulation output that effectively
summarizes experimental results and identifies
significant induced hybridization events.

Background and Objectives: NCI scientists have
been refining techniques to directly identify cloned
sequences complementary to messenger RNA that
are developmentally or hormonally regulated. This
refinement has led to a methodology which produces
autoradiographic spot images representative of cell
colony hybridization. The objective of this project is
to provide an automated procedure for a quantitative
analysis of understanding of these images.

Methods Employed: Radioactively-induced cell
colonies are placed into microliter wells, grown on
agar, transferred to filter paper.and hybridized to
end-labeled mRNA or cDNA probes.
Autoradiographs of the filters are digitized and the
density of each spot relative to background is
established by means of CSL-developed image
processing software operational on the DCRT Evans
and Sutherland PDP-1 1 /70 computer system.
Compensation for variations in background, film
exposure conditions, and hybridization are included
in the methodology. A variety of graphical output
including scatter diagrams, histograms, and listings is
provided.

Significance to Biomedical Research: Classical
solution hybridization techniques are too
cumbersome to be performed en masse. The
methodology developed allows quantitative
hybridization studies on a large number of
sequences. Earlier qualitative assessment of
autoradiographic spot images is now superseded
with automated procedures yielding more accurate,
more reproducible data. Computer graphic
presentation of results greatly facilitates identification
of significant experimental events.

Proposed Course: Production image analysis has
started and will continue. Further software
refinements, to include more complete automated
analysis and new graphics software, are planned.

Cataract Grading via Computerized Slit-lamp
Image Analysis

The aim of this project is to develop an objective
cataract grading scheme--a goal having high priority
among cataract researchers. Slit-lamp camera
images of the human eye lens are entered into the
DCRT Image Processing System via
microdensitometry methods. A method for
quantitating opacity along the visual axis for
purposes of comparing similar images of a given
lens has been developed. Early results demonstrate
the need for improved quality control in image
preparation to assure the success of the
methodology. Experiments are being conducted to
further determine the accuracy limitations of this
approach.

Background and Objectives: A major problem for
cataract researchers has been the lack of an
objective, reproducible in vivo cataract classification
scheme. Subjective classification methods are
currently depended upon. With the tremendous
variability in the morphology of cataracts, it is difficult
to rely on such methodology either in survey work or
in longitudinal studies. Development of an objective
cataract grading scheme is seen as a high priority
item among cataract researchers.

Methods Employed: Images of the human eye lens
obtained from Topcon and Zeiss slit-lamp cameras
are digitized via microdensitometry and the resultant
qualified image representations are entered into the
DCRT Image Processing System for analysis.
Analysis consists of computing a histogram of the
density(opacity) values within a narrow band
centered about the visual axis. The resultant
histogram is partitioned into five equal bands and a
corresponding color isodensitometric image is
displayed. A quantitative distribution of percent
involvement for each of the five bands is also
provided. Time-spaced images of the same eye lens
may be compared with these results to track disease
progression or regression.

Major Findings: The interactive computer system
developed for quantitating visual axis opacity is
operational and easy to use. Analysis of initial
prototype images suggests the need for improved
quality control in all aspects of image preparation.

Significance to Biomedical Research: Development
of an objective cataract grading scheme is seen as a
high priority item among cataract researchers.

Proposed Course: Studies on a larger population of
images are planned. These studies should result in
procedures to facilitate image comparison. The
studies should also provide accuracy measurements
for variables introduced by factors such as camera
type, photographic procedures, microdensitometry
procedures, and computer analysis.

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ZOl CT00076-02

October I, 1980 to Septentier 30, 1981

linage Analysis In Coirputerijed Tomography (CT) Contrast Kate

PI: Jares M. DeLeo
Michael Verness

Computer Systeir

IS Anali^st

Diagnostic Radiology (DR). CC

Coonuter Systenis Laboratory

Systems Design Section

DCflT, NIH. Bethesda. Marylan

20305

10m«Hn«„ 1'^'""

*;" 1*"""'

The intent of this project i

efficacy of a ne« experiment

the liver. Software for oprf
Inaqe Processinq System. Hea

to provide a tool for
F coitputerized tomogra

the quantita
m (Cf) to *
at was develo

tl.e analysis
ed at the NIH

the demonstration of e
classical image te*tu

s are being

injection tomograms. Several
tried as discriminating featu
effectiveness.

Image Analysis In Computerized Tomography
(CT) Contrast Material Evaluation

The intent of this project is to provide a tool for the
quantitative analysis of liver and spleen section of
computerized tomograms (CT) to demonstrate
efficacy of a new experimental contrast material that
was developed at the NIH Clinical Center as an aid
in the demonstration of early metastatic disease of
the liver. Software for performing this analysis is fully
operational on the Image Processing System.
Measurements have been made on pre- and post-
injection tomograms. Several classical image texture
measurements are being tried as discriminating
features in the demonstration of contrast material
effectiveness.

Background and Objectives: The objective of this
project Is to provide a procedure for performing
statistical analysis of attenuation values lying within
any specified closed amorphous contour of
computerized tomogram (CT) images. This
procedure is to be used for quantitative analysis of
liver and spleen sections of CT images in order to
demonstrate the efficacy of a new experimental
contrast material that was developed at the NIH
Clinical Center to aid the demonstration of early
metastatic disease of the liver.

Methods Employed: CT images are transported by
means of magnetic tape from the Diagnostic
Radiology Department (DR) of the Clinical Center to
the Image Processing Facility in DCRT. Interactive
software has been written and implemented to read
the CT images from magnetic tape, draw selected
contours to indicate areas of interest, and perform
statistical analysis on the attenuation values within '
the chosen areas. Liver and spleen sections of pre-
and post-injection images are processed and
compared.

Significance to Biomedical Research: Most current
CT computer systems provide limited statistical
analysis within small fixed-shape contours (circles or
squares). The approach presented here offers
unlimited analysis within any shape contour. The
software may be easily extended to measure other
features based on groupings of attenuation values;
such features could be useful in further
differentiating image elements and diseased areas.
The software has obvious extension to the analysis
of other types of biomedical images.

Proposed Course: Analysis of liver and spleen
sections on pre- and post-injection tomograms are
continually being performed as images are made
available. It is intended to explore the usefulness o
several classical image texture measurements in th
demonstration of contrast material effectiveness.

1. 1960 to Si>pteiii>er 30. 1981

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Ial9« «n.lysH In AuWmut Hjdlolhtrapj treawent PUralBg

ai me uiTma '

Jmt H. DrLro Computer Syjtwii toi.l, it
Ell Ol.llteln Chlel

est. OC«T
HO . «C1

Itodlatlon Ootol09y Brjnch (BOl. NCI
Coflputer Syttcm Laboratory
Systems DtsWn Section

0.0 1 0.0 1

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—

This project u directed to»ardi finding iimroved ci»lhodi o

analyting

coavuterlied tonnqraphy (CT) images in order to provide opt

mate dati^
Irvlenented and

automated radio therapy treatment plannina. various alqori
enhancement, contour detection, e.tractlon. follo-lno. coor
coioresslon. and three-dimensional representation have heen

tested. The project has been Inactive during the past year

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201 CT 0005S-02 CSL

JJOflter. L .1960 to Swlciftcr 30. 1981

OmLto^tenKsL,
Automated Pulnonary Phystoloqy Testing

Ldwrence D. N<de1 .

PDS. CSL. DCRT
PB. IR NHLBI

PulMMry Branch, NHLBI

Coaputer Systens Uboratory

Project Development Section
0(.((]_. NIH. Bethestfa. HO 20205

Image Analysis in Automated Radiotherapy
Treatment Planning

This project is directed towards finding improved
methods of analyzing computerized tomography (CT)
images in order to provide optimal methods of
automated radio therapy treatment planning. Various
algorithms for contrast enhancement, contour
detection, extraction, following, coordinate data
compression, and three-dimensional representation
have been implemented and tested. The project has
been inactive during the past year.

Background and Objectives: The objective of this
project is to find improved computerized methods for
isolating specific organs and diseased areas in
computerized tomography (CT) images for the
purpose of improving upon computer-assisted
methods of radiotherapy treatment planning.

Methods Employed: CT scans are transported by
magnetic tape to the Evans and Sutherland System
in DCRT, where they are entered and analyzed.
Analysis consists of applying a variety of classical
and experimental algorithms for contrast
enhancement, density slicing, texture analysis,
contour detection, contour extraction, contour
following, contour coordinate data compression, and
three-dimensional reconstruction.

Significance to Biomedical Research:

Improvements in computer-assisted radiotherapy
treatment planning should result in improved patient
care.

Proposed Course: Plans for future work have not
been specified at the time of this writing.

Automated Pulmonary Physiology Testing

Procedures such as exercise testing, pulmonary
compliance, and work of breathing have been found
successful for evaluating pulmonary function. By
exercising a patient on a treadmill and gradually
increasing the workload (i.e., speed and incline), the
physician can better assess cardio-pulmonary
disease, which in its early stages generally does not
manifest itself except under physical exertion. In
order to help the physician perform these procedures
more effectively, a microcomputer system has been
developed to enable automated realtime collection,
analysis, and display of pulmonary compliance data.
Work is in progress to complete an automated
exercise procedure as well. Data is stored in a local
disk data base for future reference.

Background and Objectives: Physicians monitor
pulmonary parameters during exercise to better
assess pulmonary function and to diagnose
pulmonary dysfunction that only manifests itself

under physical exertion. Procedures such as
pulmonary compliance and inspiratory muscle
strength also give insight into respiratory function.

Until recently, pulmonary treadmill exercise testing
was performed manually at NIH. Data were written
down and later entered into a programmable
calculator for determination of results. Additional
summary statistics and a final report were prepared
by hand. Work of breathing and pulmonary
compliance measurements, done in the same lab,
were likewise performed manually.

In order to speed both exam and data analysis time,
and to improve accuracy, these procedures are
being automated with a microcomputer system.

Methods Employed: The microcomputer system is
a DEC MINC-11/03 (Modular Instrument Computer)
containing an LSI-1 1 microprocessor, 32K words of
memory, auxiliary disk storage, and analog-to-digital
and digital-to-analog conversion capability. There is
also a video graphics display, a keyboard console, a
hard copy unit for printing the video display, and a
line printer.

In determining pulmonary compliance,
transpulmonary pressure (the difference between
alveolar pressure, i.e., mouth pressure with mouth
shutter closed, and esophageal pressure, as
measured by a balloon transducer swallowed by the
patient) and lung volume (measured with a wedge
spirometer) are determined by the computer as the
physician repeatedly closes a mouth shutter
throughout a patient's inhalation or exhalation. A
graphical plot of the data is then produced to aid in
evaluating the 'stretchability' of the patient's lungs.

In a similar manner, a patient's relative inspiratory
muscle strength is determined by measuring the
most negative pressure developed when inspiring
against a closed mouth shutter.

During the treadmill exercise procedure, the
computer monitors expired volume and flow via a
Tissot spirometer and pneumotach, respectively.
Inspired and expired oxygen, carbon dioxide, and
nitrogen concentrations are monitored via a Perkin
Elmer mass spectrometer gas analyzer. Acid/base
and gas concentrations are determined offline from a
sample of the patient's arterial blood, and entered at
the keyboard. Pulmonary volumes, flows, and oxygen
consumption-a measure of how hard the patient
actually works to perform a given level of exercise-
are then calculated.

Progress in FYS 1: TherMINC-11 microcomputer
and related peripherals were installed and
functioning by November 1980. The manual data

er on V

entry exercise analysis package developed earlier
the CSL LSI-1 1 /03 development system was directly
transferred to the MINC, immediately enabling the
automatic processing of exercise data. Due to a
change in clinical priorities, it was decided to first
automate the compliance and inspiratory muscle
strength tests, and then proceed further with the
exercise protocol.

Utilizing the MINC's realtime data acquisition and
graphics capabilities, subsequently, software was
developed to enable a full automation of the
compliance and inspiratory muscle strength
procedures. Only minimal modifications to the
existing pulmonary hardware were required. In
addition to the capabilities for data acquisition,
analysis, and display, a scheme for storing data
locally on disk allowing subsequent retrieval was
developed. Later on, the stored data will be
incorporated with the central pulmonary data base
being developed by DMB.

Proposed Course: First, the existing exercise
protocol will be completed. Then, having automated
all existing pulmonary lab procedures, we will use the
computer for work that could not be done by manual
methods. For example, we plan to include closed
loop computer control of treadmill speed. By
monitoring heart rate and dynamically varying the
treadmill speed, it should be possible to apply a
more constant workload to the patient, thus leading
to more stable results. In addition to performing
more complicated laboratory procedures, additional
forms of mathematical analysis will be applied to the
data in order to gain further insight into the patient's
pulmonary function. Having developed a general-
purpose tool for pulmonary data collection, it will be
this latter portion of the project that has the potential
for advancing the state-of-the-art in pulmonary
medicine.

Publications:

Nadel, L. D.: Automated Pulmonary Analysis by an On-line Microcomputer.
In Nair, 8. (Ed.): Proceedings of the Conference on Computers in
Criticai Care and Puimonary Medicine. New York, Plenum Press (in
press).

SiSSfltiS'tS'-?™!™ !ST'

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201 C

r 00060-02 CSl

Octolier 1. IMO to Septtoter

30. 1981

Hlasurewnt of Tranieplthel u

1 (teslsunu of Kfdney Tubule

«wu, LMMiiom *w iaiiir<ni irfiii*!

ad, iM iinii ff MiKim i

a i» ui cnu

ict £fl9ln«er CSL. OCRT

FpIIom LKEH. NHLBl

Ijhnratftry af XldnCX and EttttfOljff HeUboll««. NHJl

fniipMt»r Sy^t^an Laboratory

Project Dewl opnw t_ Sec 1 1 on

ncRT NlH, H^thg^d*. KirvUnd 20M5

0 3

: Mas upgraded In FV8I

Measurement of Transepithelial Resistance of
Kidney Tubule

A microcomputer-based instrument was developed in
FY80 to facilitate determination of transepithelial
resistance of an in vitro perparation of kidney tubule.
The instrument controls the onset, intensity, and
duration of a series of electric current pulses through
the preparation; measures the induced voltage
changes; and prints those values. The instrument
was upgraded in FY81 to include online calculation
of the transepithelial resistance and other
parameters of interest.

Background and Objectives: The objective is to
automatically measure the transepithelial resistance
of in vitro preparations of kidney tubule. A
microprocessor-based instrument was developed to
facilitate these measurements. Based on operational
directives entered by the user, the instrument
controls the polarity, duration, and intensity of each
of a series of current pulses through the tubule
preparation, and determines and records the steady
state voltages induced at either end of the
preparation. Transepithelial resistance and other
parameters are calculated from these values.

Significance to Biomedical Research: Previous
manual methods for obtaining these measurements
were time-consuming and prone to error. With the
control instrument, a complete set of measurements
can be made in a few moments. The experiment can
easily be rerun under the same or a different set of
conditions to test repeatability and consistency.

Progress in FY81: The capability to calculate the
resistances and other parameters using a complex
set of equations derived from a transmission line
model was added to the instrument. This was
accomplished by adding floating point math
hardware and software to utilize it. The calculated
values for every current pulse are now available to
the investigator immediately following execution of
the pulse sequence. Of particular interest is the
immediate display of the tubule diameter. A close
correpondence of the calculated diameter with the
actual diameter indicates that the preparation is
intact and that other calculations are valid.

Proposed Course: We may make a few minor
software changes to tailor the instrument's user-
interaction features to this experiment. No major
effort is anticipated for the future.

Publications:

Hauser, S E and Alfneida. A : A Control and Data Processing Instrument
lor Kidney Tubule Research. Biomedical Sciences Instrumentation 17:
13-19. 1981.

_Qctolier U isao to September 3Q. 1981
Electron Microanalysis Facility

s'tsTiir !?!*«?; ."Wiiu.H^^cDw^^^^

Electron Microanalysis Facility

Physical Scientis

KHLBI. NIADOK, NIMH. NINCE

Computer Systems Laborator

_Ecaleci ()evelop<nent Sectic

-^nrRi^^tmt.. fletnesda. fiD ;

5.2

1 6E1B is developing i

I Energy loss Spectrometry
I Dispersive X-ray Spectra

tranetry.

ZOI HS 10058-03
ZOl RS 10059-03
ZOl CT 00042-03

SSScTiiS'BWrH!! SW

.l'zJ";il!«iiil

ZOl CTO0053-O2

CSL

Computer Assistance for Blind Computer Users 1

PI: Scott [. Allen Medical Besearch Analyst CSL, OCRT '
David C. Songco Electronics Engineer CSL. DCRT
Perry S. Plenico Chief. Project Development Section CSL, DCRT
Oavld M, Stoffel Computer Programmer CSL. OCRT

;

cco*iuT>iw mm (u .-,)
None

0 1 1 n » 1

M* have developed a voice output terminal for us

by Mind computer
igram running in a

'by

cortlning a voice lynt^esl^e^ with a te.fto-speech p
for presenting visual data In audible form.

CSL in collaboration with BEIB is developing an
automated electron nnicroanalysis facility consisting
of two electron microscopes interfaced to a
computer system. The facility will be used for
research into the elemental composition of biological
specimens, and for the development of new
techniques in electron microscopy. CSL is designing
and implementing the computer system, which will
acquire and display the spectra and images
produced by Electron Energy Loss Spectrometry,
Energy-Dispersive X-ray Spectrometry, and
Wavelength-Dispersive X-ray Spectrometry.

See also:
Z01 RS 10058-03
ZOl RS 10059-03
ZOl CT 00042-03

Background and Objectives: The Computer
Systems Laboratory is designing and implementing a
computer system as part of the BEIB Microanalysis
Facility. The facility consists of two electron
microscopes, and will be used for research into the
elemental composition of biological specimens and
for developing new techniques in electron
microscopy. Work on this project is now in its third
year.

One of the electron microscopes is an Hitachi H-
700H 200 keV Scanning Transmission Electron
Microscope (STEM) equipped with:

• a lithium-drafted silicon [Si(Li)] detector
connected to a Kevex 7000 Analytical
Spectrometer for performing Energy-Dispersive
X-ray Spectrometry (EDS);

• an electron spectrometer for performing
Electron Energy Loss Spectrometry (EELS); and

• detectors for forward-scattered, back-scattered,
secondary, and sample electron current signals.

The other electron microscope is a Cameca 50 keV
Electron Microprobe equipped with:

• an Si(Li) detector for performing EDS;

• three Wavelength Dispersive X-ray (WDS)
spectrometers; and,

• detectors for forward-scattered, back-scattered,
secondary, and sample electron current signals.

A PDP-1 1 /60 computer system ultimately will be
interfaced to both microscopes to perform the
following functions:

• control electron beam position, stage position,
and the various detectors;

• acquire spectra and image data from all
detectors;

• process and display the spectra and Innage data;

• monitor and display a wide variety of
'housekeeping' parameters, including: lens
currents, lens temperatures, beam current, beam
energy, pump temperatures, coolant flow rates,
vacuum pressures, water leak detectors, floor
vibrations, ambient AC fields, power supply
voltages, room temperature, and room humidity.

Progress in FY81: CSL's software efforts this year
have been concentrated on four aspects of data
acquisition from the STEM:

1. acquisition of EELS spectral data and control of
STEM beam position,

2. acquisition, calibration, monitoring, and display
of housekeeping parameters,

3. retrieval of empirical X-ray information, and

4. installation and programming of the color
display systems.

EELS data acquisition and control of the STEM
beam position is done by a satellite processor
connected to the PDP-11/60 by a high-speed link.
Software has been wntten that allows the STEM
operator to define areas of a specimen as targets for
data acquisition and to collect EDS, EELS, and
electron current signal data from the target areas.
The data is acquired in SPECTRUM mode, which
produces a single X-ray and/or EEL spectrum from
the target area along with as many as four electron
current signal images.

EDS data acquisition is done by the Kevex 7000,
which is connected directly to the computer.
Software has been developed to: allow programs on
the 1 1 /60 to directly communicate with and control
the Kevex 7000; save or restore spectra and
associated information to or from user library files;
allow programs on the 1 1/60 to access, insert, or
delete spectra contained in user library files. This
software is currently being used by BEIB scientists
for research into methods of processing EDS and
EELS spectra to remove background and resolve
overlapping peaks/edges.

Housekeeping parameters are acquired by the
computer by means of an Analogies AN5400 data
acquisition subsystem. ,Software has been developed
to acquire, monitor, and display these parameters.

Calibration parameters for housekeeping and other
signals are managed by a Calibration Utility that was
developed this year. This utility maintains calibration
information on a disk file and allows it to be listed,
updated, and restored to memory-resident tables at
system boot.
To simplify the operation of the data acquisition and

display software that is being developed, a menu
selection scheme is used. The menu selection
software is completely table-dnven so that it is easy
to add new functions as they become available.
Currently, the housekeeping parameter display and
specimen target definition functions can be activated
through menu selection.

Work has begun on software to retrieve information
associated with X-ray emitting electron energy
transitions within atoms. This software will allow an
operator or another program to specify an element
and the transition(s) of interest using a convenient
notation. It will then look up the associated transition
energies and relative peak amplitudes. Conversely,
an energy range may be specified, in which case a
list of the transitions within that range will be
retrieved. This work is being done under contract by
Systex, Inc.

A DeAnza ID5400 color display system was
delivered in October 1980 and was successfully
interfaced to the PDP-11/60. Work has begun on
software to support image display and processing.

A second satellite processor for interfacing the
microprobe to the computer was delivered in FY81
and is currently connected to CSL's PDP-11/70
system where it is used for development of software
for the STEM satellite.

Proposed Course: Next year, we expect to:

• implement additional modes of acquisition for
EELS and EDS spectra and images and the four
electron current signals from the STEM;

• have a package to facilitate the display and
processing of EDS, EEL, and electron current
signal images on the DeAnza display system;

• begin work on the Cameca microprobe interface.

Computer Assistance for Blind Computer Users

We have developed a voice output terminal for use
by blind computer professionals. Full word unlimited
vocabulary speech output is made possible by
combining a voice synthesizer with a text-to-speech
program running in a microcomputer. We are working
with our blind users to develop additional techniques
for presenting visual data in audible form.

Background and Objectives: In previous years we
have developed a voice output terminal that
combines unl.mited vocabulary with extensive text
review capabilities. Three terminals were provided to
different Government agencies and proved to be a
valuable asset to the visually impaired computer
professionals who used them. Similar voice output
terminals are now marketed by the private sector. At
least two of these are based on CSL work.*

?^Ti&t

'ts'.irr!iR !W «.;;:• rr/."',,?.,.,.

201 CT00OS2-02 CSL

October

. 1980 to September 30, 198)

Httaboll
OTHER:

Energy Neasurements

D. C. Songco Electronics Engineer CSt, DCRT
». ». Henai.r Chler, HES tC, IR, NHLBI |

Non«

_Co»pmer
Project

S/stems Laboratory

Developwnt Section

'"DCRT.*NiH?Bethesda. HD 20205 I

0.5 P'"'**^' Q_5 !<""'"'

11 Bo«{i:)

a (.0 .««»..«

rocomputer- based instrument was developed t

B Study eneroy transduc-

lion pnenomena or respiring raemhrSnes. tiectrodes are interfaced to the mfcro-
eo«iputer to measure concentrations of specific ions, of protons, and of oxygen.
Program! are being developed to assay the change in ph across the membrane and
the ratios of ion movements to oxygen uptake.

siScrits'iS'.iS'rxffisrir'

fil

ilf'iiii.',

!01 n000»5-02

CSL

October 1. 1980 toSeoteober 30.

1981

InforHtion Technology Project

Crawford S. BrOMi, H.D,
Oavld M. stoffel

relopnent CSL, DCRT

Progress in FY81: This year saw rapid
developments of voice synthesis technology which
resulted in the availability of integrated circuits,
costing less than one hundred dollars, for the
synthetic generation of English phonemes. We have
incorporated these devices into our voice output
terminal. This has resulted in not only reduced size
and cost of the units but in enhanced capabilities in
terms of rate of speech and intelligibility.

Proposed Course: Prior work, both by CSL and the
private sector, has concentrated on the presentation
of sequential, linear text in audible form. We plan
additional studies in cooperation with our blind user-
colleagues aimed at presenting text in other formats
commonly employed on computers. Examples
include tables, forms, and lists.

Metabolic Energy Measurements

A microcomputer-based instrument was developed
to study energy transduction phenomena of respiring
membranes. Electrodes are interfaced to the
microcomputer to measure concentrations of specific
ions, of protons, and of oxygen. Programs are being
developed to assay the change in ph across the
membrane and the ratios of ion movements to
oxygen uptake.

Background and Objectives: CSL has collaborated
with the LC, IR, NHLBI for a number of years in the
development of new techniques for the study of
bioenergetics. This effort began with the
development of the Potentiometric Titration
Controller, which continues to be used in the
investigation of energy transfer phenomena at the
energy parameters of respiring membranes. To be
included are determinations of membrane potential
and the concentrations gradient for protons across
the membrane. New methods are also being
developed to measure the rate of oxygen uptake and
the ratio of protons and other ion movements to the
atoms of oxygen consumed.

Progress in FY81: The microcomputer system
designed in FY80 has been installed. A single board
microcomputer was used in conjunction with a 6-
channel D/A converter and a 16-channel A/D
converter with programmable gain. A high speed
mathematics module was interfaced to the system to
enhance realtime calculations. As proposed last
year, the data acquisition and control software were
developed on the disk-based Potentiometric Titration
Controller system and down-loaded to the target
system. By utilizing the existing development
facilities, only the hardware specific to the new
experiments needed to be purchased.

An electrode was constructed specifically for the
nnembrane-soluble probe, tetraphenylphosponium
(TPP), and this electrode has been shown to exhibit
Nernstian behavior in the measurment of low
concentrations of TPP in solution. A program has
been developed which calculates in realtime the
electric potential across a respiring membrane based
on the internal volume of membrane vesicles in the
suspension being analyzed, the external volume of
the solution, and the voltage sensed by the TPP
specific electrode. The membrane potential
measured by this procedure has been found to
agree with that determined by the traditional
technique of flow dialysis, which is much more
cumbersome and time-consuming.

Proposed Course: Development of the system to
determine energy parameters of respiring
membranes by use of electrodes will continue.
Emphasis will be placed on using the pH and oxygen
electrodes to assay the change in pH across the
membrane and the ratios of ion movements to
oxygen uptake.

Medical Information Technology Project

This project involves the application of
microprocessor technology and improved man-
machine interface methods to permit physicians and
their associates to more directly communicate with
computer record systems. This year we have begun
implementation of concepts developed in previous
years. A pilot study involving medical recordkeeping
by direct input of examining physicians and staff is
underway.

Background and Objectives: The use of computers
within the biomedical community is increasing as the
cost of systems is decreasing due to technological
innovation. Enhancements in the area of man-
machine interfaces must keep pace with the rapid
advance of computer hardware and software
technology. With this in mind, we have investigated
devices, methods, and structures that could provide
a more human-oriented interface while maintaining
an acceptable level of flexibility and efficiency.

Progress in FY81: This year we have identified an
area in which we can apply concepts developed in
previous years. In collaboration with a practicing
dermatologist, we have begun the development of a
clinical care system which will allow the physician to
store and retneve the data contained in a medical
record. This data includes histories, physical
examinations, progress notes, treatments, and
procedures.

The immediate objective of the pilot study underway

is to provide the physician with rapid and simple
access to a dedicated microcomputer system.
Disease-specific and problem-specific forms and
protocols are used to prompt the user through the
hierarchy of programs available. Much of the
software is table-driven to allow the physician to add
and modify not only the data base but the logic of
the presentation. This approach also provides a
convenient means of adapting the programs to other
clinical care and research protocols. To support this
effort, we are working in two main areas. The
clinicans are designing the disease-specific protocols
and formats as well as a general workup logic. The
computer programmers are developing a generalized
software system to provide a convenient, assistive
interface for physicians to use. This software will aid
the physician in accessing and selecting data from
complex tree-structured files, and in entering data via
a CRT terminal by simple menu selection for form
fill-out methods.

Proposed Course: Both the clinical forms and
clinical data access software are being developed on
the CSL time-shared computer system. Online
program trials from the dermatologist's office are in
progress. We expect to be able to transfer
operations of the software to a dedicated
microcomputer system situated in the physician's
office by the first quarter of FY82. At a later time, we
plan to perform experiments using a touch screen,
bar codes, and special cursor controls for data
selection and entry.

Laboratory of
Applied Studies

Eugene K. Harris, Chief

Summary of Activities

Computer-aided analysis of electrocardiograms.

J. Bailey, M. Horton (LAS); cardiologists and
biomedical engineers in the U.S.A., and abroad. To
evaluate the utility of leading computer programs for
ECG interpretation, and to search for optimal
computer-based methods of extracting medically
significant ECG patterns. A Gompanson of IBM and
GRI (Glasgow Royal Infirmary) ECG programs,
including clinical documentation and semantic
equivalences of output statements, has been
published. A study of serial ECG's has begun jointly
with staff of the Framingham Heart Study, NHLBI.

Computer systems for nuclear medicine. J.

Bailey, M. Douglas, and others (LAS); H. Ostrow
(CSL); M. Green, et al. (CC, Nuclear Medicine).
Development and application of computer systems
to such diagnostic imaging activities as ECG-gated
radionuclide angiocardiography, functional mapping,
and other scintigraphic studies of the kidney, brain,
heart, and lung. In collaboration with Nuclear
Medicine (CC) and the Cardiology Branch (NHLBI),
various parameters measunng regional heart wall
mobility are being studied for their discriminating
ability in normal volunteers and heart patients. Data
collection in the renal scintigraphy study to detect
arterial stenosis in dogs has been completed.
Results are now being analyzed and written for
publication.

Computer-based studies of pulmonary
pathophysiology and respiratory disease. J.

Bailey, R. Burgess, and others (LAS); R. Crystal, A.
Nienhuis (NHLBI); A. Jones (CC, Nuclear Medicine).
To achieve better understanding of pulmonary
pathophysiology through use of computer-based
models of pulmonary gas exchange and respiratory
mechanics, comparing predicted values with real
patient data. A joint study of gas exchange in normal
volunteers and patients at rest or exercising has
advanced with development of a reliable gas
analysis system and receipt of computer-controlled
exercise test equipment.

Statistical research in clinical pathology. E Harris,
M. Horton, A. Albert (LAS); G. Shakarji (DMB);
clinical chemists and others in the U.S.A., Europe,
and Japan. Application of variance component, time
series and other analyses to descnption of reference
distributions of clinical laboratory tests, to serial
studies of blood chemistries in health and disease,
and to the design of criteria for recommended
precision and accuracy of laboratory methods. A
comparative study of the sensitivity and specificity of
univariate and multivanate time series models, using
real and simulated data, is nearing completion. A
chapter on statistical aspects of reference values in
clinical pathology has been published. New research
has begun on statistical methods for dynamic
assessment of risk in acute illness.

Computer-based studies in ultrasonography. R.

Burgess, M. Douglas, J. Bailey, E. Pottala (LAS); B.
Maron. Ultrasonography allows non-invasive
visualization of many organs without the hazard of
ionizing radiation. This project involves development
of minicomputer systems for image enhancement,
pattern recognition, and three-dimensional
reconstruction from ultrasound data sources,
principally wide-angle phased array
echocardiography. Bone structures opaque to sound
necessitate development of an esophageal
transducer interfaced to a minicomputer. Lack of
staff time during FY81 forced deferral of this effort
until FY82.

Mathematical Modeling of biological processes.

J. Fletcher (LAS); R. Schubert (Louisiana Tech.
University). Development and application of
mathematical models in studies of substrate
transport in the microcirculation, in diffusion
processes in physiology, and in macromolecule-
ligand binding equilibria. A theoretical reanalysis of
concurrent flow models for organ perfusion
experiments has been completed. Modeling and
expenmental work on microcirculatory processes in
the autoregulation of oxygen supply within an organ
is continuing.

Mechanisms of active transport/biochemical
kinetics. B. Bunow (LAS); A. Kaplan (NCI); D.
Mikulecky (Medical College of Virginia; J. Kernevez
(University of Tecii., Compiegne, France).
Experimental and mathematical studies of the energy
mechanisms for active transport and of multi-state
biochemical kinetics in cells and membranes.
Theoretical studies last year revealed the
insufficiency of current, widely accepted methods
and hypotheses to explain the energizing or
localizing of active transprot mechanisms.
Collaborative work with NIH scientists has begun on
the use of newly implemented network simulation
programs to improve the understanding of active
transport mechanisms in membranes.

Hybrid computing to analyze physiologic signals
and construct simulation models. E. Pottala, J.
Wolpert (LAS); various NIH and FDA scientists.
Using LAS minicomputer system (MAC-16) for
hardware simulation of physiologic functions and for
analysis of analog signals (myogram, EEG, etc.). An
operating system developed and implemented last
year has been used extensively for A/D conversion
and spectral density analysis of EEG's and EMG's of
patients in various studies with the Medical
Neurology Branch, NINCDS, and of ECG's in a
cardiac drug toxicity study sponsored by the FDA.

Image processing in electron-loss spectroscopy.

M. Douglas, E. Pottala (LAS); J. Costa (NIMH);
Development and implementation of mathematical
models and image enchancement techniques to
analyze computer-acquired information from
electron-loss and X-ray spectra indicating the
location of extremely small quantities of important
chemical elements and active protein molecules
within cells. Image processing capabilities developed
on the newly expanded DeAnza system have been
used to determine fluorine distributions within the
dense bodies of blood platelets as a possible model
for intracellular patient monitoring of therapeutic
drugs.

Mathematical and computational methods for
nonlinear equations. R. Shrager, R. Hendler
(NHLBI); A. Schechter (NIADDK). Study of methods
of fitting nonlinear models and mathematical
methods of spectral analysis. A decomposition
procedure for the analysis of the spectra of mixtures
of chemical reactants to determine individual
physico-chemical characteristics and reactive
mechanisms has been completed and is being
tested in several experimental applications.

giis^inaiaiS'fss^M'riiKfw^

INI«A«wi''«SH«rMQJECI

m CToono7-i3 las

October 1. 1980 to Septenher 3D, 1981

St«,sUca,»..a.hi„c„„,ca,P«.o,.,,

PI: E.K. HarHs "^ """Thief. Lflb. of Applied Sturties LAS OCRT
OTHERS: A. Albert Fogarty International LAS DCRT

G. Shakarji Sgpv. Systems Analyst DHB DCRI
M.R. Morton Computer Systems Analyst LAS OCRT
L.H. Norton Research Hathenatician LSI DCRT
R. Eltn Clinical Pathology CC
G.Z. Williams Institute for Health

San Francisco, CA
T. Yasaka PL Medical Service nept.

Osaka, Japan
G. Siest and Centre du Medccine
R. Gueguen Preventive, Uancy, France

Laboratory of Applied Studies

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consisting of short

patients with myocardial infarction. The purpose

experience in the use of these statistical predic
detect changes and trends within individuals, tak

series varies from daily to weekly, 6-inonth, and
between oTiservat ions. Parallel conputer-based si

Mathematical investigations into the properties o
nodel of linear change are continuing.

astlng methods.

Numerical methods for the solution of
mathematical models describing reaction-
diffusion and other processes in biological
systems. M. Bieterman, J. Fletcher, B. Bunow (LAS);
I. Babuska (University of Maryland). Study,
development, and implementation of efficient, flexible
numerical methods for the solution of nonlinear
ordinary and partial differential equations involved in
modeling dynamic physiological processes. Research
and testing continued during FY82 on the use of
finite element numerical methods for the solution of
time-dependent reaction-diffusion equations.
Mathematical theory has been delevoped for the
adaptive solution of coupled systems of kinetic
equations. Applications to laser light scattering in
gels and some hydrodynamic models of blood flow
are currently in progress.

Research Projects

statistical Research in Clinical Pathology

Univariate and multivariate time series models and
discriminant techniques are being applied to various
data bases consisting of short series of
measurements of serum biochemistries in healthy
subjects and patients with myocardial infarction. The
purpose is to gain practical experience in the use of
these statistical predictive techniques to detect
changes and trends within individuals, taking into
account biological variation and measurement error.
The time scale of these series varies from daily to
weekly, 6-month, and 12-month intervals between
observations. Parallel computer-based simulation
studies are also underway, particularly to estimate
the relative sensitivities and specificities of
multivariate and univariate forecasting methods.
Mathematical investigations into the properties of a
new stochastic model of linear change are
continuing.

Objectives: To investigate applications of statistical
theory, particularly the use of variance components,
discriminant analysis, and the theory of discrete and
continuous time series, to the interpretation of serial
clinical laboratory measurements in healthy subjects
and patients with acute and chronic disease.

Recent Background: During the past several years,
the major effort in this project has been devoted to
the application of recently developed mathematical-
statistical models to various data bases of serial
biochemistries in healthy subjects. The smallest of
these data collections, weekly measurements of 10
common constituents in 37 male volunteers over a
5-month period, arose from a cooperatively designed
study with the Clinical Research Centre, Harrow,

England. Larger studies, in San Francisco and in
Osaka, Japan, involve hundreds of men and women
undergoing annual or semi-annual examination
including clinical chemistry and hematology
measurements. Running parallel with these studies
has been a rapidly growing interest among many
clinical laboratory workers and clinicians in the
statistical bases of reference values commonly used
in diagnosis and the evaluation of therapy. In
particular, the need to take account of within-person
biological variability over time is becoming more
widely recognized among pathologists and others
who interpret clinical laboratory reports.

Progress during FY81: The application of
multivariate and univariate time series models to
selected groups of semi-annual measurements from
a large-scale health maintenance program in Japan
made considerable progress. A preliminary report
was presented at an international meeting on the
subject of automated health testing in Tokyo,
October 1980. Current findings, based on both these
and computer-generated observations, indicate that
multivariate subject-specific reference regions, like
their counterparts derived from cross-sectional
population-based data, are much more conservative
in their interpretation of clinical laboratory results
than are univariate reference ranges. At the same
time, the multivanate region will occasionally show
sensitivity to a combination of results, each of which
appears normal when tested separately. Work is
continuing to implement and test the multivariate
random walk model, whose application to short
series is much more difficult than the stationary
homeostatic model.

Mathematical study continues of the univariate
stochastic linear growth model able to detect true
changes in slope, free of effects of measurement
errors and random 'ups and downs.' In cooperation
with the Laboratory of Statistical and Mathematical
Methodology, research into the asymptotic properties
of this model has been completed and efforts have
been directed towards obtaining more efficient
estimates of the parameters than are now available
from current methods based on the variances of
second and third differences.

In a new area of research, methods involving
discretized response curves are being developed to
deal with rapidly changing biochemical variables, as
in patients under intensive care for myocardial
infarction. The object here is to discriminate as early
as possible the probable outcome of the patient's
condition using only the most appropriate
measurements at each stage.

Studies with collaborating scientists outside NIH on

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Laboratory of Appl i ed Studies

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the transferability of reference values in clinical
pathology are still in the exploratory stage with
appropriate methods under development. In another
area, practical procedures for studying the heritability
of quantitative blood levels of certain constituents
such as cholesterol or of such characteristics as
blood pressure have been researched and proposed
for use in analyzing data from family health
maintenance programs.

Medical Significance: The development, testing, and
routine use of univariate stochastic models to
describe and forecast sequential results of laboratory
tests in individual cases have proven useful when
applied to periodic monitoring of healthy individuals
as part of a general program of preventive medicine,
introduction of multivariate models for this purpose
may prove even more valuable since many
laboratory tests are interpreted as part of a multi-test
organ battery, or in concert with other
physiologically-related measurements (e.g., calcium,
total protein, albumin). However, the sensitivity and
specificity of multivariate, as compared with
univariate, methods-whether for diagnostic or
monitoring purposes-needs careful assessment
based on simulation studies and real patient data.
The perfection of practical, yet mathematically
sound, methods for reliable prediction of patient
outcome based on dynamic risk assessments as
new data become available has great potential for
improving the efficiency and efficacy of medical care
in both acute and chronic illness.

Future Course: Current studies on the statistical
properties of univariate and multivariate time series
models should be completed by the end of FY81,
except for mathematical-statistical research on the
linear growth model which will continue during next
year. Development and testing of methods for
judging the transferability of reference values in
clinical chemistry will proceed more rapidly as the
time series studies are concluded and prepared for
publication. Research in dynamic risk assessment
will continue and may extend to studies of chronic
disease in cooperation with the Arthritis and
Rheumatism Branch, NIADDK.

Publications:

Harris, E.K.: Further applications of time series analysis to short series of

biochemical measurements. Proceedings of Workshop on Reference

Values in Clinical Pathology. Helsinki, 1981 (in press).
Harris, E.K.: Regression, least squares and correlation. In Seligson, D., M.D.

(Ed.): Handbook of Clinical Chemistry. CRC Press (in press).
Harris, E.K.: Statistical aspects of reference values in clinical pathology. In

Stefanini, M., and Benson, E. (Eds.); Progress in Clinical Pathology

New York, Grune & Stratton, Inc., 1981, Vol. VIII, pp. 45-66.
Harris, E.K.: Use of statistical models to detect subject-specific changes.

Proceedings of International Conference on Automated f\Aultiphasic

Health Testing & Services. Tokyo, 1980 (in press).

Mathematical Models of Binding Equilibria

The objective of this project is the study of
mathematical models of ligand-receptor or ligand-
macromolecule binding studies at equilibrium. The
models are examined for mathematical as well as for
conceptual validity and are studied to determine their
suitability for fitting to experimentally obtained
laboratory data. The appropriateness of various
model fitting critena are studied and general
guidelines and computational algorithms are
designed for computer-aided interactive model fitting.

Background: Mathematical models of
macromolecule-ligand binding equilibria have been
investigated since 1966. This continuing effort has
revised many of the concepts related to the binding
of ligands to macromolecules, particularly small ions
to proteins. This project has produced an interactive
methodology for the fitting of binding models to data
and has developed other computer oriented tools for
the analysis of data from laboratory experiments.

Progress in FY81: In FY81 numerous requests for
copies of exportable computer algorithms were
honored and some consultation was provided.
Preliminary studies of cooperative binding in
Aspartate Transcarbamylase in collaboration with the
Clinical Pharmacology Branch of NCI were not
experimentally reproducible. Activity in this area has
been suspended until the experimental procedure
can be improved.

Significance to Biomedical Research: The fitting of
models to experimentally obtained data is a
procedure used to estimate unknown parameters in
mathematical models. The proper choice of a model,
a choice of goodness of fit criteria, and the ability to
estimate the unknown parameters is a basic need of
biomedical research. The estimation of unknown
biochemical parameters contributes to new
biomedical insight and adds to basic scientific
knowledge only if the fitted models represent the
underlying biological process and the unknown
parameters can be readily and accurately estimated.
A thorough and continuing critique of such models
and their appropriateness for the interpretation of
current laboratory and clinical experiments is
therefore essential to the growth of fundamental
knowledge in these areas.

The cumulated findings of the previous AMS
research in this area has been collected in the form
of a summary report. This report details the various
alternative models, graphical presentations of data,
and algorithms for fitting models to data. Fitting
algorithms are also available for fitting with other
than the least squares criteria. The development of

these criteria is detailed elsewhere. Publication of
this summary report was delayed again due to
extensive revision requirements caused by the
computer center conversion to the new version of
WYLBUR.

Some mathematical considerations of new
experimental designs are being explored in
collaboration with Dr. Roy of NIADDK. The questions
involve the ultrafiltration techniques and the
measurement of 8-amino-adenosine binding. The
experimental procedures have not yet been
validated.

Proposed Course: Applications of existing and new
methodology to data analysis will continue to be
made as they are requested by collaborating
laboratories. Computer programs, reprints and
reports continue to be provided to requesting
consultees. Publication of the summary report, which
was again delayed due to conversion problems in
the new version of WYLBUR special train print, is
expected in FY82. Analytical development of new
models and continued research in this area will
emphasize validation of experimental techniques,
multi-receptor models, and conformational changes
in macromolecules due to binding of ions.

Publications and Abstracts: none

Mathematical Modeling of Substrate Transport in
Physiological Environments

Mathematical models of microcirculatory structure
and function are developed from conceptual models
into systems of coupled ordinary and/or partial
differential equations. Methods of solution of these
nonclassical formulations are developed and tested
and satisfactory cost effective methods are used to
explore the properties of these models. The results
are interpreted in terms of microcirculatory
physiology and are published in the scientific
literature.

One objective of this project is to study whole organ
and organ tissue level phenomena by means of
mathematical models in an effort to determine
relationships between variables that govern the
organ response to physiologic challenges.

Background and Objectives: The objectives of this
project are to develop mathematical models that can
be used to simulate microcirculatory physiology and
to explain, interpret and/or predict physiologic
behavior and limits. Such models should lead to a
better understanding of the biological control
processes and should suggest improved clinical
approaches to microcirculatory disorders.

iNiiAiwuL MiURCH nojjci joi CT00033-05 LAS

October 1. 1960 to September 30. 1981

Analysis of Coupled Transport and Biochemical Kinetics

PI: B. BunoH, Dr. Expert LAS DCRT

OTHEfiS: J. Kernevez, Dr. Professor Univ. of Tech. Compiegne,

A. Kaplan, Dr. Research Biochemist DCCP HCl

0. Mikulecky. Dr. Professor Medical College of Virginia

None

Laboratory of Applied Studies

A^,,l,.d^^the™nci Section

MRT. NiH.'Bethesda. Maryland ^0^05

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This project 1nve"t^gat« thTee'fundVmental problems in biology: (1) the role
of dynamic patterns in embryoloqiy and evolution, {2) the kinetics of enjvmes

normal cells in culture. The first area involves investigation of the role
which sitrultaneoos reaction and diffusion might play in the spatial and temporal

special emphasis on limitations in inferring molecular mechanism solely from

for data acquisition, display, and transmission, as well as mathematical
analysis of kinetic Studies on lactate dehydrogenase, an enzyme whose function
and molecular form is altered in hepatocytes in tissue culture subject to
chemical transformation to a malignant state. Oiqital computer simulation.

ijai LiLularly by means or network mooeiinq [anquaqes. numerical solution of

these investigations.

The mathematical modeling of organ substrate
supply by the microcirculation has been under study
since FY69. The substrate of primary interest is
oxygen. Such modeling studies are aimed at the
prediction of threshold and critical limits of substrate
supply necessary to sustain cell function under a
variety of physiologic conditions. The responses of
models to varying blood flow, blood hemoglobin
characteristics, tissue metabloic rate, tissue binding
proteins, and other physiologic parameters have
been examined. The complex interaction of
microcirculatory geometry, nonlinear oxygen
hemoglobin dissociation properties, intracellular
binding proteins, and substrate dependent metabolic
rates requires a detailed description to achieve
physiologic validity. These models require the
mathematical and numerical computer solution of a
system of coupled equations from a distributed
parameter model which are of an unusual nonlinear
type. The objective of the computations is to identify
mathematical models of organ microcirculation
having characteristics that correlate with
experimentally obtained measurements. Such
models can then be used to examine probable organ
response to physiologic challenge.

Significance to Biomedical Researcii: Such modeling
is necessary to predict the state of local tissue
conditions since direct measuremenfs are generally
not possible and must be inferred from boundary
observations. Studies of this type have the potential
of predicting tissue oxygenation and reoxygenation in
ischemia, hypoxia, anemia, coronary obstructions,
sickle cell anemia, shock, and other conditions of
substrate normal and abnormal physiology.

Mathematical models offer the only technique
available for the quantitative study of possible
autoregulatory mechanisms. The qualitative and
quantitative nature of such mechanisms can be
explored by means of appropriate models.

Proposed Course: It is anticipated that the research
course of this project will have the following stages.

(a) Reexamine the Krogh cylinder model and its
adequacy for the representation of perfused organ
microcirculation.

(b) Develop exact mathematical solutions for the
Krogh model that exhibit tissue axial diffusion and
capillary axial diffusion for the steady state constant
metabolic rate experiments with perfused organs.

(c) Develop or modify numerical algorithms that
will compute substrate levels for nonconstant
metabolic rates and other nonlinear effects.

(d) Develop algorithms for the direct comparison of
distributed substrate level computations with

experimentally obtained micro-electrode
measurements.

(e) Identify those critical ranges of parameters that
control organ response to physiologic challenge.

Progress in FY81: During FY81 attempts were made
to use mathematical solutions in the existing
literature to validate an experimental design for
perfused organ studies. The numerical results
revealed that these solutions, for the cell-free
perfused Krogh cylinder model, were mathematically
incorrect. Our efforts were subsequently redirected
to the development of new, intricate, mathematically
correct, solutions of the Krogh cylinder model. The
analytical construction and examination of these
mathematical solutions is being completed, and
these solutions are being explored parametrically for
critical ranges and limits. Two preliminary reports on
these properties have been presented at
international meetings, and a detailed theoretical
publication has been submitted.

The following stages of the proposed course have
been accomplished.

(a) Reexamine the Krogh cylinder model and its
adequacy for the representation of perfused organ
microcirculation.

Fletcher, J.E,: Simulation; Procedures and Pitfalls. Proceedings of the 34th
ACEMB meeting. Houston. Texas. 1981 (abstract),

Fletcher, J.E,. and Jolly. M,; The Computation of Substrate Levels in Per-
fused Tissues, Proceedings of the Annual Siam Meeting. Houston,
Texas, 1980 (abstract),

Fletcher, J,E., and Schubert, R,W,: Substrate Level Prediction and Histo-
grams in Perfused Tissues, Proceedings of the 34th ACEMB meeting
Houston, Texas. October 1981 (abstract),

Fletcher, J,E,, and Schubert, R.W,: The Theoretical Prediction of Substrate
Levels and Their Histograms in Cell Free Perfused Tissues, Proceed-
ings of the International Meeting of OTT Society. Detroit, Michigan,
August 1981. Plenum Press (in press).

Analysis of Coupled Transport and Biochemical
Kinetics

This project investigates three fundamental in
biology: (1) the role of dynamic patterns in
embryology, (2) the kinetics of enzymes in cell
membranes, and (3) the kinetics of enzymes from
malignant and normal cells. The first area involves
the role which simultaneous reaction and diffusion
might play in the spatial and temporal organization of
organ shapes and surface markings. The second
area involves enzyme kinetics with special emphasis
on limitations in inferring molecular mechanism
solely from gross observations. The third area
involves the integration of instrumentation for data
acquisition, display, transmission, and mathematical
analysis of kinetic studies on lactate dehydrogenase,
an enzyme whose function is altered in hepatocytes
a malignant state. Digital computer simulation,
particularly by means of network modeling
languages, numerical solution of differential
equations, and nonlinear regression analysis are the
main tools in these investigations.

• Dynamic Patterns
Bac/<ground and Objectives: Temporal and spatial
organization is universal in living organisms. What
are the mechanisms which produce it? The
equations describing diffusion of chemically reacting
molecules possess solutions which spontaneously
develop spatial and temporal patterns of
concentration. Because reaction and molecular
motion are the predominant physico-chemical
processes of living organisms, it is tempting to
suppose that the one is the mechanism of the other.
The objectives of this project are to develop
numerical methods to solve reaction-diffusion
equations so as to investigate the principles
controlling pattern formation.

Progress in FY81: The bifurcation diagram of a
reaction-diffusion equation summarizes the
multiplicity and stability of solutions. This year the
bifurcation diagram for the model equations
developed previously was successfully computed.
Techniques from functional analysis have been
applied to determine the multiplicity of solutions. One
technical manuscnpt, long in press, has appeared. A
popular presentation is in press, and another
popularization has been solicited. The technique for
computing bifurcation diagrams has appeared as an
internal report at a collaborating institution and will
shortly be submitted for publication.
Significance to Biomedical Research: Patterns
generated by reaction and diffusion have been
hypothesized to play a role in a variety of
developmental processes in biology. The validity of

these hypotheses has never been critically tested.
Several critical questions about such patterns are
addressed: What is the relation between pattern
form and the shape of the medium in which the
pattern grows? Is there a relation between the
patterns seen and the molecular mechanism of the
reaction? Are the patterns unique and stable?

Future Course: A formalism for dealing with
bifurcation to temporally periodic solutions has been
acquired. During FY82 this theory will be used to
direct experimental research into spatially distributed
oscillations in a membrane containing the
immobilized enzyme phosphofructokinase.
• Kinetics of Enzymes in Membranes

Background and Objectives: Studies of the
mechanism of membrane transport and excitable
membranes are generally less precise than studies
of the mechanisms of enzymes in solution. This
uncertainty arises because it is difficult to manipulate
the environment of the interior of a biological
membrane and also difficult to measure responses
there. There are two objectives to this project: to
determine the extent to which the actual organization
of models for membrane-associated processes can
be correctly inferred from the kinds of experimental
measurements currently made, and to develop a
formalism within which complex kinetics can be
entered rapidly and accurately as data into a
simulation program.

Progress in FY81: During FY81 the network
simulation languages SPICE and NET-2 were
installed on the IBM 370 central computers. Several
collaborative projects have shown the utility of these
languages for rapidly building and testing models for
a variety of biological phenomena. In the area of
membrane transport, SPICE modeling of several
molecularly distinct schemes showed them to be
experimentally indistinguishable. This material was
presented at the Polish Winter School of Membrane
Transport and has been submitted for publication. To
demonstrate the utility of network modeling to the
NIH community, a course is conducted through
DCRT; this year a dozen investigators attended. A
book on the application of network methods to
physiological simulation is in preparation, as is a
manuscript on use of network methods for
physiological models based upon partial differential
equations. Examples from the areas of
microcirculation and axon physiology are illustrated.
Recently, a second type of network, called a state
transition network, has been employed successfully
in the characterization of several types of membrane
processes. The means of translating such networks
into SPICE, gaining considerably in the size and

generality of models that can be considered, has
been demonstrated. An invited illustrative paper was
delivered at a recent conference on NET-2
conducted by the Navy.

Significance for Biomedical Research): The choice of
a model for a biological process strongly conditions
the design of experiments to confirm and extend it.
By making the analysis of models sufficiently simple,
an investigator is given the freedom to consider
many models. From comparisons among the models
using simulation, it should be possible to develop
incisive experiments which permit scientifically valid,
rather than arbitrary, selection among the models.
The network languages nicely complement the
MLAB system in permitting users to model
phenomena too complex to be conveniently
described in MLAB.

Future Course: During FY82, an effort will continue
to proselytize the NIH community on the utility of
network modeling. A compendium of transition state
networks, currently in preparation, will provide the
basis for development of the concept of
distinguishable classes of models in a number of H
areas of membrane biology. The extent to which B
current experimental techniques actually provide
confirming data for the models which they employ
can then be determined.

• Kinetics of Lactate Dehydrogenase(LDH) from
Normal and Malignant Hepatocytes ^

Bacliground and Objectives: When the enzyme LDH ™
is isolated from normal and malignant hepatocytes

grown in tissue culture, there are differences both in h

the activity of the enzyme and its sensitivity to H

inhibition by a reaction product. The objective of this ™
project is to characterize the differences in LDH from

various sources, emphasizing particularly the h

differences between normal and transformed cells. ■

Progress in FY81: The method of kinetic analysis
was applied to LDH obtained from several sources,
including normal and transformed hepatocytes.
Differences detected in this way were also reflected
in iso-electric focusing studies on the enzyme from
the two sources. The apparatus for performing the
kinetic studies was installed at NIH. A microcomputer
was purchased and installed by the principal
investigator that permits data from stopped-flow
spectrophotometry of LDH kinetics to be stored,
edited, and transfered to NIH computers for further
analysis. Software for this purpose has been
acquired. A manuscript describing the work is about
to be submitted.

Significance to Biomedical Research Differences in
the enzyme not evident from other types of analysis

can be shown through kinetic studies. The method of
kinetic analysis employed here distinguishes
between LDH from normal and chemically
transformed hepatocytes, whereas the enzymes from
these two sources are indistingusihable by isozyme
analysis. The technique is probably applicable to
LDH from other organ sources, although this remains
to be shown.

Future Course: During FY82 the new computer will
be employed to extend this type of analysis to cells
from other types of malignancies.

Publications:

Bunow. B-: Cellular Enzymology: Edect of compartmentation on steady
slate kinetics, J. Theor Biol. 84 611-628. 1980,

Bunow. B,: Turing and the physico-chemical basis of biological patterns. In
Prewitt. J, (Ed,): IEEE Turing memorial 1980 (in press),

Bunow. B,, Kernevez. J P , Duban. MC. Jolly. G,. and Thomas. D,: Pattern
formation by reaction-diffusion instabilities: Application to morphogane-
sis in Drosophila, J. Theor. Biol 84: 629-649. 1980,

Bunow. B, and Kernevez. J P . Reaction-diffusion patterns as a basis for
biological form-some discouraging results. Abstracts ol American
Math. Soc 1-521. 1980.

Bunow. B,. and Mikulecky, D.C: On the feasibility of using flux meas-
urements to distinguish among active transport models. Polish Winter
School ol Membrane Transport 1981 (in press),

Bunow. B . and fvlikulecky. D C: Where does metabolic energy couple into
the active transport process? J Theor. Biol (in press),

Kernevez. J,P . Jolly. G . Thomas. D , and Bunow. B,: Pattern formation and
wave propagation in the S-A system In Bardos. C , Lasry. J M., and
Schatzman, 1^, (Eds.): Lecture Notes in Mathematics 782: 201-221.
Springer-Verlag. 1980

Sharan, M,. Kernevez. J P , and Bunow. B : On numerical exploration of
bifurcating branches of solutions in reaction diffusion equations model-
ing enzymatically active artificial membranes. Research report ol the
Department ol Applied Mathematics. University of Technology of Com-
piegne, Compiegne. France. 50 pp

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Numerical Appronination T«:finiques for the Solution of
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Reaction- Diffusion

OTHER: J.E. Fletcher Chief, AMS

B. Bunow Bioinatheniatician. AMS
1. fiabuska Professor, Institute of Physi
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Nonlinear Equations

Methods are developed for solving nonlinear
equations frequently encountered in mathematical
modeling at NIH, usually in the context of
constrained nonlinear least squares or in the solution
to nonlinear differential equations. Related problems,
such as asymptotic error analysis and the efficient
treatment of sparse systems, are also considered.

Background and Objectives: The objective of the m
project is to develop methods for solving the ■

nonlinear equations frequently encountered in
descriptions of biomedical problems at NIH. General
categories of problems for which solutions were
developed here (partially or wholly) are nonlinear
least squares with linear constraints, nonstiff and stiff
ordinary differential equations, and nonlinear curve
fitting in norms other than least squares. In addition,
every project with which this one interfaces (i.e.,
collaborations) presents its own set of special
equations which must be solved, in either the
analytic or numerical sense. Methods which prove to
be of general utility are developed into accessible
computer programs or routines, e.g., MODELAIDE
and MLAB.

Progress in FY81:

• MLAB Projects

Gary Knott, (DCRT). The root-finder has been
revised with considerable improvement in efficiency
and the techniques are being described in a
manuscript in progress. An extension of the curve-
fitter is being considered which could include not
only least-pth power fits (added this year) but also
maximum likelihood and M-estimation in which the
likelihood function itself may contain parameters.
The approach thus far has been to use the current
Levenberg-Marquardt algorithm but alter the manner
in which the function to be fit is presented to the
algorithm.

• GABA Metabolism

E. Anthony Jones, Dan Schafer, Peter Ferenci,
(NIADDK). GABA is a neurotransmitter which is
stored only in brain cells. In normal animals, GABA
concentration is higher in plasma than it is in
cerebro-spinal fluid, and higher still in the portal vein.
Recent experiments indicate that gut bacteria
produce GABA which is then mostly degraded in the
liver. When the liver fails, the blood-brain barrier
breaks down, and the role of GABA in this process is
not well understood. Data is now being processed
on the metabolism of 3H-GABA from normal rabbits
and rabbits in liver failure to determine the resulting
alteration in GABA metabolism. Other experiments

(e.g., impairment of GABA metabolism without liver
failure) will follow.

• Equilibrium Studies of Magnesium Phosphate
Lev Jacobson (NIADDK). The physiologically
important reactions between Mg and P04 are not
well understood. Various models are being applied to
the fitting of NMR and pH data, with considerable
improvement in data expected when a divalent metal
electrode is used to detect magnesium ions.

• Analysis of Experimental Spectra

R.W. Hendler, D.Y. Setty, Dan Robertson (NHLBI). A
paper on the use of singular value decomposition
(SVD) in data matrices to detect chemical transitions
and their associated spectra is in the final stages of
revision. New data from beef heart mitochondria
indicate that cytochromes in mammalian cells have
essentially the same mechanism for passing
electrons as that observed in the bacteria. Spectra
to verify this will soon be forthcoming for processing
by SVD or a related method. A paper on oxygen
uptake and proton release by cells and reconstituted
vesicles has been submitted.

• Phytic Acid Titration.

William Evans (Dept. of Agriculture, New Orleans).
Phytic acid is a chelating agent which may be a
factor in metal-deficiency diseases. A manuscript, on
the liganding mechanism, has been revised and
resubmitted to The Journal of Agriculture and Food
Chemistry.

• Hemoglobin production

A.N, Schechter, Ann Dean, Francois Erard
(NIADDK). An abnormal human cell line, called k562
cells, can be induced by addition of hemin to
produce embryonic and fetal hemoglobins. Inhibitors
of cell division cause these cells to accumulate
hemoglobin, and the combined effect is a hundred-
fold increase in Hb concentration. Can all the effects
observed be explained by a simple kinetic model in
which only hemin controls production rates? The
data are now being processed.

Significance to Biomedical Research: These
methods are essential for the resolution of problems
of data analysis in metabolism, cell growth, chemical
kinetics, and spectral analysis (UV, IR, CD, ORD,
NMR, ESR).

Proposed Course: The new root-finder will be
compared with the current techniques in the existing
literature and the results will be published. The
maximum-likelihood and M-estimation curve-fitter will
be developed and tested. If it proves feasible, the
syntax of MLAB will be modified to permit easy use.
The new data from beef-heart mitochondna will be
processed by the SVD technique. Simultaneous

measurements from pH and divalent-metal
electrodes are expected to clarify the modeling of
the magnesium phosphate system.

Publications and Abstracts:

Berk, P D . Blaschke, T F , Shrager. R I . Waggoner. J G : Phenobarbitol
does not increase hepaticheme turnover in Man Gaslroenlerology 79:
1004. 1980

Numerical Approximation Techniques for the
Solution of Reaction Diffusion Systems in
Biology

The use of mathematical models to describe
reaction-diffusion systems and other biological
processes requires the implementation of reliable,
computationally efficient algorithms for the computer
solution of nonlinearly coupled partial differential
equations. New numerical approximation techniques
are studied and related software is developed for the
solution of model reaction-diffusion systems. Existing
methods and previously written programs are altered
and applied to other biological problems.

Background and Objectives: Mathematical models
describing many biological and physicochemical
processes involve systems of coupled ordinary and
partial differential equations that first must be
formulated and then solved via computer. It often
happens that the necessary numencal algorithms do
not exist in the literature, the related computer
programs are unavailable, or that applicable software
requires a large amount of computer time, rendenng
its implementation impractical. The two objectives of
this project are the development of new, efficient
numerical techniques for the solution of equations
describing reaction and diffusion processes and the
modification and implementation of existing
programs to solve other specific biological problems.

Progress in FY81 The investigation of an adaptive
'method of lines' solution approach and the
implementation of known techniques for the
approximate numerical solution of time-dependent
partial differential equation systems ansing in biology
have continued in FY81 .

Significance to Biomedical Research: A variety of
reaction, diffusion, and transport processes occurnng
in biomedical application areas are modeled by
equations which can be solved by the techniques
being developed. Among these processes are
oxygen transport in the microcirculation, embryologic
pattern formation, nerve impulse transmission, and
population dynamics of ecological systems. Effective
modeling of such nonlinear distributed parameter
systems involving both reaction and diffusion
requires the use of accurate, computationally

"•™'"

ffct iwowi»n» tiCHiaci u.s. otMHiMtNi or

ZOl CTO0O34-05 LAS

""""'"" October 1. 1980 to Septerter 30. 1981 j

Conputer-based Studies in Pulmonary Pathophysiology
and Respiratory Disease

PI:

OTHEBS:

R. C. Burgess Senior Staff Fellow LAS DCRT 1
A. H. Nienhuls Chief CHB NHLBI 1
J. J. Bailey Chief. MAS LAS DCRT
R. G. Crystal Chief PB NHLBI

E. K. Harris Chief LAS DCRT \
M. R. Horton Comiuter Systems Analyst LAS DCRT
E. W, Pottala Electronics Engineer LAS DCRT

Clinical HeiiBlolo^. Pulmonary Branch. NHLBI, Nuclear Medicine Dept.. CC 1
Branch. NHLBI |

Laboratory

of Applied Studies

Applied fc

theratics Section, Medical Applications Section

KRT. NIH.

Bethesda. Maryland 20205

2.0

|..«.si.«.L, B..l„

J I.I «««.»
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Tills project— through a collaborative effort of LAS with the Nuclear Medicine
Departaient, CC and the Clinical Hematology and Pulmonary Branches, NHLBI— is
directed toward a deeper understanding of pulmonary pathophysiology through
the construction of computer-based rrodels of pulmonary gas exchange and
respiratory mechanics and comparisons of model predictions with real patient

efficient numerical algorithms. These methods and
other standard techniques are available to the NIH
biomedical community as research tools and can be
modified or used directly to solve problems of
physiologic interest.

In the 'method of lines' approach the finite element
technique is used to approximate the spatial
variables. This yields a system of ordinary differential
equations which can be solved, for example, by one
of the many high quality software packages
available. The scheme is adaptive in that decisions
concerning mesh selection and refinement are made^
by the computer during the problem solution. Such HI
decisions are based upon reliable a posteriori VI

estimates of the error between the exact solution
and the computed approximate solution. Changes in
the mesh structure are made in order to control the
error and increase the efficiency of the solution
process. Such schemes are especially applicable to
dynamic biological systems whose behavior is
localized in space.

Work has been completed which extends the full
mathematical framework of the a posteriori error
analysis developed for single, steady-state equations
by I. Babuska and W. Rheinboldt to coupled, time-
dependent linear systems of partial differential
equations. Adaptive mesh selection strategies based
upon these estimates have been developed and are
being implemented in computer programs on the NIH
IBM System 370. The accuracy and efficiency of the
adaptive procedure are to be tested on a collection
of nonlinear problems of biological interest.

In addition to the above investigation, recent
collaborative efforts have been initiated with two NIH
researchers:

1. A preliminary study with Dr. Robert Lutz, DPS/
BEI, has been completed. The study examined the
solution of the Navier-Stokes equations for a two-
dimensional model of blood flow through a section of
an inelastic canine aorta model. This collaboration
will involve implementing a fluid dynamics finite
element code, which will either be obtained and
modified, or designed and written by LAS. Computed
wall shear stresses and blood velocity profiles are to
be compared to laboratory experimental data and
used in a parametric study of factors relevant to the
onset of atherosclerosis.

2. Work with Dr. Ralph Nossal of DCRT/PSL is
underway to determine if modified versions of the
Bathe-Wilson finite element code could prove useful
in deducing the elastic properties of gels from light
scattering measurements. In a mechanically excited
gel, the frequencies of standing waves are related tr
the elastic properties of the gel. In most

experiments, these frequencies can be only
approximated crudely. The objective here is to
develop a scheme for approximating these
frequencies by a finite element technique.

These collaborative projects will continue at levels
determined by LAS/AMS priorities and manpower.

Publications and Abstracts: None

Computer-based Studies in Pulmonary
Pathophysiology and Respiratory Disease

This project-through a collaborative effort of LAS
with the Nuclear Medicine Department, CC and the
Clinical Hematology and Pulmonary Branches,
NHLBI--is directed toward a deeper understanding of
pulmonary pathophysiology through the construction
of computer-based models of pulmonary gas
exchange and respiratory mechanics and
comparisons of model predictions with real patient
data.

Bacliground and Objectives: Numerous attempts
have been made in the past to quantify pulmonary
function. Inhomogeneities in the lung required certain
simplifying assumptions to be made tending to
obscure the true nature of lung function.
Furthermore, certain nonlinearities inherent in the
lung system allowed only partial quantitative models
and sometimes these could only be expressed in the
form of nomograms or graphs.

Within recent years it has been possible to apply
computer technology to numerous diagnostic tools,
viz, spirometry, dynamic compliance studies, multiple
inert gas studies, pulmonary scintigraphy, cardiac
catheter studies, and blood gas studies.

The objectives of this program include the use of
computer technology to refine diagnostic methods
and to construct models for pulmonary gas
exchange and respiratory mechanics.

Progress in FY81: The existing system for analysis
of gas exchange was tested extensively. It was
found that instabilities in the gas analysis lines and in
the analog circuitry prevented any hope of obtaining
reliable data. Therefore, the system was completely
re-designed. Literature on exercise-testing
laboratories was reviewed; the state-of-the-art in
commercial equipment was analyzed; and one of the
most advanced exercise-testing laboratories
(Wasserman in California) was visited. LAS
developed specifications and directed purchase of
the equipment, much of which has been delivered.
The basic components of the new system include:
an LSI-1 1 based computer for rapid data acquisition
and processing; a pneumotachometer and mass
spectrometer to provide flow and concentration data;

and a bicycle ergometer and treadmill whose work
loads can be varied under direct computer control.

Significance: In certain diseases of the lungs
(restrictive, obstructive, etc.), blood
(hemoglobinopathy sickle cell anemia, polycythmia).
and cardiovascular system, the assessment of the
patient's condition at various points in the course of
disease may be no better than a subjective
impression given by the patient, his family, or his
physician. An alternative, and potentially more
objective, method of assessment involves the use of
continuous exercise to quantitatively evaluate the
overall ability of the patient to meet the demands of
exercise. This is accomplished by monitoring his
ECG, blood pressure, blood gases and lactate,
oxygen consumption, etc., in a reliable and
reproducible manner. The detection of 'anaerobic
threshold' may be of particular clinical importance
when considering response to therapy or disease
progression.

The sensation of 'shortness of breath' is poorly
understood. This phenomenon clearly has
components of neural as well as clinical origin. Non-
steady state exercise measurements should give
additional insight into the origin of this complaint in
patients with vanous disease processes. This data,
in conjunction with other parameters, should improve
prognostic accuracy and aid the theraupeutic
decision-making process.

Proposed Course: Configuration and interfacing of
the system is in progress and will continue into
FY82. Many components from the old system (e.g.,
bicycle ergometer, Tektronix display) will be
incorporated. When assembled, the new
configuration will be tested extensively for reliability.
Subsequently, a normal data base using volunteers
will be acquired as a baseline against which the
tests in pathological conditions can be compared.

Publications: None

October 1. 1980 to Scpteinbc

Mybriri Cwipirtlng for t

PI: r.M. Pottala

OnrERS: J.J. BaHey
I. iaar
H.C. Van Ars-ldle

Phar(naca1o<]fs
Tug. Aid
Vlstttng Scic

lanoralory of Applied '

Jl£aL_tlllU_afiii£ilA^

Id 1 yze physiologic

doviilop physioloqic simutati

n models

use hybrid canputinci techmq
electrocardioirain, eloctroen

ephaloqrain

si^irisiais'^^of SSI"** it^"

.l^iFsilimfcT

ZOl

October I. 1980 to September 30. 1981

Computer Systems for Nuclear Medicine

PI: J.J. Railey Chief, Med. Appl. Sec.
S.L. flacharach Physicist
M.A. Douglas Comp. Syst. Analyst
fi.C. Burgess Senior Staff Fellow

OTHERS: ».G. Ostrow Engineer

M.v, Greun Ch. Appl. Physics Sec.
A.E. Jones Chief. Diagnostic Imaging
G.S. Johnston Chief
R.O. 8onow Clinical Associate

Cf!

DCRT
CC

Nuclear Medicine nepartiront. CC, NIH
Conputer Systems Laboratory, OCRT, HIH

Medical Applications Section

1.1 1 3.0 1 o'.l

3 10 K«« «•*«» □ ,., H^« ,.».tS □ (.

"'■'"

This project involves computer-based qathenatical

*n.lv

patt<^rn recognition, and ,maqe processlm in support

Center

and colUhorating Institutes. Applications Include

sclninraphy. renal dynamics

reMtlonsMps.

Wssi

investigation of l-iybrid Computing for the
Construction of Simulation Models and for the
Analysis of Physiologic Signals

This project was undertaken to develop physiologic
simulation nnodels using hybrid computing and also
to use hybrid computing techniques to analyze
physiologic signals such as electrocardiogram,
electroencephalogram, and electromyogram.

Background and Objectives: This was extensively
described in last year's Annual Report (FY80) pages
144-146.

Progress During FY81: The Medical Neurology
Branch, NINCDS, has studied electromyograms with
intra-muscular probes to determine muscle fiber
conduction velocities in various disease states
(references 1 and 2). Analog-to-digital conversion
and spectral analysis were performed on the MAC- Jj
16 system. The Medical Neurology Branch also ™!
analyzed EEG's on patients being treated for hepatic
coma, using the MAC-16 system.

The Division of Cardio-Renal Drug Products, FDA, is
investigating the early detection of cardiac toxicity
resulting from drug therapy. Rat electrocardiograms
are being used to determine the sensitivity of
detection. Analog-to-digital conversion of the data
has been completed to provide data for the analysis
programs.

Significance: In some simulation models, certain
pieces or functions can be split off and implemented
in hardware circuitry or in a set of microprocessors. Jl
This has several advantages. First, parallel ™

processing is allowed, which can shorten computing
time and make interactive model testing feasible.
Second, the hardware circuitry or microprocessors
are usually quite inexpensive. Third, some models
are so complicated and extensive that their
implementation on a large scale digital computer is
not feasible; however, with hybrid computing, such
models may be achieved. An example was the
model of the Purkinje network in the alligator
cerebellum, which required a system of 35 cells
connected by nonlinear differential equations
(completed in FY76). Another example was the
simulation of retinal cone cells (described FY79).

Currently, the effect on cardiac behavior of various
drugs~in particular, cancer chemotherapy agents-is
monitored by a single lead electrocardiogram (ECG)
in animals. The end point for cardiac toxicity is
terminal ventricular tachycardia. The current study is
investigating multiple lead ECG's and the computer
analysis of this data to provide more sensitive and
accurate end points for drug effects.

Proposed Course: No new projects involving
simulation models are being undertaken at this time.
However, the capability remains, should a
collaborative project be proposed in the future. For
example, the Laboratory of Neurotoxicology,
NINCDS, has studied a rat preparation with bipolar
electrodes in the sensory cortex and in two layers of
the hippocampus. The theta activity generators in
the hippocampus produce certain correlated
spindling activities in the sensory cortex, varying
according to degree of a drug-induced, immobility
state. Data already collected will be analyzed, using
the fy/IAC-16 system. Whether additional study is
needed using a simulation model remains to be
investigated.

The MAC-16 system will have continued use for
ECG processing from the Framingham Heart Study
(see project report on electrocardiography).

Analysis of FDA data on cardiotoxicity has begun
and will continue in FY82.

Publications and Abstracts:

Yaar, I.. Shapiro, MB. Mitz. AH,, and Poltala. E,W,: A computer assisted
monitoring of muscle fiber conduction in full interference patterns: ALS
versus normal subiects, A preliminary report, Ttie Amencan Association
of Electromyography and Electrodiagnosis Meeting, Philadelphia. Penn-
sylvania. 1980. Eleclroencephol- Clin. Neurohysiol. 50:245P. 1980 (ab-
stract)

Yaar. I,, Shapiro, M.B.. Mitz, A,R,, and Pottala. E,W.; Introducing a new
computer assisted technique for measunng muscle fiber conduction
velocity at full interference pattern, American Neurological Association,
Boston, Massachusetts. 1980, Ann. Neurology 8:124. 1980. and Trans-
actions of the Amencan Neurological Association 1980 (abstract),

Yaar, I , Shapiro, MB. and Pottala, E W,: An EEG power spectral analysis
of dopaminergic mechanisms in patients with hepatic coma, Amencan
Electroencephalographic Society meeting Boston. Massachusetts.
1980. Electroenceph. C/in. Neurophysiol. 51:31P, 1981 (abstract).

Computer Systems for Nuclear Medicine

This project involves computer-based mathematical
analysis, pattern recognition, and image processing
in support of diagnostic activities in the Nuclear
Medicine Department of the Clinical Center and
collaborating Institutes. Applications include
computerized ECG-gated radionuclide
angiocardiography and myocardial perfusion
scintigraphy, renal dynamics, and pulmonary
ventilation-perfusion relationships.

Bacl<ground and Objectives: Since FY72, LAS and
CSL have collaborated with the Nuclear Medicine
Department, CC in the acquisition and development
of several minicomputer systems that gather and
process data from the scintillation cameras in the
Nuclear Medicine Department.

The objective of this program is to continue
development of computer-based algorithms, which
have already found wide-ranging applications,
including: fitting mathematical models; mapping the
parameters of such models over time and in different
regions of an organ; image processing; interpolation,
expansion, and contraction of image arrays; and
pattern recognition.

Progress during FYS 1:

Renal Scintigraphy-V^ ork in FY76 showed a
significant enhancement of radionuclide renography
by the use of functional maps, and, since FY77,
functional maps have come into routine clinical use
in the Nuclear Medicine Department. In FY79-80 a
pilot study of partial renal artery ligation was carried
out on four dogs. The results of this study were
reported at the Society of Nuclear Medicine, and a
manuscript is now in preparation. In FY81 the
techniques of the pilot study were improved in
several ways:

• The studies are uniformly performed with 1-123
iodohippuran, improving the signal noise ratio
about 16-20 fold;

• A radio-transparent table was designed so that
positioning of the animal could be carefully
controlled;

• Precise positioning of the kidneys under the
gamma camera was guided by technecium-99m
DPTA given in minute doses; and

• The software has been entirely rewritten to work
in conjunction with the current Nuclear Medicine
Operating System and to decrease image
variability.

Data on nine dogs including renal scintigraphy and

KS"js.s'i!;'rr!i!"

;S!.T'

,Zil!:L

ZOl CT00002-11 LAS

""'» ""■" October 1.

1980 to September 30. 1981.

Cofrpiiter-Aided

Analysis of Electrocardiograms

PI: J. J. Bailey

OTHERS: E. K. Harris
H. E. Wonbte
P. tecFarlane

D. Savage
S. Allen

Chief, HUS

Computer Systems Analyst

Chief

Kedica! Cardiology

Framingham Heart Study
Medical Research Analyst:

LAS DCRT
LAS DCRT

LAS OCRT

Glasgow Royal Infirmary
Scotland

CSL DCRT

co«p<iu.i« u.iii 0. ..,1

HBrtMNO.

Medical Appl

'"'""" ""krt'.'^IH. Bethesda, Karyland E0E05 1

fflOFessiMAL, \atm, ^

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These studies continu
computer analysis fo

ing sin

ce 1970 have been direc

ed toward the

contrast angiography before and after renal artery
ligation has been collected. Preliminary results
suggest a vast improvement in technique over the
pilot study.

Cardiac Scintigraphy-\n collaboration with Nuclear
Medicine and the Cardiology Branch, LAS has begun
investigation of several parameters reflecting mobility
of the heart wall including ejection fraction, time-to-
end-systole, phase (of a fitted cosine curve), and
ratios of areas over/under the time-activity curve of
a blood pool scan. Programs have been written to
compute these parameters globally or for any of four
sectors of the heart image. The test data base
includes rest and exercise studies on 40 normal
volunteers, 10 patients with chest pain but
completely normal cardiac studies (including ECG
and coronary angiogram), 10 patients before
beginning adriamycin therapy, and 15 patients with
coronary disease and known resting apical
abnormalities (hypokinesis, akinesis, or dyskinesis).
Preliminary results suggest that ejection fraction and
phase are the best parameters for separating normal
from abnormal cases.

Image Processing Deve/opments--Jhe DECsystem-
10 based image processing packages, IMAGE and
PSTACK, continue to be expanded and used both
for dynamic scintigraphic images and for electron
microscopy images.

In the past year, the LAS DeAnza image processing
system has undergone rapid expansion. Two major
interactive software packages have been developed.
The first, PICTUR, currently includes a variety of
edge detection and tracking routines and alignment
procedures in addition to display and image
enhancement options.

The second, MOVIE, is aimed at time varying image
sequences. During the past year this package has
been enlarged to include generation of flow/volume
loops, phase/amplitude maps and a variety of
enhanced dynamic display procedures. These two
packages are designed to be compatible with one
another; transition from the use of one package to
the other is invisible to the user.
A magnetic tape drive to facilitate data interchange
and a disk drive to improve storage capabilities have
been purchased and are being interfaced into the
system.

Proposed Course:

Renal Scintigraphy--A project planned in FY80 would
have allowed the use of renal scintigraphy to study
patients with renal vascular hypertension in
collaboration with the Hypertension Branch, NHLBI;
it is still awaiting FDA approval of 1-123 iodohippuran

as a diagnostic agent. Extension of the canine
studies with different lesions is under discussion.

Cardiac Scintigraphy-fK statistical analysis of the
data collected will be pursued, one possible outcome
of which might be a discriminant function of ejection
fraction and phase to achieve optimal separation of
normals from abnormals. Another interesting study
will involve those patients with myopathy secondary
to adriamycin therapy, using each patient before
therapy as his own control. Those patients who have
normal contractility at rest but abnormalities upon
exercise form another interesting data base.

Image Processing--lhe DeAnza image processing
system is to be expanded from its current 256x256
image size to a 512x480 image. This expansion,
together with the new magnetic tape drive and the
disk drive, will facilitate study of paired myocardial
(Thallium) and blood pool image sequences. Refined
edge detection, assessment of wall motion
abnormalities and perfusion, and determination of
'absolute' volumes, if possible, are planned.

A model is to be developed to demonstrate the
effect of known amounts of additive noise on the
detectability of regional wall motion abnormalities.

Publications: None.

Computer-Aided Analysis of Electrocardiograms

These studies continuing since 1970 have been
directed toward the evaluation of accuracy, clinical
utility, and cost effectiveness of various computer
systems for analysis of routine electrocardiograms
(ECG's). Further studies will involve new methods of
feature extraction and design of criteria by computer
techniques and their use in epidemiological studies.

Background and Objectives: This has been
extensively described in last year's Annual Report
(FY80), pages 111-114.

Progress during FY81: A study of 300 ECG's from
the Royal Infirmary in Scotland was published
(bibliography follows). This study resulted in the
comparison of two EGG programs using guidelines
and definitions that were developed by LAS. This
method of evaluation, when applied to two or more
programs, can reveal their relative strength and
weaknesses. The reason for a program failure can
often be pinpointed to a specific defect in pattern
recognition, measurement algorithm, or design of
criteria.

In FY80, the Framlngham Heart Study proposed
longitudinal studies of routine ECG's in that
population. In FY81, LAS collected ECG's on 200
subjects, including 100 blacks, and 25 normals
repeated 4 times.

Significance: See Annual Report (FY80), pages
111-114.

Proposed Course: Testing of ECG programs
developed by other organizations was largely
completed in FY79. However the development of 12-
or 15- lead ECG data acquistion devices and the use
of sophisticated feature extraction methods (e.g.,
Karhunen-Loeve expansion) opens the possibility for
further investigation of ECG diagnostic systems.

Meanwhile LAS continues to study the epidemiologic
significance of the routine ECG in collaboration with
the investigators of the Framingham Heart Study.
The ECG correlates of such heart diseases as
coronary disease, mitral prolapse, and asymmetnc
septal hypertrophy in a free-living population are of
particular interest.

Studies of statistical variance within and between
individuals already begun will extend into FY82. A
separate study to test a black population for
differences is planned.

Publications and Abstracts:

Bailey. J J : The future of gold standards and computenzed eieclrocardio-
grapfiy In Tolan. G,D and Pryor. T A (Eds.): Computenzed Inlerprela-
tion ot the ECG V New York. Engineering Foundation. 1980. pp. 229-
233,

Bailey JJ.. Berson. AS,. Jacl^son, L,K,, fylilliken. J, A,, Stevens. Jfyl,, Totan.
G,D,. and Wolf. H,K,: Evaluation Methodologies lor ECG diagnostic
systems In Bonner, RE and Pryor. T A, (Eds,); Computerized Interpre-
tation of ttie ECG VI. New York. Engineering Foundation. 1981 (in
press),

Bailey, J.J., and Harns. E K,: Evaluation o( ECG interpretation: Truth versus
beauty In Tolan,G.D. and Pryor, T,A. (Eds): Computenzed Interpreta-
tion of Itie ECG V. New York. Engineering Foundation, 1980, pp 179-
182,

Bailey, J,J., and Horlon, M,R,: Type A electrocardiogram data bases: Pur-
pose and development. In Wolf. H,K., and Macfarlane, P W. (Eds):
Optimization of Computer-ECG Processing New York, North-Holland
Publishing Company, 1980. pp, 189-195,

Macfarlane, PW. Chen, C,Y , and Bailey. J, J,: A companson of point
scoring techniques for the diagnosis of LVH, In Macfarlane, PW, (Ed.):
New Frontiers in Electrocardiology. London. Pitman Medical Publ. Co.,
1981 (in press)

Macfarlane, PW,, Melville, D,l,, Horlon, M.R,. and Bailey. J J, Comparative
evaluation of the IBM (12 lead) and Glasgow Royal Infirmary (3 ortho-
gonal lead) ECG computer programs Circulation 63: 354, 1981,

■KOJtCI «««« (S« ■« «. IM. .p.«^

,l"rl?°ii:'k'"!!i'l

ZOl aO0043-O

LAS

nut Of PNOJtCT (W ch.r«t.r. «r l.»)

Computer-based studies in ultrasonography

Pi: E.W. Pottala
OTHERS: H.A. Douglas

UAS DCRT
CG NIILBI
LAS OCR!
LAS nCRT

Cardiology Branch, NHL8I

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This project involves collaboration of LAS, with
Br^nrh NHI Rl . It IS directed toward computer-based

the Cardiology
orocessinq for
ensional

wide-angle, phased array echo-cardiography.

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October 1. 1980 to Septenber 30, 1981

Computer Based Analysis and lnage Processing in Electron
Microscopy and X-ray and Electron-Loss Spectroscopy

PI: H. A. Douglas Computer Systems Analyst
J. L. Costa Medical Officer

OTHERS: E. W. Pottala Elec. Eng.

LAS DCRT
CN BIHH

CSL DCRT

Clinical Neuropharmacology, NIMH, Laboratory of Chemistry, NIADDK

Laboratory of Applied Studies

Hedical Applications Section

DCRT. NIH. Bethesda. Maryland 20205

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This project tnvoWes collabo

t of conputer-based mathematical and

tatistica!

analyses, pattern recognition

data, princi

ally x-ra,s
studieTTn

and electron energy loss spec

Computer-based studies in ultrasonography

This project involves collaboration of LAS, with the
Cardiology Branch, NHLBI. It is directed toward
computer-based processing for image enhancement,
pattern recognition, and three-dimensional
reconstruction from ultrasound data. The principal
sources of data are wide-angle, phased array echo-
cardiography.

Background and Objectives: Ultrasonography allows
non-invasive visualization of many organs without the
hazard of ionizing radiation. Due to its safe nature
and little or no patient discomfort, it is an excellent
tool for screening and multiple repeat follow-up
studies. Unfortunately, the presence of bone, which
is completely opaque to sound waves, and certain
processing practices have limited this technique.
Using the computer, it is possible to overcome or
circumvent many of these limitations. This project is
directed toward ultrasound studies of the heart but
could be expanded later to other organs.

Progress in FY80: The acquisition of real data
requires the development of an esophageal
transducer with interfacing to a minicomputer
system. Lack of staff has resulted in deferment of
this objective until FY82.

Meanwhile development of hardware (DeAnza
System) and software (PICTUR) for general image
processing has continued (see Nuclear Medicine and
Electron Microscopy Sections).

Significance: Patients with hypertrophic
cardiomyopathy have an increased risk of sudden
death. Unfortunately, many of these persons are not
diagnosed ante-mortum because they are
asymptomatic. A reliable technique to screen those
persons with a family history of hypertrophic
cardiomyopathy would be of great use, because
prophylactic drug therapy is probably feasible.
Unfortunately, many different patterns of hypertrophy
appear to exist in the population afflicted.
Techniques are needed to assess the distribution of
hypertrophy in those patients with uncommon
distributions, especially those missed by traditional
M-mode echocardiographic techniques. Additionally,
it is likely that the prognosis may differ among the
various patterns of hypertrophy. The use of this
technique to determine regional wall motion
abnormalities and other parameters of left ventricular
function in patients with coronary artery disease
could prove superior to the techniques of nuclear
cardiology.

Proposed Course: To overcome the above
mentioned problem, a phased array transducer

capable of use in the esophagus will be developed.
This transducer will scan in a transverse plane.
Multiple parallel images can be obtained by moving
the transducer up or down in the esophagus. The
transducer must be small enough to be easily
tolerated by patients and will need to interface to the
Varian electronics. Modifications to the existing
reconstruction software will be made to permit use of
the new images. Additional work is needed to
capture the Varian data for image analysis and
processing by the DeAnza system.

Groups of normal volunteers and patients with
hypertrophic cardiomyopathy or coronary artery
disease will be studied using this new method of
echocardiography.

Publications and Abstracts: None

Computer Based Analysis and Image Processing
in Electron Microscopy and X-ray and Electron-
Loss Spectroscopy

This project involves collaboration of LAS and
several NIH Institutes. It is directed toward the
development of computer-based mathematical and
statistical analyses, pattern recognition, and image
processing of data, principally X-rays and electron
energy loss spectra, derived from biological
specimens studied in an analytical electron
microscope.

Background and Objectives: Microanalysis using
electron and/or x-ray beams is a relatively new tool
in biology which promises to reveal correlations
between structure and function on sub-cellular and
molecular levels. However, the extent to which this
potential can be realized depends critically upon the
use of computer methods, both in the acquisition of
raw data and in the subsequent analysis of the data.

The Microscopic Analysis Section/BEIB in
collaboration with CSL/DCRT is constructing a
facility where digital acquisition of raw data can be
performed. In the meantime several NIH
investigators currently obtain raw data at other sites.
The data is brought back to the NIH campus for
analysis.

Of particular interest are the electron-energy loss
spectra (inelastically scattered electrons) that
contain information about the chemical composition
of the specimen, the back-scattered electrons, and
the elastically scattered electrons (both related to
the mass density of various specimen regions). The
physics of these various types of electrons, as well
as the measured specimen current and secondary
electrons emitted, needs to be elucidated in order to
formulate the proper mathematical or statistical
models that can combine this information into a
'true' or corrected elemental map on a pixel-by-pixel
basis. These models should adjust for contributions
of neighboring pixels as well as a Poisson process in
some cases. The relationship between elemental
(energy-loss) peaks, zero-loss (transmission) peaks,
and the plasmon peaks, as well as the background
contribution, requires further exploration and
quantification.

The potential resolution for chemical analyses of
specimens is in the range of 10-6 to 10-20 gms. and
the spatial resolution is in the order of 100 to 1000
square Angstroms. In addition, maps up to 1024 x
1024 pixels can be constructed. The further
development of this tool will require a new kind of
image processing which will differ radically from the
usual sort applied to nuclear medicine, x-ray devices,

and ultrasound.

An array processor (CSPI MAP200) has been
acquired by LAS. The speed of the array processor
should make several procedures fast enough to
become part of normal analyses. For example, a
complex FFT (1024) can be accomplished in only 20
milliseconds; a Gaussian curve fitting can be
shortened from 8 hours to 10 minutes. Hence, many
image processing algorithms, which can be
developed offline on the DECsystem-10, can
subsequently be implemented on the array processor
and allowed to operate almost in realtime.

Progress During FY81: In FY80 the array processor
was tested extensively and was returned to the
vendor due to faults detected in a number of printed
circuits and in the power supply. In FY81 the array
processor was sent back to NIH, interfaced with the
PDP 1 160 in the BEIB Facility, and tested fully.
Development of analysis programs for it is now
proceeding as originally anticipated.

The DeAnza image processing system has been
enlarged by the acquisition of additional hardware (a
1600 bpi tape drive and an RL02 disk drive) and by
the further development of two major interactive
software packages. (See project report on Nuclear
Medicine.)

The PICTUR package, particularly, has been used
extensively for the investigation of the characteristics
of dense bodies in digitally acquired electron
micrographs of platelets. Assumptions of their
geometry and composition based on their two-
dimensional grey scale images have been
investigated. A subsection of PICTUR, ALIGN, has
been used to spatially align pairs of digitized images;
for example, to produce composite elemental maps
from paired pre-edge and fluorine K-edge filtered
images.

Significance: The ultimate biological goal is to relate
structure and function at the subcellular and
molecular levels. Certain active molecules (e.g.,
enzymes, neurotransmitters, hormones, antibodies,
etc.) can be tagged with appropriate labels (e.g.,
fluorine) and then localized and quantified within
cells by means of this tool. It should also be possible
to determine the distribution of double bonds within
membranes, microtubules, and cytoplasmic
organelles. The distribution of elements of great
biological importance (viz, calcium, magnesium,
nitrogen, sulfur, and oxygen) also can be determined.

Thus, the research potential of this tool has
widespread applications in all areas of biology
concerned with ultrastructure, much as the
development of the imaging capability of the electron
72

microscope itself has provided important insights in
almost every area of biology.

Proposed Course: The study of the basic physics
and the formulation of appropriate mathematical/
statistical models needed to achieve the analytical
capabilities will require extensive work with
phantoms, i.e., specimens of known composition that
are very thin, prepared by such means as vacuum
evaporation. There will need to be extensive studies
of the signal/noise ratio in phantoms and in
biological specimens. Potential problems with
contamination and with specimen destruction by the
high energy beam also need to be studied.
Sophisticated algorithms for element recognition and
location, image enhancement, etc., need to be
designed and, where practicable, implemented on
the array processor for rapid turnaround.

LAS proposes to undertake some of these objectives
in collaboration with participating wet laboratories.
The DeAnza system is to be upgraded from a
maximum image size of 256 x 256 to 512 x 480.
Images acquired at Brookhaven are 512 x 512;
hence this expansion plus the new magnetic tape
drive will allow more rapid processing of the images
obviating the need for data compression or
partitioning.

Publications and Abstracts:

Douglas, M.A., Hui, S.W., Costa, J.L., and Bailey, J, J.: Computerized proc-
essing and subtraction of energy-filtered electron images as an aid to
elemental analysis. In Bailey, G.W. (Ed): Proceedings of the Thirty-
Eighth Meeting EMSA. Baton Rouge, Claitor's Publisfiing Division,
1980, pp 128-129.

Physical Sciences
Laboratory

George H. Weiss, Chief

Summary of Activities

Consulting Services. George H. Weiss (PSL);
James E. Kiefer (PSL); J. Shapiro (CC); A. Pikus
(CC); D. F. Dillon (Walter Reed); M. Brodsky (NIDA).
A statistical analysis of data comparing auditory
deficits in patients with osteogenesis imperfecta,
their families, and normal volunteers has been
completed. Several types of auditory abnormalities
have been shown to characterize both patients and
close family members. These results suggest
audiologic measurements as a useful diagnostic tool.
Analysis of posttraumatic epilepsy in head-injured
Vietnam veterans has led to a simple formula
relating the time to first occurrence of postinjury fits
to a cluster of symptoms. The formula, suggested in
two earlier analyses, will be valuable in estimating
benefits due to victims of head injury. We have
developed a mathematical formalism to describe
data on the rate of entrance of drug addicts to
treatment facilities. The simplest one of a class of
models suffices to describe the rate data for a
number of years with excellent accuracy.

Theory of Biochemical Separation Techniques.

George H. Weiss (PSL). This project applies
mathematical methods to the interpretation of data
from and the design of experiments involving
ultracentrifugation, electrophoresis, and
chromatography. Little, outside of planning for an
experiment to determine optimal methods for
determining molecular weight distributions, was done
this year. On the completion of equipment by Marc
Lewis (BEIB) the experiments will be started.

Actin in Nonmuscle Cells-Biophysical and
Biochemical Studies. Stephen L. Brenner (PSL).
Studies on the mechanism of polymerization of actin
have led to the discovery of monomer actin ATPase
activity. Further kinetic studies are being pursued to
verify a new species of monomeric actin.

Theory and Application of Nuclear Magnetic
Resonance Spectroscopy. James A. Ferretti (PSL);
G. H. Weiss (PSL); J. E. Kiefer (PSL); R. J. Highet
(NHLBI). Experiments utilizing two dimensional
Fourier transform spectroscopy have been

performed on a number of molecules. The technique
allows an order of magnitude of greater accuracy
than the comparable one-dimensional methods. An
investigation of the accuracy of measuring chemical
shifts has been completed and a number of
improvements to present practice have been
suggested.

Correlation Function Spectroscopy/Laser Light
Scattering. Ralph J. Nossal (PSL). Techniques are
being developed for the application of laser Doppler
techniques to measure blood flow in tissue
microvasculature. The theory that has been worked
out has been found in excellent agreement with
experiments on artificial blood cells. A theory is
presently under development for interpreting
experiments on blood flow in muscle.

Cell Motility and Chemotaxis. Ralph J. Nossal
(PSL). Little has been done on this project in the
past year.

Theory and Measurement of Intermolecular
Forces. V. Adrian Parsegian (PSL); M. Prouty (PSL);
B. K. Lee (PSL); A. N. Schechter (NIADDK); R. P.
Rand (Brock University). Measurements of
intermolecular forces in proteins or nucleic acids
using the osmotic stress methods developed in this
Laboratory are now underway. Because sickle cell
hemoglobin has been gelled, the investigators will
undertake a systematic measurement of
thermodynamic data on gelation and crystallization.
B. K. Lee has written a number of programs to
integrate crystallographic data on proteins into a
project that will explore the way that proteins
assemble into more complicated structures.

Studies in Mathematics and Statistics. George H.

Weiss (PSL); J. E. Kiefer (PSL). A review article on
random walks in chemical physics was completed. A
study of order statistics of diffusion processes is
presently underway.

Diffusion of Molecules on Cell Surfaces and Light
Scattering from Fluids. Nahum Gershon (PSL); B.
Aizenbud (MIT). The investigators have found that

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Consulting Services

PI: George H. Weiss. Chief. PSL
James E. Kiefer. PSL, DCRT

DCRT

A. Plkus. M.Sc. CC. OPD: W. f. Caven
Halter fieed; H. Srodsky. NIDA; G. Kno
N.M.; E. Laska. Ph.D., Rockland State

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ed): David Dillon, H.D.,

Physical Sclwces Laboratory

HCI.ON

Division of Computer Research and Technology

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Members of the PSL provide consu

We have cwrcleted a study on the phan
finding that it is effective at dimin
facts. A considerable amount of work

was spent on the
imperfecta. An

several areas of applied

esV^ble streak art!-'' ''"
study of audioloqic
nalysis ot post traumatic

as been developed.

lable data. Several
solved to yield asympto-

epilepsv in head-iniured Vietnam vetc

ans IS being com

uler storage wer

tic formulae.

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4 PSL

Oc'tobeT'Tr 1980 to September 30. 1981

Theory of Biochemical Separation Techniques I

PI; George H. Heiss, Chief. PSL. OCRT I

H. S. Lewis, Ph.D., BEI6, 1. G. Darvey, Ph.D., University of Sydney

Physical Sciences Laboratory

Division of ConDuter Research and Technology

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This project explores the
interpretation of experiments

n biochemistry. Prepar

lions to collec

0 progress

data collection equtpment is 1
Is possible on the conlenolate

mm are being made by D
stalled on Or, Le»is' u
study.

the effect of surface curvature does not greatly
affect diffusion constants calculated using
fluorescence photobleaching recovery methods. The
light scattering spectrum from viscoelastic fluids was
derived.

Quantitative Analysis of the Electronmicroscopy
of Cells and their Plasma Membrane. Nahum
Gershon (PSL); P. Gorden (NIADDK); K. Porter (U.
Colorado); L. Jarett (U. of Pennsylvania). Work is in
progress on the analysis of hormone binding to their
receptors on cell membranes using statistical
analysis of digitized electronmicrographs. In
particular, a study was completed on the spatial
distribution of binding sites by cytochalasins B and
D.

Computerized Typesetting of Scientific Papers.

V. Adrian Parsegian (PSL); N. Crawford (PSL); M.
Douglas (LAS); M. Norton (LAS); M. McNeel (PSL);
P. Miller (OD); J. Prewitt (OD); R. Fajman (CCB); J.
Fajman (CCB). This project is intended to produce
magnetic tape versions of material for publication, for
direct typesetting. A program is presently being
written to write tapes on the IBM System 370 using
WYLBUR. The tape writing program is also being
generalized to prepare manuscripts for several
journals.

Research Projects

Consulting Services

Members of the PSL provide consulting services in
several areas of applied mathennatics and tfie
phiysical sciences to researchers at NIH and
elsewhere. We have completed a study on the
phantom view method in computerized tomography,
finding that it is effective at diminishing certain
undesirable streak artifacts. A considerable amount
of work was spent on the study of audiologic defects
in patients with osteogenesis imperfecta. An analysis
of post traumatic epilepsy in head-injured Vietnam
veterans is being completed and a model that fits
data very well on the rate of occurrence of fits has
been developed. A mathematical model for the
entrance of drug addicts into treatment facilities was
devised and shown to give an excellent fit to
available data. Several combinatorial problems
related to computer storage were solved to yield
asymptotic formulae.

A study of the phantom view method for diminishing
image artifacts due to interpolation in computerized
tomography has been completed with Dr. Rodney
Brooks and a paper has been submitted for
publication.

Study of the occurrence of posttraumatic epilepsy in
a group of head-injured veterans has shown that the
occurrence of epileptic fits in different injury
categories follows a negative exponential distribution
to a good approximation. The incidence varies with
severity of injury but the average time to first fit
appears to be independent of injury. Further work
has gone into planning a second phase of the study
of these veterans, in which as many as possible will
be called in for an extensive examination. Several
questions can then be answered that are presently
obscured by a non-uniform follow up time.

A study of audiologic defects in patients with
osteogenesis imperfecta has shown that there is a
marked excess of audiologic defects both in
diseased patients and in otherwise unaffected close
relatives. Further investigations are planned. Dr.
Susan Hauser, CSL, DCRT, has coupled a digitizer
to the Clinical Center otoadmittance meter allowing
the collection of data with a previously unattainable
accuracy. A study of the features of normal
tympanograms will be undertaken with the new
equipment.

Together with M. Brodsky we have developed a
model for the rate of entrance of drug addicts into
treatment facilities. The model gives a good fit to the
data and allows early prediction of the number of

addicts in a given cohort to use these facilities.

Several combinatorial problems were solved for Dr.
Gary Knott, LSM, DCRT, which will be used in the
analysis of computer data storage algorithms.

Keyword Descriptors: Image reconstruction,
interpolation, computerized tomography, audiologic
defects, osteogenesis imperfecta, mathematical
models.

Publications:

Meirowsky, A M,, Caveness, W. F.. Rish. B. L. Dillon, J. D. Mohr. J. P..

Kisller, J. P . and Weiss, G. H.: Cerebrospinal fluid complicating nnissile

wounds ol the brain. J. Neurosurgery 54:44-47. 1981.
Mohr, J, P., Weiss. G. H , Caveness, W. F., Dillon. J. D., Meirowsky. A. M.,

and Rish, B L : Language and motor deficits following penetrating head

injunes in Vietnam. Neurology 30^273-1279. 1980.
Rish, B, L . Dillon. J D , Caveness. W F . Mohr, J P , Kistler. J. P.. and

Weiss. G. H. The evolution of craniotomy as a debndement technique

for penetrating craniocerebral injuries. J. Neurosurgery 53:772-775,

1980.

Theory of Biochemical Separation Techniques

This project explores the use of mathematical
techniques applied to the interpretation of
experiments in biochemistry. Preparations to collect
data on fractionated serum albumin are being made
by Dr. Marc Lewis. Until data collection equipment is
installed on Dr. Lewis' ultracentrifuge no progress is
possible on the contemplated study.

Keyword Descriptors: Biochemical separation,
ultracentrifugation, enzyme kinetics.

Publications:

Weiss. G H : Can one measure rate constants using chromatographic
melhods'' Separation Sci. 16:75-80, 1981

Weiss, G. H., and Darvey. I. G.: A note on the choice of substrate concen-
tration in enzyme kinetics. J. Theoretical Biology (in press)

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Actin in Nonmuscle Cells - BtODhysical and Bioch

mical Studies

PI: Stephen L. Brenner, Research Chemis
Other: E. 0. Korn. Chief. LCB, NHL8I

Laboratory of Cell Biology. NHLBI

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actin. a major component of the motile apparatus

effects of the drug cytochalasin, which accelera
led to the postulafioJ of a oe. species of monom

olynterization of the protein
ot all eukaryotic cells.

ed. Kinetic analysis of the
es this ATPase activity, have

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October 1, 1980 to Septerrtier 1, 1981

Theory and Application of Nuclear Magnetic Resonance Spectroscopy

PI: James A. Ferretti, Ph.D., Research Cheipist, PSL. DCRT

G. R. Marshall, Ph.D., Professor of Physiology, Department of Physiology |

and Biophysics, Washington University School of Medicine, i

St. Louis. MO
flollie J. Myers, Ph.D., Professor of Chemistry, Department of Chemistry,

University Of California. Berkeley, CA
Oaraes A. Kiefer, and G. H. Weiss, Ph.D.. Chief. PSL. DCRT
R. J. Highet. Ph.D.. Laboratory of Chemistry, NBLBI
Lance R. Pohl . Ph.D.; Terrence A. Marks. Ph.D.; and Jack S. Henson, Ph.O.

Laboratory of Clinical Pharmacology. NHLBI
William M. Egan. Ph.D.. Bureau of Biologies. FDA. Bethesda, MD

Division of Convuter Research and Technology

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The purpose of this project is to develop new me

thods in nuclear magnetic
:ility of existing techni-

and conformational problems in small peptides and pro
is the development of two-dimensional Fourier transfo

blems in organic molecules
rm NHR spectroscopy.

Ihe importance of this technique is that it permits one to restrict one nuclear
parameter to one dimension and a second parameter to the other dimension.
A second part of the project Is to determine best data processing techniques

for precise deteririi nation of chemical shifts.

Actin in Nonmuscle Cells-Biophysical and
Biochemical Studies

Studies were continued on the mechanism of
polymerization of the protein actin, a major
component of the motile apparatus of all eukaryotic
cells.

A monomer actin ATPase activity was discovered.
Kinetic analysis of the effects of the drug
cytochalasin, which accelerates this ATPase activity,
have led to the postulation of a new species of
monomeric actin that may be an essential
intermediate in actin polymerization.

Actin is one of the major proteins of the cytoskeleton
of all eukaryotic cells. As such, it is involved in many
different motile processes and in the regulation of
cell shape and cell organization. Actin is a globular
molecule of molecular weight 42,000 that
polymerizes into double helical filaments under ionic
conditions similar to those of the cytoplasm of cells.

It is in this polymerized form (microfilaments) that
actin presumably functions in non-muscle cells just
as it is the polymerized form of actin (the thin
filaments) that functions in muscle contraction. In
contrast to the situation in muscle, most of the actin
in non-muscle cells is unpolymerized and its
polymerization is spatially and temporally regulated
so that the microfilaments occur in the cell when and
where they are needed for specific motile events.
The regulation of actin polymerization has been the
focus of our research this year.

1 . Identification of a new species of monomeric
actin. We have shown in the past two years that the
cytochalasins, a group of natural products that are
potent inhibitors of a variety of motile processes in
eukaryotic cells, have pronounced effects on actin
polymerization in vitro. One of these effects is the
uncoupling of actin ATPase activity from actin
polymerization. Normally, when polymerization
occurs, a monomer actin bound ATP is hydrolyzed to
polymer bound ADP. Cytochalasins greatly increase
the rate of ATP hydrolysis even while inhibiting actin
polymerization. We have now shown that this effect
is due to the acceleration of a monomeric actin
ATPase cycle, which can exist independent of the
ATPase associated with monomer addition to
polymer. Kinetic analysis of the effects of four
cytochalasins on actin from two sources (rabbit
muscle and Acanthamoeba, a soil amoeba) requires
the existence of an until now unknown species of
actin monomer. Formation of this intermediate is the
rate determining step in the monomer ATPase cycle
when cytochalasins are present. In the absence of
cytochalasins, disappearance of this intermediate is

rate limiting. The coupling of the monomer ATPase
cycle to the polymerization of actin, and the possible
role of the newly discovered actin species as an
obligatory intermediate in actin polymerization, are
under investigation.

2. Equilibrium Studies of Actin Polymerization. It is
now clear that the polymerization of actin ATP is
extremely complex (see above). Actin with bound
ADP will also polymerize. The result is an equilibrium
system of actin filaments (containing bound ADP)
and monomeric ADP actin. The ADP actin system
may provide a useful tool for understanding actin
polymerization since it uncouples the polymerization
process from the hydrolysis of nucleotide in an
equilibrium, rather than a steady-state system. We
have begun a detailed study of ADP actin
polymerization using the techniques of
ultracentrifugation, high-shear viscometry, and light
scattering.

Because ATP hydrolysis is not obligatory for actin to
polymerize, and because cellular energy stores are
depleted when ATP is used, we continue to search
for a role for nucleotide hydrolysis in actin
polymerization. It is possible that it is at the level of
the monomeric actin, and not the hydrolysis
associated with polymerization per se, at which
regulation is affected. Efforts will be made to
examine this idea through the use of
nonhydrolyzable ATP analogs, cytochalasins, and
inhibitors or promoters of actin ATPase activity as
well as purified proteins known to have direct effects
on the state of actin assembly.

Keyword Descriptors: polymerization, actin,
cytochalasin, cytoskeleton, eukaryotic.

Publications:

Brenner. S- L-, and Korn. E. D: Stimulation of actin ATPase activity by
cytochalasins provides evidence for a new species ol monomenc actin.
J. Biol. Chem. (in press).

Theory and Application of Nuclear Magnetic
Resonance Spectroscopy

The purpose of this project is to develop new
methods in nuclear magnetic resonance
spectroscopy, to extend and determine the utility of
existing techniques, and to apply these techniques to
structural problems in organic molecules and
conformational problems in small peptides and
proteins. Of current interest is the development of
two-dimensional Fourier transform NMR
spectroscopy. The importance of this technique is
that it permits one to restrict one nuclear parameter
to one dimension and a second parameter to the
other dimension. A second part of the project is to
determine best data processing techniques for
precise determination of chemical shifts.

Since the acquisition of the NT-360 NMR
spectrometer 18 months ago, we have been carrying
out various experiments on complex organic and
biological molecules, which were heretofore
impossible. The major emphasis in this project has
been the application of multiple pulse and two-
dimensional Fourier transform NMR spectroscopy.
The principal idea behind multiple pulse experiments
is to map out the behavior of the nuclear
magnetization during an evolution period as well as
during a detection period after the last radio
frequency pulse. Because this permits many choices
for the second frequency axis, the advantages of
two-dimensional spectroscopy are numerous and
include: correlating frequencies of pairs of nuclei to
simplify assignments, improving spectral resolution,
measuring cross relaxation processes for distance
determinations, and studying multiple quantum
coherence phenomena.

In one study, we have determined the structures of
two stereoisomeric metabolites isolated by HPLC
from the bile of rats treated intraperitoneally with
bromobenzene. The 2D J spectra of both
metabolites permitted complete resolution of all the
transitions and allowed us to carry out the
assignments of lines. These results demonstrated
that the metabolites were formed by the opening of
aryl epoxide intermediates by glutathione. This study
also enabled us to demonstrate the feasibility of
studying spectra in the presence of a strong water
peak.

We are applying a three-pulse experiment followed
by a two-dimensional Fourier transformation to
investigate cross relaxation pathways in rigid organic
molecules. Cross relaxation analysis allows the
estimation of internuclear distances, yields rotation
correlation times, and produces information on
molecular complexes. We have carried out such

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Correlation Functiwi Spectroscopy/Laser Light Sc

ttering

PI: R. J. Hossal, Ph.D.. Research Physicis

■ "'•• °"^

J. Gladner, Ph.D.. LBC. NIAODK
fl. Bopner. Ph.D.. BEIB, DPS

0{.)«iii.i.

E.per™enta, and the.ret.ca

1 Studies have been

ioloqical qeJs. viscoelastic

p.l,»er s.1„?io»s. a.P silla

s also are being pertonned

blood flp» in tissue r.icro«asculatore.

ZOI CT 00017-09 PSL

Cell Motility and C

I Septenter 30. 1981

, J. Nossal, Research Physicist, PSL. DCRT

DW<sif»n of Conputer Research and Technoloi

>loped. Mathematical i

studies on veratraldehyde and a series of Enkephalin
analogs. Specific interactions are demonstrated in
the Enkephalen derivatives. We are attempting to
quantitate the results on veratraldehyde in order to
evaluate the competitive inter- and intramolecular
dipolar contributions to the nuclear Overhauser
enhancement factor.

We are continuing to study molecular motions in
oligopeptides using spin-lattice relaxation times, spin-
spin relaxation times, and NOE factors as vi^ell as
using the two-dimensional techniques for structural
investigations on these systems. We are attempting
a complete assignment of the proton spectrum of
Bleomycin. We have carried out a complete
temperature and field dependence study on
Bradykynin and evaluated the motional parameters.
We have also carried out a study on liver alcohol
dehydrogenase, by investigating the cadmium-113
chemical shifts where the cadmium-113 replaced
Zinc at both the catalytic and non-catalytic sites. We
are attempting to learn more about the nature of the
metal ion coordination at the catalytic site.

We have investigated, by a simulation study, the
error in measured chemical shifts when various
strategies are used for filtering and smoothing the
data and for estimating peak position. We have
found that curve-fitting the data in a neighborhood of
the observed maximum is always considerably more
accurate than simply choosing the position of the
peak maximum as the true maximum. Further, the
use of a matched filter leads to a considerable
improvement over the use of no filter, and the
improvement is not sensitive to the choice of filter
constant.

Keyword Descriptors: Nuclear Magnetic Resonance,
two-dimensional, Fourier transform, bile metabolite,
liner alcohol dehydrogenase. Enkephalin.

Publications:

Egan. W., Ferretti, J. A., and Marshall, G. R.: Relaxation parameters and
motional properties in biological macromolecules. Bui/. Magnet. Reso-
nance 2■.^5-^^ , 1981.

Ferretti, James A., Highet, Robert J., Pohl, Lance R., Marks, Terrence R.,
and Hinson, Jack A.: Application of 2D J-resolved spectroscopy in the
structural investigation of bile metabolites. Abstract, 22nd Experimental
NMR Conference, 1981.

Gupta, R. K., Ferretti, J. A., Becker, E. D., and Weiss, G. H.: A modified fast
inversion recovery technique for spin-lattice relaxation measurements.
J. Magnet. Resonance 38:447-452, 1981.

Weiss, G. H., Ferretti, J. A., and Kiefer, J. E.: A study of precision in the
measurement of chemical shifts. J. Magnet Resonance (in press).

Correlation Function Spectroscopy/Laser Light
Scattering

Experimental and theoretical studies have been
performed to develop laser inelastic light scattering
methods for studying biological gels, viscoelastic
polymer solutions, and similar materials. Studies also
are being performed in order to understand how
laser Doppler techniques can be used to measure
blood flow in tissue microvasculature.

Quasielastic light scattering has been used to study
dynamical properties of various biological substances
and model systems. Emphasis has been on
developing novel applications of this relatively new
technology and on devising physical and
mathematical theories in support of experimental
protocols. Current work continues on schemes for 1)
non-invasive surveillance of blood flow and 2) non-
perturbative probes of the mechanical properties of
soft polymer gels similar to those found in biological
cells and within tissue interstitia.

A collaboration with R. Bonner (BEIB, DRS) and P.
Bowen (NHLBI) has resulted in publication of a
theory which relates quasielastic light scattering
measurements to blood flow in tissue
microvasculature. This theory accounts for diffuse
scattering by immobile tissue constituents and for
multiple interactions of photons with moving blood
cells. The theory has been tested with an
experimental analog in which particles flow through a
fiber capillary bundle imbedded in a composite gel,
the latter containing polymer microspheres which
impart optical properties characteristic of those of
biological tissue. Dr. Bonner and Mr. Bowen have
been using their laser Doppler flowmeter in various
clinical studies and we have continued to collaborate
on related theoretical and experimental problems.
Attempts currently are being made to provide a
theory for interpreting measurements of tissue blood
flow in moving heart muscle.

Efforts to apply quasielastic light scattering to
studies of dilute polymer networks recently have
involved improvements in instrumentation and
development of methodology for measuring lattice
damping parameters ('internal viscosity'). An
apparatus has been constructed to facilitate torsional
excitation of a sample by an external mechanical
field. Also, a fiber optics version of the spectrometer
has been developed which promises to be
particularly useful for studying small specimens. Data
have been acquired to characterize the dependence
of internal dissipation on such variables as polymer
concentration, crosslink density, and solvent
viscosity; also, we have begun work on a theory to
relate those measurements to microscopic physical

properties of a gel. Our collaboration with Dr. J.
Gladner (NIADDK), on studies of the biophysical
chemistry of polymer networks which arise during
blood coagulation, has been reinitiated.

Keyword Descriptors: Laser light scattering
macromolecules, diffusion coefficients, correlation
functions, gels, blood flow, Doppler flowmeter.

Publications:

Bonner. R . and Nossal. R : A model (or laser Doppler measurements o(
blood (low in tissues Applied Optics 20:2097-2108. 1981

Nossal, R : Quasielastic light scaltenng from polymer gels. In Chen. S H .
Chu, B, and Nossal. R. (Eds.); Scallenng Techniques Applied to Supra-
molecular and Nonequilibnum Systems. New York. Plenum Publ. Corp.,
(in press),

Nossal, R . and Jolly. M Shear waves m cylindrical gels J AppI Phys (in
press)

Cell Motility and Chemotaxis

This project has been undertaken to study vanous
aspects of cell locomotion, including the
mathematical basis of macroscopic assays for
leukocyte chemotaxis. New procedures for
measuring parameters of cell migration, including
computer assisted tracking techniques, are being
developed. Mathematical relationships between
microscopic cell motion and macroscopic response
are derived.

This study relates to cell locomotion and chemotaxis.
Recent emphasis has been on examining certain
immunologic aspects of leukocyte migration and on
constructing physical models of signal transduction
occurring at the surfaces of chemoresponsive cells.

During the past year this project has been carried on
with reduced effort while laboratory personnel have
been otherwise occupied (cf. project Z01-CT00021-
10 PSL). Literature searches have been performed in
order to identify in vitro models of polymerizing
cytoskeletal structures which might be amenable to
study by recently developed quasielastic laser light
scattering techniques. Attention also has been given
to assimilating information on physical theories
concerning detection of chemotoxins by receptors at
the surfaces of motile cells. A previously prepared
review of mathematical theories of chemotactic
responses was published.

Keyword Descriptors: Cell locomotion, leukocyte
chemotaxis, capillary migration assays.

Publications:

Nossal, R.: Mathematical theones of topotaxiS- In Jager. W,. Rost. H., and
Taulu, P (Eds): Biological Growth and Spread Mathematical Theories
and Applications Heidelberg. Spnnger-Verlag. 1980. pp 410-440.

ZOl CT 00026-06 (

October 1. IMP to September

in. Ph.O.. PSL. DCRT

.0.. PSL. DCRT

1.0.. Brock Universitj

. N. Schechler, H.D., LCB. NIflDDK

Physical Sciences laboratory

Division of Cotrputer Research ;

*ojEcrilSatfi'B"iioir'S!If*'hhI l^^"

ilfilss^ffiiicT

201 CT 00024-06 PSL

October 1, 1980 to September 30. 1981

Studies in Mathematics and Statistics

PI: Georqe H, Weiss, Chief. PSL. DCRT
Other: James E. Kiefer. PSL. OCHT

Ph.D., Univ. of Ca1 ifnrnia-San Diego; K. Lindenberq. Ph.D., Univ. of California-
San Dieqo; J. Rice. Ph.D., Univ. of Ca1ifornia-San Oiego; M. F. Shlesinger,
Ph.D.. Univ. of Maryland. College Park.

Physical Sciences Laboratory

lECIlC*

Oivtsion of Computer Research and Technology

'o.a 1 ' ols \' 0.3

:j(.J «u««;wBJtctS a i») HUKU. nssut! □(O-eiiwh

A co<nirehens(ye reylew
logles tn chemical physics i

rticle on the applications of random walk methodo-
in the orocess of completion. A study of. some

oroblems related to the

matching of DNA sequences

Theory and Measurement of Intermolecular
Forces

Our capacity to determine intermolecular forces in
aqueous or physiological milieux now covers proteins
and nucleic acids as well as phospholipid bilayer
membranes. There is good evidence that hydration
forces dominate interactions near contact. These
forces are due to the disturbance of water by
charges on the exterior of large molecules or
aggregates.

Exponentially decaying hydration forces, first
characterized quantitatively between bilayer
membranes, are typically repulsive. They depend on
the chemical identity and packing of water polar
soluble groups on the membrane surface. They
vanish when an opposing body sticks more strongly
to these water soluble groups than does water.

Measurements of intermolecular forces in proteins or
nucleic acid are now underway using osmotic stress
methods developed for membranes. Evidence is
strong for the action of hydration forces between
parallel DNA double helices.

Programs written on the DCRT molecular display
system are being developed to examine contacts
between proteins in crystals and between nucleic
acids in condensed arrays.

Our activities this year have been to examine the
consequences on membrane processes of earlier
measurements of forces between bilayer membranes
and to develop several methods for identifying and
measuring forces experienced by proteins and
nucleic acids.

Beginning from the systematic determination of
electrostatic, dispersion, and hydration forces
between a large range of phospholipid bilayer
membranes, we have been able to correlate the
intermembrane forces with the ability or inability of
vesicular membranes to fuse. Exponentially growing
hydration repulsive forces dominate below 30
angstroms separation. Their strength varies with the
density and identity of water soluble groups on the
membrane surface. This repulsive force collapses
upon addition of substances, such as calcium, with
phosphatidylserine membranes that bind more
strongly than does water to these water soluble
groups.

Electrostatic interactions, seen beyond 20 to 30
angstroms membrane separation, almost follow the
behavior expected from double layer theory. A
systematic deviation from that theory gives evidence
for perturbation of water structure around ions in
solution.

Methods of measurement analogous to those used
to determine membrane-membrane forces are now
successfully being applied to the aggregation,
gelation and crystallization of proteins and to the
packing of parallel double helical strands of DNA.
Sickle cell hemoglobin has been successfully gelled
(Prouty, Schechter) under conditions where one can
measure the work of removal of water from the
protein and water mixture. Systematic collection of
thermodynamic data on gelation and crystallization
now appears feasible. Similarly measurements on
the repulsive force versus separation curve for
parallel DNA helices are now in progress.

These molecular studies are complemented by a
major study of protein and nucleic acid contact using
the DCRT molecular graphics facility. To this end a
computer program has now been written (Lee) to
construct protein crystal structures by combining
atomic coordinates with the crystal symmetry. As in
previous studies of contacts stabilizing protein
dimers and tetramers, the stable association of
peptides involves close approach and tight fits. We
expect that the lessons learned from these studies
will be helpful in work anticipated on the self
assembly of elaborate protein structures.

Keyword Descriptors: phospholipid bilayer
membranes, hydration forces, electrostatic forces,
dispersion forces, ionic solutions, protein gelation,
nucleic acids.

Publications:

Lis, L. J.. Lis. W T.. Parsegian. V A., and Rand. R P.: Adsorption of
divalent cations to a variety of phosphatidylcholine bilayers. Biochemis-
try 20^77^■^777. 1981

Lis, L, J,. McAlister, M,. Fuller, N.. Rand, R. P., and Parsegian. V A.;
Interactions between neutral phospholipid bilayer membranes. Biophys
J. (in press)

Lis, L. J.. McAlister, M . Fuller. N,. Rand, R, P, and Parsegian. V.A.:
Measurement ol the lateral compressibility ol several phospholipid bi-
layers. Biophys J (in press).

Lis. L J,. Parsegian, V A , and Rand. R P.: Binding ot divalent cations to
dipalmitoylphosphatidylcholine bilayers and its effect on bilayer interac-
tion, S/oc/7ems/ry 20:1761-1770. 1981

Parsegian, V. A,: Forces between membranes approaching contact. Scandi-
navian J. ol Clinical Investigation A^ MS. 39-47,1981.

Parsegian. V, A,. Rand. R. P . and Slamatoff. J : Perturbation ot membrane
structure by uranyl acetate labeling. Biophys- J. 33:475-478, 1981

Parsegian, V. A., and Weiss. G H.: Spectroscopic parameters for computa-
tion of van der Waals forces. J, Colloid interlace Sci. 81:285-289. 1981.

Studies in Mathematics and Statistics

A comprehensive review article on the applications
of random walk methodologies in chemical physics is
in the process of completion. A study of some order
statistics related to random walks and diffusion
processes has been completed. Several statistical
problems related to the matching of DNA sequences
are under investigation.

A review article on random walks in chemical
physics is being completed and will be submitted to
Advances in Ciiemical P/iysics. In addition we have
applied some rigorous results on the number of
distinct sites visited in a finite random walk to the
study of materials with trapping sites. Together with
R. J. Rubin we have developed statistical results on
the probability of visiting a set of points by a lattice
random walk and with M. F. Shiesinger we have
studied properties of the expected number of distinct
sites visited during an n-step lattice random walk.
We have studied order statistics of diffusing
particles. Together with K. E. Shuler we are
analyzing combinatorial problems related to the
matching of DNA sequences. These problems are
currently studied by simulation techniques, leading to
results of questionable generality, but some analytic
progress is possible and some results on matching
probabilities have been obtained.

Keyword Descriptors: Random walks, diffusion
processes, trapping sites, first passage time
problems, sequence matching.

Publications:

Kiefer, J E., and Weiss, G H,: A companson ol two methods lor accelerat-
ing the convergence of Fourier series Computers and Mathematics (in

press).
Lindenberg. K., Seshadn, V E., Shuler. K E,, and Weiss. G. H.: Lattice

random walks for sets of random walkers J. Statistical Physics 23:11-

25, 1980
Oppenheim. I . Shuler. K E . and Weiss. G H.: Stochastic processes. In

Lerner. R G . and Trigg. G L (Eds ): Encyclopedia of Physics. New

York, Addison-Wesley. 1980. pp. 964-967
Weiss. G. H : Asymptotic form for random walk survival probabilities on 3-D

lattices with traps Proc Natl Acad. Sa. USA 77:1273-1274, 1980.
Weiss. G H First passage times for one dimensional random walks. J

Statistical Physics 24:581-589. 1981
Weiss. G H Note on lattice random walks with an excluded point. J.

Mathematical Physics 22 562-563, 1 981 .
Weiss. G, H., and Shiesinger. M, F : On the expected number of distinct

points in a subset visited by an N-slep random walk. J. Statistical

Physics (in press).

sssris.

:ipa IWMMIIW tlCH^EE

.uu'\"oX»l.?..ci.

«,o.Ec. H^m

ZOl CT OOOai-03 PSL

'"«"»;'"

. 1980 to Septerrber 30. 1981

QMntita
Hsabnne

l,e An.l,s s of the ElectronmKroscoor of Cells and their Plas«a

"f" ^ ^ ,„,s'eiTpr"rr'""°'"'"

Other:

n •; hool of Medicine, Philadelphia,

P to NIADDK

r' ''"'' Sv't^^'-l^nd ^

' P C Ph 0 n . s !y Of Colorado. Bo.lder. Colorado i

Ht ssberaer Ph 0 PSL DCRT

Physical

Sciences Laboratory

of Computer Research and Technolociy

1.8 1 0.7 1 0.1 i

,»( BO«[£S)

.(.) ««•»

WB«rS aWHWU-KSSUtS DIOMIIHEB

Gl.D "..-.ufi

(.J) iNitR.^f.:,

af r.l".

Ss^rmernbra^irS^e^OTfd^q°mon5meric^"^ |

etJ on rat adipocyte eel! surfaces while thev are uniformly distributed 1

groups a

Se's^cr/parVjr:.

'es and coalef pits on

ad'poc?te-likI fibroblasts.

of oo'rw.lr1zan™ JeliLr' ""^cSleclilS' .n'ceik

has heen pursued usinq

of mcrtr

'ins^drcells°anrits

qanizalion and oolvmeruation of cytoskeletal

relation to transmembrane siqnalling.

I Septeniber 30. 1981

Diffusion of Molecules on Cell Surfaces and Light Scattering from F

T!!!!S

At-^or

etical study was....-

,...,,

photob leach

nq recovery, f^,,

mentranes. u «.i.
not affect the _. :.

In the

second part hydrodyriamic
astic fluids were derive

equations

viscoelastl

fluids were studied.

Quantitative Analysis of the Eiectronmicroscopy
of cells and their plasma membranes

In this study, the distributions of insulin binding sites
on the surface of rat adipocytes and liver plasma
membranes were studied using monomeric ferritin-
insulin viewed by eiectronmicroscopy and analyzed
by newly developed quantitative methods. It shows
that insulin binding sites are non-randomly distributed
on rat adipocyte cell surfaces while they are
uniformly distributed on liver plasma membranes.
The quantitative characteristics of the receptor
groups and the mode of action of cytochalasin B and
D have been elucidated.

In the second part we have been looking at the
organization of intramembraneous particles on
lymphocytes and coated pits on adipocyte-like
fibroblasts.

In the third part of this investigation, the three
dimensional structure of polymerization centers for
macromolecules in cells has been pursued using
three-dimensional reconstruction and image analysis
techniques.

The fourth part is an experimental study of the
effects of aggregation of membrane proteins on the
organization and polymerization of cytoskeletal
elements inside cells and its relation to
transmembrane signalling.

We have developed quantitative methods to analyze
electronmicrographs of biological systems. The
methods include digitization of micrographs and
computational analysis of their contents (e.g., protein
particles on membranes).

The binding of hormones to their receptors on cell
membranes is believed to be the first step in their
biological action. Insulin binding sites appear in
groups on the plasma membranes of rat adipocytes
and as separated sites on rat liver plasma
membranes. These configurations are seen on
electronmicrographs of these membranes using
insulin bound to monomeric ferritin particles. The
present study used computer analysis of the spatial
distribution of these insulin binding sites and of the
effects on this distribution by the disrupting agent
cytochalasin B and also by cytochalasin D. This
study points out that the distance between adjacent
sites in a group does not seem to exceed 400
angstroms. Also, the relative change by Cytochalasin
B in distribution of this insulin preparation in groups
of 1 , 2, and 5 or greater was not affected by the
defined separation distance (at least up to 600
angstroms) used to define a group. Cytochalasin B
appears to disrupt portions of groups of insulin
without regard to distances between adjacent

receptor sites within a group. Computational analysis
of nnorphological studies on insulin and other
receptors should provide more information than
visual analysis.

To further the understanding of insulin action,
experiments are done on fibroblasts transformed into
adipocyte-like cells. These cells look and respond to
insulin as do adipocyte cells. Coated pits were
inferred to participate in the mechanism of insulin
action in some cells. We would like to study the
reorganization of coated pits on membranes of ceils
undergoing this type of transformation and examine
what the changes are in spatial distributions on the
membranes during this kind of differentiation. This is
part of a broader study of the membrane's structure
in the undifferentiated and in adipocyte phenotype of
the 3T301 cells.

A three-dimensional arrangement of some cell
organelles is important to cell function. At the
present time electronmicroscopy is the only method
available to visualize microfilaments, microtubules,
and cell membranes at sufficient resolution to study
their arrangement and interrelationships. Using
electron micrographs produced by the high voltage
electron microscope (a national resource sponsored
by NIH) in Boulder, Colorado; the new digitizing
system being constructed at PSL; and the
computational facilities at DCRT; the three-
dimensional location of organelles in cells is being
measured and their structure is going to be
elucidated. This will shed light on what determines
and maintains cell form in normal and malignant
cells. This work is done with R. Nossal, K. Porter, B.
Bowers and M. Weissberger. The method has been
developed and the analysis of the data has been
initiated.

Membrane proteins can interact with various
components inside the cell, e.g., cytoskeletal
elements. We have looked for possible physical
mechanisms to account for the attachment of
membrane proteins to cytoskeletal filaments, e.g., by
entanglement or by polymerization of cytoskeletal
elements around aggregated membrane proteins.

There are some indications, on the visible light
microscopic level, that these cytoskeletal structures
are affected by changes in the location of cell
surface proteins. We have developed an electron
microscopic method that makes it possible to
observe these structures inside the cell. In order to
enhance the visibility of the cytoskeletal
microfilaments we use the Evans & Sutherland
facilities for image display and analysis. With this
method we plan to quantitate the amount and
morphology of cytoskeletal elements. In doing so.

changes in the cytoskeleton will be detected and
correlated with changes in cell surface proteins.
These studies might shed light on how signals are
transferred through membranes to cell interiors.

Keyword Descriptors: Insulin binding sites, insulin
receptors, cytochalasin B, membrane proteins,
electronmicroscopy, coated pits, high voltage
electronmicroscopy, digitization of
electronmicrographs, cell surfaces, microfilaments,
cytoskeleton.

Publications:

Gershon. N D . Smith, R M . and Jaretl, L : Computer assisted analysis o(
fernlininsulin receptor sites on adipocytes and the effect of cytochala-
sin B on groups of insulin receptor sites. J. Membr. Biol 58:155-160,
1981

Diffusion of Molecules on Cell Surfaces and Light
Scattering from Fluids

A theoretical study was carried out to determine the
rate of cell surface curvature on the observed
diffusion rate of membrane proteins using
fluorescence photobleaching recovery. For with a
similar geometry to natural microvillous membranes,
it was found that the assumption that the membrane
is curved does not affect the calculated diffusion
constant to a large extent.

In the second part, hydrodynamic equations and the
light scattering spectrum from viscoelastic fluids
were derived. Two cases, fluid-like and solid-like
viscoelastic fluids, were studied.

A. Diffusion of Molecules on Cell Surfaces.
Fluorescence photobleaching recovery (FPR)
techniques have been used to study lateral
movement of molecules on membranes. Fluorescent
molecules within a circular spot are bleached and
the time dependence of the fluorescence recovery in
the spot is measured. The physical interpretation of
these results in terms of diffusion along the
membranes is based on the assumption that the
surface is planar. However, biological membranes
may be nonplanar, e.g., they may have blebs and
microvilli. To study the effect of nonplananty on the
diffusion rate, the diffusion equation for motion on
curved surfaces was derived. This equation was
employed in studying the diffusion along a 'wavy'
surface of the form Acos(kx)cos(ky). The numerical
calculations show that for k = 10 (micrometers)-l and
a bleached spot of 1 micrometers in diameter, the
time dependence of the intensity of fluorescence in
the bleached spot depends on A at low values of A
(0, .1, and .5 micrometers) while the dependence on
A at higher values of A (.5 compared with 1 and 2
micrometers) is weak. Assuming that the membrane
is planar, the interpretation of FPR measurements

riled Typesetting of Sct«

ZOl CT 00066-OZ PSL

lalyst, LAS. OCRT

lioohysical Journal, Goverr

1 nf Coirputpr Rpsparch and TechnolDgs

The object of this project is to be able to produce magneti
laterial intended for publication. Those tapes can be "hung"
copy editing/typesetting computer systems of the publisher.

ii writing progrd

way of retyping maten

in page charges I

might yield a diffusion constant that is 40 percent
(for A=1) of the real diffusion coefficient along the
curved surface. These results suggest that the
transition fronn a plane to a surface with small
microvilli slows the diffusion process while the
transition from small to large microvilli practically
does not affect the diffusion rate of molecules in the
bleached area.

B. Light Scattering from Microelastic Fluids.
Viscoelastic systems, as all other macroscopic
systems, can be studied by phenomenological and
statistical approaches. The common
phenomenological approach consists of three
stages:

1 . The finding of the stress-deformative structure
of the system

2. The construction of differential equations of
motion. [This construction usually involves some
phenomenological (transport) coefficients.]

3. The carrying out of some, usually mechanical,
experiments estimating values for these
coefficients.

However, this scheme may not always be applied.
The problem is that there is a wide class of fluid
systems, namely, overcooled liquids, which do not
permit (because of their instability) usual rheological
experiments in order to define their structure. For
such systems, nonmechanical experiments became
very important.

In this work we continued the phenomenological
study of the two simplest viscoelastic systems:
Kelvin body (the solid-like system) and Maxwell body
(the fluid-like system). We generalized and corrected
the dynamical equations for these systems and
calculated the vertical-horizontal (VH) spectrum of
light scattered by these systems. We found that the
form of these spectra can sometimes uniquely define
the structure of the system.

For the solid-like system we have derived the
hydrodynamic equations and the VH light scattering
spectrum using a molecular approach.

Keyword Descriptors: Membrane proteins mobility,
lateral diffusion, microvilli, fluorescence
photobleaching recovery, light scattering,
hydrodynamic equations, viscoelastic fluids.

Publications:

Aizenbud, B. M.. and Gershon. N.D.: Hydrodynamic equations and VH light
scattering from viscoelastic (solid-like and fluid-like) systems. Pfieno-
menological approach. Physica A (in press).

Computerized Typesetting of Scientific Papers

The object of this project is to be able to produce
magnetic tape versions of material intended for
publication. Those tapes can be 'hung' directly on
the copy editing/typesetting computer systems of
the publisher.

Our method is to write programs using WYLBUR files
as source material that will produce magnetic tapes
to the specifications of each publisher. The
execution of these tape writing programs should be
as simple as requesting a paper copy of the same
text.

Such electronic conversion of texts has been shown
to be cheaper, faster, and more accurate than the
old way of retyping material by the publisher.
Typesetting costs can be halved. Already one journal
is offering a major discount in page charges to
authors submitting 'compuscripts.' Others should
follow. The ultimate savings to NIH are expected to
be significant.

It has been shown that the texts of many if not most
of the scientific papers produced on magnetic
memory typewriters ('word processors') at NIH can
be transferred into the WYLBUR system. Many
papers are also keyed directly into WYLBUR. A
program by Bonnie Douglas and Martha Norton is
being used and improved by Nancy Crawford to
produce magnetic tape records of such texts. These
tapes are then suitable for text conversion
electronically to typeset galleys without retyping
manuscripts.

Our early success in producing a paper (by John
Fletcher, LAS/DCRT) in this way has lead to an
agreement with the Biophysical Society, its publisher
Rockefeller University Press, and its printer Science
Press, to supply us with magnetic discs, cards or
tapes of papers for experimentation. The object here
is to obtain material in order to learn to transfer
various forms of magnetic record into the WYLBUR
system and then to produce typesetter-ready
magnetic tapes from WYLBUR.

The original tape writing program is being transferred
by M. McNeel from the PDP-10 system to the IBM
370 system to allow direct writing of tapes using
WYLBUR command procedures. Features of the
new WYLBUR system are being incorporated to
allow far more efficient tape writing. The tape writing
program is being generalized to prepare material for
other publishers. Initial experiments have been
performed by Waverly Press under the auspices of
the Journal of Biological Chemistry and a new
collaboration is being established with the Computer
Society.

With the automatic conversion of texts that would
otherwise be laboriously retyped and with the
likelihood that publishers' copy editing can now be
done at a terminal rather than on paper copy, the
new system provides speed, accuracy and cost
savings. Consequent reduction in page charges is
already a fact with the Biophysical Journal. Other
journals appear ready to grant similar reductions
when similar procedures are available.

Keyword Descriptors: computer typesetting,
WYLBUR, computerized composition, magnetic tape,
floppy disc, magnetic card, compuscripts.

Publications: None.

Data Management
Branch

J. Emmett Ward, Chief

Summary of Activities

Clinical Information Utility (CIU). Clinical Support
Section (DMB). This ongoing major effort nnaintains a
data base for research and patient care in the NIH
Clinical Center. During this past fiscal year a number
of improvements were made: the Surgical Pathology
subsystem and database were fully implemented
using the SNOP System to encode the diagnoses;
the general design of an integrated database was
completed; a subsystem was defined, designed, and
implemented for purging cumulative laboratory data
from the weekly production runs; software was
developed for producing final cumulative laboratory
summaries; several modifications were made to the
CIU that reduce the run and connect times for
producing the weekly laboratory summaries and
updating the databases; and a subsystem was
designed to preprocess clinical laboratory data for
the integrated database.

Combined Cardiology/Heart Surgery Data
System. Larry Martin (DMB/ASPS); Roger Dailey
(DMB/DBAS); C. Mcintosh (NHLBI); D. Rosing
(NHLBI). This combined system provides a
chronological record of the medical activity of NHLBI
Cardiology and Heart Surgery Branch patients. In
FY81 effort was directed toward meeting the routine
and ad hoc reporting requirements and new
statistical needs of the NHLBI physicians and
researchers and the system was expanded to
include nuclear angiogram information. An online
private disk was assigned to the project during the
year to improve data query and analysis response
time.

Pulmonary Function Data System. Judy Mahaffey
(DMB/ASPS); Ronald Crystal (NHLBI/IRPB); Larry
Nadel (DCRT/CSL). The Pulmonary Branch of
NHLBI has requested the development of a
combined computerized data base for pulmonary
function and exercise testing data to replace existing
separate ones. It is planned that the system will
interface a NOVA and an LSI-11 minicomputer. This
year analysis was completed and a design proposal
was prepared during the last year.

Analysis of SLE Nephritis Patients. George
Shakarji (DMB/OC); John H. Klippel (NIADDK); John
Decker (NIADDK). The storage phase of the
development and implementation of this ongoing
project is now completed with major modifications
included. The system has the capability of storing
and retrieving chemistry and therapy data on all SLE
(Systemic Lupus Erythematorus) nephritis patients.
Data on a subset of SLE patients, participating in the
immunosuppressive trials and assigned to receive
either prednisone only or the combination of
prednisone and cyclophosphamide, are now being
studied to evaluate certain chemistry constituents.

Multivariate and Univariate Forecasts for Blood
Constituents. George Shakarji (DMB/OC); Eugene
K. Harris (DCRT/LAS). This study, which is part of
continuing studies on variability of blood chemicals in
normal people, uses data compiled through the
health maintenance program in Japan. The database
includes 15 to 18 semiannual values for 6
biochemical tests in over 16,000 men and women
between the ages of 20 and 70. Programming for
this study involved univariate and multivariate time
series systems. Programs were completed to
compute homeostatic and random walk (non-
stationary) models for both the univariate and
multivariate analyses. All of the methodologies were
applied to the database to compute and compare
results and predictions.

Psychobiology Patient Information System.

Dennis George (DMB/ASPS); Steve Soroka (DMB/
ASPS); Frank Putnam (NIMH/BP). The purpose of
this project is to condense a large amount of data
for a small number of patients studied by the
Biochemical Psychiatry Branch into a format that is
useful for research analysis. During the last year
analysis was completed and a design proposal was
submitted for a system that extracts and reformats
data from the Clinical Information Utility for analysis
by existing statistical packages.

Dyslipidemia Computerized Recordkeeping
System. George Roberts (DMB/SAS); Ernst

Schaefer (NHLBI/MDB). This system keeps records
on clinical laboratory data for normal and
dyslipidemic subjects and provides for routine
reporting as well as for ad hoc queries and
preparation of selected subfiles for statistical
analysis. An individual history report program was
supplied during FY81. For current reporting requests,
the new SAS online graphics package was used.

BRIGHT Augmentation. Brian Cole (DMB/SAS);
David Rodbard (NICHD/BES); Jay Shapiro (CC). A
computer system is being developed on the
DECsystem-10 that will enable Clinical Center
investigators to analyze their own clinical data.
Available thus far are a t-test module and a plotting
module. Also to be included are descriptive statistics,
chi-square test, linear regression, ANOVA, normality
test, non-parametric tests, and life table analysis.
Modules are to be added as requested by
investigators.

Diet Composition/Menus. Diane Feskanich (DMB/
SAS); Dennis Sprecher (NHLBI). This is a system for
determining the nutritional profiles of patient menus.
With appropriate modifications, the 'MR FIT'
nutritional coding tape and diet composition
programs were made operational at NIH. An input
module for Dyslipidemia patients' dietary records has
been supplied.

Survival System. Diane Feskanich (DMB/SAS);
Ardyce Asire (NCI). This life table analysis system
was originally developed in the 1960's to support the
End Results in Cancer studies of NCI. Maintenance
and improvement of the system is now the primary
goal. During FY81 the system was sent to: Rhode
Island Health Services Research, Inc.; Department of
Health, San Juan, Puerto Rico; and Rosewell Park
Memorial Institute, Dept. of Health, Buffalo, NY.

Prevalence of Major Neurological Diseases-
Nigeria. Joe Huston, Mary Lee Dante (DMB/SAS);
Bruce Schoenberg (NINCDS/NS); Dr. Osuntokun
(University of Ibadan). This WHO-sponsored study
consists of four parts: census and health screen,
evaluation of risk factors, neurological exam results,
and follow-up. A pilot study was done to determine
validity and usefulness of the questions and worth of
the questionnaire. Processing of these pilot forms
led to many suggestions for improving the study
protocol and questionnaire format.

Neurological Screening Summary. Brian Cole
(DMB/SAS); B. Schoenberg, D. Anderson (NINCDS/
NS). A survey of neurological disorders was made in
a Mississippi county; this study examines the
epilepsy, stroke, psychomotor delay/cerebral palsy,
transient ischemic attacks, and Parkinson's Disease

data. Extensive validity checks and consistency
editing were required. Preliminary analysis of
Parkinson's Disease, including frequency tables and
bar graphs, has been supplied.

Seroepidemiology Data Processing System. Judy
Mahaffey (DMB/ASPS); Paul Levine (NCI). The
Clinical Studies Section, NCI Laboratory of Viral
Carcinogenesis, is trying to find characteristics of
serum samples that can be used to predict cancer.
To this end, a computer system has been designed
to manage all data necessary for efficient inventory
control, test results feedback, and statistical analysis.
The system is now operational and reports from the
system are being sent to collaborating scientists in
the U.S., Ghana, Greenland, and Singapore. During
the past year a new contractor took over the the
running of this system, and was provided with
assistance in setting up to correctly run the system.

Idiopathic Hypereosinophilic Syndrome Protocol.

Brian Cole (DMB/SAS); John Harley (NIAID). A data
base is being set up that will allow easy storage,
retrieval, and analysis of a large amount of data that
has been paper-collected on hypereosinophilic
patients since 1967. Information drawn from the CIU
will be included. In FY81 drug therapy information
was extracted from the CIU and patient response
patterns studied.

Physiologic and Behavioral Responses to
Apomorphine. Diane Feskanich (DMB/SAS); Neal
Cutler (NIMH). The effects of apomorphine on
physiological and psychological variables are being
studied in groups of patients and volunteers, male
and female. Graphs have been run on time of peak
hypothermal response, mean duration of the
response, and time of rebound by age, sex, and
other variables. Also being examined is the
development of brain tolerance to the drug.

Smithsonian Tick Collection Query/Retrieval
System. Diane Feskanich (DMB/SAS); Carleton
Clifford, Jim Kearins (NIAID/RML). The Rocky
Mountain Lab has catalogued its tick collection on
tape and sent the data to the Smithsonian Institution.
DMB is supplying the ability to query this file from
Montana using the DCRT central computer facilities.
During FY81 Ms. Feskanich assisted RML in the
selection of a DataPoint word processor for
installation in Montana, and ensured that the
software would interface with DCRT software. Ms.
Feskanich has provided interactive DataPoint
programs for data entry and query/report and will be
training RML personnel in use of the word processor
when it is installed.

Monkey Management System. Diane Feskanich

(DMB/SAS); Robert Williams (NICHD/ERRB). A data
base is being developed of bibliographic and medical
information, plus the experimental history of each
monkey in a colony of 500 to 1,000 monkeys, with a
turnover of 300 each year. The system will be used
to select appropriate individuals for specific
experiments, and to prepare daily work assignments
for caretakers and technicians.

Musculoskeletal Model. Sig Knisley (DMB/SAS);
Richard Lymn (NIADDK/ABSDP). This is a study of
the structure of live muscle fibers as they contract.
From a model, diffraction patterns will be computed
and compared with real diffraction patterns produced
by living muscle fibers. During FY81 myosin data has
been processed with the PDP-10, linked with the
PDP-11, and put up on the Evans and Sutherland
picture system and the frame buffer for 3-D
conformational analysis and manipulation.

Wild Mouse Breeding Colony Data Processing
System. Vivian Pelham (DMB/ASPS); Ernest Plata
(NCI). The Laboratory of Viral Carcinogenesis, NCI
Division of Cancer Cause and Prevention, breeds
and raises a rare and valuable strain of wild Asian
mice originally acquired from Vietnam, A system that
will maintain all data collected on these animals and
aid in selective breeding, carcinogenesis studies,
aging studies, etc., was completed during the past
year.

Canine Breeding Colony Data Processing
System. Peter Basa (DMB/DBAS); Dennis George
(DfvlB/ASPS); T. Wolfle (DRS/VRB/ACS). The goal
of this project was to develop a system to assist the
Veterinary Resources Branch, DRS, with its record
keeping and work scheduling. The system is
complete. DRS is now in the process of installing a
word processing system (CADO) in Poolesville to
handle all data entry, maintenance, etc. When this is
complete, DMB will work on interfacing the two
systems.

Strain Specificities Reference System. Steve
Soroka (DMB/ASPS); David Sachs (NCI). A
computer system is being developed for the Division
of Cancer Biology and Diagnosis, NCI Immunology
Branch, to assist in transplantation biology research.
The system will be used to help locate existing
cogeneric mouse strain products and/or to design
mouse strain products with specific antigens that are
used in experiments relative to the development of
sera. Analysis was completed and a design proposal
was prepared during the past year.

Ectromelia Epidemiologic Survey. Dennis George
(DMB/ASPS); Gordon Wallace (NIAID). This project
provides the data processing services necessary to

determine the environmental factors that most likely
contribute to the spread of Ectromelia (Mouse Pox).
The project was completed during the past year.
Using the results from the study, Dr. Wallace wrote a
paper, which he presented at a National Conference
on Lab Animal Diseases in October, 1980.

Estimating Q Matrix in the Kalman Recursion.

George Shakarji (DMB/OC); Eugene Harns (DCRT/
LAS). A package has been implemented that would
estimate the matrix of 'shift' variances and
covariances, or the Q matrix. The package assumes
either that Q is unknown, in which case the weight
function and the matrix of predicted values can be
calculated directly, or that Q is unknown but that the
series of observations is long.

Multivariate Time Series Packages. George
Shakarji (DMB/OC); Eugene Harris (DCRT/LAS).
Two packages that would input multivariate
observation vectors of related tests were completed
and tested. The homeostatic approach assumes the
existence of a constant set point about which the
sehal measurements fluctuate; successive
observation vectors are presumed to be mutually
independent. The non-stationary, random walk
approach does not assume any constant
homeostatic subpoint. It postulates instead that the
true value at any time is shifted randomly from a
previous time. In this procedure the predicted value
is a weighted (exponentially smoothed) average of
past results.

Materiel Management System (MMS). Marvin
Katz, Ron Wicks (DMB). This ongoing administrative
project utilizes data base technology in support of
NIH-wide procurement, receiving, and payment
activities. As the MMS entered its fourth year of
development and operation, much time was spent in
enhancing existing software. During FY81 some 50
change control items successfully went into
production. New developmental efforts implemented
were:

1. Provision of a delegated interface to MMS for
the B/I/D's Administrative Offices. This interface
includes: procurement entry at point of origin, receipt
of entry, and online review and control of all
pertinent data by the Administrative Office. This
feature will be phased into the B/l/D's as terminals
become available.

2. Development of a new numbering system for
the delegated procurement actions that originate in
the B/I/D's.

3. Streamlining of DFM Accounts Payable
functions by automatic voucher generation as part of
the Treasury schedule preparation.

4. Development and implementation of an invoice
entry subsystem for DFM.

5. Completion of subsystem design for a stock
inventory subsystem.

6. Cutover to production of a source subsystem
thiat allows blanket purchiase agreements and
indefinite delivery contracts to control telephone
charge order and record of call validity.

Requirements Analysis for Financial Management
Data Base. Clare Hoover, Jeff Schriver (DMB/
DBECS); Harry Hsu (SIMCOM/USAF). As an adjunct
to the full statement of Division of Financial
Management accounting requirements, the study
participants: developed a complete structured flow
chart of the existing Central Accounting System
(CAS); defined the detailed flow of key CAS
transactions; and created a matrix of all transactions,
master files, and their processing relationships.
These documents will be used as the basis for
evaluating vendor accounting packages.

General Support for Central Accounting System.

Clare Hoover, John Price, Jeff Schriver (DMB/
DBECS). During the fiscal year, the Data Base
Enhancement and Control Section developed
enhancements and new programs, and conducted
studies for, the Central Accounting System. Because
this support involved almost 80 separate projects of
varying size, they will not be enumerated here.

Performance Index/Grant Awardees. Mary Lee
Dante (DMB/SAS); William Parker (NINCDS/EAP).
Under study is a system for tracking K07, K04, and
F32 applicants. To do this, information must be
acquired from the IMPAC and CRISP files, organized
(by category, principal investigator, and grant), and
printed in matrix format. If pursued, this can be
generalized for other requests.

DRR Grants Subproject System. Vivian Pelham
(DMB/ASPS); Jean Babb (DRR). The existing DRR
Grants Subproject System, which uses Conversation
Programming System, is being evaluated. A proposal
was made for the redesign of this system to make
use of more current, supportable technology. The
proposal was accepted and the system currently is
being developed.

Vogl's office is currently using it to answer inquiries--
from NIH Directors' offices, the White House,
Congress, and the public--that relate to dollar
amounts and percentages of grant money being
spent in the area of nutrition.

Review and Evaluation Branch Grants
Information System. Penny Brogan (DMB/ASPS);
Harry Canter (NCI). The computerized Research
Analysis and Evaluation Branch Grants Information
System, a highly specialized grants management
system, was designed and implemented for the
Division of Cancer Grants, NCI. Enhancements are
currently being made to the Intramural and Funded
Grants subsystems, and the system is being
extended to include contract data. In the future, a
Training Grants system will be developed and history
file maintenance will be added to the Intramural
projects and unfunded grants systems.

NIH International Activities and Personnel
Monitoring System. Penny Brogan (DMB/ASPS);
Libby Low (FIC). A system has been developed to
process financial and visa data on the foreign guest
workers and foreign visitors at NIH. The Fogarty
International Center is currently using this system to
provide reports for the Visiting Program, for foreign
nationals, and for foreign embassies. The growth of
the current data files will necessitate a future
revision of the system to separate current data from
historic data. During the past year an analysis of all
FIC requirements was completed and a design
proposal with recommendations for improving their
system was prepared.

Committee on Academic Science and
Engineering (CASE) Reports. Darius Georg (DMB/
ASPS); J. Bailey (OD/OPPE). This project involves a
broad spectrum of data processing support required
for the collection and reporting of DHHS obligations
to institutes of higher education, research and
development centers, and non-profit institutions. This
is an ongoing project.

MMS Query and Reports. Jane Blessley (DMB/
ASPS); Joe Campbell (DMB/DBAS). This project
provides an economical method for the selection
and reporting of data from the NIH Administrative
Data Base. Ms. Blessley provides recurring and ad
hoc reports from the data base for all segments of
the NIH community.

System for Statistical Complaints of
Discrimination at NIH. Darius Georg (DMB/ASPS);
G. Yee (OD/DEO); M. Williams (OD/DEO). This
project establishes and maintains a file that provides
statistical data, on a case by case basis, of formal
and informal complaints of discrimination at NIH. In

the past year Mr. Georg revised and simplified the
retrieval process.

ARMS/TDCS Interface. Dennis George (DMB/
ASPS); B. Hughes (OPA/P); A. Amatucci (OA/M).
This project is intended to create an NIH Personnel
System that is a composite of the current NIH
personnel system (ARMS) and the DHHS Personnel
System (TDCS). In the past year the analysis and
design of the proposed system was completed. The
ARMS Steering Committee has approved the
proposal and the system is presently being
implemented.

Radiation Safety Control System. Charles Twigg
(DMB/ASPS); R. Zoon (DRS/RSB). This system is
designed to monitor the use and users of radioactive
isotopes at NIH. When complete, this system will
include five subsystems: inventory and bioassay, lab
survey and airborne release, waste processed and
activity balance, training, and film badges. In the past
year extensions were made to the inventory and
bioassay subsystems to satisfy Nuclear Regulatory
Commission requirements. Development of the lab
survey and airborne release subsystem was begun.
All subsystems have been completed except the
waste processed and lab survey.

Electrical Safety Program System. Larry Martin
(DMB/ASPS); Steve Soroka (DMB/ASPS); Howard
Metz (DRS/BEIB). The chief of Scientific Equipment
Services of the Biomedical Engineering and
Instrumentation Branch has requested a system to
help monitor maintenance of equipment at the
Clinical Center. A system is being designed to
computerize the results of routine electrical safety
checks and preventive maintenance performed on
hospital equipment. The system will be used by DRS
to schedule equipment checks, to provide reviews on
instruments checked by contractors and by the CC,
and to provide statistical information on different
types and repair histories of equipment. A design
proposal has been accepted, and the system is
currently being implemented.

Design Billing System. Peter Basa (DMB/ASPS);
Robert Weymouth (DRS/OD). This project converts
the manual accounting system for the Design Unit in
MAPB/DRS to a computerized system. Analysis,
design, and development of the system were
completed during this year.

Information System of Extramural Scientists.

Darius Georg (DMB/ASPS); William Rhode (00/
OPPE). This system creates a data base of
information drawn from various sources in order to
perform analysis of various patterns of involvement
in NIH science review activities by extramural

scientists. The data base was created during the
year and reports are being run as requested.

Medical Records Auditing System. Judy Mahaffey
(DMB/ASPS); Gloria Burich (CC/MRD). The purpose
of this system is to assist Medical Records in the
monitoring and reporting of the status of medical
records from the time they enter the department until
they leave. When the system is developed, it should
replace four manual systems now being used by the
Medical Records Department. During the past year
analysis was completed and a proposal was
submitted. The proposal has been accepted, and the
system is currently being implemented.

Correspondence Control System. Steve Soroka
(DMB/ASPS); Dennis George (DMB/ASPS); Zaven
Khachaturian (NIA/OD). The objective of this system
is to monitor the status of staff assignments and
correspondence assigned to NIA for processing and
review, and to provide a query facility that will allow
NIA personnel to locate correspondence (old and
current) pertaining to a current issue or problem.
During the last year analysis was completed and a
design proposal was submitted for approval.

AIRS Personnel System. Vivian Pelham (DMB/
ASPS); L. Lee Manuel (DCRT/OD). This project
involved a complete revision of this system due to
the discontinuation by CCB of the Conversation
Programming System. Analysis, design, and
implementation were completed during this year.

HMO Label Programs. George Roberts (DMB/
SAS); Lois Eberhart (OHMO/OPS). The Office of
Health Maintenance Organizations maintains several
address lists. They were provided with an interactive
updating capability, a number of reports, and a
gummed label option.

Space Management System. George Roberts
(DMB/SAS). This system provides a method
whereby the Office of Research Services can keep
track of all space in all buildings occupied by NIH.
The Fort Dietrick facility was added to this system
during FY81.

Chinese Personalities and Institutions in
Biomedicine. Judy Mahaffey (DMB/ASPS); Joseph
Quinn (FIC); Joseph Lee (FIC). International
exchanges in the field of biomedicine between the
U.S. and the People's Republic of China have
increased rapidly. The Fogarty International Center
has requested DMB services to design a system for
the computerization of data on biomedical scientists
and institutions in the PRC. The system will be used
by the FIC officials in bnefing NIH and non-NIH
scientists interested in biomedical research in China.

During the year, analysis was completed and a
design proposal was submitted to FIC.

Selective Dissemination of Information. Sig

Knisley (DMB/SAS). SAS has continued its support
of the current awareness search for both Chemical
Biological Activities (CBAC) and Biosciences
Information System (BIOSIS). Retrospective
searches are referred to the NIH Library staff.

Sickle Cell Disease, Health/Science Seminar
Evaluation. George Roberts (DMB/SAS); Katrina
Johnson (NHLBI/SCDB). A battery of tests probing
general knowledge of Sickle Cell Disease is given to
groups of teachers prior to a two-day seminar on the
disease. Then a post-test is given to measure the
value of the seminar. Some analysis was done on a
set of tests already scored, mainly for the purpose of
evaluating the test questions. Advice also was
provided during the process of requesting proposals
from contractors for administering the program.

SLANG (Structured Language) Compiler. Bob

Magnuson (DMB/OC). SLANG is designed to assist
programmers to generate block structured assembly
language code on the IBM system 370. The features
added include automatic indentation, generic
statement numbering, boxed comments, and
program structure display.

Voice Input and Synthesis Support. Bob

Magnuson (DMB/OC). As a follow-up to DMB's initial
voice input project, this section is examining the
feasibility of developing voice input/output
applications by way of microprocessors, which can
act alone or as front end processors to larger
computers. This year was spent modifying the design
of a microsystem with plug-in peripherals, purchasing
some hardware, and providing appropriate software.

SFOR (Structured FORTRAN) Compiler. Bob

Magnuson (DMB/OC). Designed to assist
programmers writing structured programs, the SFOR
compiler generates block-structured IBM FORTRAN
source code. There are six different kinds of blocks
available to the FORTRAN programmer-
CASENTRY, FOR, IF, LOOP, REPEAT, and WHILE.

RMAG Products Support. R. Magnuson (DMB/
OC). Necessary support is provided for RMAG, SLR,
Logic Subroutines, Arithmetic Subroutine, SLANG,
REFORMATGEN, REPORTGEN, TRANSACTGEN,
Standardized Update, Voice Input, and SFOR. This
ongoing support includes software maintenance,
customer assistance, and the teaching of formal
DCRT courses on these products. In particular, a
special effort had to be mounted to change over to
the new WYLBUR format data sets.

Computer Center
Branch

Joseph D. Naughton, Chief

Summary of Activities

New Languages. An entirely new version of
WYLBUR, designed and implennented by the Center
over the past several years, was made operational in
a full production nnode in early January. In addition to
retaining all the capabilities of the previous version,
the new version provides many new functions
including document formatting, pattern matching,
catalogue and PDS support, session recovery, and
command procedures (EXEC files), plus many
enhancements to existing facilities. The new version
uses much less CPU time than its predecessor at
the same level of user load and can accommodate
many more simultaneous users.

SPEAKEASY, a computing language for scientific
and mathematical problem solving, became available
under TSO on the System 370. Developed by a
physicist at the Argonne National Laboratory,
SPEAKEASY provides a quick and simple means of
formulating mathematical problems and obtaining
results. The language contains over 500 functions
and commands that perform matrix and array
operations, numerical differentiation and integration,
statistics, and character processing. Because its
notation and syntax are similar to those used in
mathematics, it provides extensive new scientific and
mathematical capabilities without burdening the user
with the details often inherent in computer
programming. SPEAKEASY may be self-taught at
NIH through two online facilities; TUTORIAL and
HELP.

The IBM PASCAL/VS Compiler was tested and
installed on the System 370, and is available for
interactive use under TSO or for batch processing.
PASCAL is a relatively small but very powerful
language that has become widely used throughout
the data processing industry. It is a very concise
language with few defaults or implicit conversions,
making it easy to use. The PASCAL/VS compiler
contains many extensions to the International
Standards Organization proposed PASCAL standard.
It provides the ability to divide programs into
separately compilable sections, a debugging facility,

and numerous other features.

The Conversational Programming System (CPS), the
first interactive programming facility offered at NIH,
was replaced by the more modern VS BASIC, an
improved version offering many features not
previously available. Guidelines were developed to
assist users in converting CPS-PL/I programs to use
the PL/I Optimizing Compiler under TSO. The
command procedures facility of WYLBUR provided a
viable mechanism for rewriting some programs.

New Software. Two powerful new graphics
packages were made available on the IBM System
370. TELL-A-GRAF, an interactive system that uses
conversational commands, may be used to create a
variety of graphs and charts. The system is easy to
learn and does not require programming experience.
The other program, DISSPLA, is a library of
subroutines that can be called by the user's
program. Although some programming experience is
necessary, DISSPLA is also easy to use and enables
the user to integrate data analysis and graphical
display into a single program. Both TELL-A-GRAF
and DISSPLA are capable of driving a wide variety of
graphics devices.

A new software package was installed to assist
users in the diagnosis of program abends that cause
dumps. ABEND-AID analyzes program abends,
extracts diagnostic information, and presents the
results in a few easy to understand pages. This
enables users to analyze abends without having to
go through the painstaking process of interpreting a
dump.

Output Facilities. The OMNIGRAPH package was
enhanced by the implementation of a library of 1,377
different alphabetic and graphic characters known as
Hershey's fonts. These high quality, esthetically
pleasing characters and symbols, manually digitized
by Dr. Allen V. Hershey of the Naval Weapons
Laboratory, greatly enhanced the appearance of
graphs and plots generated by OMNIGRAPH and
MLAB users.

All standard output forms provided by the Computer

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Center were made directly available through JES2,
the component of the Operating System that handles
printer/punch output. This change eliminated the
need for creating and processing a SPOUT tape,
thereby reducing the overhead and cost for creating
output at the NIH Computer Utility, and provided the
ability to examine, reroute, locate the output of a job
during any stage of its processing. By reducing
operator involvement, the possibility of error was
also decreased and turnaround was improved. An
easier mechanism for users who require printed
labels was developed. Each of the 21 different types
of standard labels is now identified with a simple
four-character name and an appropriate carriage
control loop is automatically requested by JES2.

Communications Improvements. The link between
the DECsystem-10 and IBM System 370 was
strengthened by the addition of a second
communication line between the two systems. This
doubled the capacity of the link and ensured that
jobs get through quickly. In addition, the effective
speed of the link was further increased by several
software improvements, nearly doubling the speed of
transmission on each communication line.

Documentation/Publications. Publications by the
Computer Center are oriented toward familiarizing
users of the Computer Utility with the computer
services, languages, and training available. Ten new
publications and ten revised or updated titles were
released this year.

Over 1 ,200 pages of documentation were prepared
for the new version of WYLBUR, including a
Fundamentals manual and four additional manuals
on document formatting, command procedures,
batch processing, and general editing. Other
documentation included a Master Index; two
reference handbooks to give the syntax of the
language in concise form; and a special edition of
INTERFACE, the Computer Center's technical notes,
which introduced the new version in considerable
detail and described specific differences between the
new version and the old.

Seven editions of INTERFACE including the special
WYLBUR edition and the Annual Index were issued
this year. Two new features were added, 'WYLBUR
Wisdom' and 'MLAB NOTEBOOK.' INTERFACE a\so
ran a five part series written by Dr. Benes L. Trus,
Computer Systems Laboratory, describing various
techniques of scientific image processing using the
Center's Surface Display System.

User Training and Assistance. Seven new lecture
courses were added to the Computer Center training
program this year, including 'Managing and
Processing Data Sets at NIH,' 'Dynamic Biological
Stimulation,' and 'BRIGHT--A System for the
Creation and Use of Data Tables.' The popular
WYBLUR introductory course was divided into two
courses, one focusing on secretarial applications and
the other on data processing applications. New
seminars this year included 'Introduction to Scientific
Data Analysis at NIH,' 'IMSL: International
Mathematical and Statistical Library,' and 'Graphical
Representation of Multivariate Data.' There were 71
sessions of 41 different classroom courses given to
over 1,600 students during the year.

Self-study courses, involving either programmed
instruction, workbook, audiovisual, or computer-
assisted learning, continued to be popular. 'PL/I
Programming,' a new independent study program
written by IBM, was added to the roster this year.

Programmer Trouble Reports (PTR's) researched
and answered dunng the year numbered 2,745. User
Services applied over 4,000 system software fixes
during the year and installed 14 new releases of
current software packages. There were 23,000 calls
or visits by users for assistance during the years.

developed by others for experimentally determining
the pairing of nucleic acid bases. This project has
developed a technique for displaying the two-
dimensional structure of general nucleic acid
sequences. Two-dimensional diagrams for the 16S
fragment of the ribosome (1.6 kilo bases) have been
generated. A complete language has been
developed for input, manipulation and display of
nucleic acid two-dimensional structures. Copies of
the program package have been exported to other
institutions.

An attempt has been made to synthesize the three-
dimensional structure of general nucleic acid
sequences. Because crystallography has been done
on only a few nucleic acid structures (straight helix
DNA and RNA, and two tRNA's) the cntical insights
needed for general structure synthesis are still
missing. Modeling techniques are being developed to
solve this problem.

Research Projects

In addition to the many activities, services, and
facilities for NIH, the Computer Center Branch
serves biomedical computing with its research work.
The DECsystem-10 and the molecular graphics
systems have been used to develop techniques for
creating and displaying two- and three-dimensions of
genetic control molecules. It is now clear that both
DNA and RNA fold up into complex structures.
Algohthms have been developed to create
reasonable folding patterns for rather long nucleic
acid sequences. A two-dimensional display algorithm
has been developed to layout many of these
complex structures. Using the layout algorithm it is
possible to study the dynamics of the folding
process by making movies. By understanding the
dynamics of folding, it may be possible to
understand how processing and gene control
function.

Nucleic Acid Structure Synthesis and Display

Rapid advances in nucleic acid determination have
led to questions about the secondary and tertiary
structure of DNA and RNA. It is clear now that the
sequence alone of a nucleic acid is not sufficient to
determine many of the processing and control
functions. Computer techniques have been

Office of the
Director

Arnold W. Pratt, M.D.

Summary of Activities

Library Automation. E. Chu; J. Mahaffey (DMB); J.
Knight (CSL). In conjunction with other DCRT staff,
the DCRT Librarian applies computer techniques to
DCRT needs, advises other libraries, and maintains
knowledge of work done outside NIH. (Details of
activity in FY81 appear in Volume I of the Annual
Report.)

DCRT Publication File. P. O. Miller; R. Baxter
(DMB). In FY79 the Information Office began to
create a file of citations for all papers published by
DCRT authors. In FY81 additional work was done to
correct errors in the file.

Text-to-tape Copy Preparation. P. O. Miller. This
project is an offshoot of work begun in 1 979 as part
of a joint PSL/LAS/OD effort. In FY81, a JCL was
written for creating a WYLBUR tape to drive GPO
typesetting equipment Documentation was begun in
an effort to make the technique available to all NIH
Information Offices.

DCRT Communications Program. P. O. Miller; W.
C. Mohler. Previously called the DCRT Information
Program, this is an ongoing project to develop
improved and coordinated communication
techniques to support DCRT activities. It has four
parts: Analyzing Needs, Creating and Evaluating
Products, Developing Resources, and Education. In
FY81 work continued on developing and distributing
information products, including a videotape about
computer terminals to aid handicapped programmers
and a slide show about DCRT work.

Who at NIH uses DCRT for what? W. C. Mohler;
L. L. Manuel. DCRT services support activities
throughout NIH for more than 3,000 registered users
on some 1,100 accounts. A survey in FY79 and
FY80 asked users to categorize the types of NIH
activities supported by each account in the previous
year. The FY81 survey in conjunction with the PAS
account update confirmed previously observed
difficulties in obtaining consistent and usable
information by this collection mechanism. The
project was stopped.

Clinical Data Management and Analysis. W. C.

Mohler; B. Cole (DMB); D. Rodbard (NICHD); J. R.
Shapiro (Clinical Center). In spite of the rapid growth
in use of data management and statistical packages
provided for NIH scientists on DCRT computers,
there is a perceived need for facilities that would be
easier to learn and use in NIH clinical research
projects. In FY81 work began using BRIGHT, a
table-oriented data management/analysis package
on the DECsystem-10, developing added data
analysis and display programs and exploring their
usefulness for a few NIH clinicians on data sets from
the Clinical Information Utility.

Multi-function Microprocessor Interface. A. W.

Pratt; D. Songco (CSL). The project begun in FYBG
seeks to adapt a variety of information acquisition
techniques on a single microcomputer as a versatile
data input/output interface for biomedical scientists
and clinicians.

Medical Linguistics. A. W. Pratt, et al. This is a
long-term project to define a set of semantic and
syntactic forms that can aid in the analysis and
interpretation of written medical statements.

Image Processing, Decision Analysis, and
Computer Architectures. J. M. S. Prewitt.
(Summaries for projects in this group of activities
were not available in FY81.)

Research Projects

October t. 1980 to Septcnter 30. 1981

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DrVISION OF COMPUTER RESEARCH AND TECHNOLOGY

FISCAL ANNUAL VOLUME 1

YEAR REPORT

1982

rVHT T

KDCRTRT

Foreword

The Division of Computer Research and Technology DCRT progranns focus on three primary activities:
has primary responsibility for incorporating the power conducting research, developing computer systems,
of modern computers into the biomedical programs and providing computer facilities,
and administrative procedures of NIH. DCRT serves jhe fiscal year 1982 annual report descnbes our
as a scientific and technological resource for other yvork in two volumes:

parts of PHS, and for other Federal organizations Volume 1 gives an overview of the work of

with biomedical and statistical computing needs. each group, highlighting the year's

accomplishments;

Volume 2 gives details about the projects and
activities of each group.

From the Director

I am pleased to submit this Annual Report for the
Division of Computer Research and Technology.
It serves to remind all of us of the extent and
breadth of subject matter involved in the conduct
and management of the NIH biomedical research
program. Biomedical computing has matured and
become another essential element of the scien-
tific excellence of NIH.

One has to be aware of increasing involvement
and contributions of applied mathematics, statis-
tics, engineering, and computer science across
all biomedical research. The following examples,
limited only to clinical medicine, serve to il-
lustrate how DCRT mal<es these several discip-
lines productive throughout NIH.

The Computer Systems Laboratory is broadly in-
volved in both the laboratory and clinical research
programs in many Institutes and several Depart-
ments of the Clinical Center. Current clinical
work includes;

• The Radiation Therapy System with the
Radiation Oncology Branch of the National
Cancer Institute,

• Automated systems for the Pulmonary
Branch of the National Heart, Lung, and
Blood Institute,

• The Positron Emission Tomography Facility,
the focus of exciting collaborative projects
among staff of the National Institute on Ag-
ing and the National Institute of Neuro-
logical and Communicative Disorders and
Stroke, and

• Other projects in the Medical Intensive Care
Unit, Electrocardiography/Heart Station, and
Anesthesiology Service of the Clinical
Center and its Departments of Clinical
Pathology, Nuclear Medicine, and Rehabilita-
tion Medicine.

The Laboratory of Applied Studies has been ac-
tive in a variety of clinical research projects.
Many of these have been collaborations with
users of the systems designed by CSL. Areas of
activity currently include laboratory medicine,
electrocardiography, and pulmonary medicine.

The Laboratory of Statistical and Mathematical
Methodology provides mathematical tools and
consultation for clinicians from all Institutes. In
addition, it too has collaborative projects with
medical scientists. Even the Physical Sciences
Laboratory, with its major focus on physics and
chemistry, consults on a few clinical research
projects.

The Data Management Branch has created scores
of computer programs for clinical scientists in
the Institutes and for departments in the Clinical
Center. Its Clinical Information Utility project pro-
vides the archival data base for information col-
lected by the Clinical Center medical information
system. DMB is working with members of the In-
stitutes and Clinical Center to develop better
systems to retrieve and analyze this archived
data.

Finally, the Computer Center Branch provides the
reliable, accessible, modern central computing
facilities that support hundreds of clinical
research projects and virtually all of the adminis-
trative activities without which research and pa-
tient care could not go forward at NIH.

rtytyf^ci iJjncufJf ^

Arnold W. Pratt, M.D.
DCRT Director

Contents

Computer Systems Laboratory 1

Provides consultation and collaboration in the design
and implementation of specialized computer systems
for laboratory and clinical applications.

Laboratory of Applied Studies 7

Physical Sciences Laboratory 1 1

Conducts research in mathematical theory and
practical instrumentation to explain biological
phenomena in terms of chemistry and physics at
subcellular molecular levels.

Laboratory of Statistical and Mathematical
Methodology 15

Data Management Branch 21

Serves as a central resource of systems analysis,
design, and programming for data processing
projects relating to scientific, technical, management,
and administrative data.

Computer Center Branch 25

Designs, implements, and operates the NIH
Computer Center; provides assistance, training, and
technical communications to the more than 8,000
users of the Central Utility.

Office of ADR Policy Coordination 31

Coordinates the complex Federal policies and
procedures that govern getting and using computers
at NIH.

Office of Administrative Management 33

Provides general administrative management support
for the Division's work.

Office of Scientific and Technical
Communication 35

Serves as a central source of information about
DCRT activities and about computer-related
disciplines.

Computer Systems
Laboratory

Alan M. Demmerle, Chief

Function and Scope of Work

The Computer Systems Laboratory--26 professionals
representing the disciplines of engineering, computer
science, medicine, and chemistry--is the major
source of expertise at NIH for minicomputer and
microcomputer technology. CSL engineers and
scientists, in collaboration with NIH intramural
laboratory and clinical investigators, apply this
technology in the areas of laboratory automation and
patient care. Some projects are occasionally
undertaken with NIH extramural program staff and
with other Federal agencies. CSL's multidisciplinary
approach aids both the recognition of problem areas
that will benefit from automation and the
interpretation of research needs in terms of
computer methods.

Computers may be used only in an adjunctive
manner--for example, as a more convenient means
to acquire laboratory and clinical data--or they may
be integral parts of an elaborate instrumentation
system, such as a computer-controlled mass
spectrometer. Advances in large scale circuit
integration (LSI)-the microprocessor revolution-have
brought about the miniaturization of computer
components and a dramatic decline in their prices
and power requirements. CSL engineers are now
able to use microprocessors to deal with problems
that once defied solution because of cost, size, or
manpower constraints.

CSL projects range in size from consulting activities
of a few days' or weeks' duration to large-scale
efforts taking many manyears. Much CSL work
involves the development of new methods or
technology or is influenced strongly by the changing
needs of research. Thus, it is often difficult to predict
the long-term scope at the outset of a project.

FY82 Highlights

This year, CSL engineers and scientists worked on
32 projects, representing collaboration with almost

all of the NIH Institutes. Some of these projects
require only limited resources, while others take
many manyears. The latter deserve particular
emphasis because of both their sheer magnitude
and the importance of the patient care or research
activity they support.

One of these large scale efforts is the Radiation
Therapy Project, a collaborative effort with the
Radiation Oncology Branch, NCI. This project began
in late 1975. Since then, it has experienced
modifications to both the original goals and
implementation techniques. At project inception,
short-term priorities focused on integrating scans
from a recently acquired CAT scanner into a
computerized treatment planning system. More
ambitious goals included three-dimensional treatment
planning, treatment plan optimization, and dynamic
treatment planning. Short-term goals were quickly
achieved. Despite changes in program emphasis and
significant technical problems, a limited three-
dimensional capability has been implemented.
Optimization requirements, however, have been
reduced and are being satisfied through pseudo-
optimization techniques that use interactive beam
manipulation.

Aspirations for achieving dynamic therapy have
remained dormant. Instead, efforts were expended
upon supplementing traditional isodose curves with
point dose calculations, upon producing implanted
seed calculations, and upon generating sophisticated
treatment plan displays that emphasize particular
structures or magnify special features.

The original treatment planning system consisted of
a Digital Equipment Corporation PDP-11/70
computer with treatment planning software
developed by J. R. Cunningham and marketed by
Atomic Energy of Canada Limited (AECL). Clinical
use of this system began at NIH in 1977 in a single
user mode. Two years ago, the AECL software was
replaced by algorithms developed by J. Van de
Geijn. Sophisticated displays featuring up to eight

beams, CAT or ultrasound scan, and point dose or
isodose curves on one screen also have been
operational for some time.

The core hardware configuration remains essentially
the same as originally purchased except for the
addition of new display equipment. However, the
original single user software implementation has
been replaced by new software that supports
multiple treatment planning stations. The success of
the system can be measured by its high use by the
Radiation Oncology Branch, and by the fact that a
number of commercial firms have expressed interest
in including it in their product line.

Another major project in the Clinical Center that was
completed this year is the computerized ECG
Management System. The Heart Station of the
Clinical Center is responsible for obtaining and
interpreting electrocardiograms (ECG's) from
hundreds of patients each week, and for maintaining
a filing system for all previous ECG records.

With the impending completion and occupancy of
the new Ambulatory Care and Research Facility
(ACRF), the Clinical Center wanted a new
comprehensive computer-based system to facilitate
the processing of the projected ECG workload and
to provide a practical method for long-term storage
and retrieval.

The project's requirements included analog-to-digital
conversions of ECG waveforms, computer-assisted
interpretation of the ECG data, physician approval of
all interpretations, automatic generation of final
diagnostic reports, and generation and maintenance
of a data base of all tracings and interpretations in
machine readable form. An additional requirement
was the ability to search the data base using
selection factors to be specified by researchers
engaged in the wide class of retrospective clinical
studies envisioned for the ACRF.

CSL developed the Request for Proposals for the
system in 1979. The procurement process
culminated with the purchase of a Hewlett-Packard
ECG Management System that was specifically
configured and programmed to conform to the
Clinical Center's operational procedures, reliability
needs, and report format requirements. Relatively
rapid installation of the computer system was
achieved by using an existing computer site in
Building 10. The Clinical Center's telephone network
was adapted so that the system's portable ECG
machines could be used to transmit ECG's from all
patient care areas or patient rooms to the centrally
located ECG computer facility.

Routine clinical use of the ECG diagnostic computer
system began in January 1 982 after a short

orientation session for the heart station's ECG
technicians. CSL expects to provide software
modifications to support future research protocols.

Other major clinical activities on which CSL worked
during FY82 are as follows:

• Intensive Care Units (ICU's): CSL is involved in
the automation of three ICU's. The general
goals are to capture patient vital signs, generate
comprehensive displays of patient status and
trends on demand, and substantially simplify
medical recordkeeping. Data archival is
expected to facilitate research in areas such as
noninvasive intervention.

• Nuclear Medicine: In this project, the design
and implementation of a stand-alone computer
system facilitates the analysis of digitized patient
brain scans obtained on floppy discs from the
Nuclear Medicine Department's PET Scanner.
Three Institutes currently use this system for
diagnostic purposes and for pursuing basic
research in the areas of schizophrenia, epilepsy,
and aging.

• Gait Laboratory: The Automated Biomechanics
Laboratory System involves the measurement of
limb and spine position in space, forces in the
hand and between foot and ground, and
electrical activity of limb muscles. Designed for
use with arthritic, orthopedic, and neurological
patients, as well as amputees, it is anticipated
that the data collected will assist in the
evaluation of drug therapy and orthotic and
prosthetic devices.

• Clinical Pathology: Work with the Clinical
Center's Clinical Pathology Department centers
on the automation of laboratory procedures that
have resisted computerization by conventional
methods. A major innovation is the development
of a microcomputer-based system to facilitate
the recording of differential white cell counts.

• Pulmonary Laboratory: Automated methods for
evaluating pulmonary function using such
procedures as measurement of pulmonary
compliance and work of breathing and exercise
testing on a treadmill have been developed. The
goals are improved speed and accuracy in test
performance and evaluation by the NHLBI staff
who provide this service in the Clinical Center.

In the laboratory automation area, CSL work on the
Distributed Laboratory Data Acquisition and
Control System (DLDACS) for the laboratories of
NIADDK in Building 2 was largely completed this
year. Planning and design of this system began in
1 976; it replaces a centralized data acquistion and
processing system developed by CSL over a decade

ago. The system is designed as a local computer
network consisting of a group of microcomputers
that communicate with a host processor by way of a
front-end communications processor that, in turn,
performs a file store-and-forward function. Each
satellite microcomputer performs data acquisition
and control for a single instrument or experiment.
Acquired data files may be stored locally, however,
they are normally transferred via the network to the
host processor.

Development of DLDACS was phased over a period
of several years to avoid interfering with the
research of users of the old, centralized data
acquisition system. In fact, the communications
processor initially was connected to the old
Honeywell-516 central computer, and one satellite
microcomputer was put into operation early in 1979.
Since then, additional satellites have been added,
one at a time, in place of the hardwired instrument
interfaces used in the old system. There are
currently eight satellite processors in use. This year,
the final step of replacing the H-516 processor with
a multiuser DEC PDP-11/70 was made. Because of
the design of the local network, this major
accomplishment was completed without requiring
any changes to the satellite microcomputer software.

Other large CSL projects in NIH Research
laboratories during FY82 were:

• Electron Microanalysis: CSL is collaborating
with the Biomedical Engineering and
Instrumentation Branch, DRS, in the
development of an automated electron
microanalysis facility for use by NIH scientists. It
will be used for research into the elemental
composition of biological specimens and for
developing new techniques in electron
microscopy. Some of these, such as electron
energy loss imaging, can only be done with the
aid of a computer.

• FMF Cell Sorters: CSL pioneered data
management systems for FMF cell sorters at
NIH. Support for data acquisition, display, and
analysis is provided for four Becton-Dickinson
FACS II FMF/Cell Sorters. Two additional FMF/
Cell Sorters used at the Naval Medical Center in
collaborative programs with NCI are also
supported.

• Molecular Interactions System: A
microcomputer-based data system supervises
the acquisition and processing of information
from an analytical ultracentrifuge and a circular
dichroic spectropolarimeter used in NHLBI to
investigate the interactions between human
lipoprotein subunits. Capabilities include
acquisition, display, and preprocessing of data

from the ultracentrifuge and spectropolarimeter.
After limited local processing, files are
transferred to the central facilities' PDP-10 for
further processing.
• Animal Management: The Small Animal Section
of DRS supplies large numbers of rodents to
NIH investigators and also serves as an
international genetic resource. CSL is assisting
the Section in the design and procurement of a
computer system to improve their colony
management and breeding research programs.
CSL also invested considerable effort this year in the
development of new computer-related technology to
support biomedical and clinical research.

The Medical Information Technology Project, now

in its third year, achieved a major milestone this year
with the installation of a computer in a physician's
office for field trials. This project involves research
into source data automation techniques for patient-
physician encounters in primary care settings.

One outgrowth of the project is a system that (under
the physician's supervision) automatically produces
prescriptions and advice on followup home care,
both of which are keyed to diagnosis. It is this
prescription and advice system, initially tailored for
use in a dermatologic practice, that is undergoing
field trials.

In operation, the physician gives the system a
diagnosis for the patient examined, followed by the
selection of one or more drugs appropriate for that
diagnosis. The system's drug formulary contains
medications the physician would normally prescribe.
Using this formulary, the system displays a default
formulation for each drug prescribed based on the
diagnosis and, when necessary, on other factors
such as the patient's age, sex, or weight. The
physician may simply approve the default selections
or he may alter them to fit particular circumstances.
Once approved, the computer prints the
prescriptions on blank prescription forms.

In addition to the drug formulary, the computer
system's data base also contains numerous generic
advice 'modules' containing advice on followup
home care, additional information about a drug and
its use, and disease information. Based on the
diagnosis and the medication regimen prescribed,
the computer, again subject to the physician's
supervision, selects from among these advice
'modules' and tailors them to the situation at hand.
As is the case with prescriptions, the computer then
prints them for the patient.

The computer system just described benefits both
the physician and the patient. The physician's time is

saved because the computer produces accurate,
legible prescriptions, thus eliminating the need to
write them in longhand. Furthermore, summaries of
the prescriptions and instructions to the patient can
be produced for inclusion in the patient's record. The
patient benefits by receiving detailed printed
instructions about his disorder and any drugs
prescribed for him. Thus, problems resulting from the
patient forgetting or misunderstanding instructions
given to him orally by the doctor may be avoided.

The Image Processing System, another area of
advanced technology, involves the implementation of
both general-purpose and special-purpose hardware
and software to meet the growing image processing
requirements of the NIH community. Until recently,
this effort was conducted using the Evans and
Sutherland facility at DCRT, however, a new system
using state-of-the-art equipment has been designed
and is being procured. It is expected that a special
application of this technology will be to provide the
NIH Clinical Center with a medical imaging network.

Future Plans/Trends

FY83 can be expected to present an increased
demand for computers in laboratory and patient care
settings. More complex research goals of biomedical
research investigators point to a greater need for
automation in the laboratory. Technological
developments in large-scale circuit integration
continue to lead to lower costs and smaller sizes for
computers. The current popularity of 'personal'
computers is resulting in greater awareness on the
part of NIH scientists of the potential benefits of
computers. Concurrently, in common with many
other organizations, CSL is faced with contracting
personnel and budgetary resources.

In response to the challenge imposed by this
conflicting set of circumstances, CSL expects to
maintain high quality engineering and laboratory
computer support to NIH programs by continuing
policies developed in the past for managing resource
issues. For example, CSL staff will continue to be
deployed on projects promising maximum impact to
the NIH community-those that serve a significant
number of scientists, affect the quality of patient
care, or represent general-purpose developments.

Finally, a trend toward greater emphasis on software
engineering, begun several years ago with the
introduction of microprocessors, is expected to
continue with concomitant improvements in
productivity. Many of CSL's engineering design
functions-instrument interfaces, data acquisition
devices, special signal processors-are now
accomplished with microcomputers. Because of the
adaptability of software, these new design concepts
readily meet the changing needs of research
programs.

Publications and Presentations

Barrett, W.: An Iterative Algorithm lor Multiple Threshold Detection. Pro-
ceedings ol the IEEE Computer Society Conference on Pattern Recog-
nition and Image Processing. 1981, pp. 273-278.

Bonow, R., Ostrow, H., Rosing, D. Lipson, L., Kent. K.. and Allen, S.:
Verapamil-induced Changes in Ventncular Volume and Diastolic Func-
tion in Hypertrophic Cardiomyopathy. Mechanisms for Reduced Subval-
vular Gradient and Improved Symptoms. Circulation 64;IV-11, 1981.

Bonow, R., Ostrow, H., Rosing, D., Lipson, L., Kent. K.. Allen, S., Bachrach,
S., Green, M., and Epstein. S.: Scintillation Probe Measurement ol Left
Ventncular Cardiomyopathy. Circulation &4A\/-35. 1981.

Fiori, C, Gorlen, K., and Gibson, D : Comments on the Computenzation ol
an Analytical Microscopy Microscope, Proceedings of the Thirty-ninth
Annual Meeting of the Electron Microscopy Society of America. Baton
Rouge, Claitor's Publishing Division, 1981, pp 246-249

Fion, C. E.. Myklebust, R. L., and Gorlen, K. E.: Sequential Simplex: A
Procedure for Resolving Spectral Interlerence in Energy Dispersive X-
ray Spectrometry. Energy Dispersive X-ray Spectrometry Gaithers-
burg, MD, National Bureau of Standards, 1979, pp. 233-272,

Fiori, C. E., Swyt, C. R.. and Gorlen, K E.: Application of the Top-Hat Digital
Filter to a Nonlinear Spectral Unraveling Procedure in Energy-Disper-
sive X-ray Microanalysis. Microbeam Analysis San Francisco, San
Francisco Press, Inc., 1981, pp. 320-324.

Gershon, N., Porter, K., and Trus, B.: The Microtrabecular Lattice and the
Cytoskeleton. Their Volume, Surface Area and the Diffusion of Mole-
cules Through It. The Aharon Katizir-Katchalsky Symposium on Biologi-
cal Structure and Coupled Flows. Rehovot, Israel, June 6-11, 1982.

Hagins, W., Foster, M., George, J., and Trus, B : Combined X-ray Microana-
lysis and Radioautography of Diffusible Elements in Aqueous Suspen-
sions of Cells and Cell Fragments. Proceedings of the Microbeam
Analysis Society August 1982

Keogh. B., Gadek, J., Pnce, D., Nadel, L., and Crystal, R.: Remarkable
Similanties in Exercise Gas Exchange Parameters in Markedly Dispa-
rate Diseases: Compansons Between Idiopathic Pulmonary Fibrosis
and 1 -Antitrypsin Deficiency American Review of Respiratory Disease
125:257, 1982.

McGee, P , Trus, B., and Steven, A.: Techniques to Evaluate the Perform-
ance of Scanning Microdensitometers in the Digitization ol Electron
Micrographs. Micron Journal May 1982.

Nadel, L. D.: Automated Pulmonary Analysis by an Online Microcomputer.
In Nair, S. (Ed.): Computers in Cntical Care and Pulmonary Medicine
(in press).

Nadel, L D Breath-By-Brealh Pulmonary Exercise Testing Using an Online
Microcomputer First IEEE Computer Society International Conference
on Medical Computer Science, Computational Medicine (MEDCOMP
82) Philadelphia, September 25. 1982

Nikodem, V., Trus, B . and Rail, J : Two-dimensional Gel Analysis of Rat
Liver Nuclear Proteins after Thyroidectomy and Thyroid Hormone
Treatment. Proceedings of the National Academy of Sciences. USA
78:4411-4415, 1981

Piez. K . and Trus. B.: A New Model for the Packing ol Type-I Collagen
Molecules in the Native Fibril. Bioscience Reports 1 Great Bntain.
1981. pp. 801-810

Steven. A , Senwer, P., and Trus, B : Molecular Packing in Bacteriophase T7
Capsid Visualized at 2 5 nm Resolution in Computer-Processed Elec-
tron Micrographs Eighth Biennial Conference on Bactenophase As-
sembly Falls Creek Park, Tennessee, May 9-14, 1982

Steven, A , Trus, B , Pultz, C ., and V>/urtz, M.: The Molecular Organization
of Beet Necrotic Yellow Vein Virus Journal of Virology New York,
Academic Press. 1981, pp 428-438

Tate, R , Schullz, A . and Osborne, J Computer-Assisted Analysis of apo-
lipoprotein subunit interactions Federation Proceedings 41:874, 1982.

Trus, B , and Elzinga, M : Computer Modeling of a 17.000 Dalton Fragment
of Myosin Structural Aspects of Recognition and Assembly in Biologi-
cal Macromolecules. Rehovot. Israel, 1981, p 361

Trus, B , Serwer, P , and Steven, A Capsid Fine Structure ol Bacteriophase
T7 Determined by Image Processing ol Electron Micrographs Tenth
International Congress on Electron Microscopy Hamburg, Germany.
August 17-24, 1982.

Trus, B . and Steven, A : Computer Processing ol Electron Micrographs of
Periodic Biological Specimens Washington Society of Electron Micros-
copy Annual Picture Meeting Bethesda, MD. May 6, 1982,

Trus, B , and Steven, A : Digital Image Processing ol Electron Micrographs-
The PIC System. Journal of Ultramicroscopy 6:383-386. 1 981

Laboratory of
Applied Studies

Eugene K. Harris, Chief

Functions

The Laboratory of Applied Studies (LAS) has three
main purposes:

1 . in collaboration with biomedical scientists, to
apply mathematical theory and computing science to
the construction, testing, and improvement of
mathematical models of physiological processes--
particularly reaction-diffusion kinetics, transport of
substrate to tissues, and the control of metabolism
within cells and tissues;

2. in collaboration with clinicians, to develop and
apply mathematical or statistical theory and special-
purpose computing procedures (analog or digital as
required) to facilitate research projects aimed at
improving the diagnosis of disease and assessment
of treatment;

Two sections carry out these primary LAS functions:

Applied Mathematics Section"AMS"(John E.
Fletcher, Ph.D., Chief). This staff of five includes
specialists in applied mathematics, computer
science, biomathematics, and medicine.

Medical Applications Section-MAS"(James J.
Bailey, M.D., Chief). This five-member staff includes
physician-scientists, electronic engineers, and
computer systems analysts.
The Chief, LAS, is a biostatistician with training in
public health and the basic medical sciences.

Scope of Work

• biochemists and ptiarmacologists at NIH, at the
Medical College of Virginia, and at other
universities in the U.S.A. and in France working
on models for receptors of drugs or other
ligands, on the kinetics of enzymes in
membranes, and on other problems in tissue
metabolism

• physiologists and chemical engineers in the
U.S. A and Europe studying the transport of
substrate within the microcirculation and the
regulation of tissue perfusion

• clinicians in the cardiology, pulmonary, and
hematology branches of NHLBI; in the arthritis
and rheumatism branch of NIADDK; and in the
medical intensive care unit and the departments
of diagnostic radiology and diagnostic imaging of
the Clinical Center

Highlights of the Year's Activities

Work continued in computer-based studies of
pulmonary gas exchange during exercise in patients
with respiratory disease. Despite unfortunate delays
due to problems with the vendor-supplied software,
which have now been resolved, considerable
progress can be reported in this collaborative project
with the Pulmonary Branch and the Clinical
Hematology Branch, NHLBI. Interfaces to the
exercise equipment to enable online computer
control have been designed and built by Drs. R.
Burgess and E. Pottala, while system programming
for realtime control of these devices and for analysis

of accompanying data on C02 and 02 pressures
and content is being completed by IV1. Norton.
Preliminary studies of healthy subjects have begun.

Dr. A. Albert, Fogarty International Research Fellow
In LAS, has contributed to the theory of dynamic risk
assessment in acute disease by creating very
general, yet practical, methods for sequential
analysis of time-dependent multivariate measurement
vectors obtained during the course of the patient's
illness. Combining these methods with discriminant
function techniques enables daily reassessment of
probable patient outcome. The procedures have
been applied sucessfully to patients under intensive
care following myocardial infarction. In addition. Dr.
Albert has published a generalized theory and
method of computing multivariate likelihood ratios for
combinations of discrete and continuous variables.
This work represents a substantial advance in the
calculation of diagnostic probabilities (predictive
values of specified illnesses).

Theoretical work by Dr. M. Bieterman on the
adaptive finite element method for the solution of
reaction-diffusion equations resulted in new software
routines for the efficient cost-effective solution of
many of the complex systems of partial differential
equations that arise from biological models. These
routines, known as Femoll are now available on the
NIH central computer systems.

Studies by B. Bunow and E. Pottala of network
modeling languages have demonstrated that network
models are feasible for use as biological simulators.
Although computer times for these models on the
NIH central system are presently excessive, their use
on dedicated systems such as the VAX or similar
machines has established their utility. Presently,
interested NIH scientists are being instructed in
network methods, and exploratory applications are
underway in collaboration with NIH researchers on
problems of nerve conduction and facilitated
diffusion in tissues. One advantage of these
simulations is that a functional rather than a
mathematical description of the biological process
suffices as a requirement to initiate study of its
stimulus-response characteristics.

A comprehensive report summarizing Dr. J.
Fletcher's past decade of research on the analysis
and interpretation of equilibrium binding data through
mathematical models has been completed and is
being distributed to interested scientists worldwide.

During FY82 LAS staff members participated in
various teaching and consulting, or advisory,
activities.

J. Fletcher continued to serve as Chairman of the
Mathematics and Computer Science Departments,
Foundation for Advanced Education in the Sciences.

J. Bailey continued as a member of an NHLBI site-
visiting team concerned with computer analysis of
exercise ECG's. He also serves as consultant on
common standards for quantitative
electrocardiography for a program in medicine and
public health, sponsored by the European Economic
Community.

E. Harris continued to be a consultant in applied
statistics to the Food and Drug Administration's
Division of Medical Devices and Diagnostic Products.
Dr. Harris also serves as consultant statistician to
the College of American Pathologists and to the
International Federation of Clinical Chemistry (Expert
Panel on the Theory of Reference Values), and is a
member of the Board of Editors of Clinical
Chemistry.

Future Plans

Testing of the computer-controlled system for
measuring pulmonary gas exchange in exercise will
continue on healthy volunteer subjects. Studies to
evaluate cardiorespiratory abilities in patients and
controls will be specified in cooperation with the
Pulmonary and Clinical Hematology Branches of
NHLBI. A new project in cooperation with the
Department of Critical Care Medicine, CC, to
investigate dysfunction in neurologically impaired
patients will be pursued through development of
microcomputer-based methods for analysis and
display of evoked potentials.

Utilizing the newly upgraded DeAnza image
processing system, a joint study with the clinical
neuropharmacology laboratory, NIMH, will continue
to develop theory and methods for interpreting
electron energy loss spectra from ultracellular
biological specimens, particularly in the study of
dense bodies in electron micrographs of blood
platelets.

The analysis of the signal/noise characteristics of
various parameters of regional ventricular wall
motion will continue jointly with the Nuclear Medicine
Department, CC, and the Cardiology Branch, NHLBI,
in an effort to improve differential diagnosis of
coronary artery disease and other cardiac
myopathies.

A major effort will be made to facilitate the
conversion of network models simulating biological
processes into forms compatible with languages
such as MLAB to enable the use of powerful data-

fitting algorithms. Training of and collaboration with
NIH scientists using network simulation modeling will
continue. In the area of numerical analysis, the
current program for approximate solution of partial
differential equations (FEM0L1) will be extended to
sets of 3 or more equations, enabling it to be of
more general use to NIH scientists using
biomathematical models.

Statistical theory developed to support the
calculation of reference values for the differences
between two or three successive measurements of
blood constituents will be published and its
application extended through collaborative studies of
selected patient groups. Investigation of relative
sensitivities of multivariate and univariate reference
ranges will progress using clinical chemistry data and
followup diagnostic information from a large health
maintenance program.

Publications and Presentations List

Albert, A.: Atypicalily indices as reference values (or laboratory data Amer.
J Clin. Pathol 76: 421-425. 1981

Albert, A : On the use and computation of likelihood ratios in Clinical
Chemistry Clin- Chem. 5: 1113-1119, 1 982

Albert, A,, Chapelle, JR., Heusghem, C, Kulbertus, HE, and Hams, E.K.:
Evaluation of risi< using serial laboratory data in acute myocardial in-
farction In Heusghem, C. Albert, A., and Benson, E S. (Eds): Ad-
vanced Interpretation of Clinical Laboratory Data. Nev» York, Marcel
Dekker (in press).

Bailey J J , Berson, AS. Jackson, L K , Milliken, J A., Stevens, J.M.. Toian,
G D, and Wolf, H K : Evaluation Methodologies for ECG diagnostic
systems In Bonner, RE., and Pryor, T A (Eds): Computerized Inter-
pretation of the ECG VI New York. Engineering Foundation (in press).

Bunow, B: All things flow and change-some thoughts on the role of
reaction and transport in biology J Wash Acad Sci (in press).

Bunow, 8 : Turing and the physico-chemical basis of biological patterns. In
Prewitt, J (Ed): IEEE Turing Memorial (in press)

Bunow, B , and Mikulecky, DC : On the feasibility of using flux meas-
urements to distinguish among active transport models. Polish Winter
School ol Membrane Transport (in press).

Burgess, R C: An instrument lo add evoked potential capability to the
standard electroencephalograph. EEC and Clin Neurophysiol. 53: 33,
1981.

Evans, W.J., McCourtney, J.E., and Shrager, R I : Titration Studies of Phytic
Acid. J. Am Oil Chemists' Soc. 59: 189-191, 1982.

Fletcher, J E The Analysis ol Equilibrium Binding Data by the Fitting of
Models. May 1982, 102 pp.

Fletcher, J.E , and Schubert, R,W.: The Theoretical Prediction of Substrate
Levels and Their Histograms in Cell Free Perfused Tissues Proceed-
ings of the International Meeting of the Society of Oxygen Transport to
Tissue (ISOTTJ (in press).

Harns, E K : Further applications of lime series analysis to short senes of
biochemical measurements. In Grasbeck. R., and Alstrom, T. (Eds):
Reference Values in Laboratory Medicine. Chichester, U.K., John
Wiley & Sons, 1981, pp 167-176.

Harris, E K : Regression, least squares, and correlation. In Seligson, D.,
M.D, (Ed): Handbook of Clinical Chemistry (in press).

Harris, E.K.: Use of statistical models lo delect sub|ect-specific changes. In
Yasaka, T. (Ed): Proceedings of International Conference on Automat-
ed Multiphasic Health Testing & Services Amsterdam, Excerpta
Medica, 1981, pp. 35-44.

Harns, E.K., Yasaka, T , Horton, MR., and Shakarji, G.: Companng multivar-
iate and univariate subject-specific reference regions for blood constitu-
ents in healthy persons. Clinical Chemistry 26: 422-426, 1982

Macfarlane, P.W., Chen, C.Y., and Bailey, J.J: A companson ol point
sconng techniques for the diagnosis of LVH. In Macfarlane, P.W. (Ed):
New Frontiers in Eteclrocardiology (in press).

Shrager, R.I , and Hendler. R.W.: Titration ol Individual Components in a
Mixture with Resolution ol Difference Spectra, pKs, and Resox Transi-
tions. Anal Chem. 544: 1147-1152, 1982.

Physical Sciences
Laboratory

George H. Weiss, Chief

Function and Scope of Work

The Physical Sciences Laboratory carries out
research in support of NIH programs and in pursuit
of its mennbers' interests in the areas of physics,
physical chemistry, applied mathematics, and applied
computer technology, it has an active research
program in its areas of expertise and provides
consulting services to other NIH scientists in
theoretical physics, chemistry, and applied
mathematics. Members of PSL develop theory and
often develop instrumentation for biomedical
experiments.

The PSL staff consists of seven professionals who
work in the areas of:

• biophysics

• light scattering, as applied to problems in
determining structure and function of biologically
interesting gels and other forms of matter

• nuclear magnetic resonance, as applied to
kinetic and configurational properties of
molecules

• the use of image processing techniques to
interpret electronmicrographs of membrane
structure

• the physical chemistry of actin, and

• applied mathematics in areas suggested by
investigations at NIH.

All of the members of the Laboratory collaborate
with scientists both on and off the NIH campus. For
example, crystallographic data bearing on
intermolecular forces is generated at Brock
University, Canada, in collaboration with members of
PSL in a joint theoretical and experimental project in
that general area. A new project has been initiated
together with members of the Clinical Center and the
Computer Systems Laboratory, DCRT, on the use
and interpretation of ultrasonic data in the study of
tongue motion in different parts of speech.

FY82 Accomplishments

A joint project between members of PSL and Brock
University has succeeded, for the first time, in
directly measuring the force between biological
macromolecules. This has provided a good picture of
how the force between parallel DNA helices behaves
in response to changes in distance, as well as
elucidating the effect of structure on this force. An
extension of this work will allow the determination of
important thermodynamic parameters of proteins.

The applicability of two-dimensional Fourier
Transform Spectroscopy to the determination of
kinetic parameters for enzyme reactions was
demonstrated for the first time, in a study of the
isomerization of glucose-6-phosphate. This work
required not only the techniques of physical
chemistry, but also the development of a suitable
theory as well as the study of the effects of
instrumental noise on the calculation of parameters.

Work has continued on light scattenng techniques as
applied to the determination of mechanical rigidity
and internal viscosity of polymer gels. The current
emphasis is on the structure and properties of
polyacrylamide gels because of their technological
importance, but studies are also underway on gels
formed from glycoproteins and clots formed from
reconstituted human plasma. This research requires
expertise both in the development of a considerable
body of theory to interpret experimental data as well
as experimental skill in the modification of available
equipment to perform the relevant measurements.

A theory of errors of parameter estimates in positron
emission tomography has been developed and will
be incorporated into programs in use on the PET
scanner. This theory is part of a continuing study of
the optimal design of experiments that includes
present analyses of NMR and chromatography
experiments in addition to the PET study.

Dr. Adrian Parsegian has been elected President of
the Biophysical Society. Dr. George Weiss has been
appointed Biostatistics Editor of Cancer
Investigations.

PSL partially sponsored an international meeting on
Random Walks in Physics and Biology, which was
held at the National Bureau of Standards from June
28 to July 1, 1982. Dr. George Weiss was Chairman
of the organizing committee for the meeting.

Future Plans/Trends

Research in PSL will continue along lines already
initiated. A new joint project with the Speech
Pathology Department of the Clinical Center and
CSL will study the combination of ultrasound and
image processing techniques on the study of tongue
position in speech.

With the recent access to an x-ray spectrometer on
the NIH campus, Drs. Parsegian and Lee will be able
to extend their measurements of intermolecular force
constants to study nucleic acids. A large project is
being planned on the use of molecular graphics
programs to investigate molecular contacts in protein
crystals.

Further studies will be undertaken in the relation of
instrumental noise to the precision of parameter
estimates in NMR measurements. These studies
should point the way to optimization of such
experiments. Dr. Ferretti will be joining NHLBI in the
near future but collaboration on these problems will
continue.

Publications

Aizenbud, B., and Gershon, N. D.: Diffusion of molecules on biological
membranes of nonplanar form--a theoretical study. Biophys. J. (in
press).

Aizenbud B., and Gershon, N. D.: Diffusion of Molecules on Microvillous
Biological Membranes. In Perelson, A. C, DeLisi, C, and Wiegel. F. W.
(Eds.): Cell Surface Phenomena. New York, Marcel Dekker (in press).

Aizenbud, B. M., and Gershon, N. D.: Hydrodynamic equations and VH light
scattenng from viscoelastic (solid-like and fluid-like) systems. Pheno-
menological approach. Physica A 107:126-142, 1981,

Aizenbud. B , and Gershon. N. D,: Hydrodynamic equations and VH light
scattering from viscoelastic (solid like) systems. II. Molecular approach.
Physica A (in press)

Brenner, S. L., and Korn, E. D.: Stimulation of actin ATPase activity by
cytochalasins provides evidence for a new species of monomeric actin.
J. Biol Chem. 256:8663-8670. 1981.

Chen. S-H., Chu. B.. and Nossal. R. (Eds): Scattenng Techniques Applied
to Supramolecules and Nonequilibnum Systems NATO ASI Series B.
Vol. 73. New York. Plenum Press. 1981.

Ciarkowski. J. E., FerrettI, J. A., and Marshall. G. R.: Comparative conforma-
tional studies of angiotensin II and two sterically constrained analogs
by 600 MHz proton spectroscopy. J. Am. Chem. Soc. (in press).

Jacobson. L., and Ferretti. J. A.: The determination of a phosphorus-phos-
phorus nuclear Overhauser enhancement by two-dimensional magne-
tization exchange spectroscopy. J. Amer. Chem. Soc. (in press).

Kiefer. J. E.. and Weiss. G. H.: A comparison of two methods for accelerat-
ing the convergence of Fourier series Comp. and Math. 7:327-336.
1981.

Lis, L. J., McAlister, M., Fuller, N , Rand, R. P, and Parsegian, V A.:
Interactions between neutral phospholipid bilayer membranes. Biophys.
J. 37:657-666. 1982.

Lis, L. J., McAlister, M.. Fuller, N., Rand, R. P., and Parsegian, V. A.:
Measurement of the lateral compressibility of several phospholipid bi-
layers Biophys J. 37:667-672. 1982.

Marks. T. J.. Pohl. L. R., Gillette. J. R.. Hong. M.. Highet. R. J., Ferretti, J.
A., and Henson. J. A.: Stereoselective formation of bromobenzene
glutathione conjugates. Chem. Bio. Interactions (in press).

Nossal, R.: Laser Light Scattering. In Methods of Experimental Physics.
New York, Academic Press, 1982, pp. 299-336.

Nossal. R.: Ouasielastic Light Scattenng from Polymer Gels. In Chen, S-H.,
Chu. B.. and Nossal. R. (Eds.): Scattering Techniques Applied to Supra-
molecules and Nonequilibnum Systems. New York. Plenum Press,
1981. pp. 301-320.

Nossal. R.: Stochastic aspects of biological locomotion. J. Stat Phys. (in
press).

Nossal. R., and Jolly, M.: Shear waves and 'internal viscosity' in cylindncal
gels. J. AppI Phys. (in press).

Parsegian, V. A. (Ed): Protein-Lipid Interactions in Membranes. The Rocke-
feller University Press, 1982, 401 pp

Rish, B. L., Caveness, W. L., Dillon. J. D.. Kistler. J. P.. Mohr. J. P.. and
Weiss. G. H : Analysis of brain abscess following penetrating craniocer-
ebral injuries in Vietnam /Veorosurge/y 9:535-541. 1981

Rubin, R J., and Weiss. G. H : Random walks on lattices: The problem ol
visits to a set of points revisited J. Math Phys. 23:250-253. 1982.

Shapiro. J R . Pikus. A.. Weiss. G H , and Rowe. D W.: Hearing and
middle ear function in osteogenesis imperfecta. J. Am. Med. Assoc
247:2120-2126. 1982.

Weiss. G H : Optimal parameters for the measurement of the half-width of
a Gaussian peak. Sep Sci <S Tech (in press)

Weiss. G H.: Random walks and their applications. Amer. Sci (in press).

Weiss. G H.. Caveness. W F . Einsiedel-Lechtape. H., and McNeel, M L.:
Life expectancy and causes of death in a group of head-in|ured veter-
ans Arch. Neurol (in press).

Weiss, G H , Feeney. D M., Caveness, W. F., Oillon, J. 0.. Kistler. J. P„
Mohr, J P , and Rish, B L : Prognostic factors for the occurrence of
posttraumatic epilepsy. Arch. Neurol (in press).

Weiss, G. H., Ferretti, J. A., Kiefer. J A.: A study o( precision in the
measurement of chemical shifts. J. Mag Res. 46:69-83. 1982

Weiss. G. H.. and Rice. J.: A combinatonal problem in pharmacology J.
Math Biol (in press)

Weiss. G. H.. and Rubin. R. J.: Random walks: Theory and selected appli-
cations. Adv Chem. Phys. (in press).

Weiss, G. H., and Shiesinger. M. F : On the expected number of distinct
points in a subset visited by an N-step random walk. J. Slat Phys.
27:355-363. 1982.

Weiss. G H . Talben. A., and Brooks. R A.: The use of phantom views to
reduce CT streaks due to insufficient sampling. Phys in Biol and Med
(in press).

Laboratory of Statistical and
l\/lathematical l\/lethodology

James E. Mosimann, Chief

Function and Scope of Work

The Laboratory of Statistical and Mathematical
Methodology (LSM) combines research in
mathematical statistics, mathematics, computer, and
information science with collaboration and service in
these areas to NIH researchers and administrators.
LSM staff interact with all NIH Institutes, with other
Federal agencies outside DHHS, and with biomedical
researchers worldwide.

In addition to the position of chief, the Laboratory
has fourteen full-time professional positions
distributed among four sections:

• The Biomathematics and Computer Science
Section (BCS), directed by a mathematician,
performs independent research and provides
consultation and collaboration in the specialties
of its four computer and mathematical scientists.

A major part of LSM activity is the offering of
statistical and mathematical systems/packages to
the NIH user community. LSM accepts responsibility

for evaluation of new systems/packages and their
suitability for NIH. When it offers a system/package
to the NIH community, LSM makes three basic
commitments:

1 . Maintenance of the package, with adequate
documentation, through NIH computer system
changes, system/package updates, and corrections.

2. Rapid response to queries concerning user
access to a system/package program, including job
control language and program parameters.

• BMD and BMDP, Biomedical Computer
Programs, UCLA.

• SPSS and SCSS, Statistical Package for the
Social Sciences, SPSS, Inc.

• SAS, SAS/GRAPH and SAS/ETS, Statistical
Analysis System, SAS Institute, Inc.

• P-STAT Statistical Package, P-STAT, Inc.

• IMSL, International Mathematical and Statistical
Libraries, IMSL, Inc.

• MSTAT1, Collection of Mathematical and
Statistical Programs, DCRT.

In FY82 alone the SSS staff responded to over
5,500 quehes concerning use of these packages.
Also during this year, every system/package went
through at least one major update.

The Biomathematics and Computer Science Section
maintains several systems/packages and specialized
systems on the DECsystem-10 of the Computer
Center. Foremost in use is the interpretive system
MLAB, designed (by LSM scientists) for
biomathematical modeling. C-LAB, previously an
independent package for pattern recognition and
cluster analysis, has now been incorporated into
MLAB. The Unified Generator Package, written and
maintained by a BCS staff member, is on DCRT's
IBM System 370.

Uses per month of

Statistical packages supported by LSIVI'

58800
54600 -
50400 -
46200 -
42000 -
37800 -
33600 -
29400 -
25200 -
21000 -
16800 -
12600

8400

4200 H

JUN 75 JUN 76 JUN 77 JUN 78 JUN 79 JUN '80 JUN '81 JUN '82

'Packages supported by the Statistical Software Section only. Does not include
packages supported by the Biomathematics and Computer Sciences Section.

As a result of LSM's policy of not only supporting the
use of these systems/packages but also aiding in
the interpretation of their output, the statisticians of
the Statistical Methodology Section provide
consultation over a wide range of scientific fields.
Some very brief consultations are very successful
because there is a known answer to the question at
hand. Other consultations involve extensive time and
statistical/mathematical/computer science research
as well.

Research projects in LSM vary widely, from studies
of natural language processing for medical
information systems and studies of efficient
algorithms for information retrieval to studies in
mathematics and statistical methodologies for
biomedical applications.

FY82 Accomplishments

FY82 was LSM's eighth year as a separate entity
within DCRT. The volume of its computational and
consultative services continued to expand; its
research activities decreased slightly, with one
project terminated.

Computation

In FY82, LSM continued to expand teaching and
documentation for supported systems/packages.
LSM taught eight introductory courses for SAS, two
for SPSS, and two for BMDP. In addition, two
introductory courses and one advanced course were
taught for MLAB, plus an introductory course for
BRIGHT (a package supported by DMB) and two
courses on computer graphics at NIH. The tenth
edition of the MLAB Reference Manual is now being
printed. The DCRT Mathematical and Statistical
Program Manual was updated in FY82.

BCS staff contributed to the implementation of
overlay facilities on the DECsystem-10, and MLAB
was redesigned in a segmented form to use overlay,
so that software for seldom-used operations is
loaded into computer memory only when needed.
MLAB software was substantially enlarged by
incorporation of C-LAB operators, of new
OMNIGRAPH character fonts and codes for display
of mathematical formulas, and of new, more
informative error messages.

Consultation, Collaboration, and Research

As in FY81, LSM consultation and research in FY82
was closely tied to the use of the computer. Most
consultations (55 percent) involved statistical advice
combined with considerable computer use. Others
(40 percent) involved computer use alone and a
small fraction (5 percent) involved mathematical or
statistical advice with only limited computer use.

In FY82, LSM research, collaborative, and
consultative efforts merged more closely and were
less distinguishable among themselves. In a number
of studies, statistical methodologies were developed
for, or modified to suit, specific biomedical problems.

The results of LSM research on simultaneous
confidence intervals for ratios appeared in the
Journal of the American Statistical Association in
1982. A study was completed on the connection
between statistical and algebraic independence,
applicable to the sample covariance matrix of
multivariate data.

In statistical discriminant analyses--a subject of LSM
research in collaboration with Dr. J. Darroch, Flinders
University, South Australia, and Dr. H. Hoffman,
DRS--methods adapted for size and shape variables

are being used to study genetic variation in
laboratory mice with reference to purity of breeding
stocks. A separate study of independence of size
and shape variables before and after scale change
appeared in FY82, along with other LSM studies of
statistical distributions. A collaborative study was
undertaken with Dr. P. Turkeltaub (BB/DPB) on
clinical symptoms and allergic reactions to pollen.
LSM also participated actively in a study of Chagas
disease (Dr. F. Neva, NIAID/LPD) and continued
collaborative work in various studies of
schistosomiasis (Dr. A. Cheever, NIAID/LPD).

New studies in linear models were initiated in FY82,
and two of these have been completed. The first
gives optimal linear model estimates of variance
components, while the second presents a solution to
the multivariate analysis of variance with unbalanced
data. A collaborative study on the spatial distribution
of blue cones in the retina with Drs. S. Schein (NEI/
CB) and F. de Monasterio (NEI/LVR) is near
completion. An algorithm related to this work has
been published. A study of patients with systemic
lupus erythematosus in collaboration with Dr. T.
Chused (NIAID/LMI) is near completion.

In computer science, a study of hashing with
coalescing lists for information storage and retrieval
was completed and submitted for publication. A
method of resolving overlapping spots on two-
dimensional electrophoretic gels was studied;
programs implementing the method are under
development. Studies of equivalence of module
theories and of classification of Riemannian
geometries by N-algebras (with possible applications
to size and shape analysis) continued. A pilot study
of computer 'reading' of technical text was
completed. This involved computer translation of
syntactic and semantic content of a simplified
chapter of a computer programming textbook into
operational structures in the procedural language
PROLOG.

In medical linguistics, research studies on the
morphosemantic structuring of medical terms derived
from Greek and Latin were continued. Previous work
on computer parsing of medical words into
morphemes via suffix analysis was extended to more
than 1,500 terms representing 6 kinds of surgical
procedure. The results are applicable to the
construction of dictionaries suitable for information
retrieval by computer. Also studied were rules for
morphosemantic transforms useful for computer
substitution of terms in the automatic encoding of
medical text. The MIS-developed encoder program
for automatic assignment of SNOP (Systematic

Nomenclature of Pathology) codes to surgical
pathology diagnoses was used on a routine basis
(Dr. J. Costa, NCI/LP). Collaborative studies on the
improvement and modification of the SNOP
dictionary with Dr. Donald E. Henson (NCI/BCPC)
continued in FY82. An LSM linguist also served as a
consultant on a machine translation project at
Georgetown University.

LSM research on the 'symmetric axis' method of
describing biological shapes was discontinued this
year, due to the retirement of the principal
investigator. Computer software for symmetric axis
analysis and reconstruction of figures will be
maintained. Programs and documentation are sent to
biomedical researchers on request.

Future Plans/Trends

Publications

Buck, J., Buck, E., Hanson, F. E., Case, J. F., Mets, L., and Atta, G.: Control
of flashing in fireflies IV. Free run pacemaking in a synchronic pterop-
tyx. Journal of Comparative Physiology 144: 277-286, 1981.

DeBlas, A. L., Ratnaparkhi, M. V., and (ulosimann, J. E.: Estimation of the
number of monoclonal hybridomas in a cell fusion experiment. In Vuna-
kis, H. v., and Lagone, J. J. (Eds.): Immuriocfiemical Techniques (a
volume of Methods in Enzymology). New York, N. Y., Academic Press
(in press).

DeBlas, A. L, Ratnaparkhi, M. V., and Mosimann, J. E.: Estimation of the
number of monoclonal hybridomas in a cell fusion experiment. Journal
of immunological Methods ^5: 109-115, 1981.

Grimes, A. M., Mueller, H. G., and Malley, J. D.: Examination of binaural
amplification in children. Ear and Hearing 2: 208-210, 1981.

Hutchinson, G.: A complete logic for n-permutable congruence lattices.
Algebra Universalis 1 3: 206-224, 1 981 .

Hutchinson, G.: Exact embedding functors between categories of modules.
Journal of Pure and Applied Algebra 25: 1 07-1 1 1 , 1 982.

Knott, G. D.: Graphics Facilities in MLAB. In Sproull, R. (Ed.): Computer
Graphics, a section of Chang, S. (Ed.): Handbook of Computer and
Electrical Engineering (in press).

Knott, G. D.: Fixed-bucket binary storage trees. J. of Algorithms (in press).

Malley, J. 0.: Simultaneous confidence intervals for ratios of normal means.
Journal of The American Statistical Association 77: 170-176, 1982.

Mosimann, J. E., and Malley, J. D.: The Independence of Size and Shape
Before and After Scale Change. In Taillie, C, Patil, G. P., and Baldes-
sari, B. (Eds.): Statistical Distributions in Scientific Work. Vol. 4, Models,
Structures and Characterizations. Dordrecht, Holland, D. Reidel Pub-
lishing Co., 1981, pp. 137-145.

O'Connor, M. A.: Invariant metrics on cones. Proc. of the Conference on
Invariant Metrics and Holomorphic Maps. Rome, Italy, Istituto di Alta
Matematica F. Severi di C.N.R. (in press).

Ratnaparkhi, M. V.: On splitting model and related characterization of some
statistical distributions. In Taillie, C, Patil, G. P., and Baldessari, B.
(Eds.): Statistical Distributions in Scientific Work, Vol. 4, Models, Struc-
tures and Characterizations. Dordrecht, Holland, D. Reidel Publishing
Co., 1981, pp. 357-363.

Ratnaparkhi, M. V.: Some bivariate distributions of (X,Y) where the condi-
tional distribution of Y, given X is either beta or unit-gamma. In Taillie,
C, Patil, G. P., and Baldessari, B. (Eds.): Statistical Distributions in
Scientific Work, Vol. 4, Models, Structures and Characterizations. Dor-
drecht, Holland, D. Reidel Publishing Co., 1981, pp. 389-400.

Roux, J. J. J., and Ratnaparkhi, M. V.: On matrix-variate beta type I distribu-
tion and related characterization of Wishart distribution. In Taillie, C,
Patil, G. P., and Baldessari, B. (Eds.): Statistical Distributions in Scientif-
ic Work, Vol. 4, Models, Structures and Characterizations. Dordrecht,
Holland, D. Reidel Publishing Co., 1981. pp. 375-378.

Shapiro, M.: A note on Lee and Schacter's algorithm for Delaunay triangula-
tion. International Journal of Computer and Information Sciences (in
press).

Yaar, I., Shapiro, M., and Pottala, E.: Spectral analysis of the EEG in
hepatic encephalopathy treated with levodopa. Electroencaphalography
and Clinical Neurophysiology 52: 61 7-625, 1 981 .

Data Management
Branch

J. Emmett Ward, Chief

Functions and Scope of Work

The Data Management Branch (DMB) provides
advice and assistance to research investigators,
program officials, and administrators throughout NIH
in planning for and obtaining computer data
processing services. In this role the branch is a
central NIH resource for systems analysis, design,
and programming. There are currently 47 permanent
full time employees whose disciplines include
computer science, mathematics, and statistics.

DMB staff design and create computer-based data
management systems that provide practical solutions
to the unique mix of administrative, scientific, and
management data processing problems encountered
at NIH. Each new computer system user is provided
comprehensive training in all system facilities and
functions of the system provided by DMB. In addition
DMB staff teach courses about programming tools;
provide advice on data management techniques to
NIH programmers; serve as consultants to the B/l/
D's for obtaining and monitoring contracting services
for computer systems development; and create and
maintain general purpose, user-oriented
programming tools to speed building and improve
operation of applications systems.

DMB comprises five sections. The Applied Systems
Programming Section (ASPS) and the Scientific
Applications Section (SAS) provide general
computer systems analysis and programming
services for all of the B/I/D's. The ASPS supports
general data management, and the SAS handles
those projects that require scientific data analysis.

The Data Base Applications Section and the Data
Base Enchancement and Control Section develop
and maintain the central administrative data base for
NIH materiel and financial management. The Clinical
Support Section develops and maintains the
Clinical Information Utility as a data base for
research and patient care in the Clinical Center.

FY82 Accomplishments

The Clinical Information Utility is a long term effort
that, when completed, will provide a unique archive
of integrated data for use in patient care and
research. Efforts to date have involved the
development of software to acquire and to make
available data from the Medical Information System
and the individual clinical service activities. The
integration of these individual data bases has now
begun. The design of this effort will provide users
with a single source for most of the clinical service
data and all of the medical information system data.
It will allow authorized users to make requests for
information and will provide either reports or sub-files
of the data, which will be produced in a format
acceptable to BRIGHT for further perusal and
analysis.

BRIGHT is a user-friendly interactive program
designed to make data entry, correction, updating,
manipulation, retrieval, formatting, and printing of
tabular data bases easier. The first DCRT training
course for BRIGHT was taught in early December
1981 and a formal seminar introducing the system to
the clinical associates was conducted in March 1982
in the Clinical Center. BRIGHT has had several new
features added during the fiscal year and it is a
much more versatile and easily used package for
data and graphics display, table-making,
computation, and analysis.

To assist the Records Processing Section in the
Medical Records Department of the Clinical Center,
a tracking system for the medical records audit
process was designed and implemented. This
system provides a mechanism for monitoring the
status of medical records in process and for
following up with physicians concerning delinquent
reports. This system has had a significant impact in
that it has not only reduced the manual effort
involved in the audit process but also improved the
organization of the followup procedure.

The NIH Administrative Data Base is an ongoing
development project that uses data base technology
in support of NIH-wide materiel and financial
management. This project expanded on several
fronts. A vendor credit system was added to the
accounts payable procedure; an alphabetic search
capability was made available for the vendor data
base; all miscellaneous obligations such as training
orders, utilities, tuition, work requests, etc., were
programmed to flow through the ADB; and a facility
to produce Purchase Orders (SF-147's) online was
added for reprints and professional services.

Extending the availability of ADB functions to the B/
l/D's is also well under way. in collaboration wth the
Office of Research Services and the Training
Assistance Branch, DPM, B/i/D terminal locations
have been identified and contracts have been
negotiated for conducting training on delegated
procurement and receiving. Current plans call for all
B/I/D's to be making full use of these functions by
early Fall, 1 982.

From July 1 982 through February 1 983 the stock
requisitioning and the central and self service stores'
inventory systems will be phased in. Full conversion
to this new set of functions should be in place by the
end of the first quarter of calendar year 1983.

Development of the new financial management
system for the ADB is under way and a detailed
design document should be available in November
1982. Plans call for implementing the fund
certification, fund control, and general ledger
modules of this system by utilizing off-the-shelf
software, modified to fit NIH requirements.

For a detailed review of the many other important
projects in which the Data Management Branch has
been involved, please refer to the project reports in
Volume 2. These projects are too numerous to
highlight in the summary.

In the area of general support for NIH activities,
DMB continued to maintain and teach courses on
the Inquiry and Reporting System (IRS) and
MARKIV; to support NIH use of Chemical Biological
Activities (CBAC) and Biosciences Information
System (BIOSIS) current awareness searches on a
biweekly and semimonthly basis, respectively; to
maintain and distribute the NCI Survival System; and
to consult with and assist NIH programmers and
contractors, enabling facile use of DCRT computer
facilities.

Future Plans/Trends

During the next year, the Administrative Data Base
will expand to include all central inventory functions
and work will have begun to bring other inventory
systems (e.g.. Planning and Control Branch,
Biomedical Engineering and Instrumentation Branch,
and Pharmacy) under this umbrella. The financial
management system fund certification, fund control,
and general ledger modules should be well on their
way to completion by the end of FY83. Stock
requisitioning should be installed in all of the B/I/D's
and open market requisitioning should be ready for a
pilot test by the end of the next fiscal year.

The Clinical Information Utility will have a completely
integrated data base that will provide an effective
link among the user, the clinical data and the
analysis.

Its role as a central resource for computer
applications development throughout the B/I/D's will
continue to receive primary support by DMB.

Publications

George, D.: Epizootiology of an Outbreak of Mousepox at the National
Institutes of Health. Laboratory Animal Science 31 :609-61 5, 1 981 .

Harris, E.K., Yasaka, T., Norton, MR,, and Shakarji, G,: Connpanng Multivar-
iate and Univariate Subiect-specific Reference Regions for Blood Con-
stituents in Healthy Persons. Clinfcal Chemistry 28: 422-426, 1982.

Rodbard, D.. Cole. B., and Munson. P.J.: The Need for Innovative Ap-
proaches to Radioimmunoassay Quality Control. In Wilson. D. W. (Ed.):
Quality Control of Radioimmunoassays. 1982. pp. 251-260.

Computer Center
Branch

Joseph D. Naughton, Chief

Function

The Computer Center Branch (CCB), the largest
component of DCRT, designs and operates the NIH
Central Computer Utility and its associated
telecommunications facilities; conducts a formal
computer training program; and provides technical
documentation, programming support, and
consultation on the use of computers in support of
scientific and administrative programs throughout
NIH.

Because the Computer Center receives no direct
appropriation, all services are provided strictly on a
fee-for-service/cost recovery basis.

Two large, interconnected, multicomputer facilities--
the IBM System 370 and the DECsystem-10--form
the nucleus of the NIH Computer Utility. Each facility
is linked by telephone lines to hundreds of remote
interactive terminals and computers located
throughout NIH and many other Federal agencies.
System software is either designed and implemented
by Computer Center personnel or acquired from
other sources and adapted to meet the unique
needs of the NIH biomedical research and
administrative user community.

A specialized staff of professional, technical, and
administrative personnel keep the NIH Computer
Utility functioning smoothly 24 hours a day.
Experienced computer systems programmers and
analysts develop and maintain operating system
software. They also offer technical consultation,
design and teach training courses, and write
technical documentation on the use of the Utility. A
staff of experienced computer systems technicians
operates the Computer Utility's hardware and
telecommunications network, and provides data
entry services. Systems management professionals
establish long term program goals and ensure the
design integrity of the Utility.

A number of research and development projects are
also conducted by the Computer Center. These

include the design and installation of data security
facilities for over 300,000 online data sets, the
design and implementation of communications
networking facilities to make possible the rapid
exchange of information among research
investigators, the development of improved graphic
output facilities, and the exploration of new training
methods.

Scope of Work

The NIH Computer Center plans, designs,
implements, and operates a large, general-purpose
Central Computer Utility. This Utility provides a
variety of computational services in support of a
dynamic and diverse user community of over 10,000
research scientists, administrators, secretaries, and
programmers throughout the Federal Government.

The primary component of the NIH Computer Utility
is a uniquely configured, 'loosely coupled' system
designed around 5 IBM 3081 processors with 80
million bytes of directly addressable memory. A
peripheral complex of 115 tape drives, 300 disk
drives, 2 mass storage systems, 1 1 high speed
printers, card reader/punches, microfiche output
units, and teleprocessing facilities for over 1 ,000
communications lines assure adequate data storage,
input/output, and communication capabilities. Over
2,000 interactive terminals and 143 Remote Job
Entry (RJE) computers located in users' offices and
laboratories make the power of the Utility available
at the source of the problem whenever needed.

Operating in a multiprogramming mode, this facility
provides timesharing and batch processing, graphic
services, and data base management facilities. The
IBM System 370 facility operates 24 hours a day,
and it currently processes over 13,000 batch jobs
and 7,000 interactive sessions daily.

The other major component of the NIH Computer
Utility is the DECsystem-10 timesharing facility. This
facility is designed around one DK and two KL-10

processors with five million bytes of directly
addressable memory, and it provides timesharing
services and data communications support to over
2,000 laboratory research investigators throughout
NIH. Ten tape drives, 31 disk drives, and a variety of
teleprocessing facilities make up the peripheral
complex.

The NIH Computer Utilty provides a variety of
programming languages-including FORTRAN,
COBOL, PASCAL, BASIC, Assembler, PL/I, and
SAIL--as well as a data base/data management
system (IMS), the TELL-A-GRAF interactive graphics
package, and a comprehensive library of statistical
and utility programs. Online computing and batch job
submission are available interactively on the IBM
System 370 through WYLBUR and TSO, and
through timesharing services on the DECsystem-10.
Several facilities for job output on paper and
microfiche are available, and there are programs for
creating two-dimensional or three-dimensional
graphic displays for advanced research projects.

The users of the Computer Utility's IBM System 370
are informed of current programming standards and
available facilities in a comprehensive manual, the
Computer Center Users Guide. The DECsystem-10
Timesharing Guide provides similar information for
users of this system. Changes in the Utility are
announced to users through INTERFACE, a
periodic technical newsletter. An in-house training
program offers 40 courses four times a year, to help
users develop expertise in the use of the Utility.

NIH COMPUTER UTILITY
System 370 Services

i^ 6S 69 70

Calendar Year

Through the years, the workload of the NIH
Computer Utility has increased steadily.

Highlights of FY82
Accomplishments

As in past years, the user demand and workload of
the NIH Computer Utility showed steady growth in
1982. A record number of jobs-over 6.5 million-
were processed on the IBM System 370 during the
year, and over 93 percent of these jobs were
completed and available to the user in less than two
hours. The DECsystem-1 0 facility also ran at a
record pace, processing approximately 120,000
interactive timesharing sessions during the year.
Overall, the Computer Utility processed an average
of 26,000 job-sessions per day, a seven percent
increase over last year.

A major highlight of the past year was the
completion of an eight-month transition plan for
installing the newly acquired IBM System 370
hardware. Over 1 00 hundred new tape drives, 250
disk drives, and 5 new Central Processing Units
were put into productive use without interrupting
normal service. The new IBM hardware has
increased power, capacity, and reliability to meet the
growing needs of Computer Utility users. Major new
IBM System 370 components installed during the
year include:

• Five 3081 Dyadic Processor Complexes-IBM's
most powerful processor, the 3081 , supports
two processors in one physical unit. Each 3081
processor provides more than twice the
processing power of its predecessor, the 3033
processor, in a unit smaller than a single 3033.
Installation of the 3081 complexes resulted in a
dramatic improvement in batch job turnaround
time and interactive response time, and has
increased the capability for processing complex
applications in the most cost effective and
efficient manner possible.

• One hundred fifteen 3420-6 drives-These
advanced tape drives increase the speed and
reliability of tape processing through the use of
6250 bpi reading and recording density.

• The 3380 Direct Access Storage Device-The
3380, IBM's newest disk drive, can store three
times as much data as the 3330 disk it replaces.
The 3380 also has a data transfer rate that is
twice the speed of the older 3330 units. Online
data storage was restructured to permit storage
of data sets that range in size from a few bytes
up to many millions of bytes. Over 300,000
online user data sets were successfully
transferred to the new 3380 disks. The
increased availability of high speed online
storage, a direct result of the conversion to
3380 disks, made it possible to phase out the
technologically obsolete 3330 private mountable
volumes. Use of 3380 disks for online data

storage substantially improves the capacity and
cost-effectiveness of the NIH Computer Utility.
• IBM 3850 Mass Storage System (MSS)--The
MSS became fully operational this year, resulting
in a significant improvement in turnaround time.
This also increased cost effectiveness,
expanded online storage capability, and
permitted substantial amounts of offline data to
be stored online inexpensively. Data space
equivalent to more than 29 billion bytes has
already been allocated on MSS volumes (at
about one-ninth the cost of online direct access
data storage space). Implementation of the 3850
MSS has allowed the maxium size of online data
sets for batch jobs to be quadrupled. Users
have found that the low charge for MSS
storage, in addition to the savings that arise
from fewer tape and disk mounts and faster
processing time, make the MSS a very attractive
alternative to other data storage media. The
3850 MSS has also been made available,
through the MERCURY intersystem file mover,
to users of the DECsystem-10 for storage of
large rarely-accessed files.
The installation of the new processors and storage
devices expanded the computational capability of the
NIH Computer Utility dramatically. As a result, the
limits on CPU time, scratch disk space, region size,
and terminal idle time were all increased. This
permits user batch jobs and interactive sessions to
use significantly more of each of these resources. In
addition, a new job class (class E) was established
to serve the needs of the larger job that does not
require volume mounting. The new larger limits
improve job turnaround time, permit greater flexibility
in job class selection, and allow the running of larger
jobs during the prime shift.

DECsystem-10 users also received significant
enhancements in timesharing services during the
year. The installation of the latest version of the
Symmetric Multiprocessing (SMP) operating system
both increased reliability and extended the
availability of timesharing services for users. In
addition, maximum real memory size was increased
by 25 percent, and timesharing hours were extended
to allow unattended service during the night.

As in the past, software was enhanced to meet the
needs of the user community. This year's additions
include TVEDIT, a new text editor on the
DECsystem-10 that uses no command words, and
POSTER, an easy-to-use program on the
DECsystem-10 that generates customized posters
and slides for textual material.

The building renovation program that began two
years ago is nearly completed. A new, larger,
modern user terminal room with a variety of
interactive terminals and a Remote Job Entry (RJE)

terminal was put into operation on the first floor of
Building 12A. Efficient and comfortable, the User
Area provides an effective work environment and is
equipped with adequate power and air conditioning
facilities to support the growing needs of users for
years to come.

The custom-designed training facility-equipped with
sound-insulated walls, carpeting, large work tables,
and cushioned chairs to provide a comfortable
learning environment-is now being used for
Computer Center training classes. Comfort and
safety are enhanced by vanable lighting that allows
illumination for note-taking while the screen area is
dimmed, by dust-free chalkless marker boards, and
by built-in projection facilities that eliminate the
hazard of trailing electrical cords.

This year, the Molecular Graphics System operated
by CCB was used to solve structure problems where
very little information was available. An algorithm
was devloped to determine from first principles the
shape of RNA molecules in three dimensions. The
algorithm successfully reconstructed PHE- and SER-
tRNA molecules. Models of the limulus hemocyanin
complex were developed from image-enhanced
electron microscope data. Using symmetry
constraints, the space-filling representation of
macromolecular structure was extended to represent
structures of several million daltons. The models of
several viruses-including adenovirus, the Semliki
Forest virus, and polyoma virus-were also
constructed.

Future Plans

The coming year will see the next steps in the
Computer Center's continuing plans to provide better
services at equivalent or reduced costs.

The installation of 64 IBM 3380 disk actuators during
early FY83 will complete the total replacement of all
hardware comprising the IBM System 370 facility.
During the year, the disk drives on the DECsystem-
10 facility will be replaced by RP07 drives that have
a capacity two and one half times that of the current
RP06 drives.

Following the completion of the installation, the
major emphasis of the Computer Center staff for
FY83 will be directed toward the design and
implementation of facilities and procedures to
increase system availability. A number of new,
realtime performance monitoring tools will be
incorporated into the system to permit the early
detection of faults or performance deterioration. New
problem diagnosis methods and procedures to
permit the rapid identification and resolution of
problems will be investigated. Steps will be taken to
minimize scheduled system shutdowns for dumps,
data migration, fix application, equipment installs and
maintenance, and to isolate services for improved
reliability and availability. Fail soft, back-up, and
recovery procedures will be improved to minimize
recovery time when failures do occur.

The teleprocessing facilities of the NIH Computer
Utility will be expanded and improved to provide
additional capacity to support more remote terminal
users and to offer new functions and higher speed
services. Facilities will be investigated to support a
greater variety of terminal types, including word
processors, on all services provided by the
Computer Utility and to support more convenient
methods of switching among services. During the
year, the Computer Center will replace its interactive
CRT and hardcopy terminals with new, more modern
units and a procurement will be initiated to acquire
new Remote Job Entry (RJE) workstations.

The Computer Center will invest significant effort in
the installation of improved physical and technical
security facilities to insure the privacy of user data.
Access to the physical plant and computer output
boxes will be controlled by an electronic access
control system. New software security facilities will
permit the 'owner' of sensitive data and programs
stored on the Utility to exert more specific levels of
control over access to them.

The coming year also will see an emphasis on the
development of new self-study training courses for
users and the completion of the audiovisual facilities
in the new training rooms. In addition to these
rooms, the ongoing building renovation program will
include construction of offices for the Systems Team
and Office of the Chief, CCB, on the second floor of
Building 12; the Plotter and Microfiche Units will
move to new quarters on the first floor of Building
12A.

Publications

Berzofsky. J. A.. Buckenmeyer. G.K., Hicks. G., Gurd, F.R.N., Feldmann.
R.J.. and Mina, J.: Topographic antigenic determinants, recognized by
monoclonal antibodies to sperm whale myoglobin. J. Blot. Chem. 257:
3189-3198. 1982.

Feldmann, R.J.. Potter, M.. and Glaudemans, C.P.J.: A hypottietical space-
filling model of the V-regions of the galactan-binding myeloma immun-
oglobulin J539. Mol. Immun. 18:683-698.1981

Furie. B.. Bing. D.H., Feldmann. R.J.. Robinson, D.J.. Burnier. J. P.. and
Fune. B.C.: Computer-generated models of blood coagulation Factor
Xa, Factor IXa. and Thrombin based upon structural homology with
other serine proteases. J. Biol Chem. 257: 3875-3883. 1982.

Pawlita. M.. I^ushinski. E.. Feldmann. R.J.. and Potter. M.: A monoclonal
antibody that defines an idiotope with two subsiles in galactan-binding
myeloma proteins. J. Exp. Med. 1981: 1946-1956. 1981.

Office of the
Director

Arnold W. Pratt, M.D., Director

Three separate units make up the Office of the
Director, DCRT: the Office of ADP Policy
Coordination, the Office of Administrative
Management, and the Office of Scientific and
Technical Communication.

These offices complement the work of the six
Laboratories and Branches by:

• coordinating the complex Federal policies and
procedures that govern getting and using
computers at NIH

• providing general administrative management
support for the Division's work

• serving as a central source of information about
DCRT activities and about computer-related
disciplines.

Office of ADP Policy Coordination

Henry J. Juenemann, Chief

Function and Scope of Work

The Office of ADP Policy Coordination, under the
direction of the Assistant Director of the Division, has
four closely related functions:

Lit serves as a focus for NIH-wide coordination of
Automatic Data Processing (ADP) policy matters.

2. It serves as a central NIH point of contact with
the Public Health Service, the Department of Health
and Human Services, other HHS Agencies, and the
General Services Administration on policy and
regulatory questions.

3. It provides the point of contact for those NIH
procurement and contracting matters that must be
cleared by DCRT prior to procurement or contracting
action.

4.lt also provides advice and assistance to NIH
staff and others concerning the internal operations of
DCRT in matters of ADP policy and procurement.

The activities of the Office include:

• advising the Director of DCRT and, through him,
the Director of NIH on ADP policy matters

• reviewing and evaluating proposals from NIH B/
l/D's for procurements and contracts related to
computing and ADP

• directing the development of the annual NIH
ADP Plan

• assisting the NIH Division of Management Policy
on questions relating to its responsibility for
administrative and management computer
applications

• representing NIH in PHS and DHHS policy
formulation efforts

• working with HHS and GSA staff to obtain
necessary approvals for NIH on procurements
and contracts, and

• answering inquiries from scientists and
administrators who are confused by the whole
process.

FY82 Accomplishments

A major set of tasks accomplished during FY82
involved obtaining PHS, HHS, and GSA approval for
full recompetition of three contracts under which
DCRT supplies the three types of NIH Standard
Terminals to users. This required extending the
present contracts in order to provide adequate lead
time for the reprocurements. It also required six sets
of interlocking clearances and three minor and three
major solicitation packages. The tasks were
accomplished during FY82 in a way that provided
continuous terminal support to users of the DCRT-
operated NIH computer utility.

During the year, this office reviewed nearly 400
proposals for acquisition of ADP equipment and/or
services and commented on approximately 100
research contracts involving ADP. Each was
reviewed to ensure that it was justified and was in
conformance with PHS, HHS, GSA, and 0MB
guidelines. Suggestions and assistance were
provided to the NIH Procurement Branch and to the
various Research Contract Branches as to the most
expeditious procurement route to follow. In many
cases one or more of the Laboratories and Branches
of DCRT assisted by providing expertise to help in
the review of technical aspects of the proposals.

In addition, the office was heavily involved in the
development of specifications, RFP's, and
clearances for a variety of specialized automated
systems, including many minicomputers for
laboratory use. A contract was awarded for the
automation of the NIH Library; implementation of the
initial phases of that project is underway. A
delegation of procurement authority was obtained
from GSA for a long term project to automate the
data handling associated with the Division of
Research Services' animal breeding program.
Preparation of the necessary solicitation package
and conduct of the procurement was underway
during the latter part of FY82. Likewise, GSA
delegations of authority were obtained for the total
reprogramming of the National Library of Medicine's
MEDLARS system and for the upgrading of the
hardware that will be required to develop, test, and
operate the new and improved MEDLARS System.

l\\e Annual ADP Plan that combines projections of
new ADP initiatives and required ADP expenditures
for all Bureaus, Institutes, Divisions, and Offices of
NIH was completed. It details an NIH ADP program
projected to be 75.5 million dollars and 772 work
years in FY83 growing to 80.5 million dollars and

788 work years in FY84 and to 83.9 million dollars
and 853 work years in FY88. Although the accuracy
of the out-year projection must be regarded with
caution, the trend of ADP and computing
involvement in the scientific and managerial life of
NIH is unmistakable.

Future Plans/Trends

FY83 will be marked by major changes in the
structure, staffing, and focus of NIH's ADP Policy
Coordination function. These changes, the nature of
which are not predictable at this writing, should be
accomplished during the last quarter of FY82.

Office of Administrative Management

L. Lee Manuel, Chief

Function and Scope of Work

The Office of Administrative Management, under the
direction of the Executive Officer, consists of 1 5
people, organized functionally into three sections:
finance, personnel, and general administration. The
office serves as liaison between these functions and
the NIH Office of Administration, Office of Research
Services and with other NIH, PHS, and DHHS
offices. It handles a broad range of administrative
managerial functions for an NIH research division of
almost 300 people.

Fiscal Year 1982
Accomplishments

The Administrative Office processed a variety of
procurements and acquired approximately 30 million
dollars in supplies and equipment during FY82. Day-
to-day management activities conducted by this staff
included: procurement purchases and contracts;
processing of travel and training requests;
administration of property, space, and
communications; payroll; and mail/messenger
services. In October 1981 the Administrative staff
began using the Delegated Procurement System
(DELPRO), a subsystem of the NIH Materiel
Management System (MMS). This process allows B/
l/D personnel to enter and control their own
delegated procurement data such as ICO's and
ROC's, Repair Orders, reprint orders, FACS book
orders, and professional services requests.

Based on a decision by the Director, DCRT, the
Budget Office developed budgets at the laboratory
level and implemented a reporting system to allow
Lab/Branch Chiefs to track actual obligations against
their budgets. This has resulted in greater awareness
of spending patterns and more accurate
recordkeeping. The need for even more detail by the
Lab/Branch Chiefs will undoubtedly result in some
modifications, but the reporting system has proved to
be a valuable management tool. The office also

participated in setting and reviewing rates for Service
and Supply Fund data processing activities. This was
especially challenging in a year of major equipment
transition in the Computer Center.

The Project Control Office continued to process
requests for new accounts, register new users, and
prepare billing data for the NIH computer facility. The
office also successfully completed its major annual
update of information on over 10,000 users and
2,000 accounts. Several modifications, including the
elimination of some reports, were made to the
Project Accounting System.

The Personnel Office processed approximately 400
personnel actions that included promotions,
reassignments, temporary appointments, excepted
appointments, transfers, and career-conditional
appointments. The Department continued to operate
under a partial hiring resthction most of the year,
making outside recruitment and selection difficult.

A new Departmental performance appraisal system
was implemented this year, effective October 1, 1981,
as a result of the Civil Service Reform Act of 1978.
Personnel Office staff conducted training and
orientation for all supervisors and employees on the
implementation of the new Employee Performance
Management System (EPMS). This massive effort
involved 12 separate sessions, each conducted by
either the Personnel Officer or the Personnel
Management Specialist. The Personnel Officer
serves as the coordinator for EPMS and provides
assistance to employees and supervisors on a
continuing basis.

The writing of new factor evaluation position
descriptions in the GS-334-0 series for all computer
specializations in DCRT was coordinated by the
Personnel Office with the assistance of contract
personnel who conducted workshops on the Factor
Evaluation System for the 334 series. The Personnel
Office staff carried out the classification of these
positions.

The Executive Officer and Assistant Director served
on a work group witli the Director and staff of the
NIH Division of Management Policy to prepare a
position paper with alternative recommendations for
the Director, DCRT, and for the Associate Director
for Administration, NIH, concerning the ADP policy
functions at NIH. The paper described the functions
associated with this process and addressed certain
issues that should be resolved.

The Executive Officer also coordinated the
preparation of the Annual Research Plan and
represented the Division within OD, NIH, as Program
Planning Officer. He also served the Division as its
international representative to the Fogarty
International Center and as its legislative contact
with the Division of Legislative Analysis, OPPE, NIH.
This required keeping abreast of issues in these

areas and advising the Division's staff as necessary
on items that might have an impact on DCRT
programs.

A new Full Time Equivalency (FTE) system was
implemented to track DCRT employment against
NIH-mandated ceilings.

Future Plans/Trends

The 0AM will continue its efforts in providing
administrative management support to the Division's
programs. A new 0MB Circular, A-123, titled 'Internal
Control Systems' will probably be implemented at
NIH during the coming year. This Circular prescribes
policies and standards to be followed in establishing
and maintaining internal controls in program and
administrative activities.

Office of Scientific and Technical
Communications

William C. Mohler, M.D., Chief

Functions

The DCRT Office of Scientific and Technical
Communications (OSTC), under the direction of the
Associate Director, DCRT, includes:

• the DCRT Library, which maintains a high quality
collection of materials for use by DCRT and NIH
staff and serves as a resource for other libraries;

• the DCRT Information Office, which serves as
the focus for providing the NIH community and
the professional and lay public with information
about DCRT's activities and related applications
of computing in biomedical research;

• scientific work in related areas of pattern
recognition, multidimensional information
processing, and applications to medical decision
making.

Scope of Activities

The DCRT Information Office handles the full range
of activities of an NIH Information Office. The
Information Officer, assisted by a Public Affairs
Specialist, answers inquiries, produces and
distributes print and audiovisual materials, and
arranges briefings for visitors. The office coordinates
special events, works with members of the media,
and provides advice, assistance, and educational
resources on communications for the DCRT staff. It
also responds to all Freedom of Information requests
coming to DCRT.

A major part of the Information Office program is
directed within NIH toward improving an
understanding of the Division's work and the
application of computing to biomedical research. But
the scope of its communications includes Federal
agencies, schools, libraries, private industry, medical
organizations, representatives of the media, and a
wide variety of individual scientists, engineers, other
professionals, and lay persons.

The DCRT Library is a fully independent, special
library, staffed by the Librarian and a Library
Technician. The Library provides a full range of
services and has access to a wide variety of online
information services and data bases. The collection
of monographs, periodicals, and other documents
covers subjects related to the work of DCRT. These
include computer science, mathematics, statistics,
electronic engineering, information science, and
management.

The Library supports the work of the DCRT staff and
serves as a resource for employees in the rest of
NIH. It is an integral part of the Washington area
network of special libraries and cooperates with
libraries outside the area to share resources. It does
this through organizations such as the Interlibrary
Users Association of the Washington/Baltimore
Area, the Metropolitan Washington Library Council,
FEDLINK (a Federal library consortium), and the
national OCLC (Online Computer Library Center)
network.

The other activities of OSTC derive from the
interests of its scientific professionals. They work
with other professionals at NIH and with medical and
technical groups, both government and private,
outside of NIH.

Highlights of FY82

Dr. Prewitt was very active in FY82. She was the
leader in organizing two major scientific meetings:
MEDCOMP '82, the First International Conference
on Medical Computer Science sponsored by the
IEEE Computer Society, and the First International
Symposium on Medical Imaging and Image
Interpretation. Her collaborations with physicians,
mathematicians, engineers, and computer
professionals led to papers and presentations on
medical decision making and on pattern recognition
applied to biomedical images. She began an
appointment as Stocker Professor of Electrical

Engineering at Ohio University under the aegis of the
Intergovernmental Personnel Act.

The DCRT Information Office underwent several
changes. In the first quarter, Mrs. Hodges moved to
work full time on the needs of the Data Management
Branch for informational materials describing their
computer systems. Despite this, the Office had
another productive year. This is even more
noteworthy in light of other assignments undertaken
by its staff and new restrictions placed upon public
information activities in the general effort to cut costs
and improve efficiency throughout the Federal
Government.

As part of this effort, the Information Officer, Mrs.
Miller, went on detail for four months to the Office of
the Assistant Secretary for Public Affairs, DHHS, to
assist with several projects involving public affairs
and computer expertise:

1. A study in response to 0MB Circular M-81-14,
'Federal Information Centers,' for which the
Department must develop an implementation plan to
consolidate, eliminate, and improve its existing
clearinghouses and resource centers.

2. The systems review process mandated by
Public Law 96-511, the Paperwork Reduction Act.

3. The Department's response to H.R. 4758, which
proposes legislation on the government sale of data
processing and telecommunications services, and
cost recovery of same.

4. A project to design and implement a data
processing system to keep track of Department-wide
public affairs budgets and publications, as part of a
DHHS Control Plan mandated by 0MB Bulletin Bi-
le, 'Elimination and Consolidation of Government
Periodicals and Recurring Pamphlets.'

During her absence, Mr. Hall handled the office,
within the limits of his temporary appointment.

In spite of these constraints, the staff covered the
many routine day-to-day activities and provided
consultations on a variety of communications
services. These included arranging publicity for
MLAB courses, assisting in slide production for a
presentation of BRIGHT, obtaining contract editorial
services for Division staff members, and assisting
the DCRT director in responding to administrative
requests.

In addition to coordinating, editing, and producing the
DCRT Annual Report, the Office carried out the
following major efforts during the year:
• Printed materials about DCRT activities went to
over 6,000 people. To provide current
information on DCRT activities, the Office
produced complete revisions of the old
brochures describing the Laboratory of Applied

Studies and the DCRT Library, and it obtained
reprints of Computers at NIH: Tools for the
Advancement of Medicine and of the DCRT
Fiscal Year 1981 Annual Report, Volume 2.

• The Office wrote articles for the NIH Record and
helped other DHHS groups report DCRT
activities. The PHS covered WYLBUR in its
publication Future Office; the Clinical Center and
the NIH Audiovisual Branch prepared NIH
Record articles citing work in DCRT.

• The Division received mention in several private
media throughout the year. These included the
SIGBIO Newsletter, VoiceNews (a newsletter on
voice technology). Current Health (a magazine
for high school students). Sky (Delta Airlines' in-
flight magazine), and Omni (a half-hour
television science magazine). Film footage of
molecular graphics was taken for future use on
a CBS television program. The Body Human.
The Information Office arranged for regional
computer voice technology experts to be
interviewed on the Illinois public television
network.

• The short sound/slide show describing the
Division and highlighting each laboratory and
branch was completely revised to help brief
visitors and orient new employees.

• Work on the DCRT bibliography involved
correcting and updating records on over 1 ,000
scientific papers written by DCRT researchers
over the last 1 2 years.

The Information Officer continued to explore the
economics of electronic typesetting. As Chair of the
NIH Printing Committee, she advised others on these
methods. She also served on the Board of Directors
of the Washington chapter of Women in
Communications, Inc., a national organization for
public relations, journalism, broadcasting, and
communications professionals.

The DCRT Library also had a busy year improving
service while managing fixed space, budget cuts,
and changing technology.

A complete redesign of the Library brochure now
helps users more readily locate monographs,
documents, journals, and reference materials. New
signs made by the Library staff identify shelf areas,
sections of the card catalog, and locations for return
of materials. The Librarian, Mrs. Chu, compiled the
prototype for a series of bibliographies covering
specific subject areas of the library's collection.

A fourth online bibliographic reference service
provided better coverage for the wide range of
technical and scientific needs of users of the Library.
The hidden cost to this breadth of coverage is the

time that the Librarian and the Library Technician,
Ms. Florentine, must spend mastering system
updates and the idiosyncracies of the data files and
indexing strategies. The Librarian attended the
District of Columbia Online Users group meetings to
share experiences with such systems and to keep
current with new developments in this emerging
technology.

Budget restrictions caused a reduction of monograph
purchases and a complete review of the list of serial
acquisitions. In spite of this, space limitations
required continued attention to weeding out less
useful materials and to conversions of essential
journal holdings to microforms. With the aid of the
DCRT Library Committee, a review of the collection
led to removal of some 50 monographs, 400
documents, and 200 journal volumes.

A multistage, multiyear project continued to cope
with the new Anglo-American Cataloging Rules
(AACR2). This effort is complicated by the high cost
of computer-based library systems. None yet meets
the needs and budget of our small special library.
The Library's own computer-based circulation control
system continues to perform well at a reasonable
cost. For the moment the strategy to approach
computer-based cataloging remains use of the OCLC
data base to create a machine readable file of items
in the collection, edited according to AACR2 and
local conventions. These can be produced on tape
by FEDLINK at the appropriate time.

Much of the Library's work is aided by the Librarian's
active role in professional organizations. She
continued as a FEDLINK delegate to the OCLC
Users Council and served on the Council's Executive
Committee as Council Secretary. She completed the
first of two years as a Director on the Executive
Board of the District of Columbia Library Association,
an organization of some 1 ,000 Washington area
librarians.

Nevertheless, there is reason to be optimistic for the
immediate future. Both the Librarian and the
Information Officer have plans to meet these
challenges. Dr. Prewitt's appointment to an endowed
position at Ohio University will allow her to pursue
her work in the coming year without some of the
current limits on funds, personnel, and equipment
that exist in the Division.

Plans

Plans for the coming year will follow the general
lines of work in FY82. The current Federal emphasis
on control of publications and audiovisual products
will offer a significant restraint for providing
information about DCRT activities to the NIH
community and to the many groups outside NIH that
have expressed interest in DCRT work. The
continuing trend toward limited budgets in the face
of persistent inflation will require efforts to cut costs
while maintaining a high level of service in the
Library and a high quality of products from the
Information Office.

Publications and Presentations

Computers at NIH: Tools for the Advancement of Medicine. NIH Publication
No. 82-1039, reprinted 1982, 20 pp.

Data l^anagemenl Branch. NIH Publication No. 81-1927, Fall 1981, 16 pp.

DCRT Library. January 1982, 24 pp.

Division of Computer Research and Technology Fiscal Year 1981 Annual
Report, Volume 1. October 1981, 44 pp.

Division of Computer Research and Technology Fiscal Year 1981 Annual
Report, Volume 2. October 1981, 100 pp.

Dwyer, A.J., Glaubiger, D., Ecker, J.G., Doppman, J.L., Prewitt, J. M.S., and
Plunkett, J.: The Radiograptiic Followup of Patients with Ewing Sarco-
ma: A Demonstration of a General Method. Radiology (in press).

Dwyer, A.J., Prewitt, J. M.S., Ecker, J.G., and Plunkett, J.: The Use of the
Hazard Rate to Allay the Peril of Inappropriate Followup: An Optimiz-
ation Approach to Patient Management. Journal of IVIedical Decision
Making (in press).

Herron, R., Dwyer, S.J., and Prewitt, J. M.S.: Computer Graphics for Medical
Imaging. NGGA Tutorial T-11 Summary, 1981.

Kroop, D.O., and Prewitt, J. M.S.: Computer Security in Medicine. MED-
COMP '82, Philadelphia, PA, September 23-26, 1982 (in press).

Laboratory of Applied Studies. NIH Publication No. 82-1928, April 1982, 16
PP-

Miller, P.O.: Text-to-tape Copy Preparation. In Torrence, S.R. (Ed.): Pro-
ceedings of the 1981 Annual Conference of the National Association of
Government Communicators. 1981, pp. 262-265.

Prewitt, J. M.S.: How to Asses Image and Signal Processing Technology in
Health Care. Feierliche Erotfnung des Neubaus des Instituts fur Medi-
zinische Informatik und Systemforschung (MEDIS) der Gesellschaft fur
Strahlen- und Umweltforschung (GSF), Neuherberg, Germany, June 14,
1982.

Prewitt, J.M.S.: Medical Computer Science: Whither or Wither? MEDCOMP,
IEEE Computer Society, Silver Spring, MD, 1982.

Prewitt, J. M.S.: New Developments in Image Processing and Analysis: Par-
allel Computer for Medical Application. SIAM National Visiting Lecture,
University of Florida, Gainesville, FL, October 14, 1981.

Prewitt, J. M.S.: Pattern Recognition in Medicine. World Congress on Medi-
cal Physics and Biomedical Engineering, Hamburg, Germany, Septem-
ber 7-9, 1982.

Prewitt, J.M.S.: Segmentation of Cell Images: Art or Science? Cytometry
2:122, 1981.

Prewitt, J. M.S.: The Diagnostic Performance of Leukocyte Counters. Cyto-
metry 2: 122, 1981.

Prewitt, J. M.S., Clyman, J., Lander, W.B., Lehman, J.S., Ranade, S.M., and
Wu, S.C: Cytologic and Nuclear Shape: Fourier Characterization. Inter-
national Conference on High Resolution Ceil Image Analysis. North
Hollywood, CA, January 24-26, 1982.

Prewitt, J. M.S., and Lander, W.B.: Cytologic and Nuclear Shape: Fourier
Characterizations. Analytical and Quantitative Cytology 4: 156, 1982.

Prewitt, J.M.S., Plantholt, M., Simpson, M., Edberg, T., and Sanfeliu, A.: The
Graph-Theoretic Characterization of Tissue Textures. Cytometry 2: 1 22,
1981.

Prewitt, J.M.S., Ranade, S.M., Wu, S.C, and Lehman, J.S.: Cytologic and
Nuclear Shape: Fourier Characterizations. Cytometry 2: 1 22, 1 981 .

Ranft, U., Fu, K-S, and Prewitt, J. M.S.: Segmentation of Transverse Section
Pictures of Muscle Tissue. World Congress on Medical Physics and
Biomedical Engineering. Hamburg, Germany, September 7-9, 1982 (in
press).

Schuette, W.H., MacCollum, M.A., Smith, C.E., Prewitt, J.M.S., and Shack-
ney, S.E.: An Iterative Method for the Decomposition of DNA Histo-
grams. Annual Meeting of Cell Kinetics Society, March 1982.

Schuette, W.H., Shackney, S.E., Smith C.E., and Prewitt, J. M.S.: An Iterative
Method for the Decomposition of Gaussian Distortions from DNA Histo-
grams. MEDCOMP, Philadelphia, PA, September 23-26, 1982 (in
press).

DCRT

Division of Computer Research and Technology
National Institutes of Health
Bethesda, Maryland 20205

DIVISION OF COMPUTER RESEARCH AND TECHNOLOGY

FISCAL

YEAR

1982

ANNUAL
REPORT

VOLUME 2

DOXRIW

LALajajJaj

Foreword

The Division of Computer Research and Technology DCRT programs focus on three primary activities:
has primary responsibility for incorporating the power conducting research, developing computer systems,
of modern computers into the biomedical programs and providing computer facilities.

and administrative procedures of NIH. DCRT serves jhe fiscal year 1982 annual report describes our
as a scientific and technological resource for other work in two volumes:

parts of PHS, and for other Federal organizations Volume 1 gives an overview of the work of

with biomedical and statistical computing needs. each group, highlighting the year's

accomplishments;

Volume 2 gives details about the projects and
activities of each group.

Contents

Computer Systems Laboratory

Clinical Research, Patient Care, Epidemiology 1

Laboratory Investigation 3

Program Management and Administration 4

Biomedical Communications and Conference

Support 5

Computer Research and Technique Development 5

Research Projects

Computer Support for Flow Microfluorimetry/Cell

Sorters (FMF) 5

Cardiac Scintillation Probe 7

Computerized Radiation Therapy 8

Medical Intensive Care Unit Patient Monitoring

Computer System 9

Automated Management of Critically III

Patients 11

Positron Emission Tomography (PET) Scan Image

Analysis in Aging Studies 11

Computer Assisted Tomography (CAT) Scan

Image Analysis in Aging Studies 13

Computer Analysis of Autoradiographic Images

of Recombinant DNA Colonies 13

Cataract Grading via Computerized Slit-Lamp

Image Analysis 14

Robust Boundary Detection of Necturus Gall

Bladder Cells 15

Rehabilitation Medicine Computer System 16

Positron Emission Tomography (PET)

Facility 18

Computer Assisted Hematology Morphology

Data Handling System 19

Automated Pulmonary Physiology Testing 19

Assessment of Tongue Motion During Speech

Using Ultrasonic Imaging Techniques 21

Anesthesia Computer System 22

Medical Information Technology Project 23

Molecular Graphics and Sequence Analysis 24

Computer Analysis of Gel Electrophoresis 25

Morphometric Analysis of Normal and Neoplastic

Tissue Cultures 26

Virus Structure As Determined by Image

Processing of Electron Micrographs 27

Image Processing of Electron Micrographs 28

Potentiometric Titration Controller 29

Metabolic Energy Measurements 30

Electron Energy Measurements 30

Electron Microanalysis Facility 31

Molecular Interactions Laboratory Data

System 33

Californium-252 Plasma Desorption Mass

Spectrometer Data System 34

Distributed Laboratory Data Acquisition and

Control System 34

Image Processing Facility 36

Analytic Models of Computer System

Performance 37

Laboratory of Applied Studies

Clinical Research and Patient Care 41

Laboratory Investigation 42

Computer Research and Development 42

Research Projects

Statistical Research in Clinical Pathology 43

Mathematical Models of Binding Equilibria 44

Mathematical Modeling of Substrate Transport in

Physiological Environments 44

Analysis of Coupled Transport and Biochemical

Kinetics 46

Nonlinear Equations 48

Numerical Approximation Techniques for the

Solution of Reaction-Diffusion Systems in

Biology 50

Monitoring of the CNS in Critically III

Patients 51

Computer-based Studies in Pulmonary

Pathophysiology and Respiratory

Disease 52

Investigation of Hybrid Computing for the

Construction of Simulation Models and for

the Analysis of Physiologic Signals 53

Computer Systems for Nuclear Medicine 53

Computer-Aided Analysis of

Electrocardiograms 54

Computer-based Studies in Ultrasonography 55

Computer Based Analysis and Image

Processing in Electron Microscopy and X-ray

and Electron-Loss Spectroscopy 56

Physical Sciences Laboratory Data Management Branch

Summary of Activities 59 Clinical Research, Patient Care, Epidemiology 83

Research Projects Laboratory Investigation 85

Consulting Services 60 Program Management and Administration 86

Studies in Mathematics and Statistics 61 Biomedical Communications Applications 87

Theory of Biochemical Separation Computer Research and Technique Development 88

Techniques 61

Correlation Function Spectroscopy/Laser Light

Scattering 62 Computer Center Branch

Cell Motility and Chemotaxis 63 Summary of Projects 91

Two-dimensional Fourier Transform Nuclear Research Projects

Magnetic Resonance Spectroscopy 63 Computer Representation of Virus and other

Precision in the Measurement of NMR Macromolecular Assemblies 93

Parameters 64

Theory and Measurement of Intermolecular

Forces 64 Office of the Director

Analysis of Intracellular pH by 31 P Nuclear c, x a *• x-

Magnetic Resonance Spectroscopy 65 Summary of Activities 95

Quantitative Analysis of Cell Electronmicroscopy research Projects

and Plasma Membranes 65 Electronic Typesetting Methods 96

Diffusion of Molecules on Cell Surfaces and

Light Scattering from Fluids 66

Control of Actin Assembly In Nonmuscle

Cells....67
Computerized Typesetting of Scientific

Papers 68

Laboratory of Statistical and Mathematical
Methodology

Clinical Research, Patient Care, Epidemiology 72

Laboratory Investigation 72

Program Management and Administration....73
Biomedical Communications Applications.....73
Computer Research and Technique Development

Automated Data Processing of Medical
Language 73

Cluster Analysis 74

Research Topics in Computer Science 75

Discrete Mathematics and Applications 76

Mutivariate Statistical Analysis 77

Linear Methods in Statistics 78

Non-numerical Programming Techniques and
Applications 78

Topics in Geometry and Analysis 80

Computer Systems
Laboratory

Alan M. Demmerle, Chief

Clinical Research, Patient Care,
Epidemiology

Computer Support for Flow Microfluorimetry
(FMF) /Cell Sorters (NCI, NHLBI), This project
provides support for the acquisition, display, and
analysis of data from four Becton-Dickinson FACS-
11 and one Coulter MDADS FMF in NCI and NHLBI.
All five systems currently use Digital Equipment
Corporation PDP-11 computers with RT-11 single
user operating system. CSL is developing an RSX-
11M multi-user system to replace RT-11 in some
high volume applications. This system will feature an
LSI-11 microcomputer (satellite) that will interact
independently with the FMF operator during
parameter entry and will acquire data and send it to
a PDP-1 1 computer (host) for storage through an
interprocessor link.

Cardiac Scintillation Probe (CC, NHLBI). This
nonimaging ECG-gated scintillation probe, when
used in conjunction with left ventricular (LV)
catheterization, permits simultaneous quantification
of the variation of LV volume and pressure. The
system can continuously derive parameters such as
LV compliance, ejection fraction, filling and ejection
rates, and various temporal relationships. The probe
continues to be used to study the effects of
nephidipine and verapermil on patients with
asymmetric septal hypertrophy. In addition, a new
protocol studying drug effects on patients with
coronary artery disease was initiated. The probe is
also being used to monitor the left ventricle
performance of patients in the Medical Intensive
Care Unit.

Nuclear Medicine Computer Systems (CC). CSL
has continued consultation and support for the
imaging systems in the Nuclear Medicine
Department, CC, to assess their changing needs and
anticipated growth in the new Ambulatory Care
Research Facility (ACRF).

In the ACRF the three existing systems were placed
in individual scan rooms and a central system was
purchased to provide a central viewing station for
processed studies, data storage, and increased
program development capability. A distributed
system was implemented to provide communication
between the systems. Investigations using high
efficiency camera systems and their potential
applications were also initiated.

Computerized Radiation Therapy (NCI). CSL
developed a computer system, now in clinical
operation in the Radiation Oncology Branch, NCI, to
use the detailed contour and density information
available from computer assisted tomography to
improve radiation treatment planning. This system for
external beam treatment planning is based on a
generalized 3-D dose field model that covers photon,
electron, and neutron beams.

The computer program and most of its clinical
implementation has been completed for the photon
and electron fields available from the local 6 MV and
12 MV linear accelerators. The current capabilities
include interactive simulation of most irradiation
techniques devices. The system enables the display
of dose distributions computed in several transverse
contours and overlaid on corresponding CT scans.

Medical Intensive Care Unit Patient Monitoring
Computer System (CC). The dynamic events
occurring within the Clinical Center's Medical
Intensive Care Unit are monitored by a unique
multiple-computer system. Capabilities of the system
include data acquisition and analysis, medical
recordkeeping, tabular and graphical data display,
and feedback control as required in support of
patient care and research protocols.

The facility contains a state-of-the-art catheterization
laboratory with flexible computerized physiologic
monitoring features, and a high resolution x-ray
system with digital subtraction angiography

capability. Of primary interest is the study of the
etiology and therapy of septic shock.

Automated Management of Critically III Patients

(CC). This new research project is concerned with a
systems approach to the management of critically ill
patients in a clinical setting. The ultimate goal is the
utilization of computer-based instrumentation to aid
in the differential diagnosis of disease states, and
the implementation of therapeutic modalities through
automated technology.

A state variable approach is utilized in the
mathematical modeling of pertinent pharmacokinetic
and physiologic processes. Several alternative
methods for closed-loop automated medical
interventions are being investigated.

The Biomedical Image Analysis Project (NHLBI,
NEI, NCI, NIADDK, NIDR). This project is oriented
toward the development of general-purpose
algorithms and techniques for image input (including
digitization), image enhancement (including contrast
enhancement), feature extraction (including edge
detection, contour extraction, contour following,
contour coordinate compression, and shape and
texture analysis), three-dimensional representation,
image reconstruction (including Fourier filtering,
combining images, symmetrization), and other
techniques of image processing and image
reconstruction. The capability is used in work with a
number of NIH researchers.

Automated ECG Processing (CC). The Clinical
Center's Heart Station was automated last year with
a computer system that provides for the online
acquisition, analysis, storage, and retrieval of
diagnostic electrocardiograms. The newest versions
of the vendor's turnkey software and diagnostic
criteria packages were installed and the system was
placed in routine clinical operation. The ECG
analysis package will be modified by CSL as
necessary to customize the ECG analysis process in
order to satisfy NIH requirements.

Rehabilitation Medicine Computer System (CC).
This project involves the development of computer
techniques in collaboration with the Department of
Rehabilitation Medicine of the NIH Clinical Center.
CSL has recommended computer techniques to
automatically acquire anatomical and performance
information, perform calculations, and display the
results to the medical staff. The automated
techniques include the measurement of body forces
(hand and ground reaction forces), electromyograms
(electrical activity of the muscle), and body
kinematics (the position and angles of the limbs and
and joints in space and time). The medical staff will
enter additional data into a data base with computer

generated forms displayed on a terminal screen, and
perform inquiries and generate reports using the
accumulated data. A competitive procurement is
underway and system installation is targeted for the
early spring of 1 983.

Positron Emission Tomography (PET) Facility

(CC). Various NIH Institutes use the PET Facility of
the Nuclear Medicine Department. To meet
increased demand for PET scans and analysis, CSL
ordered and installed peripherals on the PET
computer system to handle the increased data flow.
To increase the image data analysis capability, CSL
implemented an offline minicomputer system and
modified existing image analysis software. In
collaboration with Institute scientists, this system was
programmed to compute local cerebral metabolic
activities with radioactive deoxyglucose utilization.

Computer Assisted Hematology Data Handling
System (CC). In February 1 982, CSL, in
collaboration with the Clinical Pathology Department,
CC, completed the design and installation of a
microcomputer-based system that allows entry of
manual white cell differential, red cell morphology,
and platelet estimates. It replaces the old method of
manual offline counting and transcription to mark
sense cards. A menu-driven CRT display at four user
stations is used with a variety of dynamic formats.
Data can be compared with automated cell counting
results, which are displayed at the top of the screen.
Results are then transferred online to the Clinical
Pathology Laboratory Computer System via a direct
serial communications line.

Automated Pulmonary Physiology Testing

(NHLBI). Fully-automated lung static compliance and
inspiratory muscle strength procedures are now
routinely performed in the Pulmonary Branch's
pulmonary physiology/exercise laboratory. Under the
control of a MINC 11 /03 computer system, data is
acquired and analyzed in realtime, with graphical and
textual reports produced at the completion of each
procedure.

Steady-state treadmill exercise testing has been
partially automated. Although data is manually
entered, analysis and report generation are fully
computerized. Work is in progress to enable
automatic realtime acquisition of exercise data with
breath-by-breath analysis and thus makes the
procedure entirely noninvasive. Once the steady
state procedure is successfully implemented, a
nonsteady state protocol is planned.

Pulmonary Branch Support (NHLBI). This project
assists the Pulmonary Branch in its computer and
data processing needs. CSL continued to help

maintain the computer portion of the two Collins
automated pulmonary function analyzers. The
BRIGHT software package, operating on the
DECsystem-10, was identified as one means for
managing pulmonary patient data. CSL provided
introductory training and helped organize a general
scheme to enable investigators to develop and
maintain individualized data storage and analysis
capabilities using BRIGHT.

Assessment of Tongue Motion During Speech
Using Ultrasonic Imaging Techniques (GC). A
collaborative effort with the Departments of
Rehabilitation Medicine and Diagnostic Radiology,
CG, GSL, and the Physical Sciences Laboratory,
DGRT, initiated to develop both a system and an
analytical technique for realtime ultrasonic imaging of
the tongue. Using an existing realtime diagnostic
scanner, several normal subjects were scanned
during the utterance of specific phonemes. The
resultant images were digitized and analyzed for
reliability and repeatability. fVlathematical techniques
are under investigation for describing the patterns of
tongue motion obtained. New instrumentation is
being evaluated to implement this technique in the
new AGRF Speech Lab scheduled for operation in
FY83.

Anesthesia Computer System (GG). This is a
collaborative effort with the Anesthesiology Service,
GG, to evaluate improved instrumentation techniques
and to identify and investigate ways that automation
can benefit anesthesia. Project emphasis is on
adjunctive monitoring and automated recordkeeping
in the operating room. Efforts this year centered on
the development of a project plan to guide future
work.

Medical Information Technology Project. This
project is concerned with the development of better
ways to automate the essential physician
contribution to the health care record. This year, in
collaboration with a practicing dermatologist, we are
field testing an ambulatory patient care treatment
system. It is designed to help the physician generate
patient information and treatment schedules,
pharmacy prescriptions, medical and surgical reports,
laboratory test orders, and referral letters to other
doctors. Interaction with the system consists of high-
speed friendly menu selections with many default
fields preselected. Because most of the clinical
software is table driven, it can be adapted to other
clinical care and research environments.

Laboratory Investigation

Molecular Graphics and Sequence Analysis

(NIADDK. NGI, NIDR). The sequence of some

regular proteins, together with other structural
information such as data from x-ray diffraction, fiber
diffraction, electron microscopy, and spectroscopic
analysis can be used to evaluate models of the
protein structure. Four projects have been using both
modeling techniques developed at NIH. We have
recently published a new interpretation of the x-ray
diffraction data for collagen fibrils. Analysis of
cyanogen bromide fragments of keratin filaments are
being studied to understand their structure and to
compare keratin with other filamentous proteins.
Analysis of myosin and streptococcal M proteins is
continuing as sequences become available.

Potentiometric Titration Controller (NHLBl). The
Potentiometric Titration Gontroller previously
developed by GSL and LGB, NHLBl, has been
greatly enhanced by replacing the original
spectrophotometer with a rapid scan
spectrophotometer (RSS) that is capable of
capturing and storing multiple complete optical
spectra. As before, the solution potential is
established by microcomputer-controlled electric
currents, and the amounts of electron transport
carriers are determined from spectral data. With the
new system, it is possible to acquire scans in
milliseconds instead of the 20 to 30 seconds needed
by the earlier spectrophotometer. The system is now
being used to study the electron transport chain in
mammalian mitochondria.

Metabolic Energy Measurements (NHLBl). A
microcomputer-based instrument has been designed
to study the energy transduction phenomena of
respiring membranes. Electrodes interfaced to the
microcomputer via an A/D converter allow
membrane potential and protonmotive force to be
calculated. The computer also monitors a pH
electrode and an oxygen-measuring electrode. The
oxygen uptake rate of the cellular material is
calculated as is the proton extrusion rate and the
proton-to-oxygen ratio. Users can observe all
quantified parameters on a multipen plotter as they
alter the medium of the experiment.

Electron Microanalysis Facility (DRS). GSL is
collaborating with BEIB, DRS, to develop an
automated electron microanalysis facility consisting
of two electron microscopes interfaced to a PDP-11/
60 computer system. The facility will be used for
research into the elemental composition of biological
specimens, and for the development of new
techniques in electron microscopy. GSL is designing
and implementing the computer system, which will
acquire and display the spectra and images resulting
from Electron Energy Loss (EEL) and energy
dispersive x-ray spectrometry (EDS). This year,

software for acquiring EEL and EDS spectra and
EEL, EDS, and electron current signal images was
completed. Basic software for displaying this data
was also completed. A large data base of empirical
x-ray emission and absorption data was compiled
and validated, and retrieval software implemented.
Software for the analytical spectrometer, and for
'housekeeping' data acquisition and calibration was
improved. A user interface for most data acquisition
and display functions was designed and
implemented.

Electron Microanalysis Computer System

(NINCDS). Late in FY81, the Laboratory of
Neuropathology and Neuroanatomical Sciences,
NINCDS, requested assistance in setting up a
minicomputer system to be connected to a JEOL
JEM-100CX electron microscope equipped with a
Kevex 7000 Analytical Spectrometer, an Energy
Dispersive x-ray detector, and an Electron Energy
Loss Spectrometer. CSL recommended the purchase
of a system compatible with the BEIB Electron
Microanalysis Facility so that software developed for
that project could be used without modification. A
PDP-11/34 was delivered. CSL installed the
operating system along with the Kevex 7000 and x-
ray emission data base software developed for the
BEIB facility.

Microelisa Data Logger (NHLBI). A microprocessor-
based instrument has been developed to record data
from a Dynatech Microelisa Autoreader, a
commercially available spectrophotometer. This
special purpose instrument is another variation on
CSL's digital cassette data recorder. The instrument
receives ASCII data from the Microelisa via an
RS232 interface port, edits and formats the data for
recording, and writes blocks of data onto a digital
cassette tape. The instrument will either be
transparent to communications between terminal and
modem or, when directed by the operator, will read
tape records and transmit the data over a
communications line via the modem. Using a STD
microprocessor bus has resulted in a more compact
instrument requiring less power and less unused
circuit board 'real estate' than our previous designs.

Molecular Interactions Laboratory Data System

(NHLBI). This microcomputer (PDP-03) data system
supervises the acquisition and processing of
information from an analytical ultracentrifuge and a
circular dichroic spectropolarimeter used in MDB,
NHLBI, to investigate the interactions between
human lipoprotein subunits. Preprocessed data are
transferred to the DECsystem-10 for further analysis
under MLAB using predefined procedures invoked by
a few simple commands. The results of a study of
system performance with very dilute solutions were

presented at the 1 982 FASEB meeting in New
Orleans. Plans are now underway for the
modification of the ultracentrifuge interface to
provide greater noise immunity and for the addition
of a digital plotter to the system.

Californium-252 Plasma Desorption Mass
Spectrometer Data System (NHLBI). After delays
caused by hardware design problems, software
upgrades, and facilities renovations, both the
spectrometer and a data system modeled after one
in use at Texas A&M University have been installed
and are now functional. This instrument provides NIH
the capabilities of mass analysis for compounds
difficult or impossible to analyze by other mass
spectrometric means. It also extends the range of
mass analysis to compounds with molecular weights
in excess of 5000.

DLDACS Project (NIADDK). An integrated
laboratory data acquisition and processing system
has been developed for LCP and LMB, NIADDK. The
system is configured with thirteen satellites coupled
through a local network to a host processor. At each
satellite, a dedicated microcomputer system
performs data acquisition from and control over an
instrument/experiment. Although acquired data files
may be stored locally, they are normally transferred
via the network to a host storage medium. The local
network allows the host storage medium to appear
as a virtual storage device to the satellites. The hub
of the network, the concentrator, utilizes DMA
hardware on all communications links and performs
a file store and forward function. Processing
software provided at the host allows LDACS data
files to be added, subtracted, averaged, smoothed,
baseline corrected, integrated, differentiated,
multiplied by a constant, or added to a constant. The
results may be displayed graphically on a Tektronix
terminal, typed at a terminal, printed on the line
printer, plotted on an X-Y plotter, or transmitted to
the NIH DECsystem-10 for additional processing.

Program Management And
Administration

Small Animal Section Data Base Management
System (DRS). In FY82, CSL revised and expanded
the functional specifications developed in FY81 to
generate a Request for Proposals for a small animal
data management system for the Small Animal
Section (SAS), VRB, DRS. We issued a Sources
Sought to test the market for currently operating
animal data management systems. Sixteen vendors
responded, of which only three had the necessary
experience to be evaluated as qualified. The RFP will
be issued in the final quarter of FY82. Responses

will be evaluated by early FY83. We anticipate that a
contract will be signed in the second quarter of
FY83.

Library Automation (DRS). A CSL study performed
in FY79 recommended that the NIH Library purchase
a commercially available library system. Because
none of the available systems could completely
satisfy the Library's requirements, the study
emphasized system flexibility in order to allow CSL
programmers to make modifications and additions to
the system. Due to administrative delays the
procurement process did not start until late FY81.

During FY82 , CSL has been heavily involved in a
series of complex contract negotiations occasioned
by an early admission from the contractor that work
could not be performed In the promised time frame.
The period of the contract was eventually extended
for several months in return for substantial cost and
technical concessions. In addition, CSL is
supervising site preparation and providing
programming support for conversion and editing of
part of the data base not covered by the contract.

Biomedical Communications And
Conference Support

Computers in Cardiology Conference. CSL

continued its support of the annual International
Conference on Computers in Cardiology. The
Conference provides a forum for direct interaction
and exchange between physicians, computer
scientists, and engineers who are involved in various
aspects of clinical computer systems in the field of
cardiology.

Computer Research And
Technique Development

Image Processing Facility. This project is intended
to provide a utility to display and analyze digital
images. The system will consist of a powerful 32-bit
computer with a mixture of medium and high
resolution video displays. Also, the system will
include a microdensitometer to allow precise
digitization of images. The computer and peripherals
have been purchased and procurement of the
display subsystem is in progress. Site preparation is
also underway and completed system installation is
forecast for early 1983.

Analytic Models of Computer System
Performance. This new project involves the
development of analytic models that can be used to
evaluate the performance of computer systems.
During the past year, tools for modeling and
analyzing computer systems using the graph

theoretic model called Timed Place-Transition (P-T)
Nets were developed. A method was developed for
evaluating computer system performance with Timed
P-T Net models. This method was used to model
and analyze the bus arbitration techniques that occur
in digital systems. Important upper bounds on the
average time a device waits for the bus and the
average time the shared bus is not used were
derived. In addition, a state variable P-T Net model
of the interconnection of two or more
microprocessors was developed. This model
provides a framework for determining the avoidance
of deadlock and the maintenance of throughput in
multiple microprocessor systems.

Research Projects

Computer Support for Flow Microfluorimetry/Cell
Sorters (FMF)

This project provides PDP-11 computer support at
various levels for four Becton-Dickinson FACS II and
one Coulter MDADS flow cytometry/electronic cell
sorting instruments. Data acquisition is via an NIH
designed interface to the computer. Data display and
analysis for high sample throughput is the principal
system feature. Software currently running under the
RT-11 operating system is being converted to
function under the RSX-11M operating system in
order to allow more sophisticated recordkeeping and
more effective support of current and anticipated
workloads. New hardware and software capabilities
are being added during the conversion effort. Upon
completion the RSX System will be installed on the
Immunology Branch, NCI computer.

Objectives and Methods: Since FY75 CSL has
provided engineering, system integration, and
software support necessary to meet the data
acquisiton, data display, and analysis needs of
several investigators using flow cytometry/electronic
cell sorting instruments at NIH. Software
development and testing is done on a Digital
Equipment Corporation (DEC) PDP-11/40 computer
system owned by CSL. This allows investigators to
have full use of their systems while new software is
being developed.

All systems are currently using the RT-11 single-user
operating system. The systems allow data collection
of up to four parameters on individual cells. Typically
these are light scatter, two frequencies of
fluorescence, and cell volume. The data can be
collected in single parameter or correlated dual
parameter modes. Data analysis and display
programs allow the experimenter to produce various
statistics and hard copy displays from the acquired

data. The displays include three-dimensional
pictures, contour maps, and vertical slice sections.

Progress in FY82: In FY82, CSL continued to
support FACS-ll/PDP-11/34 systems for I, NCI;
LP,NCI; EA,H; EEB, NCI; and a Coulter MDADS/
PDP-11 /34 system for MO.NCI.

The major effort in FY82 was continuing the
conversion of RT-1 1 programs to run under the RSX-
1 1 M multi-user operating system as well as adding
functionality to these programs. The RSX-1 1 M
system is initially being developed for one system in
order to provide more effective support of current
and anticipated workloads and more sophisticated
data acquisition and recordkeeping functions. This
system will be available to other NIH FMF sites as
needs require after its implementation in the
Immunology Branch, NCI.

It was decided in FY81 to replace the DEC VT-1 1
graphics display device with a Tektronix 4025 and to
support this terminal on the RSX system. A new
graphics software package was needed to drive the
4025 initially for the RSX-11M system. In conjunction
with the T4025, a contract was negotiated with
Electronic Data Systems, Inc., to assist CSL
personnel in developing software packages for
displaying graphs on any terminal that is capable of
performing Tektronix 4010 style graphics.

All four of the major FMF data display and analysis
programs were rewritten to run under RSX-1 1 M,
using the new graphics software package and the
Tektronix 4025 terminal that was delivered in the first
quarter of FY82. Several minor improvements to the
RT-1 1 display and analysis programs were made in
FY82 in order to accommodate immediate needs of
our supported users.

The new data acquisition system environment
consists of a PDP-1 1 host computer running RSX-
11M and up to eight LSI-11 based satellites, each
running RT-1 1 , connected to the host via an
interprocessor link.

Data acquired by a satellite is usually sent over the
link and stored at the host site (Remote Storage
Mode). However, in the event of a link failure, data is
stored at the satellite site (Local Storage Mode). The
satellite link software is common to all satellites, but
distinct from the host link software. Together, the
host and satellite link software provides file transfer
capability.

The development of the link software was completed
in FY82 and the hardware for a complete satellite
system has been acquired. The acquisition portion of
the LSI-1 1 acquisition system has been written and
is being tested.

An important feature of the satellite system is the
ability to create a 'laboratory notebook' as a
permanent hard copy rather than continuing this as a
manual task as in the existing PDP-1 1 /34 system.
This 'notebook' concept is an integral part of the
software that provides interaction with the operator
via a DEC VT-1 00 terminal. Special features of the
VT-1 00 are used to provide the operator with an
easy-to-use single screen menu. Errors are reported
in detail on the terminal screen. This interactive
software was completed in FY82.

During the third quarter of FY82, the DEC PDP-11/
40 computer system used for development of
software for CSL-supported FMF systems was
relocated to Building 12A from Building 10. CSL has
also responded to many external requests and has
provided copies of the interface hardware
schematics, software, and documentation to FMF
sites in the U.S., Europe, and Australia.

Proposed Course: In the forthcoming year, CSL
plans to complete the first RSX-1 1 M based FMF
system and LSI-1 1 based data acquisition system
and put them into operation at the I, NCI facility. If
resources permit, the RT-1 1 software will be
rewritten to use the T4025 graphics terminal as a
replacement for the VT-1 1. CSL will also continue to
support existing RT-11 based FMF sites at NIH.

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ZOl CT00050-03 CSL

""nctober"!, 1981 to September 30, 1982

Computer Support"Vo" no"Microfluorimetry/Cel 1 Sorter (FHF)

PI: R. J. Romanoff Computer Specialist CSL, nCRT

OTHERS: R. Fico Electronics Engineer CSL, nCRT
E. S. Loiederman Computer Aid CSL, DCRT
S. 0. Sharrow Chemist I, NCI
A. R. Schultz Chief. Processor Design

Section CSL, nCRT

I, NCI: LP, NCI: EEB, NCI: HO, NCI: EA, NHLBI

L»fl/BBANCH

CHECK APPHOPRIAie eox{£s)

Dt«l) "INORS a (.J) I'HERVIEWS

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This project provides PDP-11 computer support at various levels for four
Becton-Dlckinson FACS II and one Coulter MDADS flow cytometry/electronic
cell sorting instrument. Data acquisition is via an NIH- designed
interface to the computer. Data display and analysis for high sample
throughput is the principle system feature. Software currently running under
the RT-11 operating system is being converted to function under the RSX-UM
operating system in order to allow more sophisticated recordkeeping and
more effective support of current "and anticipated workloads.

Cardiac Scintillation Probe

Background and Objectives: The development of the
cardiac scintillation probe is a continuation of CSL's
collaboration with the Nuclear Medicine Department,
CC, and the Cardiology Branch, NHLBI. Originally
this collaboration resulted in the development of a
noninvasive cardiac imaging technique known as
ECG-gated scintigraphic angiography. In addition to
visualizing global LV cardiac function, the images
produced by this technique can be processed to
produce a time-activity curve that represents
changes in ventricular volume over a cardiac cycle.
This time-activity curve (LV volume curve) can be
used to calculate various parameters of cardiac
function such as ejection fraction, peak ejection rate,
peak filling rate, and their temporal relationships. The
imaging technique has been used with great success
to characterize various cardiac related diseases.
However, if the images are not required, then this
time-activity curve could be generated by a much
smaller and simpler system using a single small Nal
detector and microcomputer system. In 1977 CSL
began the development of a cardiac scintillation
probe system, which could produce this time activity
curve. The system is easily transportable and allows
continuous monitoring of cardiac function at the

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. 1982

Cardiac

CI (M Eh.r.ct.r. or U..)

Scintillation Probe

nRtOHNa EHSlCtO ON IHt MIOJE

PI:

H. G. Ostrow

Electronics Engineer CSL. DCRT

OIHEBS

S. I. Allen

Medical Besearch Analyst CSL. OCRI

S. Bacharach

Physicist NH. CC
Physicist NH. CC

R. Bonow

Cardiologist CB, NHLBI

D. Rosen

Cardiologist CB, NHLBI

COOPtHlIINC t

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Nuclea

Medicine, CC, Cdrdldo

gy Branch, KHLBl

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Processor Design Section
DCRT. NIH. Bethesda MO 20205

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CSL cont

nued the dewelopment o

Its Cardiac Sclnttllatlon Probe System

begun In

1977. This nonimaging

ECG-gated scintillation probe, when used in

conjunct

on with left ventricul

r (LV) catherizatlon. permits simultaneous

quanttf 1

atlon of the variation

of LV volume and pressure. By simultaneously

rneasurln

LV volume and LV pres

ure. parameters such as LV compliance can be

continue

ion to such measurements as ejection fraction.

filling

nd ejection rates, and

temporal relationships. This year the probe

continued to be used to study t

e effects of nephldlpine and verapermil on

patients

with asymmetric septal

hypertrophy. In addition, a new protocol

Studying

the drug's effects on patients with coronary artery disease was

tnltUte

. The probe is also tw

\nq used to monitor the left ventricle

per forma

ce of patients in the

edical Intensive Care Unit. The pressure-volum^

relation

hips produced by the probe system allowed the effects of drugs to be

quant ita

permit t

e system to be easily

sed on a routine basis by Clinical Center

the proh

and In quantifying the llmtfatlon nf IhP tPrhninne. 1

bedside or other location in the Clinical Center
outside the Nuclear Medicine Department.

Methods: The system consists of a 3-inch diameter
Nal scintillation probe, probe electronics,
microcomputer system, and display. The system is
programmed to acquire scintillation data from the
probe, process the data, and plot and display various
parameters of left ventricular (LV) function. This
nonimaging, ECG-gated probe, when used in
conjunction with ventricular catheterization, permits
simultaneous quantification of the variation of LV
volume and LV pressure. Parameters such as LV
compliance can be continuously monitored. In the
catheterization laboratory, pressure-volume
measurements are used to study the effects of drugs
on patients with various heart diseases.

Progress in FY82: This year the probe continued to
be used in the catheterization laboratory to study the
effects of nephidipine and verapermil on patients
with asymmetric septal hypertrophy (ASH). The
pressure volume data from these studies were
transferred to the PDP-10 system and software was
written to analyze the data to determine additional
parameters to assess the effects of these drugs. The
verapermil studies have been concluded. The
pressure-volume data has provided information to
help understand the positive effects of the drug in
this particular disease.

A new protocol studying drug effects on patients with
coronary artery disease was initiated. As with the
ASH study the data is being analyzed to determine
the parameters that best characterized the effects of
the drug.

Results of the drug intervention studies indicated
changes in ventricular parameters previously not
used. Nine studies were designed and performed in
order to quantitate the limitations of techniques in
measuring these parameters.

The Medical Intensive Care Unit, CC, has started to
perform ECG-gated Scintiangiographic studies.
Because using the Pho/Gamma camera on a routine
basis at the bedside is difficult, software was written
on the HP system to use the probe in this
application.

Significance to Biomedical Research: Nuclear
Medicine techniques provide a relatively noninvasive
procedure to access left ventricular function. The
cardiac scintillation probe permits this capability to
be used for clinical research studies at the bedside
and in the catheterization laboratory. The pressure
volume relationship produced by the probe system
allows the effects of drugs to be quantitated in a
manner not before possible.

Proposed Course: Development activities in
response to new applications are expected to
continue. CSL will investigate making the probe and
camera systems compatible. Making the systems
compatible to the extent possible will reduce the
resources required to support the probe system and
allow new capabilities developed for the camera
systems to be implemented quickly on the probe
system.

Computerized Radiation Therapy

CSL has developed a computer system, now in
clinical operation in the Radiation Oncology Branch,
NCI, to use the detailed contour and density
information available from ultrasound or computer
assisted tomography to improve radiation treatment
planning. This system for external beam treatment
planning is based on a generalized 3-D dose field
model that covers photon, electron, and neutron
beams.

Both the computer program and most of its clinical
implementation have been completed for the photon
and electron fields available from the local 6 mv and
12 mv linear accelerators. The current capabilities
include interactive simulation of most irradiation
techniques, including the effects of most beam
modifying devices. The system enables the display
of dose distributions computed in several transverse
contours and overlaid on corresponding CT or
ultrasound scans.

Background and Objectives: To develop and
implement a generalized system for computer-
assisted radiation treatment simulation.

Methods Employed: The dose field model developed
by Jan van de Geijn was implemented in RSX-1 1 M
FORTRAN and experimentally tested to cover
irregularly shaped beams as well as irregularly-
shaped shielding blocks. A facility has been
developed that enables the computation and display
of dose distributions in planes perpendicular to the
beam axes.

Progress in FY82: The capabilities of the graphics
input system, the use of CT and ultrasound images
in addition to mechanically-obtained patient contours,
and the color display system have been further
expanded. Eight user terminals and two DeAnza 10
5000 color display systems have been added to
allow the PDP 1 1 /70 computer system to be used
for treatment planning and system development.

I^ajor Findings: The system, although continuing to
be expanded, is in routine use for clinical treatment
planning, in comparison to other existing systems, it
offers high speed computation and display of

complete dose distributions in multiple slices
superimposed on CT or ultrasound images, including
effects of wedge filters, irregular shielding blocks,
and diaphragm rotation. Several modes of display
are available.

Proposed Course: Future plans include:
implementation of the beam's eye view option for
regular and irregular electron fields, extension of the
current software package to include point source
(seed) calculation, and extension of the capabilities
to compute and display dose distributions in sagittal,
coronal, and beam's eye view sections of the patient
on an interactive basis.

Pubiications:

van de Geijn, J., Chien, l-Chu, Cheng, C. P., and Fredrickson, H.A.: A
Unified 3-D Beam Model tor External Beam Dose Distributors. Proceed-
ings of the VIII International Conference on Computers in Radiottierapy,
Tokyo, Japan, 1 980.

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PROJECT HU«BE«

ZOl CT00052-03 CSL

""october^l. 1981 to September 30, 1982 |

TITLE OF PFfOJECI (80 ch.r.clrrs or U=s)

Computerized Radiation Therapy

pSoF£blSHr"HloNNEL'™«£J^H*^riE'p^^^^^ *'*" ^"^^^ "^ PAIN^IPAL INVEST ICATOHS ANO ALL OTHER

PI: H. Fredrickson Computer Systems Analyst CSL, DCRT

OTHERS: J. Van de Geijn Head, Radiation Physics

Automation Section ROB, OCT,

NCI

D. Syed Head, Systems Design Section CSL. DCRT

E. Glatstein Chief, Radiation Oncology

Branch ROB, OCT,

NCI

B. Fraass Staff Fellow ROB. OCT.

NCI

L. Freeman Computer Programmer CSL, DCRT

COOPEHATIIIC UNIT! {If any)

Radiation Oncology Branch, NCI

Computer Systems Laboratory |

Systems Design Section

DCRT, NIH, Bethesda, HD 20205

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CHECK APPROPRIATE aOx(ES)

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DM) MINORS a (.2) iriTERV.E-S

CSL has developed a computer system, now in clinical operation in

the Radiation Oncology Branch, NCI, to use the detailed contour

and density information available from ultrasound or computer

assisted tomography to improve radiation treatment planning. This

system for external beam treatment planning is based on a

generalized 3-D dose field model that covers photon, electron, and

Both the computer program and most of its clinical implementation

have been completed for the photon and electron fields available

from the local 6 mu and 12 mv linear accelerators. The current

techniques, including the effects of most beam modifying devices.

The system enable?, the display of dose distributions computed in

several transverse contours and overlaid on corresponding CAT or

Medical Intensive Care Unit Patient Monitoring
Computer System

The dynamic events occurring within the Clinical
Center's Medical Intensive Care Unit are monitored
by a unique multiple-computer system. Capabilities of
the system include online data acquisition and
analysis, medical recordkeeping, tabular and
graphical data displays, and feedback control, as
required in support of patient care and research
protocols. Elements include a minicomputer-based
Patient Data Management Subsystem, a Software
Development Subsystem, and a Medical Mass
Spectrometer Subsystem.

The facility also contains a state-of-the-art
catheterization laboratory that includes a flexible
computerized Vascular Research Subsystem, with
physiologic waveform processing features, and a
high-resolution x-ray system with digital subtraction
angiography capability.

Of primary interest is the utilization of the Medical
Intensive Care Unit's computer systems in the study
of the etiology and therapy of septic shock.

Background and Objectives: The Medical Intensive
Care Unit (MICU), which is administered by the
Department of Critical Care Medicine in the Clinical
Center, receives critically ill patients from clinical
programs of NIH. The MICU comprises a five-bed
ward area, a pair of isolation beds, and a vascular
research laboratory. The research goals of this unit
include the development of techniques for
automated patient monitoring and noninvasive
measurements of the cardiovascular and respiratory
systems. In addition, catheterization studies are
performed as necessary to obtain data that are
available only through invasive methodology.

Working with Clinical Center staff, CSL contributed to
the engineering design of the intensive care unit.
CSL also undertook the specification, procurement,
and installation of the bedside patient monitoring
equipment and the four computer systems:

1 . a Patient Data Management System used for
automatically monitoring patient variables, manually
entering patient data, retrieving information online,
and keeping medical records;

2. a Vascular Research Subsystem used for
acquiring and processing cardiovascular pressure
waveforms, measuring cardiac output, displaying
measured results online, and generating a cardiac
catheterization report;

3. a Software Development Subsystem used for
developing software for the above described
systems; and

4. a Medical Mass Spectrometer Subsystem used
for monitoring both the patient ainway gases and the
gases delivered by the patient's respirator at all
seven MICU beds.

The first three systems were purchased from the
Hewlett-Packard Corporation and all use identical
minicomputers. The Chemetron Corporation
manufactures the microcomputer-based mass
spectrometer system. This year, additional
subsystems have been incorporated within the MICU
complex.

Major Findings: The automation of the MICU has
aided the medical staff by managing the large
amount of data needed for the care of the critically ill
patient, performing desired calculations, and allowing
measurements that would not othenwise be possible.

Progress in FY82: Modifications to the Vascular
Research Subsystem were completed to allow the
data generated to be collected by the Patient Data
Management Subsystem's computer, in addition to
the Vascular Research Subsystem's computer. A
mobile noncomputerized Vascular Research
Subsystem was added to the MICU to allow bedside
monitoring with research quality instrumentation. This
mobile subsystem also interfaces to the Patient Data
Management Subsystem's computer.

In order to provide pulmonary function monitoring for
the critically ill population within the MICU, a Collins
Pulmonary Function Testing Subsystem was
integrated into the MICU. This microprocessor-based
subsystem contains the spirometer and gas
analyzers necessary for the calculation of pulmonary
function parameters, such as vital capacity and lung
volumes, and for the generation of flow-volume
loops.

A Hewlett-Packard Respiratory Research Subsystem
was obtained to provide for the computation of
pulmonary mechanics parameters, such as work of
breathing and lung compliance and resistance. This
subsystem also utilizes airway pressure and flow
transducers to develop pressure-volume loops, in
addition to flow-volume loops.

A Microprocessor-Controlled Arrhythmia Monitoring
Subsystem was added to the Nurses' Station in the
MICU to provide for the central monitoring of cardiac
arrhythmias. This display station provides an
electrocardiogram memory and provides
simultaneous hard copy records of the
electrocardiogram and arterial pressure waveforms,
as aids in the detection of transient arrhythmias.

In order to supplement the electrocardiographic and
cardiac catheterization data descriptors of cardiac
function, a Hewlett-Packard Microprocessor
Controlled Ultrasound Imaging Subsystem was
installed in the MICU. This subsystem provides
multiformat displays of cardiac structure and allows
the visualization of intracardiac abnormalities. In
addition, this Ultrasound Imaging Subsystem
interfaces to the Software Development Subsystem
to allow sophisticated image processing with NIH-
developed programs.

A Cardiac Probe, which was developed jointly by
CSL staff and the Clinical Center's Nuclear Medicine
Department, is being adapted for use in the MICU.
This device provides left ventricular volume data by
counting gamma ray induced scintillations, after the
administration of injectable radioisotopes. Software is
being completed to allow data from the Cardiac
Probe to be collected, analyzed, and displayed
utilizing the Software Development Subsystem's
computer.

A Philips X-ray Imaging System was installed within
the MICU Catheterization Laboratory. CSL staff
assisted in the specification and supervision of
catheterization laboratory alterations necessary for
system installation. Shielding was installed to protect
the MICU computer room from exposure to
electromagnetic interference from the x-ray system's
generator and power supplies. The x-ray Imaging
System includes a Computerized Digital Vascular
Imaging Subsystem that provides the capability for
digital subtraction angiography. A video switching
device added to the Vascular Research Subsystem
allows video displays produced by the Vascular
Research Subsystem, the Patient Data Management
Subsystem, and the Digital Vascular Imaging
Subsystem to share a single Philips Video Monitor.

Significance to Biomedical Researcti: This project is
focused on the application of multifaceted diagnostic
modalities to clinical research and the care of the
critically ill patient. Any new developments made on
this project will benefit many users of automated
systems, as well as patient care and clinical
research within the MICU at NIH.

Proposed Course: Future efforts will center on
hardware and software modifications necessary to
enhance the system's ability to support patient care
and reserch protocols. Possible modifications to the
primary Patient Data Management Subsystem
include the addition of urine output measurement
scales and the computerization of fluid infusion
therapy utilizing existing microprocessor-controlled
infusion pumps.

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ZOl CT00054-03 CSL

October 1. 19fil to Seotember 30. 1982

Medical Intensive Care Unit Patient Monitoring

Computer System

UAHIS, UeORATORY AMD INSTlTUie AFFILIATIONS, AND TITLES OF PRIH

IP«L INVJSrl««IORS .«0 ILL DIHM

PI: K. M. Kempner Electronic

s Engineer CSL, OCRT

OTHERS: J. E. Parrillo. H.D. Chief, Cri

L. W. Freeman Computer P

S. L. Huntley Supv. Crit

Technician

tical Care

CCHO, CC
s Engineer CSL. OCRT
rogrammer CSL, OCRT
cal Care
s CCMn, CC

Critical Care Medicine Department. Clinical Center

LAB/BHAriCH

Computer Systems Laboratory

Systems Design Section

OCRT, NIH, Bethesda, MD 20205

1.0 1 1.0 1

CHECK APPflOPBIATE BOX(ES)

a (c) m„c.

□(.1) MINORS D(«2) INTERVIEWS

SUMMARY OF WORK (!00 »ord. or 1«= - underlio. kcy-ord = )

The dynamic events occurring within the Clinica
Intensive Care Unit are monitored by a unique mu
system. Capabilities of the system include onl
and analysis, medical recordkeeping, tabular an
displays, and Teedback control, as required in
care and research protocols. Elements include
Patient Data Management Subsystem, a Software D
and a Medical Mass Spectrometer Subsystem,

Center's Medical
tiple-computer
ne data acquisition
d graphical data
support of patient

evelopment Subsystem,

The facility also contains a state-of-the-art c
laboratory that includes a flexible computerize
Subsystem, with physiologic waveform processing
high-resolution x-ray system with digital subtr
capability.

d Vascular Research

features, and a
action angiography

^-^----^'

INIRABUfiAL'*REsLHCH PflOJECT

ZOl CT00099-01 CSL

TITLE OF PROJECT (8D characters or less)

Automated Management of Critically 111 Patients

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INVESTIGATORS AND ALL OTHER

PI: K. M. Kempner Electrc

nics Engr. CSL, OCRT

OTHERS: J. E. Parrillo M.n. Chief,
N. fleClaris, Sc.fl. Profes

Critical Care

Medicine CCMO, CC

or. Electrical

Engr. Oept. Univ. of MO

COOPERATING yillTS (.1 4"y)

Critical Care Medicine Department, CC
Electrical Engineering Department, Univ. of MD

LAB/BRANCH

CM HUMAN SUBJECTS Q (b) HUMAN TISSUES

n {=) NEITHER

D (-1) MINORS aU2) INTERVIEWS

SUMMARY OF WORK (200 wgrda or Ui= - underline koy-ordi)

This research project is concerned with a system
management of critically ill patients in a clinic

approach to Che
al setting. The

ultimate goal is the utilization of computer-base
to aid in the differential diagnosis of disease
implementation of therapeutic modalities through
technology.

d instrumentation
tates and the

ft state variable approach is utilized in the matti
of pertinent pharmacokinetic and physiologic proc
clinical data and realtime monitored values are
validation. Several alternative methods for clos
medical interventions are being investigated.

ematical modeling
esses. Empirical
tilized in model

Automated Management of Critically III Patients

This research project is concerned with a systems
approach to the management of critically ill patients
in a clinical setting. The ultimate goal is the utilization
of computer-based instrumentation to aid in the
differential diagnosis of disease states and the
implementation of therapeutic modalities through
automated technology.

A state variable approach is utilized in the
mathematical modeling of pertinent pharmacokinetic
and physiologic processes. Empirical clinical data
and realtime monitored values are utilized in model
validation. Several alternative methods for closed-
loop automated medical interventions are being
investigated.

Background and Objectives: Noninvasive diagnostic
and therapeutic techniques generally involve the
application of sophisticated electronic technology
and mathematical modeling techniques to the
detection of pathophysiologic states. Particularly
interesting and important problems involve
cardiovascular disorders that give rise to low output
syndrome.

There is no singular cause for this syndrome, and
therefore effective therapy requires the differential
diagnosis of numerous contributory disturbances in
cardiovascular homeostasis. Effective therapy
principally involves the administration of one or more
fluids and/or drugs in a critical care unit
environment.

Methods Employed: In order to accomplish the goal
of developing systems capable of assisting in the
medical management of a critically ill patient on a
closed-loop basis, it will be necessary to develop
validated models. Calculated physiologic parameters
will be compared to measured physiologic data as
the patient's response to the selected therapy
progresses.

A mathematical formulation of the relevant
subsystems will be developed for a patient in a
critical care unit setting. This includes the modeling
of three principal subsystems: Pharmacokinetics,
Drug/Receptor Interactions, and Cardiovascular
Dynamics.

Progress In FY82: An extensive literature search and
a formal analysis were performed on the three major
relevant subsystems. The literature search indicated
that these three areas have previously been treated
as distinct and unconnected problems. There has
been little effort to combine them in a manner
suitable for addressing the problem proposed.

The mathematical formulations necessary to
describe these systems are being finalized. Particular
care is being paid to the selection of variables so
that the subsystem models will couple in a
physiologically sound as well as a computationally
efficient manner.

Significance to Biomedical Research: The use of
automated systems in the implementation of
therapeutic protocols within a critical care unit adds
a new treatment modality and will have a major
effect on protocol design. It will afford improvements
in protocol design for patient care, clinical drug trials,
and the study of the etiology and therapy of specific
disease entities. In addition, the automation of
therapeutic interventions, as proposed, will
significantly expand the clinical and research data
bases.

Proposed Course: Following the development of the
mathematical formulation of the three major
subsystems, these subsystems will be implemented
in software on the DCRT Central Computer Facility.
The software will be utilized in a simulation mode to
analyze actual patient data, and to generate
recommendations for therapy along with predicted
physiologic data values.

Existing critical care protocols will be investigated to
identify those components in which automated
therapeutic modalities can easily be accommodated,
within the framework of this research effort. An
important aspect to be evaluated is the risk to the
patient versus the realizable benefits.

Selected protocols will be implemented utilizing the
closed-loop techniques developed in this project,
with the objective of carrying out controlled clinical
trials and quantitatively evaluating their effectiveness.

Positron Emission Tomography (PET) Scan
Image Analysis in Aging Studies

Procedures for transporting Positron Emission
Tomography (PET) Scan and Computer Assisted
Tomography (CAT) Scan images from the NIH
Clinical Center to the DCRT Image Processing
Facility have been established. An interactive
computer procedure for delineating anatomical areas
of interest on a CAT scan and computing metabolic
activity from the corresponding area on the related
PET scan has been developed. Improved methods
for establishing external coordinates to align
corresponding PET and CAT scans continue to be
explored.

Background and Objectives: Positron Emission
Tomography (PET) scanning performed in the
Nuclear Medicine Department of the NIH Clinical
Center provides a spatially-sequenced series of
images of regional cerebral glucose metabolism in
man. The Laboratory of Neurosciences of the
National Institute on Aging wishes to incorporate
PET scanning technology in the study of diseases
associated with aging. The initial goal of this project
is to delineate brain substructures represented in
spatially sequenced Computer Assisted Tomography
(CAT) scan images and to determine metabolic
activity in these substructures from corresponding
spatially sequenced PET scan images.

Methods Employed: Computer Assisted Tomography
(CAT) Scan and Positron Emission Tomography
(PET) Scan images are transported from the NIH
Clinical Center to the DCRT Image Processing
Facility via magnetic tape. An analyst trained in
neuroanatomy aligns associated CAT and PET Scan
images by means of reference markers seen on both
images. These markers are provided by a head-
holding device worn by the subject during CAT and
PET scanning. The analyst then 'draws' contours
around regions of interest on the CAT Scan. The
computer determines corresponding regions on the
PET Scan and computes metabolic activity in that
region of the brain.

Progress in FY82: Radiation-to-glucose conversion
equations were finalized and further investigation of
a suitable head-holder to provide reference markers
external to the brain continued. Image processing
software is close to completion. A project entitled
'Computer Assisted Tomography (CAT) Scan Image
Analysis in Aging Studies' closely related to this work
was started and is reported in this Annual Report.

Significance to Biomedical Research: It is anticipated
that this work will provide a basis for evaluating the
utility of PET scanning in studying diseases
associated with aging. Successful implementation of
an external coordinate system should provide for
accurate anatomical region designation via higher
resolution CAT scan images to measure
physiological processes from corresponding lower
resolution PET scan images.

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,l™sfi!lfZi°i

ZOl CT00083-02 CSL

Positron Emission Tomography (PET) Scan Image Analysis in

PI: J. M. neLeo Computer Systems Analyst CSL, DCRT
OTHERS: S. I. Rapoport Chief LN. NIA

Laboratory of Neurosciences (LN). NIA; Nuclear Medicine
Department (NM). CC; Oiagnostic Radiology (DR), CC

LAB/BR«NCH

Systems Desiqn Section

nCRT. NIH. flethesda. Mn 20205

.1 1 .1 1

CHECK APPROPRIATE BOX(eS)

D[*l) M.NORS Q(.3) IHICRVIEWS

been developed. Improved methods for establishing external

explored.

Zni CT00086-01 CSL

I September 30, 19i

iisted Tomography (CAT) Scan Image Ana'

S. I. Hapoport Chief

alyst CSL, nCRT
I LN, NIA

DCRT. NIH. Bethesda. MP 20205

D{'?) INI

interactive image analysis computer procedure to measure
rious parameters from Computer Assisted Tomography (CAT) scans

the human brain has been designed and implemented on the DCRT
age Processing Facility.

Computer Assisted Tomography (CAT) Scan
Image Analysis in Aging Studies

An interactive image analysis computer procedure to
measure various parameters from Computer Assisted
Tomography (CAT) scans of the human brain has
been designed and implemented on the DCRT
Image Processing Facility.

Background and Objectives: This new project has
been initiated to study changes in the human brain
structure during normal aging and during brain
disease processes associated with aging by means
of measurements made from Computer Assisted
Tomography (CAT) scans of human brains.

Methods Employed: CAT scans are transported to
the DCRT Image Processing Facility via magnetic
tape. Through interactive analysis of the CAT scan
images, an investigator is able to obtain a wide
variety of descriptive measurements such as sizes
and attenuation values of brain substructures and
percent composition of white matter, grey matter,
and cerebral spinal fluid.

Progress in FY82: Software was developed to
determine the following measurements from CAT
Scans of the human brain:

1) Bicaudate Index

2) Ventricle/Brain Area Ratio

3) Width of Ventricles

4) Percentage composition of CSF, white matter
and gray matter

5) Cortical measurements

6) Sylvian Fissure

7) Interhemispheric Fissure

8) General Length and Area measurements
Using this software, measurements were made on
scans of several normal subjects.

Significance to Biomedical Research: This
quantification methodology will greatly augment
visual interpretation of brain CAT scans. It may
provide a deeper understanding of brain structure
changes during normal aging and disease processes.
It is also possible that this work will produce new
diagnostic tools.

Proposed Course: Further refinement of the software
is planned. A study to determine morphological brain
changes related to aging will be conducted.

Computer Analysis of Autoradiographic Images
of Recombinant DNA Colonies

A computerized methodology for analyzing
autoradiographic spot images associated with
recombinant DNA bacterial colonies has been
developed in collaboration with scientists in NCI.
This system represents a unique refinement in a
method to directly identify cloned DNA sequences
complementary to messenger RNA that are
developmentally or hormonally induced.

Spot density measurements are computed from
digitized images produced via microdensitometry.
These measurements are corrected for variability in
exposure and local background, calibrated to
hybridization standards, and normalized for
comparison purposes. The system provides a variety
of graphical and tabular output that effectively
summarizes experimental results and identifies
significant induced hybridization events.

Background and Objectives: NCI scientists have
been refining techniques to identify cloned DNA
sequences complementary to messenger RNA that
are developmentally or hormonally regulated. This
refinement has led to a methodology that produces
autoradiographic spot images representative of the
amount of hybridization. The objective of this project
is to provide an automated procedure for a
quantitative analysis of these images.

Methods Employed: Cloned bacteria are grown on
agar in microliter wells, transferred to filter paper,
and hybridized to end-labeled mRNA or cDNA
probes. Autoradiographs of the filters are digitized
and the density of each spot relative to background
is established by means of CSL-developed image
processing software operational on the DCRT Evans
and Sutherland PDP-11/70 computer system.
Compensation for variations in background, film
exposure conditions, and hybridization are included
in the methodology. A variety of graphical output
including scatter diagrams, histograms, and listings is
provided.

Progress in FY82: Software development was
completed and several experiments were conducted.
Two papers are in preparation. The first paper
discusses both the application of this system to
analyzing the in vivo response of rat liver to
glucocorticoids, as well as the application to other
biological systems. The second paper will describe
the computerized image analysis methodology and
procedure in detail.

Significance to Biomedical Researclr. The
methodology developed allows quantitative
hybridization studies on a large number of
sequences. Earlier qualitative assessment of
autoradiographic spot images is now superseded
with automated procedures yielding more accurate,
more reproducible data. Computer graphic
presentation of results greatly facilitates identification
of significant experimental events.

Proposed Course: Additional experiments are
planned. It is anticipated that the methodology
developed here will be discovered to have
applicability to other areas of biomedical research,
as demonstrated by inquiries from other NIH
biomedical research investigators.

jhTihsohiah science inforuation exchange

U.S. OEPARIHENT OF

™^'S.!Kk'8F"»""

ZOl CT00084-02 CSL

PERIOD CDVERtD

October 1. 1981 to September 30. 1982

TITLE OF PROJECT (80 ch.r.ctcrs or l.ss)

Computer Analysis of Autoradiographic Images of Recombinant DNA

Colonies

TOF^SslZL^Ersora'ENjwE^OriiE'pJrECT *"" "^'"^ "^ """^'"'" """""""^ *'" *'"'■ """

PI: J. H, DeLeo Computer Systems Analyst CSL, DCRT

OTHERS: Floyd Taub Research Associate LR, C

Brad Thompson Section Chief LB, C

Laboratory of Biology (LB), C

nCRT. NIH. Bethesda. HD 20205

TOTAL «*N»E«S: 1 PROFESSIONAL. OtHEfl,

t).:i 1 n.ii 1

CHECK APPROPRIATE aOK{ES)

a(.l) MINORS n{"?) INTERVIEWS

SUHMART OF uORK (200 yonSs or less - underline key-ord,)

A computerized methodology for analyzing autoradiographic spot images

associated with recombinant DNA bacterial colonies has been developed

in collaboration with scientists in NCI. This system represents a

unique refinement in a method to directly identify cloned sequences

complementary to messenger RNA that are developmentally or hormonally

induced.

Spot density measurements are computed from digitized images produced

via microdensitometry. Tliese measurements are corrected for variability

in exposure and local background, calibrated to hybridization standards.

and normalized for comparison purposes. The system provides a variety

of graphical and tabular output that effectively summarizes experimental

results and identifies significant induced hybridization events.

Cataract Grading via Computerized Slit-Lamp
Image Analysis

A new interactive image analysis procedure for
analyzing and comparing slit-lamp camera images of
human eye lenses has been developed and
implemented on the DCRT Image Processing
System. This procedure features television camera
image digitization, interest area delineation by means
of a flexible oval template, data calibration and
standardization, and computation of a variety of
statistical measurements for descriptive and
comparative purposes. Also, an experiment has been
designed to analyze the contribution to measurement
variance due to photographic procedure, film and
film processing, digitization, and analyst judgment
factors.

Bacl<ground and Objectives: A major problem for
cataract researchers has been the lack of an
objective, reproducible, in-vivo cataract classification
scheme. Subjective classification methods are
currently depended upon. With the tremendous
variability in the morphology of cataracts, it is difficult
to rely on such methodology either in survey works
or in longitudinal studies. Development of an
objective cataract grading scheme is seen as a high
priority item among cataract researchers.

i\4etiiods Employed: Photographs of human eye
lenses obtained from Topcon and Zeiss slit-lamp
cameras are digitized via microdensitometry or
television signal quantitation. Resulting digitalized
images are transported via magnetic tape to the
DCRT Image Processing System for interactive
analysis. The image analyst first defines and
positions an oval window template over the area of
interest using dials and then points to a 5-band
calibration strip (an integral part of the image) using
a graph-pen. A histogram distribution of the pixel
values within the template is formed, scaled,
calibrated, and processed to generate various
statistical measurements used to describe and
compare images. Colored isodensitometric
representations of the eye lens may be displayed.
Time-spaced photographs of an individual patient
may be processed to produce an historical summary
of lens opacity changes over time. This is viewed to
be useful as an epidemiological tool for advancing
our understanding of the cataract disease process,
as well as in evaluating the effectiveness of
therapeutic protocols such as the administration of
anticataract drugs.

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""'"■' Sis'i"'"'""

ZOl CT00085-02 CSl

October 1. 1981 to <ientember 30. 19R?

Cataract Grading via Computerized Slit-Lamp
Image Analysis

M«ES, L»80R*I0KT MID mSTITUIE tfFILUTIOHS, UtO TITLES Of PRINCIPAL INV£STIG»IOBS AUD »U OTH£H

PI: J. H. OeLeo Computer Systems Analyst CSL. OCRT
OTHERS: R. 0. Sperduto M.D. BE. NEI

CMPmilM WITS (i1 .r,,)

Office of Biometry S Epidemiology (BE), NEI
Division of Ophthalmology. Harvard Medical School

Svstems Design Section

CHt« APPflOPHUIE B0.(t5)

D{.) «U*»N SUBJECTS Q(t) t-g-M TISSUES U(.) NEITHER

n(.l) -INORS D(.0 INUBVK-S

A new Interactive image analysis procedure for analyzing
and comparing slit-lamp camera images of human eye lenses
has been developed and implemented on the DCRT Image
Processing System. This procedure features television
camera image digitization, interest area delineation by
means of a flexible oval template, data calibration and
standardization, and computation of a variety of statistical
measurements for descriptive and comparative purposes. Also,

variance due to photographic procedure, film and film processing,
digitization, and analyst judgment factors has been designed.

S'8S=.i

201 CTOOOa7-01 CSL

October 1. 1961 to September 30, 1J82

.i or "PflOJiCI (eO'.h.r.cl.r. er U.,)

Robust Boundary Detection of Necturus Gall Bladder Cells

PI: J. M. OeLeo

OTHER: K. Spring

Computer Systems Analyst CSL, OCRT
Research Physiologist LKEH, NHL8I

MINC will (II ..
LKEN. KHL6I

Computer Systems Laboratory

Systems Design Section

DCRT, NIH. Bethesda. HD 20205

lange hist(

from video

Ma/or Findings in FY82: The new interactive innage
analysis system, which produces descriptive
measurements and colored isodensitometric images
from slit-lamp camera images of human eye lenses,
is fully operational and easy to use. Measurement
variance due to image analyst techniques seems to
be insignificant. Calibration and standardization
procedures should considerably reduce variance due
to film, film processing, and digitization factors. The
largest potential source of variance is in the quality
control exercised by the photographer. This factor
requires further study.

Significance to Biomedical Research: Development
of an objective cataract grading scheme is seen as a
high priority item among cataract researchers.

Proposed Course: A vigorous analysis of variance is
planned after adequate study and improvement of
image capture methodology. Use of supplemental
views, such as frontal and retroillumination views, is
being considered.

Robust Boundary Detection of Necturus Gall
Bladder Cells

A robust boundary detection algorithm for automated
planimetry of Necturus gall bladder cells has been
designed to enhance an existing methodology that
computes cell volume change histories from video
images of cells visualized in a light microscope.

Bacl<ground and Objectives: Epithelial cells of
Necturus gall bladder regulate their volume after a
change in osmolality of their bathing solution. The
Laboratory of Kidney and Electrolyte Metabolism,
NHLBI, has developed a computerized methodology
for time-tracking cell volume changes through
interactive planimetry of video images of cells
visualized in a light microscope. The Computer
Systems Laboratory has been requested to develop
a specialized robust cell boundary detection
algorithm to enhance overall throughput processing
efficiency.

Methods Employed: The specialized robust cell
boundary detection algorithm conceived operates as
follows:

1. The investigator points to the center of the cell.

2. Opacity values are collected along 72 rays
emanating from the center. The rays are of fixed
length and 5 degrees apart.

3. Each ray of opacity values is processed as
follows:

• Scale opacity values (0 to 255).

• Accept a single minimum as a tentative edge
point.

• Confirm edge point by scaled gradient and
localized texture parameters if necessary.

4. Check neighboring pairs of tentative edge
points, rejecting pairs that fail the test.

5. Attempt to specify missing edge points by step
3 applied over a narrower segment of the ray as
determined by radii of a certified near neighbor edge
point and a priori data specifying expected edge
point radii lower and upper range values as a
function of the angular distance to the nearest ray
having a certified edge point.

6. Sequentially connect the edge points.

7. Compute the enclosed area.

8. Repeat steps 1 to 7 over all cell slices to obtain
the required volume.

Significance to Biomedical Research: Application of
quantitative light microscopic techniques to study cell
volume changes due to fluid and ion transport in
living epithelial tissues has already proven to be a
powerful and effective research tool. An accurate,
efficient, robust cell boundary detector algorithm
would greatly improve upon the utility efficiency and
throughput speed of this methodology.

Proposed Course: It is planned to implement, test,
and refine the robust cell boundary detector
algorithm described above on the DCRT Image
Processing Facility. Upon successful development,
consideration will be given to alternative approaches
for implementing the algorithm in production mode.

Rehabilitation lUledicine Computer System

This project involves the development of computer
techniques in collaboration with the Department of
Rehabilitation Medicine of the NIH Clinical Center.
CSL has recommended computer techniques that
can be used to automatically acquire anatomical and
physiological information from patients, perform the
required calculations on the data obtained, and
display the necessary results to the medical staff.
The automated techniques include the measurement
of body forces (hand and ground reaction forces),
electromyograms (electrical activity of the muscles),
and body kinematics (the position and angles of the
limbs and joints in space and time). An Automated
Biomechanics Laboratory System that provides
these measurements will be purchased in late FY82.
The computer part of the system will allow the
medical staff to enter patient and staff data into a
data base with computer-generated forms displayed
on a terminal screen, and to perform inquiries and
generate reports using the accumulated data. In
FY83, the physical space will be designed to
accommodate this system in a new area of the
Clinical Center.

ZOl CT00081-02 CSL

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ine Department Computer System

OTHERS: H. 0. Jarret
W. Schneiderw
N, L. Gerber

,, Biomechanical Engineer
Physical Therapy ServiCi
Rehabilitation Medicine

CSL, DCRT

RH, CC

RM, CC

R«. CC

itation Medicine Department, Clinical Center

computer Systems Laboratory

Systems Design Section

DCRT. niH. Bethesda. HP 20205

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Background and Objectives: The Department of
Rehabilitation Medicine provides physiatric
evaluation and treatment, physical therapy,
occupational therapy, and speech therapy for NIH
Clinical Center patients referred by Institute
physicians. In addition, it develops various indices to
evaluate these services. This department supports
the efforts of, and collaborates with. Institute
physicians engaged in research relevant to physical
rehabilitation medicine. It also initiates both clinical
and basic research independent of Institutes in the
rehabilitation of mentally and physically handicapped
individuals.

In support of these goals, CSL is developing a
computer system. Initially, the department will use
the system for the following three projects:

1 . The Automated Biomechanics Laboratory: a
laboratory that will be used to automatically measure
the position of the limb segments in space, the
forces in the lower limbs, and the electromyographic
signals from the muscles in the limbs;

2. The Hand Dynamometer Instrument: a device
that will be used to measure the magnitude and
direction of the forces in the hand and to develop
clinical tests to diagnose the mechanical and
functional status of the hand, arm, and shoulder;

3. The Physical Therapy Quality Assurance
System: a data base system that will be used to
assess medical staff effectiveness in providing the
types of patient care needed, determine staff
workload and scheduling, and identify areas for
clinical research for the Physical Therapy Service.
Progress in FY82: During the past year, CSL
determined the instrumentation and computer
requirements for the Department of Rehabilitation
Medicine. A considerable amount of specialized
instrumentation is needed to perform the required
automated measurements. This includes: five motion
cameras with light sources that are used to acquire
the spatial coordinates of anatomical points on the
patient's body with reflective markers, force plates
that are used to measure patient ground reaction
force, and hard wired or telemetry electromyogram
acquisition equipment that is used to measure
patient muscle activity. CSL prepared a Request for
Proposals for an Automated Biomechanics
Laboratory System that will be used to obtain the
necessary transducers, instrumentation, and
computer hardware and software.

The Physical Therapy Quality Assurance Data Base
System was initially implemented on a small
computer system. It will be transferred to the larger
computer that is purchased with the biomechanics
laboratory system. The Biomedical Engineering and
Instrumentation Branch of NIH's Division of

Research Services continued development of the
hand dynamometer instrument.

Also, during the past year, a collaboration was
initiated with the Gait Analysis Laboratory,
Department of Orthopedic Surgery, Children's
Hospital Medical Center and Harvard Medical
School. In the future, computer programs, patient
data, and engineering and medical expertise will be
exchanged with this group.

Significance to Biomedical Research!: The computer
system will be used with arthritic, orthopedic, and
neurological patients and with amputees in order to
evaluate drug therapy, orthotic and prosthetic
devices, and medical interventions. It will also be
used as a teaching tool to help these patients learn
to function with their disability in an efficient manner.
Many hospitals in the United States are presently
establishing automated biomechanics and gait
analysis laboratories. Therefore, any new
developments made on this project will benefit users
of these automated systems, as well as patient care
and clinical research within the Department of
Rehabilitation Medicine at NIH.

Proposed Course: The Department of Rehabilitation
Medicine expects to purchase an Automated
Biomechanics Laboratory System during the coming
year. As the Department is moving to a new location
in the Clinical Center, the new area will be designed
to accommodate the cameras, force plates, EMG
equipment, computer hardware, and patient
measurement area.

Also, during the coming year, a study will be done to
determine the type of force plate that will best meet
the measurement requirements of the Department.
Comparisons will be made between small modular
versus large force plates and piezoelectric versus
strain gauge force plate transducers. In addition,
methods for accurately determining the velocity and
acceleration of anatomical points from acquired
motion data will be investigated including the
required camera resolution and frame rate and digital
differentiation techniques.

Positron Emission Tomography (PET) Facility

The PET facility of the Nuclear Medicine Department
is used to collect and analyze images of the human
brain for diagnosis and scientific research. The
facility includes a PET Scanner that receives data
consisting of gamma emissions from patients and a
minicomputer system that operates the scanner,
reconstructs the data into cross-sectional slices, and
performs other analysis. The facility also includes an
offline minicomputer system having an image array
processor and color display that is used to
interactively perform numerous image enhancement
and analysis functions. Various NIH Institutes use
this facility to research the aging process,
schizophrenia, epilepsy, and other brain functions
and disorders.

Background and Objectives: In late FY81, the
Nuclear Medicine Department requested assistance
in improving their PET computer facility. At that time,
the PET facility was receiving increased usage by
various Institutes and had recently lost some of its
technical staff. Our goal was to improve the existing
system's hardware and software, to establish
guidelines for collecting and storing patient data, and
to provide an image analysis system that could be
readily operational.

Progress in FY82: To improve scan data flow and
acquisition, we purchased and installed larger disks,
a tape drive, and a floating point unit. To improve
image data analysis, we purchased the offline
minicomputer system and installed and modified
image analysis software provided by NIMH. We also
programmed the analysis system to compute local
cerebral metabolic activity with radioactive
deoxyglucose utilization.

Proposed Course: NIH will be purchasing new PET
scanners and there will be increasing demand for
image analysis and for the storage and retrieval of
large quantities of data. We will analyze these future
demands and recommend appropriate solutions.

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Positron Emission Tomography (PET) Facility

P«OF£SS10NAL PEflSONHEL ENCACED OH THE PROJECT

PI: A. J. Pashayan Computer Specialist CSL, nCRT

OTHERS: W. L. Risso Electronics Engineer CSL, nCHT

R. M. Kessler. M.n. Hearl. Positron Emission

Tomography Section MM, CC

Nuclear Medicine, Clinical Center

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The PET facility of the Nuclear Medicine Oepartment is used to

collect and analyze images of the human brain for diagnosis and

scientific research. The facility includes a PET Scanner which

receives data consisting of gamma ei^issions from patients and a

minicomputer system that operates the scanner, reconstructs the

data into cross-sectional slices, and performs other analysis.

The facility also includes an offline minicomputer system

having an image array processor and color display that is used to

interactively perform numerous image enhancement and analysis

functions. Various NIH Institutes use this facility to research

the aging process, schizophrenia, epilepsy, and other hrain

functions and disorders.

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PROJECT NUMBER

ZOl CTn0096-0

CSL

Computer Assisted Hematology Morphology Data Handling System

PflOFESSIONAL PEHSONNEL ENCAGED ON THE PflOJECI

PI: n. C. Songco Electronics Engineer CSL

ncRT

OTHERS: L. Wang Electronics Engineer CSL

t)CRT

J. A. nonlon. M.O., Ph.fl. Staff Physician CP

A. Faust Prograrmer CP

£. W. Lundy Technologist CP

6. L. Wages Chief Technologist CP

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CPD, CC

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SUMMARY OF UORK (20O .ord= or le=i - unitrV.n, k.,.ortO

Cell morphology evaluation is a major component of the workl

of the Hematology Service of the Clinical Pathology Departme

CC. Manual white cell differential counting is the predomin

method of analyzing white cell morphology. Previously,

technologists performed manual differentials and recorded th

data on mark sense cards for later entry into the Clinical

Pathology Laboratory Computer (CPLC). This approach led to

of technologist time. The goal of this project was to desig

and develop an alternative method of handling the cell

morphology evaluation.

18 '"•■■

Computer Assisted Hematology Morphology
Data Handling System

Cell morphology evaluation is a major component of
the workload of the Hematology Service of the
Clinical Pathology Department, CC. Manual white cell
differential counting is the predominant method of
analyzing white cell morphology. Previously,
technologists performed manual differentials and
recorded the data on mark sense cards for later
entry into the Clinical Pathology Laboratory
Computer (CPLC). This approach led to transcription
errors, turnaround time lags, and inefficient use of
technologist time. The goal of this project was to
design and develop an alternative method of
handling the cell morphology evaluation.

Background and Objectives: CSL, in collaboration
with the Clinical Pathology Department, CC, has
developed a computer-assisted hematology
morphology data handling system with the following
characteristics: 1) allows direct entry of manual
differentials, red cell morphology, and platelet
estimates; 2) displays Coulter automated cell
counting data for comparison; and 3) links in realtime
to the CPLC.

Progress FY82: System development and installation
was completed this year.

The technologists were involved in the human
factors design of the system including specifying cell
types, screen and keyboard layout, procedure
definition, and 'help' and system messages. The
acceptance and use of the system was both
immediate and enthusiastic. Based on an average
daily workload of 230 analyses, the system has
decreased the manpower requirements by 50%,
changed turnaround time for release of certified
results from hours to minutes, and reduced
transcription time and errors.

A Digital Equipment Corporation (DEC) LSI-11
microcomputer with dual floppy disk drives was used,
with four VT100 CRT terminals as user stations.
Extensive use of DEC forms software was made to
allow flexibility in redefining screens and
nomenclature. The system is linked to the CPLC via
a direct 1200-baud serial line. The user responds to
menus at each stage of the procedure. Help
messages are available at any time providing online
instruction and verification of procedures.

Proposed Course: Because the present system is
already used to capacity, it will be necessary to add
or replace hardware and software in order to add
additional tasks. Plans are now undenway to increase
the capability of the present system by using

cartridge disk drives and modifying the system
software or upgrading from RT-1 1 to the more
powerful RSX11-M operating system. If this is done,
local data storage would be available for a
morphology quality control program. Composite lists
of platelet counts versus platelet estimates could be
generated. Additional user stations could be added if
the workload increased. This expansion is, however,
predicated on the availability of financial and
manpower resources.

Publications:

Donlon, J. A.. Wang, L., Lundy, E., Wages. B., Faust. A.. Songco. DC; A
Computer Assisted Hematology Morphology Data Handling System.
Symposium on Computer Applications in Medical Care, 1983 (in press).

Automated Pulmonary Physiology Testing

Procedures such as exercise testing, pulmonary
compliance, and muscle strength have been found
successful for evaluating pulmonary function. By
exercising a patient on a treadmill and gradually
increasing the workload (i.e., speed and incline), the
physician can better assess cardiopulmonary
disease, which in its early stages generally does not
manifest itself except under physical exertion. In
order to help the physician perform these procedures
more effectively, a microcomputer system has been
developed to enable automated realtime collection,
analysis, and display of pulmonary compliance and
inspiratory muscle strength data. Steady-state
treadmill exercise testing has been only partially
automated. Although data is manually entered, data
analysis and report generation are fully
computerized. Work is in progress to enable
automatic realtime acquisition of exercise data with
breath-by-breath analysis. The breath-by-breath
technique allows determination of the anaerobic
threshold noninvasively, without the need for arterial
catheterization. The anaerobic threshold is used as a
measure of an individual's 'fitness.' Patient data is
stored on a local disk data base for future reference.

Background and Objectives: Physicians monitor
pulmonary parameters during exercise to better
assess pulmonary function and to diagnose
pulmonary dysfunction that only manifests itself
under physical exertion. Procedures such as
pulmonary compliance and inspiratory muscle
strength also give insight into respiratory function.

Until last year, pulmonary treadmill exercise testing
was performed manually at NIH. Data were written
down and later entered into a programmable
calculator for determination of results. Additional
summary statistics and a final report were prepared
by hand. Inspiratory muscle strength and pulmonary
compliance measurements, done in the same lab,
likewise were performed manually.

In order to speed both exam and data analysis time,
and to improve accuracy, these procedures were
automated with a microcomputer system.

Methods Employed: The microcomputer system is a
DEC MINC-11/03 (Modular Instrument Computer)
containing an LSI-1 1 microprocessor, 32K words of
memory, auxiliary disk storage, and analog-to-digital
and digital-to-analog conversion capability. There is
also a video graphics display, a keyboard console, a
hard copy unit for printing the video display, and a
line printer.

In determining pulmonary compliance,
transpulmonary pressure (the difference between
alveolar pressure, i.e., mouth pressure with mouth
shutter closed, and esophageal pressure, as
measured by a balloon transducer swallowed by the
patient) and lung volume (measured with a wedge
spirometer) are determined by the computer as the
physician repeatedly closes a mouth shutter
throughout a patient's inhalation or exhalation. A
graphical plot of the data and an exponential least
squares curve fit of the data is then produced to aid
in evaluating the 'stretchability' of the patient's lungs.

During the steady state treadmill procedure, the
computer monitors expired volume and flow via a
Tissot spirometer and pneumotach, respectively, as
the patient is subjected to stepped increases in
exercise, each time starting from a resting state.
Expired oxygen, carbon dioxide, and nitrogen
concentrations are monitored via a Perkin-Elmer
mass spectrometer gas analyzer. Traditionally, in
order to determine the patient's anaerobic threshold
(i.e., point where the body begins to rely heavily on
anaerobic metabolism and produce lactic acid), the
patient is catheterized in order to obtain arterial
blood samples at each steady state level. Acid/base
and gas concentrations are determined offline by a
blood gas analyzer from a sample of the patient's
arterial blood, and entered at the keyboard.
Pulmonary volumes, flows, and oxygen
consumption-a measure of how hard the patient
actually works to perform a given level of exercise-
are then calculated.

When one has the capability to automatically monitor
air flow and expiratory gas concentrations in
realtime, the anaerobic threshold can be determined
noninvasively without the need for blood p02
obtained from arterial catheterization. Anaerobic
threshold is determined from measures of exhaled
02, C02, and respiratory quotient. Breath-by-breath
analysis also allows the performance of nonsteady
state exercise testing, where the patient is subjected
to continuously increasing levels of exercise. This
methodology provides a more dynamic picture of the
patient's cardiopulmonary performance.

Progress in FY82: The MINC computer system is
now used routinely to perform the static pulmonary
compliance and inspiratory muscle strength
procedures. The graphics capability of the MINC VT-
105 console terminal was found to fall short of the
lab's needs due to the one 'Y' per 'X' plotting
limitation. As a result, a Retrographics VT-100
terminal was procured, providing Tektronix
compatible bit-mapped raster graphics capability.
Using a CSL graphics package, all pulmonary
graphics routines were rewritten for Retrographics
compatibility.

Throughout the year, several programs were written
to aid pulmonary personnel in the analysis and
organization of data obtained from other areas of the
pulmonary clinical and research service.

Work continued on fully automating the treadmill
exercise system. However, a change in clinical
priorities re-directed efforts towards the development
of a breath-by-breath steady state exercise system
rather than simply automating the technique currently
performed. Completion of this goal is planned for the
end of FY82.

Proposed Course: Once the breath-by-breath steady
state exercise procedure is completed, the system
will be adapted to perform a nonsteady state
procedure as well. Although there are now no
immediate plans to add additional procedures to the
system, having developed a general purpose tool for
pulmonary data collection, new procedures or
modified techniques can be easily incorporated into
the existing protocol. For example, the computer
may enable closed loop control of treadmill speed.

By monitoring heart rate and dynamically varying
treadmill speed in response to heart rate changes, it
should be possible to apply a more constant
workload to the patient, thus leading to more stable
results. In addition to the potential for performing
new physiology procedures, additional mathematical
analyses can be applied to the data in order to gain
further insight into a patient's pulmonary function.

Publications:

Nadel, L.D.: Automated Pulmonary Analysis by an Online Microcomputer, In
Nair, S. (Ed.): Computers in Crillcal Care ar)d Pulmonary Medicine (in
press).

Nadel. LD.: Breath-to-breath Pulmonary Exercise Testing Using an Online
Microcomputer. First IEEE Computer Society International Conference
on Medical Computer Science. Computational Medicine (MED-
COMP'82), Philadelphia. September 25, 1982,

Keogh, B., Gadek, J., Price, D,. Nadel. L.. and Crystal, R.: Remarkable
Similarities in Exercise Gas Exchange Parameters in Markedly Dispa-
rate Diseases: Comparisons Between Idiopathic Pulmonary Fibrosis
and 1 -Antitrypsin Deficiency. American Review ol Respiratory Disease
125: 157, April 1982.

Assessment of Tongue Motion During Speech
Using Ultrasonic Imaging Techniques

This project is directed at developing a system
capable of ultrasonically imaging the tongue in
realtime. In addition to obtaining and integrating the
necessary hardware, mathematical techniques must
be identified and developed to analyze and describe
images of continual tongue motion. Thus far, the
tongues of several normal subjects have been
imaged using a realtime ultrasonic body scanner in
conjunction with a videotape recorder. Anatomical
features of interest, as the subject vocalizes specific
phonemes, are extracted using a graphic tablet
followed by preliminary computer analysis. Efforts
are presently being devoted to identifying and
developing mathematical techniques for analyzing
and describing the patterns of continuous tongue
motion. Once we complete an evaluation of the
ultrasonic scanners commercially available, we plan
to purchase and build where necessary the hardware
required to implement this technique in our new
speech laboratory, scheduled for operation in FY83.

Background and Objectives: Speech investigators
have traditionally used radiographic methods for
studying tongue motion during speech and
swallowing. These techniques, however, are
somewhat cumbersome and are not suitable for
general screening, diagnosis, or therapy due to the

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(Ictober 1, 19fil to September 30. 1982

Automated Pulmonary Physiology Testing

PI: L. n. Nadel. Ph.n. Staff Fellow POS. rSL, DCRT

OTHERS: B, A. Keogh, M.n. Expert PB, IR NHLRI
P. S. Plexico Chief, Project nevelopment

Section CSL. nCBT

COOPEfiMINC UNirS (.1 .r,J

Pulmonary Branch, NHLBI

Computer Systems Laboratory

Project nevelopment Section

OCRT. NIH. Bethesda. HD 2020S

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SUMH^RY gf WORK (JOt. -ord. or 1 od.rll.. k.^ord*)

Procedures such as exercise testing, pulmonary compliance, and
muscle strength have been found successful for evaluating pulmonary

the workload {i.e., speed and incline), the physician can better assess
cardiopulmonary disease, which in its early stages generally does not
manifest itself except under physical exertion. In order to help the
physician perform these procedures more effectively, a microcomputer system
has been developed to enable automated realtime collection, analysis and
display of pulmona'-y compliance and inspiratory muscle strength data.

ZOl CT0O094-O1 CSL

nrtnhpr l,^iq«l *" ^Jeptpmher 30.

Tongue Motion During Speech

PI:

L. n. Nadel, Ph.D.

OTHERS: R. C. Sonies
T. H. Shawkei
H.L. Stone, i

Chief
Oept.

' Diagnostic Radiology. CC
Consultant, Speech Pathology
Oept. of Rehabilitation Med.,
Chief. Physical Sciences Laboratory
PSL. OCRT

Department of Rehabilitai
Radiologiy, CC; PSL. OCRT

, CC; Oept. of Diagnostii

Project Development Section
DCRT. NIH, Bethesda. MP 20205

veloping a systej

r. the tongues i

nual tongue
'i dent ape

mi nary compi
ifying and ■

extracted using a graphic tablet followed I
ling mathematical techniques for analyzing .

harmful effects of x-rays. It is hoped that the
development of an ultrasonic system for visualizing
lingual function and performance will prove valuable
for the general screening and diagnosis of speech
pathology. Used as a tool for biofeedback, such a
system might be of assistance in helping a patient to
correct speech difficulties. As one learns more of the
details of tongue motion in swallowing and speech,
this imaging system may be of potential value in the
fields of neurology and dentistry.

Methods Employed: Using an existing realtime
ultrasonic diagnostic body scanner (ATL), several
normal subjects were scanned during the utterance
of specific phonemes. The resultant images were
photographed and digitized using a graphic tablet
interfaced to a DECsystem-10 computer. The data
was statistically analyzed for reliability and
repeatability. Although mathematical techniques for
describing the patterns of tongue motion obtained
are presently under investigation, some interesting
observations already have been made. New
instrumentation is presently being evaluated to
implement this technique without the need for an
intermediate photograph. In order to observe one's
natural tongue motion, a critical task will involve
developing a means to mount the ultrasonic probe
so as not to interfere with or influence the patient's
speech. Additionally, variable positioning or
nonconstant pressure on the transducer will affect
the final image.

Progress in FY82: In order to demonstrate the
feasibility of the above-mentioned technique, the oral
cavities of several normal subjects were scanned
using a realtime ultrasonic body scanner, by placing
the ultrasonic transducer two centimeters behind the
mental symphysis of the patient's mandible. Each
subject was asked to repeat specific phonemes
while mouth images were continuously recorded on
a videotape recorder. Using the recorder's freeze-
frame capability in conjunction with a multi-image x-
ray formatter, the desired images were copied onto
negative film. The negatives were developed into
positive prints. By placing the resultant prints on a
graphic tablet connected by telephone to a
DECsystem-10 computer, the polar coordinates of
anatomical areas of interest, namely, the tongue
surface and the genioglossus muscle, could be
readily determined. The digitization technique was
repeated by several observers in order to statistically
determine the accuracy and reliability of both the
ultrasonic imaging and digitization techniques.
Preliminary observations were made regarding
tongue motion for vocalizing particular phonemes.

Since the Rehabilitation Medicine Department wishes
to outfit its new speech lab with an ultrasonic

imaging and analysis capability, various equipment
and methods are being evaluated for integration into
a tongue analysis system.

Proposed Course: The required system hardware will
be ordered early in FY83. The development of
methodology and software for analysis of tongue
images will continue. A means for placing an
ultrasonic transducer with constant position and
pressure two centimeters behind the mental
symphysis of the patient's mandible will be further
investigated and developed. Once all the system
hardware is obtained, the various components will be
interfaced and the necessary control and processing
software will be written. Normal volunteers will then
be scanned in order to obtain baseline values of
tongue motion. Shortly thereafter, patients with
speech problems will be observed as well. In the
future, we also plan to use this system to study
swallowing defects.

Anesthesia Computer System

This project involves evaluating improved
instrumentation techniques and identifying and
investigating ways that automation can benefit
anesthesia. Project emphasis is on adjunctive
monitoring and automated recordkeeping in the
operating room.

Background and Objectives: While computers and
automation have been used in intensive care
settings for some time, little previous work has been
reported on their application in operating rooms. Two
areas of potential benefit with an anesthesia
computer have been identified.

1. Adjunctive monitoring, i.e., using the computer
for monitoring and display of patient parameters. The
main goals are a unified, easy-to-read display; limit
detection and trend analysis of the parameters; and
archiving of the measurements for later use in
research or anesthesia mishap analysis.

2. Automated recordkeeping, in which the
computer would not only record the results of
monitoring, but also would make provision for a
record of drug administration, for free text notes by
the anesthesiologist, and for producing a printed
record suitable for inclusion in the patient's record.
An advantage of such a system is that it will allow
the anesthesiologist to devote more time to the
patient by simplifying the tasks of observing and
recording measurements.

Progress in FY82: Most effort this year has been
expended on developing a project plan for future
work.

Proposed Course: The project plan will be
completed, needed resources will be sought, and

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ZOl CT00093-01 CSL

nrtnhPr 1 1981 to Seoter

Anesthesia Computei

Anesthesia 5eri

Computer Systems Laboratory

Project Bevelopment Sectii

DCRT. WIH. Bethesda. HP 20205

This project involves evaluating improved instrume
techniques and identifying and investigating ways
can benefit anesthesia. Project emphasis is on ad

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October 1. 1981 to September 30. 1982

Medical Information Technology Project

PI: S.I. Allen Medical Research Analyst CSL. ncUT

OTHERS: 0. C. Songco Electronics Engineer CSL. nCRT
C. S. Brown Consulting Dermatologist
P. S. Plexico Chief. Project Development Sec. CSL, DCRT
A. W. Pratt Director DCRT

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This project involves the application of microprocessor technology
and improved man-machine interface methods to permit physicians and
their associates to more directly cormunicate with computer record
systems. A pilot study involving medical transactions input directly
by practicing physicians is underway. The goal is to develop better
ways to automate the essential physician contribution to the health
care record that is used in both research and patient care.

efforts to accomplish the project plan will proceed to
the extent that resources become available. The
most likely scenario is the development of a
'demonstration' operating room to test the
hypotheses that adjunctive monitoring and
automated recordkeeping are advantageous.

Medical Information Technology Project

This project involves the application of
microprocessor technology and improved man-
machine interface methods to permit physicians and
their associates to more directly communicate with
computer record systems. A pilot study involving
medical transactions input directly by practicing
physicians is underway. The goal is to develop better
ways to automate the essential physician
contribution to the health care record that is used in
both research and patient care.

Background and Objectives: The use of computers in
medical and hospital practice is increasing as the
cost of systems is decreasing due to technological
innovation. However, few physicians are comfortable
with current machine interfaces. With this in mind,
we are investigating devices and methods that
provide a more capable, attractive interface while
maintaining an acceptable level of flexibility and
efficiency. The ultimate aim is to increase physician
productivity in patient diagnosis and treatment and to
increase patient understanding of disease processes
and management plans.

Methods: Much of the clinical software is table-
driven to allow the physician to add and modify the
data bases. This approach also provides a
convenient means of adapting the programs to other
clinical care and research environments. Both the
clinical data base and processing software are being
developed and tested on the CSL time-shared
computer system. Finished programs, ready for use
in patient care, are then transfered to a compatible
microcomputer system situated in the physician's
office.

Progress in FY82: In collaboration with a practicing
dermatologist, we are field testing an ambulatory
patient care transaction system. This system allows
the physician to input, store, retrieve, and
disseminate patient data needed by various
members of the health care team as well as by the
patient. The immediate data processing focus
includes machine generation of patient information
and treatment schedules, pharmacy prescriptions,
medical and surgical procedure reports, laboratory
test orders, and referral letters to other doctors.

Disease-specific and problem-specific protocols are
used to lead the user through a restricted tree-
structured hierarchy cf relevant diagnoses,

treatments, drugs, tests, and procedures. Where
appropriate, protocols are modified by such factors
as patient age, sex, weight, disease stage, and
therapeutic response specified by the physician.
When all workups and treatments are indicated, the
computer then produces hardcopy treatment plans
for the patient, record summaries for the doctor,
prescriptions for the pharmacist, and test requests
for specified laboratories.

Proposed Course: Selected physician-operated
modules will be tested to support critical diagnostic
and therapeutic functions in ambulatory care.
Programming logic to support isolated patient
encounters also will be expanded to handle followup
visits. The conventional CRT and keyboard terminal
employed now will be replaced with faster I/O
devices that are tailored to this medical application.
For example, we plan to use graphic input to
facilitate the capture of anatomic disease
descriptions and keyboard substitutes to speed
menu item selection.

Molecular Graphics and Sequence Analysis

The sequence of some regular proteins, together
with other structural information such as data from x-
ray diffraction, fiber diffraction, electron microscopy,
and spectroscopic analysis can be used to evaluate
models of the protein structure. Four such analyses
are studies of collagen (with NIDR), keratin (with
NIADDK and NCI), myosin (with Brookhaven), and
streptococcal M proteins (with Rockefeller).

The crystallographic structure of type I collagen
fibrils had previously contained some controversial
assumptions. A new model has been proposed this
year that seems to resolve these difficulties and
encompasses all of the experimental evidence into
one structurally simple model.

As the sequence of keratin cyanogen bromide
fragments becomes available, an anaylsis of the
sequence is proceeding by studying the periodicities
in the sequence, and by predicting conformational
properties of the specific amino acids in local regions
of the chain. It is anticipated that the experimental
results may be able to clearly specify if any of the
proposed two or three models are correct.

Analysis of myosin and streptococcal M proteins is
continuing as sequences become available. This
project is presently capable of easily evaluating new
sequences for periodicities or regularities.

Background and Objectives: While it would be
somewhat idealistic to attempt to predict the
structure of a globular or irregular protein, it is
currently possible to convincingly model and predict

the structure of regular (helical) proteins. With the
current knowledge of the structure of the collagen
helix, synthetic protein analogues of collagen,
tropomyosin, and other regular proteins, one can
extend this technology to new proteins as the
sequence is experimentally determined if there are
known points of similarity.

Significance to Biomedical Researcii: Many proteins
do not form three-dimensional crystalline solids
whose structures can be analyzed by classical x-ray
diffraction. However, if these proteins are regular,
comparison and analogy with related proteins can be
used to model the unknown structures in order to
understand the structure and functioning of the
proteins. In addition, one can use computer models
to analyze two or more possible candidates and
determine the most likely protein structure.

Progress in FY82: A new model of collagen has
been proposed that reconciles previously diverse
data from a variety of experimental sources. A new
analysis has begun that will use the sequence of
keratin filaments to compare the structure to
proposed models and to other proteins whose
structure has been well characterized.

Methods Empioyed: Standard Fourier methods have
been used to analyze the sequences and to cross-
correlate sequences. These sequence regularities
are usually correlated with structural features, such
as the collagen triple helix, the alpha helix, or the
tropomyosin double-stranded alpha helix. In addition,
software was written to model the collagen helix and
double-stranded alpha helices on the Evans and
Sutherland Picture System. This unique hardware
allows three-dimensional analysis of proposed
structures, both using traditional wire models, and by
using CPK 'ball' models in three dimensions, where
the size of the ball is related to the size of the
individual amino acid, and the color of the ball is
related to the function of the amino acid.

Proposed Course: As new sequences of regular
(helical) proteins become available, it is relatively
easy to model these sequences and describe their
structures both graphically and quantitatively.

Publications:

Trus, B. L., and Elzinga, M.: Computer Modeling of A 17,000 Dalton Frag-
ment of tvlyosin. In Balaban, M., Sussman, J. L., Traub, W., and Yonath,
A. (Eds.): Structural Aspects of Recognition and Assembly in Biological
Macromolecules, Rehovot, Israel (in press).

Piez, K. A., and Trus, B. L.: A new model for packing of type-l collagen
molecules in the native fibril. Bioscience Reports 1:801-810, 1981.

OMIIN SCIENCE INFOM
T HIM6CR (Oe 101 <■*•

ZOl CT00090-01 CSL

October 1, 19fll i

PI: B. L, Trus

OTHERS: A, C. Stevei
P. M. Steini
R, L. Jerni.

Research Chemist

LPB, NIAOOK
OB, NCI
Chemtst LTB.nCBO

Brookhaven Nat
The Rockefelle
The RocVefelle

LPB, NIAnilK; OB. NCI; LTB, NCI; Oology nept.. BNL; Microbiology.
Rockfeller University

_ Systems Pes! gn Sectlqi

nCRT. NIH. Bethsda, HP 20205

The sequi
diffract

NCI), myosin (w

r proteins, toi

iscopy, and spei

th NIDR). keral
en), and strepl

'JI(c?'iSelR't!"iiJi'™"h!; !S!3"

™''s,^is;!f""';"

ZOl CT00080-02 CSL

October 1. 1981 to Sept

mber 30. 1982

Computer Analysis of Ge

Electrophoresis

PI; B.L. Trus

Research Chemist CSL. OCRT

OTHERS: R. Goldman

Staff Fello» LBP. NIAOOK

V. NUocJem

Staff Fellow CE. NIAOOK

J. E. Ran

Oirector NIAOOK

R. felstcd

Research Chemist BCRP*. NCI

* Baltimore Cancer Research Program

CI>Ofl««tl»G »»IIS (If ..,1

LBP. NIAOOK; CE.NIAODK;

BCRP.NCI

LM/BRtNCH 1

Computer Systems Laboratory |

tOtm ll*NTE«RS> jPflOfESSim*Li lOIHERl 1

CHeCK *RPROPfll»It BlUlES)

] (.) »Ul» SutJECIS a (

D(.0">.O.S □ (.,) ■.■ER.Ii.E

.rli., l.,..ra,)

This project was designed

and accurately quantitate

ne- and two-dimensional gels. Quantitative

comparisons of two gels is

semi-automatic, and one project has

used methods developed her

to separate the results of double-labeled

radiography of protein gel

using color negative film and appropriate

because 3H and spillover of 14C

are recorded in the hlue s

nsitive layer of the film while HC alone

is recorded in the green o

red sensitive layer. This method was

used to analyze the effect

of growth rate and medium composition

on the relative levels of

ndividual proteins in a pathogenic

strain of Escherichia coll

Computer Analysis of Gel Electrophoresis

This project was designed to allow NIH scientists to
easily and accurately quantitate one- and two-
dinnensional gels. Quantitative comparisons of two
gels is semi-automatic, and one project has used
methods developed here to separate the results of
double-labeled radiography of protein gels using
color negative film and appropriate filters. This is
possible because 3H and spillover of 14C are
recorded in the blue sensitive layer of the film while
14C alone is recorded in the green or red sensitive
layer. This method was used to analyze the effect of
growth rate and medium composition on the relative
levels of individual proteins in a pathogenic strain of
Escherichia coli.

Background and Objectives: The primary objective of
this project has been to develop experimental
techniques and computer software to easily and
automatically quantitate two-dimensional gels. In
addition, analysis of one-dimensional gels is equally
accurate and feasible. Initially only Coomassie blue
stained gels were analyzed, but currently
autoradiographs are equally amenable to processing.

Significance to Biomedical Researcli: Use of gel
electrophoresis and autoradiographs is
commonplace in chemical, biochemical, and
biomedical research. However, the quantitation of
these gels is difficult. We have developed systems
that accurately and easily provide this quantitation to
the scientist. A number of laboraties outside of NIH
have requested our software for private use.

Progress in FY82: This project has produced many
useful results to a number of scientists at NIH. As
new gels require analysis, further fine tuning of the
methods will continue to improve the product. In
addition, we have used the methods to analyze color
negative film (rephotographed through appropriate
color filters) so as to analyze the growth rates and
medium composition on the relative levels of
individual proteins in a pathogenic strain of
Escherichia coli. These results are being submitted
for publication.

Methods Employed: Gels were rephotographed onto
Ektapan 4162 black and white film. Color films were
photographed through appropriate color filters. The
black and white negative was scanned on the
Perkin-Elmer microdensitometer and stored on tape
for later processing. A computer program CINT was
used to analyze the two-dimensional gels, and
another program OVERLP was used to correlate two
gels when necessary or desired. PIC was used in the
one-dimensional analyses.

Proposed Course: Computer software is being
expanded to provide for better matching of two gels.
All software is essentially machine independent so
as to be transferred to the newly-acquired image
processing laboratory. Additional options are being
added to the software so as to provide additional
flexibility to the research scientist.

Publication:

Nikodem, V. M., Trus, B. L, and Rail, J. E.: Two-dimensional gel analysis of
rat liver nuclear proteins after thyroidectomy and thyroid hormone treat-
ment. Proceedings of the National Academy of Science 78:441 1 -441 5,
1981.

lylTHSDNlAH SCIENCE IHFORBATICW EXCHANGE

HFAI

H-ANoTuirSE^iCES

PROJECT NUNBER

ZOl CT0n091-01 CSL

INTRA

mUL RESEARCH PBOJECT

198?

Horphometric Analysis of Normal

and Neoplastic Tissue Cultures

PfiCFESSIOMAL PEHSONNEL ENCAGEO ON THE PROJECT

PI: R. L. Trus flesearc

h Chemist CSL. flCRT

OTHEflS: K. K. Sanford Chief,

In Vitro Carcinogenesis Section

LCMB, NCI

G. Jones Microbi

ologist LCMB, fJCl

CCOPE«AT,^C ONHM^. .".) :^-.<J|

"^i^'

L*B/BR*riCH

uraraar

Systems Design Section 1

INSTIIUIE AJJO LOCATION

CHECK APPROPRIATE B0X{ES)

3(.) HUNAN SUBJECTS Q (">) HW

^TISSUES D(c) NEITHER

D(.l) NINORS Q(,2) INTERVIEWS

SWUIAHY OF «0R»! {im .oM^ or U„ - u.d.rli.

l..,-onjO

This project was designed to s

tudy the morphonietric differences

between normal and tumorigenic

fibroblastic cell lines. Initially,

human, rat, and mouse cell lin

es were selected for analysis. The

cells were photographed from

iving cultures without staining or

fixing. The types of criterii

n being used by the computer to aid

shape, and chromatin texture and clumping.

Morphometric Analysis of Normal and Neoplastic
Tissue Cultures

This project was designed to study the morphometric
differences between normal and tumorigenic
fibroblastic cell lines. Initially, human, rat, and mouse
cell lines were selected for analysis. The cells were
photographed from living cultures without staining or
fixing. The types of criterion being used by the
computer to aid in differentiating between normal
and tumorigenic cells include nucleus and nucleolus
size and shape, and chromatin texture and clumping.

Background and Objectives: This project, which was
begun this year, uses standard techniques of image
processing as applied to these low contrast
unstained specimens as well as techniques
developed at NIH. We hope to demonstrate that it is
possible and practical to differentiate between
normal and tumorigenic cells in a nondestructive
manner. We are using many of the same criterion
used by the pathologist in differentiating stained and
fixed sections.

Significance to Biomedical Research: We hope to
demonstrate that this nondestructive method can be
used with confidence to determine if a culture is
normal. This method would be important for studies
of carcinogenesis in cultures.

Progress in FY82: Software was developed to
perform a pilot study on three types of cultures.
Preliminary results suggest that it may be possible to
determine statistical differences between normal and
abnormal cells.

Methods Employed: Cell cultures were photographed
through a light microscope onto 35 mm black and
white film. The film was digitized by a Perkin-Elmer
1010G microdensitometer with a 50 microns squared
aperture. Images were viewed on a video frame
buffer, and interactively processed. Results are
stored in log files for each sample, and files are
pooled for each type of culture yielding better
statistics. The mouse and rat cultures underwent
spontaneous neoplastic transformation, while the
human fibroblast line was exposed to chemical
carcinogens to generate the tumorigenic line.

Proposed Course: After the analysis of the three pilot
studies, we expect to continue analysis of additional
cell lines, and are considering nonlethal staining
techniques.

Virus Structure As Determined by Image
Processing of Electron Micrographs

A new virus structure, that of bacteriophage T7, has
been determined by image processing of electron
micrographs. We analyzed T7 poiycapsid tubes
because these structures are more amenable to
image processing. Optical diffraction revealed that
the polycapsids were based on cylindrical foldings of
a hexagonal lattice with a spacing of 12.6 nm, which
is similar to the lattice constant for other complex
icosahedral phage capsids defined to date. However,
the details of the T7 capsomer differ from the other
results.

Background and Objectives: Viruses are significantly
smaller than bacteria, and as a result are not seen in
a light microscope. Information about their structure
usually comes from electron microscopy, which is
limited by resolution, low contrast, and noise. If
staining is used, then the resolution is limited by the
size of the stain, and often has noise as a result of
uneven staining. However, because virus structures
are generally periodic, they are a perfect candidate
for image processing.

Virus shells are composed of one or a few proteins
that form simple repetitive geometric forms. The
forms or containers can be, for example, cylinders,
icosahedra, or spheres. There are classes of
structures, and knowledge of the fine structure of
one coat protein can be used to understand the
structures of other similar viruses in the class. It is
our primary objective to add to the pool of
information, and to be able to use this information to
increase our understanding about how virus structure
relates to function and activity. This project was
described under project number Z01 CT00082-01
CSLin FY81.

Progress in FY82: The results of a study of a virus
previously determined by us, beet necrotic yellow
vein virus, were published. In addition, the results of
the structural determination of the T7 virus were
presented at two meetings, and are being submitted
for publication. These results are especially
significant because another virus (polyoma), which
has significant similarities to T7, was recently
reported to have significantly differing geometry.

Significance to Biomedical Researcti: This project
should be considered as basic research whose aim
is to increase our understanding of the structure and
functions of viruses in general, as well as subclasses
of viruses similar to those studied to date.

Mettiods Employed: The micrographs were taken
with a Philips EM400T microscope, and the best
negatives were preselected by optical diffraction.

Negatives were digitized on a Perkin-Elmer 1010G
microdensitometer and analyzed by means of the
PIC computer system. Results were photowritten on
the Perkin-Elmer microdensitometer. Typical
processing of the images consisted of Fourier
filtering of up to 50 unit cells and symmetrization of
the results as needed.

Proposed Course: We anticipate evaluating other
viruses for suitability for examination with these
methods, and continuing with this project to
determine the structure of various classes of viruses.

Publications:

Steven, A, C, Trus, B. L-. Putz. C. and Wurtz, M.; The Molecular Organiza-
tion of Beet Necrotic Yellow Vein Virus. Virology 113:428-438, 1981.

Steven, A. C, Serwer, P., and Trus, B. L.: Molecular Packing in Bacteno-
phage T7 Capsid Visualized at 2.5 nm Resolution in Computer Proc-
essed Electron Micrographs. Eighth Biennial Conference on Bacteno-
phage Assembly, Fall Creek Falls Park, Tennessee, May 9-14, 1982.

Trus, B. L., Sender, P., and Steven. A. C: Capsid Fine Structure of Bacterio-
phage T7 Determined by Image Processing of Electron Micrographs.
Tenth International Congress on Electron Microscopy, Hamburg, Ger-
many, August 17-24, 1982.

ZOl CI0009Z-01 CSL

October 1. IQfil to September 30. 198?

I As netermined by Image Processing or Electron

Research Chemist
Visiting Scientis

LPB, NIADDK; The I

I Science Center

Computer Systems Laboratory

Systems Design Section

DCRT, NIH, Rethesda.

s structure, th
essing of elect

t of bacteriophage T7
on micrographs. We an

has been determined
alyzed T7 poiycapsid

ffraction revca
1 foldings of a
imilar to the 1
1 phage capsids
the 17 capsome

ed that the poiycapsid
hexagonal lattice with

defined to date. Howe
differ from the other

to image processing
s were based on

a spacing of 12.6 ntt
er complex
.er, the details of

results.

Image Processing of Electron Micrographs

This project was designed to facilitate structure
determination from electron microscopy by providing
suitable software, hardware, and scientific expertise
to allow other scientists, primarily at NIH, to use
image processing and computer reconstruction to
determine or understand a specimen's structure.

Two new applications that began this year are
analysis and identification of small particles by
electron beam excited x-ray microanalysis as applied
to aqueous suspensions of vertebrate retinal rod
cells and the analysis of the microtrabecular lattice
and the cytoskeleton to determine volume, surface
area, and the diffusion of molecules.

A study of densitometer techniques was completed
and published. Studies continued from FY81 include
analysis of keratin, membrane structure, and muscle
structure.

Background and Objectives: The objective of this
project is to develop a general-purpose software
package for the analysis of electron micrographs. In
addition, the computer analysis requires optimal
utilization of the available hardware and the
availability of a research scientist capable of
providing logistical support. Techniques and software
developed in this project have been used
independently of this project both at NIH and at
laboratories outside NIH.

Significance to Biomedicai Researcii: Computer
analysis of electron micrographs is still a relatively
recent addition to the tools available to scientists for
structural analysis. Few laboratories have the
combined software and hardware capability to
perform the image processing and image
reconstruction available at NIH. These techniques
are especially powerful when applied to two-
dimensional crystalline structures. In addition, we can
correlate and align similar particles that are not
crystalline, and correct for a number of artifacts and
experimental problems.

Progress in FY82: This project has had some growth
in software, but primarily has grown in the utilization
of programs and the PIC system. It is feasible for an
NIH scientist to bring in a problem and obtain
preliminary results in a relatively short period of time.
Then a decision is made to expand the preliminary
study into a project, or to use the results that were
obtained.

One study, in collaboration with NIADDK, used the
computer to analyze digital information to analyze
small particles by electron beam excited x-ray
microanalysis for particles in aqueous suspension.
This novel approach was applied to the isolated
outer segments of vertebrate retinal rod cells and
was used to study the distribution of K, Os, P, and
45Ca in unstable objects.

Another study, in collaboration with the Physical
Sciences Laboratory, DCRT, examined the
microtrabecular lattice and the cytoskeleton. Images
were digitized and analyzed for the fraction of
interlinked slender strands versus the amount of
open spaces.

Proposed Course: This project will continue software
development as needed and will be converted to use
the new image processing facility as it becomes
available. In addition, new biological structures that
become available for analysis will be examined.

Publications:

McGee, P. A., Trus, B. L., and Steven, A. C: Techniques to Evaluate the
performance of Scanning Microdensitometers in the Digitization of
Electron Micrographs. Micron (in press).

Trus, B. L, and Steven, A. C: Computer Processing of Electron Micro-
graphs of Periodic Biological Specimens. Washington Society of Elec-
tron Microscopy Annual Picture Meeting, Uniformed Services, University
of the Health Sciences, Bethesda, MD, May 6, 1982.

Gershon, N. D., Porter, K. R., and Trus, B. L.: The Microtrabecular Lattice
and the Cytoskeleton. Their Volume, Surface Area and the Diffusion of
Molecules Through It. Aharon Katzir-Katchalsky Symposium on Biologi-
cal Structue and Coupled Flovws, Rehovot, Israel, June 6-11, 1982.

Hagins, W. A., Foster, M. C, George, J. G., and Trus, B. L: Combined X-ray
Microanalysis and Radioautography of Diffusible Elements in Aqueous
Suspensions of Cells and Cell Fragments. Proceedings of Microbeam
Analysis Society, August 1982.

Trus, B., and Steven, A.: Digital Image Processing of Electron Micrographs-
The PIC System. Journal of Ultramicroscopy Q: 383-386, 1981.

s!;"™iiii.M

foS wf'SJrfhu ii^T'

HUL'.H'.No'S'Lfv.C.S

fflojici Nu.e«.

201 CT0008e-02 CSL

October 1. 1981 to Septanber 30, 1982

TITLE Of PflOJ£

CT (80 chir*c(*r» or I.»]

Image

recessing of Electron Hicrographs

™»KstS""

trsd'ENjwiJ'oJ'Tie'SSi"'; *"" '"'" " """"*'■ '"""'"""* *"" *^^ """

PI:

B. L. Trus Research Chemist CSL, DCRT

OTHERS :

A. C. Steven Visiting Scientist LPB. NIADDK

H. A. Hagins Chief. Section on Membrane Biophysics

LCP, NIAODK

H. C. Foster IPA Appomtee/Guest Worker LCP. NIADDK

J. G. George Laboratory Technician LCP. NIADOf.

N. D. Gershon Senior Staff Fellow dsl. DCRT

K. Porter University of Colorado and Fogarty

Scholar

eO0P.«*IIHt UN

IS tM .',)

LPB, Hit

L<|/S>.«C.

DDK; LCP. NIADDK; PSL. DCRT; University of Colorado

Computer

Systons Laboratory

Systems

Design Section

DCRT. NIH. Bethesda, HD 2020S

■2 1 .2 1

J (.) MWAh S

It BO<((S)

Dl.M-.NOBS

D{.2) iNimit-s

This project was designed to facilitate structure determination 1

from el

ectron microscopy by providing suitable software, hardware.

entific expertise to allow other scientists, primarily at NIH

image processing and computer reconstruction to determine or

underst

and a specimen's structure.

Two new

applications that began this year are the analysis and identi-

ficatio

n of small particles by electron beam excited x-ray microanalysis

as appl

led to aqueous suspensions of vertebrate retinal rod cells and

ysis of the microtrabecular lattice and the cytoskeleton to

ne volume, surface area, and the diffusion of molecules.

ZOl CTO0095-01 CSL

QcLQber-1. lisi tn ;;pnt.emt?pr 3(1. iqfl?

-Project DevelQpmeat SgclJ.flg_

L M*hu?Js! "^"' '^^'^'"j'^'V "" ''"^"''

The original configuration was usee
bacteria system. This year a new sj
rapid scan spectrophotometer (RSS)
mammalian eel 1s.

Potentiometric Titration Controller

A Potentiometric Titration Controller was developed
to study the electron transport chain at the cell level.
The details of this system have been reported in
previous years. The original configuration was used
to study the E. coli bacteria system. This year a new
system incorporating a rapid scan
spectrophotometer (RSS) is being used to study
mammalian cells.

Background and Objectives: The exact nature of the
respiratory chain in the mitochondria of mammalian
cells is still not known. The carriers are various iron-
containing molecules that have different affinities
(and corresponding voltages) by which they hold
electrons. The amount of energy liberated by
passage of an electron from one carrier to another
can be determined by the difference in redox
potentials of these carriers. The redox potential is
the voltage at which the carrier is equally reduced
and oxidized and it can be determined by a Nernst
relationship.

The original Potentiometric Titration Controller could
fix solution potential using electric currents under
program control. The amounts of oxidized and
reduced transport carriers were determined by
calculations based on voltages obtained from the
spectrophotometer corresponding to optical
transmittance and wavelength. A wavelength scan
motor was driven under computer control to change
the wavelength and obtain complete spectra.

Progress in FY82: The Potentiometric Titration
Controller has been greatly enhanced with the
addition of a Rapid Scan spectrophotometer (RSS)
in place of the original device. As before, the
solution potential is fixed by using electric currents
and the amounts of oxidized and reduced electron
transport carriers are determined using spectral data.
Now, however, complete optical spectra can be
taken in milliseconds instead of the 20 to 30
seconds required by the earlier system. Instead of
controlling a wavelength drive motor to acquire
spectra, entire scans are initiated under
microcomputer control. Complete scan data is stored
In an internal memory buffer of the RSS. Either
single scans or up to 64 rapid successive scans can
be taken and stored in the buffer. Data is then
transferred to the controller via a 9600 baud serial
link and recorded on disk. As before, selected data
is then transferred via modem to the DECsystem-10
for further analysis and graphics.

Proposed Course: The earlier Potentiometric Titration
Controller was used to study the electron transport
chain of a bacterial system, E. coli. A similar
approach using the new RSS will now be used to
extend these studies to the chain in mammalian
mitochondria. In addition, the new system will enable
us to study other important kinetic features of
respiratory systems not possible with the original
system.

Metabolic Energy Measurements

A microcomputer-based instrument has been
developed to study cellular energy transduction
phenomena. Specially designed electrodes have
been constructed and interfaced to the
microcomputer to calculate membrane potential and
protonmotive force. Derived paramaters are recorded
in realtime on a multipen plotter via D/A converters.
The user can observe all parameters as he perturbs
alterations to the medium in which the respiring and
energy transducing systems are suspended.

Background and Objectives: Cellular energy is
derived from the oxidation of substrates. Electrons
removed from these substrates are passed through a
chain of respiratory carriers-eventually, oxygen.
During the process, energy is stored in the form of a
gradient of protons across the cell or mitochondrial
membrane. The difference in the number of protons
inside the cell and outside the cell results in an
electrochemical potential or protonmotive force. This
electrochemical potential has two components, an
electrical potential across the membrane, and a
chemical potential characterized by a difference in
pH. These quantities are very difficult to measure
and current techniques are cumbersome and time-
consuming.

Progress in FY82: In FY80 and FY81 we developed
a microcomputer-based system that is capable of
realtime monitoring of these components. In FY82
specific electrodes have been designed and
constructed that respond to changes in electrical
potential and to changes in pH. The voltage signals
from these electrodes are amplified and sent to the
microcomputer via an analog-to-digital converter.
The computer stores the signals after digitally
filtering out noise and correcting for the nonlinearity
of the electrode transfer functions. It then computes
the electrical potential and the difference in pH from
the measured electrode voltages, and from these
determines protonmotive force.

The microcomputer also monitors signals from a pH
electrode and an oxygen-measuring electrode. The
computer program corrects for relaxation time delays
in electrode responses and filters out noise. The
oxygen uptake rate of the cellular material is
calculated as are the protron extrusion rate and the
proton-to-oxygen ratio. All derived parameters are
calculated in realtime and are output via D/A
converters to a multipen plotter. In this manner the
user can observe all quantified paramaters in parallel
as he alters the medium in which the respiring and
energy-transducing system is suspended.

Proposed Course: Hardware and software
development are now complete and all programs
reside in ROM and therefore do not require
downloading as before. The emphasis next year will
be on acquiring and analyzing data. New hardware
and software will be developed as the need arises.

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October 1, 1981 to September 30, 19S2 1

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PI:

D. C. Songco Electronics Engineer CSL, DCRT

OTHERS: R. V. Hendler Chief, BES LCB, IR, NHLBI |

0. H. Setty Visiting Associate LCB. IR, NHLBI

R. Shrager Mathematician LAS, DCRT

W. Friauf Chief, EEES BEIR. DRS

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microcomputer-based instriwient has been developed to study
ellular energy transduction phenomena. Specially designed
lectrodes have been constructed and interfaced to the
icrocomputer to calculate membrane potential and

protonmotive force. Derived paramaters are recorded in realtime I

n a multipen plotter via D/A converters. The user can observe

11 parameters as he perturbs alterations to the medium in

hich the respiring and energy transducing systems are suspended.

Electron Microanalysis Facility

CSL is collaborating with BEIB, DRS, in developing
an automated electron microanalysis facility
consisting of two electron microscopes interfaced to
a computer system. The facility will be used for
research into the elemental composition of biological
specimens, and for the development of new
techniques in electron microscopy. CSL is designing
and implementing the computer system, which will
acquire and display the spectra and images
produced by Electron Energy Loss Spectrometry,
Energy-Dispersive x-ray Spectrometry, and
Wavelength Dispersive x-ray Spectrometry. (See
also: Z01 RS1 0058-04 and Z01 RS1 0059-04.)

Background and Objectives: The Computer Systems
Laboratory is designing and implementing a
computer system as part of the BEIB Electron Beam
Imaging and Microspectroscopy Facility. The facility
consists of two electron microscopes and will be
used for research into the elemental composition of
biological specimens and for developing new
techniques in electron microscopy.

One of the electron microscopes is a Hitachi H-700H
200 keV Scanning Transmission Electron
Microscope (STEM) equipped with:

• a lithium-drifted silicon (Si(Li)) detector
connected to a Kevex 7000 Analytical
Spectrometer for performing Energy-Dispersive
x-ray Spectrometry (EDS)

• an electron spectrometer for performing
Electron Energy Loss Spectrometry (EELS)

• detectors for bright and dark field electron
current signals.

The other electron microscope is a Cameca 50 keV
Electron Microprobe equipped with:

• a Si(Li) detector for performing EDS

• three Wavelength Dispersive x-ray (WDS)
spectrometers

• detectors for bright and dark field electron
current signals.

A PDP-11/60 computer system is being interfaced to
both microscopes to perform the following functions:

• control electron beam position, stage position,
and the various detectors

• acquire spectral and image data from all
detectors

• process and display the spectral and image data

• monitor and display a wide variety of
'housekeeping' parameters, including: lens
currents, lens temperatures, beam current, beam

energy, pump temperatures, coolant flow,
vacuum pressures, water leak detectors, power
supply voltages, room temperature, and room
humidity.
Progress in FY82: CSL's software efforts this year
have been concentrated on these aspects of data
acquisition from the STEM:

• improvement of EEL spectral data acquisition
and display

• implementation of EEL and EDS image
acquisition and display

• implementation of fast electron current signal
acquisition and display

• retrieval of empirical x-ray spectral data

• improvement of the Kevex 7000 and
housekeeping data acquisition software

• development of a user interface.

EELS data acquisition and control of the STEM
beam position is done by a satellite processor
connected to the PDP-11/60 by a high-speed link.
Software has been written that allows the STEM
operator to define areas of a specimen as targets for
data acquisition and to collect EDS, EELS, and
electron current signal data from the target areas.

Three data acquisition modes have been
implemented:

• SPECTRUM mode produces a single x-ray and/
or EEL spectrum from the target area.

• IMAGE mode produces any combinatin of EEL,
EDS, or electron current signal images from the
target area.

• FAST IMAGE mode produces only current signal
images, but at high speed.

Software has been developed this fiscal year for
display and scaling of EEL spectra using the Kevex
7000. Also, EEL, EDS, and electron current signal
images can be displayed on the DeAnza ID5400
Display System, where zoom, scroll, and contrast/
brightness enhancement can be performed.

Software to retrieve empirical x-ray spectral data
produced by electron energy transitions within
ionized atoms was completed. This software allows
an operator or another programmer to specify an
element and the transitions or absorption lines of
interest using either Siegbahn or Shell-Pair notation.
It then looks up the associated energies and relative
peak intensities. Conversely, an energy range may
be specified, in which case the transitions and
absorption lines within that range are retrieved. The
x-ray data base was assembled by BEIB from
multiple sources, and contains over 3000 entries.
The contractor validated this data by fitting each x-
ray line series to a model based on Moseley's Law

and flagging for inspection any entry showing a large
deviation from the theoretical value. The resulting
data base is probably the most complete and
accurate available in machine-readable form, and
has been sent to over ten extramural requestors.

EDS data acquisition is done by the Kevex 7000,
which is connected directly to the computer.
Software has been developed to allow programs on
the 1 1 /60 to control the KEVEX 7000 and to save or
restore spectra to or from disk files. During this fiscal
year this software was improved to make it much
more efficient and easier to use. It was also installed
on a PDP-1 1 /34 computer system connected to a
JEOL JEM-100CX electron microscope for the
Laboratory of Neuropathology and Neuroanatomical
Sciences, NINCDS.

Housekeeping parameters are acquired by the
computer by means of an Analogies AN5400 data
acquisition subsystem. Software has been developed
to acquire, monitor, and display the STEM beam
energy, magnification, lens currents, pump
temperatures, and coolant flow. Improved calibration
parameter maintenance utilities also have been
developed.

A menu selection scheme simplifies the operation of
the data acquisition and display software. The menu
selection software is completely table-driven so that
it is easy to add new functions as they become
available. Menu selection terminates with the display
of a form for entering or modifying the parameters
for the chosen function. Each form records the
parameters last used and restores them as defaults
the next time it is selected. This greatly simplifies
operation, because most forms have dozens of
parameters, few of which are changed with each
use. Currently, forms for data acquisition and display
functions, housekeeping parameter display, and
specimen target definition can be activated through
menu selection.

The microprobe was connected directly to the 1 1 /60
with a serial interface, and BEIB has developed
software for acquiring WDS data.

Proposed Course: Next year, we expect to:

• implement primitive image processing functions,

• enhance the data acquisition software, and

• automate reading of the STEM beam current.
Publications:

Fiori, C. E., Gorlen, K. E., and Gibson, C: Comments on the Computeriza-
tion of an Analytical Electron Microscope. Proceedings of the Thirty-
Ninth Annual (Meeting of the Electron Microscopy Society of America.
Baton Rouge, Claitor's Publishing Division, 1981, pp. 246-249.

Fiori, C. E., Myklebust, R. L, and Gorlen, K. E.: Sequential Simplex: A
Procedure for Resolving Spectral Interference in Energy Dispersive X-
ray Spectrometry. Energy Dispersive X-ray Spectrometry. Gaithersburg,
IvID., National Bureau of Standards Special Publication 604, 1979, pp.
233-272.

Fiori, C. E., Swyt, C. P., and Gorlen, K. E.: Application of the Top-Hat Digital
Filter to a Nonlinear Spectral Unraveling Procedure in Energy-Disper-
sive X-ray fvlicroanalysis. fi/licrobeam Analysis. San Francisco, San
Francisco Press, Inc., 1981, pp. 320-324.

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Elect

on Microanalysis Facility

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OTHEBS:

C. E. Fiori Physical Scientist

L. K. Barden Electronics Engine

J. S. Del Priore Mathematician

P. S. Plexico Chief, Project flev

C. C. Gibson

H. S. Eden

J. R. Ellis

G. R. Hook

R. n. Leapman

C. R. Swyt

clopment

BEIB
CSL
CSL
CSL
BEIR
BEIB
BEIB
BEIB
BEIB
BEIB

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nCRT
DCRT
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Systems Laboratory

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tron microanalysis facility consisting o
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:ron Energy Loss Spectrometry, Energy-Oi
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See

also: ZOl RS1005e-04
Zni RSin059-l)4

Molecular Interactions Laboratory Data System

Objectives and Methods: As a supplement to the
ultracentrifuge data system, a microcomputer-based
data acquisition and analysis system was developed
for use with a Gary Model 61 CD spectropolarimeter.
The system consists of a simple, flexible CD
spectropolarimeter/microcomputer interface and an
interactive data processing program system by which
CD spectra may be acquired, averaged, subtracted,
converted to mean residue ellipticities, printed, and
stored for future use. Stored data may also be
transferred conveniently to a large computer facility
for semi-automatic conformation analysis. The
system overcomes some of the difficulties
encountered in attempting the visual interpretation of
noisy CD spectral recordings and in providing
additional data manipulation capabilities not easily
realizable with manual methods.

The CD spectropolarimeter is interfaced with the
microcomputer system via a special highly noise-
immune interface scheme based on the conversion
of the signals from the spectropolarimeter to pulse
trains. These pulse trains are then transmitted via
current loops to a CSL-designed timer/counter
interface board in the microcomputer. The operating
software consists of two programs that interact with
the user through a standardized combination of
menus and dynamically alterable displays. One
program provides data acquisition, processing,
output, and storage functions, while the other
program provides all but acquisition and includes the
capability to edit the operating parameters of a scan
file stored on the diskette.

Progress in FY82: Considerable effort was spent this
fiscal year in testing the system and in developing
tools on the DECsystem-10 for the graphic display of
spectra. The results of a study of system
performance with very dilute solutions were
presented at the 1982 FASEB meeting in New
Orleans. The CD data system has proven to be
efficient and easy to use; over 900 scans on several
hundred samples have been processed in the past
year. The time required to process a CD scan into
mean residue ellipticities has been reduced from
several hours to less than 30 seconds. In addition.

an arbitrary number of scans may be averaged,
difference spectra may be generated quickly, and
data at any stage of reduction may be stored for
future retrieval and manipulation. With this system
usable CD measurements have been obtained at
protein concentrations below 1 microgram per
milliliter.

Proposed Course: Plans for the future include
modification of the ultracentrifuge interface to
provide greater noise immunity and the addition of
support for a digital plotter that has recently been
added to the system.

Publication:

Tate, R., Schultz, A., and Osborne, J.: Computer-Assisted Analysis of apo-
lipoprotein subunit interactions. Federation Proceedings 41: 874, 1982

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Molecular Interactions Laboratory Data System

NueS, LtBOnilORY HDD IMSTIIUIE tfFILUIICNt, MO ItlLiS tf miMClrU. IHVtIIICA

raOFESSIONAL PCRSOMNa ENCACEO ON 1H( PftOJECT

PI: R. L. Tate. Ph.D. Computer Specialist

CSL, IKRT

OTHERS: 0. C. Osborne, Ph.O. Research Chemist

MPB. NHLBI

A. R. Schulti. Jr. Head, Processor Oeslan

Section

CSL. DCRT

COOPtRMINO UNIIS (.« ..,)

HOB. NHLfll

LAB/ennNCH

Processor Design Section

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This microcomputer (POP U/03) data system supervises th

acquisition

and processing of information from an analytical ultrace

trifuge and a

circular dichroic spectropolarimeter used in TOB. NHLBI.

the interactions hetween human lipoprotein subunits. Cur

ent capabilities

include acquisition, display, and preprocessing of data

rom the

ultracentrifuge and transfer of preprocessed data files

OECsystem-in for further analysis under MLflB using prede

ined procedures

invoked hy a few simple cotmands. Software support for tl

e spectro-

polarimeter includes the ability to add. subtract, and av

spectra and to transfer files to the POP-IO for further a

nalysis. The

results of a study of system performance with very dilute

solutions were

presented at the 198? FASfR meeting in New Orleans. Plans

underway for modification of the ultracentrifuge ioterfac

e to

|^0V|ide qp||ter noise immunity and for the addition of a

digital plotter

Californium-252 Plasma Desorption Mass
Spectrometer Data System

Background and Objectives: The Californium-252
time-of-fliglit (TOF) mass spectrometer employs
nuclear fission fragments to ionize samples that
frequently have proven intractable to other methods
of analysis. In this instrument, fission fragments
generated by the radioactive decay of a thin film of
252-Cf impact on a thin layer of sample deposited on
a conductive plastic film, producing a localized
plasma. The sample molecules produced within this
plasma are extracted by an electric field and briefly
accelerated down an evacuated tube toward a
microchannel plate ion detector. The elapsed times
between the ionization event and the arrival of the
ions produced are measured with an ultraprecise
clock capable of measuring time intervals of
hundreds of milliseconds with a resolution of 800
picoseconds. The elapsed time measurements are
then sent to a computer where they are sorted,
tallied, converted to mass units, and displayed. The
extended range of the timing clock coupled with the
unique characteristics of the ionization process make
this mass spectrometer ideally suited to the
investigation of the high molecular weight
compounds typical of biological materials. The TOF
mass spectrometer, which is not commercially
available, was developed at Texas A & M University
by Dr. Ronald Macfariane under a NHLBI contract.
The data system was specified to be compatible with
interface hardware and software available from Dr.
Macfariane. The need for realtime sorting of a large
volume of input data puts unusual and stringent
demands on the data system that controls the
spectrometer and acquires and processes its data
output. Realtime performance and the ability to
access very large data arrays in main memory are
key considerations.

Progress in FY82: After delays necessitated by
hardware design problems, software upgrades, and
facilities renovations, both the spectrometer and a
data system modeled after one in use at Texas A &
M University have been installed in the laboratory of
Dr. Henry Fates, LC, NHLBI, and will soon be
functional. This instrument will provide NIH the
capabilities of mass analysis for compounds that
have proven difficult or impossible to analyze by
other mass spectrometric means, also extending the
range of mass analysis to compounds with molecular
weights in excess of 5000.

Proposed Course: Expansion of the computer
system to include a line printer and additional
memory is currently planned. Modifications to the
mass spectrometer are also in progress to enhance
its safety and reliability. Plans are being developed
to implement computer control of sample changing
as well.

Distributed Laboratory Data Acquisition and
Control System

Bac/<ground and Objectives: A system of
microcomputers capable of independently controlling
and acquiring data from an instrument/experiment
was proposed in December 1976 as the best system
architecture of upgrading laboratory data processing.
A prototype laboratory data acquisition and control
system (LDACS) computer and essential elements of
the communication system were developed.

Satellites perform the realtime data acquisition and
instrument control functions. Their configuration
includes a Digital Equipment Corporation (DEC) LSI-
11 microcomputer, a 28K word memory, low density
random access storage, graphics terminal, and all
the necessary I/O hardware to interface the
instrument/experiment. Software developed by CSL
for each satellite, running under DEC'S RT-1 1
operating system, provides the user with a 'turn-key'
system. Presently, the system is configured with
eight satellites, supporting eleven instruments,
connected (via the communications computer) to a
DEC PDP1 1 /70 host processor. Instruments
connected to the network include:
spectrophotometer, CARY 14, CARY 118, CARY
219, two Perkin-Elmer 580B's, a
microspectrophotometer (designed by NIADDK);
spectropolarimeters, CARY 60, Jasco J500A; a
Varian Electron spin resonance spectrometer; I. S.
Co. Model 1440 liquid chromatograph; and a
stimulus response retina experiment.

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October I. 1<581 to September 30. 193?

Cdlifornium-252 Plasma nesorption Mass Spectrometer Data System

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PI: R. L. Tate, Ph.n. Computer Specialist CSL, DCRT
OTHfR: H. M. Fales. Ph.D. Chief LC. NHLRI

COOI-tfiAIIHC UN.IS (.t ..,,)

LC. NKLBI

Processor Design Section

DCRT. NIH. Bethesda. MD 2020B

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T*ie Californium-2S2 plasma desorption mass spectrometer puts unusual and
stringent demands on the data system that controls the spectrometer and
acquires and processes its data output. Realtime performance and the
ability to access very large data arrays in main memory are key
considerations, ftfter delays necessitated by hardware design problems,
software upgrades, and facilities renovations, both the spectrometer and
a data system design modeled after one in use at Texas ARM University
have been installed and are now functional. This instrument now provides
NIH the capabilities of mass analysis for compounds that have proven
difficult or impossible to analyze by other mass spectrometric means.
It also extends the range of mass analysis to compounds with molecular
weights in excess of 5000.

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Distributed Laboratory Data Acquisition and Control System

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PI: J. I. Powell Electronics Engineer CSL. nCRT

OTHERS: W. H. Jennings Physicist LCP, NIADDK
E. R. O'Bryan Electronics Engineer CSL. nCRT
A. R. Schultz, Jr. Chief. Processor Design

Section CSL. nCRI

LCP and LHB. NIAODK

LAe/BAANCH

Computer Systems Laboratory

Processor Design Section

DCRT. NIH, Bethesda. HD 20205

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An integrated laboratory data acquisition and processing system has
been developed for LCP and LHB, NIAODK. The system is configured
with satellites coupled through a local networli to a host processor.
At each satellite a dedicated microcomputer system performs data
acquisition , rom and control over an instrument/experiment.
Although acquired data files may be stored locally, they are
normally transferred via the network to a host storage mediuifl. The
local network allows the host storage medium to appear as a
'virtual' storage device to the satellites.

The local network includes a software nnodule,
installed as a handler under the RT-11 operating
system, at each satellite. Each satellite is connected
via a hardwired serial link to a front end
communications computer. The communications
computer performs a file store and forward function.
Received files are placed on a first-in-first-out queue.
Files are transferred from the queue to the host via a
parallel DMA link. The communications task running
on the host maps the files to the appropriate
directory area based on the identity of the satellite
that originated the transfer and the extension of the
file being transferred.

The host processor, a DEC PDP 11/70, is configured
with: 640K words of memory, a high speed printer/
plotter, an X-Y plotter, a 9-track magnetic tape drive,
dual floppy disk drives, and two large capacity disk
drives. DEC's multiuser, multitasking operating
system, RSX-1 1 M, is used to service the processing
needs of the users. User access to the host is
provided by hardwired links between terminals and
host timesharing ports. Processing software provided
at the host allows LDACS data files to be: added,
subtracted, averaged, smoothed, baseline corrected,
integrated, differentiated, multiplied by a constant,
and added to a constant. The results may be
displayed graphically on a Tektronix terminal, typed
at a terminal, printed on the line printer, plotted on
an X-Y plotter or transmitted to the DECsystem-10
for additional processing.

Progress in FY82: One new satellite, supporting a
second Perkin-Elmer 580B spectrophotometer, was
added to the system in FY82. LDACS software
supporting the acquisition of ESR data versus time,
and software supporting acquisition of MSP data
versus wavelength (wavelength controlled by the
LDACS) was added this fiscal year.

General processing programs were developed and
installed for the PDP-11/70 allowing manipulation of
LDACS data files and printing/plotting of the results.
Special purpose programs were provided for
processing of spectrophotometer melting run data
and processing of data files from an MSP
experiment.

The last vestige of the 1 1 -year-old centralized data
acquisition and processing system, the Honeywell-
516 computer, was removed from the configuration.

User's manuals for the CARY 219, PE 580B's, and
the stimulus response retina experiment were written
under contract.

Documentation of minor modifications and additions
to the software libraries developed for LDACS were
completed under contract. Retrofitting of LDACS
units was initiated with programs utilizing the
software libraries and incorporating (where required)
the multipurpose counter/timer module, and the
temperature control unit (both developed by CSL).

Proposed Course: Support for the system will
continue. The retrofitting of LDACS units with up-to-
date software will be completed. Documentation of
the system will be given a high priority, with the
objective of completing an LDACS User's Guide for
each LDACS and completing all systems
documentation.

The original scope of the project (upgrading the H-
516 centralized system) is approaching completion.
However, it is anticipated that some level of long-
term support will continue. New satellites or
instruments may be added to the system, and
existing LDACS acquisition programs may be
modified to enhance data acquisition or to
incorporate new instrument/experiment setups.
Occasionally, special-purpose programs are required
to process a set of experimental data.

Publication:

Powell, J. I., Fico, R., Jennings, W. H., O'Bryan, E. R., Schultz, Jr., A. R.: A
Local Network for Distributed Laboratory Microcomputers. Tutorial-Mi-
crocomputer Network, 1981, pp. 263-268.

, Engineer CSL, DCRT

CSL. DCRT
CSL, nCRT

DCRT, SIH, Bethesda. HP 20205

-rays, micrographs i
e system is complett

ility to display and analyze
of a powerful 32-bit
gh resolution displays.

other images. The computer
construction of the physica
Procurement of the first of
expected early in FY83.

Image Processing Facility

This project is intended to provide a utility to display
and analyze digital images. The system will consist
of a powerful 32-bit computer with a mixture of
medium- and high-resolution displays. Also, the
system will include a microdensitometer to allow
precise digitization of x-rays, micrographs, and other
images. The computer and peripherals have been
purchased, and construction of the physical space to
house the system is complete. Procurement of the
first of the displays is underway, with delivery
expected early in FY83.

Bac/<ground arid Objectives: This project arose in
response to a critically overcrowded situation that
exists on the present DCRT Evans and Sutherland
Graphics computer. As image processing
applications at NIH have increased, the limited
resources of that graphics system have been
saturated. During FY80, CSL, in collaboration with
present and potential users designed a new general-
purpose computer facility to aid the acquisition,
display, and analysis of images such as electron

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ZOl CT00fl97

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October 1, 1981 to September 30, 1982

Analytic Models of Computer System Performance

PI: R. L. Kartino Electronics Engineer CSL

OTHER: R. W. Newcomb Professor, Electrical

Engineering Oepartment Univ

DCRT
of HD

COOPEHArinC UNITG {H .ny)

University of Maryland

Computer Systems Laboratory

Systems Oesign Section

DCRT. NIH. Bethesda, HD 20205

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This project involves the deyelopment of analytic models that
used to evaluate the performance of computer systems. During
past year, tools for modeling and analyzing computer systems u
the graph theoretic rnodel called Timed Place-Transition (P-T)
were developed. This included the introduction of four specia
nodes, the determination of new methods for finding net invari

structure. Using these results, a method was developed for
evaluating computer system performance with Timed P-T Net mode
This method was used to model and analyze the bus arbitration
techniques that occur in digital systems. In addition, a stat
variable P-T Net model of the interconnection of two or more
microprocessors was developed. This model provides a framewor
determining the avoidance of deadlock and the maintenance of
throughput in multiple microprocessor systems. In FY83, this
with Timed P-T Nets will be continued.

an be
ing

for

micrographs, CAT scans, and radiographs. This
facility will be available for use by the NIH
community.

Progress in FY82: The system will be based on a 32-
bit, one megabyte computer, with a smaller 16-bit
processor to handle image acquisition. A multidisplay
raster scan frame buffer will provide several users
concurrent access to the central processor. Images
will be digitized when necessary through a
microdensitometer or a vidicon camera. Hard copy
will be provided by a camera system.

All currently budgeted equipment and software have
been ordered; some already has been received and
the rest is scheduled for delivery in the next few
months. The physical space has been completed
with all power and cooling.

Significance to Biomedical Researclr. Study of
images obtained in the biomedical laboratory is
proving more and more fruitful as technology is able
to supply the proper tools at a reasonable cost.
Biomedical scientists are employing image analysis
for a wide variety of research goals, and the use of
such techniques is expected to grow very rapidly in
the near future.

Proposed Course: As the equipment is delivered, it
will be integrated into a system. The development of
systems and applications software, as well as the
transfer of existing image packages from the Evans
and Sutherland system, will proceed.

Analytic Models of Computer System
Performance

This project involves the development of analytic
models that can be used to evaluate the
performance of computer systems. During the past
year, tools for modeling and analyzing computer
systems using the graph theoretic model called
Timed Place-Transition (P-T) Nets were developed.
This included the introduction of four special nodes,
the determination of new methods for finding net
invariants, and the derivation of new relationships
among net variables from net structure. Using these
results, a method was developed for evaluating
computer system performance with Timed P-T Net
models. This method was used to model and
analyze the bus arbitration techniques that occur in
digital systems. In addition, a state variable P-T Net
model of the interconnection of two or more
microprocessors was developed. This model
provides a framework for determining the avoidance
of deadlock and the maintenance of throughput in
multiple microprocessor systems. In FY83, this work
with Timed P-T Nets will be continued.

Background and Objectives: There are two major
approaches to evaluating the performance of a
computer system: simulation and analytic modeling.
Simulation models have been a popular form of
modeling for years but can be difficult and costly to
construct, validate, and run. Recent advances in
analytic modeling techniques, which can be used to
model many aspects of a computer system, have
provided new tools for evaluating computer system
performance.

There are two major types of analytic modeling
techniques: graph theoretic and queueing theory
models. A number of graph theoretic models have
been found to be useful for the analytic modeling of
computer systems. These include such graph
models as Place-Transition (Petri) Nets, Parallel
Program Schemata, Computation Graphs, and
Marked Graphs. Queueing theory models have also
been found to be useful for the modeling of
computer systems because they can capture
important features of actual systems, and algorithms
that solve the equations of these models are
available as queueing network evaluation packages.

These analytic models provide useful tools when
designing computer systems and deciding among
alternative hardware or software configurations. In
particular, with the integrated circuits that are
currently available, it is technically and economically
feasible to build systems consisting of many central
processing units. Many processor and memory
configurations also are possible now that memories
can be placed in close proximity to the processors.
Methods are needed for designing systems now
possible with this new technology. Various structures
must be considered and analytic methods for
evaluating alternatives must be developed.

Methods Employed: Timed Place-Transition (P-T)
Nets are the modeling technique used to develop
tools for evaluating computer system performance.
The advantages of modeling with these nets are
that: large and complex systems can be represented
in a manner that is easy to understand due to the
graphical and precise nature of these nets; the
behavior of the modeled system can be analyzed
using developed results of the P-T Net theory; and a
system can be synthesized hierarchically with the
ability to use different levels of abstraction and
refinement. In addition, the usefulness of P-T Nets
as models results from their ability to represent both
concurrency and conflict in a system. Concurrency
occurs when more than one event is taking place in
a system at one time and conflict occurs when a
decision must be made among alternatives. In order
to evaluate the performance of computer systems

including sucii things as waiting times and
ttiroughputs, the time parameter is added to the P-T
Net model.

Progress in FY82: During the past year, tools for
modeling and analyzing computer systems using
Timed P-T Nets were developed. This included the
introduction of four special nodes, the determination
of new methods for finding net invariants, and the
derivation of new relationships among net variables
from net structure. Using these results, a method
was developed for evaluating computer system
performance with Timed P-T Net Models. This
method was used to model and analyze the bus
arbitration techniques that occur in digital systems.
From these models, important upper bounds on the
average time a device waits for the bus and the
average time the shared bus is not used were
derived. This work demonstrates that the results that
can be obtained concerning the performance of a
computer system using Timed P-T Net models is

dependent on the structure of the net that accurately
portrays the system.

A state variable P-T Net model of the
interconnection of two or more microprocessors with
input and output devices was developed. This model
provides a useful framework for modeling and
analyzing multiple microprocessor systems. For
example, it can be used to determine the avoidance
of deadlock and the maintenance of throughput in
such systems.

Proposed Course: The work on using Timed P-T Net
models for evaluating computer system performance
will be continued, including the derivation of more
relationships among net variables based on the
structure of these nets and the development of a
Timed P-T Net model where time is associated with
both the places and transitions of the net. Also, this
graph theoretic model will be compared with
queueing theory models of computer system
performance.

38.

Laboratory of
Applied Studies

Eugene K. Harris, Chief

Clinical Research and Patient
Care

Computer-aided analysis of electrocardiograms.

J. Bailey, M. Horton (LAS); cardiologists and
biomedical engineers in the U.S.A. and abroad. The
purpose of this project is to evaluate the utility of
leading connputer programs for ECG interpretation,
and to search for optimal computer-based methods
of extracting medically significant ECG patterns. A
study of the components of variance in ECG
parameters has been completed, using data from the
Framingham Heart Project; a manuscript is being
prepared.

Computer systems for nuclear medicine. J.

Bailey, M. Douglas, R. Burgess (LAS); H. Ostrow
(CSL); M. Green, et al. (CC, Nuclear Medicine). This
project involves development and aplication of
computer systems to such diagnostic imaging
activities as ECG-gated radionuclide ventriculography
and dynamic scintigraphic studies of other organs
(e.g., kidneys, lungs). A study of 79 radionuclide
ventriculograms has revealed average signal-to-noise
characteristics, optimum filtering, and optimum
segmentation for detection of regional abnormalities;
a series of manuscripts is being prepared. A study of
segmental artery sterosis in canines using functional
maps of renal scintigraphic data has been published.

Computer-based studies of pulmonary
pathophysiology and respiratory disease. J.

Bailey, R. Burgess, M. Horton, E. Pottala (LAS); R.
Crystal, A. Nienhuis (NHLBI); A. Jones (CC, Nuclear
Medicine). These studies attempt to achieve better
understanding of pulmonary pathophysiology through
use of computer-based models of pulmonary gas
exchange and respiratory mechanics, comparing
predicted values with real patient data. A
minicomputer-based system for analyzing gas
exchange during exercise was purchased and
installed. Development of programs to analyze mass
spectrometer and flowmeter data and to control the
treadmill and bicycle is nearly complete.

Statistical research in clinical pathology. E. Harris,
M. Horton, A. Albert (LAS); G. Shakarji, F. VanSant
(DMB); clinical chemists and others in the U.S.A.,
Europe, and Japan. This research involves
application of statistical theory to clinical laboratory
tests, including serial studies of blood chemistries in
health and disease.Multivariate subject-specific
reference regions were shown by computer
simulation studies and applications to real data to be
substantially more specific against false positive
results than corresponding univariate reference
ranges. A collaborative study to explore relative
sensitivities in various diseases has begun. A
statistical method for deriving reference differences
as criteria for evaluating the significance of observed
changes has been extended and applied to a
comprehensive data base of serial data from healthy
subjects. A method for sequential assessment of risk
in acute disease has been developed by combining
discriminant function with analysis of response
curves. The method has tested successfully in
application to patients under intensive care following
myocardial infarction.

Computer-based studies in ultrasonography. M.

Douglas, J. Bailey, E. Pottala (LAS); B. Maron
(NHLBI). Ultrasonography allows noninvasive
visualization of many organs without the hazard of
ionizing radiation. This project involves development
of minicomputer systems for image enhancement,
pattern recognition, and three-dimensional
reconstruction from ultrasound data sources,
principally wide-angle phased array
echocardiography. A principal difficulty in
echocardiogram studies is separating gross cardiac
motion from regional wall movement in a quantitative
way. To resolve this problem, we have begun to
study the use of reliable fiducial points, such as the
papillary muscles or the intersection of mitral cusps.
Further progress in this project awaits upgrading of
the DeAnza system by the vendor.

Laboratory Investigation

Mathematical modeling of biological processes.

J. Fletcher (LAS); R. Schubert (Louisiana Tech.
University). Scientists are developing and applying
mathematical models in studies of substrate
transport in the microcirculation, in diffusion
processes in physiology, and in macromolecule-
ligand binding equilibria. A new unified model has
been developed for the microcirculation during a
perfused organ experiment. Parametric studies of
this model's properties are underway. A final
summary report on mathematical models for
equilibrium binding experiments was published and
distributed. A new investigation of capillary
hematocrit and oxyhemoglobin unloading effects in
capillaries was begun.

Mechanisms of active transport/biochemical
kinetics. B. Bunow (LAS); A. Kaplan (NCI); D.
Mikulecky (Medical College of Virginia); J. Kernevez
(University of Tech., Compiegne, France).
Experimental and mathematical studies of the energy
mechanisms for active transport and of multistate
biochemical kinetics in cells and membranes
continue. Network modeling methods were applied
through collaboration with NIH scientists to problems
including cellular metabolism, neural networks, nerve
conduction, and tissue oxygenation. A realistic
mathematical model for isoelectric focusing has
been derived and programmed for computer solution.

Hybrid computing to analyze physiologic signals
and construct simulation models. E. Pottala, B.
Bunow (LAS); T. Colburn (NIMH); various NIH and
FDA scientists. This project uses the LAS
minicomputer system (MAC-16) for hardware
simulation of physiologic functions and for analysis
of analog signals (myogram, EEG, etc.). Two
network simulation languages were implemented on
the IBM System 370 and the VAX system (NIMH).
This will facilitate model building and make
simulation models more accessible for investigators
on campus.

Image processing in electron-loss spectroscopy.

M. Douglas, (LAS); J. Costa (NIMH). This project
involves the development and implementation of
mathematical models and image enhancement
techniques to analyze computer-acquired information
from electron-loss and x-ray spectra indicating the
location of extremely small quantities of important
chemical elements and active protein molecules
within cells. Activities in this area have been delayed
while the vendor completes upgrading of the DeAnza
system as originally planned.

Computer Research and
Development

Mathematical and computational methods for
nonlinear equations. R. Shrager, R. Hendler
(NHLBI); A. Schechter (NIADDK). Work continues in
the study of methods of fitting nonlinear models and
mathematical methods of spectral analysis. An
algorithm was developed for rapid solution of one
nonlinear equation in one unknown. The method
does not require derivatives and guarantees the
answer to full machine precision. The algorithm has
been installed in MLAB. A program to simulate the
oxygen saturation of hemoglobin from the primary
regulators pH, PC02, and 2,3-DPG is now under
development. Also under development is a program
to optimize the wavelength selection in the design of
hemoglobin saturation analyzers.

Numerical methods for the solution of
mathematical models describing reaction-
diffusion and other processes in biological
systems. M. Bieterman, J. Fletcher, B. Bunow (LAS);
I. Babuska (University of Maryland). Ongoing study,
development, and implementation of efficient, flexible
numerical methods for the solution of nonlinear
ordinary and partial differential equations is involved
in modeling dynamic physiological processes.
Theoretical work was completed on the adaptive
finite element method for solving systems of reaction
diffusion equations. Program packages have been
implemented on the IBM System 370 and are
currently undergoing testing. Preliminary applications
have been made to problems in nerve conduction,
facilitated diffusion in tissues, developmental biology,
and ecosystems.

Research Projects

statistical Research in Clinical Pathology

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Progress during FY82: The study of the relative
specificities of univariate and multivariate reference
regions, applied to subject-specific serial
observations, has been completed and published.
Results from computer simulations were confirmed
by analysis of semiannual series of clinical chemistry
measurements in 700 longterm participants in health
maintenance programs in Tokyo and Osaka, Japan.
Multivariate reference regions were shown to be
much more specific than corresponding univariate
regions, thus capable of avoiding many false alarms.
A statistical comparison of regional data bases of
clinical chemistries in healthy individuals has begun.
This work is part of a general investigation into the
transferability of clinical data among population
groups and geographic areas.

New research was undertaken on the development
and application of a statistical method for estimating
'reference changes,' that is, critical differences
between successive measurements of a biochemical
constituent in an individual. At the present time, such
criteria are left to the judgement of the individual
physician and are known to vary widely even among
residents in the same hospital. The proposed
method, allowing for serial correlation, has been
tested on serial observations of calcium and alkaline
phosphatase in healthy subjects. A paper describing
the method and its uses is in preparation.

The main research project under A. Albert's Fogarty
International Research fellowship has been
concerned with the development and testing of
models to assess changing risk probabilities in
patients with acute diseases. Several methods have
been proposed and successfully applied to existing
data bases of patients with acute myocardial
infarction, and children treated in intensive care
units. Besides this project. Dr. Albert has also
undertaken studies on ways to improve laboratory
data interpretation and made available to the NIH
research community a program for multiple group
logistic discrimination.

Proposed Course: A study of the relative sensitivity
of multivariate reference regions will be initiated in
collaboration with Dr. Yasaka. This will entail
incorporating into the data bank followup information
on the clinical status of individuals examined.

Further development and applicaton of the statistical
methodology proposed for calculation of reference
changes will be undertaken for selected patient
groups in collaboration with members of the Clinical
Pathology Department at the University of Virginia
Medical School. Continued joint efforts in this area
and in the general application of stochastic time
series to patient data will be initiated with Dr. Albert,
Fogarty Research Fellow in this Laboratory, upon his
return in 1982 to the University of Liege.

The statistical comparison of regional data bases in
Japan will continue.

Publications:

Albert, A.: Atypicality indices as reference values for laboratory data. Amer.
J. Clin. Pathol. 76: 421-425, 1981.

Albert, A.: Discriminant analysis based on multivariate response curves: an
approach to dynamic prognosis. Statistics in Medicine (in press).

Albert, A.: On the use and computation of likelihood ratios in Clinical
Chemistry. Clin Cliem. 5: 1113-1119, 1982.

Albert, A., Chapelle, J. P., Heusghem, C, Kulbertus, H.E., and Harris, E.K.:
Evaluation of risk using serial laboratory data in acute myocardial in-
farction. In Heusghem, C, Albert, A., and Benson, E.S. (Eds.):
Advanced Interpolation of Clinical Laboratory Data. New York, H/larcel
Dekker (in press).

Harris, E.K.: Further applications of time series analysis to short series of
biochemical measurements. In Grasbeck, R., and Alstrom, T. (Eds.):
Reference Values in Laboratory Medicine. Chichester, U.K., John Wiley
&Sons, 1981, pp. 167-176.

Harris, E.K.: Regression, least squares, and correlation. In Seligson, D.,
M.D. (Ed.): Handbook of Clinical Chemistry. CRC Press (in press).

Harris, E.K.: Use of statistical models to detect subject specific changes. In
Yasaka, T. (Ed.): Proceedings of the International Conference on Auto-
mated Multiphasic Health Testing & Sen/ices. Amsterdam, Excerpta
Medica, 1981, pp. 35-44.

Harris, E.K., Yasaka, T., Horton, M.R., and Shakarji, G.: Comparing Multivar-
iate and Univariate subject-specific reference regions for blood con-
stituents in healthy persons. Clinical Chemistry, 28: 422-426, 1982.

Mathematical Models of Binding Equilibria

The objective of this project is the study of
mathematical models of ligand-receptor or ligand-
macromolecule binding studies at equilibrium. The
models are examined for mathematical as well as for
conceptual validity and are studied to determine their
suitability for fitting to experimentally obtained
laboratory data. The appropriateness of various
model fitting criteria are studied and general
guidelines and computational algorithms are
designed for computer-aided interactive model fitting.

Progress in FY82: Numerous requests for copies of
exportable computer algorithms were honored and a
number of B/l/D consultations were provided. A
summary report including collected results from
fifteen years of research in this area was completed.
It is now available for general distribution to the
biomedical community.

Proposed Course: Applications of existing and new
methodology to data analysis will continue to be
made as they are requested by collaborating
laboratories. Computer programs, reprints, and
reports continue to be provided to requesting
consultees. Analytical development of new models
and continued research in fitting methodology in this
area will emphasize validation of experimental
techniques, multi-receptor models, and
conformational changes in macromolecules due to
binding of ions.

Publications and Abstracts:

Fletcher, J E.: The Analysis of Equilbrium Binding Data by the Fitting of
Models. July 1982.

Mathematical Modeling of Substrate Transport in
Physiological Environments

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Progress in FY82: The details of a new, intricate,
mathematically correct, solution to the generalized
Krogh cylinder model were completed. A second
effort was begun to investigate the kinetics of red
cell and free hemoglobin offloading during capillary
transit. This work is still in the exploratory stages. A
manuscript describing the first effort has been
accepted for publication. Two preliminary reports on
the findings from these studies were presented at
international meetings.

It is anticipated that the research course of this
project will have the following stages.

1. Reexamine the Krogh cylinder models in the
literature and their adequacy for the representation
of perfused organ microcirculation.

2. Develop exact mathematical solutions for
extended Krogh models that exhibit tissue axial
diffusion and capillary axial diffusion for the steady
state constant metabolic rate experiments with
perfused organs.

3. Develop or modify numerical algorithms that will
compute substrate levels for nonconstant metabolic
rates and other nonlinear effects.

4. Develop algorithms for the direct comparison of
distributed substrate level computations with
experimentally obtained microelectrode
measurements.

5. Identify those critical ranges of parameters that
control organ response to physiologic challenge.
Publications and Abstracts:

Fletcher. J.E.; Diffusional Transport Coupling in an Ideal Capillary Tissue
structure. SI AM 30th Anniversary Meeting. Stanford University. 1982.

Fletcher, J.E,. and Schubert, R.W,: On the Computation of Substrate Levels
in Perfused Tissues. Mathemalical Biosciences (in press).

Fletcher, J.E., and Schubert. R,W.: The Theoretical Prediction of Substrate
Levels and Their Histograms in Cell Free Perfused Tissues. Proceed-
ings of the International Meeting of the OTT Society. Detroit, Michigan,
August 1981, Plenum Press (in press).

Schubert, R.W., Fletcher, J.E., and Reneau, D.D.: A Simplified Model for
Predicting Myocardial P02 Histograms. The First Southern Biomedical
Engineering Conference. LSU Medical Center. Shreveporl, LA, 1982.

Analysis of Coupled Transport and Biochemical
Kinetics

This project investigates six fundamental problems in
biology: (1) the role of dynamic patterns in
embryology and evolution, (2) the kinetics of
enzymes located in cell membranes, (3) the kinetics
of enzymes derived from malignant and normal ceils
in culture, (4) mathematical modeling of isoelectric
focusing studies, (5) thermodynamics of bioenergetic
mechanisms in mitochondria, and (6) development of
a new paradigm for biological modeling based upon
topological representation and use of network
modeling languages. Simulation on digital computers,
particularly with network modeling languages,
numerical solution of differential equations, and
nonlinear regression analysis are the main tools in
these investigations. While these problems are
diverse in their biological background, they ail share
in a common basis of mathematical and physical
content through the role played by conservation laws
and the mathematical methods involved in their
resolution.

• Dynamic Patterns

Progress in FY82: This project is now essentially
complete. Two manuscripts are still in press.

• The Kinetics of Enzymes in Membranes
Background and Objectives: Studies of the
mechanism of membrane transport and energy
transduction by membranes are generally less
conclusive than studies of the mechanisms of
enzymes in solution. This uncertainty arises because
it is difficult both to manipulate the environment of
the interior of a biological membrane and to measure
responses there. The objective of this project is to
determine the extent to which the actual organization
of membrane-associated processes can be correctly
inferred from the application of models to the kinds
of experimental measurements currently made.

Significance for Biomedical Researchi: Studies of
membrane-associated enzymes, such as those of
mitochondria, for example, are made by measuring
external concentration changes, from which one
attempts to infer biochemical organization. This
process is quite unreliable, as witnessed by the
continuing controversy over the biochemical
organization of bioenergetics. By our work, we wish
to demonstrate that this unreliability is intrinsic, that it
results from the nature of the methods used to study
such systems, and that it is not to be remedied by
performing yet another experiment of the kinds
currently popular, no matter how ingenious.

Progress in FY82: An experimental system involving
an enzyme immobilized in a polymer film had been
previously prepared and studied. A manuscript
describing the behavior of this system has been
completed and will soon be submitted. This project is
now complete.

• Kinetics of Lactate Dehydrogenase (LDH) from
Normal and Malignant Hepatocytes

Progress in FY82: The major collaborator in this
project has been inactive this year because of
complications associated with a move to a new
laboratory in Frederick.

Future Course: During FY83 the computer system
will be installed in the new lab. Hopefully the
experimental program can be reactivated.

• Mathematical Modeling of Isoelectric Focusing
Bacl<ground and Objectives: Isoelectric focusing is a
very widely employed experimental tool in
biochemistry. Its purpose is to separate and identify
the protein components of mixtures, e.g., the
extracted contents of cells and tissues. Despite the
effectiveness of currently used procedures, the
application of isoelectric focusing proceeds on an ad
hoc basis, and it is quite likely that these current
procedures are less than optimal. The goal of this
research is to place isoelectric focusing on a firm
footing of physical chemistry through the derivation
and solution of predictive equations to describe the
process and its dependence upon experimentally
controllable parameters.

Significance to Biomedical Research: Separation of
proteins has an important role in the preparation of
biologicals such as enzymes and vaccines for
medical research and treatment. Improvement in the
techniques of separation will lead to reduced
expense for production of these materials and
increased supplies and variety. Identificatin of
proteins plays an essential role in diagnostic clinical
chemistry as well as basic biological research.
Improvement in identification procedures by reducing
the sample size or time to resolution will permit more
extensive studies on precisely defined preparations.

Progress in FY82: The physical-chemical principles
involved in isoelectric focusing have now been
identified. The mathematical equations turn out to be
highly coupled, nonlinear partial differential equations

with very unusual boundary conditions. A FORTRAN
program providing for numerical solution of these
equations has been developed but not completely
debugged. Unfortunately, the computer time to run
this program was too great to permit its completion
with the scheduling algorithm in place on the DCRT
computer during FY82.

Future Course: The scheduling algorithm on the
DCRT computer has been modified to permit
efficient running of the FORTRAN program. The
program will be completed to the point of verification
of its functional correctness. Run time for production
using the program will still be too excessive to permit
extensive studies. A Cray-1 computer in France is to
be used for preliminary production runs.

• Thermodynamics of Bioenergetic Systems
Background and Objectives: The mechanism by
which the generally reduced components of nutrients
are oxidized in mitochondria is still quite obscure,
although most of the components of this pathway
have been identified. The membrane association of
the components of the pathway makes it difficult to
proceed in the usual biochemical manner of
molecular dissection and reconstitution. Most
experimental studies are made on systems that are
quite structurally complex. Nevertheless, interest
focuses on the usual biochemical question: What is
the sequence of molecular forms involved in the
bioenergetic pathway? The role of ubiquinone in this
pathway is the particular object of our interest in this
project.

Significance to Biomedical Research: An
understanding of the mechanism of the central
energy-yielding process of living organisms is clearly
essential. Thermodynamic analyis has shown that
the accepted explanation for oxidant-induced
reduction of cytochrome b in the presence of
antimycin cannot be correct. Thermodynamic
analysis combined with new experimental techniques
developed by one collaborator (R. Hendler), and
analyzed with methods developed by another
collaborator (R. Shrager), promises to provide a
basis for a correct explanation of this phenomenon.

Progress in FY82: During this year, the problem
was identified, and the thermodynamic inconsistency
of the current models for oxidant-induced reduction
of cytochrome b was demonstrated. This work has
been presented in seminar form, and a manuscript is
in preparation.

Future Course: During FY83, we will attempt to
provide an explanation that is consistent with
thermodynamics, and to design and perform
experiments to test its correctness. These
experiments will be based on the recently

demonstrated ability to characterize small spectral
shifts in cytochromes undergoing conformational
change.

• Network Modeling in Biology
Background and Objectives: Mathematical modeling
in biology is especially difficult because of the need
to be familiar with both the biological basis of
problems and the mathematical tools required for
their solution. Network modeling, supplemented with
effective modeling languages, largely obviates the
need for extensive mathematical sophistication, and
makes the process of modeling accessible to
biologists lacking such skills. Topological modeling is
particularly appropriate to biological problems
because the objects of study generally satisfy
conservation laws. In biological systems, the
processes of flow, accumulation, and transformation
are fundamental; these are likewise the basic
operations in network modeling.

Significance for Biomedical Research: The choice of
a model for a biological process strongly conditions
the design of experiments to confirm and extend it.
By making the analysis of models sufficiently simple,
we intend to permit an investigator the freedom to
consider many models. From comparisons among
the models using simulation, it should be possible to
develop incisive experiments that permit scientifically
valid, rather than arbitrary, selection among the
models. The network languages nicely complement
the MLAB system in permitting users to model
phenomena that are too complex to be conveniently
described in MLAB.

Progress in FY82: Demonstration studies on network
modeling have been conducted in several areas: (1)
oxygen distribution and uptake in capillary beds, (2)
nerve impulse transmission in an axon model, (3)
electrical excitation of synaptic membranes, (4)
electrotonic excitation of dendritic trees, and (5)
metabolic networks in brain tumors. These studies
have shown that functional and correct models can
be constructed quickly and easily. By using available
network modeling languages, the process of model
building is focused on structures readily understood
by biological investigators, rather than on verification
of mathematical aspects. Several of these studies
will prove to be directly useful in subsequent
biological investigations. The network language,
SPICE2, has been installed on a dedicated
minicomputer in NINCDS. A course in SPICE2
programming for neurophysiologists was delivered to
representatives from several labs in this institute.
Network models are now being regularly employed in
their research. The demonstration studies described
above will be described in manuscripts in

preparaiion, and the monograph on topological
modeling is well underway.

Future Course: During FY83, collaboration with
groups using network modeling will continue. The
DCRT course in network modeling will be repeated.
The monograph should be completed this year. A
major deficiency of available network languages is in
the area of data fitting. A major effort will be made to
facilitate the interconversion of models expressed in
network terms into forms compatible with languages
such as MLAB on which data fitting is convenient.
DELIGHT, an extension of SPICE with facilities for
optimization, device libraries, and more effective
graphics, has been ordered and will be installed in
FY83.

Publications:

Bunow, B.: All things flow and change-some thoughts on the role of
reaction and transport in biology. J. Wash. Acad. Sci. (in press).

Bunow, B.: Turing and the physico-chemical basis of biological patterns. In
Prewitt, J. (Ed.): IEEE Turing Memorial. 1982 (in (in press).

Bunow, B., and Mikulecky, D.G.: On the feasibility of using flux meas-
urements to distinguish among active transport models. Polish Winter
School of Membrane Transport, (in press).

Bunow, B., and Mikulecky, D.C.: Where does metabolic energy couple into
the active transport process? J. Theor. Biol, (in press).

PROJEcft'uSeER'^D^MOI^s^thii apacJ)

ZiisiiffifcT

Z01 CTO0035-06 LAS

October 1, 19S1 to September W, 1983

Analysis of Coupled Transport and Biochemical Kinetics

INVESTIGATORS AND ALL OTHER

0tLr°; TLr^ev,. ?™'?a3sor

LflS/DCKT

A. Kaplan Hesearch

DCCP^NCl' ''""''^

D. Mikulecky Professor

Medical College

•---- »■-"-""

LAS. DCRT

„o„.

LAB/BHANCH

Applied Mathematics Section

D (=) NEITHE«

a{«l) M.HOHS D(«2) INTEBVIEWS

tal problems in biology:

;hermodynamics
d (6) development of a
n topological representation

£U the role of dynamic patterns in embryology

modeling of isoelectric focusing studies, (5)
of bioenergetic raechanisraa in mitochondria, an

coiaputers, particularly with network raodelinG languages numerical

are the main tools in these inveatigations- While these problems are
diverse in their biological background, they all share in a common
basis of mathematical and physical content through the role played by

Nonlinear Equations

Methods are developed for solving nonlinear
equations frequently encountered at NIH, usually in
the context of constrained nonlinear least squares or
in the solution to nonlinear differential equations.
Related problems, such as asymptotic error analysis,
and the efficient treatment of sparse systems, are
also considered.

Progress in FY82:

• MLAB Projects

Gary Knott (DCRT). The root-finder has been refined
so that it performs more efficiently than the best
previously published methods. A paper has been
submitted to l\/latliematics of Computation describing
the procedure and the test results. A separate
integration routine, independent of the differential
equation solver, has been installed, so that integral
expressions may now appear in differential
equations. Some problems with the curve-fitter,
reported by MLAB users, have been traced to poor
scaling of the problem (e.g., unfortunate
combinations of large and small effects of changing
this or that parameter). A rescaling procedure is
being designed to overcome the difficulty.

• Equilibrium Studies of Magnesium Phosphate
Lev Jacobson (DCRT). Improved range of
experimental data has enabled us to produce a
simple yet adequate model of Mg-H-HP04 binding
with reliable equilibrium constants. A manuscript
detailing this work has been submitted for
publication. Our contribution described how to
propose alternate physical models, express them in
reliably computable form, and suggest experiments
for model validation.

• Hemoglobin Projects

Robert Berger (NHLBI); Robert Winslow (CDC
Atlanta); Luige Rossi-Bernardi, Giulio Dossi, Michele
Samaja, and Massimo Luzzana (Ospedale San
Raffaele, Milan, Italy).

1 . Two possibly conflicting criteria govern the
design of a hemoglobin analyzer (design being the
selection of wavelengths of light to best detect
various binding states of Hb). The first, the product
of variances of estimated fractions of the various
states, is designed to reduce variance from random
errors in the data. The second criterion, norm of the
sensitivity matrix, is designed to minimize the effect
of instrumental drift (aging, misalignment, etc.), which
is very important because it cannot be 'averaged out'
by repeated measurements. Procedures are now
being tested that minimize either criterion or a
weighted sum of both.

2. Simulation of 02 Saturation of Hb involves four
governing quantities (02 pressure, C02 pressure, pH,
and 2,3-DPG concentration). An efficient model
expression is required incorporating these quantities
with a manageable number of parameters so that
various types of Hb can be modeled. We are in the
midst of designing both the validating experiments
and the model.

• Cytochromes in Mitochondria

Richard W. Hendler (NHLBI); O.H. Setty (Visiting
Associate); K.V. Subba Reddy (Visiting Fellow); Barry
Bunow (AMS, DCRT).

1. An article on analysis of titration data by Single
Value Decomposition techniques has just been
published in Analytical Biochemistry.

2. A paper on this topic is being presented to a
mathematical conference at the SIAM 30th
Anniversary Meeting.

3. Work on the midpoint potential of E. coli
cytochromes is now being extended to beef heart
mitochondria and the other mammalian cells. By
using a new rapid-scan spectrophotometer, we can
now do kinetic studies as well as more reliable
equilibrium studies.

4. A suspension of cells is given a pulse of 02.
The uptake of 02 and the production of H is
monitored by computer, which must smooth the data
and compensate for 02 and H electrode delay times,
in addition to several other monitoring functions. The
program is running and producing good results.

5. In collaboration with B. Bunow, we are
attempting to explain the oxidant-induced reduction
of one of the b-cytochromes by developing a
thermodynamically consistent model that also fits the
observations.

• Phytic Acid Titration

William Evans (Agr. Res., New Orleans). An article
on the titration of twelve H binding sites of phytic
acid has appeared in J. Am. Oil Chem. Soc.

• SVD Kinetic Studies

Ray Tate (DCRT); Jim Osborne (NHLBI); Randy
Kincaid (NHLBI). SVD is useful in resolving the
spectra of individually titrating species in a mixture
because the mathematical form of the titration is
known. Likewise, the form of kinetic relaxation may
also be known (e.g., sum of exponentials).
Therefore, complete spectra gathered as a function
of time may also be analysed by SVD. An initial set
of data involving the association of Calmodulin and
Ca using fluoresence and CD spectra is being
prepared.

Proposed Course: The curve-fitting scaling
procedures need more tests. Work continues on
every aspect of the cytochrome problem. Some
actual designs of Hb analyzers should be produced
this year. The Hb-02 saturation model should be
ready for use.

Publications:

Evans. W J . McCourlney, E.J.. and Shrager, R.I.: Titration Studies ot Phytic
Acid. J. Am. Oil Chemists' Soc. 59: 189-191, 1982

Shrager, R.I., and Hendler, R.W,: Titration of Individual Components in a
Mixture with Resolution of Difference Spectra, pK's, and Resox Transi-
tions. Anal. Chem. 544: 1147-1152, 1982.

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ncrettiOMU. tuittrntx. £iMtw» oh the ntojcci

PI: R.I. ShraBor Mathomatlclan LAS DCRT

OTHERS: G,D. Knott Coapiter Sp.cl.Uat L3M DCRT

J.E. Fletcher Rooenrch Nathonsticlnn US DCRT

LB, HHLBI

Laboratory of Applied Studies

Applied Hatheiutics Section

DCBT, NIH, Bethesda. HD 20205

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Methods are developed for solving nonlinear equattona frequently

leoaC aijuarea or in the aolu

tion to nonlinear differential equations. 1

Related problems, such as asymptotic error analysie, and the efficient

Numerica! ApproximatiOuj Techniques for the
Solution of Reaction-Diffusion Systems in
Biology

A novel numerical method of lines, used to
approximately solve partial differential equations
governing models of reaction-diffusion systems in
biology, has been developed and analyzed. The
somewhat general program FEMOL 1 , which
implements the computational procedure, includes
various user-oriented adaptive features. These
features include automatic space and time mesh
selections, which are made by the computer and are
appropriate for the solution of any particular problem.

Progress in FY82: Various goals were achieved this
past year in the investigation of numerical
approximation techniques for the solution of
reaction-diffusion systems in biology. The most
significant of these fall into three categories:

• Software Development
A somewhat general and easy-to-use method of
lines program, FEM0L1, was developed,
implemented, and tested. FEM0L1 is presently
applicable to systems of two nonlinearly coupled
time-dependent reaction-diffusion equations in one
space dimension. This program was designed
primarily as a tool for use by laboratory researchers
and other NIH scientists in parametric studies. Many

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Numerical Approximation Techniques for the Solution of Reaction-Diffusion
Systems in Biology

OTHER: J-li. t'letcher Chief, AMS LAS DCRT
B. BunoH Bioraathematicifln, AHS LAS DCRT

„0„,

L*B/BBAriCH

Laboratory of Applied Studies

Applied Mathematics Section

DCRT, NIH, Bethesda, HD 20205

TOTAL jmEAfiS= | PH0FESS10NA^L= jOIHEfi.

°'-'™"'"™' 0... »»..». o.c.».™.

A novel numerical method of lines used to aoo

differential equations gove

nine models of reaction-

in biology, has been develo
FEHOL 1 , which iraoleraenta t

ed and analyzed. The somewhot general program
e computational procedure, includes various

of any particular prob

Standard user-oriented 'black box' features available
in much commercial software, such as automatic
estimation and control of time discretization errors,
are contained in the program. FEM0L1 also includes
a posteriori estimates of space discretization errors
and a novel adaptive procedure, in which space
meshes are modified during a problem's solution by
the computer in order to control the space
discretization errors.

• Application to Biological Models

FEM0L1 was used in computational experiments to
evaluate the effects of various numerical
approximation parameters in the method of lines
solution of equations governing models of the
microcirculation, population ecology, and electrical
impulse conduction in nerves. Such a study is
important, in that the roles of biological parameters
in models are often obscured by the effects of the
specific approximation parameters used in
computations. These experimental results form the
basis of a future publication.

• Development of Mathematical Theory
Many new mathematical results were obtained
concerning the effectiveness of the a posteriori
estimators used in FEM0L1. This theory not only
supports the computational procedures used, but
also prescribes reliable and efficient means by which
space discretization errors should be estimated and
controlled in more general problems arising in
practice and (as seen in the computational
experiments) in cases where underlying
mathematical assumptions break down. The
contents of these results were included in two
publications.

Proposed Course: Future investigations of numerical
approximation techniques used in the study of
biomathematical models will comprise (1) the
extension of the capabilities of the method of lines
program FEM0L1 , and (2) the modification and
implementation of other techniques and software
that were developed previously in LAS and
elsewhere for the solution of specific problems
encountered by NIH researchers.

Publications:

Bieterman, M., and Babuska, I.: The Finite Element Method for Parabolic

Equations. I. A Posteriori Error Estimation. Numerische Mathematik (in

press).
Bieterman, M., and Babuska, I.: The Finite Element Method for Parabolic

Equations. II. A Posteriori Error Estimation and Adaptive Approach.

Numerische Mathematik. (in press).

Monitoring of the CNS in Criticaly III Patients

This new project is a joint effort between the
Laboratory of Applied Studies and the Department of
Critical Care Medicine to design, build, and
implennent a highly clinically oriented, distributed-
processing, microcomputer-based system for
analysis and display of scalp-recorded neuroelectric
signals. As a part of the total noninvasive monitoring
effort, this tool will then be used to investigate the
degree of dysfunction in neurologically impaired
patients, correlate the indices developed with other
measures of cerebral function, and evaluate the
effectiveness of various therapeutic interventions.

Background and Objectives: In the critically ill
medical patient with multiple organ dysfunction,
impaired brain function frequently coincides with
deterioration of other major systems. However, the
degree of damage and capacity for restoration of the
brain does not necessarily parallel that of the rest of
the body. In addition, assessment of the central
nervous system is hampered by limitations imposed
by procedures (e.g., endotracheal intubation) and/or
drugs (e.g., Pavulon).

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ZOl CT0009a-0I LAS

October 1, 1981 to September 30. 1982

Monitoring of the CNS in Critically III Patients

noFEUioMu. PotsONHa £N«ueo on ihe project

PI: R.C. Burgeaa Senior Staff I'eUow LAS DCRT

C. Natanaon Senior Investisator CC CC
N.K. Korton Computer Syatens Analyst UiS DCRT
E.i(. Pottala Electronics Enfiirieer US WRT
J.J. Bailey Chief, MA.S LAS DCRT

Crlticftl Care Medicine Departnent. CC

LiB/eNtNCK

Laboratory of Applied Studies

Hedical Applications Section

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a(»0 "IMORS n(*i) INIEBvrC-S

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This neif project is a joint effort between the Laboratory of Applied
studies and the Departoent of Critical Care Kedicine to design, b'jild.
and inplewent a highly clinically oriented, diatributed-proceaalng,
oicrocomputer-baaed system for analyaia and diaolav of acelp-recorded

effort, this tool will then
developed with other meaaur

part of the total noni
be used to investigate
y impaired patienta. co
3 of cerebral function.

tBi[:Ci

rapeutic interventions.

The most frequently employed tool for evaluation of
the central nervous system, the neurological exam,
suffers from its discontinuous and subjective nature
and is highly dependent upon the examiner's skill.
Many investigators have attempted to apply various
diagnostic and monitoring techniques to the problem
of assessing the neurological status of the critical
care patient.

Past efforts have been hindered by equipment
artifacts and have required a high degree of skill on
the part of the technician and the interpreter. This
project will overcome the great difficulty of
undertaking detailed microvolt-level signal analysis
through the innovative use of state-of-the-art
technology and multidisciplinary approach.

Progress during FY82: A detailed literature search
and exhaustive commercial product evaluation has
been carried out. Dr. Burgess attended the state-of-
the-art Evoked Potential course at Duke University.
System requirements have been determined,
instrumentation design has been completed, and
equipment purchases have been initiated.

Significance: Apart from the technological task of
demonstrating a system that will reliably and semi-
automatically obtain and process data from MICU
patients, we seek answers to the following
questions:

1 . Which electrophysiological parameters can be
used to best follow the functional neurologic status
of the patients?

2. What is the optimal protocol for obtaining data
in order to balance recording requirements and
nursing care needs?

3. How can the parameters be best combined into
a meaningful profile and be best displayed to provide
comprehensive yet easy-to-assimilate clinical
information?

4. How does the information offered by this
system compare to other neurodiagnostic
techniques?

5. How does this system improve our overall care
of the patient and our understanding of the
pathophysiologic dynamics?

Proposed Course: The completed system will
include: (1) a precision analog front-end with high
noise immunity for detection, amplification, and
filtering of the spontaneous and evoked EEG activity;
(2) stimulators for delivery of visual, auditory, and
somatosensory stimuli; (3) a central processor with
intelligent peripherals for data acquisition,
manipulation, calculation, and storage; and (4) a
display capable of high resolution graphics and
printout for presentation of current and past data,
trends, and interpretive imaging.

Extensive development of both hardware and
software will be carried out during the coming year.
Instrumentation to be built includes a CPU interfaced
preamplifier/filter and a computer control for the
stimulators. A hardware as well as a software
interface for an array processor will have to be
developed. Programs will enable simultaneous
stimulation, data acquisition, storage, and display.
Operating in the realtime environment and employing
an array processor for rapid computation will require
complex and flexible data handling routines.

Publications:

Burgess, R.C.; An instrument to add evoked potential capability to the
standard electroencephalograph. EEG and Clin. Neurophysiol. 53: 33,
1981.

™"'""''^'""™"™'"

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Z01 CT0OO54-06 LAS

Pen<OD COVERED

TITLE Of PHOJEtl (BO ch.r.cl.rr or less) '

Computer-baaed Studies in Pulmonary Pathophyaiology

R.G. Crystal Chief

M.R. Horton Computer Syateraa Analyst
E.W. Pottala Electronics Bngineer
J.J. Bailey Chief, HAS

CHB NHLBI
LAS DCRT

Clinical Hematology, Pulmonary Branch, NHLBI, Nuclear He

icine Dept., CC

Laboratory of Applied Studies

Medical Applications Section

DCRT, HIH, Bethesda. HD 2020!j

lUIHL MnrtAHK. jPHOFESSIOHAL: lOIMEHi

CHECK APPROPRIATE eOX(ES)

3 («) HUMAN SUBJECTS D (b) HUMAH TISSUES g (c) NEITHER

D{-1) MINORS a{.?) .NTERVIEWS

Medicine Department, CC and the Clinical Hematology
NKLBI — ia directed toward a deeper understanding of

pulm

^Imonary Branches,

pathophysiology through the

construction of computer

d models of

ugh comparisons of

model predictions with real patient data.

Computer-based Studies in Pulmonary
Pathiophiysiology and Respiratory Disease

This project-through a collaborative effort of LAS
with the Nuclear Medicine Department, CC and the
Clinical Hematology and Pulmonary Branches,
NHLBI--is directed toward a deeper understanding of
pulmonary pathophysiology through the construction
of computer-based models of pulmonary gas
exchange and respiratory mechanics and through
comparisons of model predictions with real patient
data.

Progress in FY82: The system designed, specified,
and purchased during FY81 for breath-by-breath
analysis of pulmonary gas exchange has been
assembled. Interfaces for the bicycle ergometer and
treadmill controllers to enable online computer
control and data acquisition were designed and built.
Necessary support equipment, such as an expired
gas cooler and an analog tape deck controller, were
fabricated. LAS has been developing software to
effectuate realtime exercise testing and has been
performing calibration of the individual instruments
as well as the integrated system.

Proposed Course: Preliminary testing of the new
system on volunteer subjects is just beginning and
substantial additional data will be collected for both
system validation and establishment of a baseline
data base. Numerous studies of the gas transport
system are possible. An experimental protocol to
evaluate the use of Hydralazine in sickle cell disease
in collaboration with the NHLBI Hematology Branch
has been approved. Studies of cardiorespiratory
ability in both patients and athletes are in the
planning stages in collaboration with the NHLBI
Pulmonary Branch.

Publications: None.

Investigation of Hybrid Computing for the
Construction of Simulation Models and for the
Analysis of Physiologic Signals

This project was undertaken to develop physiologic
simulation models using hybrid computing and also
to use hybrid computing techniques to analyze
physiologic signals such as electrocardiogram,
electroencephalogram, and electromyogram.

Progress During FY82: The study of neural signals in
the rat (hippocampus and sensory cortex) has been
deferred by that investigator and only recently re-
initiated.

The Division of Cardio-Renal Drug Products, FDA, is
investigating the early detection of cardiac toxicity
resulting from drug therapy. Rat electrocardiograms
are being used to determine the sensitivity of
detection. The data has been redigitized and
reformatted so that it can be analyzed by an
automatic vector cardiographic program acquired by
LAS several years ago.

Two simulation languages, NET2 and SPICE2, have
been implemented on NIH computer systems. Both
languages are available on the IBM System 370, and
SPICE2 is also available on the VAX computer

; \T.'!f

201 CT00004-1 '

, 1-4M1 t.n ?;tfptffinh..T- ''

PI: E.W. Pottala

OTHERS: J.J. Bailey

evelop phyaiologK

imputing technliue3

belonging to the Technical Development Section,
NIMH. The single retinal cone cell model has been
used to verify the above systems; a manuscript is in
preparation.

Proposed Course: The MAC-16 system will have
continued use for ECG processing from the
Framingham Heart Study (see project report on
electrocardiography).

Analysis of FDA data on rat electrocardiograms will
continue in FY83.

Network simulation studies will continue with the
development and implementation of additional
physiologic models using SPICE2 and NET2.

Publications and Abstracts: None.

Computer Systems for Nuclear Medicine

This project involves computer-based mathematical
analysis, pattern recognition, and image processing
in support of diagnostic activities in the Nuclear
Medicine Department of the Clinical Center and in
collaborating Institutes. Applications include
computerized ECG-gated radionuclide
angiocardiography and myocardial perfusion
scintigraphy, renal dynamics, and pulmonary
ventilation-perfusion relationships.

Progress during FY82:

• Renal Scintigraphy

The results of preliminary work carried out in FY76-
FY80 have been published in several journals. These
studies demonstrated significant enhancement of
routine renography using functional mapping
techniques. After a technical development and
software upgrading effort was accomplished in FY81,
definitive evaluation of the technique was carried out
in nine dogs. Contrast angiography, routine
radionuclide renography, and functional renal
mapping were performed before, one month after,
and 12 months after unilateral renal artery ligation.
Histopathological study of kidneys removed from the
sacrificed dogs is now underway. A manuscript
correlating the pathological findings with the
functional maps is in preparation.

• Cardiac Scintigraphy

In collaboration with Nuclear Medicine and the
Cardiology Branch, LAS has begun investigation of
several parameters reflecting mobility of the heart
wall including ejection fraction, regional emptying
time, phase (of first Fourier harmonic), and maximum
ejection rate. Programs have been written to
compute these parameters globally or for any
sectors of the heart image. The test data base

includes rest and exercise studies on 40 normal
volunteers, 24 patients with coronary disease and
known resting apical abnormalities (hypokinesis,
akinesis, or dyskinesis), and 15 patients with
cardiomyopathy.

• Image Processing
Signal-to-noise (S/N) ratio and Fourier harmonic
content of global and regional time-activity curves
(TACs) were thoroughly studied in this data base.
These studies showed that the physiological signal is
largely contained in four or fewer harmonics and that
higher harmonics probably represent noise relating
to the counting statistics of the TAG. They further
showed that smaller regions have relatively higher
noise and that regions smaller than 1/4 of the
ventricular region-of-interest produce higher
proportions of TACs that cannot be distinguished
from background TACs in terms of S/N ratio or
harmonic content. Hence, regional parameters
extracted from such TACs are unreliable. Finally,
these studies showed that global ejection fraction is
a good classifier of normal and abnormal cases but
regional ejection fraction does not appear to be
additionally helpful in separating apical abnormalities
(related to coronary artery disease) from diffuse
abnormalities (related to cardiomyopathy). However,
regional emptying time (time to the minimum of the
TAC) does appear to separate apical from diffuse
abnormalities. A series of manuscripts describing
these studies is in preparation.

SKITHSONIWI SCIENCE INFORMATION EXCHANGE

■ ""^'^BLrH|TT*^^tE^'lc^'^^

:„:

T NUMBER

CT00005-I 1 LAS

October 1. 1981 to September 50. 1982 |

C»p„..

S.,te„ for »„=!«.. M.dicin,

OTHEKS;

S.L. Bacharach Physicist

J.J. Bailey Chief, Hed. Appl. Sec.
R.C. Burgeaa Senior Staff Fellow
K.A. Douglas Comp. Syst. Analyst
P.P. van Rijk Visiting Scientist
H.V. Green Ch. Appl. Physics Sec.
A.E. Jones Chief, Diagnostic Imaging
H.C. Oatrow Engineer

CB NHLBI
LAS DCRT
LAS DCRT
LAS DCRT

llZZ

TS (if .",)

Medicine Department, CC, NIH
r Syatema Laboratory, DCRT, HIH

LAB/ BRANCH

□ry of Applied Studies

Medical

Applications Section

DCHT. NIH. Betheada, HD 20205

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:(.) HUMAN
a(..) HINORS

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,™.

SUHMAHV OF UORK (200 .ordg or Icsi - un

This project involves
pattern recognition, and i

and collaboratine Instttut
KCC-Kated radionuclide an«
aclotigraphy, renal dynani

computer-tl'sed mathematical

analyaia.

nage processing in support diagnostic

ocardiosraphv and myocardial perfusion
a, and pulmonary vantilation-nerfusion

Proposed Course:

• Renal Scintigraphy

Further evaluation and refinement of the functional
mapping technique is planned utilizing alternative
renal lesions in canine subjects. Limitations as well
as advantages of functional mapping in
pathophysiology of various etiologies will be
explored.

• Cardiac Scintigraphy

A statistical analysis of the data base will be
pursued, one possible outcome of which might be a
discriminant function with various parameters to
achieve optimal separation of normals from
abnormals. Another interesting study will involve
those patients with myopathy secondary to
adriamycin therapy, using each patient before
therapy as his own control. Other patients who have
normal contractility at rest but abnormalities upon
exercise form an additional interesting data base.

• Image Processing

When the expanded DeAnza system together with
magnetic tape and disk drives are operational, it will
facilitate study of paired myocardial (Thallium) and
blood pool image sequences. Refined edge
detection, assessment of wall motion abnormalities
and perfusion, and more accurate determination of
volumes are planned.

A model to demonstrate the effect of known
amounts of additive noise on the detectability of
regional wall motion abnormalities is planned.

Publications: None.

Computer-Aided Analysis of Electrocardiograms

These studies, continuing since 1 970, have been
directed toward the evaluation of accuracy, clinical
utility, and cost effectiveness of various computer
systems for analysis of routine electrocardiograms

(ECG's). Further studies will involve new methods of
feature extraction and design of criteria by computer
techniques and their use in epidemiological studies.

Progress during FY82: A set of ECGs was recorded
on four different occasions on each of four staff
members of the Framingham Heart Project. One
ECG from each member was digitized at 1000
samples/sec and the others at 250 samples/sec.
From these data the analytic variation, within person
variation, and group biological variation were
estimated and compared with similar studies done by
Simonson in 1949. A manuscript is in preparation.

Proposed Course: Georgetown University Medical
Center has acquired 12 simultaneous lead ECGs on
a group of patients with documented cardiac
disease. GUMC has proposed a collaborative project
with LAS to evaluate three of the better-known
programs using this data base.

Meanwhile, LAS continues to study the
epidemiologic significance of the routine ECG in
collaboration with the investigators of the
Framingham Heart Study. The ECG correlates of
such heart diseases as coronary disease, mitral
prolapse, and asymmetric septal hypertrophy in a
free-living population are of particular interest.

Publications and Abstracts:

Bailey J.J.. Berson. AS., Jackson, L.K., Mllliken, J. A.. Stevens, J.M., Tolan,
G.O., and Wolf, H.K.: Evaluation Mettiodologies for ECG diagnostic
systems. In Bonner, R.E., and Pryor, T.A. (Eds): Computerized Inter-
pretation of the ECG VI. New York, Engineering Foundation, 1981 (in
press).

Macfarlane, P.W., Ctien, C.Y.. and Bailey, J. J.: A comparison of point
scoring tecfiniques for the diagnosis of LVH. In Macfarlane, P.W. (Ed.):
New Frontiers in Electrocardiology. New York, Jofin Wiley & Sons,
1981 (in press).

Computer-based studies in ultrasonography

This project involves collaboration between LAS and
the Cardiology Branch, NHLBI. It is directed toward
computer-based processing for image enhancement,
pattern recognition, and three-dimensional
reconstruction from ultrasound data. Wide-angle,
phased array echocardiography is the principal
source of data.

Progress in FY81: Resolution of hardware and
software defects in the upgraded DeAnza image
processing system has forced deferral of further
work on this project (see project on Computer Based
Analysis and Image Processing in Electron
Microscopy).

Publications and Abstracts: None.

SoJt6l"iiMw'[3"iOT'2?ll*(iit Jm"T'

IITUMIUL NEtCUGH flOJECT

201 CT0O0O2-12 LAS

October 1, 1^1 to S«pt«fflber ?0, t9ti2.

Coaputer- Aided Analysis of Bl«ctrooardl08»aui

HMt£S, L«BOR*TOnY UO INSTITUTE iFflLUTIOHl, AM TIILtS Cf POIHCIPAL IKVC&TISATORS MO HA. OTHtH

PI: J.J. Bslley Chief, HAS US DCRT

QTHEBS: E.K. HorrlB ChlBf LAS DCfiT
H.R. Horlon Conputer S/stems Analyst US DCRT
D. Savage PrsBtnghBO Heart Study NHLBI

Medical ApplicationB Section

CHECK (PMOfftMIt BO«(tSj

D (.)«»..« suijccls D(i.)«u.»iissut. DW«iiHS«

Dl-O CilNOS D(.») KIMVUK

~££lFi?;!rJj

Yne'eS"'l970, have been directed toward the

or snalysia of routine electrocardiORrama

epidemiological studies.

ODputer t«chnlque9 and their use In

^oj£Cl"Ni«EH'fo"lOT'2!If*lhhI J"?J!!'^'

IHTIUMU. aEUAMH mJECT

ZOl

CTOO045-O4 LAS

Computer- baaed studies in ultrasonography

KUttS, L»BORHORY m INSTITUTE tfflLUTIWS, Mt> IITltS Of PRINCIPM. INVfSTI

J.J, Bailey

LAS DCfiT
CB SHLBI

CDdPERMING UNITS {il .«,}

Cardlolo^ Branch, NKLBI

L*B/BS»NeH

Uboratory of Applied Studies

DCRT. HIH. Bethesda, KD 20205

U.4 1 0.2 1 0.2

C«l« .rPROPRUU BOl{tl)

K.J Hu-w suBjeeis d (0 w"M nssuEs u (0 «'"'»

a(.l) K.NOfiS DM) IhlERVU-S

SUHKARl OF .^ORK (200 .on]» «r l<i> - undarlln* t,.,.ORl>)

This project involves collaboration of LAS, with the
Branch, NHLBI. It is directed toward computet^besed pro
iBawe enhancetnent, pattern recognition, and three-dimens
reconstruction fron ultrasound data. The principal sour
Mide-angle, phased array echocardiography.

Cardiology
ceaainfi for

Computer Based Analysis and Image Processing
in Electron Microscopy and X-ray and Electron-
Loss Spectroscopy

This project involves collaboration of LAS with
several NIH Institutes. It is directed toward the
development of computer-based mathematical and
statistical analyses, pattern recognition, and image
processing of data, principally x-rays and electron
energy loss spectra, derived from biological
specimens studied in an analytical electron
microscope.

Progress During FY82: The DeAnza image
processing system has been upgraded from a
maximum image size of 256 by 256 pixels to a
maximum of 512 by 480 pixels. Testing of this
upgraded system revealed many serious hardware
defects. The vendor has spent most of FY82
resolving these problems. The same vendor provided
the hardware interface between the DeAnza system
and the magnetic tape and disk drives. This interface
has also been sent back to the vendor for
correction. Consequently many projects depending
upon this system have been delayed (see Ultrasound
and Nuclear Medicine).

Statistical analyses currently are being performed to
determine the sample size necessary to detect
reliably changes in density of dense bodies in
digitally acquired electron micrographs of platelets.

LAS proposes to undertake some of these objectives
in collaboration with participating wet laboratories.
The DeAnza system has been upgraded from a
maximum image size of 256 x 256 pixels to 512 x
480 pixels. Images acquired at Brookhaven are 512
X 512 pixels; when the expanded system with the
new magnetic tape and disk drives is operational, it
will allow more rapid processing of the images
obviating the need for data compression or
partitioning.

Publications and Abstracts: None.

5So;£ci"iSUe

jij««!,j;f™«;i™ ™

'T »tS:'; mmS\i%Ki^

PBOJECT BB.BEB

'""■'SoS'lf^™'"

ZOl CT00042-04 LAS

"ocL'bTr"

1, 1981 to Septe

■ber 30, 19S2

1..=)

Compute

^^^''d X-rav^and

nd Image Processing in Electron
Klectron-Loas Spectroscopy

IIAUES, LABOR

TOBY AHO INSIIIUTE tf

ILUIIOHS, AND TITLES Of PBIHCIP6L IHVESTIGAIOBS ABB ALL OTHEB

OTHfflS:

H.A. Douglas
j!l. Costa

Computer Systems Analyst LAS DCRT

J.J. Bailey

COOPERATINC

»ITS (if .»,)

Clinical Neuropharmacology, HIHH, Laboratory of Cheoistry, NIADDK. 1

LAB/BR*NCH
Laborat

udies

Applications Sec

tion

DCRI, IIIH, Bethcada, KO 2020?

D(.) »mu

1 1 2

UtE BOI(ES)

0(1.) BBMAH IISSIJES a(i)«ElIBEB

0 (..)..«.

S D (.^) l«tE.V.E.S

OBK (200 ■.«. .r U::

collaboraUon^of LAS and several lUH

™?Se,'a

tical md'staUst

ted toward the development o

f computer-based

nition, and image

df?f5S

ing or data, prin
from biological

lipally X-rays and electron energy loss spectra

specimens studied in an analytical electron

Physical Sciences
Laboratory

George H. Weiss, Chief

Summary of Activities

Consulting Services. R. A. Brooks (SN, NINCDS); J.
Shapiro (CC, DIR); A. Pikus (CC, OPD); J. D. Dillon
(Walter Reed Medical Center); B. Sonies, M. Stone
(CC, REHAB); L. Nadel (CSL, DCRT); G. Knott (LSM,
DCRT); H. Edelhoch (CE, NIADDK). Members of PSL
collaborate with and advise researchers at NIH in
several areas of applied mathematics and applied
physics.

A study on the lifespans of German veterans who
sustained head injuries in World War I has been
completed. A comparison of data on these veterans
and on uninjured veterans showed that the lifespans
were little affected by injuries until approximately the
age of 60, after which death rates in the injured
group exceeded those in the control group. Further,
the only reliable prognostic factor for the occurrence
of early death was posttraumatic epilepsy, while
other measures of severity of injury showed no
predictive value.

A theory that enables one to calculate the statistical
errors in parameters estimated from positron
emission tomography data has been developed. The
validation of this theory by simulation will be
undertaken and then application to the data of Dr.
Rodney Brooks will be made.

A joint effort with members of the Speech
Rehabilitation Department of the Clinical Center and
with Dr. Lawrence Nadel of the Computer Systems
Lab has begun on the use and quantitation of
ultrasonic imaging to the study of tongue
configuration in speech. So far the ultrasonic images
have been digitized, and various studies completed
on the reliability of measurements processed in this
way.

Studies in Mathematics and Statistics. George H.
Weiss (PSL). A meeting on random walks and their
application to the physical and biological sciences
was held at the National Bureau of Standards on
June 28-July 1, with participants from around the

world. PSL has worked on several applications of
random walk theory to physical problems. One is the
configuration of polymer chains near surfaces, and
another is a problem derived from crystallography. A
second project that has been completed relates to
order statistics of diffusion processes that may or
may not be spatially homogeneous.

Several statistical tests for examining the
relatedness of DNA sequences from different
species have been developed. Heretofore, tests of
relatedness were produced by simulation only; our
tests, while not comprehensive, are nevertheless
exact.

Correlation Function Spectroscopy/Laser Light
Scattering. Ralph J. Nossal (PSL). Studies have
been completed on changes in mechanical
properties occurring near the gel-sol transition in
polymer gels. A theory is being developed to relate
macroscopic measured parameters to the underlying
microscopic structure of the gel. The techniques that
have been developed in this project are currently
being used to investigate properties of gels formed
from glycoproteins and of clots formed from
reconstituted human plasma.

Two-dimensional Fourier Transform Nuclear
Magnetic Resonance Spectroscopy. James A.
Ferretti (PSL). Considerable progress has been
made in applying two-dimensional NMR
spectroscopy to the measurement of rate constants
in enzyme reactions. In principle it has been shown
that one can monitor all of the pathways in a
complex exchanging system.

Theory and Measurement of Intermolecular
Forces. Adrian Parsegian (PSL). For the first time
ever, measurements of the forces between
molecules have been made using a combination of
thermodynamics and crystallographic methods. In
particular these measurements have been made for
the repulsive forces between parallel DNA double
helices.

Quantitative Analysis of Cell Electronmicroscopy
and Plasma Membranes. Nahum Gershon (PSL).
This project uses image processing techniques to
interpret eiectronmicrograph pictures. Measurements
have been made of the volume, surface area, and
pore size of the cytoskeleton of cells. These
measurements show that the cytoskeleton occupies
a small volume of the cytoplasm contrary to what is
usually assumed. A computer system is being
assembled to study three-dimensional cell structure.

Research Projects

Consulting Services

Consulting services are provided to NIH researchers
on problems requiring knowledge of advanced
techniques in applied mathematics, physics, and
statistics. Projects have been completed relating to
interpolation errors in computerized tomography, to
the occurrence of audiologic defects in patients and
relatives of patients having osteogenesis imperfecta,
on the consequences of head injuries for life span,
and on the occurrence and time course of
posttraumatic epilepsy.

A project has been started on the estimation of
errors in parameters measured by positron emission
tomography, and a theory has been developed to
estimate expected errors from the data. Another
project with the Clinical Center is on the use of
ultrasonic measurements to characterize tongue
position in speech. The biochemical characterization
of coated and uncoated vesicles by a combination of
ultracentrifugal techniques and light scattering is
another project recently initiated.

Publications:

Rish, B. L, Caveness, W. L., Dillon, J. D., Kistler, J. P., Mohr, J. P., and
Weiss, G. H.; Analysis of brain abscess following penetrating craniocer-
ebral injuries in Vietnam. Neurosurgery B■.5'i5-5A^ , 1981.

Shapiro, J. R., Pil<us, A., Weiss, G. H., and Rowe, D. W.: Hearing and
middle ear function in osteogenesis imperfecta. J. Am. Med. Assoc.
247:2120-2126, 1982.

Weiss, G. H., Caveness, W. F., Einsiedel-Lechtape, H., and McNeel, M. L:
Life expectancy and causes of death in a group of head injured veter-
ans. Arch. Neurol, (in press).

Weiss, G. H., Feeney, D. M., Caveness, W. F., Dillon, J. D., Kistler, J. P.,
Mohr, J. P., and Rish, B. L.: Prognostic factors for the occurrence of
posttraumatic epilepsy. Arch. Neurol, (in press).

Weiss, G. H., and Rice, J.: A combinatorial problem in pharmacology. J.
Math. Biol, (in press).

Weiss, G. H., Talbert, A., and Brooks, R. A.: The use of phantom views to
reduce CT streaks due to insufficient sampling. Phys in Biol and Med.
(in press).

™'""

is.g'&f .!!':;:'!

ON EACHANCE

tHTR

isiif

PROJECT

ZCl

CT 00022-15 PSL

n^rnh^r 1 1QR1 rn R«prPTnhPr Ifl . 19R?

.o„„U.„sS„vU»

paofEss

ONAL PERSONNEL ENGAC

ED ON THE PROJECT

PI:

George H. W

eiss. Chief,

SL, DCRT

Other

Ja-es E. Ki

efer, PSL. DC

Ralph Noss.

COOP£fiA

IHC UNITS (if ..,)

R. A. Brooks.

SN, NINCDS;

J. Shapiro

CC, DIR; A. Piku

st;„°

D; J. D. DiUon

Walter Reed

Rlfc"K'"

"'isS: 5?r;

; H. Edelhoch, CE

DivU

'„p"of°cl.'C»t«

Research 5 le

hnology

TOTAL HANYE-HS: j PROFESSIONAL: |OT«£R: j

n(.)

PROmiATE hoXes)

D (.) HO.

D(0 <

EITHER

D(..)

INORS D (■!) INTER

>IE>S

CF WORK (!00 -onJs c

re'p'tovided't

'»irresear

blems re oiring k

„„-

ledge

Of advanced tec

hniqnes in ap

lied mathem

atics, phys

cs, and statistic

oJ pa

aphy, to the oc

teogeneSis^m

erfec?a' on

^Chrconsequ

ences ofhlad'inj

ries

A°pro

ect'ha"'b«n st

arted°™"thr

stimatioro

f "err or fir

sttraumatic epile

bv po

itron emission

tomography, 3

d a theory

nas been dev

eloped to estimat

i'3

use of oltraso
ochemical chara

i^-^

light scatt

eEFifS

thcr project tece

atio,
tly

studies in Mathematics and Statistics

A comprehensive review article on random walks
and their application in chemical physics and biology
has been completed. Arrangements for an
international meeting on random walks and their
applications, sponsored by NIH and NBS were
made, and the meeting was held from June 28 to
July 1, 1982. Several statistical tests have been
developed for measuring the relatedness of DNA
sequences from different species. A study of first
passage problems for diffusion processes with
spatially inhomogeneous transition coefficients has
been completed.

Publications:

Kiefer, J. E., and Weiss. G. H.: A comparison of two methods for accelerat-
ing the convergence of Fourier series. Comp. and Math. 7:327-336,
1981.

Rubin, R. J., and Weiss, G. H.: Random walks on lattices: The problem of
visits to a set of points revisited. J. Math. Phys. 23:250-253, 1982.

Weiss, G. H.: Random walks and their applications. Amer. Sci. (in press).

Weiss, G. H., and Rubin. R. J,: Random walks: Theory and selected appli-
cations. Adv. Chem. Phys. (in press).

Weiss, G. H.. and Shiesinger. M. F.: On the expected number of distinct
points in a subset visited by an N-step random walk. J. Stat Phys.
27:355-363. 1982.

-'"'■'""" ■™-'"'"

ZOl CT 00024-07 PSL

October I. 1981 to September 30. 1982

—"«—-—"

Oth.,: /"".ieferJ^SL. KRT

eooPHAIlNC »»MS (i' ■">) B. J. Rubin, Ph. D.. Senior

Scientist, KBS; K. E. Shuler.
erg, Ph.D.. Univ. of Clifornla-

LAB/eR*NCH

Physic.l Science. Ubor.tor,

Division o£ Computer Research & Technology

0.8 ' 1 "„""■' ■ 1°'""' 5 3

CB!C« .ffRlBll.H I10.(£S)

D(.| KUl... SUIJSCIB D(t)HB.U,IISS«lS

D(.i)»i«o«s Dl.i) l».M.I£.S

a (•) >si'«i»

nd their application in chemical
•cnts tor in international
.ponsored by NIH and NBS were

Theory of Biochemical Separation Techniques

The techniques of applied mathematics and statistics
are applied to the design and analysis of biochemical
experiments.

Several methods have been compared for estimating
peak height and half-width of chromatographic
peaks. These have led to a clear choice among
methods currently being used. A similar investigation
has been undertaken on Lorentzian peaks that arise
in NMR measurements. A theory of kinetic tailing in
chromatography has been developed using
techniques devised for the study of hopping
conduction in solids.

Publications:

Weiss, G. H.: Optimal parameters for the measurement of the half-width of
a Gaussian peak. Sep. Sci. S Tech. (in press).

5Si;r^fis.?£'tss\rs::*fi^s^^^:5'^

■I^isii!'!!!^

„ ZOl CT 00014-15 PSL

October 1, 1981 to September 30, 1982 1

Theory oE Biochemical Separation Techniques

PI: George H. Weiss, Chief, PSL, DCRT

COOPtBATIHG wm (it ««,]

John Rice, Professor of Statistics, University of

California-San Diego

LAB/eniNCH

CM£W *PPflOPBI*I{ 80«(£S)

□(e) NEITNfH

peak height snd half-width
d for the study of hoppine

graphy has been developed using techniques devise

Correlation Function Spectroscopy/Laser Light
Scattering

Methods have been developed that utilize dynamic
light scattering techniques to probe the mechanical
rigidity and internal viscosity of polymer gels. Recent
emphasis has been on characterizing changes in
mechanical properties that occur near the gel-sol
transition, as crosslink density and polymer
concentrations are varied. The influence of solvent
viscosity on the dissipation of mechanical excitation
is also being assessed, to facilitate the formulation
of a mathematical model to explain the dependence
of measured macroscopic parameters on
microscopic gel structure. Polyacrylamide gels have
been used as model networks in these
investigations, in part because of the technological
importance of such polymers in biochemical
separation procedures. Biological materials that have
been studied by these techniques recently have
included gels formed from glycoproteins obtained
from sputum and clots formed from reconstituted
human plasma (cf. project Z01 CT 00017-10 PSL).
Other activities mainly have involved obtaining
information on particle size distributions needed by
other investigators at NIH, including data on
liposomes, 'coated vesicles' obtained from bovine
brain and polymethane coating material scraped
from implanted pacemaker electrodes. Collaborative
studies to support the further development of a laser
Doppler blood flowmeter also have been performed.

Publications:

Chen, S-H., Chu, B., and Nossal, R. (Eds.): Scattering Tectiniques Applied
to Supramoiecuies and Nonequiiibrium Systems. NATO ASI Series B:
73, New York, Plenum Press, 1981.

Nossal, R.: Laser Light Scattering. Methods of Experimentai Ptiysics 20:
299-336, 1982.

Nossal, R.: Quasielastic Light Scattering from Polymer Gels. In Chen, S-H.,
Chu, B., and Nossal, R. (Eds.): Scattering Techniques Applied to Supra-
moiecuies and Nonequiiibrium Systems. New York, Plenum Press,
1981, pp. 301-320.

Nossal, R.: Stochastic aspects of biological locomotion. J. Stat Phys. (in
press).

Nossal, R., and Jolly, M.: Shear waves and 'internal viscosity' in cylindrical
gels. J. AppI Phys. (in press).

Cell Motility and Chemotaxis

This project has been undertaken to study various
aspects of cell locomotion, including the
mathennatical basis of macroscopic assays for
leukocyte chemotaxis. Procedures for measuring
parameters of cell migration, e.g., computer-assisted
tracking techniques, have been developed.

Recent emphasis has been on perfecting laser
quasielastic light scattering techniques for
nonperturbative measurements of the mechanical
properties of soft protein gels that, when examined
by conventional rheometers, are structurally unstable
(cf. project Z01 CT 00021-11 PSL). The objective is
to examine cytoplasmic extracts from motile cells, in
order to understand how the polymerization of
cytoskeletal networks and the generation of
contractile force therein actually takes place. In order
to gain practical experience in acquiring such data,
various measurements have been performed on
polymer networks formed from fibrin, which in many
respects is a similar but more readily available
material.

Two-dimensional Fourier Transform Nuclear
Magnetic Resonance Spectroscopy

Two-dimensional Fourier transform Nuclear Magnetic
Resonance (NMR) spectroscopy has been applied to
determine the structure of conjugates of glutathione
and to study enzyme-catalyzed rates of exchange.
Unidirectional rates have been determined for the
phosphoglucose isomerase catalyzed isomerization
and anomerization of glucose-6-phosphate and
fructose-6-phosphate, for the adenyl kinase
exchange of adenosine diphosphate to adenosine
triphosphate with creatine to form adenosine
diphosphate and creatine phosphate. From these
studies mechanisms of the reactions were proposed
and it was demonstrated that two-dimensional NMR
spectroscopy is capable of monitoring
simultaneously all of the pathways in a complex
exchanging system.

Publications:

Jacobson, L., and Ferretti, J. A.: The determination of a phosphorus-phos-
ptiorus nuclear Overhauser enhancement by two dimensional magne-
tization exchange spectroscopy. J. Amer. Chem. Soc. (in press).

Marks, T, J,, Pohl, L. R., Gillette, J. R., Hong, M., Highet, R. J., Ferretti, J.
A., and Henson, J. A.: Stereoselective formation of bromobenzene
glutathione conjugates. Chem. Bio. Interactions (in press).

EHITHSOMUN SCIENCE INFORHlTIM EXCHANGE
PfiOJECI NUMER (Oo HOT «• (hit •»<:•)

iI.«iKil»™i!l

201 CT 00017-10 PSL

October 1. 1981 to Septeiiber 30. 1982

IIILE I mOJEEI (M .».r..>.,. .r 1...)
Ctll Motility md Che.ot.xi.

COOPE««II«C UNItS (II ..,)

J. GlailnBr, Ph.D., LBC, NIADDK

L»e/BR»NCH

Physical Sciences Laboratory

""""

Division of Cos^uter Research and Technology

IQUt ...YE.R^S,^ |™<,ESSI».t. jO,»E»,

CHECK APmOPRUIE eox{ES)

J (.) «U... SU.J.CIS a (.1 .C.» TISSUES

Dl.D.I.ORS aW) iHIERvii.s

EIEHE.

Recent enphssis has been on perfecting laser qusa

sspeets
s.ys fo

polymer

r leukocyte chemotaxis.
light scattering

tr.ctile force therein

siirir

a.s'S!j'.K':r!Jf: sw

HE."t'l5'.°«c'Sl".rs."lCES

"•■"

ZOl

CT 00025-07 PSL

Octobe

r I, 1981 to Septeslier I. 198!

ritu Of

PROJECT (eO chincl.n or Iti.]

Two-0

mensional Fourier Transform Nuclear Magnetic

Resonanc

e Spectroscopy

Tof"^.'

'o.T™imrEL'£i"«ErorTit'"S"c; '"° ■""' " """"'

1 I..ESTIC.

TOR! .»« .tt OTHER

Lev Jacobson, PSl'

R. J. Highet! PhD.l Laboratory of Chemis

;;.=

logy, NHLBl

LH/BRAN

Physic

"l Sciences Laboratory

seen OH

DiviBion of Computer Research and Technology

I0T«l«N««5. pOfESSIONAU |(,IH«^ ^

CMtCK *P

WOmiATE (O.(IS)

«.H SURJECTS Q (t] HUIAII TISSUES
IHORS a (.i) IHTEfldEwS

U (■) HE

T.IR

suuHini

C» -OflH (ISO .srds or l*>t - uHO.rll.<* l..,.onl.)

mensional Fourier transform Nuclear Magnetic

f"c"n"g^

e (NMR) spectros-
tes of glutathione

study enzyme catalyzed rstes of exchsnge.
een determined for the phosphoglucose isomer

kinase exchsnge of adenosine diphosphate to
ne to form adenosine diphosphate and creatin
s mechanisms of the reactions were proposed

!"ih§i

e triphosphate with

Precision in the IVIeasurement of NIUIR
Parameters

A study of the precision in the estimate of peak
positions in spectroscopy was carried out. This study
was carried out by considering both instrumental
noise and error due to a finite digitization rate.
Different strategies for estimating peak position were
compared. The comparison showed that it is always
desirable to use some form of curve fitting the peak
rather than using the position of the digital maximum
as the peak position estimate. It was shown that it is
very difficult to estimate changes in peak position
that are less than ten percent of the line width.

A method for the estimation of peak areas for
nuclear Overhauser enhancement factors was
developed. Although this study constituted a
preliminary investigation, which did not directly
consider all sources of error, it was found that the
peak area can be determined with high precision in
the presence of substantial phase error. This method
(called the product method) involves multiplying the
peak height with the width at one-half peak height to
compute peak area.

Publications:

Weiss, G. H., Ferretti, J. A., Kiefer, J. A.: A study of precision in the
measurement of chemical shifts. J. Mag. Res. 46:69-83, 1 982.

P.O.SOT ««..£

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1981 to September 30. 1982

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HolecuUr

graphics on the DCRT and NIADDK ays
Inr contacts corresponding to mcaau

™«'r

are being uaed Co visualize
ts of molecular aaaembly.

Theory and Measurement of Intermolecular
Forces

During this year we have achieved the first direct
measurement of a force between molecules. The
repulsion between parallel DNA double helices is an
exponentially decaying hydration force similar to that
observed previously between bilayer membranes. Its
magnitude depends strongly on the identity of ionic
species bound to the DNA molecule. Its decay and
lack of dependence on ionic strength show that at 0
to 20 Angstroms separations intermolecular forces
differ qualitatively from the predictions of
polyelectrolyte theory. The results correspond
closely to an intuitive macroscopic theory of water
polarization and work of water removal from
molecular surfaces.

Creation of protein gels and crystals under osmotic
stress has enabled us to create the equivalent of
phase diagrams for assembling proteins with the
consequent determination of thermodynamic
parameters.

Molecular graphics on the DCRT and NIADDK
systems are being used to visualize the molecular
contacts corresponding to measurements of
molecular assembly. In this way we hope to derive
useful and accurate potentials for molecular contact.

Publications:

Lis, L. J., McAlister, M.. Fuller, N., Rand. R. P.. and Parsegian. V.A.:

Interactions between neutral phospholipid bilayer membranes. Biophys.

J. 37:657-666. 1982.
Lis, L. J., McAlister, M., Fuller. N., Rand, R. P.. and Parsegian. V. A.:

Measurement of the lateral compressibility of several phospholipid bi-

layers. Biophys. J 37:667-672. 1982.
Parsegian, V. A.: Protein-Lipid Interactions in Memtiranes. The Rockefeller

University Press. 1982, 401 pp.

Analysis of Intracellular pH by 31 P Nuclear
Magnetic Resonance Spectroscopy

Binding constants of various magnesium/
orthophosphate complexes were experimentally
determined. Precision and accuracy of intracellular
pH measurements based on orthophosphate 31 P
NMR chemical shift were thoroughly analyzed in
terms of intracellular magnesium ions availability and
limited instrumental S/N ratio. It was demonstrated
that the presence of free magnesium ions has only a
marginal effect on pH-dependent Intracellular
orthophosphate chemical shift and no effect on
derived intracellular pH estimates.

lalyais of Intracellular pH by P Nuclear Magnetic Resonance Spe<

Research k Technology

lium/orthophosphati

Quantitative Analysis of Cell Electronmicroscopy
and Plasma Membranes

In this study, we have initiated a three-dimensional
reconstruction of microtubule nucleatlon centers of
the erythrophorus of Holocentrus as viewed by high
voltage electron micrographs.

So far, we have measured the functional volume,
surface area, and pore size of the mictrotubecular
lattice and the cytoskeleton of cells and found that
they occupy only a relatively small volume of the
cytoplasm, contrary to what was intuitively assumed
before. These results were correlated with recent
measurements of diffusion of molecules throughout
the cytoplasm.

In addition we have begun to construct a stereo
image analysis system that Includes color graphics.
This system will be used to study the three-
dimensional structure of cells and their biological
functions.

We have developed quantitative methods to analyze
electronmicrographs of biological systems. The
methods include digitization of electron-micrographs,
manually or automatically, and computational

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October 1, 1981 to SepceDl>er 30, 19S2

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Quantitative Analysis of Cell Electronmcroacopy and Plasi

na Henbranea

PI: N. Gerahon. Ph.D.. Visiting Sci.nti.t. PSL.

DCRT

K. Porter, Ph.D., Fogarty Scholar, Fogarty I

1
1

Physical Sciences Laboratory

SECtroh

Division of Computer Research and Technology

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nstruction of microtu-

bule nucleatlon centers of the erythrophorus of Holoeentr

us as vifwed by high

voltsge electron micrographs.

So far. we have •eaiured the functional voIu,ne. surface a

r<-«. and pore sice

of the mictrotubecular lattice and the cytoskeleton of ce

lis and found that

they occupy only a relatively small volume of the cytopla

sm. contrary to what

measurements of diffusion of molecules throughout the cyt

oplasm.

In addition ue have begun to construct a stereo-image ana

lysis system that

structure of cells and their biological functions.

analysis of their contents (e.g., proteins on
membranes or cytoplasmic organelles and structural
elements).

All kinds of eukaryotic cells possess the capacity to
control their form, their size and to regenerate lost
parts. A general loss of these capabilities is
characteristic of neoplastic cells. It seems, therefore,
that there must exist in ceils a mechanism for form
control, a structurally continuous system that fills the
cytoplasm and derives functional properties from its
organization around a single center or complexes of
many centers. Those units of organization, in
addition to giving the cell its form, account for the
nonrandom disposition of better-known organelles
such as endoplasmic reticulum, Golgi bodies,
microtubules, and to a lesser extent, mitochondria.
We are constructing an image analysis with color
graphics that will enable us to study the organization
of cells in three dimensions. We use electron
micrographs produced by the high voltage electron
microscope (a national resource sponsored by NIH)
in Boulder, Colorado and other micrographs taken at
NIH. This concept of the cytoplasm is best illustrated
by the red chromatophore of the tropical fish,
Holocentrus. We already have initiated a study of the
three-dimensional recontraction of the microtubule
nucleation centers in these cells. These centers are
dispersed in patterns that repeat from cell to cell.

In addition, using a stereo image analysis system
and the PIC image processing system, we have
measured the fractional volume of the various
elements of the cytoplasm together with their
surface area and the size of their pores. These
results indicate that the microtubular lattice and the
cytoskeleton occupy only a small fraction of the
cytoplasm volume. These findings mean that these
structures cannot physically obstruct the diffusion of
molecules through the cytoplasm to a large extent
but rather slow it by other means (e.g., chemical
attraction). This result shows that the previous
intuitive impression that these structures occupy a
significant portion of the cytoplasm volume is not
valid.

Diffusion of lUlolecules on Cell Surfaces and Light
Scattering from Fluids

In this study we evaluated the effect of cell
nonplanarity (e.g., due to the existence of microvilli
and blebs) on the rate of diffusion of proteins and
lipids in cell membranes using fluorescence
photobleaching recovery. For simulated microvillous
membranes, we found that the existence of
curvature does not affect the measured diffusion
coefficient by spot photobleaching recovery, contrary
to naive intuition. On the other hand, diffusion along
surfaces curved along one direction only depends
strongly on the nonplanarity. It was found that the
amount of nonplanarity needed to explain results of
measured diffusion anisotropy in fibroblasts is far
beyond what exists in nature.

In the second part, we derived hydrodynamic
equations and the light scattering spectrum from
microelastic fluids. We studied two cases, fluid-like
and solid-like viscoelastic fluids.

Publications:

Aizenbud, B., and Gershon, N. D.: Diffusion of molecules on biological

membranes of nonplanar form - a theoretical study. Biophys. J. (in

press).
Aizenbud B., and Gershon, N. D.: Diffusion of Molecules on Microvillous

Biological Membranes. In Perelson, A, C, DeLisi, C, and Wiegel, F. W.

(Eds.): Cell Surface Phenomena. New York, Marcel Dekker (in press).
Aizenbud, B., and Gershon, N. D.: Hydrodynamic equations and VH light

scattering from viscoelastic (solid like) systems. II. Molecular approach.

Physica A (in press).
Aizenbud, B. M., and Gershon, N. D.: Hydrodynamic equations and VH light

scattering from viscoelastic (solid-like and fluid-like) systems. Pheno-

menological approach. Physica A 107:126-142, 1981.

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Physical Sciences Laboratory

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ZOl CT 00040-04 I

1, 1981 to Septeidier 20, 1982

Control of Actin Assenbly in Nonmuscle Cells

PI: Stephen L.

of Computer Research and Technology

Control of Actin Assembly in Nonmuscle Cells

The protein actin is a major cytoskeletal component
of all eukaryotic cells, serving both structural and
motility-related functions. The G-actin monomer
binds one ATP, which is hydrolyzed upon
polymerization to polymeric F-actin. Studies in this
laboratory are aimed at elucidating the detailed
mechanism of polymerization, the role of ATP
hydrolysis, and the cellular control mechanisms for
actin assembly and disassembly.

The actin polymer has two ends that, by virtue of
ATP hydrolysis, can have different monomer/
polymer equilibrium constants. As a result, actin
monomers may treadmill through the filaments with
net monomer addition occurring at one end of the
filament and net loss at the opposite end while the
filament maintains constant length. Direct evidence
for treadmilling has been obtained this year using
actin covalently modified with a fluorescent probe
(N-pyrenyliodo-acetamide) that has a 20-30-fold
fluorescence enhancement when G-actin
polymerizes. Trace amounts of this probe, when
added to a G-actin/F-actin solution at steady state,
are incorporated from the G-pool into F-actin with
kinetics implying a treadmill mechanism. ATP
hydrolysis rates, measured concurrently, indicate a
high degree of efficiency for the treadmill, with as
few as 1-2 ATP molecules hydrolyzed for every new
actin protomer incorporated. The efficiency is a
strong function of ionic conditions with no
treadmilling occurring in the absence of free divalent
cations. ATP hydrolysis is obligatory; no monomer
incorporation occurs when G ADP actin is used.
Cytochalasin, a drug that we have shown to cap the
end of actin filaments, strongly inhibits monomer
incorporation at steady state.

We are currently isolating several proteins from
motile nonmuscle cells to determine their effects on
actin polymerization, steady state monomer-polymer
exchange, and nucleotide hydrolysis with the goal of
understanding the control of assembly and
disassembly of the actin filament in these cells.

Publications:

Brenner. S. L., and Korn. E. D.: Stimulation of actin ATPase activity by
cytoctialaslns provides evidence for a new species of monomeric actin.
J. Biol. Chem. 256:8663-8670, 1981,

Computerized Typesetting of Scientific Papers

The object of this project is to prepare computer disl<
or magnetic tape versions of scientific papers
intended for publication. This material can be sent
directly--on the phone or tape--to publishers'
copyediting/typesetting computer systems.

Our current efforts emphasized facilitation of
magnetic tape production and file preparation for
transmission. This year we overcame formidable
coding problems to write tapes, destined for outside
use, on the IBM System 370 directly from WYLBUR
files. We also initiated a series of telephone
transmissions of WYLBUR files. Over 30 scientific
articles have been transmitted this year either using
one of the tape writing programs or by telephone.

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ificant.

Laboratory of Statistical and
l\/iathematicai i\/lethodology

James E. Mosimann, Chief

LSM activities can be divided into three areas:
computation, consultation, and research.

Statistical Systems/Pacl<ages Support. During this
year, as in the past year, the Statistical Software
Section of LSM maintained the following program
packages and programs:

• BMD, BMDP: Biomedical Computer Programs,
UCLA.

• SPSS, SCSS: Statistical Package for the Social
Sciences, SPSS, Inc.

• SAS, SAS/GRAPH, SAS/ETS: Statistical
Analysis System, SAS Institute, Inc.

• P-STAT: Statistical Package, P-STAT, Inc.

• IMSL: International Mathematical and Statistical
Libraries, IMSL, Inc.

• MSTAT1: Collection of Mathematical and
Statistical Programs, DCRT.

During the year every system /package went through
at least one major update. The SSS staff answered
over 5,500 calls for assistance, and taught a total of
twelve courses on these systems/packages; two
each on the SPSS and BMDP packages and eight
courses on the SAS system.

The use of program packages continues to increase.
The average accesses per month of all the statistical
packages rose from around 33,000 during FY81 to
over 45,000 in FY82. For the sixth year in a row,
SAS experienced the largest increase of any of the
packages. SAS averages over 37,000 accesses per
month, up from 24,000 per month in FY81. The
average number of accesses per month for SPSS

decreased from 6,000 to 4,600. The average
combined accesses of the BMDP and BMD
packages was 2,500, about the same as in FY81. As
an example of a package used for specialized
purposes, PSTAT averaged 30 accesses per month,
down from 60 average accesses per month in FY81.
The main programs and subroutines in MSTAT1
averaged 1 ,300 accesses per month, in contrast with
650 in FY81. Accesses to the IMSL package cannot
be counted, but it is estimated that usage increased
during FY82.

The DCRT Mathematical and Statistical Program
Manual was updated in FY82.

IVILAB Support and Incorporation of C-LAB into
MLAB. The Biomathematics and Computer Science
Section maintains the DECsystem-10 interpretive
program MLAB, a package designed and
implemented by BCS staff. During FY82, several
hundred biomedical researchers at NIH used this
package for modeling and graphical display tasks.
MLAB is part of the NIH-funded Prophet system, the
SUMEX-AIM system at Stanford University, and the
NIH-EPA Chemical Information System. It has been
distributed to various universities and research
centers at their request. During FY82, BCS staff
assisted in implementing overlay facilities on the
DECsystem-10, and redesigned MLAB in a
segmented form to use overlay. This reduces the
load on the DECsystem-10, and user costs in many
cases, because software for seldom-used operations
is not loaded into computer memory except when it
is needed. This made it possible to incorporate C-
LAB, a previously independent package for
clustering and multivariate data analysis, into the
MLAB package. Other additions to MLAB were: new
OMNIGRAPH character fonts for graphical displays
of mathematical formulas or scientific text, and a
new, more informative system of error messages.
One advanced and three introductory courses were
taught for MLAB. Two articles on MLAB techniques
appeared in INTERFACE. The tenth edition of the

MLAB Reference Manual is being printed, and will be
distributed in FY82.

Support for the Unified Generator Pacltage. This
package, developed by a BCS staff member,
generates IBM System 370 assembly language
programs. The compatibility of the package with new
WYLBUR was maintained. As before, assistance was
provided for users on request.

Support for Other Software. BCS continues to
maintain certain special-purpose software and to
assist users upon request. The PROLOG package,
obtained from the University of Edinburgh, is
designed for analysis of non-numerical data by
aggregation of procedural rules; it has been used in
LSM linguistic research. A program developed by
BCS for interactive construction of an index for a
document file has been supported. Various LSM-
created programs for analysis and reconstruction of
biological shapes using the symmetric axis method
have been supported. A procedure simplifying the
generation of users' IBM System 370 data set
listings was developed and made available.

LSM consultations in FY82 were of the following
types:

• Mathematical, statistical, and computer science
advice with limited computer use (5%)

• Mathematical or statistical advice with
considerable computer use (55%)

• Computational advice alone (40%).

The large computer use in these figures results from
the continued availability and use of general purpose
statistical and mathematical packages like SAS and
MLAB. The diverse nature of LSM consulting is
indicated by the projects and activities listed below.

Clinical Research, Patient Care,
Epidemiology

Cancer Survival Study. R. Wesley (NCI/DCT/BRB).
Patient survival-time data was analyzed. LSM
assisted in modeling and nonstandard curve-fitting
for maximum likelihood estimates of survival
distribution parameters.

Obstetrical Care Study. P. Vietze (NICHD/MRDD).
Long-term effects of two-day rooming-in after
delivery were studied. Five categories of behavior

were monitored by an observer of experimental an
control mother-child pairs at five time points from
birth to six months. LSM assisted with statistical
advice on design and data analysis.

Diagnostic Study of Systemic Lupus
Erythematosus. T. Chused (NIAID/LMI). Eleven
clinical variables were evaluated, for ability to
diagnose and estimate severity, in 87 patients with
SLE plus a control group. LSM assisted in linear
regression and discriminant analysis, which
determined that a variable obtained as a ratio of cell
counts was a good discriminator between the normal
group and the SLE patients. Three presence-
absence variables were significant in predicting this
cell count ratio.

Laboratory Investigation

Anti-Bovine Gamma Globulin Radioimmunoassay.

Michael Miller (NIADDK/A&R). Tolerance to a
thymic-dependent antigen was tested in autoimmune
mice. LSM assisted in designing procedures using
MLAB to prepare standard curves from control
experiments.

IVIedian Lethal Dose Analysis. R. Evarts (NCI/
DCCP). Maximum likelihood estimates of median
lethal doses (LD 50's) of compounds administered to
groups of mice were calculated. LSM assisted in
application of probit analysis techniques.

IVIultiple-Site Binding. J. Dunn (NCI/DCCP). In a
series of chemical reactions, many F molecules bind
stepwise to a G molecule, with distinct affinities. LSM
assisted in modeling and analysis, using MLAB.

Receptor Characterization. M. Bissonette
(NIADDK/DD). A mathematical model for the
characterization of VIP and secretin receptors in rat
pancreatic acini in terms of receptor number and
receptor affinity was studied. LSM assisted in
simultaneously curve-fitting several nonlinear
functional forms to respective data, using MLAB.

Metal Ion Protein Binding. C. Chatterji (NIAID/LC).
Optical absorbance experiments measured metal ion
binding to a protein constituent of snake venom.
LSM continued to assist in curve-fitting models to
absorbance data.

Analysis of Simultaneous Binding Reactions. L.

Jacobson (NICHD/LCP). Simultaneous binding
reactions are studied by obtaining NMR scanner
absorbances at specific frequencies. LSM continued
to assist in mathematical modeling of equilibrium
constant estimates.

Zinc-Activated Enzyme IModei. P. B. Chock
(NHLBI/IR/LB). A twelve-compartment model for
zinc activation was studied. LSM assisted in
developing combinatorial aspects of the model.

DNA Sequence {Matching. P. Senapathy (NIADDK/
LEP). Various natural DNA sequences are studied in
terms of sequence lengths between identical k-
tuples. LSM provided software for generating gap
statistics, and assisted in use of MLAB to compare
data with negative binomial distribution models.

Bile Secretion Modeling. E. Feytmans (U. of
Namur, Belgium). Secretion of bile under stimulation
by taurocholate was measured in a patient
population. LSM assisted in modeling and curve-
fitting problems arising from delayed laminar flow in
a catheter.

Duck Motion Study. W. Schleidt (U. of Maryland).
Various aspects of duck motion were observed. LSM
assisted in computer generation of graphical displays
of idealized motions, using MLAB.

Induced Stroke Experiments. P. Ting (NINCDS/
LNNS). Stroke was induced in one side at several
sites in groups of dogs, and blood flow, pressure and
blood gases were monitored. At several post-stroke
sacrifice times the breakdown of the blood-brain
barrier and related nerve damage were evaluated.
LSM assisted with statistical advice on problems of
experimental design and data analysis.

Program Management and
Administration

Review and Verification of NRC Personnel Data.

A. R. Frost, Jr. (NRC); C. Gellman (Technassociates,
Inc.). Files of the NRC Automated Personnel System
were reviewed, verified, and corrected. The Unified
Generator Package was used to create software for
updating the files and generating reports. LSM
assisted in use of the package, use of generated
programs, and in the design of related software. The
resulting system was used on a production basis for
over three months, with as many as six clerks
working full-time to prepare input transactions, and
performed completely satisfactorily.

Investigator Career Profile Study. F. Harding
(NHLBI/DBDR); C. Crafford (JWK International).
Data on investigators associated with NIH grants are
evaluated for the effects of past NIH-supported
training programs and assessments of national
needs and currently available researchers. LSM
provided assistance in the use of the Unified
Generator Package to create data base software, in
the use of generated updating, reformatting, and
reporting systems, and in the training of users. Work

in the period covered by this report involved the
addition to the data base of information on grantees
in FY78, and preparation of reports analyzing this
data.

Biomedical Communications
Applications

Gastric Ulcer Data Base. C. Sniderman, S.
Humphreys (NLM). Methods for natural language
querying of gastric ulcer data are being developed.
LSM assisted in design of a parser for English
sentences and of related information retrieval
routines.

Computer Research and
Technique Development

Symmetric Axis Analysis. R. Webber, A. Davis
(NIDR/CIBI). CIBI staff have developed a number of
applications of the symmetric axis method for
describing and analyzing biomedical images. LSM
assisted in modifications of symmetric axis software
and preparation of a PDP-1 1 export package for CIBI
use.

Automated Data Processing of Medical Language

Research was continued on the compositional lexical
semantics of medical terms derived from Greek and
Latin. Medical compound words can be regarded as
'conjunctions' of larger semantic classes,
represented by their Greek-Latin components. The
relation between compound words and their
constituents may be characterized as hierarchial.
Medical compound words often represent certain
units of meaning that could be likewise expressed by
phrases consisting of separated components of
compound words in English or other foreign
languages. Additional standardization through
medical compound word processing will be beneficial
to retrieval performance.

A list was prepared of 40 semantically productive
Greek and Latin terminal morphemes (-ITIS, -
ECTOMY, etc.), the frequency of which was high.
Medical compound words concurring with the
selected terminal morphemes were analyzed
according to semantic constituents and the
compositional semantic patterns were established.
The algorithm for semantic interpretation and
paraphrasing of Greek-Latin terms into English was
developed for -ITIS forms and surgical procedure
forms (-ECTOMY, -STOMY, -TOMY, -PLASTY). The
paraphrasing rules mentioned above will be used as
a model for the development of additional
paraphrasing rules for other medical components

derived from Greek-Latin. Tlie development of
paraphrasing rules will increase substantially the
interpretive power of the lexicon and make it
possible to interpret synonymous phrases that are
not contained in the dictionary but that occur in
medical context. Morphological analysis for the
identification of productive terminal morphemes as
markers of parts of speech classes, and the set of
morphosyntactic transformation rules by which
canonical nominal forms are derived from adjectives
and noun plurals, were tested on the MEDLAR
corpus. It was necessary to add 37 transformation
rules to the existing tree to cover the MEDLAR
corpus.

Work was continued on the preparation of syntactic
and semantic rules for the Viral Hepatitis Data Base
information system.

Proposed Course:

1. Combination of research studies in medical
language at present level (morphology, syntax,
semantics).

2.Creation of lexicographic data base to be used
for the merge of medical dictionaries and extraction
of microglossaries.

3. Continuation of collaboration in the encoding of
surgical pathology data with the Laboratory of
Pathology, NCI, to refine the medical dictionary and
study the language of diagnoses.
Publications: None.

?!K"isi.y't!SMr:ri!?:.'3"

liZsiiffifl

ZOl CT 00001 11 LSM

""""ocloSIr 1. 1961 through September 30. 1982

Automated Data Processing of Medical Language

PI: H. C. Pacak Computer Systems

Other: G. Dunham Computer Programm
S. Harper Computer Programm

Inalyst LSB

DCfiT
DCRT

None

Laboratory of Statistical and Mathematical

Methodology

Kedical Information Science Section

'""'Ml*:'' WS^thesda. Maryland 20205

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Cluster Analysis

The main objective of this project is the application
of computer cluster analysis and related methods to
NIH researcher problems. This year, nearest
neighbor algorithms based on the latest published
research and extensions to it were developed and
tested, and algorithms for analyzing spacial point
patterns were developed for testing patterns of
retinal cones for regularity.

An improved algorithm for the computation of the
Delaunay triangulation of a set of points was derived,
programmed, and published. The dual of the
triangulation is the set of Voronoi regions for the
points. They define neighboring points and the
nearest neighbor regions around each point.
Measurements on the regions, e.g., areas and
angles, can be used to test for randomness of a set
of points.

The spacial pattern of blue cones, obtained from
macaque retinas, appear to have some kind of
regularity. Models of regular point patterns with
different amounts of error were fit to the data in
order to study the underlying nature of the regularity
and to determine the amount of disorder. Three
statistics based on nearest neighbor distances and
angles between the pairs of points were used in
testing models. Disturbed lattice models, using a
regular lattice of points with random error at each
point, could not be fit to the data. However, a model
that considered each point (cone) as a soft ball with
a minimum distance required between any pair of
balls, fit the data very well.

Proposed Course: Other areas of the retina and
other point patterns will be studied with this model to
estimate the degree of regularity of cones in different
regions of the retina.

Pubiications:

Shapiro, M.: A note on Lee and Schacter's algorithm for Delaunay triangula-
tion. International Journal of Computer and Information Sciences (in
press).

Yaar, I., Shapiro, M., and Pottala, E.: Spectral analysis of the EEG in
hepatic encephalopathy treated with levodopa. Electroencephalography
and Clinical Neurophysiology 52: 61 7-625, 1 981 .

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October 1, 1961 through September 30. 1982

Cluster Anal/sis

PI: M. B. Shapiro Research Kathenatlolan LSH

Other: F. de Monasterlo Head LVR

S. Scheln Expert LVR

«EI

Laboratory of Vision Research

Laboratory of Statistical and Kathenstlcal Kethodology

Statistical Hethodology Section

DCRT, NIH. Bethesda, Maryland 20205

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Nearest neighbor algorithms

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oped for

AlKorlthms for analvilnR spacial point patterns were
testing patterns or retinal cones for regularity.

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October 1. 1981 through September 30, 1982

TIIU OF MIOJECT (80 ch.r.cUr. or 1,.0

Hesearch Topics In Computer Science

P.I. CD. Knott Computer Specialist LSH
Other : None

DCRT

None

L.B/BRWCH

Laboratory or Statistical and Mathematical Methodology

Blomathematics and Computer Science Section

DCRT. NIH. Bethesda, Maryland 20205

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computer

Various storane and retrieval algorithms have been

is useful because such algorithms are used In almost
programs. Thus biomedical computation in particular
Improved storage and retrieval methods.

Research Topics in Computer Science

The object of this project is to develop theoretical
bases for new computer methods that will expand
and improve the use of computing in biomedical
computation. The methods used are the application
of known algorithms and the development of new
pertinent theorems involving combinatoric and other
related mathematics. Research work in storage and
retrieval algorithms and their efficiency has been the
primary topic of concern.

Various storage and retrieval algorithms have been
studied. The development of flexible and efficient
storage and retrieval algorithms is useful because
such algorithms are used in almost all computer
programs. Thus biomedical computation in particular
can benefit from improved storage and retrieval
methods.

Currently, a study of hashing storage and retrieval
methods is underway. This has resulted in the
analysis of the performance of the hashing methods
that resolve collisions using direct-chaining with
coalescing lists.

Much effort has gone into studying the B-Tree data
structure for large files and developing a deletion
algorithm to efficiently remove items from B-Trees.

Routines to store, retrieve, and delete items in a
hash table, which employ direct-chaining with and
without coalescing lists, have been prepared. The
analysis of these algorithms has been recently
completed and the results are to be published.

Publications:

Knott. G. D.: Fixed-bucket binary storage trees. J. of Algorithms (in press).
Knott. G. D.: Graphics Facilities in MLAB. In Sproull. R. (Ed.): Computer

Grapliics, in Chang. S. (Ed.): Har)dbook of Computer and Electrical

Engineering (in press).

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Laboratory of Statistical and Hathematical Methodology

""'Biomathe.atic3 and Computer Science Section

DCHT. NIH. Bethesda, Maryland 20205

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Inclusion relations between vector spaces and relat

Preparation of scientific manuscripts by computer g
printer-plotters on minicomputers was investigated.

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Discrete Mathematics and Applications

The project objective is to develop mathematical
theory and computational techniques using discrete
mathematics (algebra, combinatorics, and graph
theory), and to apply such methods to problems of
biomedical research and computer science.

Studies of inclusion relations between theories of
modules over a ring continued. A manuscript
prepared in the previous fiscal year was revised and
accepted for publication. New research was directed
towards (1) interrelating different mathematical
theories of modules, (2) determining whether the
lattice equations satisfied for a theory of modules
was sufficient to determine all of the theory, and (3)
classifying the rings that lead to the same module
theory.

In computer science, the minicomputer software for
computer generation of scientific manuscripts (text
and figures) was completed and tested. Tests of the
TEX system (developed at Stanford) for computer
generation of scientific text were performed.

Proposed Course: Study of module theory will
continue in the areas indicated above. Computer
software to generate scientific manuscripts will be
augmented by creation of mainframe software for
high-speed generation of page displays using the
advanced capabilities of Tektronix 4114 graphical
display terminals.

Publications:

Hutchinson, G.: A complete logic for n-permutable congruence lattices.

Algebra Universalis 13: 206-224, 1981.
Hutchinson, G.: Exact embedding functors between categories of modules.

J. of Pure and Applied Algebra 25; 107-111, 1982.

Multivariate Statistical Analysis

The objective of this project is the study of
multivariate ratios or proportions.

Study continued on multivariate statistical methods
(size-shape methods) for analyzing ratios having a
multivariate lognormal distribution. Studies also were
continued on ratios that follow an Inverted Dirichlet
distribution. A paper on special invariant discriminant
analyses for size and shape variables (with J. N.
Darroch) was written. The principal investigator
presented a review of this work at Cornell University,
Ithaca, N. Y.

Publications:

DeBlas, A. L., Ratnaparkhl. M. V., and Mosimann, J. E.: Estimation of the
number of monoclonal fiybridomas in a cell fusion experiment. J. of
Immunological Methods 45: 1 09-1 1 5, 1 981 .

DeBlas, A, L,, Ralnaparkhi, M, V., and Mosimann, J. E.,: Estimation of the
number of monoclonal hybndomas in a cell fusion experiment. In Vuna-
kis, H. v., and Lagone, J. J. (Eds.): Immunochemical Techniques (a
volume of Methods In Enzymology). Academic Press, New York, N. Y.
(in press).

Mosimann, J. E., and Malley, J. D.: The Independence of Size and Shape
Before and After Scale Change. In Taillie, C, Patil, G. P., and Baldes-
sari, B. (Eds.): Statistical Distributions in Scientific Work, Vol.4, Models,
Structures and Characterizations. Dordrecht, Holland, D. Reidel Pub-
lishing Co., 1981, pp. 137-145.

Ratnaparkhi, M. V.: On splitting model and related characterization of some
statistical distributions. In Taillie, C, Patil, G. P., and Baldessan, B.
(Eds.): Statistical Distributions in Scientific Work, Vol. 4, Models, Struc-
tures and Characterizations. Dordrecht, Holland, D. Reidel Publishing
Co., 1981, pp. 357-363.

Ratnaparkhi, M. V.: Some bivariate distributions of (X,Y) where the condi-
tional distribution of Y. given X is either beta or unit-gamma. In Taillie,
C, Patil, G. P., and Baldessari, B. (Eds.): Statistical Distributions in
Scientific Work, Vol. 4, Models, Structures and Characterizations. Dor-
drecht, Holland, D. Reidel Publishing Co., 1981, pp. 389-400.

Roux, J. J, J., and Ratnaparkhi, M. V.: On matnx-vanate beta type I distribu-
tion and related characterization of Wisharl distribution. In Taillie, C,
Patil, G. P., and Baldessari, B, (Eds.): Statistical Distributions in Scientif-
ic Work, Vol. 4, Models, Structures and Characterizations. Dordrecht,
Holland, D. Reidel Publishing Co., 1981, pp. 375-378.

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^""VEo^'or 1, 1981 ctirough Scptenbcr 30, 1982

Multivariate Statistical Analysis

PI: J.E. Moslraann Oil.r. LSK L3K KIIT

H.V. Ratnaparkhi Associate ProTessor

Wright state Unlverslt»
Dayton, Ohio

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Office of the Chief

OCRT. HIH. Bethesds, Harylani) 2020;

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The objective of thia project Is tne atudy of aultlvarlate
ratios or proportions.

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methods in statistics are applied to biomedical

data

Linear Methods in Statistics

Linear methods in statistics, as applied to biomedical
data analysis, continue to be studied. Additional
results were obtained on statistical and algebraic
independence of random variables. A study of linear
methods in variance component estimation was
undertaken and a paper submitted for review and
publication. Further, a new procedure was developed
to treat unbalanced multivariate analysis of variance,
and was submitted for review and publication. The
method allows well-specified, rigorous tests of
ANOVA models in the context of unequal cell
sample sizes in the design layout; this is the most
commonly occurring kind of data in the multivariate
setting. The method was applied to schistosoma
mansoni resistance to re-infectivity and the results
were submitted to the Journal of Tropical Medicine
and Hygiene as well as to a biostatistics journal.

Publications:

Grimes, A. M., Mueller, H. G., and Malley, J. D.: Examination of binaural
amplification in children. Ear and Hearing 2: 208-210, 1981.

Malley, J. D.: Simultaneous confidence intervals for ratios of normal means.
J. of The American Statistical Association 77: 170-176, 1982.

Malley, J. D.: Statistical and algebraic independence. Annals of Statistics (in
press).

Non-numerical Programming Techniques and
Applications

Several applications of non-numerical programming
techniques were pursued during the year. These
projects involved use of the PROLOG and REDUCE
computer languages, and the Unified Generator
Package, and were mostly in the general area of
computational linguistics. The two projects
accounting for the most effort were an investigation
into automated analysis of instructional text, and
research on automatic interpretation of medical
terminology in terms of the constituent morphemes
of individual words.

Investigations into the development of a PROLOG
program that can analyze material from an English-
language textbook were continued during this
reporting period. A program capable of analyzing
paragraphs describing how to form legal BASIC
expressions was extended into one capable of
analyzing a discussion of the LET statement of the
BASIC language. This extension involves the
simultaneous treatment of syntactic and semantic
considerations about the subject matter being
'comprehended' by the program. As a result of
analyzing the textual material, the PROLOG program
assimilates enough knowledge not only to parse, but
also to interpret a LET statement. A detailed report
has been written about this research, emphasizing
the interconnections between syntactic and semantic
concepts.

A second project in the area of computational
linguistics involved the creation of a PROLOG
program to analyze medical terms denoting surgical
procedures in terms of their constituent morphemes
(e.g., 'cysticolithectomy' is 'excision (-ectomy) of
calculus (-lith-) from cystic duct (cystico-).' Six
classes of surgical procedures were considered, an
existing lexicon of morphemes was substantially
enlarged, and the program/lexicon combination was
tested on over 1 ,500 terms, taken mostly from
medical dictionaries. Over 75 percent of the terms,
including nearly all of those commonly used, can be
interpreted automatically. The remainder presumably
would have to be listed in a lexicon of whole words
('full forms').

Other efforts during this reporting period included the
formatting and editing of a data base of surgical
pathology summary diagnoses, which were then
indexed using the Unified Generator Package to
obtain frequency data on the terms used in the
diagnoses. These and similar frequencies will be
used in a forthcoming LSM project on word
frequency distributions. For another project, the
symbolic algebraic manipulation language REDUCE
was used to assist in factoring a sixth-degree
polynomial of interest in the theory of iterated maps
on the unit interval.

Publications: None.

K'-a-rKSiKsr*

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ZOI a 00017-0*1 LSH

'"""oJlUbCT

1. 1981 through Septenbvr 30, 1982

wlcal Programing Techniques and Appllaatlons

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H.G. Pacak Computer Systems Analyst LSM OCRT

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Laboratory of SUtlstleal •!(] WtHeaatleal Hethodology |

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IH. Bethesda, Maryland 20205

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the year. TTieae pr
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of medical ternlnology In terms or the constituent morphemea of Individual

Topics in Geometry and Analysis

The project objective is to develop mathematical and
computational techniques using geometry and
mathematical analysis, and to apply such methods to
problems of biomedical research and computer
science.

An algorithm for high accuracy identification and
description of protein spots in two-dimensional
electrophoretic gels was developed and coded.
Testing of the program has begun.

In order to study convex cones a parametrization of
all (non-isomorphic) N-algebras was studied. To
determine smoothness properties of this
parametrization and for its intrinsic interest a related
set of Lie groups endowed with a left-invariant
Riemannian geometry was studied.

At this point, the eye is the most accurate and
effective detection device for protein spots in two-
dimensional electrophoretic gels. The edges of the
spots can generally be well fit by parabolic
segments. An algorithm has been developed to
model parabolic fitting by the eye utilizing a
'parabolic spacial second derivative' and other
analogues of cues used by the eye. This has been
coded as a Pascal program on a VAX computer.
(This work is in collaboration with LGCB, NIMH.)

By developing alternate characterizations of some of
the axioms of an N-algebra and studying N-algebra
isomorphisms in these terms, a parameter space for
the algebras can be constructed as the intersection
of hyperplanes and a sphere in an appropriate vector
space. A unique (with respect to N-algebra
isomorphism class) parametrization space is then
obtained as the quotient of the subset of the vector
space by a tensor product of two lower dimensional
orthogonal groups. By evaluating canonical
Riemannian geometry of a cone of generalized
positive definite symmetric matrices with respect to a
particular field of bases, one uses the standard
diffeomorphism from the triangular group of a T-
algebra onto its related cone to endow the Lie group
with a left-invariant Riemannian metric that is
isomorphic to the geometry of the cone. This
enables it to be seen that the parametrization is in
fact polynomial.

Publications:

O'Connor, M. A.: Invariant metrics on cones. Proc. of the Conference on
Invariant Metrics and Hoiomorptiic h/laps, Rome, Italy, Istituto di Alta
Matematica F. Sever! di C.N.R. (in press).

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201 a

00079-02 LSH

October 1, 1981 through September 30. 1982 |

liTUS Of PSOJECT (•» ■h.r.i..r= .r I,,-.)

Topics in Geometry and Analysis

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P.I. M.A. O'Connor staff Fellou LSH OC

Other: C.R. Nerrll Senior Hesearch Scientist LGCB «I

Uboratory of General and Comparative Biochemistry

'■"/BtygHratory of Statistical and Mathematical Methodology

Biomathematics and Computer Science Section

DCRT. NIH, Bethesda. Maryland 20205

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«n algorithm for high accuracy Identification and descrlptio

spots in two-dimensional electrophoretic ael s was developed

In order to study convex cones a parametrization of all {nnn-

isomorphic)

Data Management
Branch

J. Emmett Ward, Chief

Clinical Research, Patient Care,
Epidemiology

Clinical Support Section. During this past fiscal
year a number of projects were developed and
successfully completed:

• the development of a set of programs to
translate and format MIS Raw Purged Data

• the development of a system of programs for
preprocessing MIS Purged Data

• the design and development of a set of
programs to build and update the integrated
data base

• the writing of programs to translate and
preprocess clinical laboratory data for the
integrated data base

• the development of a procedure to automatically
transmit chemistry and hematology data from
the CIU data base to the PDP-10 System

• the transfer of data sets from mountable disk
packs to mass storage, and

• the modification of a number of programs to
support maintenance and retrieval of clinical
data for the integrated data base.

BRIGHT STAT-PACK. Brian Cole, Jeanne Grillo
(DMB/SAS); David Rodbard, Peter Munson (NICHD/
BES); Jay Shapiro (CC). A computer system has
been developed on the DECsystem-10 that enables
Clinical Center investigators to analyze their own
clinical data. Available thus far are t-test, basic
statistics, weighted linear regression, chi-square,
frequency distributions, and high-quality basic
graphics. The system provides a convenient method
of obtaining clinical data from the NIH Clinical
Information Utility, and interfaces with both MLAB
and SAS.

Effects of Bromocriptine on Schizophrenic
Patients. Diane Feskanich (DMB/SAS); Neal Cutler
(NIMH/BP). Statistical analyses were performed to
study the effects of Bromocriptine on physiological
and psychological variables. Camera-ready graphs

were produced, from which slides were made to
illustrate a presentation by Dr. Cutler.

Survival System. Diane Feskanich (DMB/SAS);
Ardyce Asire (NCI). This life table analysis system
was originally developed in the 1960's to support the
End Results in Cancer studies of NCI. Maintenance
and improvement of the system is now the primary
goal. The system has been sent to tumor registries
and hospitals both in the U.S. and elsewhere. During
FY82 the system was expanded to handle more than
two racial groups.

Prevalence of Major Neurological Diseases:
Nigeria. Diane Feskanich, Jeanne Grillo (DMB/SAS);
Bruce Schoenberg (NINCDS/NS); Dr. Osuntokun
(University of Ibadan). This WHO-sponsored study
consists of four parts: (1) census and health screen,
(2) evaluation of risk factors, (3) neurological exam
results, and (4) followup. A pilot study was done for
Part 1 to determine validity and usefulness of
questions and goodness of the questionnaire. During
FY82 a new pilot was begun, based on information
from the FY81 pilot. New forms were developed, and
edit and update programs were written.

Alcohol and Memory. Mary Lee Dante (DMB/SAS);
Elizabeth Parker (ADA). Test results from four types
of tests measuring the performance of male college
students under the effects of alcohol were
computerized and scored, and a data base suitable
for analysis was created.

Cerebral Palsy/Neonates. Diane Feskanich (DMB/
SAS); Tatiana Kudrjavcev (NINCDS/NS). Ms.
Feskanich received tapes of birth certificates and
neonatal and fetal death certificates from the
University of Rochester. During FY82 focus was on
looking at low birthweight for age as a predictor of
cerebral palsy in the newborn. Frequency
distributions and counts were produced for this
study.

Nutrient Data Base. Diane Feskanich (DMB/SAS);
Elaine Offutt (CC/NUTR). The USDA nutrient data

base was obtained and programs were written to
calculate nutrient intakes from daily foods records for
research studies. A comparison of the numerous
nutrient data banks available for purchase is being
conducted to determine the one best suited for use
in an interactive setting by Clinical Center
nutritionists.

Combined Cardiology/Heart Surgery Data
System. Larry Martin (DMB/ASPS); Roger Dailey
(DMB/DBAS); C. Mcintosh, D. Rosing (NHLBI). This
combined system provides a chronological record of
the medical activity of NHLBI Cardiology and Heart
Surgery Branch patients. In FY82 effort was directed
toward meeting the routine and ad hoc reporting
requirements and statistical needs of the NHLBI
physicians and researchers. The system was
expanded to include a graded exercise form and a
physical examination form. A program and command
processor were written to produce assorted
bibliographies of pertinent papers and publications.

NIADDK Study of the Incidence and Prevelance
of Kidney and Urinary Tract Diseases in the
Armed Forces. Darius Georg (DMB/ASPS); N.
Cummings (NIAID). This study is being conducted to
evaluate the research needs in this area and to
correlate the research needs with the occurrence of
morbidity and mortality of the disease. This system is
currently in the raw data evaluation stage.

Sleep Study System. Darius Georg, Peter Basa
(DMB/ASPS); Christian Gillin (NIMH/BPE). This
system is being developed to provide a
computerized method for scoring sleep data.
Analysis and design have been completed. Programs
to edit, update, and report on the data have been
written. Other information such as drug
administration and behavioral and clinical ratings
may be added to the system at a later date.

Psychobiology Patient Information System.

Dennis George, Steven Soroka (DMB/ASPS); Frank
Putnam (NIMH/BP). The purpose of this project is to
condense a large amount of data for a small number
of patients into a format that is useful for research
analysis. During the last year the data was converted
into a fixed format and programs have been written
to produce reports in both hard copy and graphic
form. This data was extracted from the CC/MIS data
base.

Analysis of SLE Nephritis Patient Data. George
Shakarji (DMB/OC); John Klippel (NIADDK).
Collection of patient therapy data and
implementation of our computer storage and retrieval
system was begun. Complete chemistry and therapy
data has been stored on over 1 00 SLE (Systemic
Lupus Erythematosis) nephritis patients. Investigators

have had ready access to the data base to get up-
to-date information and analysis on trends in patient
progress.

Forecasting Trends of SLE Nephritis Patients.

George Shakarji (DMB/OC); John Klippel (NIADDK).
Trend and forecasting analysis systems are being
implemented to detect and forecast relationships
among three groups of SLE patients, namely: those
who are on dialysis, those who have doubled their
creatinine, and a control group. Results from DNA
Binding, Serum Creatinine, C3, Serum Albumin, Qual
protein, RBC/HPF, and Hemoglobin are being
analyzed for correlational relationships among these
data. It is hoped that analysis will indicate and
predict certain long term outcomes based on the
relationships of these data in the three groups.

Subject Specific Reference Regions for Blood
Chemistry Data. George Shakarji (DMB/OC);
Eugene K. Harris (DCRT/LAS). This study is a part
of the continuing studies on defining reference
regions, both univariate and multivariate, as applied
to subject specific variability in clinical chemistry
results for blood. Programs were written and
completed to examine both theoretical and empirical
properties: first through computer simulation, then by
application to serial clinical assays collected over a
long period of time (seven to nine years).

Analysis of Means and Variances of Chemistry
Data in Normal Subjects. George Shakarji, David
VanSant (DMB/OC); Eugene K. Harris (DCRT/LAS).
A package was designed and generalized to analyze
serial measurements of analytes for within and
across subjects. This package computes tests of
normality for within-subject data, computes serial
correlations and moments for each individual's data,
and then proceeds to perform analysis of variance
and covariance over all the subjects.

Dyslipidemia Computerized Recordkeeping
System. George Roberts (DMB/SAS); Ernst
Schaefer (NHLBI/DMB). This system keeps records
on clinical laboratory data for normal and
dyslipidemic subjects and provides for routine
reporting, ad hoc queries, and preparation of
selected subfiles for statistical analysis. During FY82
work was begun on nutritional studies of these
patients' diets. The analysis of the effects of
Neomycin on cholesterol levels was also begun.

Penicillin Study. Vivian Pelham, Charles Twigg
(DMB/ASPS); Dorothy Sogn (DIR/NIAID). This
system is being developed to collect data and
provide reports from the clinical trials of skin testing
with major and minor penicillin derivatives in
hospitalized adults. Analysis and design were

completed during the year and the system is being
implemented.

Laboratory Investigation

Smithsonian Tick Collection Query/Retrieval
System. Diane Feskanich (DMB/SAS); Carleton
Clifford, Jim Keirans (NIAID/RML). The Rocky
Mountain Lab has catalogued their tick collection on
tape at the Smithsonian Institution. DMB is supplying
the ability to update and query this file from Montana
using the DCRT central computer facilities. During
FY82 Ms. Feskanich installed interactive programs
for data entry on the DataPoint word processor in
Montana, ensured that the software would interface
with DCRT software, and trained RML personnel in
use of the software. She has also been acting as
intermediary in the data flow between RML and the
Smithsonian.

Monkey Management System. Diane Feskanich
(DMB/SAS); Robert Williams (NICHD/PRB). A data
base of the bibliographic and experimental history,
plus the current medical status and experimental
protocol for each monkey, was built. Programs were
developed for data entry, editing, updating, and
reporting. The system is being used to select
appropriate individuals for specific experiments, and
to prepare daily work assignments for caretakers and
technicians. Future enhancements will include
special reporting facilities.

Graphics. George Roberts (DMB/SAS); David
Rodbard (NICHD/BES); Doris Wallace (DRG/RAE).
Mr. Roberts has provided assistance to NIH research
scientists and administrators who are learning how to
use the new graphics capabilities. During FY82 he
also began the development of a front-end package
that will be able to accept existing sequential data
files, apply user requested transformations, and
produce TELL-A-GRAF data files. The user will be
able to generate his own TELL-A-GRAF data file by
supplying the appropriate algebraic equations in
Fortran notation.

Molecular Modeling. Sigurd Knisley (DMB/SAS).
During FY82 Mr. Knisley has been working on
modifications to the shaded surface molecular
display developed by Richard Feldmann and Tom
Porter (DCRT). Currently available are a
transparency option, which allows the viewer to see
internal features or contact interfaces between
molecules, and a variable illumination angle, which
improves three-dimensionality.

Seroepidemiology Data Processing System. Judy
Mahaffey (DMB/ASPS); Paul Levine (NCI). The
Clinical Studies Section, NCI Laboratory of Viral
Carcinogenesis, is trying to find characteristics of

serum samples that can be used to predict cancer.
To this end, a computer system has been designed
to manage all data necessary for efficient inventory
control, test results feedback, and statistical analysis.
The system is now operational and reports from the
system are being sent to collaborating scientists in
the U.S., Ghana, Greenland, and Singapore. During
the past year a new contractor took over the running
of this system. DMB provided assistance in setting
them up to correctly run the system.

Primate Colony Carcinogen Study. John Parks
(DMB/ASPS); Susan M. Sieber-Fabro (NCI/DCT).
The purpose of this project is to develop a system to
maintain and search data generated from a colony of
approximately 2,000 nonhuman primates. The
system as originally requested became operational
during the last year. Future enhancements will be
added as requested by user.

Canine Breeding Colony Data Processing
System. Peter Basa (DMB/DBAS); Dennis George
(DMB/ASPS); T. Wolfle (DRS/VRB/ACS). The goal
of this project was to develop a system to assist the
Veterinary Resources Branch, DRS, with its
recordkeeping and work scheduling. The system is
complete. DRS is now in the process of installing a
word processor system (CADO) in Poolesville to
handle all data entry, maintenance, etc. When this is
complete, DMB will work on interfacing the two
systems.

Strain Specificities Reference System Steve
Soroka (DMB/ASPS); David Sachs (NCI). A
computer system is being developed for the Division
of Cancer Biology and Diagnosis, NCI Immunology
Branch, to assist in transplantation biology research.
The system will be used to help locate existing
cogeneric mouse strain products and/or to design
mouse strain products having specific antigens that
are used in experiments relative to the development
of sera. The project has been temporarily suspended
until new coding schemes and structures are
developed and implemented by the sponsor.

Finite Element Package. David VanSant (DMB/OC);

Warren Pince (NIEHS). This is an easy-to-use finite
element program for solving a large class of elliptic
(steady state), parabolic (time dependent), and
equivalent partial differential equation problems in
general two-dimensional regions. This package has a
preprocessor program that allows the user to supply
the problem description in a greatly simplified form
so that no knowledge of FORTRAN is required.
Graphical output can also be produced. Scalar,
vector, and stress fields can be displayed via the
Calcomp plotter.

Program Management and
Administration

Administrative Data Base (ADB). Marvin Katz,
Ron Wicks (DMB). This ongoing administrative
project utilizes data base technology in support of
NIH-wide materiel and financial management. As the
Materiel Management System (MMS) entered its fifth
year of development and operation, much time was
spent in enhancing existing software. During FY82
some 50 change control items successfully went into
production. Several new developmental efforts were
implemented:

1 . Requirements analysis for development of a
data base Financial Management System (FMS) has
been completed. It is anticipated that development
of the FMS using contractor personnel will
commence in late FY82.

2. Deployment of the delegated interface to MMS
in the B/l/D Administrative offices continues. By the
end of FY82 this effort will be essentially completed.

3. The development of the stock inventory system
is proceeding. This system will be phased into
production during late FY82 and FY83.

4. A vendor credit capability has been added to
the accounts payable system.

5. An ability to search the NIH vendor data base
using alphabetic names directly at the ADB terminal
has been added.

6. The procurement system has been extended to
include entry of DFM miscellaneous obligations and
training orders. The online production of SF-147's
has been added for reprints and for personal service
contracts.

7. The requirements for open market requisition
processing are being reviewed.

Full-Time Equivalency. Dennis George, Mike Letke
(DMB/ASPS); George Roberts (DMB/SAS); John
Hartinger (NCI/FMB). A system was built for
monitoring the ceiling levels and full-time equivalency
manyears for NIH. Data input, update, and query
facilities are available, and report programs usable
by all B/I/D's and by Central Budget have been
provided.

DRR Grants Subproject System. Vivian Pelham
(DMB/ASPS); Jean Babb (DRR). The existing DRR
Grants Subproject System that used CPS was
evaluated. A proposal was made for the redesign of
this system to make use of more current,
supportable technology. The proposal was accepted,
and the system was developed and turned over to
the user during the past year.

NIH Nutrition Grants Monitoring System. Judy
Mahaffey (DMB/ASPS); Thomas VogI (OD). A
system has been designed for the NIH Nutrition

Coordinating Committee to assist them in monitoring
and reporting data on biomedical and behavioral
nutrition research at NIH and at other agencies
within DHHS. The system is operational and Dr.
Vogl's office is currently using it to answer inquiries
from NIH directors' offices, the White House, fl

Congress, and the public as they relate to dollar V
amounts and percentages of grant money being
spent in the area of nutrition. This is an ongoing
project with the data base being created each fiscal
year.

Review and Evaluation Branch Grants
Information System (GENIUS). Penny Brogan
(DMB/ASPS); Harry Canter (NCI). The computerized
Research Analysis and Evaluation Branch
Information System, a highly specialized system, was
designed and implemented for the Division of Cancer
Grants, NCI. The system provides information on
grants, contracts, intramural projects, and unfunded
grants. The grants and contracts systems are
'generalized' so they can provide information from
any NIH Institute. In the future, a Training Grants
system will be developed, and history file
maintenance must be added to the intramural
projects and unfunded grants systems. Additional
programs must be written to pick up more contract
information from the NCI-CMS system.

NIH International Activities and Personnel
Monitoring System. Penny Brogan (DMB/ASPS);
Libby Low (FIC). A system provides the Fogarty
International Center with the ability to maintain and
query a data base with information on foreign
scientists who are in the U. S. to perform health
research. Most of these scientists are working at
NIH. The system provides query capability as well as
regularly scheduled preprogrammed reports. The
existing system is being revised to include more
accurate dating and editing capabilities, new reports,
etc. Fourteen programs of the revised system are
complete and operating. About sixteen programs still
need to be written.

Employee Health System and Accident Reporting
System. Vivian Pelham , Steve Soroka (DMB/
ASPS); Julio Rivera, John Leach (ORS/S). A system
is being developed to combine the employee health
and accident reporting systems. Analysis and design
has been completed and the system is currently
being implemented.

development centers, and nonprofit institutions. This
is an ongoing project.

MMS Query and Reports. Jane Blessley (DMB/
ASPS). This project is intended to provide an
economical method for the selection and reporting of
data from the NIH Administrative Data Base. Ms.
Blessley provides recurring and ad hoc reports from
the data base for all segments of the NIH
community. During the past year she trained and
turned over the responsibility for this project to
another unit of DMB.

System for Controlling and Monitoring
Complaints of Discrimination at NIH. Darius Georg
(DMB/ASPS); G. Yee, M. Williams (OD/DEO). This
project establishes and maintains a file that provides
statistical data, on a case-by-case basis, of formal
and informal complaints of discrimination at NIH. In
the past year Mr. Georg revised and simplified the
retrieval process.

System for Classifying NIH Research and
Development Awards. Darius Georg (DMB/ASPS);
William Rhode (OPPE/RA). The objective of this
project is to test the feasibility of and then develop a
computer system based on CRISP index terms for
categorizing by basic research, applied research, and
development and to show percentage distribution of
dollars associated with each category. If the system
proves feasible, the data will be used to prepare
annual reports to the Office of Management and
Budget (0MB) and the National Science Foundation
(NSF).

ARMS/TDCS Interface (TAPS). Dennis George
(DMB/ASPS); B. Hughes (OPA/P); A. Amatucci (OA/
M). This project is intended to create an NIH
Personnel System that is a composite of the current
NIH personnel system (ARMS) and the DHHS
Personnel System (TDCS). The system was
completed and turned over to the Office of the
Director/Systems and Action Branch during the year.

Radiation Safety Control System. Charles Twigg
(DMB/ASPS); R. Zoon (DRS/RSB). This system is
designed to monitor the use and users of radioactive
isotopes at NIH. When complete, this system will
include five subsystems. They are: (1) Inventory and
Bioassay, (2) Lab Survey and Airborne Release, (3)
Waste Processed and Activity Balance, (4) Training,
and (5) Film Badges. In the past year, online
collection and update of Form NIH88 was tested and
implemented. Development of the lab survey and
airborne release subsystem was begun. All
subsystems except the Waste Processed and Lab
Survey have been completed.

Electrical Safety Program System. Larry Martin,
Steve Soroka (DMB/ASPS); Howard Metz (DRS/

BEIB). The chief of Scientific Equipment Services of
the Biomedical Engineering and Instrumentation
Branch has requested a system to help monitor
maintenance of equipment at the Clinical Center. A
system is being designed to computerize the results
of routine electrical safety checks and of preventive
maintenance performed on hospital equipment. The
system will be used by DRS to schedule equipment
checks, to provide reviews on instruments checked
by contractors and by the Clinical Center, and to
provide statistical information on repair histories of
different types of equipment. The system was
completed and turned over to the user during the
year.

Interferon Production Monitoring System. Dennis
George (DMB/ASPS); Hilton Levy (NIAID/LVD). The
purpose of this project is to develop a system to
monitor the production and subsequent use of
interferon on an experimental basis. Various
production techniques and use protocols are to be
monitored in both human and animal subjects. Initial
analysis and design have been started.

Information System of Extramural Scientists.

Darius Georg (DMB/ASPS); William Rhode (OD/
OPPE). This project involves the creation of a data
base drawn from various sources to perform analysis
of patterns of involvement in NIH science review
activities by extramural scientists. The data base has
been created and reports are being run as
requested.

Medical Records Auditing System. Judy Mahaffey
(DMB/ASPS); Gloria Burich (CC/MRD). The purpose
of this system is to assist the Medical Records
Department in the monitoring and reporting of the
status of medical records from the time they enter
the department until they leave. When the system is
developed it should replace four manual systems
now being used. The work-in-process portion of the
system was completed during the past year. Work is
now focusing on the 'audit' segment of the system.

AIRS Personnel System. Steve Soroka (DMB/
ASPS); L. Lee Manuel (DCRT/OD). This project will
involve a complete revision of the system due to the
availability of the new TAPS file. Analysis, design,
and implementation are currently in progress.

Biomedical Communications
Applications

Selective Dissemination of Information. Sigurd
Knisley (DMB/SAS). SAS has continued its support
of the current awareness search for both Chemical
Biological Activities (CBAC) and the Biosciences

Information System (BIOSIS). Retrospective
searches are referred to the NIH Library staff.

Editorial Data Base Management System. Brian
Cole (DMB/SAS); Judith Prewitt (DCRT/OD). A
system is being built using the interactive capabilities
of the DECsystem-10 that will allow professional
journal editors and conference chairmen to track
information on paper submission and refereeing.

Bibliographic Data Base. Sigurd Knisley (DMB/
SAS); Curtis Harris (NCI/DCCP). Bibliographic
information and keywords drawn from Dr. Harris'
reprints of scientific articles were entered into the
computer files. A system of searching this
information and printing it for direct inclusion into
book and journal bibliographies was set up using the
powerful new tools available in WYLBUR.

Chinese Personalities and Institutions in
Biomedicine. Judy Mahaffey (DMB/ASPS); Joseph
Quinn, Joseph Lee (FIC). Due to a rapid increase in
international exchanges in the field of biomedicine
between the U.S. and the People's Republic of
China, the Fogarty International Center has
requested DMB services to design a system for the
computerization of data on biomedical scientists and
institutions in the PRC. The system will be used by
the FIC officials in briefing NIH and non-NIH
scientists interested in biomedical research in China.

Computer Research and
Technique Development

SFOR (Structured FORTRAN) Compiler. Bob

Magnuson (DMB/OC). The SFOR compiler, which
generates block-structured IBM FORTRAN source
code, was further enhanced to assist programmers'
writing structured programs. There are six different
kinds of blocks available to the FORTRAN
programmer-CASENTRY, FOR, IF, LOOP, REPEAT,
and WHILE.

RMAG Products Support. Bob Magnuson (DMB/
OC). Necessary support is provided for RMAG, SLR,
Logic Subroutines, Arithmetic Subroutine, SLANG,
Voice Input, and SFOR. This ongoing support
includes software maintenance, customer
assistance, and the teaching of formal DCRT
courses on the use of these products. In particular, a
special effort had to be mounted to change over to
the new WYLBUR format data sets.

PDOC: Program Documentation System. Bob

own. The PDOC system generates good-looking
boxed comments that really stand out in explaining a
program. PDOC permits symbolic referencing-
forward or backward~of the generated code line
numbers or of the generated document section
numbers. There is a command for underlining.
Various kinds of heads are created within the
generated document, and are placed automatically
within optional tables of contents. PDOC has an
INCLUDE command, which permits inclusion of
different files as parts of the PDOC source. A PDOC
file consists of a source program to be documented
to which you have added interspersed PDOC
commands and WYLBUR Document Formatter
commands. Hence, both the program and its
documentation can be maintained within the same
PDOC file. When running PDOC, the user can elect
to have all or part of the contained code extracted
and placed into an active file. There it can be
compared, compiled, tested, saved, or run.

CP Tools. Bob Magnuson (DMB/OC). CP Tools is
an integrated set of WYLBUR command procedures.
Stored as members of a partitioned data set, only
one of these tools need be accessed by a single
user-defined command. When that tool is executed,
it selects the tool actually wanted, passing along any
included keyword parameters (taken from the
command line argument). The tools include an
NIH7000 editor that permits TV editing' of the user's
data sets, combined with all of WYLBUR editing,
plus 'token editing' (for changing variables or
keywords without affecting other parts with identical
substrings). Another tool gives online help on the
various tools. Other tools include JCL generators for
running SLANG and SFOR, as well as for
microfiching any number of hold jobs. There are
tools for setting the NIH7000 tabs as well as its PF
keys to whatever the user wants. One of the tools
formats text into TYPE commands with NIH7000
screen underlines, thus simplifying the task of
creating screen help messages.

Computer Center
Branch

Joseph D. Naughton, Chief

Summary of Projects

New Software.

TVEDIT, a powerful full-screen text editor, was made
available on the DECsystem-10. TVEDIT provides an
up-to-date, visible copy of the portion of the file
being edited on the terminal screen. Nearly all of
TVEDIT's commands are issued using labeled keys
on the NIH7000 terminal keyboard, eliminating the
need for memorizing commands. Editing changes
are shown immediately, and the cursor may be
moved to any location on the screen, making it
possible for the user accurately to construct tables,
diagrams, and flow charts. These features give
TVEDIT remarkable versatility and ease of use.

POSTER was developed to fill the need for an easy
way to prepare slides, posters, and transparencies of
textual material for use as visual aids at scientific
meetings and symposia. In the past, titles, captions,
and summaries had to be hand-lettered or typed,
photographed, and then enlarged. POSTER
eliminates these steps and prepares posters directly
or produces high quality copies for slides and
transparencies. A variety of formatting capabilitites,
24 typefaces, numerous specialized symbols, and
commands for underlining and generating sub- and
super-scripts are all available in POSTER.

The entire online data storage facility of the NIH
Computer Utility was completely redesigned during
the year. The installation of some 224 actuators IBM
3380 Disk Drives, together with the use of the 3850
Mass Storage System, provided a tremendous
increase in capacity permitting the online storage of
both larger and greater numbers of user data bases
in a more reliable and cost effective manner. Three
new data storage categories-Open, Controlled, and
Dedicated-provide online data storage facilities for
data sets ranging from a few bytes to more than 100
million bytes online DASD. The Mass Storage
System provides online storage for data bases

exceeding this size. After extensive internal testing
by the Computer Center, a plan to transfer all active
user data sets to the new online storage structure
was developed. Using a phased parallel approach
with an elaborate back-up/recovery procedure some
300,000 online data sets were transferred during the
last six months of the year with no interruption in
service to users. The transfer will be completed
during the early part of FY83. When complete, the
NIH Computer Utility will have more than 141 billion
bytes of online DASD data storage capacity available
to users. It is anticipated that this, together with
availability of some 236 billion bytes of data storage
space on the Mass Storage System, will be
adequate to meet users' needs for several years into
the future.

Output Facilities. This past year saw the
retirement of SPOUT, a facility that was originally
designed to handle nonstandard output in an offline
fashion. Improvements in the JES2 portion of the
operating system and the use of high quality printing
produced by the versatile 3800 laser printers made it
feasible to allow the use of nonstandard forms
online. Appropriate software changes were
implemented gradually, and by July all standard
forms as well as user-supplied forms became
available online. Eliminating SPOUT reduced both
processing overhead and manual handling of tapes,
thereby increasing efficiency and accuracy. Two
new CalComp 1055 Plotters replaced the old model
1036 plotters that had been in use since July 1977.
The new plotters operate at almost three times the
speed of the old ones and have the ability to plot in
four colors. Better quality output and faster
turnaround was provided to graphics users, at no
increase in cost.

Communications Linlt. MERCURY, the
communications link between the IBM System 370
and the DECsystem-10, is vital to obtaining the
maximum effectiveness from both systems. Several
hardware and software improvements were
implemented this year to enable the MERCURY
program to keep pace with new developments on
the IBM System 370. The most significant
enhancement allows the DECsystem-10 users to
take advantage of the IBM 3850 Mass Storage
System for infrequently-used data sets. As the year
comes to a close, new hardware was acquired to
improve both the speed and reliability of the
MERCURY link.

Documentation and Publications. Providing
current documentation for all services was an
important challenge in this year of transition.
INTERFACE continued to be the users' most
important source of up-to-the-minute information.
Eight issues and an Annual Index were published
during the fiscal year. The Computer Center Users
Guide also reflected the increased pace of change.
For the first time it was completely revised twice
within one year and required four updates to keep
users informed of the most current and complete
system technical details at all times. A new contract
was established to make printing of the Users Guide
more timely and reliable.

Other publications are oriented toward familiarizing
users of the Computer Utility with the services,
languages, and training available. Seven new
publications were released this year and 12 others
were either revised or updated.

User Training. A variety of intensive courses
designed to acquaint the user with the computer
services and languages available were offered
through the Computer Center Training Program. The
Training Program accommodated 2,244 students in
190 sessions of 64 different courses during the year.
Special effort was made this year to designate
courses at elementary, intermediate, and advanced
levels, in order to meet the diverse needs of the user
community.

Many extra sessions of the introductory WYLBUR
courses were offered to make the capabilities of

New WYLBUR available to users. Other courses
covered: the many computer languages used at NIH;
the software packages available for statistics,
computation, and graphics; and the operating
systems of the IBM System 370 and the
DECsystem-10.

Those unable to attend regular classroom courses
were able to choose from 26 self-study courses,
ranging from introductory surveys of computers and
programming to advanced discussions of the IBM
System 370 and DECsystem-10 operating systems.

Customer Assistance and Systems IViaintenance.

Customer assistance has always been an important
part of the Computer Center's services, and even
more so in FY82. The number of Programmer
Trouble Reports (PTR's) researched and answered
during the year rose to a record high of 5,148. This
was partly due to the new, easier-to-use PTR
command developed for WYLBUR. Although the
Programmer Assistance and Liaison Unit continued
to operate under restricted hours, it recorded more
than 37,500 calls or visits from customers needing
assistance.

Installation of new hardware and software on the
IBM System 370 required significant changes to the
operating system. The number of SYSGENS
installed during the year rose to 106. Nearly 11,000
'fixes,' both preventive and corrective, were tested
and applied to the system, and 1 0 new releases of
current software packages were installed.

Research Projects

In addition to the many activities, services, and
facilities it provides NIH, the Computer Center also
serves biomedical computing with its research work
in molecular graphics.

Computer Representation of Virus and other
IMacromolecular Assemblies

Over the past five years, a computer raster display
has been used to represent the surface structure of
macromolecules. Shaded spheres are the primitives
of the representation. In globular protein and nucleic
acid structures, each sphere represents one atom or
at times one amino acid. In representing viruses, the
sphere primitive has been used in some cases to
represent one whole protein. In other cases, the
spheres are used to represent the shape of a portion
of a protein.

Symmetry of the viruses plays an important part in
making the computer model look realistic. Once the
shape of a protomer is modeled, it is then iterated
over the (icosahedral) symmetry of the assembly. A
model of limulus hemocyanin has been constructed
starting from image-enhanced electron microscope
data. Twenty spheres are used to represent the
kidney bean shape of each of the 48 70,000-dalton
proteins in the assembly. Fifty spheres were used to
represent the low resolution shape of the muscle
actin obtained from electron diffraction.

The generalization of surface shape representation
obtained using spheres as primitives indicates that it
will be possible to model subcellular organizations by
computer.

Publications:

Berzofsky, J. A., Buckenmeyer. G.K.. Hicks, G.. Gurd, F.R.N., Feldmann,
R.J., and MIna. J.: Topographic antigenic determinants, recognized by
monoclonal antibodies to sperm whale myoglobin. J. Biol. Chem. 257:
3189-3198, 1982.

Feldmann, R.J.. Potter, M., and Glaudemans, C.P.J. : A hypothetical space-
filling model of the V-regions of the galactan-binding myeloma Immun-
oglobulin J539. Mol. Immun. 18: 683-698, 1981.

Pawllta, M., fulushinski, E., Feldmann, R.J., and Potter, U:. A monoclonal
antibody that defines an Idiotope with two subsites in galactan-binding
myeloma proteins. J. Exp. Med. 1981: 1946-1956, 1981.

ZOt CT00089-01 CCB

October 1, 1981 through Septsabcr 30. 1982

Computer Rcpreaentatlon of Virus and other ttooroMleoular Aaseobllea

P.I. Hicnard J. Feldaann. CCB, DCItT. Coaputer Spealillst

CMfEN^riNC W.tl (II ..,)

Coaputer Center Branch

DCRT. HJH. Bethesda. HD 20205

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CMtCK iPCftOMUIt BOll[ES]

Over the past five yeara, a computer raster display haa been used to represent

spnere represents one atom or at times one amino acid. In representing viruses, 1
the sphere primitive has been used In some cases to represent one whole protein.

protein. Syiwnetry of the viruses plays an important part In making the computer

Iterated over the Clcosanedral) symmetry oi the assembly. A model oi limulus
hemocyanin has been constructed starting from Image-enhanced electron microscope
data. 7\<enty spheres are used to represent the kidney bean shape of each of the
U8 70.000-dalton proteins In tne assembly. Klfty spheres were used to represent
the low resolution shape of the muscle actln obtained from electron diffraction.
The generalization of surface ahape representation obtained using spheres as
primitives Indicates that It will be possible to model sub-cellular organizations
by computer.

Office of the
Director

Arnold W. Pratt, M.D., Director

Summary of Activities

Library Automation. E. Chu (OD); J. Mahaffey
(DMB); J. Knight (CSL). In conjunction with other
DCRT staff, the DCRT Librarian applies computer
techniques to DCRT needs, advises other libraries,
and maintains knowledge of work done outside NIH.
In FY82 work on this project has been limited to a
few modifications on the existing systems.

DCRT Publication File. K. Griffin, P.O. Miller (OD);
R. Baxter (DMB). This ongoing project was begun in
1979 to create a file of citations for all papers
published by DCRT authors. In FY82 additional work
was done to correct errors in the file; a usable
product should be available in the first quarter of the
next fiscal year.

Electronic Typesetting Methods. P.O. Miller (OD).
This project is an offshoot of work begun in 1979 as
a part of a joint PSL/LAS/OD effort. It involves
creating a specially-coded magnetic tape of
WYLBUR text that can be used directly by
computerized typesetting equipment at GPO. The
technique has been shared with NIH and other
Federal public affairs communities, through the NIH
Printing Committee and the National Association of
Government Communicators.

DCRT Communications Program. P.O. Miller, W.C.
Mohler (OD). Previously called the DCRT Information
Program, this is an ongoing project to develop
improved and coordinated communication
techniques to support DCRT activities. It has four
parts: Analyzing Needs, Creating and Evaluating
Products, Developing Resources, and Education. In
FY82 work continued on developing and distributing
products. As the OMB-imposed moratorium on
publications and audiovisuals continues, new
methods are being explored for communication
between DCRT and the various groups that have
needs for information about its work.

Clinical Data Management and Analysis. W.C.
Mohler (OD); B. Cole (DMB); D. Rodbard (NICHD);

J.R. Shapiro (Clinical Center). In spite of the rapid
growth in use of data management and statistical
packages provided for NIH scientists on DCRT
computers, there is a perceived need for facilities
that would be easier to learn and use in NIH clinical
research projects. In FY82 work continued using
BRIGHT, a table-oriented data management/analysis
package on the DECsystem-10, developing added
data analysis and display programs. Two
presentations were made to medical staff fellows
and other scientists with an interest in clinical data
processing. Discussion began to examine the utility
of a seminar series on clinical computer applications.

Multi-function Microprocessor Interface. A.W.
Pratt (OD); D. Songco (CSL). This project, begun in
FY80, seeks to adapt a variety of information
acquisition techniques on a single microcomputer as
a versatile data input/output interface for biomedical
scientists and clinicians. Work in FY82 is discussed
in detail in the Computer Systems Laboratory report.

Medical Linguistics. A.W. Pratt (OD), et al. This is a
long-term project to define a set of semantic and
syntactic forms that can aid in the analysis and
interpretation of written medical statements.

Research Projects

Electronic Typesetting Methods.

Using the WYLBUR system, text is first collected and
stored for publication production. Then, a magnetic
tape of the data is furnished to GPO for direct
typesetting input. Typesetting costs have been
reduced eighty percent.

The technique has been made available to others in
the public affairs community.

Future plans include exploration of interfaces to link
equipment over telecommunications lines without
hand-carrying tape, along with participating in the
development of Gen Code, a proposed ANSI
standard for encoding text for machine processing.

S'S?.J."

Oc tober 1, 1981 through September 30, 1982

Electronic Typesetting Methods

Graphic Syatems Development Divtsioi

PrlntlnB Office

Dethesda, .MP_ 20205

Using the WYLBUR system, text Is fii
production. Then, a magnetic tape i
typesetting input. Typesetting cosl

stored for publlcatioi
lished to GPO for din
:d eighty percent.

: public affairs

DCRT

Ovwon o( Computer Research and Technotogy
Nabond ^isMutes ol HeaWi
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Division of
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Fiscal Year t9a3
Annual Report
Volume 1

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Foreword

ill

The Division of Computer Research and Technology DCRT programs focus on three pnmary activities

has primary responsibility for incorporating the power of conducting research, developing computer systems,
nnodern computers into the biomedical programs and and providing computer facilities

administrative procedures of NIH. DCRT serves as a jhe fiscal year 1983 annual report descnbes our work

scientific and technological resource for other parts of in two volumes:

PHS, and for other Federal organizations with Volume 1 gives an overview of the worV of each

biomedical and statistical computing needs. group, highlighting the year s accomplishments;

Volume 2 gives details atx>ut tf^ protects and
activities of each group

From the Director

During 1 983 the Division of Computer Research and
Technology was again broadly and actively involved in
the conduct and management of science across all of
NIH. The DCRT laboratories and branches are integral
parts of the extensive biomedical computing activities
within the core of NIH scientific excellence. Indeed,
mathematics, statistics, engineenng, and other
elements of computer science are now recognized
throughout the world as essential elements in
biomedical science.

In 1963, when NIH first considered bringing these
disciplines together in a new division, this was a novel
idea. The concept has proved so successful that two
decades later the task now facing us, DCRT and NIH,
is to build upon the high level of technological success
and move to one that can truly be called an Intellectual
Era of biomedical computing.

The Technological Era of computing is still a dominant
force after three decades. Clever digital engineenng
continues to pack more processing power, storage, and
communication capacity into smaller, cheaper, and
eventually more reliable boxes. The plethora of new
hardware is matched by new offerings of software.

However, better computer technology alone is not
enough to create the intellectual linkage between the
power of computing and the substance of modern
science. The committee report in 1963 that led to
formation of DCRT recognized this when it said at the
outset;

The Committee was deeply impressed by the power of
this technology and the promise it holds for contributing
a new level of insight into problems in the life sciences.
It was equally impressed by the magnitude of the
resources... especially intellectual that its large scale
application demands.

Results of great practical benefit m latjoratones. clinics,
and offices across NIH demonstrate the importance of
mathematicians, engineers, and computer experts as
intellectual resources in accomplishing that linkage But
the greatest benefits can occur only when an
equivalent intellectual contribution emerges from the
biomedical scientists in this collat>oration Then the
intellectual union of computing and science can move
forward to advance the underlying theory of biomedical
science and to generate advances m the information
sciences. Progress arises from the engagement of fwst
class minds m a context where the focus on
information processing is fully engaged m the
environment of biomedical research

The challenge to DCRT and NIH m 1983 is still the one
presented in 1963, to amass and focus the best
available intellectual resources on the important and
pervasive opportunities for biomedical computing at
NIH.

Ui^^^d i\

Arnold W. Pratt. M.D.
DCRT Director

•J%c.^,Jf^

Contents

Physical Sciences Laboratory 1

Laboratory of Applied Studies 5

Laboratory of Statistical and

Mathematical Methodology 11

Computer Systems Laboratory 17

Data Management Branch 23

Computer Center Branch 27

Office of the Director 3 3

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Physical Sciences Laboratory

ieorge H. Weiss, Chief

function and Scope of Work

;he Physical Sciences Laboratory works in areas of
hysics, chemistry, and applied mathematics relevant to
/■oblems in the biological sciences and medicine. Its
rogram consists of two parts; internally-generated
jsearch, and consultation and collaboration with other
IIH scientists in its areas of expertise.

SL's program originally involved theoretical analysis
nly; it now includes a considerable experimental
omponent as well. These expenments are in the areas
f crystallography and light scattering and embody
asults originally developed theoretically by members of
ne laboratory.

he PSL staff consists of five professionals and several
isitors who work in the areas of:

1. The structure and elucidation of forces determining
the structure of membranes and other biological
surfaces by a combination of crystallographic and
thermodynamic methods.

2. Light scattering from biologically interesting
systems, and the determination of dynamic properties
of these systems by suitable interpretation of such
experiments.

3. The use of image processing techniques for
interpreting and reconstructing the three-dimensional
structure of cells from multiple electron micrographs.

4. The application of the techniques of applied
mathematics to problems in the physical and
chemical sciences.

Because of the wide range of interests of members of
the laboratory, a number of collaborative efforts, both
with NIH scientists and with others, have been formed.
Some of the data on intermolecular forces are being
generated by scientists at Brock University, Canada.
The electron micrograph images that are the
experimental data for the image reconstruction project,
are generated at the University of Colorado.
Techniques for the analysis and optimization of kinetic
experiments are being developed in response to
problems in nuclear magnetic resonance and positron
emission tomography that have ansen at NIH.

FY83 Accomplishments

This year has seen the methodology used to measure
forces between DNA double helices extended to the
study of the effects of ionic species bound to the
molecular surface. Further results using the technique
developed by PSL members allow measurement of the
pressure needed to pack DNA in a viral head The
experimental results suggest a variety of theoretical
investigations on effects of hydration forces on bilayer
deformation and on models of cell membrane fusion A
significant finding in this project is that the commonly
accepted double-layer theory used to analyze forces m
the immediate vicinity of membranes is badly in error
and must be replaced by a more realistic theory.

Computational techniques have been developed for
random walk models that have long been used in
identifying crystallographic space groups from x-ray
scattering data. Until now use of these models was
restncted to a very small number of space groups, but
the methods developed and still under development will
allow routine use of statistical methods for the most
commonly occurring space groups

A study using light scattering techniques has been
completed on the effects of subunit crosslmking on clot
strength. These techniques are presently being applied
to analyze the shear moduli of polymer gels, relating
them to such system charactenstics as crosslink
density and polymer concentration. This investigation,
when completed, will shed light on how such variables
affect the dissipation of mechanical excitations.
A technique has been developed for the elimination of
phase error in nuclear Overhauser effect
measurements commonly used m nuclear magnetic
resonance. Extensions of this technique will prove to
be useful for the interpretation of kinetic data from two-
dimensional Fourier transform NMR expenments
A computer system has been assembled for three-
dimensional reconstruction of cells from sets of
electron micrographs

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Physical Sciences Laboratory

Beorge H. Weiss, Chief

Punction and Scope of Work

fhe Physical Sciences Laboratory works in areas of

jhysics, chemistry, and applied mathematics relevant to
|)roblems in the biological sciences and medicine. Its
)rogram consists of two parts: internally-generated
esearch, and consultation and collaboration with other
>JIH scientists in its areas of expertise.

'SL's program originally involved theoretical analysis
jnly; it now includes a considerable expenmental
component as well. These experiments are in the areas
3f crystallography and light scattering and embody
esults originally developed theoretically by members of
:he laboratory.

The PSL staff consists of five professionals and several
>/isitors who work in the areas of:

1 . The structure and elucidation of forces determining
the structure of membranes and other biological
surfaces by a combination of crystallographic and
thermodynamic methods.

2. Light scattenng from biologically interesting
systems, and the determination of dynamic properties
of these systems by suitable interpretation of such
experiments.

3. The use of image processing techniques for
interpreting and reconstructing the three-dimensional
structure of cells from multiple electron micrographs.

4. The application of the techniques of applied
mathematics to problems in the physical and
chemical sciences.

FY83 Accomplishments

This year has seen the methodology used to measure
forces between DNA double helices extended to the
study of the effects of ionic species bound to the
molecular surface. Further results using the technique
developed by PSL members allow measurement of the
pressure needed to pack DNA in a viral head The
experimental results suggest a variety of theoretical
investigations on effects of hydration forces on bilayer
deformation and on models of cell membrane fusion A
significant finding in this project is that the commonly
accepted double-layer theory used to analyze forces m
the immediate vicinity of membranes is badly m error
and must be replaced by a more realistic theory

Computational techniques have been developed for
random walk models that have long been used in
identifying crystallographic space groups from x-ray
scattering data. Until now use of these models was
restricted to a very small number of space groups, but
the methods developed and still under development will
allow routine use of statistical methods for the most
commonly occurring space groups.

A study using light scattenng techniques has been
completed on the effects of subunit crosslmking on clot
strength. These techniques are presently being applied
to analyze the shear moduli of polymer gels, relating
them to such system charactenstics as crosslink
density and polymer concentration. This investigation,
when completed, will shed light on how such vanables
affect the dissipation of mechanical excitations
A technique has been developed for the elimination of
phase error in nuclear Overhauser effect
measurements commonly used in nuclear magnetic
resonance. Extensions of this technique will prove to
be useful for the interpretation of kinetic data from two-
dimensional Founer transform NMR expenments.
A computer system has been assembled for three-
dimensional reconstruction of cells from sets of
electron micrographs.

Future Plans/Trends

Experimental work will continue on the use of combined
thermodynamic and crystallographic methods for the
measurement of intermolecular forces, particularly
focused on the control and characterization of phase
transitions in membranes and helical molecules. In
conjunction with this, a systematic theoretical
examination of several models of membrane fusion will
be undertaken, taking into account the forces that have
been identified in PSL measurements.

A molecular modeling study of the structure of sugars
and polysaccharides will be begun. The structure of
these molecules is not completely characterized
because they are not crystallized readily. The study will
make heavy use of the molecular graphics facility
together with energy minimization and molecular
simulations.

Work, both experimental and theoretical, will continue
on the physical properties of biological polymer gels.
Mathematical theories are to be developed relating to
gelatin kinetics, to the coalescence of fibrils to form
fiber bundles, and to the mechanical dissipation
properties of idealized fibrin and actin lattices. In
addition, theoretical studies will be initiated on the
factors affecting the percolation of macromolecules
through polymer networks.

In a collaborative project with NIADDK, LCP, PSL
scientists have measured the forces between DNA
molecules in aqueous solutions. This graph shows
that the dominant contribution to the
intermolecular force is the work of removal of
water from the vicinity of the molecular surface.
This observation is contrary to all previous
expectations of polyelectrolyte interactions.

An investigation into practical computational techniques
for detailing properties of random walks used in
crystallography will be continued. Considerable success
has been achieved in these calculations so far for a
small number of space-group related random walks.
Future study will be devoted to enlarging the catalog of
results available to crystallographers.

A method for the three-dimensional reconstruction of
cellular structure is being developed using electron
micrographs. Software is being written for rotation of
the resulting images. Further study will be devoted to
estimation of the space available for diffusion in the
cytoplasmic matrix.

Dr. Adrian Parsegian has been installed as President of
the Biophysical Society. Dr. James A. Ferretti has taken
a position as section chief in NHLBI.

Divalent Cation Solutions

8 r

6 -

OD A

* Putrescine 10 mM

° 0 i

□ MgCI, 25 mM

0 CaCI, 25 mM

Interaxial Spacing (l)

Publications and Presentations

Aizenbud. B. and Gershon. N 0 Dillusion ol molecules on biological meni'
branes ol nonpianar lorm-a theoretical study Biophys J 38 287293,
1982

Aizenbud. B. and Gershon. N D Dillusion ol molecules on microvillous bio-
logical membranes In Perelson. A C . DeLisi. C . and Wiegel. F W (Eds )
Cell Surface Phenomena New York. Marcel Dekker (in press)

Aizenbud. 6 . and Gershon. N D Hydrodynamic equations and VH light scat-
tering Irom viscoelastic (solid-liKe) systems II Molecular approach PhysKa
A 108A 583-588. 1981

Balaban. R S . and Ferretti. J A Rales ol enzyme-catalyzed exchange deter-
mined by two-dimensional NMR A study ol glucose 6-phosphate anomeri-
zation and isomerizalion Proc Nail Acad So USA 80 1241-1245. 1983

Gershon. N . Porter, K . and Trus. B Microtrabecular lattice and the cyloskele-
Ion Their volume, surface area and the dillusion ol molecules through it
Biological Structures and Coupled Flows Proc ol Aharon KalirKalchalsky
Memorial Symposium Israel. 1982. pp 377-380

Gladner, J A. and Nossal. R Edects ol crosslinking on the ngidity and
proteolytic susceptibility of human fibrin clots. Thrombosis Res 30 273-278.
1983

Griffith. J P . Lee. B K . Murdock. A L . and Amelunxen. R E Molecular
symmetry of glyceraldehyde-3-phosphale dehydrogenase from bacillus
coagulans J Molecular Biology (m press)

Gruen. D W R. Marcelja. S. and Parsegian, V A Water structure near the
membrane surface In Perelson, A (Ed ) Membrane Surfaces New York,
Marcel Dekker. Inc (in press)

Jacobson. L The determination ol a phosphorus-phosphorus nuclear Over-
hauser enhancement by two-dimensional magnetization exchange spec-
troscopy J Megn Reson 49: 522. 1982

Kiefer. J E . and Weiss. G H : The Pearson random walk AlP Proceedings (m
press)

Lee. B Calculation of volume llucluation for globular protein models Proc
Nail Acad Sci USA 80 622-626, 1983

Lee. B Partial molar volume from the hard-sphere mixture model J Phys
Chem 87 112-118. 1983

Loosley-Millman. M E . Rand. R P . and Parsegian. V A Effects of monova-
lent ion binding and screening on measured electrostatic forces between
charged phospholipid bilayers Biophys J 40 221-232. 1982

Monks, T J , Pohl, L R . Gillette. J R . Hong. M . Highel, R J , Ferretti, J A .
and Hinson. J A Stereoselective formation ol bromobenzene glutathione
conjugates Chem Biol Inleraclions i^ 203-216, 1982

Nossal, R Stochastic aspects ol biological locomotion J Slat Phys 30 391-
400, 1983

Nossal, R , and Jolly. M Shear waves and internal viscosity in cylindrical gels
J AppI Phys 53 5518-5525. 1982

Nossal. R . Weiss. G H , Nandi, P K , Lippoldt, R E , and Edelhoch, H Sizes
and mass distribution ol clathnn coaled vesicles Irom bovine brain Arch
Biochem Biophys (in press)

Parsegian. V A Dimensions of the intermediate phase ol dipalmiloylphospha-
tidylcholme Biophys J (in press)

Parsegian. v A Membrane inleraclion and dafonnation Armalt N Y Acml

Set (in press)
Parsegian. v A , and Rand. R P Membrane ttaniport and Itt* activily o) miaWr

near the membrane surface Ptryncal Mamodt n m» StuOy ot C^Um

Biophysics (in p<ess)
Parsegian. V A . Rand. R P . and GmgaN. 0 LMtont lor tnt tludy ol

membrane fusion from membrarw interacMxo m phoip>x)H)id tytlemt

Ctba Found Symp (in press)
Rubin. R J . and Wetss, G H Limitir>g iNckneu ol an adiortMd pdymw

chain J Crtem Phys 78 2039-2043. 1963
Sterner, C A Litl. M , and Nossal. R Apptcabont ol dynamc hght tcatlanng

to studies of mucin structure Proceedings ol 1983 Synvo$Ktm on N0m

Techrvques in Biorheotogy (in pceM)
Steiner. C A . Lift. M . and Nossal. R Effects ol c«lcum ion on the ttrucli«« ol

canine tracheal mucin Biorheology (in press)
Stone. M , Sonies, 8 C Shawker, T H , Weiss, G H , and NaiM. L Analyvs

ot realtime ultrasound images of tongue contiguralion usirtg ■ gndK*g«x-

ing system J Phonetics (in press)
Weiss. G H Chromatographic kinetics artd the phanomerxwi ol IMkng Stp

Sci S Tech 17 1609-1622. 1982
Weiss. G H Random walks Encycl Stat Sa (in press)
Weiss. G H Random walks and their appl«ations Am So 71 6S-7I. ^9t3
Weiss, G H , Caveness, W F , Einsiedel-Lechlape, H , and McN««l. M L Uta

expectancy and causes ol death m a group ol head in|ur«d veterans ol

World War I Arch Neurol 39 741-743, 1982
Weiss, G H , Feeney. D M . Caveness, W F . Dillon, D , Kistler. J P . Mohi. J

P . and Rish. B L Prognostic factors for tt>e occurrertce ol posltrawnanc

epilepsy Arch Neurol 40 7- 10, 1983
Weiss. G H , Ferrelti, J A Kieler J E . and Jacobson. L A meffwd tor

eliminating errors due to phase imperfection m NOE maasuremants J

Mag Res (in press)
Weiss. G H . and Kiefer. J E The Pearson random waNi with unequal slap

sizes J Phys A16 489-495. 1983
Weiss. G H , and Rice, J A A combinatonal problem in pharmacotogy J

Math Biol 14 195-201, 1982
Weiss. G H . and Rice. J Optimal parameters lor the measurement ol the hall-

wtdlh of a Gaussian peak Sep Sa S Tech 17 tlOI-tflS. 1982
Weiss. G M . and Rubin. R J (Eds ) Proceedings of ttw Symposium on

Random Walks J Slat Phys 30 249-561. 1983
Weiss. G H . and Rubin, R J Random walks tl>eory and seiacted appkca-

tions Adv Chem Phys 52 363-505, 1983
Weiss, G H , Shuler, K E , and Lindenberg, K Oder statistics lor hrst passaga

times in diffusion processes J Stat Phys 31 255-278, 1983
Weiss, G H , and Szabo, A First passage problems for a class ol rnatlar

equations with separable kernels Physics (m press)
Weiss, G l-l , Talbert, A , and Brooks, R A The use ol phantom vwws to

reduce CT streaks due lo insufficient angular sampling Phys m Biol tnd

Med 27 1151-1162. 1982

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Laboratory of Applied Studies

John E. Fletcher, Ph.D., Acting Chief

Functions

The Laboratory of Applied Studies (LAS) has three
main purposes:

1. in collaboration with biomedical scientists, to apply
. mathematical theory and computing science to the
[ development, testing, and improvement of
I mathematical models of physiological processes--
I particularly reaction-diffusion kinetics, transport and
I exchange of substrates in tissues, and the
I descnption of metabolism within cells and organs;
I 2. in collaboration with clinicians, to develop and
apply mathematical or statistical theories and special-
purpose computing procedures (analog or digital as
required) to facilitate research projects aimed at
improving diagnosis of disease, assessment of
treatment, and understanding of basic physiological
and pathophysiological processes;
3. to engage in applied research in mathematics,
statistics, and computer science as necessary to
provide a sound theoretical basis for collaborative
studies, and to insure that state-of-the-art
mathematical and computational methods are
available as research tools at NIH.

Two sections carry out these primary LAS functions:
Applied Mathematics Section -AMS"(John E.
Fletcher, Ph.D., Chief). This staff of five includes
specialists in applied mathematics, computer science,
biomathematics, and biomedical engineering.
Medical Applications Section -MAS -(James J.
Bailey, M.D., Chief). This five-member staff includes
physician-scientists, electronic engineers, and
computer systems analysts.

Dr. Harris, former Chief, LAS is a biostatistician with
training in public health and the basic medical sciences.
He retired in early FY83 and continues in LAS as a
part-time guest worker.

Scope of Work

The Laboratory of Applied Studies works on projects in
basic and clinical biomedical science. Largely, these
involve collaboration with other groups at NIH,
elsewhere in the U.S.A., and abroad. The collaborating
investigators this year included:

• clinicians in the Cardiology, Clinical Hematology, and
Pulmonary Branches of NHLBI; in the Arlhntis and
Rheumatism Branch of NIADDK; and in the Cntical
Care Medicine and the Nuclear Medicine
Departments of the Clinical Center

• physiologists and biomedical engineers at the
Louisiana Technical University and elsewhere in the
U.S.A. and Europe studying the transport of
substrates within the microcirculation and the
autoregulation of tissue perfusion

• biochemists and physicians at NIH, and at
universities in the U.S.A. and in France working on
models for receptors of drugs or other ligands. on the
kinetics of enzymes in membranes, and on other
problems in tissue metabolism

• electrocardiologists and biomedical engineers in the
U.S.A.. Canada, and Europe concerned with
improved algonthms for computer-based
interpretation of ECG's and evaluation of ECG
interpretative programs

• clinical chemists and pathologists at NIH (Clinical
Pathology Department, Clinical Center) and
elsewhere in the U.S.A., in Europe, and in Japan
engaged in the collection and study of reference
values in laboratory medicine

Highlights of the Year's Activities

Although FY83 was a transition year with retirement of
some senior staff and departure of a visiting scientist, a
number of collaborative projects made substantial
progress.

In collaboration with NHLBI, a minicomputer-based
laboratory system for studying delivery of oxygen to
tissues dunng exercise through breath-by-breath
analysis of pulmonary gas exchange has undergone
extensive development in FY82-83. The equipment
interfaces, designed and fabncated by Dr. E Pottala m
FY82, are now controlled by software interfaces linked
to the main laboratory control programs

Automatic operation of the entire system, including
acquisition and analysis of ventilatory flow and gas
concentrations, as well as control of the bicycle and
treadmill, is now possible Before this report is issued.

M. Morton expects to complete the systems
programming that will allow automatic computation of
noninvasive indices of patient functional status.

Serial measurements obtained in this exercise testing
laboratory provide an objective indication of severity of
disease and efficacy of treatment in patients with lung
and blood disorders. Dr. R. Burgess, in collaboration
with the Clinical Hematology Branch, NHLBI, is carrying
out a study of drug therapy in patients with sickle cell
disease.

In a joint project with the Nuclear Medicine Department,
LAS has extensively analyzed the relationship of
signal/noise ratios to harmonic content of regional
time-activity curves in radionuclide ventriculography.
Smaller regions were shown to have lower signal/noise
ratios and a shift of harmonic content to higher
frequencies, reflecting the effect of poorer counting
statistics.

Theoretical work by Dr. M. Bieterman on the adaptive
finite element (FEM0L1) methods for the solution of
reaction-diffusion equations was essentially completed
in FY83, These routines are now available on the NIH
central computer systems. In addition, the IMSL
routines known as TWODEPEP, finite element
programs of a general type, have been implemented on
the IBM System 370.

These programs are being work-tested on models of
bioheat transfer in hyperthermia being studied by BEIB
in collaboration with the Radiation Oncology Branch,
CC, and on linear and nonlinear (Michaelis-Menten)
metabolic models for tissue substrate diffusion and
consumption.

B. Bunow and E. Pottala have studied network
modeling languages and have demonstrated that
network models are useful for biological simulation.
Implementation of network modeling software on
dedicated scientific computer systems such as the VAX
1 1/750-780 has made network modeling more
available to investigators on the NIH campus and has
established their utility on dedicated scientific
computers. Some functional errors in the larger NET2
system were discovered in FY83.

The further use of this particular system on the IBM J
System 370 computer will depend upon correction of ^
these errors by the package's developers. Presently,
interested NIH scientists are being instructed in
network methods, and exploratory applications are
underway in collaboration with NIH researchers on
problems of nerve conduction and of facilitated
diffusion in tissues.

A considerable advantage of these modeling systems is
that a functional rather than a mathematical description
of the biological process suffices as a requirement to
initiate study of its stimulus-response characteristics.

In FY82 a collaboration was initiated with FDA
physiologists to use rodent ECG's as a means of
testing for cardiotoxicity of drugs and fad diets (e.g.,
liquid protein). The frequency content of rodent ECG's
has required redesign of instrumentation and
development of wholly new ECG analysis software.

The rodent heart rate of 400-600 beats per minute
produces ECG's with a much higher frequency content
than that found in human ECG's. These signal analysis
problems were largely resolved in FY83 and currently
the ECG analysis of 38 animals before and during
various levels of drug treatment is proceeding.

The LAS DeAnza image processing system has been
upgraded from resolution of 256 x 256 pixels to 512 x
480 pixels. This upgrade will permit greater resolution
and the development of more sophisticated algorithms
for edge detection, image enhancement, and image
manipulation.

During FY83 LAS staff members participated in various
teaching and consulting, or advisory, activities.

J. Fletcher continued to serve as Chairman of the
Mathematics and Computer Science Departments of
the Foundation for Advanced Education in the
Sciences. He is currently serving on a Planning
Committee for the Director, DCRT; on a DRR ad hoc
committee to design a workscope for the NAS
Modeling Workshops; and as the DCRT representative
to the NIH Advisory Committee for Computer Usage.

J. Bailey continued as a member of an NHLBI site-
visiting team concerned with computer analysis of

exercise ECG's. He also served as a consultant on
Common Standards for Quantitative
Electrocardiography, a program in medicine and public
health, sponsored by the European Economic
Community.

Since his retirement from LAS, former Chief E. Harris
has continued to be a consultant in applied statistics to
the Food and Drug Administrations Division of Medical
Devices and Diagnostic Products. Dr. Harris also serves
as consultant statistician to the College of American
Pathologists, to the International Federation of Clinical
Chemistry (Expert Panel on the Theory of Reference
Values), and is a member of the Board of Editors of
Clinical Chemistry.

Future Plans

The minicomputer system for analyzing pulmonary gas
exchange in exercise will be tested on healthy
volunteer subjects and on selected patient groups
Studies to evaluate cardiorespiratory abilities in patients
and controls will be specified with protocols m
cooperation with the Clinical Hematology and
Pulmonary Branches of NHLBI.

The analysis of the signal/noise charactenstics of
various parameters of regional ventricular wall motion
will continue lointly with the Nuclear Medicine
Department, CC, and the Cardiology Branch, NHLBI, in
an effort to refine noninvasive, differential diagnosis of
coronary artery disease and cardiomyopathies.

40 ao uo

40 to 120

40 10 110

40 to 1M

40 to 120

Adaptive finite element methods are useful for
solving reaction-diffusion equations. Here, the
techniques solve a nerve impulse propagation
problem.

A new project in cooperation with the Department of
Critical Care Medicine, CC, to investigate dysfunction in
neurologically impaired patients will move forward to
integration and implementation of microcomputer-based
methods for analysis and display of evoked potentials
This project was suspended in late FY83 because of
procurement delays in hardware acquisition and by
problems with the NHLBI equipment.

A major effort will continue the development of a
language that will facilitate the conversion of network
models simulating biological processes into forms
compatible with languages such as MLAB, which will
permit access to powerful data-fitting algorithms.

A scientific collaboration with the Yale University
Computer Center is expected to result in new and
improved numehcal software for both the solution of
linear equations and for systems of differential
equations. The possibility of the incorporation of these
routines into the MLAB modeling package will be
explored.

The rodent ECG project is expected to extend to
analyzing sequential changes in mice infected with pure
strains of Trypanosoma Cruzi (Chagas' disease). This
extension of the rodent ECG project will be in
collaboration with investigators from the World Health
Organization and the Laboratory of Parasitic Disease
NIAID.

Utilizing the newly upgraded DeAnza image processing
system, a joint study with the Clinical
Neuropharmacology Laboratory, NIMH, will continue to
develop theory and methods for interpreting electron
energy loss spectra in intracellular organelles,
particularly in the examination of dense bodies in
electron micrographs of blood platelets.

Publications and Presentations

Albert. A Discnmjnani analysis based on mullivanale response curves: a de-
scriptive approach lo dynamic allocation Slalislics m Medicine 2 95-106
1983

Albert. A . Chapelle. JP. Heusghem. C . Kulbertus, HE. and Harns. E K
Evalualion o( risk using serial laboratory data m acute myocardial mlarclion
In Heusghem. C . Albert. A . and Benson. E S (Eds ) Advanced Inlerprela-
lion ot Clinical Laboratory Data New York. Marcel Dekker, 1982. pp 117-

Albert, A., and Rultimann, U : Prediction of an ordered categorical response

variable from serial measurement. Biometrics (in press)
Bacharach, S.L.. Green. M.V.. Vitale. D., Douglas. MA., White. G.. Bonow. R.O
and Jones. A.E.: A minimum error method for temporal fourier filtering o(
gated cardiac data information processing. Eighth IPMI Conference on
Medical Imaging (in press).
Bacharach, S.L., Green, M.V., Vilale, D„ White. G., Douglas, UA.. Bonow HO
and Jones, A.E.: Optimum number of harmonics for filtenng cardiac volume
curves. Journal ol Nuclear Medicine 24:5. 1983,
Bailey, J.J.. Berson. AS., Jackson, U.K., Stevens. J.M., Tolan, G D and Wolf
H.K.: Evaluation methodologies for ECG diagnostic systems. In Bonner'
R.E., Pryor, T.A.. Laks. MM., and Cole. S.S. (Eds.): Computenzed Interpre-
tation of the Electrocardiogram VI New York. Engineenng Foundation
1981. pp. 53-62.
Bieterman, M.: An adaptive method for reaction-diffusion equations in one

dimension. SI AM National Meeting. Denver, Colorado June 1983
Bieterman. M.: A Posterion error estimation and adaptive finite element gnds for
parabolic equations. Army Research Office Workshop on Adaptive Meth-
ods for Partial Differential Equations. College Park. Maryland February
1983 (in press).
Bieterman. M.: On using local solution information ,n a mesh modification
strategy for time-dependent equations. NASA-ICASE Workshop on Grid
Methods. Hampton, Virginia, September 1983.
Bieterman. M,. and Babuska. I.: The finite element method for parabolic equa-
tions, I. A posteriori error estimation. Numerische Mathemalik 40-339-371
1982.
Bieterman, M., and Babuska, I.: The finite element method for parabolic equa-
tions, II. A posteriori error estimation and adaptive approach. Numensche
Malhematik 40:373-406. 1982.
Bunow, B.: All things flow and change. Proc Wash. Acad Sci 7243-60 1982
Bunow. B.: Cellular Enzymology: The steady-state kinetics of compartmental-
ized enzymes. Journal of Theoretical Biology 8A:6: 1-627. 1980
Bunow. B.: Turing and the physico-chemical basts of biological patterns In

Prewitt, J. (Ed): IEEE Turing Memorial (in press)
Bunow. B.. and Mikulecky, DC: On the feasibility of using flux measurements
to distinguish among active transport models. Polish Winter Sc/iool of
Membrane Transport (in press),
de Graaf. C.N.. Douglas. MA.. Findley. S.M.. van Rijk. P.P.. Bacharach S L
Green. M.V.. and Bonow. R 0. Een algoritme voor het localiseren vari
siructuren in scintigrafische beelden Nucleair Geneeskundig Bulletin 4:42-

Douglas. M.A.. Bailey. J.J.. van Ri,k. P.P.. Bacharach. S.L . Bonow. R O . and
Green. M.V : Analysis of regional function in radionuclide ventriculography
Physiological signal, scintillation noise, and regional size Computers in
Cardiology IEEE Computer Society. Silver Spnng. MD. 1983 pp 315-318
Ferenci. P , Covell. D . Schafer. D.F , Waggoner. J.G.. Shrager. R . Berman M
and Jones. A E Metabolism o( the inhibitory neurotransmitter-ammobutyric
acid in a rabbit model of fulminant hepatic failure Hepatology (in press)
Fletcher. J E . and Schubert, R W.: Capillary wall permeability effects ,n capil-
lary-lissue structures Proceedings of 1 983 ISOTT conference HKi%\on LA
1983 (in press)
Fletcher. J E . and Schubert, R W Diffusional coupling m a hemoglob.n-free
perfused capillary-tissue structure Proceedings of the 1982 ISOTT moot-
ing Dortmond, Germany, July 1982 (in press)
Fletcher. J E . and Schubert. R w On the computation of substrate levels m

perfused tissues Mathematical Biosciences 62 7^-^06 1982
Fletcher. J E . and Schubert. H w The theoretical prediction of substrate levels
and their histograms in cell free perfused tissues Proceedings of the
International Meeting of the Society of Oxygen Transport to Tissue -IV (in
prossi

Hams, E K : Addendum to recent paper on reference values (or change
Clinical Chemistry (in press)

Hams. E.K : Regression, least squares, and correlation In Seligson. D . M 0
(Ed): Handbook ol Clinical Chemistry (in press)

Harris, E K The effects of reductions in analytic variance on the early detec-
tion of trends Proceedings ol the IV International Meeting on Clinical
Laboratory Organization and Management Uppsala, Sweden, June 29July
1, 1983 (in press)

Harris, E K , and Yasaka, T.: On the calculation of a reference change' for
comparing two consecutive measurements. Clinical Chemistry 29 25-30,
1983

Horlon, f^ H : Computing on a shoestring; Naive users, sen/ice organizations,
and computers Chi '83 Conference on Human Factors in Computing Sys-
tems, Boston, Mass , 1983

Kernevez, J P , and Bunov* B Numerical exploration of bifurcating branches of
solutions to reaction-diffusion equations describing the kinetics of immobi-
lized enzymes In Absi, E , Giowinski, R , Lascaux, P , and Veysseyre, H
(Eds): Numerical Methods lor Engineering Pans, Dunod, 1980, pp 65-79

Kernevez, J P , Joiy, G , Cuban, M C , Bunov*, B , and Thomas, D Self organi-
zation in enzyme systems Ina Novosibirsk Colloquium 1978 Novosibirsk,
Nauka. 1982, pp 257-271

IWacfarlane, P W , Chen, C Y , and Bailey, J J A comparison of point sconng
techniques for the diagnosis of LVH In de Padua, F , and Macfarlane,
PW,, (Eds); New Frontiers in Electrocardiology Wiley. 1981, pp 353-356

LAS scientists and FDA physiologists are
collaborating in a study of cardiotoxicity in rats,
produced by drugs, food additives, or fad diets.
This is a typical electrocardiogram taken from that
study. The very high quality of this tracing is made
possible by computer processing to extract a
typical complex from the average of many cardiac
cycles, thereby suppressing random muscle noise.
This high quality is necessary in order to detect the
earliest changes of cardiotoxicity.

Schubert. R W . Fletcher, J E , and Reneau, 0 0 An analytical nvxJ* for amal
diffusion in the Krogh cylin<J«r Proc»»<tngs ol Iht 1983 ISOTT comm-
ence Ruston, (JV, August 1983 (in press)

Schubert, R W , Fletcher. J E , and Reneau, 0 D A stmpMiMl mo<J»l lor p»»*c1-
ing myocardial P02 histograms Prtjc»edmgs ol Itte Frsl Southtm BmnaO-
ical Engineenng Conlerence LSUME, June 1982 (m prMt)

Setty, O H . Hendler, R W , and Shrager, R I Swnoltan^out nmtatMtnm* ol
PiyiF, delta pH, delta psi, an<j H/O ratios m tniaci E Coti Bnpltr* J ("
press)

Shrager, R I Analysis of optical spectra by SVO SIAM 1963 Nabooal MaMng.
June 6, 1983 (in press)

Shrager, R I Some piUalls m the use of denvatrve spectra PHtMchmm^y mi
PhototHOlogy (in press)

Shrager, R I SVO as a descnplioo ot chermcal uuation SIAM 30th ArvvvarMiy
Meeting, Stanford Unrversity, California, July 19, 1982

van Ri|k, P P , Bailey, J J . and de Graaf, C N GecompulenseenJe meltxxJeri
voor de detectie van regionale ventnculaire contrscueabrxxinalrtertwi Nu-
cleair Geneeskundig Bulletin 4 49-54, 1982

Winslow, R M , Samaia. M . Winslow, N J , Rossi-Bwnard", L , and Shrager, R I
Simulation of continuous blood 02' equUibrum curves over pTiysiologcal
pH, DPG, and PC02 range Journal ol AppHed PItysiology 54(2) &24-S20,
1983

iWATMEMATICALAWALYSISBIOLOGICALPHEMQMg
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Laboratory of Statistical and
Mathematical Methodology

James E. Mosimann, Chief

Function and Scope of Work

The Laboratory of Statistical and Mathematical
y^ethodology (LSM) combines research in mathematical
itatistics, mathematics, and computer and information
"science with collaboration and service in these areas to
^IH researchers and administrators. LSM staff interact
with all NIH Institutes, with other Federal agencies
outside HHS, and with biomedical researchers
worldwide.

In addition to the position of chief, the laboratory has
jsixteen full-time professional positions distributed
.among four sections;

' The Statistical Software Section (SSS) provides
I consultation to and collaboration with NIH

researchers and administrators in all computational
aspects of biomedical data analysis, including
! selection and support of large systems/packages.
Four specialists in scientific programming are led by
a computer systems analyst whose specialty is
statistics.

The Statistical Methodology Section (SMS) works
closely with the Statistical Software Section. Three
professionals in mathematical statistics provide
biostatistical consultation and do independent
research.

The Blomathematics and Computer Science
Section (BCS), directed by a mathematician,
performs independent research and provides
consultation and collaboration in the specialties of its
five computer and mathematical scientists.
The IMedical Information Science Section (MIS)
investigates and develops methods for application of
information and computer science to medical
language data processing. Two computer specialists
work under the direction of a computer systems
analyst who is an expert in computational linguistics.

A major part of LSM activity is the offering of statistical
and mathematical systems/packages to the NIH user
community. LSM accepts responsibility for evaluation of
new systems/packages and their suitability for NIH.
When it offers a system/package to the NIH
community, LSM makes three basic commitments:

1 . Maintenance of the package, with adequate
documentation, through NIH computer system
changes, system/package updates, and corrections

2. Rapid response to queries concerning user access
to a system/package program, including job control
language and program parameters.

3 Assistance in interpretation of results

As a result of LSM's policy of not only supporting the
use of these systems/packages but also aiding m the
interpretation of their output, the statisticians of the
Statistical Methodology Section provide consultation
over a wide range of scientific fields Some very brief
consultations are very successful because there is a
known answer to the question at hand Other
consultations involve extensive time and statistical/
mathematical/computer science research as well

Research projects in LSM vary widely, from studies of
natural language processing for medical information
systems and studies of efficient algonthms for
information retrieval to studies in mathematics and
statistical methodologies for biomedical applications.

FY83 Accomplishments

FY83 was LSM's ninth year as a separate entity withm
DCRT. The volume of its computational and
consultative sen/ices continued to expand; its research
activities decreased slightly, with one project
terminated

Computation

During this year, the Statistical Software Section of
LSM maintained the following systems/packages and
programs on the IBM System 370 of the DCRT
Computer Center:
. BMD and BMDP. Biomedical Computer Programs.

UCLA.
. SPSS. SPSS-X. and SCSS, Statistical Package for

the Social Sciences. SPSS, Inc.
. SAS, SAS/GRAPH. and SAS/ETS, Statistical

Analysis System, SAS Institute. Inc.

• P-STAT Statistical Package. P-STAT. Inc

• IMSL. International Mathematical and Statistical
Libranes. IMSL. Inc

• MSTAT1, Collection of Mathematical and Statistical
Programs, DCRT.

In FY83 the SSS staff responded to over 7,500 queries
concerning use of these packages. Also during this
year, BMDP and IMSL went through a major update.
NIH served as a test site for both SAS82 and SPSS-X.
Both systems will become production systems during
the next fiscal year.

STATISTICAL ANALYSIS SYSTEM

STf?flIN=B DRUO=B

LEGEND: DOSE

■o— o— o 10

SAS(Statistical Analysis System), which can be
used to draw graphs lil<e this one, is one of many
software systems/packages supported by LSM.

LSM stresses the importance of teaching the effective
use of systems/packages to the biomedical scientists
and other users of DCRT.

In FY83, LSM continued to expand teaching and
documentation for supported systems/packages LStVl
taught eight introductory courses for SAS, two for
SPSS, and two for BIVIDP. In addition, two introductory
courses and one advanced course were taught for
MLAB, plus four introductory courses on computer
graphics at NIH. The second edition of the Beginner's
Guide to MLAB is being printed now. and will be
distributed before the end of FY83.

ECS staff augmented I^LAB in FY83 by adding several
mathematical operators and by adding facilities to
permit numencal derivatives to be used for curve-fitting
of large models. Also, color graphics and scientific text
display were enhanced.

A separate program (GRAPH 1) for easy generation of
graphs was developed by SMS staff and is now being
used by the NIH community. With only a small amount
of user preparation, publication-quality graphs can be
generated.

Consultation, Collaboration, and Research

LSM consultation and research in FY83 was closely
tied to the use of the computer. Most consultations (55
percent) involved statistical advice combined with
considerable computer use. Others (40 percent)
involved computer use alone and a small fraction (5
percent) involved mathematical or statistical advice with
only limited computer use. The percentages are
unchanged from FY82.

In FY83, LSM research, collaborative, and consultative
efforts were expressed in a number of studies.
Statistical methodologies were developed for, or
modified to suit, specific biomedical problems.

A study reported in FY82 was the subject of a
publication. Statistical and Algebraic Independence,' m
the Annals of Statistics in March 1983. This study
contributes to a knowledge of properties of the sample
covariance matrix, which is the basis for statistical
discriminant analysis. Studies of discriminant methods
continued in collaboration with Dr. J. Darroch, Flinders

University. South Australia, and Dr H Hoffman. DRS.
including discriminant analyses of morphological
vanation in inbred strains of laboratory mice witti
reference to purity of breeding slocks Collaborative
work continued with Dr P Turkeltaub (BB/DPB) on
clinical symptoms and allergic reaction to pollen LSM
participation in a study of Chagas disease (Dr F Neva.
NIAID/LPD) was concluded when the edited tapes of
data were prepared for the investigator

Collaborative work in various studies of schistosomiasis
(with Dr. A. Cheever, NIAID. LPD) continued One
portion of this research precipitated the development of
a new statistical methodology that gives an exact
treatment for a multivariate analysis of variance with
unbalanced data This analysis may be applied both to
experiments with repealed measurements and to
growth curve analyses A paper on these results, which
includes multivanate as well as nonparametnc
treatment of these designs, has been submitted to a
statistical journal.

A study of nonparametnc multiple comparisons was
initiated in FY83. with particular attention being given to
theoretical as well as to computer-simulated behavior
of vanous procedures. The optimal selection of a
sequence of items based on relative ranks with ties has
been investigated, as well as an evaluation of tests for
correlated proportions with incomplete data.

A collaborative study of the spatial distribution of blue
cones in the retina with Dr S. Schein (NEI/CB) and F.
de Monasterio (NEI/LVR) was completed It was
possible to eliminate possible models on the basis of
the several statistical techniques developed Also,
studies of size and shape' vanables were continued.
These studies provide methods for studying random
proportions or ratios of common occurrence in
biomedical data.

In computer science, work continued using PROLOG
(the logical procedure language selected by the
Japanese as the basis for their fifth-generation
computer project), used here to formulate problems of
medical linguistics. A program was developed to
partially translate scientific text from an NIH input
format to the input format used by the TeX manuscnpt
13

generation system at Stanford. Studies continued in
data storage and retrieval and on mathematical
questions concerning vector spaces.

In FY83 research in medical linguistics was continued
on compositional morphosemantic analysis of medical
terms derived from Greek and Latin. A methodology
was developed for automated morphosemantic
segmentation and semantic interpretation (paraphrasing
rules) of medical compound words derived from Greek
and Latin that denote surgical procedures. This
methodology can be used with terms in the Systematic
Nomenclature of Pathology (SNOP). The establishment
of morphosemantic distribution patterns of medical
compound words and the subsequent determination of
semantic relations among them are crucially important
for automated semantic interpretation of such words.

MIS also continued its collaboration with the Laboratory
of Pathology, NCI and with the Clinical Support Section
of the Data Management Branch, DCRT to maintain
and improve the data base of Clinical Center surgical
pathology reports. The automatic encoding system
provided by MIS computed representations of the
summary diagnoses of the surgical pathology report as
written by the pathologist, in a language based on the
SNOP vocabulary. Collaboration continued with Dr.
Donald E. Henson, NCI, concerning changes in the
SNOP dictionary.

LSM collaborative research on computer analysis of
two-dimensional gel electrophoresis was discontinued
due to the departure of the principal investigator.
Results and computer programs were made available
to NIH collaborative researchers.

LSM computer scientist Dr. Gary D. Knott received the
Public Health Service Commedation Medal in June. The
award was made for his continuing leadership and
innovation in the development of MLAB, now used
worldwide to advance science through biomathematical
modeling and computer graphics.

Future Plans/Trends

No major shift in laboratory service or research is
anticipated in the coming year. Current levels of

statistical and mathematical systems/packages
support, consultation, and user assistance will be
maintained. Research projects will be continuations of
those already initiated and reported here.

Publications

Campbell, G,: Asymptotic Properties of Several Nonparamelric Multivariate Dis-
tribution Function Estimators Under Random Censonng. Survival Analysis
In Crowley, J,, and Johnson. R, A. (Eds): Institute of Mathematical Statis-
tics Lecture Notes: Monograph Senes. Haywood. Calilornia. 1982. pp. 243-
256.

Campbell, G.: Optimal Selection Based on Relative Ranks of a Sequence with
Ties. Advances in Applied Probability (in press).

Campbell, G., and Foldes, A.: Large-Sample Properties of Nonparamelric Bivar-
late Estimators with Censored Data Colloquia Mathematica Societatis
Janos Bolyai Vol. 32: Nonparamelric Statistical Inference. Budapest, Hun-
gary, 1980, pp 103-121

Cheever, A. W,. Minker, R. G.. and DuVall, R. N.: Schistosoma Japonicum m
Rabbits: Differences in the Host-Parasite Relationship Over a Seven- Year
Period. Am. J. Trap. Med Hyg. 31(3): 514-517, 1982.

DeBlas. A. L., Ratnaparkhi, M. V . and f^osimann. J E.: Estimation of the
number of monoclonal hybndomas m a cell-fusion expenmenl. In Vunakis.
H. v., and Langone. J J (Eds ): Immunochemical Techniques Methods m
Enzymology. Vol. 92 New York, Academic Press, 1983. pp. 36-39.

Knott. G. D : Direct chaining with coalescing lists Journal o1 Algonthms (in
press).

Knott. G D : Fixed-bucket binary storage trees J. of Algonthms 3: 276-287.
1982.

Malley. J D.: Statistical and algebraic independence The Annals of Statistics
11 (1): 341-345. 1983

Mosimann. J E : Discussion of Professor Aitchison's paper (The Statistical
Analysis of Compositional Data). Journal of the Royal Statistical Society B
44 (2): 168-170. 1982.

Mosimann, J. E.: Size and Shape Analysis In Johnson. N I . Kolz. S . and Read,
C B (Eds): Encyclopedia of Statistical Sciences John Wiley and Sons. Inc.
(m press).

Norton, L M : Automated Analysis of Instnjctional Text Artificial Intelligence 20:
307-344, 1983

Norton, L M , and Pacak, M G Morphosemantic Analysis of Compound Word
Forms Denoting Surgical Procedures Meltxxis of Information in Medicine
22: 29-36, 1983

O'Connor, M A : Invanant metrics on cones In Proceedings of the Conference
on Invariant Metrics and Holomorphic Maps Rome, Italy. Islituto di Alta
Matemalica F Seven di CNR Symposia Malhemalica. London and New
York. Academic Press. 1982

Shapiro, M A note on Lee and Schacter's algorithm lor Oelaunay lnar>gulation
International Journal of Computer and Information Sciences 10 (6) 413-
418. 1981

Yaar, I., and Shapiro. MBA quantitative study of the Electroencephalographic
Response to Levodopa treatment m Parkinsonian patients Oimcal Electro-
encephalography 14 (2) 82-85. 1983

Uses per month of

Statistical packages supported by LSM*

75600

JUN 75 JUN 76 JUN 77 JUN 78 JUN 79 JUN 80 JUN 81 JUN '82 JUN '93

*Packag«s supported by th« Statlttlcal Software Section only. Ooee not Include
packages supported by the Blomathematlcs and Computef Science* Section.

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Computer Systems Laboratory

Alan M. Demmerle, Chief

Function and Scope of Work

The Computer Systems Laboratory--28 professionals
representing the disciplines of engineenng, computer
science, medicine, and chemistry--is the major source
of expertise at NIH for minicomputer and
microcomputer technology.

CSL engineers and scientists, in collaboration with NIH
intramural laboratory and clinical investigators, apply
this technology in the areas of laboratory automation
and patient care. Some projects are occasionally
undertaken with NIH extramural program staff and with
other Federal agencies.

CSL's multidisciplinary approach aids both the
recognition of problem areas that will benefit from
automation and the interpretation of research needs in
terms of computer methods.

Computers may be used only in an adjunctive manner--
for example, as a more convenient means to acquire
laboratory and clinical data--or they may be integral
parts of an elaborate instrumentation system, such as a
computer-controlled mass spectrometer. Advances in
large-scale circuit integration (LSI)"the microprocessor
revolution-have brought about the miniaturization of
computer components and a dramatic decline in their
prices and power requirements. CSL engineers are now
able to use microprocessors to deal with problems that
once defied solution because of cost, size, or
manpower constraints.

CSL projects range in size from consulting activities of
a few days' or weeks' duration to large-scale efforts
taking many manyears. Much CSL work involves the
development of new methods or technology or is
influenced strongly by the changing needs of research.
Thus, it is often difficult to predict the long-term scope
at the outset of a project.

FY83 Highlights

This year, CSL engineers and scientists worked on 28
projects, representing collaboration with almost all of
the NIH Institutes. Some of these projects require only
limited resources, while others take many manyears.
The latter deserve particular emphasis because of both

their sheer magnitude and the importance of the patient
care or research activity they support.

One of these ma|or projects involves the automation of
flow cytometers/electronic cell sorters (FC/ECS)
These instruments are being used increasingly in
biomedical research, particularly in fields of laboratory
research, and in clinical studies in immunology,
cytology, and oncology CSL support tor these
instruments began in 1973, when NCI requested
development of a computer-based data acquisition,
processing, and display system for the prototype flow
cytometers developed at Stanford and Los Alamos
Scientific Labs.

Over the years, a system has evolved that is based
upon a Digital Equipment Corporation PDF 1 1/34
computer using an RT-11 operating system System
hardware includes a refresh CRT display, two disks,
magnetic tape, 64K words of memory, incremental
plotter, a link to the NIH Central Computer Facility, and
an intertace to the FC/ECS. Programs were developed
to display the data as two- or three-dimensional figures

Two-dimensional contour maps at user-selected
thresholds are also available. Integration of selected
curve segments and statistics descnbing peaks are
included upon request. The various data presentations
are a powertui tool to assist researchers m data
interpretations. Equally important is the increase m the
number of samples processed.

This system has been duplicated six times at NIH and
the Naval f^edical Center, and, m addition, many copies
of the system documentation have been requested and
sent to research centers in the U.S.. Europe, and
Australia.

In order to accommodate a high volume worKload
environment where sample throughput is important, a
new FC/ECS Computer System was developed by CSL
and installed at NCI dunng the summer of 1983 The
new system uses a Digital Equipment Corporation PDP
11/24 (host) computer running under an RSX-11M
multiuser operating system. Tektronix 4025 graphics
terminals, and Digital Equipment Corporation LSI/ 11 -23
(satellite) microcomputers for independent acquisition
of data from each of several FC/ECS instruments

The satellite computer sends acquired data through a
high-speed direct memory access (DMA) link to the
host computer where it is stored on magnetic tape or
disk. The terminal at the satellite may be used for
displaying acquired data. This is helpful in viewing
collected data files immediately after they have been
stored at the host. This terminal is also used during
data acquisition for parameter entry, display of file
recordkeeping, and error reporting.

Simultaneously with data acquisition, one or more users
may analyze data at the host using independent
graphics terminals. Processed files may be queued to a
plotter so that a terminal can be used for further
analysis while plotting proceeds. The new system can
function with a PDP-11/34 computer, however, the
PDP-11/24 supports more memory, and therefore more
users may analyze their data concurrently. CSL
anticipates the purchase of Digital Equipment
Corporation's new 11/70 chip set, when it becomes
available, so as to upgrade from the PDP-11/24 and
further improve system speed and performance.

Another project requiring substantial investment of CSL
manpower involves the development of a computer
system for data acquisition, processing, and display, in
support of the Electron Beam Imaging and
Microspectroscopy Facility in DRS/BEIB. The Facility
was developed by physicists, engineers, and computer
scientists from BEIB and CSL as a research resource
for NIH investigators. It contains an automated electron
microscope system that can analyze and display a
specimen's elemental chemical makeup as well as its
morphological microstructure.

Electron energy loss (EEL) images, generated by
measuring the characteristic amount of energy lost by
beam electrons that interact with the atoms of a
specimen, are thought to be the first in the world of this
type produced on a scanning transmission electron
microscope (STEfvi).

Another important development by project team
members is a digital filtering technique to background-
correct images produced by energy dispersive x-ray
spectrometry (EDS). The presentation of this technique
won the Corning Award for the best contributed
scientific paper at the last Joint National Meeting of the

Electron Microscopy Society of America and the
Microbeam Analysis Society.

During the past year, the first biological images were
obtained showing calcium distributions in secretory
ameloblasts. This study of the role of ameloblasts in
tooth enamel formation, done in a collaboration
between BEIB physicists and a NIDR visiting scientist,
heralded the beginning of a shift from instrumentation
and computer systems research and development to
applying the system to biological research.

Subsequently, collaborations have begun with scientists
from several other Institutes. NINCDS investigators are
obtaining aluminum and calcium maps in cells taken
from the hippocampus of victims of Parkinsonian
dementia. Nitrogen and oxygen distributions in
chromaffin cells are of interest to NIADDK investigators
in a study of the release of epinephrine, and the
Clinical Center is examining the relevance of
magnesium in cardiovascular disease by studying the
distribution of magnesium in individual lymphocytes.

To address some of the difficult problems presented by
these and other studies, CSL presently is concentrating
on improvements and refinements to the system data
acquisition, imaging, and analysis capabilities.

Development of a new Image Processing Facility for
NIH-wide use is another of CSL's major projects.
Designed to complement an existing Evans and
Sutherland System, which has in the past supported
both image analysis and molecular graphics
applications, the new facility has become operational
this year. The main components are a Digital
Equipment Corporation VAX 1 1/70 computer and a
DeAnza IP8500 Image Array Processor. Although only
one user station-comprising a 512 x 512 resolution
color monitor with joystick and digitizing tablet-is
currently available, two more stations are being
procured and should be operational soon.

Software existing on the Evans and Sutherland System
is being reprogrammed for the more powerful VAX
machine, and new programs that utilize the extended
capabilities of the DeAnza System are being
developed.

The PIC software package, a mainstay of image
processing users of the Evans and Sutherland System,
is already operational, and is the backbone of scientific
research on the new system. Current research centers
in two fields. First, high resolution structural studies for
several viruses (including vesicular stomatitis virus,
bacteriophase T7, tobacco mosaic virus, and varicella
zoster virus) are underway currently. Second, structural
analyses of fibrous proteins such as keratin, vimentin,
desmin, and actin are in progress.

These ongoing projects in macromolecular structural
determination have placed NIH at the forefront of
research in the analysis of high resolution electron
micrographs.

As more and more images become available from an
ever-increasing diversity of sources, the management
of these images poses a considerable problem. This is
particularly true in the NIH Clinical Center where it is
desired that images obtained from a vanety of
modalities (CT, PET, NMR and Ultrasound Scans,
Digital Vascular Imaging, etc.) be stored, transmitted,
cataloged, and displayed at viewing stations in
dedicated viewing areas and physicians' offices.

CSL has undertaken a study of the feasibility of
implementing a picture archiving and communication
system for the Clinical Center. Although the study has
not involved a major CSL effort thus far, the
implementation phases of such a network imply a
massive investment of manpower over a protracted
period of time.

The study has involved an investigation of the latest
advances in data storage and local network technology.
Optical laser disks, which will eventually enable up to
one year's worth of images to be stored in one
'jukebox' system, are being considered, as are
advanced local communications networks that permit
the transfer of millions of bits per second. State-of-the-
art image display and data management techniques will
be needed and are being assessed. Funding and
technological considerations may dictate phased
implementation of such a system. Resource limitations
may likewise require that substantial portions of the
project be contracted out. The study is expected to
provide the basis for such decision-making

Future Plans/Trends

FY84 can be expected to present an increased
demand for computers in laboratory and patient care
settings More complex research goals of biomedical
research investigators point to a greater need for
automation in the laboratory Technological
developments in large-scale circuit integration continue
to lead to lower costs and smaller sizes for computers
The current popularity of personal' computers is
resulting in greater awareness on the part of NIH
scientists of the potential benefits of computers

At the same time, CSL is faced with limited personnel
and budgetary resources In response to the challenge
imposed by this conflicting set of circumstances, CSL
expects to maintain high quality engineering and
laboratory computer support to NIH programs by
continuing policies developed in the past for managing
resource issues. CSL staff will be deployed on projects
promising maximum impact to the NIH community-
those that serve a significant number of scientists,
affect the quality of patient care, or represent general-
purpose developments

Publications and Presentations

Bonow, R . OSI'OW H Roi-ng D L^r.r^-. ':■■ A..i-. ^ '.'j.. _ -^. j^-'.

S . Green M , »nd Ep»le.n. S V«f«p«n»( EWect* on L»«t ventneuw Pr».

sore- Volume An«lysi« onth ■ Norwn«gmg SonMation Probe OcU««on (•»

press)
Cotnputer Systems LsborarcY June 1963
Donlon, J . Wang L . Luntfy. E . Wages. B . Feust, A . and Songco. 0 A

Computer Assisted Hematology MorpKo»ogy Data Handing SyaMm Pro-

(Medmgs ol lh« &tm Annus/ Srmpotmjm on Cam^^tr Afiptcmtont #»

UeOcM Csr«. Sneralon Wasnwiglon Hotel. Wa»»wiglon. D C Ooofter 30-

November 2. 1962. pp 270 273
Foster. M . George. J . Trus. B . and Ha»n». W So<»um. Potaaaxn. CWonna.

Magneswm. and EichangeaWe 45 Cataum Ions in Rod Outer Segmarw

by Combined x Ray Micfoana»ysrt and Ra<»oaulograprty ftaortj^ca' Joir-

ntl*y (2) 341. 1963
Gershon. N . Porter. K . and Trus. B The Cy»o**a»*c Maln» Its SirucM*.

Volume Surface A/ea. and Space tor Oiftuaon Bupf>rfKl Jamal *y (2)

S5. 1963
Gershon N Porter K. and Trus. B The MKiotfabecUar Lawoa and *m

Cyioskeieton The« Volume, Stxfaca A/ea. and the OAuaon ol MoiaciMa

Through It Joumi ot Cel Biotogy 95 (2) 406A, 1962
Gershon N Porter. K . and rrus. B The lAcroMbwaMr Laf*» and *•

Cytoskelelon The« Volume. S«*lace Area, and the Wtiaon at Uotaotfaa

Throu(^ It Proc0t<tngs of ir» Aharon K»tt-KtKt\tmy tMnotml 9rnrpo-

sum Bologcl Smxtum and Cotolta Flows Israel, mtamefconal Soarwa

Services (m press)

Goldman, R., Trus. B., and Leh/e, L.: Quanlitalive Double-Label Radiography of
Two-Dlmensional Protein Gels Using Color Negative Film and Complete
Analysis European Journal of Biochemistry 131: 473-480. 1983

Gorlen, K : A Computerized STEM lor Biological Research. Annual International
Medical and Latioratory Instrumentation, Washington, DC. November 17.
1982

Gorlen. K . Barden. L.. Del Priore. J.. Kochar. A . Florl, C, Gibson. C. and
Leapman, R : A Data Acquisition System lor an Analytical Electron Micro-
scope. Proceedings of the FALL DECUS {in press).

Green. M . Ostrow. H . Bacharach. S.. Allen, S., Bonow, R., and Johnston, G.:
Realtime Scintillation Probe Measurement of Left Ventricular Function.
Nuklear Medizine 20: 11 6- 1 23. 1 98 1

Hook. G . Fion, C , Gorlen, K., Gibson, C, Garruto, R., Fukatsu, R., Uanagihara,
R., and Gajdusek, D : Elemental Imaging of Brain Tissue Using a Computer
Controlled Electron Beam X-ray Microanalyzer Conference on Aluminum
Analysis m Biological Matenal, Charlottesville, VA, June 29-30, 1983.

Leapman, R , Fion, C, Gorlen. K.. Gibson. C. and Swyt. D.: Combined Elemen-
tal and Structural Imaging in a Computer Controlled Analytical Electron
Microscope Journal of Ultramicroscopy (in press).

Martino. R . and Gerber. L.: An Automated Biomechanics Laboratory Applied to
Rehabilitation Proceedings of the Fifth Annual Conference of the IEEE
Engineering in Medicine and Biology Society (in press).

Nadel. L. Automated Pulmonary Analysis by an Online Microcomputer. Com-
puters in Cnlical Care and Pulmonary Medicine 3: 103-1 13. 1983.

Nikodem. v.. Huang. D.. Trus. B.. and Rail. J.: The Effects of Thyroid Hormone
on In Vitro Phosphorylation. Acelylation. and Ribosylation of Rat Liver
Nuclear Proteins. Hormone and Metabolic Research (in press).

Sabnn. H . and Kertesz. A.: The Effect of Imposed Fixational Eye on Binocular
Rivalry. Perception and Psychophysics (in press).

Steinen. P., Rice. R.. Roop. D . Trus. B . and Steven, A.: Complete Amino Acid
Sequence of a Mouse Epidermal Keratin Subunit: Implications tor the
Structure of Intermediate Filaments, Nature 302: 794-800. 1983.

Steven. A.. Hainfeld. J . Wall. J.. Trus. B.. and Steinert, P.: The Distribution of
Mass in Heteropolymer Intermediate Filaments Assembled in Vitro: STEM
Analysis of Vimentin/Desmin and Bavme Epidermal Keratin. Journal of
Biological Chemistry (in press).

Steven. A.. Serwer. P., Bisher. M.. and Trus. B.: Molecular Architecture of
Bactenophase T7 Capsid. Journal of Virology 124: 109-120. 1983.

Tate. R.: Microcomputer Systems in the Laboratory: An Introduction. Serono
Symposium Series. Raven Press. 1983 (in press)

Steven. A,, Serwer. P,, and Trus. B,: Molecular Packing in Bactenophase T7
Determined by Image Processing of Electron Micrographs, Journal of Viro-
logy 124: 109-120. 1983,

Tate. R,: The Microcomputer Revolution: Enhanced Instrument Capabilities.
Annual International Medical and Laboratory Instrumentation Symposium,
Sheraton Washington Hotel, November 18, 1982.

Trus, 8.: Companson of Diffraction Patterns from Stained and Unstained Helical
Particles: Modeling Expenmenis with Actin-Like Filaments Mini-symposium
on Image Processing in Electron Microscopy, University of Pennsylvania
School of Medicine, Philadelphia, PA, March 24, 1983,

Trus, B,: Image Processing of Electron Micrographs, Chesapeake Society lor
Electron Microscopy, Uniform Services University of Health Sciences, Be-
thesda, MD, October 20, 1982,

Trus, B,: Particles by Heavy Metal Staining: Modeling Expenments with Actin-
Like Filaments, Annual Picture Meeting of the Chesapeake Society for
Electron Microscopy, University of Maryland Baltimore County, Baltimore,
MD, May 5, 1983.

STEM COMPUTER SYSTEM

Terminals

Link to
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Disk

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Bright
Dark Field
Detectors

EEL

Spectrometer

& Detector

STEM

Host
Computer
PDP 11 60

A system for controlling an electron microscope's
detectors and processing the data acquired from
the detectors requires a considerable amount of
computer hardware and software. The system
developed at NIH for application in biology consists
of a host computer and a satellite computer
interfaced to a scanning transmission electron
microscope (STEM). The STEM, which provides
analytical signals, includes a magnetic sector
electron energy loss spectrometer, an energy
dispersive x-ray detector, and conventional bright
and dark field detectors.

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Data Management Branch

J. Emmett Ward, Chief

Functions and Scope of Work

The Data Management Branch (DMB) provides advice
and assistance to research investigators, program
officials, and administrators throughout NIH in planning
for and obtaining computer data processing services. In
this role the branch is a central NIH resource for
systems analysis, design, and programming. The
Branch is also responsible for the development,
maintenance, and processing of the NIH Administrative
Data Base and the Clinical Center's Clinical Information
Utility. There are currently 50 permanent full-time
employees whose disciplines include computer science,
mathematics, and statistics.

DMB staff design and create computer-based data
management systems that provide practical solutions to
the unique mix of administrative, scientific, and
management data processing problems encountered at
NIH. Each new computer system user is provided
comprehensive training in all system facilities and
functions of the system provided by DMB. In addition
DMB staff teach courses about programming tools;
provide advice on data management techniques to NIH
programmers; serve as consultants to the B/I/D's for
obtaining and monitoring contracting services for
computer systems development; and create and
maintain general purpose, user-oriented programming
tools to speed building and improve operation of
applications systems.

DMB comprises four sections. The Applied Systems
Programming Section (ASPS) and the Scientific
Applications Section (SAS) provide general computer
systems analysis and programming services for all of
the B/I/D's. The ASPS supports general data
management, and the SAS handles those projects that
require scientific data analysis.

The Data Base Applications Section develops and
maintains the central administrative data base for NIH
materiel and financial management. The Clinical
Support Section develops and maintains the Clinical
Information Utility as a data base for research and
patient care in the Clinical Center.

FY83 Accomplishments

The Clinical Information Utility is a long term effort that,
when completed, will provide a unique archive of
integrated data for use in patient care and research.
Efforts to date have involved:

1 . the development of software to acquire and to
make available data from the NIH Clinical Center
Medical Information System and the individual clinical
service activities

2. the integration of a number of these individual data
bases, which allows random access to the integrated
data, and

3. the development of software that enables users to
make online requests for information and to receive
automatically-generated retrievals of weekly, monthly,
quarterly, and specified-time-period reports.

During FY83, the entire data base moved to Mass
Storage; three access paths were developed to enable
patient retrievals by way of the Registry File and the
Inverted File and directly into the integrated data base;
one conditional path was also added to allow access
through the inverted file. Medications, vital signs, and
Blood Bank data were added to the integrated data
base, and automatic scheduling of weekly, monthly,
and quarterly retrievals was implemented.

The NIH Administrative Data Base is an ongoing
developmental project that uses data base technology
in support of NIH-wide materiel and financial
management. Significant progress has been made
during the past year in several areas.

As of March 1983, DELPRO became fully operational
throughout NIH. This effort places purchasing and
receiving for delegated authorities in the B/I/D's, and it
required the installation of 237 terminals and the
training of more than 1 ,000 people. A new version of
the central procurement system was implemented in
May 1983. This new version is more efficient and has
been designed to be highly portable and maintainable.
Plans call for extending this software to accommodate
the delegated functions.

Because of the need to conform to the Office of
Management and Budget initiative on cash

management, a shift in pnorities occurred on the
Administrative Data Base. This shift has caused delays
in implementing the Stock Requisitioning and Central
and Self Service Stores Inventory systems.

Full cash management was achieved in the Accounts
Payable System during FY83. These functions were
phased in according to the requirements of the OfvlB
mandate while improving support for Accounts Payable
personnel.

Stock requisitioning software was completed in March
1983, and initial training and refinement of the training
manual began in April. This system was made available
to the B/I/D's in June for training. Central Stores and
Self Service Stores inventory systems will be
implemented along with stock requisitioning in October
1983.

Design of the new Financial Management System was
received during March and April 1983. Several changes
were required, and the system is now being
programmed by the contractor. Interface requirements
are being defined, conversion software is being
designed, and structured test cases are being
developed. Plans now call for implementation during
the latter half of FY84.

Another project that should be of general interest at
NIH has to do with the common problem of maintaining
and easily retrieving bibliographic data. To resolve this
problem DMB has been looking for an inexpensive
method to store and retrieve personalized bibliographic
data sets. Uses of the personal computer (PC),
bibliographic services, and individual bibliographic
references are being investigated. In a pilot test, DMB
has been successful in downloading data from the
Biosciences Information System (BIOSIS) to a PC,
adding individual references and retrieving both, using
the inverted techniques provided by a software product
called SUPERFILE.

For years now, the Clinical Center Blood Bank has
been manually preparing antibody identification panels
to identify those red cells that would be most useful in
finding compatible blood types for patients with
unusual' antibodies. In a joint effort. DMB is attempting
to computerize these accumulated years of knowledge

to both simplify and standardize the approach. To date,
red cells to be included in antibody panels are being
identified, and the Blood Bank and DMB are working
together to investigate the nature of a panel so as to
optimize its utility to identify and quantify those features
that are most desirable.

For a detailed review of the many other important
projects in which the Data Management Branch has
been involved, please refer to the project reports in the
DCRT FY83 Annual Report. Volume 2. These projects
are too numerous to highlight in the summary.

In the area of general support for NIH activities, DMB
continued to maintain and teach courses on the Inquiry
and Reporting System (IRS) and MARKIV; to support
NIH use of Chemical Biological Activities (CBAC) and
Biosciences Information System (BIOSIS) current
awareness searches on a biweekly and semimonthly
basis, respectively; to maintain and distribute the NCI
Survival System; and to consult with and assist NIH
programmers and contractors, enabling facile use of
DCRT computer facilities.

Future Plans/Trends

Plans with the ADB call for the development of the
Market Requisitioning System during the next fiscal
year with full implementation in early FY85. As usual
DMB will implement this system in phases to make new
capabilities available as early as possible. During the
second half of FY84, DMB plans to start adding the
inventories such as Clinical Center Pharmacy, Planning
and Control Branch, Biomedical Engineering and
Instrumentation Branch, and NIEHS to the ADB.
Priorities for these inventories have not yet been
established.

The Financial Management System will be added to the
ADB dunng the latter half of FY84, and DMB will begin
development of the new property system at that time.

Future CIU efforts will concentrate on improving data
accessibility. For less complex retrievals by Medical
Records personnel, a 'user friendly' retrieval assistance
system will be developed. In a more general user
sense, software will be developed to support ad hoc

formulation of retrievals, online definition of output
formats and electronic delivery of output. As full
integration of the data base nears completion, the
classes of data that can be transmitted to the PDP-10
for subfile creation and analysis will be expanded.

Its role as a central resource for computer applications
development throughout the B/I/D's will continue to
receive pnmary support by DMB.

Publications

Data Managentanl Branct) Juty 1M3

Rodbard. 0, Cote. B. •nd Munaon. PJ Ovvatopmam ol t Fn»n««». S«M
Teaching. Interactive Statietical Package hx Ana»irs« o< Cmcal Re•earc^
DaU Seventh Annual Meeting ol the Soc«ly tor Cofnputef ApiAcatnrw •>
Me<*cal Care. 1983

The NIH Admnuntnf Data Bsaa Ju*y 19*3

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PANEL 9 1 ANTIGEN PROFILE

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+ 000 + 00 + 0 + +

+ 000 + 0 + 0 + +

+ 00 + 0 + + + + +

0+ + + 0 + + + +

0 + 0 + + 0 + + 0 +

0 + + 0 + + ♦♦0

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In cooperation with the Clinical Center Blood Bank,
DMB is attempting to computerize reagent red cell
selection used to find compatible blood types for
patients with unusual antibodies.

— 25

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Computer Center Branch

Joseph D. Naughton, Chief

Function

The Computer Center Branch, the largest component
of DCRT, designs, operates, and maintains the NIH
Central Computer Utility and its associated
telecommunications facilities. The Center staff also
provide direct support to the users of the Utility by
conducting a formal computer training program, writing
and publishing technical documentation, and providing
programming assistance and consultation on the use of
the Utility in support of scientific and administrative
programs throughout NIH.

The NIH Computer Utility consists of two large
multicomputer facilities designed around large scale
IBM and DEC mainframe processors. The facilities are
linked together by a complex set of communications
facilities and are connected by telecommunications
lines to thousands of remote interactive terminals and
computers located throughout NIH and many other
Federal agencies. The systems hardware is
complemented by an extensive array of software that
either has been designed and implemented by
Computer Center personnel or acquired from other
sources and adapted to meet the unique needs of the
NIH biomedical research and administrative user
community.

The Computer Center employs a highly specialized staff
of professional, technical, and administrative personnel
to ensure smooth functioning of the NIH Computer
Utility 24 hours a day, seven days a week. Systems
software is developed and maintained by a staff of
experienced computer systems programmers and
analysts, who also provide technical consultation,
design and teach training courses, and write technical
documentation describing the use of the Utility. The
Computer Utility's hardware and telecommunications
networks are operated and maintained by computer
systems technicians and operations personnel. Data
entry services are also provided. Systems design and
management professionals are responsible for long-
term program goals and the design integrity of the
Utility. Because the Computer Center receives no
appropriated funds from Congress, the design,
operation, and maintenance of the NIH Computer Utility

is financed exclusively on a fee-for-service, cost-
recovery basis.

The Computer Center also conducts a number of
research and development projects to increase the
effectiveness of computers in support of modern
biomedical research. Current ongoing research projects
include development of facilities that will enable
microcomputers to be used in conjunction with the
Utility; enhancements of output devices to permit the
production of display mathematics and molecular
graphics; installation of a data base management
facility; and development of new training
methodologies.

Scope of Work

Chartered as a Federal Data Processing Center, the
NIH Computer Center plans, designs, implements, and
operates a large, general-purpose central computer
utility that provides a variety of computational services
in support of a dynamic and diverse user community of
over 13,000 research scientists, administrators,
secretaries, analysts, and programmers throughout the
Federal Government.

The primary component of the NIH Computer Utility is a
uniquely configured multiprocessor computer system
designed around five IBM 3081 processors with 144
million bytes of directly addressable main memory. The
peripheral complex supporting the system includes 115
tape drives, 344 disk drives, 2 mass storage systems,
1 1 high speed printers, and card reader/punches,
microfiche output units, and teleprocessing facilities
serving over 1,000 communications lines.

Operating in a multiprogramming mode, this facility
provides timesharing, text editing, and batch processing
services, as well as microfiche, graphics, plotting, and
data management facilities to users 24 hours per day.
The IBM System 370 currently processes over 14,500
batch jobs and 13,500 interactive sessions daily. Over
7.3 million jobs-sessions were processed on the system
during the past year, and more than 93.4 percent of
these were completed and available to the user in less
than two hours.

The other major component of the NIH Computer
Utility, the DECsystem-10 timesharing facility, is
designed around one DK and two KL-10 processors
with five million bytes of directly addressable memory.
This facility provides timesharing services and data
communications support to over 2,000 laboratory
research investigators throughout NIH. Ten tape drives,
31 disk drives, and a variety of teleprocessing
equipment make up the peripheral complex. Over
120,000 interactive timesharing sessions were
processed on the DECsystem-10 during the past year.

Use of the NIH Computer Utility has grown steadily
since its inception in 1967. An average of 28,944 job-
sessions were processed each day on the Computer
Utility dunng FY83. This represents an 11.5 percent
increase over last year.

The computing power of the NIH Computer Utility can
be accessed from several thousand interactive
terminals and 160 remote job entry computers located
in users' offices and laboratories throughout the United
States.

NIH COMPUTER UTILITY
System 370 Services

CALCNOAR rCAD

A variety of programming languages are available on
the NIH Computer Utility. Languages like FORTRAN.
COBOL, PASCAL, BASIC, Assembler, PL/I, SAIL, and
SPEAKEASY provide for a wide range of applications in
a variety of different research and management areas.
There is also a data base/data management system
(IMS), the TELL-A-GRAF interactive graphics package,
and a comprehensive library of statistical and utility
programs. Online computing and batch job submission
are available interactively on the IBM System 370
through WYLBUR and TSO, and through timesharing
seny/ices on the DECsystem-10. Devices for job output
on paper and microfiche are available, and there are
programs for creating two-dimensional or three-
dimensional graphics displays for advanced research
projects.

Users of the Computer Utility are informed of current
programming standards and available facilities through
two comprehensive manuals, the Computer Center
Users Guide and the DECsystem- 10 Timesharing
Guide. Changes in the Utility are announced to users
through INTERFACE, a periodic technical newsletter.
An in-house training program conducted 152 formal
classroom lecture courses to over 3,000 students and a
variety of multimedia self-study courses to help users
develop expertise in the use of the Utility this year.

Highlights of the Year's
Accomplishments

The most exciting accomplishment of FY83 was a
dramatic increase in the amount of system resources
available to user programs. Requested for several
years by many of the Utility's users, the expanded
resource limits were made possible largely by last
year's upgrade of all IBM System 370 hardware.

A number of areas were affected by the expansion of
system resources. Processor time allowed was
increased 50 percent for all job classes, except class
'E,' which was increased 87 percent. The maximum
REGION size available to all batch jobs and TSO
sessions was increased to two million bytes, thus
allowing greater flexibility for large data set processing

NIH COMPUTER UTILITY
TRAINING COURSE APPLICATIONS

5000
4750
4500
4250
4000
3750
3500
3250
3000
2750
2500
2250
2000
1750
1500
1250
1000
750
500
250
0

Legend

A RECEIVED

— I —
1981

X ACCEPTED
O REJECTED

1982

1975 1976 1977 1978 1979 1980

CALENDAR YEAR

63 73 80 62 71 78 105 152
NUMBER OF COURSE-SESSIONS TAUGHT

or matrix manipulation activities. In addition, the
maximum size of data sets eligible for storage on the
MSS was more than doubled, the amount of DASD
scratch space available to each job step was increased
100 percent to 475 million bytes, and the limit for online
printed output was raised by a factor of four to 20,000
lines.

These expanded resource limits, which represent the
most comprehensive increase in resources ever offered
by the Utility, will improve system efficiency and cost
effectiveness while providing greater flexibility and
convenience in the design and processing of user
programs, particularly for large data sets.

An entirely new system of self-study. Independent
Training Assisted by Computer (ABC), was introduced
this year in response to users' ever-growing need for
computer-related training. Designed and developed by
the Computer Center, ABC courses allow users to
study from a pnnted text, from a computer terminal, or

from a combination of both ABC courses give users
the option of taking either an entire course or only
selected parts of the material; lessons may be repeated
as often as desired and can be studied at any
convenient location. Introduction to WYLBUR' was the
first ABC course made available

Because of the widespread and growing use of
microcomputers and other intelligent' devices at NIH, a
major policy decision to develop facilities that will make
the resources and services of the Computer Utility
available to microcomputer users was announced this
year A facility was introduced to allow microcomputers
to be used as terminals to access the Utility, and a
function to permit programs and data to be transferred
between the various microcomputers and the Utility
was tested and installed An entirely new
communications service, called SNA/SDLC 3270. was
introduced on the IBM system in order to give a wider
range of devices dial-up access to the Utility

NIH COMPUTER UTILITY ^
FY83 RATE REDUCTIONS ^H

Service

Rate
FY82 FY83

Percent
Reduction!

Terminal Rental:
NIH7000/month

$176.00 $120.00

31.8

Data Storage (online):
Public/track
Dedicated/track
MSS/megabyte

Processing:

BATCH/resource hour
WYLBUR/second
ISO/second
IMS/transaction
Printing/1000 lines

Discount Processing

.03

.025

16.7

.015

.0125

16.7

3.07

2.55

16.9

$ 26.40

$ 22.20

15.9

.97

.72

25.8

1.90

1.20

36.8

.20

.18

10.0

.87

.64

26.4

50%

40%

20.0

Users of the NIH Computer Utility saved over 7 million
dollars when the largest rate reduction ever offered by
the NIH Computer Center became effective on
February 1, 1983. These savings were compounded on
July 1, 1983 when rates for interactive services on the
IBM System 370 were reduced even further. The
combined reductions ranged from 10 to 62 percent
including significant decreases in almost all areas of
batch and interactive processing, data storage and
terminal rental.

This is the 16th consecutive year that the NIH
Computer Center has been able to pass on savings to
users in the form of rate reductions. Overall, rates have
decreased 87.3 percent, from 1 75 dollars per resource
hour in 1968 to slightly over 22 dollars in 1983.

The installation of new, more cost-effective hardware
last year--together with the efforts of Computer Center
staff to improve the internal operating efficiency of the
system-has contributed significantly to reducing
operating overhead. The constantly-increasing demand
for computational services is another important factor
that makes continually decreasing rates possible. The
fixed costs and overhead of the system do not increase
in direct proportion to its processing capacity: and,
because the Utility operates as a zero balance, cost-
recovery facility, all savings resulting from improved
financial performance are returned to users in the form
of lower rates for services. Therefore, the expansion of
the system actually works to reduce per unit costs for
all users. This 'economy of scale' is one of the major
advantages of the Computer Utility concept as
implemented at NIH.

A major accomplishment of the past year was the
development of a multiphased plan to provide complete
data set security for the over 300,000 data sets stored
on the NIH Computer Utility. The new security plan,
which utilizes IBM's Resource Access Control Facility
(RACF), will enable users, at their option, to control
access to individual data sets or groups of data sets
from WYLBUR, TSO, and batch |obs. The RACF
security system allows users to: limit access to
sensitive information to authonzed users, prevent
deliberate or accidental destruction of data by
unauthorized users, and centralize access control to
data sets processed by multiple users.

Software additions and system enhancements
introduced during the year focused heavily on graphics.
GRAPH1, a new program for drawing graphs, became
available on the DECsystem-10. A graphics package
was added to the interactive language SPEAKEASY,
and color graphics capabilities were introduced on
Of^NIGRAPH. The International Mathematical and
Statistical Library underwent a major upgrade, and a
facility was added for users to obtain current status
information about online data sets and tape volumes
through the terminal.

Future Plans

Developing support facilities to encourage maximum
utilization of the Computer Utility will be a major prionty
of the coming year.

Recognizing the importance of the microcomputer and
other intelligent' microprocessor-based devices at NIH,
the Computer Center will continue to explore ways to
develop the potential of these powerful and versatile
tools. Because of the vast variety of microprocessors
available and the almost limitless array of associated
software, a great deal of planning and coordination will
be necessary to insure long-term compatibility and
maximum effectiveness. Emphasis will be placed on
researching and implementing additional functions and
facilities to enable microcomputer users to take full
advantage of the resources and services available from
the Computer Utility.

Expansion of training opportunities for Computer Utility
users, a continuing goal of the Computer Center, will be
particularly important next year A number of additional
ABC independent training courses will be developed
and implemented, while full support is continued for
classroom training and self-study courses

The coming year will see the completion of a total
security environment that is functional as well as
convenient. The overall security plan will encompass
physical security, computer room access, and control of
output distribution, as well as effective data set
protection

In keeping with the growing demand tor more
sophisticated computer graphics, development of
entranced graphic output facilities and display
mathematics capabilities will be an important pnonty
next year. In addition, all standard terminals used at
NIH will be replaced with state-of-the-art equipment
that has increased display capabilities

New interactive display terminals will replace the
NIH7000 editing display terminals Designated the
NIH8188, the new terminal will display 132 characters
per line, have twice as many function keys and four
times the memory capacity of the NIH7000
Replacements for the CT45 hard copy terminal and the
T1222 high-speed hard copy terminal will be selected
through the competitive procurement process

A foil printing utility that will allow users to generate
high quality overhead transparencies is being planned
in response to user requests. A number of
enhancements to WYLBUR, many suggested by the
user community, will be implemented, and the
Computer Center staff will continue to investigate and
evaluate currently available software offenngs to
determine which might be beneficial to users of the NIH
Computer Utility

Publications

McLaugM>n B An «ip«nmfHH Companaon o« Oaoo»Tf and Qdacac Com-
potemed Insmjctional Slr»l«»«« m tht Itfrwig o« Coir^tm Pi«V«m-
mmg 83 Nabooal Educational Cotnputng Conlaranca. BaMmera. MO.

June 6-8. 1983

" 31

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Office of the Director

Arnold W. Pratt, Director

^unction and Scope of Work

The Office of the Director provides overall program and
nanagement direction for DCRT. It includes an Equal
Employment Opportunity Office and tfiree offices
vhose activities supplement tfie work of tfie DCRT
aboratories and branches;

• The Office of ADP Policy Coordination (OADPPC) is
the central NIH focus for advice and assistance on
matters related to the complex ADP policy and
procedures governing the procurement and
management of computers in the Federal
government. It serves as the point of contact on
these matters w\\h other parts of DHHS and other
Federal agencies.

• The Office of Administrative Management (0AM)
provides general administrative and managerial
support for the work of DCRT.

■• The Office of Scientific and Technical
Communication (OSTC). including the DCRT
Information Office and the DCRT Library, sen/es as a
central source of information about DCRT activities
and about computing and related disciplines.

In addition, the Office of the Director sponsors a
number of individual research and development
projects.

FY83 Highlights

This year, the DCRT Equal Employment Opporlunity
Office developed the Division's first Affirmative Action
Program /Federal Equal Opportunity Recruitment
Program plans.

A major change took place in the Office of ADP Policy
Coordination. At the end of FY82 OADPPC Chief Mr.
Henry Juenemann retired, after experience spanning
two decades of dynamic and complex development of
computing at NIH.

In early FY83 two branches of the NIH Division of
Management Policy (DMP) were transferred to DCRT
because their work related to computer-based systems.
The personnel and responsibilities of the Systems
Policy and Planning Branch and the Systems Approval,

Review, and Coordination Branch were placed in the

OADPPC.

The functions of these branches while m DMP included
keeping an inventory of NIH software systems, clearing
new administrative systems and reviewing existing
systems, and serving as the NIH System Secunty
Office. Integration o( these functions with those of
OADPCC will result in more effective support for the
NIH scientists and managers who rely on DCRT for
help on matters related to ADP policies and
procedures.

The Office of Administrative Management again
handled the broad range of personnel, budget,
accounting, and general administrative functions that
occur in a complex NIH research and service division of
320 people with a total budget over 40 million dollars.
Although there were no ma)or changes during the year,
these activities continued to increase m volume and
complexity.

For example, the Project Control Office in the DCRT
Financial Management Office coped with a 1 5 percent
increase in the number of registered users of the NIH
Computer Center At year's end there were some
12,000 users on almost 3,000 accounts They also
participated in the NIH implementation of new billing
procedures (SIBAC) to facilitate interagency payments
across the Federal government.

The DCRT Personnel Office handled the increased
activity that followed a relaxation of most hmng
restrictions by the Department and PHS without any
substantial decrease m the complexity of hmng new
personnel from OPM registers The office also earned
the responsibility for reviewing all of the paperwork
associated with the first year of implementing the new
depanmental Employee Performance Management
System.

In addition to overseeing the Divisions administrative
functions, the DCRT Executive Officer served the
Division as its International Representative to the
Fogarty International Center, its Legislative Contact,
and Its Program Planning Officer m liaison with the NIH
Office of Program Planning and Evaluation

The DCRT Library continued to serve an active
community of users throughout NIH as well as within
DCRT. In general there was a ten to thirty percent
increase in such measures of use as books circulated,
new users registered, and interlibrary loans requested
from the library. The Librarian completed her work on
the executive boards of the District of Columbia Library
Association and the national OCLC Users Council but
replaced these activities with work on the D.C. Chapter
of the Special Library Association. The Library staff
pursued a long term interest in computer systems to
serve small libraries, in the expectation that the advent
of small computers and commercial software will make
this important in the coming year.

The Information Office encountered a 20 percent
increase in the demand for publications describing the
work of DCRT, and it responded to many special
requests for assistance and information from DCRT
staff and from people outside of DCRT and NIH. The
Office completed work on its computenzed file of
citations to the hundreds of scientific papers written
and presentations given by the DCRT staff over the last
1 5 years.

Among the projects sponsored by the Office of the
Director, the Personal Workstation Project received
great attention within the Division and other parts of
NIH. In mid-FY83 the Director organized a core group
of computer experts from several DCRT laboratories
and branches to actively explore the effective use of
personal computers as workstations in laboratories and
offices throughout NIH. The initial work of the group
centered on an examination of the IBM Personal
Computer and the many hardware and software
products that vendors have recently announced to
support and extend this basic personal computer
architecture.

Future Plans/Trends

Much of the work in the coming year will be a direct
continuation of that carried out in FY83 and previous
years to meet the needs of both the DCRT staff and
the growing community of people within NIH who use

or are interested in using computers to support their
work.

The reallocation of functions within the OADPCC and
other parts of the Office of the Director should enhance
the ability of DCRT to carry out its policy, planning, and
system review activities.

The Personal Workstation Project will extend to other
parts of the Division. Members of all DCRT laboratories
and branches will serve as the testing ground for
hardware and software components that can be of use
to others at NIH.

Publications and Presentations

Brenner, S.L.. and Kom, ED.: AMP and AOP Inhibit ATP Hydrolysis by Factin
at Steady State But Have No Effect Duong Polymerization. Twenty-seventh
Annual Meeting of the Biophysical Society, San Diego, CA February 13-16
1983.
Brenner, S L., and Kom, ED.: On the Mechanism of Actin Monomer-Polynief
Subunil Exchange at Steady State Joijmal of Biological OiemtslFy (in
press)
Brenner, S.L.. Tobacman, L S.. and Kom, ED.: The Kinetics of Actin Potymen-
zation and Monomer-Polymer Exchange at Steady State ProceeOings of
the lUB Symposium. Sydney, Australia. August, 1982 (in press).
Division of Computer Research arid Tecfinotogy Fiscal Year 1902 Annua/

Report, Volume I. October 1982, 38 pp.
Division of Computer Research and Technology Fiscal Year 1982 Annual

Report. Volume 2. October 1982, 96 pp
Dwyer. A.J., Glaubiger, D, Ecker, JG , Doppman, JL, Prewrtt. JMS, and
Plunkett, J.: The Radiographic Followup of Patients with Ewing Sarcoma: A
Demonstration of a General Method Radiology 145: 327-331, 1962
Dwyer, A.J , Prewitt, J.M S , Ecker, J G , and Plunken. J The Use of Harart
Rate to Allay the Pen! of Inappropnate Foltowup An Optimization Approach
to Patient Management Journal of MedKal Deoston Making (m press).
Kroop, DO, and Prewitt, JMS Pnvacy m Medical Infomiabon Systems:
Threats and Counlefmeasures MEDCOMP '82, Philadelphia, PA, Septem-
ber 23-25, 1982
Nalcioglu, O , and Prewitt, JMS (Eds ) Proceedings of the IntemaHonal Work-
shop on Physics and Engineenng m Medical Imaging (in press)
Prewitt. J.M S : Pattern Recognition Frontiers in Medical Imaging. Harvard Uni-
versity Information Technology Colloquium Senes, March 17. 1963
Prewitt. JMS, Shao. JX, Sahr, GF, Lipkin, LE, and Lemkm, P Corrvuter
Analysis of Myelinated Nerve Tissue Fourth iniefnalional Conference on
Automation of Diagnostic Cytology. Montreal, Canada. June 24-25, 1963
Ranft. U . Fu, K S , and Prewitt, J M S SegmenUtion of M«roscopic Trans-
verse Section Pictures of Muscle Tissue Using Split-and-Merge Technique
Proceerings of the 6th International Conference on Pattern RecognDon
October 1982, pp 626-828
Ranft. U , Fu, K S , and Prewitt, JMS Segmentation of Transverse Section
Pictures of Muscle Tissue World Congress on lUedical Physics and Bio-
medical Engineenng, Hamburg, Germany. September 7-9, 1962
Schuette, SE, Shackney. SE. Smith, CE. and Prewitt, JMS An Iterative
Method lor the Decompostion of Gaussian Oislorlions From ONA Histo-
grams MEOCOMP 82 Philadelphia PA. September 2325. 1962

W»gl«<>r»d UMTS o< Ih* NM Co«ipu««r UMtty

SEP 73 SEP 74 SEP 75

SEP '78 SEP -77 SEP 78 SEP 79 SEP 80 SEP 81 SEP 82 SEP 83

The Project Control Office processes requests for
new accounts, registers new users, and prepares
monthly billing data for the NIH Computer Utility.

DISCRIMINATION PROHIBITED: Under provisions of
applicable public laws enacted by Congress since
1964, no person in the United States shall, on the
grounds of race, color, national origin, handicap, or
age, be excluded from participation in, be denied
the benefits of, or be subjected to discrimination
under any program or activity (or, on the basis of
sex, with respect to any education program or
activity) receiving Federal financial assistance. In
addition. Executive Order 11141 prohibits
discrimination on the basis of age by contractors
and subcontractors in the performance of Federal
contracts, and Executive Order 11246 states that
no federally funded contractor may discriminate
against any employee or applicant for employment
because of race, color, religion, sex, or national
origin. Therefore, the Division of Computer
Research and Technology must be operated In
compliance with these laws and Executive Orders.

Division of
Computer
Research and
Technology

Fiscal Year 1983
Annual Report
Volume 2

us DEPARTMENT OF HEALTH
AND HUMAN SERVICES
Public Health Service
National Institutes ot Health

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Foreword

The Division of Computer Research and Technology
has primary responsibility for incorporating the power of
modern computers into the biomedical programs and
administrative procedures of NIH. DCRT serves as a
scientific and technological resource for other parts of
PHS, and for other Federal organizations with
biomedical and statistical computing needs.

DCRT programs focus on three primary activities:
conducting research, developing computer systems,
and providing computer facilities.

The fiscal year 1983 annual report describes our work
in two volumes:

Volume 1 gives an overview of the work of each

group, highlighting the year's accomplishments;

Volume 2 gives details about the projects and

activities of each group.

Contents

Physical Sciences Laiwratory 1

Consulting Services 1

Theory of Biochemical Separation
Techniques 2

Studies in Mathematics and Statistics 2

Correlation Function Spectroscopy/Laser
Light Scattering 3

Cell Motility and Chemotaxis 3

Molecular Forces in Cellular Assembly 4

Computerized Typesetting of Scientific
Papers 4

Quantitative Analysis of Cell Structure,
Membranes and Organ Development 5

Diffusion of Molecules on Cell Surfaces and
Light Scattering from Fluids 6

Effect of Solvent on Biological
Macromolecules 6

Laboratory of Applied Studies •

Computer-based Studies of Physiology and
Pathophysiology During Exercise 11

Computer Based Method of Monitoring the
CNS in Critically III Patients 12

Computer Systems for Nuclear Medicine 13

Computer-Aided Analysis of
Electrocardiograms 1*

Statistical Research in Clinical Pathology 15

Computer based analysis and image

processing in electron microscopy and x-

ray and electron-loss spectroscopy 16

Investigation of Hybrid Computing for the
Analysis of Physiologic Signals 17

Mathematical Models of Binding Equilibria 17

Mathematical Modeling of Substrate
Transport in Physiological Environments 18

Network Modeling in Biology 19

Analysis of Coupled Transport and
Biochemical Kinetics 20

Mathematical and Computational Methods

for Solving Nonlinear Equations 22

Numerical Approximation Techniques for

the Solution of Reaction-Diffusion Systems

in Biology 23

Laboratory of Statistical and

Mathematical Methodology 23

Automated Data Processing of Medical
Language 28

Cluster Analysis 29

Research Topics in Computer Science 29

Discrete Mathematics and Applications 30

Multivariate Statistical Analysis 31

Linear Methods in Statistics 31

Nonnumerical Programming Techniques

and Applications 32

Topics in Geometry and Analysis 32

Nonparametric Statistics 33

Computer Systems Laboratory 35

Computer Support for Flow Cytometry/
Electronic Cell Sorting (FC/ECS) 40

Cardiac Scintillation Probe 41

Medical Intensive Care Unit Patient
Monitoring Computer System 43

Computer Analysis of Autoradiographic
Images of Recombinant DNA Colonies 44

Computer Assisted Tomography (CAT)

Scan Image Analysis in Aging Studies 45

Robust Boundary Detection of Necturus

Gall Bladder Cells *•

Rehabilitation Medicine Department
Computer System *^

Aging Studies Image Analysis System 48

Positron Emission Tomography (PET)

Paciiity ^g

Picture Arciiiving and Communication
System ^g

Automated Management of Critically ill
Parents 50

Computer Interfaces for Clinical

Laboratory Instruments 5i

Automated Pulmonary Physiology Testing ... 52

Anesthesia Computer System 54

Medical Information Technology Project 55

Molecular Graphics, Computer Modeling,

and Sequence Analysis 55

Computer Analysis of Gel Electrophoresis 57

Morphometric Analysis of Normal and
Neoplastic Tissue Cultures 58

Virus Structure As Determined by Image
Processing of Electron Micrographs 58

Image Processing of Electron Micrographs. 59

Electron Microanalysis Facility 60

Molecular Interactions Laboratory Data
System ^2

Californium-252 Plasma Desorption Mass
Spectrometer Data System 63

Distributed Laboratory Data Acquisition

and Control System 64

Personal Computers in Laboratory
Applications ^g

Image Processing Facility 66

Medical Image Data Compression 67

Analytic Models of Computer System
Performance ^8

Verbal Access to Computers for the Blind... 69

Data ManaawroentJftnBnch t'jj

Computer Center Branch yg

Design and Development of an Advanced
Molecular Graphics Facility 80

Office of the Director eP

Personal Computer Workstations 83

Concordance Program 83

A Program for Finding Noun Phrases in
English Text 84

Actin Assembly in Nonmuscle Cells 84

Molecular modeling of the structure of
carbohydrates 85

Reprint File Index 85

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OIAI

Physical Sciences Laboratory

George H. Weiss, Chief

Summary of Activities

Consulting Services. George H. Weiss (PSL). PSL
provides consulting services to NIH researchers in
problems relating to the physical sciences, applied
mathematics, and statistics.

Theory of Biochemical Separation Techniques.

George H. Weiss (PSL). Several results were obtained
for the solution of partial differential equations
describing chromatographic systems with random
mobilities. These are necessarily approximate, malting
use of the method of averaging. They appear to
contradict the conjectured Gaussian shape of the
peaks of isolated species in ideal columns.

Studies in Mathematics and Statistics. George H.
Weiss (PSL). Several projects have been undertaken
on the application of random walk methods in the
determination of crystallographic structures. These
methods allow the experimenter to distinguish between
different space groups using available data. The
general problem of fitting a probability density function
using moments also has been studied with particular
application to crystallography, but with a wider area of
possible use.

Correlation Function Spectroscopy/Laser Light
Scattering. Ralph Nossal (PSL). Considerable time on
this project was devoted to the application of light
scattering techniques to problems arising in other work
by NIH scientists. For example, a combination of light
scattering and ultracentrifugation has been used to
characterize the heterogeneity of coated vesicles from
brain tissue.

Molecular Forces in Cellular Assembly. Adrian
Parsegian (PSL). The technique developed for
measuring the force between DNA helices in solution
has been successfully applied to find the pressure
needed to pack DNA into a viral head.

Effect of Solvent on the Properties of Biological
Macromolecules. B. Lee (PSL). This study is made
using statistical mechanical techniques. We have
shown, for example, that a protein molecule "breathes"
in aqueous solution and that the extent of this
breathing motion is directly related to the repulsion
between protein and water molecules.

Quantitative Analysis of Cell Structure, Membranes,
and Organ Development. Nahum Gershon (PSL) This
project is directed towards image reconstruction from
electron micrographs of cells taken at the University of
Colorado and NICHD. A computer system has been
assembled, and software is being written for
manipulation of the digitized images.

Research Projects

OEPAKTMI NT OF HIAI.TH AHD HUMAN URVICII ^SllC HIAITMHRVKI
NOTICC OF INTRAMURAL REUARCH PROJKCT

»«OMCt MUMa««

lOl CT000:2-lt PIL

October

I, 1962 [0 Sapteabcr 30, 19a] I

Cotnultlng Service* |

George

H. Uclia, Ph.D., Chl<f, PSL, DOT

J. E. K
NINCDS;
LCP, Kl

l.f.r. PSl'dCRT; >. J. NmkI. Ph.D.. KL, DCKT; >. ». lrook>, »,
J. A. rirr«tcl, U CH, NMLBIl J. L. tran, C DCCT B, KCli A. Siako, A

U>DK

Phy.ic.

Science! Laboratory

n of Coapucer Reaaarch and Tachnoloty 1

1.0 1 0.9 1 0.1 1

Consulting Services

Consulting services are provided to NIH researchers in
a variety of disciplines including physics, applied
mathematics, and statistics. A theory has been
developed for the calculation of sampling errors in
kinetics experiments. Two variants of the theory have
been applied, one to parameters measured in the use
of positron emission tomography, and the second to
errors incurred in Fourier transform NMR spectroscopy.
In the first of these applications the techniques allow
estimation of experimental error from available data,
but will also furnish a means of optimizing the use of
PET scanners. In the second, we have compared the
accuracy and precision of peak area estimates
obtained by curve fitting and numerical integration from
FT NMR data. Both methods are currently used by
NMR spectroscopists, but our analysis showed that
curve fitting is far superior to numerical integration.

A joint study of the validity of the Wilemski-Fixman
approximation for calculations of rates in polymer

physics is presently underway with A. Szabo.
Calculations with an exactly solvable model allow us to
estimate the limits of validity of this model, and integral
equation methods have suggested more accurate
alternatives to the much used approximation.
Together with J. Aron we have developed a
mathematical model of the kinetics of diseases with
superinfection.

A joint project has been initiated on the understanding
of the kinetics of diffusion-controlled reactions.
Approximate techniques for the solution of such
problems in polymer physics have been in the literature
for many years. An application of infinite order
perturbation theory techniques has led to an
understanding of limitations on present appproximations
and to improvements in the calculation of rates.
Publications:

stone M Sonies, B. C, Shawker, T. H., Weiss, G. H., and Nadel, L • Analysis

'^'"intr" ^''^?''' ^- ''■• ^'"^i^'lel-Lechtape, H., and McNeel, M. L ■ Life

woria war I. Arch. Neurol. 39: 741-743 1982
"""'p' and Rrsr?'; "p"'- ''"'"""''■ ''•'"■■ °'"°"' °- "^'^''-^ J- P- Mohr, J.

^^thL:;^^^^^^ '"' '^^ °~ °' p-«— .ic

"^^'pi'J^- r- ^^'''"'' '• ^- '^^'^'- '■ ^- ^"-^ J^^obson, L: A method for
C^^inTr^r '° "'^^ ''"^^'^"°" '" ^°^ -asurer^rs.'!

''''/^a,':LT4'Soi: I'ss' ""'""•°'^' ^""'^^ '" P^^armacology. .

Weiss, G H., and Szabo, A.: First passage problems for a class of master
equations mth separable kernels. /'Ays/ca (in press)

reduce CT^t'/k' h' T'.'"°'^' '^^ "'^ ^^^ "^ °' P^-- views to

OEPARTIMENT OF HEALTH AND HUMAN ■!PB(/,(-cc D.,n. .......

n ANu HUMAN SERVICES - PUBLIC HEALTH SERVICE

NOTICE OF INTRAMURAL RESEARCH PROJECT

October 1, 1982 to September 30. 1983
Theory of BiochemlcaT'se'Ir^tTonTechnlo.'.

ZOl CT0O014-16 PSL

George K. Weiss, Ph.D., ChTef. PSL. DCRT

h. D., La Jolle Institute, U JoUa, CA

Physical Scle

Division of Computi

Theory of Biochemical Separation Techniques

Mathematical techniques are developed and applied to
the design and analysis of biochemical separation
experiments. The study of chromatographic systems
with randomly varying mobilities has been initiated
partly verifying and partly contradicting speculations
about the effects of random parameters that have
appeared in the literature.

Pubiications:

Weiss, G. H.: Chromatographic kinetics and the phenomenon of tailing Sep.
Sci. & Tech. 17:1609-1622, 1982.

Weiss, G. H., and Rice, J.: Optimal parameters for the measurement of the half-
width of a Gaussian peak. Sep. Sci. & Tech. 17: 1101-1115, 1982.

DEPARTMENT OP HEALTH ANO HUMAN SERVICES - PUBLIC H

NOTICE OF INTRAMURAL RESEARCH PROJECT

ZOl CT00024-08 PSL

ISl4;;^nlverslty. Is^Ll. .-.I^'c'^^l^^f "p;!^.":i°i:f^-/-„f;-t^^ "•°-'

Division of Computi

Studies in IMathematics and Statistics

We have analyzed several aspects of Pearson random
walks that are useful in determining the space groups

of molecules from crystallographic data. In particular,
an exact expression fias been found for the probability
density of tfie projection of a Pearson random walk
near maximum extension. Useful numerical methiods
have been developed for calculating the projection
density as well as the end-to-end density for Pearson
random walks with one or two outstandingly long steps
included among a larger number of smaller steps.

Publications:

Kieler, J. E., and Weiss, G. H.: The Pearson random walk, AlP Proceedings (in
press).

Rubin, R. J., and Weiss, G. H.: Limiting thickness of an adsorbed polymer
chain. J. Cham. Phys. 78: 2039-2043, 1983.

Weiss, G. H.: Random walks and their applications. Am. Sci. 71: 65-71, 1983.

Weiss, G. H.: Random walks. Encycl. Slat. Sci. (in press).

Weiss, G. H., and Kiefer, J. E.: The Pearson random walk with unequal step
sizes. J. Phys. A: Math Gen. 16: 489-495, 1983.

Weiss, G. H., and Rubin, R. J. (Eds.): Proceedings of the Symposium on
Random Walks. J. Stat Phys 30: 249-561, 1983.

Weiss, G. H., and Rubin, R. J.: Random walks: theory and selected applica-
tions. Adv. Chem. Phys. 52: 363-505, 1983.

Weiss, G. H., Shuler, K. E., and Lindenberg, K,: Order statistics for first passage
times in diffusion processes. J. Slat Phys 31:255-278, 1983.

NOTICE OF INTRAMURAL RESEARCH PROJECT

ZOl CT00021-12 PSL

October 1. 1982 to Seotember 30. 1983

Correlation Function Spectroscopy/Laser Lluht Scatterlne

PRINCIPAL INVESTIGATOR (Ujfolh«,pro/<MlonaJpiF*Ofln<l on *ubM«u*nltM(«.,
INamt. niU, laOoroIory. and (n.llluw oWIloWon,

Ralph J. Nossal, Ph.D., Research Physicist. PSL, DCRT

R. Bonner, Ph.D., BEIB, DRS: H. Edelhoch, Ph.D., CE, NIADDK
LBC, NIADDK; H. Lltt, Ph.D., Dept. Cheo. Eng., Univ. Pennsy
Ph.D., Dept. Chem. Eng., Univ. PA; C. H. Weiss. PSL, KRT.

J. CLadner, Ph.D..
vanla; C. A. Stelner,

Physical Sciences Laboratory

0.9 1 0.8 1 0

Correlation Function Spectroscopy/ Laser Light
Scattering

Several studies involving dynamic light scattering
techniques have been undertaken in collaboration with
scientists at NIH and other research institutions. Recent
emphasis has been on developing methods to study
the properties of large lattice-like polymer structures.
These techniques have been applied, for example, to
an examination of fibrin gels and plasma clots in order
to assess the effects of subunit crosslinking on the
resistance of a clot to proteolytic degradation. Other

studies concern the development of shear ngidity in
plasma clots, the relationship between molecular
structure and the mechanical properties of
polyacrylamide gels, and the effects of calcium ions on
the conformations of mucin glycoproteins.

Assistance has been given to other research projects
for which it has been important to obtain information
about the size of particles in laboratory samples.
Notable among these is an investigation of the efficacy
of protocols for preparing "coated vesicles" from brain
tissue (cf. project Z01 CT 00022-16 PSL). Also, we
continue to provide supporting services for the
development of laser Doppler bloodflow instrumentation
and other devices utilizing quasi-elastic light scattering.

Publications:

Gladner, J A , and Nossal. R.: Effects of crosslinking on the rigidity and

proteolytic susceptibility of human fibnn clots Thrombosis Res 30:273-278.

1983.
Nossal, R., and Jolly. M : Shear waves and internal viscosity in cylindncal gels.

J. Appl. Phys 53:5518-5525. 1982
Nossal, R.. Weiss. G. H., Nandi, P K . Lippoldt, R E., and Edelhoch, H.: Sizes

and mass distribution of clalhnn coated vesicles from bovine brain. Arch.

Biochem. Biophys. (in press).
Sleiner, C A.. Litt, 1^., and Nossal, R Applications of dynamic light scattenng

to studies of mucin structure Proceedings of 1983 Symposium on New

Techniques in Biorheology (in press)
Steiner, C. A., Litt, 1^.. and Nossal. R.: Effects of calcium ions on the stnjcture

of canine tracheal mucin, Biorheology (m press).

OEPAfllMCMT OP HIALTM AM> HUMAN HRVICtS PUILIC HI AiTM HRVICI
NOTICE OF INTRAMURAl. REIEARCH PROJECT

ZOl 000017-11 HL

October 1. 1982 to S«ct««ber 30. 1983

Cell Motility and Cheaot.Als

«1. Ph.D.. »«»««rch PhirilcUt. rSL. CCTT

Physical Science. Labor.tory

slon of Co»put'

R«...rch Md T.chnoloty

Cell Motility and Chemotaxis

Theoretical and experimental analyses of various
aspects of cell locomotion have been undertaken over
the past few years. These have included formulation of
mathematical descriptions of the macroscopic response

that moving cells show in response to chemical stimuli
in order to understand the relationships between the
net movements of a population of cells and the
underlying stochastic motile behavior of individual cells
within that population. Such information is useful in
interpreting the results of in vitro assays for leukocyte
chemotaxis. Other aspects of this project include
development of laser light scattering techniques for
measuring the motility of flagellated bacteria and other
swimming microorganisms. We also have been
concerned with devising dynamic light scattering
schemes for probing the mechanical properties of
cytoplasmic gels. Current emphasis is on formulating
mathematical descriptions of the sequence of
biophysical phenomena involved in the transduction of
information about chemical gradients into the
locomotory response of chemotactic bacteria.
Publications:

Nossal, R.: Stochastic aspects of biological locomotion. J. Stat. Ptiys. 30:391-

measurements show qualitative differences from
popular theories adds to the interest in our findings.

Studies on bilayer membrane interaction have revealed
the importance of these forces in bilayer deformation
and uncovered conceptual difficulties associated with
models of cell membrane fusion.

In all these systems the paramount role of "hydration"
forces, first identified by Parsegian and Rand, is
evident. The primacy of hydration factors is emerging
as a theme of molecular assembly in cellular and
subcellular systems.

Publications:

Gruen, D. W. R., Marcelja, S., and Parsegian, V. A.: Water structure near the
membrane surface. In Perelson, A. (Ed.): Membrane Surfaces. New Yorl<
Marcel Del<ker (in press).

Loosley-Millman, M. E., Rand, R. P., and Parsegian, V. A.: Effects of monova-
lent ion binding and screening on measured electrostatic forces between
charged phospholipid bilayers. Biophiys. J. 40:221-232, 1982.

Parsegian, V. A.: Dimensions of the "intermediate" phase of dipalmitoylphos-
phatidylcholine. Bioptiys. J. (in press).

DEPARTMENT OF HEALTH AND HUMAIU <!pnv/i,.cc n. .i^. ...

t^rtu HUMAN bERVICES ■ PUBLIC HEALTH SERVICE

NOTICE OF INTRAMURAL RESEARCH PROJECT

ZOl CT00026-08 PSL

September 30^ 1983

PRINCIPAL
V. Adrian Parsegian

n Cellular Assembly

Physlcls

Rand, Ph.D., and N. Fuller
Inst. Tech., Chicago, IL;
Z. Zlmmerberg, H.D., Ph.D.

PSL, DCRT

Physical Scle

Ph.D., Brock Univ., Canada; L. J. Us, Ph.i.. lu
.A Evans, Ph.D., U. British Columbia, Canada- J
_PSL, DCRT; S. Bhlte. Ph.D.. „■ r. , T^^i^e "ps,' JU..

■°.-?!f°" °^'^°°''"'" ■'f"'-'=h and Technnln^,,

Molecular Forces in Cellular Assembly

After achieving a direct measurement of forces
between DNA double helices in solution last year, we
have systematically investigated the determination of
that force by the ionic species bound to the molecular
surface. An especially exciting byproduct of our
investigation was the realization that DNA in
bacteriophage heads is under conditions similar to
those under which we made our measurements. We
have thus determined the long sought "DNA pressure"
of packing the viral head. The fact that our

EALTH AND HUMAN SERVICES ■ PUBLIC HEALTH
NOTICE OF INTRAMURAL RESEARCH PROJECT

ZOl CT00066-04 PSL

October 1, 1982

■ September 30. 1983

Computerized Type

Ific Paper

7sr^''r^UT^-''7'T"\ "• ^""^°'^'^' PSL. DCRT; M. McHeel. Computer Systems Analys
SyiU^ L!;.? flf 'J^t'"'" '^''""^ '^"'^^^* ^S' °^T: M. Horton. Compute
lroll7sit:ii:he.T' '^"'' '^°='^^^^^^« ^^Uer^ity Pr.ss. Science PreL. "

of Computer Research and Technology

Computerized Typesetting of Scientific Papers

During the current year this project has enjoyed good
practical progress toward achieving its objective of
converting word processor output to a typeset page in
a scientific journal. There has been a shift in emphasis
from sending magnetic media such as tape to
telephonic transmission of text processed on WYLBUR
files.

We have been investigating the interaction of
microprocessors with mainframe systems to learn how

best to distribute the successive steps of initial keying,
correcting, encoding and typesetting. The expected
advent of the IBfVl Personal Computer will, together
with the PSL Micom and Osborne units, bring to three
the number of small systems that can be coordinated
with WYLBUR programs and used to send coded
information, (fvlany more small systems can, of course,
transmit material to WYLBUR for later processing.)

Our activities have attracted attention and brought
inquiry from several publishing groups in this country
and abroad. Publishers are understandably uncertain
about computerization and curious about our
experience. In collaboration with the Biophysical
Society, we recently surveyed its members to learn that
some 80 percent of the respondents can prepare
papers on word processors and about 50 percent
should have modem capability. These figures reveal the
abundant source of "compuscripts" that can now be
processed using the methods being developed here.

NOTICE OF INTRAMURAL RESEARCH PROJECT

ZOl Cr00041-0S PSL

1, 1982 to September 30, 1983

Quantitative Analysis of Cell St

and Orjtan Developmen

I.D.. Visiting Scientist, PSL, PCRT

R. Nossal, Ph.D., PSL, DCRT; K. Porter, Ph.D., Fogarty Scholar, Fogarty Inter
national Center and University of Colorado, Boulder, CO; B. Trua, Ph.D., CSL,

ch and Technology

Quantitative Analysis of Cell Structure, Membranes
and Organ Development

We have developed a new method for the three-
dimensional reconstruction of cellular structure in order
to understand this structure at a macromolecular level
and how structure is related to biochemical and
biological function. We use electron micrographs
produced by a high voltage electron microscope (a
national resource sponsored by NIH) In Boulder,
Colorado and other electron and light micrographs
taken at NIH. This method was extended to a
microcomputer with high resolution color graphics.

Software for the image digitization, alignment-of-
sectlons and for the whole image reconstruction from
the separate sections has been accomplished. We
continue now to develop software for realtime rotation
and image representation in three- and two-dimensions.

This methodology will be employed to determine the
organization of microtubule nucleatlon centers in cells.
It will be important for studies of the determinants of
cell shape and development. Cytoplasmic structure and
diffusion within cells will be also analyzed. In addition,
studies of embryonic and brain development are
planned using this newly constructed facility.

The second part of this project Is concerned with
volume, surface area, and space for diffusion of the
cytoplasmic matrix. We developed a new image
analysis method to measure the volume fraction and
the surface area occupied by cells by the gelatinous
cytoplasmic matrix (the cytoskeletion and
microtrabecular lattice). It involves analysis of electron
microscopic data using a video frame buffer (DCRT's
Evans & Sutherland System). The results obtained so
far show that these structures occupy no more than 10-
30 percent of the cytoplasmic volume. Comparing it
with protein diffusion results yielded values for binding
energies of proteins to the cytoplasmic matrix. A study
on the effect of osmotic conditions on the volume of
the cytoplasmic matrix has been initiated and will be
further studied. The use of these techniques will be
extended to study immunocytochemical systems.

Publications:

Gershon, N . Porter, K., ar)d Trus. B : The miaotrabecular lattica and the
cytoskeleton. Their volume, surface area and the ditlusion o( rDolecules
through it. Proceedings of the KaUir-Katchalsky Memonat Symposium (in
press).

NOTICE OF INTRAMURAL RESEARCH PROJECT

ZOl GT00068-04 PSL

Octobe

r I, 1982 to September 30. 1983

Dlffus

Ion of Molecules on Cell Surfaces and Light Scatt

ering from Fluids

N. Gerahon. Ph.D., Visiting Scientist. PSL. DCRT

B. Mz

enbud, Ph.D., M.I.T., Cambridge. MA

Physic

al Sciences Laboratory

°""""

DlvisI

on of Computer Research and Technology

0.2 0.1

0.1

Diffusion of [Molecules on Cell Surfaces and Light
Scattering from Fluids

Membranes are usually assumed to be planar when
diffusion coefficients are calculated from the results of
fluorescence photobleaching recovery (FPR)
experiments. It was shown that for a model system,
that under typical conditions of membrane topography,
and for the particular geometry of spot FPR, the
calculated diffusion coefficient can be weakly sensitive
to the microvilli length. However, an anisotropic
nonplanarity of membrane might lead to anisotropic
diffusion that can be detected by pattern FPR. We
found that surface corrugation alone cannot explain the
reported value of diffusion anisotropy.

Publications:

Aizenbud, B., and Gershon, N. D.: Diffusion of molecules on biological mem-
branes of nonplanar form--a theoretical study. Biophys. J. 38: 287-293,
1982.

Aizenbud, B., and Gershon, N. D.: Diffusion of molecules on microvillous bio-
logical membranes. In Perelson, A. C, DeLisi, C, and Wiegel, F. W. (Eds.):
Cell Surface Phenomena. New York, Marcel Dekker (in press).

Aizenbud, B., and Gershon, N. D.: Hydrodynamic equations and VH light scat-
tering from viscoelastic (solid-like) systems. II. Molecular approach. Physica
108A: 583-588, 1981,

NOTICE OF INTRAMURAL RESEARCH PROJECT

ZOl CT00108-01 PSL

October 1, 1982 to September 30, 1983

Effect of Solvent on Biological Macromolecules

B. Lee, Ph.D., Expert, PSL, DCRT

V. A. Parsegian, Ph.D., PSL, DCRT; D. Rau, Ph.D.,

NIADDK

Physical Sciences Laboratory ^^^^H|

SECTION -^

Division Of Computer Research and Technology

0.4 1 0.4 1

0.0

Effect of Solvent on Biological Macromolecules

Solvent can interact with the biological macromolecules
in two ways. It can bind to the solute strongly and
specifically, giving rise to, among other things, the
hydration force. With V. A. Parsegian and D. Rau, we
measured the magnitude of this force between DNA
double helices. This aspect of the study is reported by
Parsegian. In addition, we compared the protein-protein
interactions that occur in the crystal with those between
the subunits in multimeric protein complexes. We found
that the former is generally more complex than the
latter but few other generalizations were possible. This
aspect of the study will continue.

The solvent can also influence the behavior of
macromolecules in a general and nonspecific way.
Study of this aspect generally coincides with the study
of the hydrophobic phenomenon. This was studied
using statistical mechanical methods. I have
succeeded, for example, in finding the physical origin of
the hydrophobic volume shrinkage phenomenon and in
computing the extent of volume fluctuation of globular
protein molecules. However, in order to properly apply
this rigorous procedure to biological macromolecules, a
way must be found that will handle nonspherical
solutes. A new approximation scheme was discovered
to this end, and future efforts will be concentrated on
developing this approximation scheme.

Publications:

Lee, B.: Calculation of volume fluctuation for globular protein models. Proc.

Nail. Acad. Sci. USA 80; 622-626, 1983.
Lee, B.: Partial molar volume from ttie hard-sphere mixture model. J. Phys.

Chem. 87: 112-118, 1983.

.^ilSTRY i ,-s^-^i%s. u iCALANALYSISCELLLOCOMOTie
SESLASERLIGHTSCATTERINGBIOCHEMISTRYCH^
ROBABILITYDENSITYFUNCTIOHMOLECULARFORC

COMPUTER-BASEDSTUDIESMATHEMATICALTHEC
PUTINGSINGULARVALUEDECOMPOSITIONDATAF
MATHEMATICSMEDICALAPPLICATIONSSTATISTK
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Laboratory of Applied Studies

John E. Fletcher, Acting Chief

Clinical Research and Patient Care

Computer-based studies of physiology and
pathophysiology during exercise. R. Burgess, M.
Horton, E. Pottala, J. Bailey (LAS); A. Nienhuis, R.
Crystal (NHLBI). In this project, breath-by-breath
analyses of pulmonary gas exchange performed by a
laboratory minicomputer-based system are the bases
for studies of oxygen delivery to tissue in normal states
and in pulmonary, cardiovascular, and hematologic
pathophysiologies. Serial testing of a patient provides
objective indications of severity of disease and efficacy
of treatment. A protocol for studying drug therapy in
patients with sickle cell disease is being carried out.

Computer-based method of monitoring central
nervous system function in critically ill patients. R.

Burgess, M. Horton, E. Pottala, J. Bailey (LAS); 0.
Natanson, J. Parrillo (CC). The goal of this project is to
develop a microcomputer-based system for analysis
and display of scalp-recorded neuroelectrophysiological
signals following programmed stimuli (i.e., evoked
potentials). These stimuli will permit one to estimate
and to follow CNS (especially cerebral) function in
critically ill patients. Most of the equipment that was
designed in the previous year for the system has been
procured; hardware interfacing and basic software
development have been initiated.

Computer systems for nuclear medicine. M.

Douglas, J. Bailey, R. Burgess (LAS); S. Bacharach, et.
al., (CO, Nuclear fvledicine); R. Bonow (NHLBI). This
project involves development and application of
computer methods to such diagnostic imaging activities
as ECG-gated radionuclide ventriculography and
dynamic scintigraphic studies of other organs (e.g..
kidneys, lungs). Extensive studies of regional time-
activity curves in radionuclide ventriculography have
revealed important relationships between the harmonic
content of the curves, their signal-to-noise ratios, and
their average scintillation counts. This relationship
determines the reliability of various parameters of
regional cardiac function as well as the optimum design
for filtering the curves. A study of gallium scans has
revealed that the routine, noncomputerized scans have
a very narrow window for intensity response and hence

the clinicians are not seeing all the information
potentially available through computer processing.

Computer analysis of electrocardiograms. J. Bailey,
M. Horton (LAS); D. Savage, S. Palmeri (NHLBI); L.
Jackson (Georgetown University Medical Center). The
continuing goals of this project have been to evaluate
the diagnostic power and epidemiological utility of the
leading computer programs for ECG interpretation.
EGG data on several thousand cases from the
Framingham study have been collected. Of these, five
to six percent also have echocardiographic evidence
for left ventricular hypertrophy. The most accurate ECG
indicators of this condition are being identified in these
data. The ECG Laboratory of Georgetown University
Medical Center has collected simultaneous 12-lead
data on well-documented, normal and abnormal cardiac
patients; this data base also is being examined to
compare diagnostic accuracy of the Hewlett-Packard,
the IBM, and the Marquette ECG programs in a
collaborative study with LAS and NHLBI.

Statistical research in clinical pathology. E. Harris,
M. Horton, A. Albert (LAS); G. Shakarji, D. VanSant
(DMB); clinical chemists and others in the U.S.A.,
Europe, and Japan. This research involves application
of statistical theory to clinical laboratory tests, including
serial studies of blood chemistries in health and
disease. A collaborative study to explore relative
sensitivities of subject-specific, univariate and
multivariate decision criteria has progressed through
identification and collation of data from approximately
100 outpatients with independently diagnosed liver
dysfunctions. A previously reported method for deriving
reference differences as criteria to evaluate observed
changes has been extended to trends, and effects of
analytic variation on the sensitivity of these criteria
have been determined. In collaboration with clinical
pathologists, this method is now being applied to
selected categories of inpatients.

Laboratory Investigations

Computer analysis of electron and x-ray
micrographs. M. Douglas, J. Bailey (LAS); J. Costa
(NIMH). This project involves the development and

implementation of mathematical models and image
enhancement techniques to analyze computer-acquired
information from electron energy-loss and x-ray spectra
indicating the location of extremely small quantities of
important chemical elements and active protein
molecules within cells. Dense bodies in electron
micrographs of blood platelets are being examined
currently with this system.

Hybrid computing to analyze physiologic signals. E.

Pottala, H. Le, J. Bailey (LAS); J. Dvorak (NIAID); M.
Postan (WHO); W. van Arsdel (FDA). This project uses
the LAS minicomputer system (MAC-16) for analysis of
biological signals (EGG, EMG, EEG, etc.). This year,
methods for acquiring and analyzing rodent
electrocardiograms were developed so that animal
models of drug-hiduced cardiotoxicity (FDA) and
myocardial infections (NIAID, WHO) could be studied.

Mathematical modeling of biological processes. J.

Fletcher (LAS); R. Schubert (Lousiana Tech. Univ.).
Mathematical models that describe the relationships
between free and facilitated substrate diffusion,
metabolism, and microcirculatory flow transport are
being developed and evaluated. These models can
identify the critical physiological parameters for
substrate supply to tissue and to their ranges in normal
and pathophysiological states. Exploration of a new
unified model for perfused organ experiments has
continued. Limits of capillary wall permeabilities were
developed, and some analysis of the effects of
Michaelis-Menten kinetics is undenvay. A reexamination
of model conditions when hemoglobin and/or red cells
are present in the perfusing fluid is also in its early
stages.

Network modeling in biology. B. Bunow, E. Pottala
(LAS); T. Colburn (NIMH); and other NIH, FDA, and
NIOSH scientists. LAS has shown that network
simulation languages (e.g., NET2, SPICE), operating on
NIH central computers and VAX sytems at NIMH, NCI,
and NIADDK, provide a powerful modeling tool for NIH
scientists who are modeling neural, electromechanical,
and biochemical systems.

Active transport, biochemical Itinetics, and their
interactions. B. Bunow (LAS); D. Mikulecky (Medical
College of Virginia); J. Kernevez (Univ. of Tech.,

To '

Compiegne, France); R. Hendler (NHLBI). This project
examines experimental and mathematical studies of
kinetics and thermodynamics of biological processes
involving enzyme-catalyzed reactions. Thermodynamic
principles and mathematical analysis were applied, in
collaboration with NIH scientists, to problems in
membrane transport, bioenergetics, and ligand binding
A kinetic description of simultaneous reaction and
transport has been developed that shows the
inadequacy of previous irreversible thermodynamic
approaches.

Computer Research and Software
Development

Mathematical and computational methods for
solving nonlinear equations. R. Shrager (LAS); R.
Hendler, R. Kincaid (NHLBI); B. Kamgar-Parsi
(University of Maryland). A root-finc|er for one equation
in one unknown has been developed that converges to
a local root and determines machine precision of that
root. The method converges in reasonable time despite
poor initial estimates. A minimizer of a function of
several variables has been coded, and is being
extended to handle linear constraints. Algebraic-
differential systems that contain both nonlinear
algebraic and differential equations have considerable
application in biochemistry and pharmacokinetics.
Software to solve these systems is being designed and
investigated. The rootfinder, the minimizer, and the
algebraic-differential systems solver are all intended for
eventual inclusion in MLAB. Immediate research
applications of this project include simulation of whole
blood oxygen saturation, calmodulin-calcium-
magnesium interactions, oxygen uptake by
mitochondria, and GABA metabolism as affected by
hepatic failure in rabbits.

Numerical methods for the solution of
mathematical models describing reaction-diffusion
and other processes in biological systems. M.

Bieterman, J.E. Fletcher (LAS); I. Babuska (University
of Maryland). This project is concerned with the
investigation, development, and implementation of
numerical solution methods for systems of partial
differential equations that are used to model dynamic

I
I

physiological processes. Adaptive finite element
methods have been applied to and are shown to be
effective for models of facilitated diffusion in tissue,
population ecology and genetics, hyperthermia studies
involving models of bioheat transfer, and models for
nerve conduction. Software packages implementing
these methods are now available on the IBM System
370 and on the DECsystem-10.

Research Projects

NOTICE OF INTRAMURAL RESEARCH PROJECT

:01 CT00054-07

LAS

October 1, 1982 to September 30, 1985 1

Coniputer-based Studies of PhysiolORV and PathophysiolORy D

jrinR Exercise

R.C. Burgess Senior Staff Fellow IAS

DCRT

M.R. Horton Computer System Analyst, LAS KRT
(M, NHLBI: PB, >JHLBI : LCB, NIADDK

Laboraton- of Applied Studies

Medical Applications Section

NIH, DCRT. Bethesda, MD 20205

1.65 1 1.50 1 0.15

Computer-based Studies of Physiology and
Pathophysiology During Exercise

This project, through a collaborative effort of LAS with
the Clinical Hematology and Pulmonary Branches of
NHLBI, is directed toward a deeper understanding of
the physiology and pathophysiology of oxygen transport
to tissues through the use of computerized breath-by-
breath analysis of gas exchange and computer-based
models of ventilation and oxygen transport.

Progress in FY83: The hardware obtained during FY81-
82 has been configured into a comprehensive
computerized exercise laboratory. Software
developments include:

1. automatic control of the time-dependent exercise
regimen on the bicycle ergometer or treadmill,
according to a design customized to each patient;

2. facilitated daily calibration of sensors, through
extensive operator prompting;

3. acquisition of multichannel data in realtime,
conversion to actual units, and correction for humidity
and barometric pressure;

4. processing of data online to derive breath-by-
breath parameters of gas exchange; and

5. entry of patient/study identification information to
be stored with the computed breath-by-breath
parameters.

A study to evaluate the use of several classes of
vasodilators in sickle cell anemia has been underway
since October 1982. Testing of Hydralazine has been
concluded. The side effects of Hydralazine (pnmarily
tachycardia, fever, and rash) precluded the
demonstration of any beneficial effect. However, the
exercise laboratory has proved its capabilities as an
effective and objective tool for evaluating morbidity and
therapeutic efficacy in sickle cell disease.

Proposed Course: Further refinement of the software to
improve detection of the anaerobic threshold and other
functional measures has begun. A significant focus of
the FY84 effort will be the development of clinically
usable displays of both realtime data and computed
parameters.

Large scale testing of normal volunteers will be carried
out and correlated with other measures of fitness. A
preliminary test of Nifedipine in sickle cell disease
suggests that it may be beneficial; an expanded study
of this agent will be pursued during the coming year. An
experimental protocol to evaluate the effect of
colchicine in patients with sarcoidosis has been
submitted in collaboration with the Pulmonary Branch,
NHLBI, to the Human Experimentation Committee for
approval.

NOTICE OF INTRAMURAL RESEARCH PROJECT

ZOl cr00098-02 LAS

October 1. 1982 to September 30, 1983

Computer Based Method of Nfonitoring the CNS in Critically 111 Patients

R.C. Burgess Senior Staff Fellow LAS DCRT

Critical Care Medicine, Clinical Center

Laboratory of Applied Studies

Medical Applications Section

DCRT, NIH, Bethesda, MD 20205

1.05 1 0.90 1 0.15

Computer Based Method of Monitoring the CNS in
Critically III Patients

This project is a joint effort between the Laboratory of
Applied Studies and the Department of Critical Care
Medicine to design, build, and implement a highly
clinically oriented, distributed-processing,
microcomputer-based system for analysis and display
of scalp-recorded neuroelectric signals.

This tool will be used to investigate the degree of
dysfunction in neurologically impaired patients,
correlate the indices developed with other measures of
cerebral function, and evaluate the effectiveness of
various therapeutic interventions.

Background and Objectives: In the critically ill patient
with multiple organ dysfunction, impaired brain function
frequently coincides with deterioration of other major
systems. However, the degree of damage and capacity
for restoration of the brain does not necessarily parallel
that of the rest of the body. In addition, assessment of
the central nervous system is hampered by limitations
imposed by procedures (e.g., endotracheal intubation)
and/or drugs (e.g., Pavulon).

The initial phase of this project is directed toward the
development of a comprehensive, mobile,
neurodiagnostic system including:
1 . a precision analog front end for low-noise
detection, amplification, and filtering of the
spontaneous and evoked EEG activity;

2. devices to deliver programmed, visual, auditory
and somatosensory stimuli;

3. a central processor with intelligent peripherals for ^
data acquisition, manipulation, calculation, and B
storage; and ™

4. a display capable of high resolution graphics and
printout for presentation of current and past data,
trends, and interpretive imaging.

After initial development and testing has been
completed, the system will be used in the Critical Care
Unit, Clinical Center, to address the following questions:

• Which electrophysiological parameters can be used
to best follow the functional neurologic status of the
patients?

• What is the optimal protocol for obtaining data in
order to balance recording requirements and nursing
care needs?

• How can the parameters be best combined into a
meaningful profile and be best displayed to provide
comprehensive, yet easy-to-assimilate, clinical
information?

• How does the information offered by this system
compare to other neurodiagnostic techniques?

• How does this system improve care of the patient
and understanding of the pathophysiologic dynamics?

Progress in FY83: The equipment specified in the
system design that was accomplished in FY82 has
been procured. Custom mechanical and electronic
fabrication is underway. Equipment has been mounted
in a specialized rack that can be wheeled to the
bedside of the patient to be monitored. Design of the
interface between the host CPU and the array
processor has been completed. The design of software
to control simultaneous stimulation, data acquisition,
storage, and display in the realtime environment has
been initiated.

Proposed Course: Extensive development of both
hardware and software will be carried out during the
coming year. Acquisition of noise-free, microvolt-level
signals from the patient's scalp in the electrically hostile
environment of the Critical Care Unit is crucial to
reliable semi-automatic monitoring of CNS function. To
accomplish this task a computer controlled, IEEE-488

compatible, front-end preamplifier/filter will be
completed. Multiple algorithms for extracting functional
information from multimodality evoked potentials will be
implemented.

NOTICE OF INTRAMURAL RESEARCH PROJECT

ZOl CTOOOOS-12 IAS

(Tctober I. 1983 to Sentember 30. 1983

Computer System Analyst

Laboratory' of Applied Studii

Medical Appli

DCRT, NIH, Bethesda. MP 20;0S

Computer Systems for Nuclear Medicine

This project involves computer-based mathematical
analysis, pattern recognition, and image processing in
support of diagnostic activities in the Nuclear Medicine
Department of the Clinical Center and collaborating
Institutes. Applications include computerized ECG-
gated radionuclide angiocardiography and myocardial
perfusion scintigraphy, renal dynamics, and pulmonary
ventilation-perfusion relationships.

Progress in FY83: Cardiac Scintigraphy: In collaboration
with Nuclear Medicine and the Cardiology Branch, LAS
has investigated more than 40 parameters related to
mobility of the heart wall. These parameters include
ejection fraction, regional emptying time, relative
emptying time, relative stroke volume, phase (of the
first Fourier harmonic), and maximum ejection rate. All
parameters were generated for all cases in a data base
consisting of 40 normal volunteers, 24 patients with
coronary disease and known resting apical
abnormalties (akinesis or dyskinesis), and 15 patients
with cardiomyopathy. The power of each parameter to
discriminate between these 3 groups has been
evaluated. Global ejection rate and global filling fraction
are the parameters that discriminate best between
normal and abnormal cases. Relative stroke volume
and regional ejection time in the apical regions are the
best separators of apically normal from apically

abnormal cases. A manuscnpt descnbing this study is
being prepared.

Investigation of the signal to noise and Founer
harmonic content of global and regional time activity
curves (TAC's) has been completed. This study showed
that the physiological signal is largely descnbed by four
or fewer harmonics and that regions smaller than one-
fourth of the ventricular region of interest produce
TAC's that cannot be distinguished from background in
terms of S/N ratio or harmonic content.

In conjunction with the Institute for Nuclear Medicine,
University of Utrecht, the Netherlands, algorithms for
the automatic localization of structure in cardiac
scintigraphy have been refined and tested on data from
867 cases. Also, methods of detection of regions of
abnormal ventricular contraction have been
investigated.

A model has been developed to demonstrate the effect
of noise on the reliability of the various parameters
charactenzing the TAC's. Tables for parameters of
interest, such as ejection time and time to end systole,
have been prepared. Each parameter's table gives
several S/N ratios and the associated error in the
computation of the parameter. This sensitivity analysis
provides an indication of the accuracy of the
parameters in clinical use where some background
noise is unavoidable.

Whole body Gallium images are being investigated by
computer methods. The goal of this project is to
improve the quality and repeatablity of the Gallium
Index for lungs, which correlates with active
inflammation. Preliminary data has been acquired and
analyzed at a resolution of 128 x 128 picture elements
for the whole body. Lungs are outlined, and their
isotope uptake is expressed as a percentage of total
body uptake. Early results indicate that
noncomputerized scans have a very narrow intensity
window and hence the clinlicians are not seeing all the
information potentially available through computer
processing.

Renal Scintigraphy: Further documentation of changes
in dog kidneys after ligation of a segmental renal artery
was obtained by gross and histologic necropsy

examination. Visualization by functional mapping
techniques, which had been redeveloped in FY80-82,
correlated well with contrast angiography and necropsy
findings. However, an important necropsy finding was
that the lesions induced by segmental artery ligation
tended to be distributed in a coronal plane on the
dorsal or ventral surface, which was parallel to the
plane of the crystal in the scintigraphic camera.
Therefore, the focal nature of the lesion could not be
demonstrated in the scintigraphic data. The model was
redesigned with a clearer focal lesion to test further the
diagnostic potential of the functional image technique;
however, this project had to be deferred because the
new medical staff fellow who was to continue this work,
was unable to accept an NIH appointment as agreed
during FY82 recruitment.

Pulmonary Scintigraphy: Further worl< in ventilation/
perfusion scintigraphy has been deferred until the
appropriate personnel can be recruited.

Proposed Course: Cardiac Scintigraphy: A statistical
analysis of the existing data base will be continued. A
possible outcome of this might be a discriminant
function using various parameters to achieve an optimal
separation of normals from abnormals. Efforts will be
made to expand the data base in order to obtain better
statistical reliability. Another i'steresting study will
involve those patients with myopathy secondary to
adriamycin therapy, using each patient before therapy
as his own control. Other patients who have normal
contractility at rest but abnormalities upon exercise
form an additional interesting data base.

The new disk system of the DeAnza display terminal is
now operational. This should facilitate study of paired
myocardial (Thallium) and blood pool image sequences.
Refined end-diastolic and end-systolic edge detection,
methods of left ventricle segmentation, assessment of
wall motion abnormalities and perfusion, and more
accurate determination of volumes are planned.

The Gallium study will begin to acquire and analyze
images at an increased resolution of 128 x 256 or 128
x 512 picture elements. A calibrated radionuclide
source is to be placed in the field of view in order to
allow quantification of the uptake. An index of the
homogeneity of uptake (or lung texture) is to be

developed and tested. Automated lung boundary
definition is to be studied.

Publications and Abstracts:

Bacharach, S.L., Green, M.V., Vitale, D., Douglas, M.A., White, G., Bonow, R.O.,
and Jones, A.E.: A minimum error method for temporal fourler filtering of
gated cardiac data. Eighth Conference on Information Processing In Medi-
cal Imaging (In press).

Bacharach, S.L., Green, M.V., Vitale, D., White, G., Douglas, M.A., Bonow, R.O.,
and Jones A.E.; Optimum number of harmonics for filtering Cardiac Volume
Curves. J. Nucl. Med. 24:17, 1982.

de Graaf, C.N., Douglas, M.A., FIndley, S.M., van Rljk, P.P., Bacharach, S.L.,
Green, M.V., and Bonow, R.O.: Een algorithme voor het locallseren van
structuren in scintigraflsche beelden. Nucleair Geneeskundig Bulletin 4:42-
48, 1982.

Douglas, M.A., Bailey, J.J., van Rljk, P.P., Bacharach, S.L., Bonow, R.O., and
Green, M.V.: Analysis of regional function In radionuclide ventriculography:
Physiological signal, scintillation noise, and regional size. Computers in
Cardiology. Silver Spring, MD, IEEE Computer Society, 1983, pp. 315-318.

van Rljk, P.P., Bailey, J.J., and de Graaf, C.N.: Gecomputeriseerde methoden
voor de detectie van regionale ventrlculaire contractleabnormaliteitn. Nu-
cleair Geneeskundig Bulletin 4:49-54, 1982.

NOTICE OF INTRAMURAL RESEARCH PROJECT

ZOl Cr00002-13 LAS

October 1, 1982 to September 30, 1983.

Ccmputer-Aided Analysis of Electrocardiograms

iley Chief, MAS, LAS, DCRT

M.R. Horton Computer System Analyst, LAS DCRT

ECG Lab, Clinical Center ECG Lab, Georgetown Medical Center

Laboratory of Applied Studii

Medical ^pplicati

DCRT, NIH, Bethesda, MD 20205

Computer-Aided Analysis of Electrocardiograms

These studies, continuing since 1 970, are directed
toward the evaluation of accuracy, clinical utility, and
cost effectiveness of various computer programs for
analysis of resting electrocardiograms (ECG's). Further
studies will involve new methods of feature extraction
and design of criteria by computer techniques and their
use in epidemiological studies.

Data on several thousand cases from the Framingham
study have been collected. About five to six percent of
these cases also show evidence of left ventricular
enlargement by two-dimensional echocardiography. In
the younger population slight enlargement is associated

with a vigorous athletic lifestyle and an absence of
ECG stigmata for LVH. In the older population, LVH
tends to be more concentric, more pronounced, and
more often associated with other problems (e.g.,
hypertension) and with positive ECG evidence of LVH.
The variety of cases in this data base allows extensive
testing of ECG algorithms for LVH.

The vendor for the Hewlett-Packard ECG system in the
ECG Laboratory of the Clinical Center finally has
supplied programs and information so that the system
can accept digitized ECG's from outside sources. With
this extended capability, work involving a test of three
ECG programs (IBM, H-P, and Marquette) utilizing
sumultaneous 12-lead ECG data, generated at
Georgetown University Medical Center on patients with
non-ECG documentation of their disease, is proceeding
apace.

Proposed Course: Further detailed analysis of the
Framingham ECG data and correlations with non-ECG
data are planned.

The ECG Laboratory at Duke University Medical Center
has proposed joining the Georgetown-NIH ECG study.
The Duke Program will add a fourth ECG evaluation
program to the study.

The Laboratory of Systems and Bioengineering
(LADSEB), National Research Council of Italy, is
investigating the use of fuzzy set theory to assign a
degree of membership to a diagnostic category. Degree
of membership lends stability to the diagnostic
statement, in contrast to the classical, discrete,
threshold/decision tree method now used by most ECG
programs. On the other hand, this approach is not
constrained to treat diagnostic categories as disjoint
sets as is the multivariate statistical (multi-Bayesian)
approach of Pipberger and Cornfield. LAS will provide
data and consultation in collaboration with the
LADSEB.

Publications and Abstracts:

Bailey. J J . Berson. AS,. Jackson, L.K.. Stevens. J.M.. Tolan, G.D.. and Wolf.
H.K.; Evaluation methodologies tor ECG diagnostic systems. In Bonner.
RE.. Pryor. T A . Laks. MM., and Cole. S.S. (Eds ): Compulenzed Interpre-
tation of the Electrocardiogram VI. New York. Engineenng Foundation,
1981, pp. 53-62.

Macfarlane. P,W,. Chen, C Y , and Bailey. J J A comparison of point scoring
techniques tor the diagnosis ol LVH In de Padua. F , and Mactanar>e,
P.W., (Eds.): New Frontiers in Electrocardiology. Wiley. 1981. pp 353-356.

OVMUMflNTOr NtALTMAfaMUMAMiattVICat WBilC MAtTM MHVICf
NOTICf or INTRAMURAL REUARCMPROJtCT

ZOl 000007. IS IAS

Octoticr 1, 1982 to Scjitcmbcr .VI, 1<>85

Statistical Rcsrarch in ninical Pathology

E.K. Harris

LAI/INAMCH

Uboratory of Applied Studies

■ tCTlON

"KR'T^'NIH.^thesdil, M) 2020S

TOTAl MA«.1»«. |H«>M»0».l. 1 ^^^

Statistical Research in Ciinical Pathology

Univariate and multivariate time series models and
discriminant techniques are being applied to various
data bases consisting of short series of measurements
of serum biochemistries in healthy subjects and
patients with myocardial infarction. The purpose is to
gain practical experience in the use of these statistical,
predictive techniques to detect changes and trends
within individuals, taking into account biological
variation and measurement error. The time scale of
these series varies from dally to weekly, 6-month, and
12-month Intervals between observations. Parallel
computer-based simulation studies are also underway,
particularly to estimate the relative sensitivities and
specificities of multivariate and univanate forecasting
methods. Mathematical Investigations Into the
properties of a new stochastic model of linear change
are continuing.

Objectives: To investigate applications of statistical
theory, partlculary the use of vanance components,
discriminant analysis, and the theory of discrete and
continous time series, to the interpretation of serial
clinical laboratory measurements in healthy subjects
and patients with acutt and chronic disease.

Progress in FY83: The development of a statistical
method for estimating "reference change" (critical
differences between successive measurements of a

~ 15

biochemical constituent in an individual) has been
completed. Initial application has been to serial
observations of calcium and alkaline phosphatase in
healthy subjects. A paper describing the method and its
uses has been published. Collaborative studies applying
this method to patients with acute and chronic diseases
have begun at NIH and at the University of Virginia with
the aid of a comprehensive computer program
operating under the powerful statistical system, SAS.

Study of the sensitivity of multivariate reference regions
based on subject-specific data has progressed
continuously but slowly during the year. A group of
patients with specified liver dysfunctions during the
years 1974 to date has been identified from the
medical records of the Perfect Liberty Health
maintenance program in Osaka and Tokyo. The
specific variables for inclusion in the serial multivariate
vector of each patient remain to be defined.

Statistical methodology for evaluating the effects of
analytic error on the detection of trends in biochemical
measurements has been formulated and simulation
studies have been completed. These methods are
based on simple autoregressive models of serial
change. The effects of improvements in analytic
precision have been assessed, using currently
recommended limits of analytic error as guidelines. The
results are described in a manuscript to be published.
Dr. A. Albert's Fogarty International Research
fellowship terminated in August, 1982, and he has
returned to the University of Liege, Belgium. However
dunng FY83, he completed and published his major
work while in LAS, a theory of discriminant analysis
adapted to serial multivariate vectors (multivariate
response curves). He has used this theory to derive
sequential risk probabilities of outcome following
myocardial infarction and diseases of children admitted
to intensive care. Papers on both these areas of
application have been either published or submitted for
publication.

Proposed Course: During this reporting year, the
principal investigator retired from government service
but was extended "guest worker" status until
September 30, 1983. This project is therefore
terminating as an LAS-supported activity. However,

16 ' ' ■ —

investigators in the collaborating NIH laboratories may
seek to continue the intramural studies.

Publications and Abstracts:

Albert, A.: Discriminant analysis based on mulvariate response curves: a de-
scriptive approach to dynamic allocation. Statistics in Medicine 2-95-106
1983.
Albert, A., Chapelle, J.P., Heusghem, C, Kulbertus, H.E., and Harris, EK-
Evaluation of risk using serial laboratory data in acute myocardial infarction
In Heusghem, C, Albert, A„ and Benson, E.S. (Eds.): Advanced Interpreta-
tion of Clinical Laborator/ Data. New York, Marcel Dekker, 1982 pp 1 1T-
ISO.
Albert, A., and Ruttimann, U.: Prediction of an ordered categorical response

variable from serial measurement. Biometrics (in press).
Harris, E.K.: Addendum to recent paper on reference values for change. Clinical

Chemistry (in press).
Harris, E.K.: Regression, least squares, and correlation. In Seligson, D., M.D.

(Ed.): Handbook of Clinical Chemistry (in press).
Harris, E.K.: The effects of reductions in analytic variance on the early detec-
tion of trends. Proceedings of the Fourth International h/leeting on Clinical
Laboratory Organization and Management (in press).
Harris, E.K., and Yasaka, T.: On the calculation of a "reference change" for
comparing two consecutive measurements. Clinical Chemistry 2925-30
1983.

EALTH AND HUMAN SERVICES - PUBLIC HEALTH !
NOTICE OF INTRAMURAL RESEARCH PROJECT

October 1, 1982 to September 30, 1983

201 CT00042-0S LAS

Image Processln'g"yYle5?£nl3ic"ro;mp7l^7'i'ray'md Electron-loss Spectroscopy

PRINCIPAL INVESTIGATOR fl

M.A. Douglas Computer Systems Analyst LAS DCRT

Clinical Neuropharmacology Branch, NIMH

Laboratory of Applied Studies

Medical Applications Secti

PCRT, NIH, Bethesda, MD 20Z0S

Computer based analysis and image processing in
electron microscopy and x-ray and electron-loss
spectroscopy

This project is directed toward the development of
computer-based mathematical and statistical analyses,
pattern recognition, and image processing of data,
principally x-ray micrography and electron energy loss
spectra derived from the electron microscopy image of
biological specimens.

Progress in FY83: Hardware problems in the DeAnza
image processing system have been corrected by the

vendor. Incompatibilities between the DeAnza system
and the magnetic tape and disk peripherals are in the
process of being resolved. The disk drive is currently
operational at a submaximal performance level. A
series of 512 x 512 pixel electron micrographs of dense
bodies in human platelets before and after the addition
of fluorine have been acquired at the electron
microscope facility of Brookhaven National
Laboratories. These micrographs have been analyzed
and the dense bodies detected and delineated by two
different operators, each using a semi-automated edge
detection algorithm. Densities of each detected dense
body have been computed. Statistical analyses are
being performed on the data to determine the sample
size necessary to detect reliably the changes in density
of dense bodies in digitally-acquired, electron
micrographs of platelets.

Proposed Course: When the communications problems
between the DeAnza system and its periperal devices
have been resolved, important work with phantoms and
specimens of known composition then may commence.
This work is necessary in order to formulate appropriate
mathematical/statistical models to investigate changes
in the composition of platelets. At that time the signal
to noise ratio in phantoms and biological specimens
also will be examined. The effect of contamination and
specimen destruction by the high energy electron beam
will be investigated. Efforts will continue in the
development of algorithms for image enhancement and
for automated element recognition and delineation.

NOTICE OF INTHAMUBAL RESEARCH PROJECT

201 CT00004-1

2 LAS

October 1. 1982 to Seotember 50. 1983

Investigation of Hybrid Computing for the Analysis of Physiologic Signals

e7w. Pottall"' 'Electrical Engineer LAS DCRT

Laboratory of Parasitic Disease, NIAID
Division of Cardio-Renal Drug Products, FDA

Uborator)- of Applied Studies

Medical Applications Section

DCRT, NIH, Bethesda, MD 20205

tO,.LM»~Vt.^ 1 ,.0.i5..0~.L ^^^

Investigation of Hybrid Computing for the Analysis
of Physiologic Signals

This project uses hybrid computing techniques to
analyze physiologic signals such as electrocardiograms,
electroencephalograms, and electromyograms.

Progress in FY83: Over 200 ECG's from rats on various
nutritional or drug protocols have been collected by
pharmacologists at FDA. The methods of A/D
conversion, filtering, baseline corrections, beat
averaging, and vector loop generation have been
developed and debugged.

Proposed Course: Investigators at NIAID have
experimentally infected mice with Trypanosomi Cruzi
and thereby developed an animal model of Chagas"
disease. The computer methods for analyzing rat
ECG's will be applied to the ECG's being collected
from these mice.

Review of both rat and mouse ECG's will be necessary
to determine which feature parameters will be the most
accurate indicators at pathology. The design of feature
extraction and parameter measurement will require a
new analytical effort, because rodent ECG's differ
considerably from human ECG's in many features,
including a much higher frequency content.

The MAC-16 system will have continued use for ECG
processing for the Framingham Heart Study (see
project report on electrocardiography), as well as for
processing the rodent ECG's.

NOTICE OF INTRAMURAL REttARCM FROJCCT

201 CTOOOOS-l] LAS

October 1, 1982 to Sepia

Hathonatical Models of Binding Equilibrli

J.E. Fletcher Oitef, Applied mthitics Sccticp US COIT

National Cancer Institute, Division of Cancer Tre««»cnt

Laboratory of Applied Studies

Applied MathoMtics Section

DCRT. NIH, Bethesda. MD 2020S

Mathematical Models of Binding Equilibria

The objective of this project is the study of
mathematical models of ligand-receptor or ligand-
macromolecule binding studies at equilibrium.

The models are examined for mathematical as well as
for conceptual validity and the models are explored
parametrically to determine their suitability for fitting to
experimentally obtained laboratory data. The
appropriateness of various model fitting criteria are
studied and general guidelines and computational
algorithms are designed for computer-aided interactive
model fitting.

Progress in FY83: No new analytical models were
examined in FY83, although a number of literature
critiques were requested by scientific journals, and an
expository letter to the editor was published by
Mathematical Biosciences.

Requests for copies of exportable computer algorithms
continued to be filled and a number of brief Institute
consultations were provided. A summary report
including collected results from fifteen years of
research in this area is being distributed.

The principal investigator continues to serve as a
consultant, lecturer, and literature reviewer in this area.

Proposed Course: Consultations on new methodology
and data analysis will continue to be made as they are
requested by collaborating laboratories. Analytical
development of new models and continued research in
fitting methodology in this area will emphasize
validation of experimental techniques, multi-receptor
models, multi-ligand systems, and other special
systems as required by collaborating investigators.

DEPARTMENT OF HEALTH AND HUMAN SPRVlrcc dud. ... ^^.

i-in Hnu MUMTAN SERVICES ■ PUBLIC HEALTH SERVICE

NOTICE OF INTRAMURAL RESEARCH PROJECT

October 1, 1982 to September 30. 1983

ZOl CT00044-05 US

Mathematical ModelV,^°o"s'^!ibsTrate"Tra!i''y»'"r'

'RINCIPAL INVESTIGATOR (LUl olhtr prof uianai p^.onntl on .ub»

J.E. Fletcher

I Physiological Environments

Dept, of Bicmed. Engineering, LSU :
Medical School, Univ. of Virginia

Chief, Applied Mathematics Section LAS DCRT

Uboratoiy of Applied Studies

Applied Mathematics Secti

DCRT, NIH, Bethesda. MD 20205

0.65

Mathematical Modeling of Substrate Transport in
Physiological Environments

Mathematical models of microcirculatory structure and
function are developed from conceptual models into
systems of coupled ordinary and/or partial differential
equations. Methods of solution of these nonclassical
formulations are developed and tested, and satisfactory
cost effective methods are used to explore the
properties of these models. The model simulations are
interpreted in terms of microcirculatory physiology.

One objective of this project is to study whole organ
response and organ tissue level phenomena by means
of mathematical models in an effort to determine
relationships between variables that govern the organ
response to physiologic challenges.

Progress in FY83: Investigations continued into the
modeling and analysis of red cell-free perfused organ
experiments. A new model was examined for better
compatibility with the experimental design. This model
included capillary diffusion effects and examined the
effects of a varying capillary wall permeability. One
manuscript describing this model is in press, and two
others have been submitted for publication. A fully
satisfactory explanation of the tissue P02 histograms
derived from these experiments has not yet been
achieved.

Some additional investigations of models of red cell
oxygen unloading have been carried out and the results
indicate a very rapid release time. The question of

resistance to oxygen transport from intra-red cell
oxyhemoglobin to cell mitochondria appears to require
considerable reexamination. Previous explanations and
quantitations appear to be in considerable error.

Research into both of the above areas will continue in
FY84, but at a reduced level because of laboratory
management demands on the principal investigator's
time.

Publications and Abstracts:

Fletcher, J.E.. and Schubert, R.W.: Capillary wall permeability effects in capil-
lary-tissue structures. Proceedings of 1983 ISOTT conference (in press)

Fletcher, J.E., and Schubert, R.W.: Diffusional coupling in a hemoglobin-free
perfused capillary-tissue structure. Proceedings of Itie 1982 ISOTT meeting
(in press).

Fletcher, J.E., and Schubert, R.W.: On the computation of substrate levels in
perfused tissues. Mattiematical Biosciences 62:75-106, 1982.

Fletcher, J.E., and Schubert, R.W.: The theoretical prediction of substrate levels
and their histograms in cell free perfused tissues. Proceedings of the
Oxygen Transport to Tissue-IV (in press).

Schubert, R.W., Fletcher, J.E., and Reneau, D.D.: An analytical model for axial
diffusion in the Krogh cylinder. Proceedings of the 1983 ISOTT conference
(in press).

Schubert, R.W., Fletcher, J.E., and Reneau, D.D.: A simplified model for predict-
ing myocardial P02 histograms Proceedings of the First Southern Biomed-
ical Engineering Conference (in press).

NOTICE OF INTRAMURAL RESEARCH PROJECT

ZOl CT00112-01 US

'S'foVeTY^igs: to Septanber 30, 1983

^fJetv^VIT'^efiTigln'TiToYogy'' """' """" °" "' '*''^'' ' ""^'"

PRINCIPAL INVESTIGATOR ILUt otl»r proUulefal p.r.<,nn.l on .uBf*4U*nl |m(M.>

'i??." PotfaTa" """" Eneineer LAS DCRT
Medical College of Virginia; NIOSH, Blacksburg, Va.; LMB/NIADDK; I.SH/DCRT

Laboratory of Applied Studies

Medical Applications Section

'lOT"'NIH!''Blthesda, MD 20205

"'"'""s's"'" 1' 0.40 1 0.15 I

Network Modeling in Biology

This project has two parts:

1. evaluation, comparison, and demonstration of the
usefulness of network modeling languages for the
description and simulation of complex biological
models, and

2. the design, implementation, and documentation of
a new network modeling language.

Simulation, computer programming, and formal
language processing are the main tools in these
investigations.

• Network fvlodeling in Biology with Existing Network
Languages

Bac/<ground and Objectives: Mathematical modeling in
biology is especially difficult because of the need to be
familiar with both the biological basis of the problems
and the mathematical tools required for their solution.
Network modeling, supplemented with effective
languages for describing the models on computers,
largely obviates the need for extensive mathematical
sophistication, and makes the process of model
formation and testing accessible to biologists lacking
such skills. Topological modeling is particularly
appropriate to biological problems because the objects
of study generally satisfy conservation laws. In
biological systems, the processes of flow,
accumulation, and chemical transformation are
fundamental; these are likewise the basic operations in
network modeling.

Significance for Biomedical Research: The choice of a
model for a biological process strongly conditions the
design of experiments to confirm and test it. By making
the analysis of models sufficiently simple and flexible,
we intend to permit an investigator to consider many
alternative models. From comparisons among the
models using simulation, it should be possible to
develop scientifically valid, rather than arbitrary,
selection among the models. The network languages
permit users to model phenomena that are too complex
to be conveniently descnbed and simulated in MLAB.

Progress in FY83: Progress in FY83 has been slowed
by discovery of major incompatibilities between the NIH
computer system and the computer system on which
the NET-2 language was developed. Nevertheless,
some software modifications have permitted the design
of a retinal model and a model for a respirator.

A presentation on the ense and satelity of network
modeling in biology was made to the Electrical
Engineering department. University of Maryland. A
workshop/tutorial in network modeling using NET-2
was given at Naval Surface Weapons Center.

A model of subthreshold propagation of neural
electrical signals, developed by W. Rail, NIADDK, was
implemented in SPICE2. Numerical tables of signal
amplitude at various points on the neuron, which were
of higher accuracy than previously available, were
constructed for neuroscientists studying these
phenomena on actual neurons in the laboratory.

Future Course: Several NIH laboratories at NICHD and
NIADDK now use network modeling extensively and
this project will continue to provide consulting
assistance. NET-2 will be modified to restore full IBM
System 370 compatibility. A course in elementary NET-
2 programming will be offered again in DCRT. This
course is anticipated to bring new groups of users and
collaborators.
• A New Network Modeling Language

Background and Objectives: The weaknesses of
current network languages have encouraged the
development of a new network language intended to be
particularly appropriate to biological modeling. This
language will be named ALEMBIC, an acronym for A
Language for Expressing Models in Biology In
Computers. The mathematical approach of the
language is a nonlinear generalization of
compartmental analysis, while the implementation is
through a macrotranslator that produces MLAB
programs as output.

Significance for Biomedical Research): Creation of
complex models is much easier in ALEMBIC than in
MLAB. The usual progression in modeling is from an
analytical model that can be analyzed on paper to a
more complex model that is to be analyzed with MLAB,
and finally to a model that is too complex to be
conveniently expressed in MLAB. While this final class
of models is too complex to be used for data fitting, it
provides a workbench on which to test the validity of
simplifications from reality, which are ordinarily
unexamined because to do so would be too time-
consuming.

Progress in FY83: A bare-bones ALEMBIC translator
has been programmed and tested on a variety of
nontrivial problems, including examples from enzyme
kinetics, ligand binding equilibria, and membrane

20 ■

transport. The syntax for the full language has been
outlined. A working user's manual is in development.

Future Course: The completion of the ALEMBIC
translator is a major project whose completion will be a
matter of several years. However, in FY84 considerable
progress should be achieved. The user's manual will be
extended to include not only specification of the syntax,
but also a compendium of relatively elaborate examples
that call upon the full power of the language.

E OF INTRAMURAL RESEARCH PROJECT

ZOl CT00033-07 LAS

October 1, 1982 to September 30, 1983

Analysis of Coupled Transport and Biochemical Kineti

Medical College, University of Virginia; LB, NHLEI

Laboratory of Applied Studii

Applied Mathematics Sectii

DCRT, NIH, Bethesda, MD 2020S

Analysis of Coupled Transport and Biochemical
Kinetics

This project investigates two fundamental problems in
biology: the kinetics of enzymes located in cell
membranes, and the thermodynamics of bioenergetic
mechanisms in mitochondria. Mathematical analysis,
simulation on digital computers, and numerical solution
of nonlinear algebraic and differential equations are the
main tools in these investigations. While these
problems are diverse in their biological background,
they all share in a common basis of mathematical and
physical content in the role played by conservation
laws and in the mathematical methods involved in their
resolution.

• The Kinetics of Enzymes in Membranes

Background and Objectives: Studies of the mechanism
of membrane transport and energy transduction by
enzymes in membranes are generally less conclusive
than studies of the mechanisms of isolated enzymes.
This uncertainty arises because it is difficult both to
manipulate the environment of the interior of a

biological membrane and to measure responses there.
The objective of this project is to determine the extent
to which the actual organization of membrane-
associated, enzyme-catalyzed processes can be
correctly inferred from the application of models, either
detailed or phenomenological, to the kinds of
experimental measurements currently made.

Significance for Biomedical Research: Studies of
membrane-associated enzymes, such as those of
mitochondria, for example, are made by measuring
external concentration changes, from which one
attempts to infer the biochemical mechanism. This
process is evidently unreliable, as witnessed by a
decades-long controversy over almost every detail of
the mechanism. A consequence of our work is to
suggest strongly that this lack of reliability is intrinsic. It
is a result of incompatibility between the essentially
macroscopic nature of the experimental observations,
on the one hand, and the molecular character of the
questions that are posed, on the other hand. For this
reason, the problem is not to be resolved by performing
yet another experiment of the kinds currently popular,
no matter how ingenious.

Progress in FY83: One widely used alternative to the
approach described above is to seek a
phenomenological description of these systems using
classical nonequilibrium thermodynamics. The two
fundamental premises of this technique, termed
linearity and reciprocity, have been shown to lack
generality, and, indeed, to be specifically inapplicable to
systems in which chemical reactions are important.

The manuscript describing experimental work in this
area has been submitted and is under review. A second
manuscript detailing the inappropriateness of
nonequilibrium thermodynamics for characterizing this
class of biological systems has been completed, and
will be submitted shortly.

Future Course: The goal for FY83 will be to examine
the incremental response of nonlinear reaction-diffusion
systems that are maintained in a far-from-equilibrium
stationary state. Because the important examples are
all nonlinear, numerical rather than analytical methods
will be needed.
• Thermodynamics of Bioenergetic Systems

Bacl<ground and Objectives: The mechanism by which
the generally reduced components of nutrients are
oxidized in mitochondria is still elusive, although most
of the components of this pathway have been
identified. The membrane association of the
components makes it difficult to proceed in the usual
biochemical manner of molecular dissection and
reconstitution. Most experimental studies are made on
systems that are quite structurally complex.
Nevertheless, interest focuses on the usual biochemical
question: What is the sequence of molecular forms
involved in the bioenergetic pathway? The role of the
electron donor, ubiquinone, in this pathway is the
particular object of our interest in this project.

Significance for Biomedical Researcfi: An
understanding of the mechanism of the central energy-
yielding process of living organisms is clearly essential.
Thermodynamic analysis has shown that the accepted
explanation for the phenomenon of oxidant-induced
reduction of cytochrome b by ubiquinone in the
presence of antimycin cannot be correct. Presentation
of a sound physical basis for analyzing multi-electron
transfer reaction will assist many groups working on
this problem who have previously accepted an invalid
argument.

Progress in FY83: The manuscript describing this work
has been completed and has undergone external
review by leading workers in the field. It will be
submitted shortly.

Future Course: This project is essentially complete.
However, an effective basis for collaboration having
been established, subsequent projects are anticipated.

Publications and Abstracts:

Bunow, B : All things How and change Proc Wash Acad Sa 72: 43-60, 1982

Bunow. B : Cellular Enzymology: The steady-state kinetics of compartmental-
ized enzymes Journal ol TheoretKal Biology ^(>y\-%21 . 1980

Bunow. B.. and Mikulecky, DC : On the feasibility ol using flux measurements
to distinguish among active transport nxxMs. flofts/i Wmlar School of
Membrane Transport (in press).

Kernevez. J P . and Bunow B : Niimencal exploration of tjifurcaling branches of
solutions to reaction-diffusion equations descnbing the kinetics of immobi-
lized enzymes. In Absi. E . Glowinski. R . Lascaux. P . and Veysseyre. H
(Eds.): Numehcal Methods lor Enginaenng Pans, Dunod. 1980. pp 65-79.

Kernevez, J.P . Joly, G , Duban. M C . Bunow, B . and Thomas, D : Self organi-
zation in enzyme systems Ina Novosibirsk Colloquium 1978 Novosibirsk,
Nauka, 1982, pp 257-271

: OF INTRAMURAL RESEARCH PROJECT

ZOl CroOOlO-07 LAS

October 1, 1982 to September 30. 1983

Mathematical and Computational Methods for Solvine Nonlinear Eouatii

Richard I. Shrager Research Mathemati

HFD, CDC; DD, NIADDK; LB, NHLBI; IR/CM, IR/MD NHLBI

Cattedra Di Chimica e Biologica, U. of Milan, Milan, Italy; Univ. of MD

Computer Science Department ' '

Laboratory of Applied Studii

Applied Mathematics Secti'

DCRT. NIH. Bethesda. MD 20205

Mathematical and Computational Methods for
Solving Nonlinear Equations

Methods are developed for solving nonlinear equations
frequently encountered at NIH. These equations are
usually encountered in the context of constrained
nonlinear least squares problems or in the numerical
solution of nonlinear differential equations. Related
problems, such as asymptotic error analysis and the
efficient treatment of sparse matrix systems, are also
considered.

Progress in FY83: A rapid, robust root finder has been
developed and coded, and a revised manuscript
describing the technique is being resubmitted to a
journal. A new function minimizer is being coded by
guest worker Behrooz Kamgar-Parsi for eventual
inclusion in the MLAB system. A critique of a widely-
cited method for differentiating spectroscopic data has
been accepted for publication by the journal that
originally published the method. A program has been
written in the formal language REDUCE to compute
exact coefficients of certain digital filters, which are
used on laboratory computers that collect laboratory
data online.

Circular dichroism measurements are being processed
by singular value decomposition (SVD) methods. The
objective is to clarify the mechanism by which
calmodulin is altered by calcium and magnesium. This
SVD method, developed at LAS in FY82, also is being
used independently by two other laboratories in NHLBI.
Some painstaking curve-fitting work was provided to

the Liver Unit of DD, NIADDK along with advice on
which derived quantities were reliable. The objective of
this project is to determine if faulty liver metabolism
was responsible for increased GABA levels in rabbits
with hepatic failure. A paper describing this effort has
been accepted by Hepatology. In a paper with Drs.
Setty and Hendler, now revised and accepted by The
Biophysical Journai, a model of external and internal
binding of Tetraphenyl Phosphonium (a membrane-
potential probe) by bacteria was developed to show
that the most likely distortions in membrane-potential
measurements could be eliminated by a simple
calibration. A paper describing a numerical procedure
for generating a continous hemoglobin-oxygen
saturation curve while accounting for P02, PC02, pH
and 2-3 DPG over a physiological range has been
revised and published.

Proposed Course: In FY84, the calmodulin project
should be completed, the function minimizer should be
extended to handle linear constraints, and the new root
finder will be installed in MLAB. A paper describing the
root finder will be given at the 1 983 SIAM Fall Meeting.
Software, either imported or locally developed for the
solution of nonlinear differential-algebraic systems, will
be investigated; and the noise handling capacity of the
SVD-titration analysis method will be examined.

Pubiications and Abstracts:

Ferenci, P., Covell, D., Schafer, D.F., Waggoner, J.G., Shrager, R., Berman, M.,
and Jones, A.E.: Metabolism of the inhibitory neurotransmitter-aminobutyric
acid in a rabbit model of fulminant hepatic failure. Hepatology (in press).

Setty, O.H., Hendler, R.W., and Shrager, R.I.: Simultaneous measurement of
PMF, delta pH, delta psi, and H/0 ratios in intact E. Coll. Biophys. J. (in
press).

Shrager, R.I.: Analysis of optical spectra by SVD. SIAM 1983 National Meeting
(in press).

Shrager, R.I.: Some pitfalls in the use of derivative spectra. Photochemistry and
Photobiology (in press).

Shrager, R.I.: SVD as a description of chemical titration. SIAfifl 30th Anniversary
Meeting, Stanford University, California, July 19, 1982.

Winslow, R.M., Samaja, M., Winslow, N.J., Rossi-Bernardi, L, and Shrager, R.I.:
Simulation of continuous blood 02 equilibrum curves over physiological pH,
DPG, and PC02 range. Journal of Applied Physiology 54(2):524-529, 1983.

NOTICE OF INTRAMURAL RESEARCH PROJECT

201 000045-05 IAS

October 1, 198; to September 30, 1983

M. Bietermaji

Laboratory of Applied Studies

plieJ Mathemati

DCRT, NIH, Bethesda. MP 20205

Numerical Approximation Techniques for the
Solution of Reaction-Diffusion Systems in Biology

Adaptive numerical methods, which were previously
developed in LAS, have been improved and applied to
solve systems of partial differential equations describing
general reaction-diffusion processes in one space
dimension. These methods are implemented in the
program FEM0L1, which is available on the NIH IBM
System 370 and DECsystem-10. FEM0L1 features
automatic adjustment of the time and space
discretizations during the course of the computations.
These adjustments are effected in order to adapt to
local problem characteristics and to control the
discretization errors in an efficient manner.

The study of numerical techniques for time-dependent
differential equations used to model reaction-diffusion
processes has primarily consisted of the further
development, analysis, and application of adaptive finite
element methods. Adaptive numerical methods differ
from conventional schemes in that information or
feedback, which is gathered during a problem's
solution, automatically is used to improve the accuracy
and efficiency of the computations. Programs
implementing such methods are valuable tools for the
scientist examining the roles of physicochemical or
biological parameters in model systems, because the
roles can only be seen when the computed numerical
solutions are sufficiently accurate. For a fixed set of
model parameters, several applications of a
conventional program with different input discretizations
and numerical parameters are usually required to

guarantee solution accuracy. With a reliable adaptive
method, the probability that sufficiently accurate
answers are obtained in a single application of the
program is high, as most decisions concerning
appropnate discretizations and numerical parameters
are made and carried out internally by the program.

Progress in FY83: The program FEM0L1 has been
enhanced in several ways. Machine independence has
been increased and a sophisticated package of
subroutines has been added, making FEM0L1
independent of IMSL and other subroutine libraries. An
arbitrary number of nonlinear partial differential
equations, which may include nondominant, convective
transport terms, can now be handled. Computational
efficiency has been increased by incorporating a
different discretization strategy in the adaptive
procedure. Less user-supplied input is required, making
the program easier to use.

FEM0L1 has been applied to models of oxygen
transport, population ecology, population genetics,
signal transmission in nerves, and physicochemical
systems with strongly temperature-dependent kinetics.
Many published benchmark tests for these and other
models show the effectiveness of the adaptive solution
approach.

Investigations of adaptive finite element methods have
led to the design of a much improved algorithm for
automatic space-mesh modification. With this algorithm,
accurate information about solution characteristics is
obtained via computable estimates of certain "local"
quantities. This information is assimilated and
monitored at an appropriate "global" level, and the
evolving patterns, which are predicted via the many
global levels, are used in deciding when and how a
new space mesh should be constructed.

Proposed Course: The study of numerical techniques
for the solution of partial differential equations, which
model systems that describe or affect biological
processes, will proceed in three directions. First,
assistance will be given to DCRT investigators and
other NIH scientists who need to use or obtain PDE
software.

Second, adaptive numerical methods for reaction-
diffusion systems will be extended, analyzed, and
further implemented. Envisioned extensions include the
capabilities to handle strong nonlinear coupling of
higher solution component derivatives and more
general boundary conditions. Also, preliminary studies
of extensions of the present methods to two space
dimensions will be made.

Third, mathematical modeling and numerical analysis of
subsurface contaminant transport will be initiated. The
diffusion and convection of hazardous chemicals
through fractured rock and porous media are difficult
both to model and to solve via computer. Multiple
chemical reactions, radioactive decay, and anisotropic
hydrodynamic dispersion can lead to complex flow
patterns, in which the principle mechanism of transport

varies from one region of space to another. Adaptive
numerical methods, which automatically adjust to
subsurface flow patterns, will be investigated for these
problems.

Publications and Abstracts:

Bieterman, M.: An adaptive method for reaction-diffusion equations in one
dimension. SIAM Nationai Meeting. Denver, Colorado, June 1983.

Bieterman, M.: A Posteriori error estimation and adaptive finite element grids for
parabolic equations. Army Research Office Workstiop on Adaptive Metti-
ods for Partial Differential Equations (in press).

Bieterman, M.: On using local solution information in a mesh modification
strategy for time-dependent equations. NASA-ICASE Workshop on Grid
Methods. Hampton, Virginia, September 1983.

Bieterman, M., and Babuska, I.: The finite element method for parabolic equa-
tions, I. A posteriori error estimation, f^umerische Mathematik 40-339-371
1982.

Bieterman, M., and Babuska, I.: The finite element method for parabolic equa-
tions, II. A posteriori error estimation and adaptive approach. Numerische
Mathematik 40:373-406, 1 982.

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Laboratory of Statistical and
Mathematical Methodology

James E. Mosimann, Chief

LSM activities can be divided into three areas:
computation, consultation, and research.

Computation

A major part of LSM activity is the offering of statistical
and mathematical systems/packages to the NIH user
community. LSM accepts responsibility for evaluation of
new program packages and their suitability for NIH.
When LSM does support a system/package for the
NIH community, it provides maintenance,
documentation, instruction, and assistance for users to
interpret the results.

Statistical Systems/Packages Support. During this
year, the Statistical Software Section of LSM
maintained the following program packages and
programs:

• BMD, BMDP: Biomedical Computer Programs, UCLA.

• SPSS, SPSS-X, SCSS: Statistical Package for the
Social Sciences, SPSS, Inc.

• SAS, SAS/GRAPH, SAS/ETS: Statistical Analysis
System, SAS Institute, Inc.

• P-STAT: Statistical Package, P-STAT, Inc.

• IMSL: International Mathematical and Statistical
Libraries, IMSL, Inc.

• MSTAT1: Collection of Mathematical and Statistical
Programs, DCRT.

During the year BMDP and IMSL went through a major
update. NIH served as a test site for both SAS82 and
SPSS-X. Both systems will become production systems
during the next fiscal year. The SSS staff answered
over 7,500 calls for assistance, and taught a total of
twelve courses on these systems/packages; two each
on the SPSS and BMDP packages and eight courses
on the SAS system.

The use of program packages continues to increase.
The average accesses per month of all the statistical
packages rose from around 45,000 during FY82 to over
63,000 in FY83. For the seventh year in a row, SAS
experienced the largest increase of any of the
packages. SAS averages over 54,000 accesses per
month, up from 37,000 per month in FY82. The
average number of accesses per month for SPSS--

around 4,600--was about the same as in FY82. The
average combined accesses of the BMDP and BMD
packages was 2,500, about the same as in FY82. As
an example of a package used for specialized
purposes, P-STAT averaged 20 accesses per month,
down from 30 average accesses per month in FY82.
The main programs and subroutines in MSTAT1
averaged 1,600 accesses per month, in contrast with
1,300 in FY82. Accesses to the IMSL package cannot
be counted, but it is estimated that usage increased
during FY83.

MLAB Support

The Biomathematics and Computer Science Section
maintains the DECsystem-10 interpretive program
MLAB, a package designed and implemented by BCS
staff. During FY83, several hundred biomedical
researchers at NIH used this package for modeling and
graphical display tasks. MLAB is part of the NIH-funded
Prophet system, the SUMEX-AIM system at Stanford
University, and the NIH-EPA Chemical Information
System. It has been distributed to various universities
and research centers at their request. During FY83,
BCS augmented MLAB in several areas. Numerical
derivatives can now be specified for curve-fitting,
allowing analysis of somewhat larger models. Several
new mathematical operators were added. MLAB was
modified to permit use of the color graphics facilities of
OMNIGRAPH, and the facilities for graphical display of
scientific text were enhanced. One advanced course
and two introductory courses were taught for MLAB.
One article and one puzzle feature on MLAB
techniques appeared in INTERFACE. The second
edition of the MLAB Beginners Guide is being printed,
and will be distributed in FY84.

Support for the Unified Generator Package

This package, developed by a BCS staff member,
generates IBM System 370 assembly language
programs. Maintenance was performed on the package
to accommodate the upgrade from 3330 to 3380 disk
drives and the system change from the G Assembler to
the F Assembler. The bucket overflow algonthm for the
index generator was improved. As before, assistance
was provided for users on request

Support for Other Software

BCS continues to maintain certain special-purpose
software and to assist users upon request. The
PROLOG package, which the Japanese government
has adopted as a basis for their fifth-generation
computer project, is designed for analysis of
nonnumerical data by aggregation of procedural rules.
It has been used in LSM for linguistic research. A
program developed by BCS for interactive construction
of an index for a document file has been supported.
Various LSM-created programs for analysis and
reconstruction of biological shapes using the symmetric
axis method have been supported. BCS staff supported
SAS/GRAPH maintenance, especially for the Calcomp
plotter interface and the TSO command processor.

Consultation

As in previous years there was considerable variation in
the amount of time required for an LSM consultation.
Some very brief consultations are successful and are
brief precisely because there is a known answer to the
question posed. Other consultations involve extensive
time and statistical/mathematical/computer science
research as well. LSM consultations in FY83 were of
the following types:

• Mathematical, statistical and computer science
advice with limited computer use (5 percent)

• Mathematical or statistical advice with considerable
computer use (55 percent)

• Computational advice alone (40 percent).

The large computer use in these figures results from
the continued availability and use of general purpose
statistical and mathematical packages like SAS and
MLAB. These percentages are unchanged from last
year.

The diverse nature of LSM consulting is indicated by
the projects and activities listed below.

Clinical Research, Patient Care,
Epidemiology

Allergen Treatment for Ragweed Hayfever. P.

Turkeltaub (BB/DPB). The safety and efficacy of

26 ~

allergen treatment for ragweed and hayfever was
studied by analysis of clinical data. LSM provided
statistical and computational assistance for
nonparametric tests for ordered alternatives, stepwise
multiple comparison procedures, and analysis of
covariance.

Effects of Age on Taste Sensitivity. B. Cowart and J.
Weiffenbach (NIDR/DSB). Ordered sequences of taste
samples are presented to human subjects for
evaluation. LSM developed a new statistical
methodology for painwise comparison of evaluations of
ordered concentrations, for assessment of decreased
taste sensitivity with age.

Cancer Survival Studies. R. Wesley (NCI/DCT/BRB).
LSM assisted in computer generation of graphical
displays, involving Kaplan-Meier survival cun/es for
evaluation of clinical data.

Hypertransfusion and Blood Constituents. P.

Gascon (NHLBI/IR/OD). LSM gave statistical
consultation on a study of the consequences of
hypertransfusion for several blood constituents.
Comparisons were made using nonparametric tests
between normal controls and patients having one of
several diseases, each requiring high numbers of
transfusions as part of the disease treatment.

Laboratory Investigation

Receptor Characterization. M. Bissonette (NIADDK/
DD). Models for the characterization of secretin
receptors in rat pancreatic acini in terms of receptor
number and receptor affinity were studied. LSM
continued to assist in simultaneously curve-fitting
nonlinear models to experimental data.

Peptide Potencies. D. J. Goldstein (NHLBI/HE). The
effect of four naturally occurring peptides of the kinin
family (bradykinin, lysylbradykinin,
methionyllysylbradykinin, and polisteskinin) in reversing
the inhibitory effect of morphine and metenkephalin on
the electrically simulated guinea pig ileum longitudinal
muscle-myenteric plexus preparation was studied. LSM
assisted in using parallel line assay techniques to
compute the relative potencies as well as the EDSO's

(concentration required to produce a 50 percent
reversal of the opiate-induced inhibition) of the
peptides. A coauthored manuscript reporting the results
has been submitted to Science.

Effects of Oxotremorine on Whole Body Tremor in
Chronic Drug-treated Rats. M. Goldman (NINCDS/
ET). Rats were injected twice daily for 30 days with
saline, atropine, amitriptyline, thioridazine, imipramine,
d-amphetamine, or nomifensine. Seventy-two hours
after the last dose each animal was injected
subcutaneously with 0.1 mg/kg oxotremorine. The
proportion of animals displaying a supersensitive
response (moderate to severe whole body tremor for at
least three single minute intervals from 11-15 minutes)
to oxotremorine was recorded. LSM assisted in
computing confidence intervals for the proportions,
using Fisher's exact test for 2x2 tables.

Basal Membrane Thickening in Galactosemic Rats.

P. Kador (NEI/LVR). Basal membranes were analyzed
in normal rats, galactosemic rats, and galactosemic rats
treated with aldose reductase, using retinal capillary
images from electron micrographs. This study is related
to clinical management of eye complications resulting
from diabetes. LSM assisted in computer generation of
graphical displays and measurement of image features.

Cholesterol Levels in Swine. J. Cupp and H. Kruth
(NHLBI/IR/EA). Effects of high cholesterol diets on
swine are assessed by sacrificing the animals and
measuring atherosclerotic pathology. LSM provided
statistical advice in the sampling design and analysis of
a linear model that adjusts for the effects produced by
using experimental animals from the same litter.

Differential Binding of Synthetic Retinoids to Beta-
lipoproteins. E. Gross (NGI/DCDB). Experiments show
that different retinoids (Vitamin A derivatives used in
treatment of dermatologic disease) are associated in
different degrees with beta-lipoproteins; these results
have implications concerning the absorption,
distribution and metabolism of the drugs. LSM assisted
in the use of SAS/GRAPH to prepare graphical
presentations of these results.

DNA Sequence Analysis. P. Senepathy (NIADDK/
LEP). Various natural DNA sequences are compared to

assess biochemical features of sequence data. LSM
assisted in the preparation of graphical displays using
MLAB that show cleavage points of sequences under
the action of several different enzymes.

Kidney Function Modeling. C DeLisi (NCI/LTB).
Aspects of kidney function are modeled by large
systems of ordinary differential equations. LSM
provided advice in formulation of the models and in
using MLAB for generation of numerical solutions and
for curve-fitting.

Cooperative Binding of Polymers. J. Cohen
(NIADDK/LCP). Binding of n-mers was measured using
NMR data. LSM provided assistance in formulation and
analysis of a mathematical model.

Brain Tissue Analysis. S. Kumins (NICHD/ERRB).

Mixtures of damaged and undamaged enkaphalin bind
differentially to specific brain tissue sites. LSM provided
assistance in formulation and analysis of mathematical
models using MLAB.

Computer Research and Technique
Development

Computer Analysis of Two-Dimensional Gel
Electrophoresis Images. M. Miller (NCI/DCCP). LSM
provided advice on the use of Fourier analysis filtering
techniques for computer enhancement of protein spots
on gel images.

Comparison of Dental X-Ray Images. R Webber
(NIDR/CIBI). LSM provided advice on a method for
better control of computer image positioning, to reduce
problems associated with comparisons between related
images.

Probability Models for Fibrinogen Chains. G.

Crabtree (NCI/DCBD/LP). LSM assisted in developing
probability models to account for the presence or
absence of introns in the three present-day fibrinogen
chains, as derived from a single or double ancestral
gene. The model fitting used maximum likelihood and a
set of chi-square statistics.

Schematic Figure Generation. R. Hiller (NEI/BE).
LSM provided a computer program for generating

~ 27

schematic diagrams using four overlapping circles. The
circles are positioned so that the areas of the 15
regions of overlap approximate values supplied by the
user. These diagrams are being used as visual aids in
presentation of data involving four types of senile
cataract disease.

Fibrinogen Binding Displays. M. Lewis (DRS/BEI).
LSM assisted in preparation of three-dimensional
graphical displays and contour maps of data associated
with binding of fibrinogen to plasminogen, using MLAB.

Graphical Display of Hormone Levels. N. Vieira
(NICHD/NPMB). LSM assisted in preparation of MLAB
DO files for continuing production of graphs showing
hormone levels, including use of spline approximations
and generation of error bars.

Research Projects

NOTrCE OF INTRAMURAL RESEARCH PROJECT

ZOl CT

00001-12 LSM

Pctober 1, 1982 throuEh Seotember 30. 1983

Automaced Data ProcessinR of Medical LaneuaKe

"■'

M^__G. Pacak Supv. Computer Systems Analyst

LSM

DCRT

^uu^tHAFiNGUNiTSf(/ony;^_ H_ Pratt Director
G. Dunham Computer Programmer
S. Harper Computer Programmer
n u.„o„„

LSM
LSM

DCRT
DCRT
DCRT

Laboratory of Statistical and Mathematical Method

3logy

Medical Information Science Section 1

DCRT, NIH, Bids. 12A, Room 3045, Bethesda, Maryland 20205

1-5 1 """'"j"";' 1°™"-

Automated Data Processing of Medical Language

Research was continued on compositional
morphosemantic analysis of medical terms derived from
Greek and Latin. A methodology was developed for
automated morphosemantic segmentation and
semantic interpretation (paraphrasing rules) of medical
compound words derived from Greek and Latin that
denote surgical procedures. Of primary importance is
the construction of a lexicon of potential
morphosemantic constituents that associate with each
entry a semantic category used in SNOP and its
semantic interpretation in medical English. The

28 '

preparation and use of Greek-Latin morphosemantic
constituents result in a net saving in required storage
space and an increase in the lexicon's interpretation
power, because it is possible to derive semantic
interpretation from words that are not contained in a
dictionary in their full form.

The morphological analysis (stemming algorithm), which
consists of the identification of the word root and the
automatic selection of morphological word variants
from inverted file entries, was used successfully in an
end-user interface to NLM's CATLINE book catalogue
file.

Collaboration on the Clinical Information Utility
continued with the Laboratory of Pathology, NCI, and
the DCRT Data Management Branch to maintain and
improve the data base of Clinical Center surgical
pathology reports.

The automatic encoding system provided by MISS
computes a representation of the summary diagnoses
of the surgical pathology report as written by the
pathologist, in a language based on the vocabulary of
the Systematized Nomenclature of Pathology (SNOP-
NIH). Statements in this representation language
convey the site and tissue of the specimen, the specific
morphologic and histopathologic diagnoses, and
etiologic agents involved in a diagnosis.

Continued collaboration with Dr. Donald E. Henson,
NCI (Division of Resources, Centers, and Community
Activities, Organ Systems Branch), has been basic to
this work. We have begun work on specific areas of the
dictionary along the lines established for the lymphoma
vocabulary with interested specialized pathologists
including Dr. Elaine S. Jaffe, NCI (Division of Cancer
Biology and Diagnosis, Laboratory of Pathology,
Hematopathology Section).

Steps were taken to create a comprehensive
lexicographic data base relating the body of medical
nomenclature and vocabulary to itself in various logical
ways, and to existing structuring or coding systems.
The goals are: to produce the semi-automatic display of
significant relationships of one dictionary system to
another, to merge dictionaries, and to maintain and
extract special purpose microglossaries necessary for

medical language processing and data base
organization.

A paper, "Three Solutions to Problems of Categorized
Medical Nomenclatures," is in preparation.

Publications:

Norton, L M., and Pacak, M, G.: Morphosemantlc Analysis of Compound Word
Forms Denoting Surgical Procedures. Methods ol Information in Medicine
22: 29-36, 1983.

NOTICE OF INTHAMUBAL RESEARCH PROJECT

'nOJtCT NUMail*

ZOl CT 00008-09 LSM

October I , 1982 through September 30, 1983

Cluster Analysis

M. B. Shapiro Research Machemadcian

LSM

DCRT

F. de Honasterio Head
S. Schein Expert

LVR
LVR

NEI
NEI

Uboratory of Statistical and Hatheinacical Methodology

Statistical Hethodoloey Section

DCRT, NIH, Bethesda, Maryland 20205

,OT»c»A~v . 1 1.0 1

Cluster Analysis

The main objective of this project is the application of
computer cluster analysis and related methods to NIH
researcher problems.

Nearest neighbor algorithms based on the latest
published research and extensions to it were developed
and tested.

Algorithms for analyzing spacial point patterns were
developed for testing patterns of retinal cones for
regularity.

The first phase of the work on the distribution of blue
sensitive cones in the retina was completed and a
paper, "Regularity and Structure of the Spatial Pattern
of Blue Cones of Macaque Retina," was submitted for
publication in the Applications Section of the Journal ol
the American Statistical Association. The final model
developed considers each cone as an elastic ball, with
a hard core and sott surrounding shell. Models based
on disordered triangular and square lattices were
rejected. Two statistics, one based on the cumulative
distribution function of interpoint distances and the

other on the cumulative distribution function of the
central angles of Voronoi regions, were used to
evaluate models.

Future work will involve using the elastic ball model and
finding the resulting parameters for other retinal data
(e.g., blue cones at different locations in the retina) and
all cones (i.e., red sensitive and green sensitive as well
as blue sensitive).

Publications:

Shapiro, M.: A note on Lee and Schacler's algonlhm tor Delaunay tr\angulalion
International Journal ol Computer and Inlormalion Sciences 10 (6) 413-
418, 1981.

Yaar I., and Shapiro, MB A quantitative study o( the Electroencephalographic
Response to Levodopa treatment m Parkinsonian patients. Climcal Electro-
encephalography 14 (2) 82-85, 1983

PniNCIPAl IffVItTIOAION ItMH

C. D. Knott

ZOl a 00009-0* LSM

October I. 1982 through SepMlxr 30. 1983

I Coaputcr Science

Coaputer Speciallet

Laboratory of Stetletlcal end M«the«etlc«l Methodology

Blo«ethe«atlc» end Computer Science Section

DCrt. HlH. getheeda, Maryland 2020}

Research Topics in Computer Science

Various storage and retrieval algorithms have been
studied. The development of flexible and efficient
storage and retrieval algorithms is very useful, because
such algorithms are used in almost all computer
programs. Thus biomedical computation in particular
can benefit from improved storage and retrieval
methods.

Currently, a study of hashing storage and retrieval
methods is undenway. This has resulted in an analysis
of the performance of the hashing methods that
resolves collisions using direct-chaining with and
without coalescing lists. Progress has been made on
analyzing the insertion cost for direct-chaining, involving
the computation of a hard-to-derive covariance.

^ 29

The object of this project is to develop theoretical
bases for new computer methods that will expand and
improve the use of computing in biomedical
computation. The methods used are the application of
known algorithms and the development of new
pertinent theorems involving combinatoric and other
related mathematics. Research work in storage and
retrieval algorithms and their efficiency has been the
primary topic of concern.

Concurrently, an exhaustive survey of storage and
retrieval methods is undenway. This includes the
recently-introduced k-d tree method. Various
improvements and refinements in both the algorithms
and their analysis are being studied.

Routines to store, retrieve, and delete items in a hash
table that employs direct-chaining with and without
coalescing lists have been prepared. An analysis of
these algorithms has been recently completed and the
results are to be published. Further analysis is
underway.

Publications:

Knott, G. D.: Direct Chaining with Coalescing Lists. Journal of Algorithms (in

press).
Knott, G.D.: Fixed-Bucket Binary Storage Trees. The Journal of Algorithms. 3:

276-287, 1982.

NOTICE OF INTRAMURAL RESEARCH PROJECT

ZOl CT 00011-09 LSM

October 1, 1982 through September 30, 1983

Discrete Mathematics and Applications

G. Hutchinson Supv. Res. Ma thematic Ian LSM DCRT

None

Laboratory of Statistical and Mathematical Methodology

Biomathematics and Computer Science Section

DCRT. NIH, Bethesda. Maryland 20205

O.A 1 0.4 1

Discrete Mathematics and Applications

Inclusion relations between vector spaces and related
problems concerning modules over rings were studied.

Preparation of scientific manuscripts by computer
graphics methods using printer-plotters was
investigated.

The project objective is to develop mathematical theory
and computational techniques using discrete
mathematics (algebra, combinatorics, and graph
theory), and to apply such methods to problems of
biomedical research and computer science.

A study of algebraic structure possessed by
submodules of module products M x M was begun.
Preliminary findings include: construction of an
axiomatic algebraic structure representing such relation
algebras, construction of relation category analogs of
these algebras, characterization of the subcategories of
relations that are function graphs for these analogs, a
number of special results showing that certain classes
of abstract algebras are isomorphic to subalgebras of
module relation algebras, a decision procedure for the
identities satisfied in all module relation algebras in
terms of certain simple divisibility properties of the ring
of scalars, and a classification of rings determining
when two different rings lead to the same identities for
the corresponding module relation algebras.

In computer science, a DECsystem-10 program was
written and tested for conversion of the scientific
manuscript input language previously developed in this
project into the input language used by TeX (a
computer manuscript system developed at Stanford
University that has been adopted by the American
Mathematical Society). Further tests of TeX have been
performed, and LSM assisted the DECsystem-10
systems staff in their effort to implement the most
recent version (TeX82). Procurement of the Tektronix
4114 graphical display terminal is not yet completed.

Proposed Course: Study of module theory will continue
in the areas indicated above.

Computer software to generate scientific manuscripts
will be developed. It is expected that Tektronix 4114
procurement will be completed and development of
computer manuscript output will begin late in FY83.
Use of the IBM 6670 Information Distributor as an
output device for generation of scientific manuscripts
will also be investigated.

NOTICE OF INTRAMURAL RESEARCH PROJECT

ZOl CT 00013-09 LSM

October 1, 1982 chrounh September 30, 1983

Multivariate Statistical Analysis

J. E. MoBlmann Chief. LSK LSM DCRT

J. N. Darroch Flinders University. Adelaide. Australia
M. V. Ratnaparkhl Associate Professor, Wright State University.
Dayton, Ohio

L»B/Bn*NCM

Laboratory of Statistical and Mathematical Kethodology

SECTION

Office of the Chief

DCBT. NIH. Bethesda, Maryland 20205

0.3 1 0.3 1

Multivariate Statistical Analysis

The objective of this project is the study of multivariate
ratios or proportions.

Study continued on multivariate statistical methods
(size-shape methods) for analyzing ratios that follow a
multivariate lognormal distribution. A paper on
discriminant functions based on shape alone (with J. N.
Darroch) is under revision. The application of these
methods to quality control of inbred stocks of
laboratory mice was undertaken (with H. Hoffman).
These discriminant methods enable the early detection
of contamination of inbred strains. A rather complete
review of size and shape analysis was prepared, and
accepted, for the Encyclopedia of the Statistical
Sciences. Additionally, various data sets of use in size
and shape studies, which formed the basis for previous
studies, have been edited and collected as a resource
for test analyses. Additionally, specialized programs for
the analysis of size and shape data have been
developed. The principal investigator participated in the
International Workshop on Functional and Structural
Relations and Factor Analysis at the University of
Dundee (Aug. 24-Sept. 6, by invitation only) and
participated in a subsequent open meeting on the
subject on September 7-9, 1 983.

Publications:

DeBlas. A. L.. Hatnaparkhi, M. V.. and Mosimann, J E ; Estimation of the
number of monoclonal hybridomas in a cell (usion experiment In VunaKis,
H. v., and Langone, J J. (Eds): Immunochemical Techniques Methods m
Enzymology. New York, Academic Press, 1983. pp 36-39

Mosimann. J E : Size and Shape Analysis in Johnson. N i . Kotz, S . and Read,
C B (Eds ) Encyclopedia o/ SUbstical Soeoces John Wiley and Sons, inc.
(in press)

Mosimann, J E ; Discussion of Professor Ailchison's paper Journal ol Iha
Royal Stalislical Society B. 44 (2) 168- 170. 1982

OlFAATMtNl OS HtALIMAW HUMAN MKVICn AMUC MAITM HMVCt
NOnCi OF IHTMtMIRAL MMAHCHniOJiCT

101 CT 000)f-0» UM

""""october 1. 1982 through Saptaabcr JO. I9«)

Linear Methods In Statistics

MmciaAL iHvttnoATon lui ,ii, n ■»■■,< t— n i mm^t

J. D. Kailay Mathaaaclcal Statistician LSI OCRT

Nona

LAS/SnAMCM

Statistical Hathodology Sactlon

DCRT. NIH. Bethasda. Maryland J0J05

O.t 1 0.6 1

Linear Methods in Statistics

Linear methods in statistics, as applied to biomedical
data analysis, continue to be studied. The study of
optimal linear model estimates for variance component
estimation continues to be an area of investigation. An
extensive study of repeated-measures expenments was
begun, and the results will be a monograph on the
unified exposition of the problem as well as to present
an exact multivariate alternative analysis. Further,
linear, nonparametric, multivariate methods have also
been outlined. Additionally, a new approach to the
problem of descnbing and characterizing multivariate
dependence structures has been presented that ties
the practical problem of studying dependence to a
geometnc framework.

Publications:

Malley. J. D Statistical and algebraic
11 (1): 341-345. 1983

idependence The Annals ol Stabsoca

NOTICE OF INTRAMURAL RESEARCH PROJECT

ZOl CT OOOA7-05 LSM

October 1, 1982 through September 30, 1983

Nonnumerlcal Prograimning Techniques and Applications

Lewis H. Norton Research Mathematician

LSM DCRT

None

Laboratory of Statistical and Mathematical Methodology

Biomathematics and Computer Science

DCRT, NIH, Bethesda, Maryland 20205

0.4 1 0.4 1 '

Nonnumerlcal Programming Techniques and
Applications

The special purpose programming language PROLOG
is quite different from other languages, and optimum
use of it requires using new techniques and abandoning
ones used with other languages. PROLOG programs
that analyze medical terms in terms of their constituent
morphemes were refined and extensively tested.
Additional efforts in text analysis and other areas also
involved the use of PROLOG. Papers were prepared
for publication.

Research on this project has continued to focus on the
use of the special-purpose programming language
PROLOG. In a computational linguistics project,
PROLOG programs that analyze medical terms
denoting inflammations and surgical procedures were
further refined and tested. The analysis was performed
in terms of the constituent morphemes of the terms,
and required the compilation of an extensive lexicon of
such morphemes. Output from the program was used
to determine morphosemantic distribution patterns and
their relative frequencies within the corpus of terms, as
well as the semantic interpretations associated with the
more common patterns. A paper on the results of this
work for the domain of surgical procedure terminology
was written.

Additional efforts involving PROLOG included research
in the area of text analysis, where a paper based on
earlier work was revised for publication, and where text
analysis techniques reported in the literature were

implemented in PROLOG to increase comprehension of
both the techniques and the programming language.
Other small-scale projects were done, mainly to explore
other properties of PROLOG. PROLOG is quite
different from other programming languages, and
optimum use of it requires abandoning many
preconceived programming methodologies.

We are hoping to obtain a newly-released version of
PROLOG for microcomputers, in order to broaden our
investigations into the uses of this language.

During this reporting period, some further work was
performed on a project investigating the frequencies of
terms used in surgical pathology summary diagnoses.
In particular, data was collected on changes in word
frequencies over time, and frequencies of multiple use
of terms in the same summary diagnosis. Much of the
software used was created using the Unified Generator
Package.

Publications:

Norton, L.M., and Pacak, M.G.: Morphosemantic Analysis of Compound Word
Forms Denoting Surgical Procedures. Methods of Information in Medicine
22: 29-36, 1983.

NOTICE OF INTRAMUHAL RESEAHCH PROJECT

ZOl CT

00079- 03 LSM

October 1, 1982 through September 30, 1983

Topics in Geometry and Analysis

H. A. O'Connor Staff Fellow

LSM

DCRT

C. R. Merril Senior Research Scientist

D. Goldman Glinical Associate

LGCB
LGGB

NIMH
NIMH

Laboratory of Statistical and Mathematical Methodology

Biomathematics and Computer Science Section

DCRT, NIH, Bethesda, Maryland 20205

0.7 1 0.7 1

Topics in Geometry and Analysis

Improvements in accuracy and efficiency of
identification and description of protein spots in two-
dimensional gels were developed and coded. Analyjss
of general algorithms in relationship to existing edge
detection and region segmentation techniques was
undertaken.

Continuing research in the geometry of convex cones,
the connection and Riemannian curvature tensor of the
related isometric triangular Lie groups was calculated.
Results on Einstein manifolds and cones were
obtained. Previous parametrization of N-algebras was
related to sectional curvature, and thus seen to be
intrinsic.

At this point, the eye is the most accurate and effective
detection device for protein spots in two-dimensional
electrophoretic gels. The edges of the spots can
generally be well fit by parabolic segments. An
algorithm has been developed to model parabolic fitting
by the eye utilizing a "parabolic spatial second
derivative" and other analogues of cues used by the
eye. This has been coded as a Pascal program on a
VAX computer. (This work is in collaboration with
LGCB, Nlf^H.)

It is noted that the technique developed here in its
actual implementation is closely related to the higher
cortical organization proposed by Hubel and Wiesel for
the visual system. Moreover, in its global approach, the
algorithm is similar to the Hough transform, sharing
geometrical description as a goal while not suffering
susceptibility to local noise.

By developing alternate characterizations of some of
the axioms, space for the algebras can be constructed
as the intersection of hyperplanes and a sphere in an
appropriate vector space. A unique (with respect to N-
algebra isomorphism class) parametrization space is
then obtained as the quotient of the subset of the
vector space by a tensor product of two lower
dimensional orthogonal groups. By evaluating canonical
Riemannian geometry of a cone of generalized positive
definite symmetric matrices with respect to a particular
field of bases, one uses the standard diffeomorphism
from the triangular group of a T-algebra onto its related
cone to endow the Lie group with a left-invariant
Riemannian metric that is isomorphic to the geometry
of the cone.

Using this geometry on the Lie group, the connection
and Riemannian curvature tensors were calculated.
Calculation of certain sectional curvatures yields the
alternate characterization descnbed above for the N-
algebra, and shows that this and hence the
parametrization must be intrinsic. Further, it is shown
that in at least the rank 3 case, a cone is determined
by its curvature tensor. Contraction of the curvature to
the Ricci tensor and calculation of i, j coefficient for i
and j diagonal vectors yields that it equals a constant
times the dimension of the i, j subspace, so that only
products of the positive reals are Einstein spaces. The
curvature tensor can be shown to generalize that found
by C. L. Siegel for a type 1 Siegel domain built over the
cone of positive definite symmetric matrices.

Publications:

O'Connor, M A InvananI metrics on cones Proc ol the Conference on
Invariant Metrics and Holomorphic Maps. Rome. Italy. Istituto di Alts Male-
malica F Seven di CNR Symposia Mathematica. Volume XXVI. London
and New York. Academic Press, 1982

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Nonparametric Statistics

Research is concentrated on several topics of
nonparametric statistics. The study of nonparametnc
multiple comparisons has been initiated in FY83, with
particular attention to the theoretical as well as
computer simulated behavior of various procedures.
The optimal selection of a sequence of items based on
relative ranks with ties has been investigated. Thirdly,
an evaluation of tests for correlated proportions with
incomplete data has been undertaken.

Work has been initiated in FY83 in tlie area of
methodology for nonparametric multiple comparisons.
Evaluation of stepwise multiple comparison procedures
has been done both theoretically and using computer
simulations. Work is continuing in this area.

The optimal selection of a sequence of items based on
their relative ranks with the possibility of ties has been
investigated. A paper has been submitted for
publication.

An evaluation of statistical tests has been undertaken
for correlated proportions for incomplete data. A test
based on the iterative maximum likelihood estimator is

being compared with several ad hoc procedures in an
ongoing investigation.

Publications:

Campbell, G.: Asymptotic Properties of Several Nonparametric Multivariate Dis-
tribution Function Estimators Under Random Censoring. Survival Analysis.
In Crowley, J., and Johnson, R. A. (Eds.): Institute of fi/lathematical Statis-
tics Lecture Notes-H/lonograph Series. Haywood, California, 1 982, pp. 243-
256.

Campbell, G.: Optimal Selection Based on Relative Ranks of A Sequence witfi
Ties. Advances in Applied Probability (in press).

Campbell, G., and Foldes, A.: Large Sample Properties of Nonparametric Blvar-
iate Estimators witti Censored Data. Collquia lulatfiematica Socletatis Janos
Bolyai. Nonparametric Statistical Inference. Budapest, Hungary, 32: 103-
121, 1980.

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Computer Systems Laboratory

Alan M. Demmerle, Chief

Clinical Research, Patient Care,
Epidemiology

Computer Support for Flow Cytometry/Electronic
Cell Sorters (FC/ECS) (NCI, NHLBI). This project
provides support for the acquisition, display, and
analysis of data fronn instruments in NCI and NHLBI:
four Becton-Dickinson FACS-II and one Coulter
MDADS FC/ECS. All five systems currently use Digital
Equipment Corporation PDP-11 computers. Four
systems use the RT-11 operating system to process
data from one user at a time while one system uses the
RSX-11M operating system to support multiusers and
tasks simultaneously. The RSX-11M operating system,
designed for high volume applications, was used to
upgrade the I, NCI FC/ECS in FY83. This system
features an LSI-11/23 microcomputer (satellite) that
connects to an 11/24 minicomputer (host) via an
interprocessor link. A FC/ECS operator interacts with
the satellite for parameter entry and data acquistion,
which is performed independently of the host. Once
data is acquired, it is sent to the host where it is stored,
displayed, analyzed, and results are printed or plotted.

Cardiac Scintillation Probe (CC, NHLBI). This
nonimaging ECG-gated scintillation probe, when used in
conjunction with left ventricular (LV) catheterization,
permits simultaneous quantification of the variation of
LV volume and pressure. The system can continuously
derive parameters such as LV compliance, ejection
fraction, filling and ejection rates, and various temporal
relationships. The probe continues to be used to study
the effects of nephidipine and verapermil on patients
with asymmetric septal hypertrophy and coronary artery
disease. The probe is also being used to monitor the
left ventricle performance of patients in the Medical
Intensive Care Unit.

Nuclear Medicine Computer Systems (CC). CSL has
continued consultation and support for imaging systems
in the Nuclear Medicine Department to assess their
changing needs and to evaluate their increased
requirements with a view toward their anticipated
growth. This year four new viewing stations were
installed. A system for single photon tomography was
selected for purchase. A new camera interface (analog
to digital converter system) was installed and is being

evaluated as a possible replacement for the four
present camera interfaces. Investigation was initiated
into a department-wide central picture viewing and
storage system.

Medical Intensive Care Unit Patient Monitoring
Computer System (CC). Dynamic events occurnng
within the Clinical Center's Medical Intensive Care Unit
are monitored by a unique multiple-computer system.
Capabilities of the system include data acquisition and
analysis, medical recordkeeping, tabular and graphical
data display, and feedback control as required in
support of patient care and research protocols. The
Facility contains a state-of-the-art catheterization
laboratory with flexible computerized physiologic
monitoring features, and a high resolution x-ray system
with digital subtraction angiography capability. Of
primary interest is the utilization of the Medical
Intensive Care Unit's computer systems in the study of
the etiology and therapy of septic shock.

The Biomedical Image Analysis Projects (NHLBI,
NIA, NCI, NIADDK), These projects are oriented toward
the development of general-purpose algorithms and
techniques for image input (including digitization), image
enhancement (including contrast enhancement), feature
extraction (including edge detection, contour extraction,
contour following, contour coordinate compression, and
shape and texture analysis), three-dimensional
representation, image reconstruction (including Fourier
filtering, combining images, symmetrization), and other
techniques of image processing and image
reconstruction. The resultant general-purpose capability
is being accomplished through work with a number of
NIH researchers who encounter relatively similar
classes of problems in unique individual settings.

Automated ECG Processing (CC). The Clinical
Center's Heart Station was automated in FY81 with a
computer system that provides online acquisition,
analysis, storage, and retrieval of diagnostic
electrocardiograms. The newest versions of the
vendor's turnkey software and diagnostic cnteria
packages were installed recently, and the system was
placed in routine clinical operation. As utilization of this
system progresses, the medical staff will identify
specific diagnostic criteria and statements that require

"^ 35

modification to provide compliance with NIH Heart
Station standards for diagnostic electrocardiography.
The ECG analysis package will then be modified as
necessary to customize the ECG analysis process in
order to satisfy NIH requirements.

Department of Rehabilitation IVIedicine Computer
System (CC). This project involves the development of
computer techniques in collaboration with the
Department of Rehabilitation Medicine of the NIH
Clinical Center. CSL has recommended computer
techniques that can be used to automatically acquire
anatomical and physiological information from patients,
perform the required calculations on the data obtained!
and display the necessary results to the medical staff. '
The automated techniques include the measurement of
body forces (hand and ground reaction forces),
electromyograms (electrical activity of the muscles),
and body kinematics (the position and angles of the
limbs and joints in space and time). An Automated
Biomechanics Laboratory System that will provide
these measurements was purchased in FY83. The
computer part of the system will allow the medical staff
to enter patient and staff data into a data base with
computer generated forms displayed on a terminal
screen. The system also will perform inquiries and
generate reports using the accumulated data. In FY83,
the physical space for the purchased system was
designed, and the system was installed. The
Automated Biomechanics Laboratory will begin
operation with the start of FY84.

Positron Emission Tomography (PET) Facility (CC).
CSL has developed an interim offline imaging computer
to handle the substantial data analysis requirements of
the users of the Nuclear Medicine PET Facility. A
microcomputer link has been programmed to interface
scintillation counter output to the offline computer. The
PET scanner computer system has been expanded to
include new peripherals to manage increased data flow.
Picture Archiving and Communication System
(PACS) (CC). The purpose of this project is to develop
a system to store and transmit medical images and to
allow access to pictures representing different imaging
modalities from a single viewing station. Such a system
will draw on the latest technological developments in

the fields of data storage, image display, and data
communications. The system will reduce the amount of
time required to obtain images for clinical review, and
also facilitate research by making population and cross-
modality studies more feasible. During FY83 a study of
the available technology has been conducted, and an
expandable system architecture has been proposed.

Automated Management of Critically III Patients

(CC). This research project is concerned with a
systems approach to the management of critically ill
patients in a clinical setting. The ultimate goal of the
project is to use computer-based instrumentation to aid
in the differential diagnosis of disease states and the
implementation of therapeutic modalities through
automated technology. A state variable approach is
used in the mathematical modeling of pertinent
pharmacokinetic and physiologic processes. Empirical
clinical data and realtime monitored values are utilized
in model validation. Several alternative methods for
closed-loop automated medical interventions are being
investigated.

Computer Interfaces for Clinical Laboratory
Instruments (CC). Microprocessor-based interfaces,
developed by CSL, were first used in the Clinical
Pathology Department (CC) to link two Coulter
automated cell counters to the Clinical Pathology
Laboratory Computer. This was followed in February
1 982 with the development of a computer-assisted
hematology morphology data handling system. That
system was quickly used to capacity. This year we are
installing a similar system to extend the capabilities of
the present system. A total of eight user stations will be
provided for online white cell differential counting.

Automated Pulmonary Physiology Testing (NHLBI).
This project was brought to a successful completion by
mid-year. Fully automated lung static compliance and
inspiratory muscle strength procedures are now
routinely performed in the Pulmonary Branch's
pulmonary physiology/exercise laboratory. Under the
control of a MINC 1 1/03 computer system, data is
acquired and analyzed in realtime, with graphical and
textual reports produced at the completion of each
procedure. Steady state treadmill exercise testing has
been partially automated. Although data are manually

entered, analysis and report generation are fully
computerized. Due to a change in clinical priorities,
work in progress to enable automatic realtime
acquisition of exercise data with breath-by-breath
analysis was curtailed. System operations support
continued throughout the year.

Pulmonary Branch Support (NHLBI). This project
involves assisting the Pulmonary Branch to meet its
computer and data processing needs. CSL has
continued to help maintain the computer portion of the
two Collins automated pulmonary function analyzers.
Consultation was provided to help the Pulmonary
Branch more effectively use the NIH Central Computer
Facility for office and scientific applications.

Anesthesia Computer System (CC). This project is a
collaborative effort between CSL and the
Anesthesiology Service, CC to evaluate improved
instrumentation techniques and to identify and
investigate ways that automation can benefit
anesthesia. Project emphasis is on adjunctive
monitoring and automated recordkeeping in the
operating room and on a greater use of noninvasive
monitoring methods. This year work continued on the
development of plans to guide future work. An
investigation was begun of the potential usefulness of a
mass spectrometer gas analyzer in the operating room
to monitor inhaled and exhaled gas concentrations.
Various technologies are being explored to develop a
monitoring and reporting system for the operating room.

Medical Information Technology Project. This
project is concerned with the development of better
ways to automate the essential physician contribution
to the health care record. For a second year, in
collaboration with two practicing dermatologists, we are
field testing an ambulatory patient care treatment
system. It is designed to help the physician generate
patient information and treatment schedules, pharmacy
prescriptions, medical and surgical reports, laboratory
test requests and results, and referral letters to other
doctors. Physicians interact with the system using high
speed user-friendly menu selections with many default
fields preselected. Because most of the clinical
software is table driven on a microcomputer, it can be

adapted to other clinical care and research
environments.

Laboratory Investigation

Molecular Graphics and Sequence Analysis

(NIADDK, NCI, NIDR). The sequence of some regular
proteins, together with other structural information such
as data from x-ray diffraction, fiber diffraction, electron
microscopy, and spectroscopic analysis can be used to
evaluate models of the protein structure. Four projects
have been using modeling techniques developed at
NIH and sequence analysis to better understand the
protein structure. We have recently published a new
interpretation of the x-ray diffraction data for collagen
fibrils. Cyanogen bromide fragments of keratin filaments
are being studied to understand their structure and to
compare keratin with other filamentous proteins.
Analysis of myosin and streptococcal M proteins is
continuing as sequences become available.

Electron Microanalysis Facility (DRS). CSL is
collaborating with BEIB, DRS to develop an automated
electron microanalysis facility consisting of two electron
microscopes interfaced to a PDP- 11/60 computer
system. The facility is being used for research into the
elemental composition of biological specimens and for
the development of new techniques in electron
microscopy. CSL designed and implemented the
computer system, which acquires and displays the
spectra and images resulting from Electron Energy
Loss (EEL) and x-ray spectrometry. This year, both EEL
and EDS imaging became operational and are in
routine use on many biological research projects. The
EEL images are the first successfully produced on a
STEM and the first to be properly compensated for
mass thickness effects. The second electron
microscope, a Cameca electron microprobe, was
interfaced to the computer and implemented using
existing data acquisition and imaging software. Data
processing and image display capabilities of the system
were greatly enhanced.

Molecular Interactions Laboratory Data System

(NHLBI). This microcomputer (PDP-03) data system
supen/ises the acquisition and processing of

' 37

information from an analytical ultracentrifuge and a
circular dichroic spectropolarimeter used in MDB,
NHLBI to investigate the interactions between liuman
lipoprotein subunits. Preprocessed data are transferred
to the DECsystem-10 for further analysis under MLAB
using predefined procedures invoked by a few simple
commands. Additions to the system this year include a
four-pen digital plotter and the MLAB procedures for
plotting both ultracentrifuge and circular dichroism data.

Californium-252 Plasma Desorption Mass
Spectrometer Data System (NHLBI). This instrument
provides NIH the capabilities of mass analysis for
compounds difficult or impossible to analyze by other
mass spectrometric means. It also extends the range of
mass analysis to compounds with molecular weights in
excess of 5000. Hardware enhancements made in the
system this year include the addition of a line printer,
another 256K bytes of memory (total of 768K bytes),
and an additional direct memory access channel
controller to be dedicated to the mass spectrometer
interface.

Distributed Laboratory Data Acquisition and
Control System (DLDACS) (NIADDK). A Distributed
Laboratory Data Acquisition and Control System
(DLDACS) has been implemented for NIADDK. The
new system consists of a network of remote
microcomputers connected in a star configuration
through a communications processor to a central
processing computer. The remote microcomputers
handle all of the realtime data acquisition requirements
and provide instrument control functions when required.
The collected data is normalized, buffered, and
transmitted as files over a serial line, using a standard
block protocol, to the communications processor. The
communications processor serves as a store and
fonward front end for the central computer. Currently
there are eight satellites connected to the system
supporting eleven instruments. Processing software
provided at the host allows LDACS data files to be:
added, subtracted, averaged, smoothed, baseline
corrected, integrated, differentiated, multiplied by a
constant, and added to a constant. The results may be
displayed graphically on a Tektronix terminal, typed at a
terminal, printed on the line printer, or plotted on an X-

Y plotter or transmitted to the NIH DECsystem-10 for
additional processing.

Personal Computers in Laboratory Application

(DCRT). Personal computers have become a viable
alternative to assembling board-level microcomputer
systems for many laboratory applications. They offer a
substantial "head start" and form the basis for
programmable acquisition and control systems. We are
evaluating laboratory interfacing hardware and software
so that we can assist users in configuring systems for a
variety of laboratory applications.

Program Management And
Administration

Small Animal Data Base Management System (DPS).
Responses to the Request for Proposals previously
developed by CSL for a small animal data management
system were received this year. CSL was responsible
for the management of the technical evaluation and
guided the negotiations with vendors. Technical
consultation to monitor the development of the system
is being provided and is anticipated to continue over
the next few years.

Library Automation (DRS). Since FY79, CSL has been
involved in the automation of the NIH Library. This
effort has included a requirement study, a survey of the
available options, and a cost benefit analysis, and has
culminated in a recommendation to purchase a
commercially available turnkey library system.
Subsequent to system selection, CSL has continued to
support the Library by providing technical assistance
during the procurement process. During FY83, CSL has
been involved in supervising site preparation and
system installation, using the NIH Central Computer
Utility to develop software needed to edit the Library's
bibliographic data base, providing technical support to
the contractor hired to edit the data base, and training
and otherwise preparing library staff for the introduction
of the sophisticated computer-based system.

Biomedical Communications And
Conference Support

Computers in Cardiology Conference. CSL

continued its support of the annual International
Conference on Computers in Cardiology. The
Conference provides a forum for direct interaction and
exchange between physicians, computer scientists, and
engineers who are involved in various aspects of
clinical computer systems in the field of cardiology.

Microcomputers in the Laboratory. Microcomputers
in the Laboratory: An Introduction was the title of an
invited lecture presented by CSL staff member Ramon
L. Tate at the Training Course on Computers in
Endocrinology, May 30 to June 1, 1983, jointly
sponsored by the Chair of Endocrinology, University of
Sassari, Italy, and the Post Graduate school of
Endocrinology, University of Florence, Italy. The course,
which was attended by approximately 80 scientists from
Europe and the Middle East, was held in Porto Cervo,
Sardinia. Dr. Tate also conducted a workshop session
that dealt with selecting and implementing a laboratory
microcomputer system.

Minority Biomedical Research Support. CSL

supported NIH minority biomedical research assistance
programs by participating in the NIH Visiting Professor
Program and by preparing and presenting a workshop
on laboratory computing to the annual MBRS
symposium.

CSL Consulting

This year, as in past years, CSL provided consultative
assistance to several intramural and extramural
program areas.

• CSL helped the Allergenic Products Branch, Bureau
of Biologies to implement a laboratory computer
system by adapting a data acquisition software
package that we previously developed for another
project.

• Several CSL staff members served on NCI evaluation
and source selection committees for proposed
computer support contracts.

• Two activities reported last year as collaborative
projects with NHLBI (Potentiometric Titration
Controller and Metabolic Energy Measurements)
were successfully continued by NHLBI investigators
with CSL providing only occasional microcomputer
technical consultation.

• The Cardiology Branch, NHLBI, intends to purchase
a digital angiographic imaging system for their new
cardiac catheterization laboratory. CSL helped to
evaluate their requirements and surveyed the market
to identify acceptable systems.

Computer Research And Technique
Development

image Processing Facility (DCRT). This project
provides a utility to display and analyze digital images.
The system consists of a powerful 32-bit computer with
a mixture of medium and high resolution video displays.
A high resolution microdensitometer allows precise
digitization of images acquired from a variety of sources
(e.g., electron microscope). The system was installed
this year and is in use by a limited number of
investigators. Completion of the system is forecast for
1984.

Analytic Models of Computer System Performance

(DCRT). This project involves the development of
analytic models that can be used to evaluate the
performance of computer systems. During the past
year, the work on modeling and analyzing computer
systems using the graph theoretic model called timed
Place-Transition (P-T) Nets was continued. This
included the development of new methods for
determining net invariants and new models for
demonstrating the dynamics of computer systems.
Detailed models of computer bus control techniques
and the operation of a commercial array processor
were constructed. These models were analyzed using a
method that was developed for evaluating computer
system performance wi«h timed P-T Net models. The
development of a state variable P-T Net model of the
interconnection of two or more microprocessors was
continued. This model provides a framework for
determining the avoidance of deadlock and the

" ■ 39

maintenance of throughput in multiple microprocessor
systems. In FY84, timed P-T Net models will be used to
develop more analytic tools for evaluating computer
system performance.

Verbal Access to Computers for the Blind (DCRT).
Several years ago, CSL developed a voice output
terminal that permits the blind to access computers
independent of sighted assistance. This year, we
assembled and installed one of these terminals for a
blind NEI scientist to use in his laboratory. We also are
investigating the use of voice output with analytical
laboratory instrumentation. Finally, we are developing a
voice output attachment for the DCRT-supported
personal computer workstation to extend the availability
of these systems to blind users.

Medical Image Data Compression (DCRT). This
project involves reducing the number of information
carrying units used to represent a medical image in
order to improve the efficiency of transmission and
storage of such images. Various image data
compression techniques and their application to
medical images are being evaluated with regard to the
amount of compression attained and the quality of the
reconstructed image. Methods for implementing these
techniques that will be suitable to the clinical
environment are being developed.

Research Projects

NOTICE OF INTRAMURAL RESEARCH PROJECT

ZOl CT00050-04 CSL

October 1, 1982 to September 30. 1983 1

Computer Support to Flou Cytometry/Electronic Cell

ortlng (FC/ECS)

Ronald Flco, Electronics Engineer, CSL, DCRT

CSL, DCRT: R.J. Romanoff, Computer Specialist; L.K.
L. Freeman, Computer Programmer; M. Candler. Electr
S.O. Sharrow, Chemist; D.A. Stephany, Biologist.

Barden, Electronics Engineer;
nics Engineer. I, NCI;

Computer Systems Laboratory

Processor Design Section

DCRT, NIH, Bethesda, Maryland 20205

TOTAL MANYEA^ 1 PROJESSIONAU 1 OTHER,

Computer Support for Flow Cytometry/Electronic
Cell Sorting (FC/ECS)

This project provides PDP-1 1 computer support at
various levels for four Becton-Dickinson FACS II and
one Coulter MDADS FC/ECS instruments. Data
acquisition is via an NIH-designed interface to the
computer. Data display and analysis for high sample
throughput is the principal system feature. Currently,
there are two versions of data acquisition and analysis
systems developed and supported by CSL for the Cell
Sorter Community at NIH. One version uses a single
computer that runs under the RT-1 1 operating system.
Another version, referred to as the RSX system, uses
at least two computers. A host computer, a Digital
Equipment Corporation (DEC) 1 1 /24 is used to analyze
and store data. Satellite computers, one (LSI-1 1 /23)
per instrument, are used for data acquisition and are
connected to the host through a high-speed direct
memory access (DMA) link. The RSX system offers
multiuser and multitasking support, improved
recordkeeping facilities, and enhancements for data
acquisition and data analysis. An RSX system was
installed at I, NCI, during the fourth quarter of FY83.

Background and Objectives: Since FY75 CSL has
provided engineering, system integration, and software
support necessary to meet the data acquisiton, data
display, and analysis needs of several investigators
using FC/ECS instruments at NIH. Software
development and testing is done on a DEC PDP-1 1 /24
computer system owned by CSL. This allows
investigators to have full use of their systems while new
software is being developed.

Both the RT-1 1 and RSX systems allow data collection
of up to four parameters on individual cells. Typically
these are light scatter, two frequencies of fluorescence,
and cell volume. The data can be collected in single
parameter or correlated dual parameter modes. Data
analysis and display programs allow the experimenter
to produce various statistics and hardcopy displays
from the acquired data. The displays include three-
dimensional pictures, contour maps, and vertical slice
sections.

Progress in FY83: The major effort in FY83 was
continuing the development of the RSX-1 1M system.
The RSX system was developed for I, NCI in order to
provide more effective support of current and
anticipated workloads and more sophisticated data
acquisition and recordkeeping functions. This system is
available to other NIH FC/ECS sites as required.

It was decided in FY81 to replace the DEC VT-11
graphics display device with a Tektronix 4025 and to
support this terminal on the RSX system. A contract
was negotiated with Electronic Data Systems, Inc., to
assist CSL personnel in developing software packages
for displaying graphs on the T4025 or any terminal that
is driven by Tektronix 4010 graphic commands. All four
of the major FC/ECS data display and analysis
programs were rewritten to run under RSX-1 1 M, using
the new graphics software package. Several
improvements to these display and analysis programs
were made in FY83 in order to improve their use.

A tape-to-disk transfer (TDXFER) program, written and
tested in FY83, processes raw list mode data on tape
into a matrix (PHA) form and stores this matrix on disk.
A user can preview list mode data on the T4025
graphics terminal, in order to determine parameter
values necessary to process the data into matrix form.
The program is designed to automate multiple
processing loops, each with differing parameters, so
users need not interact during what may be a lengthy
period of time.

The new data acquisition system environment consists
of a PDP-1 1 host computer running RSX-1 1M and up to
eight LSI-11 based satellites, each running RT-11,
connected to the host via an interprocessor link.

Data acquired by a satellite is sent over the link and
stored at the host site. The satellite link software is
common to all satellites, but distinct from the host link
software. Together, the host and satellite link software
provides file transfer capability.

The development of the link software was completed in
FY82 and the hardware for a complete satellite system
was acquired. The acquisition hardware and software of
the LSI-1 1 system was tested in the second quarter of
FY83. The RSX satellite is designed to collect up to

four single parameters simultaneously with one
correlated dual parameter pair, or it can collect up to
two simultaneous correlated dual parameter pairs.

An important feature of the satellite system is the ability
to create a "laboratory notebook" as a permanent
hardcopy rather than continuing this as a manual task
as in the RT-11 systems. This "notebook" concept is
an integral part of the software that provides interaction
with the operator via a DEC VT-100 terminal. Errors are
reported in detail on the terminal screen.

The CSL development system was updated with a 1 1 /
24 processor in the second quarter of FY83. CSL has
also responded to many external requests and has
provided copies of the interface hardware schematics,
software, and documentation to FC/ECS sites in the
U.S., Australia, and Europe.

Proposed Course: In the forthcoming year, CSL plans
to continue development on the RSX system by adding
features that will take advantage of the data
management capability designed into the system. In
addition, new capabilities will be added to the data
analysis software and some effort is expected to be
spent on automating analysis, and/or acquisition
software so that many steps can be performed without
operator intervention. If resources permit, the RT-1 1
analysis programs will be expanded to include Cell
Cycle Analysis and several other high prionty
requirements. CSL will also continue to maintain
existing RT-11 based FC/ECS sites at NIH.

Of^AlinaiMTOfNtALTH AND HUMAN HRVIC*! HMlK HtAlIM fWVICI
NOTICE OF INTRAMURAL REUARCH PROJECT

ZOI CTaOO>l-04 CSl

October 1. 1982

icabir 30. I9S3

Cjrdiac SclntlllAtion Pro6«

H.r,.IH r.. n.rrm.. 1 1 t t l-nn 1 1- . Eii«ln««r. CM,. IKIT

;mT''""°s""'»«c'hIrAch. PKyilclic; «. Cr«««. rhyalclit. C». 10011: «.
CArdlologlst ; D. Ro»«n, Cardluloglst .

Cardiac Scintillation Probe

CSL has continued the development of its Cardiac
Scintillation Probe System begun in 1977. This
nonimaging ECG-gated scintillation probe, when used in
conjunction with left ventricular (LV) catherization,
permits simultaneous quantification of the variation of
LV volume and pressure. By simultaneously measuring
LV volume and LV pressure, parameters such as LV
compliance can be continuously monitored, in addition
to such measurements as ejection fraction, filling and
ejection rates, and temporal relationships. This year the
probe continued to be used to study the effects of
nephidipine and verapermil on patients with coronary
artery disease.

The probe is also being used to monitor the left
ventricle performance of patients in the Medical
Intensive Care Unit. The pressure-volume relationships
produced by the probe system allowed the effects of
drugs to be quantitated in a manner not possible
before. Development is continuing on increasing the
detection efficiency of the probe and in quantifying the
limitation of the technique. The cardiac scintillation
probe is a transportable device used to noninvasively
monitor left ventricular function. The system uses
Nuclear Medicine ECG-gated scintigraphic techniques
and consists of a small detector and microcomputer
system mounted on a cart.

Background and Objectives: The development of the
cardiac scintillation probe is a continuation of CSL's
collaboration with the Nuclear Medicine Department,
CC, and the Cardiology Branch, NHLBI. Originally this
collaboration resulted in the development of a
noninvasive cardiac imaging technique known as ECG-
gated scintigraphic angiography using a scintillation
camera. However, if the images are not required, then
a time-activity curve of the left ventricle could be
generated by a much smaller and simpler system. In
1 977 CSL began the development of a cardiac
scintillation probe system, using a small Nal detector
and microcomputer system. This system produces a
time activity curve (LV volume curve) that can be used
to calculate various parameters of cardiac function
such as ejection fraction, peak ejection rate, peak filling
rate, and their temporal relationships. The system is
easily transportable and allows continuous monitoring
of cardiac function at the bedside or other location in

the Clinical Center outside the Nuclear Medicine
Department.

Methods: The system consists of a three-inch diameter
Nal scintillation probe, probe electronics,
microcomputer system, and display. The system is
programmed to acquire scintillation data from the
probe, to process the data, and to plot and display
various parameters of left ventricular (LV) function. This
nonimaging, ECG-gated probe, when used in conjuction
with ventricular catheterization, permits simultaneous
quantification of the variation of LV volume and LV
pressure. Parameters such as LV compliance can be
continuously monitored. In the catheterization
laboratory, pressure-volume measurements are used to
study the effects of drugs on patients with various heart
diseases.

Progress in FY83: This year the probe continued to be
used in the catherization laboratory to study the effects
of nephidipine and verpamil on patients with coronary
artery disease. The data acquisition and some of the
processing is now being performed by the Nuclear
Medicine Department. A Hewlett-Packard computer
system has been ordered to replace the Intel
microcomputer system used for the probe. The
Hewlett-Packard computer will accomodate new
requirements for the probe system and be compatible
with the existing analysis software available in the
Nuclear Medicine Department.

The application of the probe in the Medical Intensive
Care Unit, CC is continuing to be investigated. The
probe would be used to continuously monitor left
ventricular function at the bedside.

Significance to Biomedical Researcfi: Nuclear Medicine
techniques provide a relatively noninvasive procedure
to assess left ventricular function. The cardiac
scintillation probe permits this capability to be used for
clinical research studies at the bedside and in the
catheterization laboratory. The pressure volume
relationship produced by the probe system allows the
effects of drugs to be quantitated in a manner not
before possible.

Proposed Course: Development activities in response
to new applications are expected to continue. CSL will

investigate making \he probe and camera systems
compatible. Making the system compatible to the
extent possible will reduce the resources required to
support the probe system and will allow new
capabilities developed for the camera systems to be
implemented quickly on the probe system.

Publications:

Bonow, R., Ostrow, H.. Rosing, D , Cannon, P., Allen, S , Maron, B , Bacharach,
S., Green, M,, and Epstein, S.: Verapamil Effects on Left Ventricular Pres-
sure-Volume Analysis with a Nonimaging Scintillation Probe. Circulation (in
press).

Green, 1^., Ostrow, H., Bacfiarach, S , Allen, S.. Bonow, R., and Jofinston, G.:
Realtime Scintillation Probe li^easurement of Left Ventricular Function.
Nuklear Medizine 20: 1 1 6-1 23, 1 981

NOTICE OF INTRAMURAL RESEARCH PROJECT

201 CT00054-04 CSL

October 1, 1982 to Septen^er 30, 1983

Medical Intensive Care Unit Patient Monitoring Computer SvsCen

Kenneth H. Kempner, Electronics Engineer, CSL. DCRT

CCMD, CC: J.E. Parrillo, M.D. , Chief, Critical Care Medicine; S.L. Huntley . .Supv.
Critical Care Technician. CSL. DCRT: L.W. Kreeman, Computer Prograomer; J.K.
DeLeo. Computer Systems Analyst. BEIB, DRS: J.F. Pessler, Engineering Techictan.

Computer Systems Laboratory

Systems Design Section

DCRT. NIH. Bethesda, Maryland 20205

0.8 1 0.8 1

Medical Intensive Care Unit Patient Monitoring
Computer System

The dynamic events occurring within the Clinical
Center's Medical Intensive Care Unit are monitored by
a unique multiple-computer system. Capabilities of the
system include online data acquisition and analysis,
medical recordkeeping, tabular and graphical data
displays, and feedback control, as required in support
of patient care and research protocols. Elements
include a minicomputer-based Patient Data
Management Subsystem, a Software Development
Subsystem, and a Medical Mass Spectrometer
Subsystem.

The facility also contains a state-of-the-art
catheterization laboratory that includes a flexible
computerized Vascular Research Subsystem, with
physiologic waveform processing features, and a high

resolution x-ray system with digital subtraction
angiography capability.

Of primary interest is the utilization of the Medical
Intensive Care Unit's computer systems in the study of
the etiology and therapy of septic shock.

Bacifground and Objectives: The Medical Intensive
Care Unit (MICU), which is administered by the
Department of Critical Care Medicine in the NIH Clinical
Center, receives critically ill patients from clinical
programs of NIH. The MICU comprises a five-bed ward
area, a pair of isolation beds, and a vascular research
laboratory. The research goals of this unit include the
development of techniques for automated patient
monitoring and noninvasive measurements of the
cardiovascular and respiratory systems. In addition,
catheterization studies are performed as necessary to
obtain data that are available only through invasive
methodology.

Working with Clinical Center staff, CSL contnbuted to
the engineering design of the intensive care unit. CSL
also undertook the specification, procurement, and
installation of the bedside patient monitoring equipment
and the six computer systems:

1 . a Patient Data Management System used for
automatically monitoring patient vanables, manually
entering patient data, retrieving information online,
and keeping medical records;

2. a Vascular Research Subsystem used for acquiring
and processing cardiovascular pressure waveforms,
measuring cardiac output, displaying measured
results online, and generating a cardiac
catheterization report;

3. a Software Development Subsystem used for
developing software for the above described
systems;

4. an Ultrasound Imaging Subsystem used to allow
the visualization of intracardiac structures via
multiformat displays, and facilitate the detection of
structural abnormalities and other cardiac defects;

5. a Medical Mass Spectrometer Subsystem used for
monitoring both the patient airway gases and the
gases delivered by the patient's respirator at all
seven MICU beds; and

6. a Pulmonary Function Testing Subsystem used to
calculate parameters such as vital capacity and lung
volumes, and to generate flow-volume loops.

The first four systems were purchased from the
Hewlett-Packard Corporation and all use identical
minicomputers. The Chemetron Corporation
manufacturers the microcomputer-based mass
spectrometer system. The Collins Corporation designed
and manufactured the microcomputer-controlled
Pulmonary Function Testing Subsystem.

Major Findings: The automation of the MICU has aided
the medical staff by managing the large amount of data
needed for the care of the critically ill patient,
performing desired calculations, and allowing
measurements that would not otherwise be possible.

Progress in FY83: Modifications were made to the main
Vascular Research Subsystem and the mobile
noncomputerized Vascular Research subsystem, in
order to improve their data collection capabilities and
ease of operation.

The ultrasound imaging subsystem was upgraded to
improve image resolution by doubling the number of
receiving crystals in the phased array transducer.

A Cardiac Probe, developed jointly by CSL staff and the
Clinical Center's Nuclear Medicine Department, was
interfaced to the Software Development Subsystem.
This device provides left ventricular volume data by
counting gamma ray-induced scintillations, after the
administration of injectable radioisotopes. Software was
developed to produce Beat Length Histograms and
Joint Interval Histograms from the scintillation data, as
well as single cycle and averaged left ventricular
volume curves.

Proposed Course: Future efforts will center on
hardware and software modifications necessary to
enhance the system's ability to support patient care
and research protocols. Possible modifications to the
primary Patient Data Management Subsystem include
the addition of urine output measurement scales and
the computerization of fluid infusion therapy utilizing
existing microprocessor-controlled infusion pumps.

NOTICE OF INTRAMURAL RESEARCH PROJECT

ZOl CT00084-03 CSL

1. 1982 to Seotember 30. 1983

MA Colonies

DeLeo, Conputer Systems Analyst CSL, DCRT

LB, C:

Floyd Taub, Research Associate; Brad Thompson, Sect

on Chief.

Compute

Systems Laboratory

DCRT. N

TOTAL MAN

0.1 1 0.1 1

Computer Analysis of Autoradiographic Images of
Recombinant DNA Colonies

A computerized methodology for analyzing
autoradiographic spot images associated with
recombinant DNA bacterial colonies was developed in
collaboration with scientists in NCI. This system
represents a unique refinement in a method to directly
identify cloned sequences complementary to
messenger RNA that are developmentally or
hormonally induced.

Spot density measurements are computed from
digitized images produced via microdensitometry.
These measurements are corrected for variability in
exposure and local background, calibrated to
hybridization standards, and normalized for comparison
purposes. The system provides a variety of graphical
and tabular output that effectively summarizes
experimental results and identifies significant induced
hybridization events.

Bacl<ground and Objectives: NCI scientists have been
refining techniques to directly identify cloned DNA
sequences complementary to messenger RNA that are
developmentally or hormonally regulated. This
refinement has led to a methodology that produces
autoradiographic spot images representative of the
amount of hybridization. The objective of this project is
to provide an automated procedure for a quantitative
analysis of understanding these images.

Methods Employed: Cloned bacteria are grown on agar
in microtiter wells, transferred to filter paper, and
fiybridized to end-labeled mRNA or cDNA probes.
Autoradiographs of the filters are digitized and the
density of each spot relative to background is
established by means of CSL-developed image
processing software operational on the DCRT Evans
and Sutherland PDP-11/70 computer system.
Compensation for variations in background, film
exposure conditions, and hybridization are included in
the methodology. A variety of graphical output including
scatter diagrams, histograms, and listings is provided.

Progress in FY83: A paper has been written that
describes the use of this system in analyzing the in vivo
response of rat liver to glucocorticoids, as well as the
application to other biological systems.

NOTICE OF INTRAMURAL RESEARCH PROJECT

ZOt CT00086-O2 CSL

October 1. 1982 to September 30, 1983

Computer Assisted Tomography (CAT) Scan Image Analysis in Aging Studies

James M. DeLeo. Computer Systems Analyst. CSL, DCRT

LN, NIAr M. Schwartz, Medical Staff Fellow; S.I. Rappoport. Chief.

Computer Systems Laboratory

Systems Design Section

DCRT. NIH. Bethesda. Maryland 30205

TOTAL MANV^EAW | ^^ |

Computer Assisted Tomography (CAT) Scan Image
Analysis in Aging Studies

An interactive image analysis computer procedure to
measure various parameters from Computer Assisted
Tomography (CAT) scans of the human brain was
designed and implemented on the DCRT Image
Processing Facility. This procedure was used to
measure and analyze various morphological features of
the brains of normal volunteers representing a wide age
span as well as adults with autism, Alzheimer's
Disease, and Down's Syndrome. Results were reported
at two professional meetings. Technical papers
describing this work are in preparation. Efforts to
transport this methodology to a newly installed NIH

computer system have begun and are reported
separately.

Background and Objectives: The purpose of this project
is to study changes in the human brain structure during
normal aging and during brain disease processes
associated with aging by means of measurements
made from Computer Assisted Tomography (CAT)
scans of human brains.

Methods Employed: CAT scans are transported to the

DCRT Image Processing Facility via magnetic tape.
Through interactive analysis of the CAT scan images,
an investigation is able to obtain a wide variety of
descriptive measurements such as sizes and
attenuation values of brain substructures, and percent
composition of the intracranial space in terms of white
matter, gray matter, and cerebral spinal fluid.

Progress in FY83: Several brain CAT scans of normal
volunteers were processed. Results supporting the
theses of ventricle enlargement and gray matter
reduction in normal aging were presented at meetings
of the American Academy of Neurology and the
American Psychiatry Association. Papers describing
these findings and the methodology have been written.
Efforts to transport the methodology to a newly
installed NIA computer system have begun. The need
for beam hardening and skull/brain partial voluming
corrections in brain composition estimation was found
to be necessary.

Significance to Biomedical Research: This
quantification methodology will greatly augment visual
interpretation of brain CAT scans. It may provide a
deeper understanding of brain structure associated with
normal aging and disease processes. It is also possible
that this work will produce new diagnostic tools.

During the course of this work it was discovered that
brain composition estimates were significantly biased
by radial and apical beam hardening artifacts and skull/
brain partial volume effects. Empirical corrections tor
these effects are essential for improving upon these
estimates.

Proposed Course: Future plans include submitting
technical papers for publication and completing the

' 45

transfer of the methodology to the NIA computer
system.

NOTICE OF INTRAMURAL RESEARCH PROJECT

ZOl CT0O087-02 CSL

October 1, 1982 to September 30, 1983

Robust Boundary Detection of Necturus Gall Bladder Cells

James M. DeLeo, Computer Systems Analyst, CSL, DCRT

LKEH, NHLBI: K. Spring, Research Physiologist; P. Jensen,

M.D., Guest Worker.

Computer Systems Laboratory

Systems Design Section

DCRT, NIH, Bethesda, Maryland 20205

0.4 1 0.4 1

Robust Boundary Detection of Necturus Gall
Bladder Cells

The boundary detection algorithm previously described
has been implemented, tested, and refined on the
DCRT Evans and Sutherland Image Processing Facility.
This algorithm performs automated planimetry on light
microscopy video images of optically microtomed
sections of in vivo Necturus gall bladder cells to
provide time histories of cell volume changes. The
refined algorithm searches extrema of pixel variances
along pin filters orthogonal to guided segments of radial
spokes emanating from the cell section centers. Efforts
to transport this algorithm to an NHLBI computer
system for continuing laboratory use have begun.

Background and Objectives: Epithelial cells of Necturus
gall bladder regulate their volume after a change in
osmolality of their bathing solution. The Laboratory of
Kidney and Electrolyte Metabolism has developed a
computerized methodology for time-tracking cell volume
changes through interactive planimetry of video images
of cells visualized in a light microscope. The Computer
Systems Laboratory was requested to develop a
specialized robust cell boundary detection algorithm to
enhance overall throughput processing efficiency.

Methods Employed: The refined boundary detection
algorithm works as follows:
1 . The investigator points to the center of the cell.

2. Parameters associated with locations along
segments of rays emanating from the center are
computed. The number of rays is user specified. Ray
segment selection is initially specified and later
guided by certified edge points associated with
previously processed cell sections. Computed
parameters include means and variances and their
derivatives of opacity values along pins emanating
from each ray segment pixel. The number and length
of pins are user specified.

3. Local maxima of an edge point probability function
computed from a normalized combination of
parameters collected in Step 2 are determined and
tagged as candidate edge points.

4. Candidate edge points are screened and pruned
for redundancy and for being out of range.

5. Missing edge points are searched for over
narrower ray segments as guided by certified known
neighboring edge points.

6. The final list of edge points is smoothed,
connected, and integrated to give area.

7. Steps 1 to 6 are repeated over all cell segments to
obtain cell volume.

Progress in FY83: A new set of test images were
brought over to the DCRT Image Processing System. A
variety of smoothing and filtering techniques were
tested leading to the selection of the described pin
filtering technique. Hardware and software work has
begun to make the algorithm operational in the NHLBI
research laboratory environment.

Significance to Biomedical Research: Application of
quantitative light microscopic techniques to study cell
volume changes due to fluid and ion transport in living
epithelial tissues has already proven to be a powerful
and effective research tool. An accurate, efficient,
robust cell boundary detector algorithm would greatly
improve upon the utility efficiency and throughput
speed of this methodology.

Proposed Course: Testing and refining of the algorithm
will continue. Implementation of the algorithm for
production use in the LKEM/NHLBI research laboratory
environment is planned.

0EF.RT1.ENI OF HE.LI- .NO HUMAN SE.VlCtS ■ FUSLIC MtAlTH SERVICE

P.OItCTNOM...

NOTICE OF INTRAMURAL RESEARCH PROJECT

zoi cTOOoai-0] CSL

FEniOO COVERED

October 1. 1982 ro September 30. 1983

TITLE OF PROJECT ISO cft«c(#rf orlM^ TliU fftuit fit on ant l^t btlv—nlt^ t€rd»r^l

Rehabilitation Medicine Department Computer System

>RtNCIPALINVESTIGATOn(LU(airi>rprof*M(ondJFmo>ui*loniu6M«K«iit«Mm-l

INam: Mil*, leboralort. and ln>m«l* ofniMlonl

Robert L. Martlno, Electronic Engineer, CSL. DCRT

W, CC; M.O. Jarret. Expert, Blomechanlcal Engineering; C.C. Hunt, Physical

Therapy Research Coordinator; W. Schnelderwlnd , Chief, PhyslCAl Tlierapy Service;

N.L. Cerber, Chief, RehablUation Medicine Department.

Computer Systems Laboratory

Systems Design Section

DCRT, NIH. Bethesda. Maryland 20205

TOTAL MANVEARS 1 PROFESSIONAL 1 OTHER

0.6 1 0.6 1

Rehabilitation Medicine Department Computer
System

This project involves the development of computer
techniques in collaboration with the Department of
Rehabilitation Medicine of the NIH Clinical Center. CSL
has recommended computer techniques that can be
used to automatically acquire anatomical and
physiological information from patients, to perform the
required calculations on the data obtained, and to
display the necessary results to the medical staff. The
automated techniques include the measurement of
body forces (hand and ground reaction forces),
electromyograms (electrical activity of the muscles),
and body kinematics (the position and angles of the
limbs and joints in space and time). An Automated
Biomechanics Laboratory System that provides these
measurements was purchased in FY83. The computer
part of the system will allow the medical staff to enter
patient and staff data into a data base with computer
generated forms displayed on a terminal screen, and to
perform inquiries and generate reports using the
accumulated data. In FY83, the physical space for the
purchased system was designed and the system was
installed. The Automated Biomechanics Laboratory will
begin operation at the start of FY84.

Background and Objectives: The Department of
Rehabilitation fvledicine provides physiatric evaluation
and treatment, physical therapy, occupational therapy,
and speech therapy for NIH Clinical Center patients
referred by Institute physicians. In addition, it develops
various indices to evaluate these services. This

department supports the efforts of, and collaborates
with. Institute physicians engaged in research relevant
to physical rehabilitation medicine. It also initiates both
clinical and basic research independent of the Institutes
in the rehabilitation of mentally and physically
handicapped individuals.

In support of these goals, CSL is developing a
computer system. Initially, the department will use the
system for the following three projects:

1. The Automated Biomechanics Laboratory: a
laboratory that will be used to automatically measure
the position of the limb segments in space, the
patient ground reaction forces, and the
electromyographic signals from the muscles in the
limbs;

2. The Hand Dynamometer Instrument: a device that
will be used to measure the magnitude and direction
of the forces in the hand and to develop clinical tests
to diagnose the mechanical and functional status of
the hand, arm, and shoulder;

Progress in FY83: During the past year, an Automated
Biomechanics Laboratory System was purchased from
Oxford ivledilog, Inc. The instrumentation that was
purchased included five motion cameras with infrared
light sources that are used to acquire the spatial
coordinates of anatomical points on the patient's body
with reflective markers, two force platforms that are
used to measure patient ground reaction forces, and
hard wired electromyogram acquisition hardware that is
to measure patient muscle activity. This instrumentation
is connected to a Digital Equipment Corporation VAX-
11/750 computer system that performs the necessary
data acquisition, calibration, processing, display, and
storage functions. The equipment was installed at the
Department's new Clinical Center location in an area
that was designed to accommodate the specialized
instrumentation and computer system.

~ 47

Development of the Physical Therapy Quality
Assurance Data Base System was continued on a
small computer system. It will be transferred to the
computer that was purchased with the biomechanics
laboratory system. The Biomedical Engineering and
Instrumentation Branch of NIH's Division of Research
Services continued development of the hand
dynamometer instrument.

Also, during the past year, the collaboration with the
Gait Analysis Laboratory, Department of Orthopedic
Surgery, Children's Hospital Medical Center, and
Harvard Medical School was continued. In the future,
computer programs, patient data, and engineering and
medical expertise will be exchanged with this group.

Significance to Biomedical Researcli: The computer
system will be used with arthritic, orthopedic, and
neurological patients, and with amputees in order to
evaluate drug therapy, orthotic and prosthetic devices,
and medical interventions. It will also be used as a
teaching tool to help these patients learn to function
with their disability in an efficient manner. Many medical
centers in the United States, Great Britain, Europe, and
Japan are presently establishing automated
biomechanics and gait analysis laboratories. Therefore,
any new developments made on this project will benefit
users of these automated systems, as well as patient
care and clinical research within the Department of
Rehabilitation Medicine at NIH.

Proposed Course: During the coming year, the
Automated Biomechanics Laboratory System will be
placed in clinical operation. Initially, the mechanics of
motion of amputees and the impact of prosthetic
design on gait characteristics will be evaluated. Also,
the effects bracing may have for contiguous joints of
the upper and lower extremities in arthritics will be
studied.

Many additions will be made to the system in the future
including improvement of the EMG acquisition
hardware; selection and integration of visual cameras
and video recorders, including the electronics needed
for synchronization with the motion cameras;
implementation of energy expenditure calculation
software; and the development of methods for
accurately determining the velocity and acceleration of

anatomical points from acquired motion data including
consideration of the required camera resolution and
frame rate, and digital differentiation techniques.

Publications:

Martino, R. L., and Gerber, L. H.: An Automated Biomechanics Laboratory
Applied to Rehabilitation. Proceedings of the Fifth Annual Conference of
the IEEE Engineering in Medicine and Biology Society (in press).

NOTICE OF INTRAMURAL RESEARCH PROJECT

CT00109-01 CSL

October 1, 1982 to September 30. 1983

AEinE Studies Image Analysis System

Hal A. Fredrickson, Computer Systems Analyst, CSL. DCRT

CSL, DCRT: J.M. DeLeo, Computer Systems Analyst; W.L, Risso, Elec
LN, NIA: H. Schwartz, Medical Staff Fellow; H. Creasy, Visiting A

Rapoport, Chief.

tronlcs Engineer.

Computer Systems Laboratory

Systems Design Section

DCRT, NIH, Bethesda, Maryland 20205

_^^ij^j^

O.s' 1 0.8 ' 1

WBtKH

Aging Studies Image Analysis System

The Computer Assisted Tomography (CAT) image
analysis task performed on the DCRT Evans and
Sutherland PDP-1 1 /70 computer system and reported
as Project Z01 CT-00086-02 CSL has been transferred
to a PDP-1 1/34 computer in the National Institute on
Aging. The 1 1 /34 computer is equipped with a DeAnza
IP6400 image display system with a 512 x 512 24-bit
pixel resolution. This allows the Positron Emission
Tomography (PET) scan images and the CAT images
to be analyzed on the same system with the eventual
goal of correlating PET and CAT scans.

Background and Objectives: To provide the Laboratory
of Neurosciences, NIA, an image processing facility
that will be used to measure changes in the human
brain determined by CAT and PET scans.

Methods Employed: CAT scans are obtained by
computer disk from the DCRT Evans and Sutherland
System (future CAT scans will be obtained by tape from
Diagnostic Radiology). PET scans are obtained by disk
from Diagnostic Radiology. The PET or CAT images are
then displayed on a DeAnza color monitor for analysis.
The PET image analysis software is a modification of a

package provided by NIMH. CAT analysis is based on
work developed for the DCRT Evans and Sutherland
(E&S) System by CSL.

Progress in FY83: The ability to display CAT image
data originally created using the DCRT E&S System
has been provided on the PDP-11 /34 DeAnza
configuration. Percentages and areas of CSF, white
matter and gray matter are determined.

Proposed Course: Provide the ability to work with PET
and CAT scans simultaneously. Also, to develop the
capability of outlining a region on the CAT image and
then determining the homologous region on the PET
image.

DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVIC

PROjecTNOMeE.

NOTICE OF INTRAMURAL RESEARCH PROJECT

ZOl CTOOlOO-02 CSL

"c'toLer'""l982 to September 30. 1983 |

TITLE 0<= PROJECT fHO thmtUn or lam. Till* muft fll on orw Ifti* »*l<M*n tta bordo^J

Positron Emission Tomoeraphv (PET) FacHItv

PRINCIPAL INVESTIGATOR lUtl othr proftutanol ptrtonntl on •ubnautnl PU*».>

INom: ntU. UtDomlorv. and iniUH.U afflllaNonf

Arthur J. Pashayan, Computer Specialist. CSL, DCRT

COOPERATING UNITS rl/an>(

CSL, DCRT: W.L. Risso, Electronics Engineer. NH, CC:

R.H. Kessler. N.D.. Head,

Positron Emission Tomography Section.

Computer Systems Laboratory

Systems DesiRn Section

DCRT, NIH. Bethesda, Maryland 20205

TOTAL MANVEARS 1 PROFESSIONAL lOTMeR

0.1 1 O.l 1

Positron Emission Tomography (PET) Facility

The PET facility of the Nuclear Medicine Department is
used to collect and analyze images of the human brain
for diagnosis and scientific research. The facility
includes a PET Scanner that receives data consisting
of gamma emissions from patients and a minicomputer
system that operates the scanner, reconstructs the
data into cross-sectional slices, and performs other
analysis. The facility also includes an offline
minicomputer system having an image array processor
and color display that is used to interactively perform
numerous image enhancement and analysis functions.
Various NIH Institutes use this facility to research the
aging process, schizophrenia, epilepsy, and other brain
functions and disorders.

Background and Objectives: In late FY81 , the Nuclear
Medicine Department requested assistance in

improving their PET computer facility. At that time, the
PET facility was receiving increased usage by various
Institutes and had recently lost some of its technical
staff. The goal of the project was to improve the
existing system's hardware and software, to establish
guidelines for collection and storing patient data, and to
provide an image analysis system that could be readily
operational.

Progress in FY83: There was further development in
programming the offline image system to automate
procedures for researchers to quickly and efficiently
analyze many patient scans. A microcomputer was
purchased and programmed to interface a scintillation
counter with the offline computer and programs were
written to quantize radio isotope activity in patient
plasma samples. The PET scanner computer was
programmed to include a new disc drive and other
peripherals to handle increased data flow.

Proposed Course: There will be an increasing demand
for PET scan analysis with the addition of new PET
scanners and new protocols. However, due to shortage
of staff, CSL has curtailed activity with the PET section
and hopes to resume collaboration in approximately
one year.

DiPMmiMT or HIALTH AND HUMAN UttVICIt PUCLIC HtAlTMMIIVKI
NOTICC OF INTRAMURAL ftCtt AflCH PftOJCCT

ZOl CroOI04-OI CSL

October 1. 1962 CO Scpieaber 30. I9S3

tk.v.ird U. Sabrln. Ph.D.. Staff fellow. CSL, DCItT

CSL. DCRT: D. Syad. Chl«f , Syatcaa Design Swctlon. M. CC
Staff RadloloBiat.

D.V. Kurca, N.D. ,

LAS/* RANCH

CoBpuier SystcBB Laboratory

1.: I.; 1

Picture Archiving and Communication System

This project encompasses the development of a picture
archiving and communications system (PACS) to
automate the storage and transmission of medical
images at the Clinical Center. Although centered
around the Diagnostic Radiology Department, the

' 49

system is being designed with the long term goal of
serving other imaging-oriented departments, including
Nuclear Medicine and Radiation Oncology. The system
will consist of state of the art mass storage devices,
which will be able to keep several week's worth of data
available for immediate viewing, as well as the most
advanced network communication, data management,
and image display equipment. When in place, the
system will allow the storage of images from several
modalities in a central facility and will enable physicians
to view those images from a variety of locations. A
feasibility study is currently being conducted, and
procurement is expected to begin in FY84.

Background and Objectives: In addition to the
traditional film x-ray, medical imaging today
encompasses several new and complex modalities,
among them Computed Tomography, Ultrasound,
Digital Angiography, Scintillography, Emission
Tomography, and others. Some of these modalities are
digital in nature, while others produce images in video
format. Storage of the images produced by these
devices is an arduous and space consuming task,
requiring vast film and tape libraries. A physician who
wishes to view images generated on more than one of
these must do so separately in the viewing areas for
each modality, or must obtain hardcopy reproductions
of the images. The system under study would enable
the physician to view images of all modalities at a
single location, either at a console placed in a central
viewing area, or at one in his office. Additional viewing
consoles could be placed in operating rooms, nursing
stations, and conference facilities. The system could
allow quick access to images selected by patient,
population group, illness, imaging modality, or other
factors. A computer security system will prevent
unauthorized individuals from gaining access to the
image data base.

Progress in FY83: A study of the available technology
and of the feasibility of the project has been completed.
Many system configurations were considered, and data
were collected from the manufacturers of various types
of computer, storage, communications, and display
equipment. In addition, many consultations were held
with personnel from other institutions who are

developing image management systems. A flexible and
expandable system architecture has been proposed.

Significance to Biomedicai Researcti: An image
management system like the one described above
would greatly encourage research by facilitating access
to different classes of medical images. A physician
wishing to compare images from different modalities, or
conduct longitudinal or cross populations studies would
be able to view all the images of interest in one
session, while sitting at a single viewing station.

NOTICE OF INTRAMURAL RESEARCH PROJECT

ZOl CT00099-02 CSL

October 1. 1982 to Seotember 30. 1983

TITLE OF PROJECT (80 choraefcr* or bu. Title mutt ftt an ana lint bttwiin Ihm bordtn.)
Automated Management of Criticallv 111 Patients

Kenneth M. Kempner, Electronics EnRineer, CSL, DCRT

CCMD, CC: J.E. Parrillo, M.D., Chief, Critical Care Medicine. U. MD:
N. DeClaris, Sc.D., Professor, Electrical Engineering Department.

Computer Systems Laboratory

Systems Design Section

DCRT, NIH, Bethesda, Maryland 20205

0.3 1 0.3 1

Automated Management of Critically III Patients

This research project is concerned with a systems
approach to the management of critically ill patients in
a clinical setting. The ultimate goal is the utilization of
computer-based instrumentation to aid in the differential
diagnosis of disease states and the implementation of
therapeutic modalities through automated technology.

A state variable approach is utilized in the mathematical
modeling of pertinent pharmacokinetic and physiologic
processes. Empirical clinical data and realtime
monitored values are utilized in model validation.
Several alternative methods for closed-loop automated
medical interventions are being investigated.

Bac/(ground and Objectives: Noninvasive diagnostic
and therapeutic techniques generally involve the
application of sophisticated electronic technology and
mathematical modeling techniques to the detection of
pathophysiologic states. Particularly interesting and

important problems involve cardiovascular disorders
that give rise to low output syndrome.

Methods Employed: In order to accomplish the goal of
developing systems capable of assisting in the medical
management of a critically ill patient on a closed-loop
basis, it will be necessary to develop validated models.
Calculated physiologic parameters will be compared to
measured physiologic data as the patient's response to
the selected therapy progresses.

A mathematical formulation of the relevant subsystems
will be developed for a patient in a critical care unit
setting. This includes the modeling of three principal
subsystems: Pharmacokinetics, Drug/Receptor
Interactions, and Cardiovascular Dynamics.

Progress in FY83: The mathematical formulations
necessary to describe the three major subsystems
have been completed. The package of FORTRAN
programs that will evaluate the mathematical models
are in the final stages of development.

These programs will be implemented on the DCRT
Central Facility to simulate the intensive care unit
environment, so that automated therapeutic
interventions, in response to simulated and actual
patient data, may be evaluated with regard to clinical
correlation. Program output will include
recommendations for therapy as well as predicted pre-
and post-intervention physiologic data values.

Significance to Biomedical Research: The use of
automated systems in the implementation of
therapeutic protocols within a critical care unit adds a
new treatment modality and will have a major effect on
protocol design. It will afford improvements in protocol
design for patient care, clinical drug trials, and the
study of the etiology and therapy of specific disease
entities. In addition, the automation of therapeutic
interventions, as proposed, will significantly expand the
clinical and research data bases.

Proposed Course: Existing critical care protocols will be
investigated to identify those components in which
automated therapeutic modalities can easily be
accommodated, within the framework of this research
effort. An important aspect to be evaluated is the nsk
to the patient versus the realizable benefits.

Selected protocols will be implemented utilizing the
closed-loop techniques developed in this project, with
the objective of carrying out controlled clinical tnals and
quantitatively evaluating their effectiveness.

NOTICE Of INTRAMURAL REKARCHPNOJtCT

Ml CTOOOOJJ CM

October 1. 19

...tt^tr M. nm

Coiaiuctr lnt«tf«c«« for CUnlcjl L«l)or«torv liuini-^r.

nlci En|ilii««r. CSL. DOT

nlo EntiiMtr. CF, CC: J. A. Donlon, H.D., Ph.B.

Devi!lop«ein Secllon

PCm. NIH. B«th«.il..

Computer Interfaces for Clinical Laboratory
Instruments

Microcomputers are being applied in the Clinical
Pathology Department to extend the capabilities of the
Clinical Pathology Laboratory Computer (CPLC) and to
automate data acquisition and entry for procedures not
previously automated. Two projects have been
successfully implemented in this way.

The first involved the linking of two Coulter Model S-
Plus automated cell counters with the CPLC. Coulter
results now can be certified and released by the
technologist within minutes of completion of the
analysis. The second project resulted in the
development of a Computer-Assisted Hematology
Morphology Data Handling System. Each of these
projects was characterized by the extensive
involvement of the technologists in the human factors
design considerations. This collaboration ultimately led
to the immediate and enthusiastic acceptance of the
systems.

■

Background and Objectives: After interfacing two
Coulter Model-S Plus instruments to the CPLC, the
Computer Systems Laboratory and Clinical Pathology
Department, CC, developed a Computer-assisted
Hematology Morphology Data Handling System. In
February 1 982, this system replaced the previous
method of transcribing manual white cell differential
results onto mark sense cards for later entry into the
CPLC. Four VT100 CRT terminals are used for direct
entry of manual differentials, red cell morphology, and
platelet estimates. The terminals are linked to a DEC
LSI-1 1 microcomputer that serves as a controller and
also maintains a realtime communication link to the
CPLC. With this configuration. Coulter automated cell
counting results are retrieved from the CPLC for use by
the technologist during the differential counting. When
the analysis is complete, the results are transferred
online to the CPLC. Based on an average daily
workload of 230 analyses, the system has decreased
the manpower requirements by 50 percent, changed
turnaround time for release of certified results from
hours to minutes, and reduced transcription time and
errors.

Progress in FY83: The four-station system is being
used to capacity. A second system is being installed to
accommodate at least four additional stations. This
configuration utilizes dual cartridge disk drives in place
of the floppy disk drives used in the original system.
The faster disk access coupled with the RSX1 1-M
multiuser operating system will allow us to add
additional functions and user stations to the system as
the need arises.

Proposed Course: The use of microcomputers as
programmable interfaces to Clinical Pathology
Laboratory instruments, such as the Coulter Model S-
Plus, and as interactive data entry and retrieval
stations, as with the white cell differential counting
system, has been very successful. Plans are underway
to extend this technology, possibly by using personal
computers, to other instruments and activities within the
Clinical Pathology Laboratory.

Publications:

Donlon, J., Wang, L, Lundy, E., Wages, B., Faust, A., and Songco, D.: A
Computer Assisted Hematology Morphology Data Handling System. Pro-
ceedings of the Sixth Annual Symposium on Computer Applications in

Medical Care, Sheraton Washington Hotel, Washington, DC, October 30-
November 2, 1982, pp. 270-273.

NOTICE OF INTRAMURAL RESEARCH PROJECT

ZOl CT00055-04 CSL

October 1, 1982 to September 30, 1983

Automated Pulmonary Physiology Testing

Laurence D. Nadel, Ph.D.. Senior Staff Fellou, PDS, CSL,

DCRT

PB, IR, NHLBI: B.A. Keogh, M.D. , Expert. CSL, DCRT: P
Project Development Section.

S. Plexico, Chief,

Computer Systems Laboratory

Project Development Section

DCRT, NIH, Bethesda, Maryland 20205

0.5 1 0.5 1

Automated Pulmonary Physiology Testing

Procedures such as exercise testing of pulmonary
compliance and muscle strength are useful in
evaluating pulmonary function. By exercising a patient
on a treadmill and gradually increasing the workload
(i.e., speed and incline), the physician can better
assess pulmonary disease, which in its early stages
generally does not manifest itself except under physical
exertion. To help the physician perform these
procedures more effectively, a microcomputer system
has been developed to automate realtime data
collection and analysis and to display calculations of
pulmonary compliance and inspiratory muscle strength.

Steady state treadmill exercise testing has only been
partially automated. Although data is manually entered,
data analysis and report generation are fully
computerized. Work was started to enable automatic
realtime acquisition of exercise data with breath-by-
breath analysis. However, due to a change in clinical
priorities, work was curtailed on the breath-by-breath
system. Patient data is stored on a local disk data base
for future reference.

Bacl<ground and Objectives: Physicians monitor
pulmonary parameters during exercise to better assess
pulmonary function and to diagnose pulmonary
dysfunction that only manifests itself under physical
exertion. Procedures such as pulmonary compliance

and inspiratory muscle strength also give insight into
respiratory function.

Formerly, pulmonary treadmill exercise testing data
were processed manually. Data were written down and
later entered into a programmable calculator for
determination of results. Additional summary statistics
and a final report were prepared by hand. Inspiratory
muscle strength and pulmonary compliance
measurements, done in the same lab, were likewise
performed manually. In order to speed both exam and
data analysis time, and to improve accuracy, these
procedures were automated with a microcomputer
system.

Methods Employed: The microcomputer system is a
DEC MINC-11/03 (Modular Instrument Computer)
containing an LSI-11 microprocessor, 32K words of
memory, auxiliary disk storage, and analog-to-digital
and digital-to-analog conversion capability. There is
also a video graphics display, a keyboard console, a
hardcopy unit for printing the video display, and a line
printer.

In determining pulmonary compliance, transpulmonary
pressure (the difference between alveolar pressure, i.e.,
mouth pressure with mouth shutter closed, and
esophageal pressure, as measured by a balloon
transducer swallowed by the patient) and lung volume
(measured with a wedge spirometer) are determined by
the computer as the physician repeatedly closes a
mouth shutter throughout a patient's inhalation or
exhalation. A graphical plot of the data and an
exponential least squares curve fit of the data are then
produced to aid in evaluating the "stretchability" of the
patient's lungs.

blood samples at each steady state level. Acid/base
and gas concentrations are determined offline by a
blood gas analyzer from a sample of the patient's
arterial blood, and entered at the keyboard. Pulmonary
volumes, flows, and oxygen consumption-a measure of
how hard the patient actually works to perform a given
level of exercise-are then calculated.

When air flow and expiratory gas concentrations can be
monitored in realtime, the patient's anaerobic threshold
can be determined noninvasively without the need to
measure the partial pressure of oxygen in blood via
arterial catheterization. Anaerobic threshold is
determined from measures of exhaled oxygen, carbon
dioxide, and respiratory quotient. Breath-by-breath
analysis also allows the performance of nonsteady
state exercise testing, where the patient is subjected to
continuously increasing levels of exercise to provide a
dynamic picture of cardiopulmonary performance.

Progress in FY83: The MINC computer system now is
used routinely to perform the static pulmonary
compliance and inspiratory muscle strength procedures.
Work continued on automating the treadmill exercise
system. However, a change in clinical priorities
redirected efforts towards the development of a breath-
by-breath steady state exercise system rather than
simply automating the technique currently performed. A
further change in priorities led to curtailing development
of the automated exercise system.

Proposed Course: No further work is planned at this

time.

Publications:

Nadel. L.D: Aulomated Pulmonary Analysis by an Onlme Micfocomputof In
Nair. S (Ed ): Computers m Critical Care and Pulmonary UeOane. Now
York. Plenum Press. 1983. pp 101-113.

NOTICE OF INTRAMURAL RESEARCH PROJECT

ZOl CT00O93-02 CSL

Perry S

. Plexico, Chief, Proiect Development Section

CSL,

CC: D
Senior

Lees, M.D., Chief, Anesthesia Service. CSL,
Staff Fellow; R.B. Dew, Electronics Engineer.

OCRX:

CompuCe

t Systems Laboratory

SECTION

Proiec

Development Section

DCRT. N

IH. Bethesda. Maryland 20205

TOTAL MA

1.0 1 1.0

Anesthesia Computer System

Background and Objectives:

While computers and automation have been used in
intensive care settings for some time, little previous
work has been reported on their application in
operating rooms. Three areas of potential benefit of an
anesthesia computer have been identified.

1 . Adjunctive monitoring, i.e., using the computer for
monitoring and display of patient parameters. The
main goals are a unified, easy to read display; limit
detection and trend analysis of the parameters; and
archiving of the measurements for later use in
research or anesthesia mishap analysis.

2. Automated recordkeeping, in which the computer
would not only record the results of monitoring, but
also make provisions for a record of drug
administration, for free text notes by the
anesthesiologist, and for producing a printed record
suitable for inclusion in the patient's record.

3. Noninvasive determinations of additional
parameters relevant to a patient's physiologic status.

An advantage of such a system is that it will allow the
anesthesiologist to devote more time to the patient by

simplifying the tasks of observing and recording M

measurements. An added potential advantage is an f
intelligent system of alarms to warn of a patient's
deteriorating condition. Present alarm systems often
are disarmed due to false triggering.

Progress in FY83: The project plan developed last year
was expanded to add greater detail. Engineers were
assigned to the project and work was formally begun
on system development. Using a DEC MINC 11/23
computer system and a Perkin-Elmer MGA 1100 gas
mass spectrometer, development of a prototype system
for online monitoring and trending a patient's inhaled
and exhaled gas concentrations (including gaseous
anesthetics) was begun. Only oxygen and end tidal
carbon dioxide concentrations can be monitored with
present instrumentation. Designs have been prepared
and additional equipment ordered to use this system in
conjunction with a pneumotach and pressure
transducer to derive pulmonary function parameters of
a mechanically ventilated patient.

Display technologies/systems were investigated for use
in a single consolidated patient display. Available
technologies such as voice input and handwritten
character recognition were explored as potential means
for simplified free text entry into the patient's O.R.
record.

Additional parameters, direct and derived, were sought
and investigated for incorporation into the existing
patient monitoring scheme. The emphasis has been on
gathering additional patient information through
noninvasive techniques.

Proposed Course: Development of the gas mass
spectrometer monitoring prototype system will be
completed and clinical usefulness will be evaluated.
Next, a pulmonary function capability will be added to
the system. We will strive for both trend and realtime
display. We then hope to identify available hardware
and technology to integrate the various patient
parameters into a unified display/automated patient
recordkeeping system. Technologies such as voice
input will be evaluated for entry of free text information
into the system. Necessary hardware will be purchased
and a single bed prototype system will be developed

and evaluated. Future plans include streamlining the
prototype and developing a multiple operating room
monitoring/reporting capability.

NOTICE OF INTRAMURAL RESEARCH PROJECT

ZOI cn)006S-O« CSL

October 1, 1982 to September 30. 1983

Medical Information Technology Project

Scott I. Allen. Medical Research Analyst. CSL. DCRT

CSL. DCRT: D.C. Songco. Electronics Engineer; P.S. Pie
Development Section. Others: C.S. Broun. M.D. . Consul
A.U. Pratt. H.D.. DCRT Director.

Ico, Chief. Project
Ing Dermatologist;

Computer Systems Laboratory

Project Development Section

DCRT. NIH. Bethesda. Maryland 20205

1.0 1 1.0 1

Medical Information Technology Project

This project involves the application of microprocessor
technology and improved man-machine interface
methods to permit physicians and their associates to
communicate more directly with computer record
systems. A pilot study involving medical transactions
entered directly by practicing physicians is in its second
year. The goal is to develop better ways to automate
the essential physician contribution to the health care
record that is used in both research and patient care.

Background and Objectives: The use of computers in
medical and hospital practice is increasing as the cost
of systems is decreasing due to technological
innovation. However, few physicians are comfortable
with current machine interfaces. With this in mind, we
are investigating devices and methods that provide a
more capable, attractive interface while maintaining an
acceptable level of flexibility and efficiency. The aim is
to increase physician productivity in patient diagnosis
and treatment and to increase patient understanding of
disease processes and management plans.

Progress in FY83: In collaboration with two practicing
dermatologists, we are field testing an ambulatory
patient care transaction system. This system allows the
physician to enter, store, retrieve, and disseminate
patient data needed by various members of the health
care team as well as by the patient. The immediate

data processing focus includes machine generation of
patient information and treatment schedules, pharmacy
prescriptions, and medical and surgical procedure
reports.

Disease-specific and problem-specific protocols are
used to lead the user through a restricted tree-
structured hierarchy of relevant diagnoses, treatments,
drugs, and procedures. Where appropnate, protocols
are modified by such factors as patient age, sex,
weight, disease stage, and therapeutic response
specified by physician. When all workups and
treatments are indicated, the computer produces
hardcopy treatment plans for the patient, record
summaries for the doctor, prescriptions for the
pharmacist, and test requests for specified laboratories.

Much of the clinical software is table-driven to allow the
physician to add and modify the data bases. This
approach also provides a convenient means of
adapting the programs to other clinical care and
research environments. Both the clinical data base and
processing software are being developed and tested on
the CSL time-shared computer system. Finished
programs, ready for use in patient care, are then
transfered to a compatible microcomputer system
situated in the physician's office.

Proposed Course: Selected physician-operated
modules will be enhanced to support critical diagnostic
and therapeutic functions in ambulatory care.
Programming logic to support isolated patient
encounters also will be expanded to display key data
from prior visits. Software modules to help order
laboratory tests and prepare physician referral letters
will be developed. The conventional CRT and keyboard
terminal employed now will be augmented with faster 1/
O devices that are tailored to this medical application.
For example, we plan to use graphic input to facilitate
the capture of anatomic disease descriptions and
keyboard substitutes to speed menu item selection.

NOTICE OF INTRAMURAL RESEARCH PROJECT

201 CT00090-02 CSL

October 1, 1982 to

eptember 30, 1983

Molecular Graphics,

Computer Modeling, and Sequence Analysis

Benes L. Trus, Rese

rch Chemist, CSL, DCRT

LPB, NIADDK: A.C.
Visiting Scientist.

teven. Visiting Scientist. DB, NCI: P.M. Steinert,

Computer Systems Lat

oratory

Systems Design Section |

DCRI, NIH, Bethesda

Maryland 20205

0.1

1 0.1 1

Molecular Graphics, Computer Modeling, and
Sequence Analysis

The sequence of some regular proteins, together with
other structural information such as data from x-ray
diffraction, fiber diffraction, electron microscopy, and
spectroscopic analysis can be used to evaluate models
of the protein structure. Two current studies involve
l<eratin (with NIADDK and NCI) and actin (with
NIADDK).

As the sequence of keratin cyanogen bromide
fragments becomes available, an anaylsis of the
sequence is proceeding by studying periodicities in the
sequence, and by predicting by computer the
conformational properties of the specific amino acids in
local regions of the chain. It is anticipated that the
experimental results may be able to clearly specify if
any of the proposed two or three models are correct.

Background and Objectives: It is currently possible
convincingly to model and predict the structure of
regular (helical) proteins. With the current knowledge of
the structure of the collagen helix, synthetic protein
analogues of collagen, tropomyosin, and other regular
proteins, one can extend this technology to new
proteins as the sequence is experimentally determined,
if there are known points of similarity.

Significance to Biomedical Researchi: Many proteins do
not form three-dimensional crystalline solids whose
structure can be analyzed by classical x-ray diffraction.
However, if these proteins are regular, comparison and
analogy with related proteins can be used to model the

unknown structures in order to understand the structure
and functioning of the proteins. In addition, one can use
computer models to analyze two or more possible
candidates and determine the most likely protein
structure.

Progress in FY83: A new model of collagen has been
proposed that reconciles previously diverse data from a
variety of experimental sources. A new analysis has
begun that will use the sequence of keratin filaments to
compare the structure to proposed models, and to
other proteins whose structure has been well
characterized.

Methiods Employed: Standard Fourier methods have
been used to analyze the sequences and to cross-
correlate sequences. These sequence regularities are
usually correlated with structural features, such as the
collagen triple helix, the alpha helix, or the tropomyosin
double stranded alpha helix. In addition, software was
written to model the collagen helix and double stranded
alpha helices on the Evans and Sutherland Picture
System. This unique hardware allows three-dimensional
analysis of proposed structures, both using traditional
wire models, and by using CPK "ball" models in three
dimensions, where the size of the ball is related to the
size of the individual amino acid, and the color of the
ball is related to the function of the amino acid.

Proposed Course: As new sequences of regular
(helical) proteins become available, it is relatively easy
to model these sequences and describe their structures
both graphically and quantitatively.

Publications:

steinert, P.M., Rice, R.H., Trus, B.L., and Steven. A.C: Complete Amino Acid
Sequence of a H/1ouse Epidermal Keratin Subunit: Implications for the
Structure of Intermediate Filaments. Nature 302: 794-800, 1983.

DEPfl

BTMENT OF HE»ITM AND HUMAN StRVICES fUBLlC ME.1.TM SCKVICC

CTNU-H.

NOTICE OF INTRAMURAL RESEARCH PROJECT

ZOl

CT00080-03 CSI.

Octobe

1, 1982 to September 30, 1983

TITLE OFP

ROJECT iaOcA«cl#norl»A nil* muf »( on o« lft» b*rrf»i rt* 6cr4*>«J

Compute

r Analysis of Gel Electrophoresis

>RINCIPAL

IFlVESTIGATOnitJi(ol'i*rpror«HloniiJp*rx»in*loniubH«i.«t«Mmi

iNamt. till*

tabaratory. and InllituU fl/fllloMon/

Benes L

. Trus, Research Chemist. CSL. DCRT

COOFERAT

l~= UNITS,,,..,,

LBP. N

ADDK: R. Goldman, Staff Fellow.

Compute

r Systems Laboratory

SECTION

Deslen Section

AND LOCATION

DCRT ^

IK. Bethesda. Maryland 20205

TOT»LMAN.eA«S PROFESSIONAL lOTHI. 1

Computer Analysis of Gel Electrophoresis

This project was designed to allow NIH scientists to
easily and accurately quantitate one- and two-
dimensional gels. Quantitative comparisons of two gels
is semi-automatic, and one project has used methods
developed here to separate the results of double-
labeled radiography of protein gels using color negative
film and appropriate filters. This is possible because
tritium and spillover of carbon 14 are recorded in the
blue sensitive layer of the film while carbon 14 alone is
recorded in the green or red sensitive layer. This
method was used to analyze the effect of growth rate
and medium composition on the relative levels of
individual proteins in a pathogenic strain of Escherichia
coli.

Significance to Biomedical Research: Use of gel
electrophoresis and autoradiographs is commonplace in
chemical, biochemical, and biomedical research.
However, the quantitation of these gels is difficult. We
have developed systems that accurately and easily
provide this quantitation to the scientist. A number of

laboraties outside of NIH have requested our software
for private use.

Progress in FY83: This project has produced many
useful results to a number of scientists at NIH. As new
gels require analysis, further fine tuning of the methods
will continue to improve the product. In addition, we
have used the methods to analyze color negative film
(rephotographed through appropriate color filters) so as
to analyze the growth rates and medium composition
on the relative levels of individual proteins in a
pathogenic strain of Escherichia coli. These results are
being submitted for publication.

Methods Employed: Gels were rephotographed onto
Ektapan 4162 black and white film. Color films were
photographed through appropriate color filters. The
black and white negative was scanned on the Perkin-
Elmer microdensitometer and stored on tape for later
processing. A computer program CINT was used to
analyze the two-dimensional gels, and another program
OVERLP was used to correlate two gels when
necessary or desired. PIC was used in the one-
dimensional analyses.

Proposed Course: Computer software is being
expanded to provide for better matching of two gels,
and all software is essentially machine independent for
transfer to the newly acquired image processing
laboratory. Additional options are being added to the
software to provide additional flexibility to the research
scientist.

Publications:

Goldman, RC . Leive. L . and Trus. B L Quantitative Oouble-Labol Radwgra-
phy o( TwoDimensional Protein Gels Using Colof Negative Film and Com-
puter Analysis European Journal ol Biology 131 473-480 1983

Nikodem. V M.. Huang, DR. Tnjs, B L . and Rail. J E The Effects of Thyrwd
Hormone on In Vitro Phosphorylation. Acetylalion. and Ribosylalion of Rat
Liver Proteins. Hormone and Mel. Res. (in press)

NOTICE OF INTRAMURAL RESEARCH PROJECT

ZOl CT00091-02 CSL

October 1. 1982 to Seotember 30. 1983

Benes I. Trus, Research Chemist, CSL, DCRT

LCHB, NCI: K.K. Sanford, Chief, In Vitro Carcinogenesis Section; W. Taylor;
G. Jones, Microbiologist; H. Weedon, Laboratory Technician.

Computer Systems Laboratory

Systems Design Section

DCRT, NIH, Bethesda, Maryland 20205

0.1 1 0.1 1

Morphometric Analysis of Normal and Neoplastic
Tissue Cultures

This project was designed to study the morphometric
differences between normal and tumorigenic fibroblastic
cell lines. Initially, human, rat, and mouse cell lines
were selected for analysis. The cells were
photographed from living cultures without staining or
fixing. The types of criteria being used by the computer
to aid in differentiating between normal and tumorigenic
cells include nucleus and nucleolus size and shape,
and chromatin texture and clumping.

Background and Objectives: This project, which was
begun this year, uses standard techniques of image
processing as applied to these low contrast unstained
specimens as well as techniques developed at NIH. We
hope to demonstrate that it is possible and practical to
differentiate between normal and tumorigenic cells in a
nondestructive manner. We are using many of the
same criteria used by pathologists in differentiating
stained and fixed sections.

Progress in FY83: We have developed software to
perform a pilot study on three types of cultures.
Preliminary results suggest that we are able to
determine statistical differences between normal and
abnormal cells.

l\4ethods Employed: Cell cultures were photographed
through a light microscope onto 35mm black and white
film. The film was digitized by a Perkin-Elmer 1010G
microdensitometer with a 50 square micron aperture.
Images were viewed on a video frame buffer and
processed interactively. Results are stored in log files
for each sample, and files are pooled for each type of
culture, yielding better statistics. The mouse and rat
cultures underwent spontaneous neoplastic
transformation, while the human fibroblast line was
exposed to chemical carcinogens to generate the
tumorigenic line.

Proposed Course: After the analysis of the three pilot
studies, we expect to continue analysis of additional
cell lines, and are considering nonlethal staining
techniques.

NOTICE OF INTRAMURAL RESEARCH PROJECT

ZOl CT00092-02 CSL

October 1, 1982 to September 30. 1983 |

TITLE OFPnOJECT 180 character, arltu. TIIU mutt fit on orw line bttwacn the btirden.)

Virus Structure as Determined by Image Processing of Ele

ctron Micrographs

Benes L. Trus, Research Chemist, CSL. DCRT

LPB, NIADDK: A.C. Steven, Visiting Scientist. fl

= ^^y^|

Computer Systems Laboratory

<.£.3^aMC

Systems Design Section

DCRT, NIH, Bethesda, Maryland 20205

0.4 1 OA \

Virus Structure As Determined by Image
Processing of Electron Micrographs

A new virus structure, that of bacteriophage T7, has
been published. The structure was determined by
image processing of electron micrographs. We
analyzed T7 polycapsid tubes because these structures
are more amenable to image processing. Optical
diffraction revealed that the polycapsids were based on
cylindrical foldings of a hexagonal lattice with a spacing
of 1 2.6 nm, which is similar to the lattice constant for
other complex icosahedral phage capsids defined to
date. However, the details of the T7 capsomer differ
from the other results.

Background and Objectives: Virus shells are composed
of one or a few proteins that form simple repetitive
geometric forms. The forms or containers can be, for
example, cylinders, icosahedra, or spheres. There are
classes of structures, and knowledge of the fine
structure of one coat protein can be used to
understand the structures of other similar viruses in the
class. It is our primary objective to add to the pool of
information, and to be able to use this information to
increase our understanding about how virus structure
relates to function and activity.

Significance to Biomedical Research: Viruses are
significantly smaller than bacteria, and as a result are
not seen in a light microscope. Information about their
structure usually comes from electron microscopy,
which is limited by resolution, low contrast, and noise. If
staining is used, then the resolution is limited by the
size of the stain, and often has noise as a result of
uneven staining. However, because virus structures are
generally periodic, they are a perfect candidate for
image processing. This project should be considered as
basic research whose aim is to increase our
understanding of the structure and functions of viruses
in general, as well as subclasses of viruses similar to
those studied to date.

Progress in FY83: The results of a virus previously
determined by us, beet necrotic yellow vein virus, have
been published. In addition the results of the structural
determination of the T7 virus have been presented at
two meetings, and are being submitted for publication.
These results are especially significant because
another virus (polyoma) that has significant similarities
to T7 recently has been reported to have significantly
differing geometry.

Methods Employed: The micrographs were taken with a
Philips EM400T microscope, and the best negatives
were preselected by optical diffraction. Negatives were
digitized on a Perkin-Elmer 1010G microdensitometer
and analyzed by means of the PIC computer system.
Results were photowritten on the Perkin-Elmer
microdensitometer. Typical processing of the images
consisted of Fourier filtering of up to 50-unit cells and
symmetrization of the results as needed.

Proposed Course: We anticipate evaluating other
viruses for suitability for examination with these
methods, and continuing with this ongoing project to
determine the structure of various classes of viruses.

Publications:

Steven. AC. Serwer. P , Bisher. M . and Trus. B L Molecular Architeclure of
Bactenophage T7 Capsid Virology 124: 109-120. 1983

OVAniMINT O* HIAITH AM> HUMAN URVtCtI ruanc HIALTH HIVCI
NOTICE OF INTRAMURAl REU AACM PROJECT

ZOl 000082-03 CSL

Uctobcr 1, 1982 to Septe^cr 30. 1963

In»Rc FrocceslnR of Electron HlcrosreDhs

Benes L. TruB. Research Chealst. CSL. DCRT

coo^eAAi.Nowhirt.tf*.,^ LPB, SIADMt: A.C. Steven, Visiting Sclenilet. ICP. MIADOKi
W.A. KAftins. ChUf. Section on Heabrene Biophysics; M.C. Foster. IPA Appointee/
Guest Worker; J.C. Ceorgc. Uboretory TechnlclAo. PSL. OCRT: K.D. Cerehon.

Computer SyiteM Lebor«cory

Svsteaa Oeslcn Section

WIRT. NIH. Bethesde. H«rvUnd 20205

TOIALMANVIANS 1 PMO'ISSIONAL 1 OTNin

Image Processing of Electron Micrographs

This project was designed to facilitate structure
determination from electron microscopy by providing
suitable software, hardware, and scientific expertise to
allow other scientists, primarily at NIH, to use image
processing and computer reconstruction to determine
or understand a specimen's structure.

Two new applications that began this year are analysis
and identification of small particles by electron beam
excited x-ray microanalysis as applied to aqueous
suspensions of vertebrate retinal rod cells and the
analysis of the microtrabecular lattice and the
cytoskeleton to determine their volume, surface area,
and the diffusion of molecules through it.

Studies continued from FY82 include analysis of
keratin, membrane structure, and muscle structure.

support. Techniques and software developed in this
project have been used elsewhere both at NIH and at
other laboratories.

Significance to Biomedical Researcfi: Computer
analysis of electron micrographs is still a relatively
recent addition to the tools available to scientists for
structural analysis. Few laboratories have the combined
software and hardware capability to perform the image
processing and image reconstruction available at NIH.
These techniques are especially powerful when applied
to two-dimensional crystalline structures. In addition, we
can correlate and align similar particles that are not
crystalline, and correct for a number of artifacts and
experimental problems.

Progress in FY83: This project has had some growth in
software, but primarily has grown in the utilization of
programs and the PIC system. It is feasible for an NIH
scientist to bring in a problem and obtain preliminary
results in a relatively short period of time. Then a
decision is made to expand the preliminary study into a
project, or to use the results obtained.

One study, in collaboration with NIADDK, used the
computer to examine digital information to examine
small particles by electron beam excited x-ray
microanalysis for particles in aqueous suspension. This
novel approach was applied to the isolated outer
segments of vertebrate retinal rod cells and was used
to study the distribution of potassium, osmium,
phosphorus, and calcium 45 in unstable objects.

Another study, in collaboration with PSL, DCRT, studied
the microtrabecular lattice and the cytoskeleton.
Images were digitized and analyzed for the fraction of
interlinked slender strands versus the amount of open
spaces.

Proposed Course: This project will continue software
development as needed, and will be converted to use
the new image processing facility as it becomes
available. In addition, as new biological structures
become available for analysis, these will be examined.

Publications:

Foster, M.D., George, J.S., Trus, B., and Hagins, W.A.: Na, K, Ca, Mg, and
Exchangeable Ca(45) ions in Rod Outer Segments by Combined X-ray
Microanalysis and Radioautography. Biophysical Journal ^M,2): 341, 1983.

Gershon, N., Porter, K., and Trus, B.: The Cytoplastic Matrix: Its Structure,
Volume, Surface Area, and Space for Diffusion. Biophysical Journal ^^(2):
85, 1983.

Gershon, N. D., Porter, K. R., and Trus, B. L.: The Microtrabecular Lattice and
the Cytoskeleton. Their Volume, Surface Area and the Diffusion of Mole-
cules Through It. Journal of Cell Biology 95(2): 406A, 1982.

Gershon, N. D., Porter, K. R., and Trus, B. L.: The Microtrabecular Lattice and
the Cytoskeleton. Their Volume, Surface Area and the Diffusion of Mole-
cules Through It. In Opiatka, A., and Balaban, M., (Eds.): Biological Struc-
tures and Coupled Flows. New York, Academic Press, 1983, pp. 377-380.

NOTICE OF INTRAMURAL RESEARCH PROJECT

ZOI CT00061-04 CSL

October 1, L982 to September 30, 1983

alysis Facility

Keith E. Gorlei

BEIB, DRS; C.E. Flori. Physical Scientist; C.C. Gibson; H.S. Eden; J.R. Ellis;
G.R. Hook; R.D. Leapman; C.R. Swyt. CSL, DCRT: J.S. Del Priore, Mathematician;
P.S. Plexico. Chief, Project Development.

Electron Microanalysis Facility

CSL is collaborating with BEIB, DRS, in developing an
automated electron microanalysis facility consisting of
two electron microscopes interfaced to a computer
system. The facility is being used for research into the
elemental composition of biological specimens, and for
the development of new techniques in electron
microscopy. CSL designed and implemented the
computer system, which acquires and displays the
spectra and images produced by Electron Energy Loss
Spectrometry, Energy-Dispersive x-ray Spectrometry,
and Wavelength Dispersive x-ray Spectrometry.

See also:
Z01 RS1 0058-05
Z01 RS1 0059-05

Bacl<ground and Objectives: The Computer Systems
Laboratory designed and implemented a computer
system as part of the BEIB Electron Beam Imaging and
Microspectroscopy Facility. The facility consists of two
electron microscopes, and is being used for research
into the elemental composition of biological specimens

and for developing new techniques in electron
microscopy.

One of the electron microscopes is an Hitachi H-700H
200 keV Scanning Transmission Electron Microscope
(STEM) equipped with:

• a lithium-drifted silicon (Si(Li)) detector connected to
a Kevex 7000 Analytical Spectrometer for performing
Energy-dispersive x-ray Spectrometry (EDS)

• an electron spectrometer for performing Electron
Energy Loss Spectrometry (EELS)

• detectors for bright and dark field electron current
signals.

The other electron microscope is a Cameca 50 keV
Electron Microprobe equipped with:

• a Si(Li) detector for performing EDS

• three Wavelength Dispersive x-ray (WDS)
spectrometers

• detectors for bright and dark field electron current
signals.

The PDP-11/60 computer system interfaced to both
microscopes performs the following functions:

• control electron beam position, stage position, and
the various detectors

• acquires spectral and image data from all detectors

• process and display the spectral and image data

• monitor and display a wide variety of "housekeeping"
parameters, including: lens currents, lens
temperatures, beam current, beam energy, pump
temperatures, coolant flow, vacuum pressures, water
leak detectors, power supply voltages, room
temperature, and room humidity.

Progress in FY83: This year both EEL and EDS imaging
were made operational. These techniques are now in
routine use on many biological research projects. The
EEL images are the first successfully produced on a
STEM and the first to be properly compensated for
mass-thickness effects.

A new technique was implemented for background-
correcting EDS images by applying a top-hat digital
filter to the EDS spectrum at each pixel. The
presentation of this technique at the 1982 Joint

National Meeting of Electron Microscopy Society of
America and the Microbeam Analysis Society won the
Corning award for the best contributed scientific paper.

EEL imaging was improved later in the year by using
the satellite computer to track the position of an energy
loss edge and to compensate for spectrometer dnft.
This permits images to be acquired over longer penods
of time, thus allowing elements to be imaged at lower
concentrations.

Work has begun on a more sophisticated method of
processing EEL spectra that should further improve
EEL image quality.

The WDS and current signal detectors on the Cameca
Microprobe were interfaced to the existing data
acquisition satellite so that images can be acquired
from these detectors by the same software that is used
for the STEM. This arrangement was used to produce
aluminum images of neurofibrillary tangles in the brains
of victims of Amyotrophic Lateral Sclerosis and to
produce magnesium images of lymphocytes. Addition of
a second satellite dedicated to the microprobe is
planned.

The image display and processing capabilities of the
system also were improved greatly this year. The
DeAnza display system was upgraded by the addition
of a Digital Video Array Processor, a Fourth image
memory channel, a digitizing tablet, and an 8-bit
graphics overlay channel.

The Digital Video Array Processor (DVP), which can
perform simple operations (such as add, subtract, and
shift) on digital images at video rates, was used to:

• dynamically scale current signal images as they were
loaded into the display system;

• implement a four-function "image calculator", used
for applying background and other corrections;

• rapidly smooth images via spatial convolution; and,

• calculate pixel density histograms of arbitrary regions.

The digitizing tablet provides a powerful and convenient
operator interface. All of the previous functions plus
many others such as scroll, zoom, contrast enhance,
intensity transform, region outline, annotate, save, and

— 6?

restore can be activated and controlled using the
tablet.

The forms used to control data acquisition and image
display were improved and put into production use.
New forms for modifying data acquisition parameters
were implemented.

The large amount of data produced from the two
microscopes, together with the limited amount of
available online disk storage, required the design and
implementation of two new data maintenance utilities:
ARCHIVE and AUTOBACK. The ARCHIVE utility
provides a convenient way for users to move the data
from completed or dormant projects to tape. A directory
of ARCHIVE tapes and the files they contain is
maintained online and can be listed or searched. The
AUTOBACK utility provides protection from disk
disasters. It manages a set of tapes that are used for
periodic full and incremental backup of the system and
data disks.

Last, the operating system was updated from RSX-1 1 M
V3.2 to RSX-1 1 M V4.0, the most recent release.

Proposed Course: Next year, we expect to enhance the
data acquisition software and improve the interface to
the Cameca Electron Microprobe.

Publications:

Gorlen, K., Barden, L, Del Priore, J., Kochar, A., Fiori, C, Gibson, C, and
Leapman, R.: A Data Acquisition System for an Analytical Electron Micro-
scope. Proceedings of the FALL DECUS (in press).

Leapman, R., Fiori, C, Gorlen, K., Gibson, C, and Swyt, D.: Combined Elemen-
tal and Structural Imaging in a Computer Controlled Analytical Electron
Microscope. Journal of Ultramicroscopy (in press).

NOTICE OF INTRAMURAL RESEARCH PROJECT

201

CT00057-04 CSL

October 1, 1982 to Septeinber 1983

Molecular Interactions Laboratory Data System

Ramon L. Tate, Ph.D., Computer Specialist, CSL, DCRT

MDB, NHLBI: J.C. Osborne, Ph.D., Research Chemist. CSL,
J.R., Head, Processor Design Section.

DCRT:

A.E. Schultz,

Computer Systems Laboratory

SECTION

DCRT, NIH, Bethesda, Maryland 20205

0.2 1 0.2 1

Molecular Interactions Laboratory Data System

This microcomputer (PDP 1 1 /03) data system
supervises the acquisition and processing of
information from an analytical ultracentrifuge and a
circular dichroic spectropolarimeter used in MDB,
NHLBI, to investigate the interactions between human
lipoprotein subunits. Current capabilities include
acquisition, display, and preprocessing of data from the
ultracentrifuge and transfer of preprocessed data files
to the DECsystem-10 for further analysis under MLAB
using predefined procedures invoked by a few simple
commands. Software support for the spectropolarimeter
includes the ability to add, subtract, and average CD
spectra and to transfer files to the PDP-1 0 for further
analysis. Enhancements this year include installation of
a four-pen digital plotter and a companion DECsystem-
1 0 software package for generating plots of CD and
ultracentrifuge data. Completion of this project is
anticipated when modifications to the ultracentrifuge
interface are finished to provide greater noise immunity.

Bacl<ground and Objectives: As a supplement to the
ultracentrifuge data system, a microcomputer-based
data acquisition and analysis system was developed for
use with a Cary Model 61 CD spectropolarimeter. The
system consists of a simple, flexible CD
spectropolarimeter/microcomputer interface and an
interactive data processing program system by which
CD spectra may be acquired, averaged, subtracted,
converted to mean residue ellipticities, printed, and
stored for future use. Stored data may also be

transferred conveniently to a large computer facility for

semi-automatic conformation analysis. The system
overcomes some of the difficulties encountered in
attempting the visual interpretation of noisy CD spectral
recordings and in providing additional data manipulation
capabilities not easily realizable with manual methods.
The CD spectropolarimeter is interfaced with the
microcomputer system via a special highly noise-
immune interface scheme based on the conversion of
the signals from the spectropolarimeter to pulse trains.
These pulse trains are then transmitted via current
loops to a CSL-designed timer/counter interface board
in the microcomputer. The operating software consists
of two programs that interact with the user through a
standardized combination of menus and dynamically
alterable displays. One program provides data
acquisition, processing, output, and storage functions,
while the other program provides all but acquisition and
includes the capability to edit the operating parameters
of a scan file stored on the diskette.

Progress in FY83: Support for a four-pen digital plotter
was added this year, including hardware reconfiguration
that permits system operation with or without the plotter
online. Software support also provided includes MLAB-
based routines for plotting both CD and ultracentrifuge
data with or without smoothing.

Proposed Course: Future additions to the system will
be restricted to further modification of the
ultracentrifuge interface to provide greater noise
immunity, at which time the project will be considered
completed.

Publications:

Tate, R.: Microcomputer Systems in the Laboratory An introduction Serono
Symposium Series, Raven Press, 1983 (in press).

DiFMTMMT OP HlAlTH AMI HUMAN ttltVICU 9\mJC MALIM lUIVCa

fii»crmimii

NOTICE OF INTMMUHAL MMANCHrMJICT

101 CTOOOM-« CSL

October 1. 1982 to S«Dt«ib«r 10. 1M3

IHrnwrn*. nib. l>»*i«Mf9. MM «*■•••■> fWllWl \i

Ramon I. Tate. Ph.D., Co^uter SpccUlUt, CSL. DCtT

COO*<«.T,NOUN.n.Ww.

LC. NHLBI: H.H. Falca, Ph.D.. ChUI.

LAarKMAMCH

CoBQutcr Svatvaa L4boratorv

Proceaaor D«al£n Section

,„,.,--J..'.?>'"' • '^p.o...,,... ,,,-.

Californium-252 Plasma Desorption Mass
Spectrometer Data System

The Californium-252 plasma desorption mass
spectrometer puts unusual and stringent demands on
the data system that controls the spectrometer and
acquires and processes its data output. Realtime
performance and the ability to access very large data
arrays in main memory are key considerations. After
delays necessitated by hardware design problems,
software upgrades, and facilities renovations, both the
spectrometer and a data system design modeled after
one in use at Texas A & M University have been
installed and are now functional. This instrument now
provides NIH the capabilities of mass analysis for
compounds that have proven difficult or impossible to
analyze by other mass spectrometnc means. It also
extends the range of mass analysis to compounds with
molecular weights in excess of 5000.

The Californium-252 time-of-flight (TOF) mass
spectrometer employs nuclear fission fragments to
ionize samples that frequently have proven intractable
to other methods of analysis. The TOF mass
spectrometer, which is not commercially available, was
developed at Texas A & M University by Dr. Ronald
Macfarlane under an NHLBI contract.

Background and Objectives: In this instrument, fission
fragments generated by the radioactive decay of a thin
film of 252-Cf impact on a thin layer of sample
deposited on a conductive plastic film, producing a
localized plasma. The sample molecules produced

~ 63

within this plasma are extracted by an electric field and
briefly accelerated down an evacuated tube toward a
microchannel plate ion detector. The elapsed times
between the ionization event and the arrival of the ions
produced are measured with an ultraprecise clock
capable of measuring time intervals of hundreds of
milliseconds with a resolution of 800 picoseconds. The
elapsed time measurements are then sent to a
computer where they are sorted, tallied, converted to
mass units, and displayed. The extended range of the
timing clock coupled with the unique characteristics of
the ionization process make this mass spectrometer
ideally suited to the investigation of the high molecular
weight compounds typical of biological materials. The
data system was specified to be compatible with
interface hardware and software available from Dr.
Macfarlane. The need for realtime sorting of a large
volume of input data puts unusual and stringent
demands on the data system that controls the
spectrometer and acquires and processes its data
output. Realtime performance and the ability to access
very large data arrays in main memory are key
considerations.

Progress in FY83: Numerous problems related to
implementing the software written at Texas A&M on the
newer model computer being used in Dr. Fales'
Laboratory slowed progress toward a fully functioning
system. The computer system was expanded to include
a line printer and an additional 256K bytes of memory.
Modifications were also made to the mass
spectrometer to enhance its safety and reliability.

Proposed Course: The anticipated addition of a direct
memory access channel controller dedicated solely to
the mass spectrometer interface will permit
simultaneous data acquisition and processing. An
upgrade of the mass spectrometer interface first-in/
first-out (FIFO) buffer to provide greater speed and
reliability is also planned. Software-related goals
include the reorganization and completion of system
implementation documentation and the training of
Laboratory of Chemistry personnel in system
maintenance procedures.

NOTICE OF INTRAMUHAL RESEARCH PROJECT

ZOl CT00056-04 CSL

October 1, 1982 to September 30. 1983

Distributed Laboratory Data Acaulsition and Control System

John I. Powell, Electronics Eneineer, CSL, DCRT

LCP, NIADDK: W.H. Jennings. Physicist. .CSL, DCRT: E.E. O'Bryan, Electronics
Engineer; A.R. Schultz, Jr., Chief, Processor Design Section; D.C. Carpenter,
Electronics Engineer. Svstex, Inc.: J.T. Morris, Programmer.

Computer Systems Laboratory

Processor Design Section

DCRT. NTH. Bethesda, Maryland 20205

4.0 4.0 1

Distributed Laboratory Data Acquisition and
Control System

An integrated laboratory data acquisition and
processing system has been developed for LCP and
LMB, NIADDK. The system is configured with satellites
coupled through a local network to a host processor. At
each satellite a dedicated microcomputer system
performs data acquisition from and control over an
instrument/experiment. Although acquired data files
may be stored locally, they are normally transferred via
the network to a host storage medium. The local
network allows the host storage medium to appear as a
"virtual" storage device to the satellites. The hub of the
network, the concentrator, utilizes DMA hardware on all
communications links and performs a file store and
forward function. Processing software provided at the
host allows LDACS data files to be: added, subtracted,
averaged, smoothed, baseline corrected, integrated,
differentiated, multiplied by a constant, and added to a
constant. The results may be displayed graphically on a
Tektronix terminal, typed at a terminal, printed on the
line printer, plotted on an X-Y plotter, or transmitted to
the NIH DECsystem-10 for additional processing.

Background and Objectives: A system of
microcomputers capable of independently controlling
and acquiring data from an instrument/experiment was
proposed in December 1 976 as the best system
architecture for upgrading laboratory data processing.
Initially a prototype laboratory data acquisition and
control system (LDACS) computer and essential

elements of the communication system were developed
to verify system performance.

A satellite includes a Digital Equipment Corporation
(DEC) LSI-1 1 microcomputer, 28K words memory, low
density random access storage, graphics terminal, and
all the necessary I/O hardware to interface the
instrument/experiment. Software developed by CSL for
each satellite, running under DEC'S RT-11 operating
system, provides the user with a "turn-key" system.
Presently the system is configured with nine satellites,
supporting thirteen instruments, connected (via the
concentrator) to a DEC PDP 11/70 host processor.
Instruments connected to the network include:
Spectrophotometers, Cary 14, Cary 118, Cary 210, Cary
219, two Perkin-Elmer 580B's, a
microspectrophotometer (designed by NIADDK);
Spectropolarimeters, Cary 60, Jasco J500A; a Varian
Electron spin resonance spectrometer; I.S. Co. Model
1440 liquid chromatograph; a SPEX spectrometer
(utilizing EG&G model 1420 intensified silicon
photodiode array detector and model 1218 detector
controller); and a stimulus response retina experiment.

The local network includes a software module, installed
as a handler under the RT-1 1 operating system, at
each satellite. Each satellite is connected via a
hardwired serial link to a front end concentrator. The
concentrator performs a file store and forward function.
Received files are placed on a first-in/first-out queue.
Files are transferred from the queue to the host via a
parallel DMA link. The communications task running on
the host maps the files to the appropriate directory area
based on the identity of the satellite that originated the
transfer and the extension of the file being transferred.

The host processor, a DEC PDP 11/70, is configured
with: 640K words of memory, a high speed printer/
plotter, an X-Y plotter, a 9 track magnetic tape drive,
dual floppy disk drives, and two large capacity disk
drives. DEC'S multiuser, multitasking operating system,
RSX-1 1M, is used to service the processing needs of
the users. User access to the host is provided by
hardwired links between terminals and host timesharing
ports.

Progress in FY83: A satellite, supporting data
acquisition from and control over a Cary 210

spectrophotometer, was added to the system in FY83.
LDACS software supporting acquisition of data from an
EG&G 1420 Intensified Silicon Photodiode Array
Detector and 1218 Solid State Detector Controller
(used with a SPEX spectrometer) was written and
installed. The EG&G intrument shares an LDACS with a
Perkin-Elmer 580B. Software was provided for an
experimental setup on the Varian ESR for studying red
blood cell deformability (spectral change) under sheer
stress. In addition to acquiring data from the ESR, the
LDACS controls blood flow rates during the experiment.
"Melting Run" programs, incorporating a modified
Lauda S-1 bath temperature controller that allows
computer control of the bath temperature, were
provided for the Jasco 500A, Cary 118 and 210, both
Perkin-Elmer 580Bs, and the EG&G 1218.

The general processing programs on the PDP 11/70
were improved to make them easier to use and to
extend their capabilities. Many processing applications
now are written as CLI indirect command files, which
prompt the user for necessary information, compose
task command files and then initiate the processing
program, passing it the task command file.

Two RA81 fixed Winchester disk drives and one RA60
removable disk drive were ordered to replace the PDP
11/70's two RP04 system disks. This configuration will
increase the online storage capacity by 500 percent,
sufficient to service the current and projected
requirements of this computing resource. An RL02
cartridge disk drive was ordered to provide a
convenient mechanism for long term individual data
archival.

User's manuals for the Jasco 500A, EG&G 1218,
Varian ESR, Cary 210, and Cary 118 were provided.

Proposed Course: Support for the system will continue.
The retrofitting of LDACS units with up-to-date software
and system documentation will be completed. The
original scope of the project (upgrading of the H-516
centralized system) has been completed. However, it is
anticipated that some level of long term support will
continue. New satellites or instruments may be added
to the system, and existing LDACS aquisition programs
may be modified to enhance data acquisition or to

incorporate new intruments/experiments. Occasionally
special purpose programs to process a set of
experimental data may be required.

NOTICE OF INTRAMURAL RESEARCH PROJECT

20! CT00103-01 CSL

''a5t°o'J.i?"'!",=l982 CO September 30. 1983

Personal Computers in Laboratory Applications

David C. Songco, Electronics Engineer. CSL, DCRT

Computer Systems Laboratory

Project Development Section

DCRT, NIH. Eethesda. Maryland 20205

0.4 1 0.4 1

Personal Computers in Laboratory Applications

Personal computers are a viable alternative to
assembling board level microcomputer systems. They
offer the opportunity to select from a wide array of
hardware and software. We are developing systems
based on the IBM Personal Computer to be used alone
and in clusters to serve as realtime data acquisition and
control devices as well as terminals to the central
facility.

Background and Objectives: CSL has utilized
microcomputers since early 1974 for realtime data
collection and processing. Personal computers have
become a viable alternative to these board level
systems in many applications. It is now possible to build
upon a wide array of products available from many
vendors. With the addition of A/D and D/A modules,
personal computers provide the basis for
programmable data acquisition and control systems.
While a number of personal computers can be used
effectively in laboratory situations, CSL, as part of the
OD/DCRT Personal Workstation Project, is giving
particular attention to the IBM PC.

Progress in FY83: The IBM PC was chosen because of
the extensive number of compatible products available
from many vendors. With these devices it is possible
for a user to acquire data, control experiments, process

data locally, and act as a virtual terminal to the central
facility for file transfer and additional processing.

Proposed Course: We plan to evaluate laboratory
interfacing hardware and software for the IBM PC so
that we can better assist users in configuring it for
laboratory applications. We also plan to cluster several
PC's in a local area network. In this manner, multiple
users can access a common data base while still taking
advantage of the rapid response of local processing
and displays. The system described under CSL's
Medical Information Techology Project is a possible
candidate for testing this concept.

NOTICE OF INTRAMURAL RESEARCH PROJECT

ZOl CTO0O64-O4 CSL

October 1, 1982 to Septenber 30, 1983

Image Processing Facility

Daniel Syed. Chief, Systems Design Section, CSL, DCRT

CSL, DCRT: W.L. Risso, Electronics Engineer; A.J. Pashaya
Specialist; B. Trus, Research Chemist.

, Computer

Computer Systems Laboratory

Systems Design Section

DCRT, NIH. Bethesda, Maryland 20205

2.1 1 2,1 1

Image Processing Facility

This project provides a utility to display and analyze
digital images. The system consists of a powerful 32-bit
computer with a mixture of medium resolution and high
resolution displays. A high resolution microdensitometer
allows precise digitization of x-rays, micrographs, and
other images. The computer and peripherals were
installed; the first display station was operational in
January 1983.

Bacl<ground and Objectives: This project arose in
response to a critically overcrowded situation that
exists on the present DCRT graphics computer. As
image processing applications at NIH increased, the
limited resources of that graphics system became
saturated. During FY80, CSL, in collaboration with
present and potential users designed a new general
purpose computer facility to aid the acquisition, display,
and analysis of images such as election micrographs,

CAT scans, and radiographs. During FY83, the system
was installed and programmed. The first display station
is now in use, providing the functions of the old
graphics computer with an order of magnitude increase
in efficiency.

Progress in FY83: The system is based on a 32-bit. two
megabyte computer, with a smaller 16-bit processor to
handle image acquisition. A multidisplay raster scan
frame buffer will provide several users concurrent
access to the central processor. Images are digitized
through a microdensitometer. Hardcopy will be provided
by a camera system.

Most of the hardware has been installed, checked, and
integrated into a system. Software has been written to
provide one user station, and connection of the two
computers is complete.

Significance to Biomedical Researclr. Study of images
obtained in the biomedical laboratory is proving more
and more fruitful as technology is able to supply the
proper tools at a reasonable cost. Biomedical scientists
are employing image analysis for a wide variety of
research goals, and the use of such techniques is
expected to grow very rapidly in the near future.

Proposed Course: Two more components are on order
and will be delivered early next year: an additional two
user stations, and microprocessor control for the
microdensitometer. These items will be installed and
integrated when delivered. Further development of
systems and applications software is anticipated.

NOTICE OF INTRAMURAL RESEARCH PROJECT

ZOl CT00105-01 CSL

October 1. 1982 to Se|

Medical liaace Data Comoreaslon

tlno. Ph.D.. Ele.

Engineer. CSL. DCRT

:SL, DCRT: D. Syed, Head, Systems Design Sect

DCRT. NIH- Rprhesda MarvlanH ?n?OS

H. Rftheada M«rv'»"'' ^"'"'

iL-1 I a-i_

Medical Image Data Compression

This project is concerned with the minimization of the
number of information carrying units used to represent
a medical image in order to improve the efficiency of
transmission and storage of such images. Various
image data compression techniques and their
application to medical images are being evaluated with
regard to the amount of compression attained and the
quality of the reconstructed image. Methods for
implementing these techniques suitable to the clinical
environment are being developed.

Bacl<ground and Objectives: Recently, there has been
an increase in the number of medical imaging
techniques that result in a digital image representation
including computed tomography, nuclear medicine,
positron emission tomography, ultrasonography, nuclear
magnetic resonance, and digital radiography. As a
result of this increased number of digital images, there
is a need for Picture Archive and Communication
Systems (PACS) that are capable of storing,
transmitting, and displaying such images. Because the
quantities of image data are large, it is important to
consider techniques for data compression to reduce
archival storage requirements as well as transmission
rate constraints.

Progress in FY83: This project was initiated late in
FY83. During this time, the type and characteristics of
the medical images that need to be compressed and
the techniques that are used presently for image data
compression were investigated.

Significance to Biomedical Researcti: The results of this
project will be used in a PACS for the NIH Clinical
Center and can benefit any medical center that needs
to store and transmit a large number of medical
images.

Proposed Course: Various image data compression
techniques and their application to medical images will
be evaluated with regard to the amount of compression
attained and the quality of the reconstructed Image.
Methods for implementing these techniques suitable to
the clinical environment will be developed with
consideration given to the time required for
compression and decompression.

PRINCIPAL
Robert L. Ha

NOTICE OF INTRAMURAL RESEARCH PROJECT

ZOl CT00097-O2 CSL

October 1, 1982 to September 30. 198.1

Analytic Models of Comput

i Engln

Newcomb, Professor, Electrical Engin

i Design Sec

DCRT. HIH. Bethesda. Marvlanil 707(1^

Analytic Models of Computer System Performance

This project involves the development of analytic
models that can be used to evaluate the performance
of computer systems. During the past year, the work on
modeling and analyzing computer systems using the
graph theoretic model called Timed Place-Transition (P-
T) Nets was continued. This included the development
of new methods for for determining net invariants and
new models for demonstrating the dynamics of
computer systems. Detailed models of computer bus
control techniques and the operation of a commercial
array processor were constructed. These models were
analyzed using a method that was developed for
evaluating computer system performance with Timed P-
T Net models. CSL continued to develop a state
variable P-T Net model of the interconnection of two or
more microprocessors that provides a framework for
determining the avoidance of deadlock and the
maintenance of throughput in multiple microprocessor
systems. In FY84, Timed P-T Nets will be used to
develop more analytic tools for evaluating computer
system performance.

provided new tools for evaluating computer system
performance.

There are two major types of analytic modeling
techniques: graph theoretic and queueing theory
models. A number of graph theoretic models have been
found to be useful for the analytic modeling of
computer systems. These include such graph models
as Place-Transition (Petri) Nets, Parallel Program
Schemata, Computation Graphs, and Marked Graphs.
Queueing theory models have also been found to be
useful for the modeling of computer systems because
they can capture important features of actual systems,
and algorithms that solve the equations of these
models are available as queueing network evaluation
packages.

These analytic models provide useful tools when
designing computer systems and deciding among
alternative hardware or software configurations. In
particular, with the integrated circuits that are currently
available, it is technically and economically feasible to
build systems consisting of many central processing
units. Many processor and memory configurations are
also possible now that memories can be placed in
close proximity to the processors. Methods are needed
for designing systems now possible with this new
technology. Various structures have to be considered
and analytic methods for evaluating alternatives
developed.

Methods Employed: Timed Place-Transition (P-T) Nets
are the modeling technique used to develop tools for
evaluating computer system performance. The
advantages of modeling with these nets are that: large
and complex systems can be represented in a manner
that is easy to understand due to the graphical and
precise nature of these nets, the behavior of the
modeled system can be analyzed using developed
results of the P-T Net theory, and a system can be
synthesized hierarchically with the ability to use
different levels of abstraction and refinement. In
addition, the usefulness of P-T Nets as models results
from their ability to represent both concurrency and
conflict in a system. Concurrency occurs when more
than one event is taking place in a system at one time
and conflict occurs when a decision must be made

among alternatives. In order to evaluate the
performance of computer systems including such things
as waiting times and throughputs, the time parameter is
added to the P-T Net model.

Progress in FY83: During the past year, the work on
modeling and analyzing computer systems using Timed
P-T Nets was continued. This included the development
of new methods for determining net invariants and new
models for demonstrating the dynamics of computer
systems. Detailed models of computer bus control
techniques and the operation of a commercial array
processor were constructed. These models were
analyzed using a method that was developed for
evaluating computer system performance with Timed P-
T Net models. The results of this work demonstrate
how the allocation of the resources of a computer
system determine its performance for a given
application.

The development of the state variable P-T Net model
of the interconnection of two or more microprocessors
with input and output devices was continued. In
particular, the structure was analyzed of the matrices
used to represent this model. This model can be used
to determine the avoidance of deadlock and the
maintenance of throughput in multiple microprocessor
systems.

PRIMCIML IHVIfnOAIOII tlMi m
David C. Sonico, Elect

101 CTO0I02-OI cn

lober 1. 1962 to S«pt«d>«r 10. 198]

tollimr. est. DOIT

H.D.. Hadlcal Hauarch *iulr>t. LVR, nil L.N.

Conputer Syatg— Labors

Project DevclopBcnt Sect

DCm. alH, Betheada. Maryland 2020S

Verbal Access to Computers for the Blind

Several years ago, CSL developed a voice output
terminal for the blind. This device can produce
unlimited full word English speech in place of a visual
CRT display. The visually impaired user can access
computer systems independent of sighted assistance.
This year, the CSL provided a voice output terminal to
a blind scientist in NEI. The terminal design was
upgraded to produce more intelligible speech with an
increased speed rate output control from 50 to 750
words/minute. A means of providing voice output from
analytical laboratory instrumentation is being
developed, as is a voice output attachment for the
DCRT-supported personal computer workstation.

Background and Objectives: In 1978, CSL developed a
prototype voice output terminal for use by the visually
impaired. This device has been refined in subsequent
years and has been made available to a number of
blind Federal employees. The goal of this project is to
apply current speech synthesis technology to provide
computer access for the blind.

Progress in FY83: This year, CSL began collaborating
with a scientist in the NEI. A voice output terminal was
provided to permit access to the DCRT Central Facility.
This device utilized the Votrax VSB phoneme
synthesizer, which is capable of producing full word
English speech at a rate from 50 to 750 words/minute.
The text to speech program is stored in 24K of read-
only memory and is controlled by an Intel 8080
microprocessor.

Proposed Course: Plans are underway to provide verbal developing a voice output attachment for the IBM

output from laboratory Instrumentation. In this manner, Personal Computer. This will extend the availability of

the blind scientist will be able to operate equipment in the DCRT-supported personal workstation to blind

a manner similar to his sighted colleagues. We are also users.

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Data Management Branch

J. Emmett Ward, Chief

Clinical Research, Patient Care,
Epidemiology

Clinical information Utility. During this past fiscal year
the Clinical Support Section has made a number of
enchancements and modifications to the Clinical
Information Utility (CIU):

• Four access paths were added to the CIU system.

• The CIU data base was moved to the Mass Storage
System.

• Medications, vital signs and blood banl< data were
added to the CIU data base.

• Software has been designed and developed that
integrates retrievals.

• A system was designed and developed to
automatically submit continuing retrievals, i.e., those
that are submitted weekly, monthly, quarterly or a
specified number of days. This extends last year's
capability to obtain online schedules from users of
the CIU.

BRIGHT STAT-PACK. Brian Cole (DMB/SAS); David
Rodbard, Peter Munson (NICHD/BES); Jay Shapiro
(CC). A computer system was developed on the
DECsystem-10 that enables Clinical Center
investigators to analyze their own clinical data. The
major effort this year has been the development of a
general regression package with such advanced
features as automatic model selection, automatic
weighting, and residuals analysis. Other additions to the
system included programs for statistics, graphing, and
data manipulation. Still in development are programs
for chi-squared contingency tables, bivariate Gaussians
and confidence ellipses, and linear regression with
errors in X and Y.

PET-Scans, Image Tape. Sigurd Knisley, Mary Lee
Dante (DMB/SAS); Rodney Brooks (NINCDS/SNB).
Tapes were processed with images from the PET-
Scanner augmented by information computed on a
Data General computer. A program for reducing the
number of image points from 16K to 300 was
developed, and the resulting data was delivered to
NINCDS for SAS analysis.

Seasonality Study. Judy Mahaffey, Dennis George
(DMS/ASPS); Norman Rosenthal (NIMH/CPB). This
system is being developed to systemize the collection
and storage of data for research analysis to define the
syndrome of seasonal depression. The data base will
be used in analytical studies to determine interactions
between environment and climate variations with mood
variations. The system will serve as a model for data
handling for other psychiatric studies now in progress,
e.g., premenstrual syndrome. Mark sense forms were
designed to collect patient data. These forms will be
used for all inpatient studies in the Clinical Psychology
Branch. The NCS 7001 Optical Mark Reader will be
used to facilitate the data collection and storage
processes.

Survival System. Diane Feskanich (DMB/SAS); Ardyce
Asire (NCI). This life table analysis system originally
was developed in the 1960's to support the End
Results in Cancer studies of NCI. Maintenance and
improvement of the system is now the primary goal.
The system has been sent to tumor registries and
hospitals both in the U. S. and elsewhere. Dunng FY83
a copy of the system was sent to the Central Tumor
Registry of the University of California, Los Angeles. A
number of changes were made this year, including
expansion of the system to handle up to 20 rate tables.

Prevalence of Major Neurological Diseases-Nigeria.

Mary Lee Dante, Richard Moore (DMB/SAS); Bruce
Schoenberg (NINCDS/NS); Dr. Osuntokun (U. of
Ibadan). This WHO-sponsored study consists of four
parts: census and health screen, evaluation of risk
factors, neurological exam results, and followup. A pilot
study for the census and health screen was done to
determine validity and usefulness of questions and
goodness of the questionnaire. Dunng FY83 the more
than 50,000 census forms were shipped to Bethesda
from Ibadan. The data were keyed, edited, and
corrected.

Antibody Panel Construction Program. George
Roberts (DMB/SAS); James Aubuchon (CC/BB). A
system was developed to construct panels of
ascending statistical utility from the file of blood donor
phenotypes. Panels were ranked on ability to
distinguish common antibodies and to achieve desired

p-values for each antigen. The ranking scheme will be
readjusted as results of the program are evaluated.

Evaluation of Physician Awareness of Pediatric
Oncoiogy Programs. Diane Feskanich (DMB/SAS);
Kay Robichand (NCI/DCT). In order to trace the
children referred to NCI and to determine which states/
cities/doctors are aware of and use the NCI program,
information is abstracted from the Clinical Information
Utility and fed into programs that produce lists by state
and city for each patient and each referring physician in
the Pediatric Oncology Branch. Counts by year of the
number of patients referred from each state are
produced.

NCHS Neuroiogical Causes of Death. Diane
Feskanich, Mary Lee Dante (DMB/SAS); Nadir
Bharucha (NINCDS/NS). The National Center for
Health Statistics recently released multiple cause of
death tapes for the just under two million people a year
who died in the U. S. between 1968 and 1978. Records
for all persons who had a neurological disease as
either an underlying cause of death or an associated
condition during the period 1971-1978 were extracted
from the tapes. Tables of underlying cause by
associated condition were broken down by age group,
sex, and race for each year and for all years combined
and were run. Age-adjusted rate tables and plots were
produced for all disease categories.

Combined Cardioiogy/Heart Surgery Data System.

Larry Martin (DMB/ASPS); Roger Dailey (DMB/DBAS);
C. Mcintosh, D. Rosing (NHLBI). This combined system
provides a chronological record of the medical activity
of NHLBI Cardiology and Heart Surgery Branch
patients. Efforts on this system now are directed toward
update, maintenance, ad hoc reports, and statistical
analyses. This is an ongoing effort that supports NHLBI
researchers.

Animai Heart Vaive Replacement System. Larry
Martin (DMB/ASPS); Michael Jones (NHLBI). The
purpose of the system is to collect, store, and retrieve
information on experimental heart valves implanted in
laboratory animals. The system became operational
during FY83.

Sleep Study System. Darius Georg, Peter Basa (DMB/
ASPS); Christian Gillin (NIMH/BPE). This system is
being developed to provide a computerized method for
scoring sleep data. Programs to edit, update, and
report on the data have been written and now are
being implemented by Mr. Wallace Duncan and staff in
the National Institute of Mental Health. The project's
current emphasis is on developing more reporting
options and new data transfer capabilities that will allow
this data to be used in other ongoing sleep study
systems within the Clinical Psychobiology Branch.

Analysis of SLE Nephritis Patient Data. George
Shakarji (DMB/OC); John Klippel (NIADDK). This
system to store chemistry and therapy data on all SLE
(Systemic Lupus Erythematorus) patients continues to
undergo modifications that will make it possible to
accept more versatile therapy data. To date, this
system has been used extensively to store more
information on ongoing tests with multiple entries for all
tests. The retrieval system also has been modified to
permit general-purpose use. Subsets of the stored SLE
data base are being used extensively in analytical
studies to forecast critical conditions among patients.

Evaluating of Personal Characteristics and Training
of Grant Recipients. George Shakarji (DMB/OC);
Stewart Wright (DRG). The purpose of this study is to
examine the personal characteristics and training of all
of the principal investigators who were awarded their
first grant in FY72, and to relate these to their
subsequent success at NIH through FY80. The first
step in the analysis is descriptive, involving the
production of:

• a set of frequency tables (if the variable is
categorical) or a set of descriptive statistics (if the
variable is continuous);

• a set of two-way tables (with chi-squares for
categorical variables and t-tests for continuous
variables) that contain all possible pairs of variables
(e.g., sex by age, B/l/D of training, degree; age by
B/l/D of training, degree, etc., for all other personal,
training, and success variables); and

• for categorical variables only, compression of tables
where required by unsatisfactory chi-square results
(too many low-frequency or zero calls).

The first step of the analysis is complete. The second
step, which is underway, involves the selection and use
of multivariate analyses to determine the weights of
appropriate variables of training and personal
characteristics with respect to measures of success.

Evaluation of SLE Test Data. Dave VanSant, George
Shakarji (DMB/OC); E. K. Harris, (DCRT/LAS); John
Klippel (NIADDK). This study is designed to see if the
doubling of an SLE (Systemic Lupus Erythematosis)
patient's creatinine results can be predicted by changes
in other blood chemistry measurements. The doubling
of serum creatinine in patients with SLE nephritis often
signals the onset of a severe phase in the disease.
Discriminant functions were computed from data on a
subset of matched patients; some for whom creatinine
had doubled, others in a less advanced stage of the
illness. The functions were then applied to serial data
on all patients in the study in an attempt to see how
well the doubling of creatinine could be predicted.
Results were encouraging, but the need is evident for a
larger input data set to the discriminant function
program.

Arthritis and Rheumatism Branch Outpatient
Computer Scheduling System. David VanSant,
George Shakarji (DMB/OC); Dr. Austin, Dr. Klippel
(NIADDK). A computer package has been implemented
for the scheduling of SLE patients. For each SLE
(Systemic Lupus Erythematosis) nephritis patient, a
schedule is derived, based on the category of the
patient's classification and admission date, and the
various procedures and tests to be administered to the
patient for the following month. Provisions are made for
changes in classification and procedures during the
course of the protocol.

Dyslipidemla Computerized Recordkeeping System.

George Roberts (DMB/SAS); Ernst Schaefer, Kent
Bailey (NHLBi/DMB). The Dyslipidemla system
continues to maintain and update its patient data file.
The original analysis indicated neomycin contributed to
cholesterol lowering. A second SAS data base was
created for analysis of the effect of niacin on
cholesterol.

Penicillin Study. Charles Twigg (DMB/ASPS); Dorothy
Sogn (DIR/NIAID). A computerized system to assist in

the establishment of standard procedures for penicillin
allergy determination/verification has been developed.
It collects data and produces reports from the clinical
trials of skin testing with major and minor penicillin
derivatives in hospitalized adults. Initial analysis and
design was completed during the year, and the system
is being implemented. Additional reporting capabilities
have now been defined and are being programmed.

Laboratory Investigation

Laboratory Inventory System. Diane Feskanich
(DMB/SAS); Robert Williams (NICHD/PRB). Blood
samples of the monkeys in the research colony are
routinely sent from the Pregnancy Research Branch to
Hazelton Laboratories for analysis. A system of
command procedures was created to keep track of
blood samples sent and test results returned. At
Hazelton, the system creates work protocols for the lab
technicians. The system can be quened at any time by
either PRB or Hazelton to report outstanding tests, test
results, or new tests.

Molecular Modeling. Sigurd Knisley (DMB/SAS).
During FY83 Mr. Knisley continued work on
modifications to the shaded surface molecular display
developed by Richard Feldmann and Tom Porter of
DCRT. Three-dimensionality has been further enhanced
by the addition of reflection highlighting on the spheres,
and transparency options have been increased thus
allowing more versatile applications. A computer image
of the surface binding mechanism on a mouse antibody
protein was produced for Dr. Potter (NCI) for use in an
article to be submitted for publication.

Seroepidemlology Data Processing System. Judy
Mahaffey (DMB/ASPS); Paul Levine (NCI). The Clinical
Studies Section, NCI Laboratory of Viral
Carcinogenesis, is trying to find characteristics of serum
samples that can be used to predict cancer. To this
end, a computer system has been designed to manage
all data necessary for efficient inventory control, test
results feedback, and statistical analysis The system is
now operational and reports from the system are being
sent to collaborating scientists in the U.S., Ghana,
Greenland, and Singapore. During the past year a new

"^ 73

contractor took over the running of this system. DMB
provided assistance in setting them up to run the
system correctly.

Detection of Outliers. David VanSant (DMB/OC); E.
K. Harris (DCRT/LAS). This project involves an
exploration of outlier detection methods using clinical
chemistry data. An outlier can easily inflate an
estimated standard deviation so that its presence
cannot easily be detected by rejecting observations
that are more than three standard deviations from the
mean. A program has been written that uses a method
of Downton to estimate the standard deviation in such
a way that outliers can be more readily detected. The
program is currently being used for outlier detection in
chemistry data from the University of Virginia.

Partial Differential Equation Solver. David VanSant
(DMB/OC); Warren Piver (NIEHS). This project involves
the maintenance of a partial differential equation
solving program on the IBM System 370. The program
is a product of International Mathematical and
Statistical Libraries, Inc., and is leased from IMSL by
the investigator. At the investigator's request, a new
version of the program offering improved convergence
properties was obtained from IMSL and implemented in
1 983. This system is an easy-to-use finite element
program that solves a large class of elliptic (steady
state), parabolic (time-dependent) and eigenvalue
partial differential equation problems in general two-
dimensional regions. It has a preprocessor program
that allows a user to supply the problem description in
a greatly simplified form so that no knowledge of
FORTRAN is required. Graphical output can also be
produced; scalar, vector and stress fields can be
displayed via the Calcomp plotter. We will keep this job
active a while longer just to ascertain that it is
completely debugged.

Program Management and
Administration

Administrative Data Base (ADB). Marvin Katz, Ron
Wicks (DMB). This ongoing project utilizes data base
technology in support of NIH-wide materiel and
financial management activities. As the Materiel
Management System (MMS) entered its fifth year of

development and operation, much time was spent in
enhancing existing software. During FY83 some 99
change control items successfully went into production.
The following are several new developmental efforts
that were also implemented:

• The design and development of the Stock
Requisitioning, and the central stores and self service
stores inventories; development of new central
procurement software; and implementation of
comprehensive cash management procedures. New
procurement software and cash management
procedures were both implemented during May 1983.

• The development of the Financial Management
System (FMS). Personnel from the American
Management System (AMS), the Division of Financial
Management (DFM), and DCRT cooperated in a joint
review of the detailed document design and
functional description of the new FMS, which was
enlarged to include open document processing as
well as fund certification, fund control, and general
ledger modules.

• We continue to maintain the NIH Central Accounting
System. New DHHS requirements concerning audit
disallowances made it necessary to change the
effect of five accounting transactions being used by
CAS and to add six new transactions. We had to
modify the tables that drive the CAS, the master file
update programs, and the effected report programs.
This major project had to be coordinated with DFM,
DCRT, and other users of the CAS.

Management/Service and Supply Fund System. A.

Kelly, R. Edwards, R. W. Edwards, W. Vincent (DMB/
CSS); S. George (DFM). The Clinical Support Section
designed and developed a retrieval and reporting
system for the Division of Financial Management that
produces financial statements for both the
Management Fund and the Service and Supply Fund.
This system, which runs both in batch and interactive
modes, is used by DFM accountants to monitor its
assigned accounts and to produce monthly, quarterly,
and annual reports for the B/I/D's. Additionally, DFM
can use the system to answer specific questions
concerning NIH accounts.

Full-Tlme Equivalency. Mike Letke (DMB/ASPS).
George Roberts (DMB/SAS); John Hartinger (NCI/
FMB). This system for monitoring the ceiling levels and
full-time equivalency manyears for NIH was built in
FY82. During FY83 straight line and accession/
separation year-end projections were added to the
ceilinged reports, and special experts were combined
with NIH consultants/experts.

Freedom of Information Act System. Dennis George
(DMB/ASPA); Nancy Cherry (NHLBI). This system
tracks FOIA requests from receipt through completion
and provides reports giving hours of work and costs
incurred in responding to FOIA requests. Analysis and
design have been completed, and the system currently
is being implemented.

NIH Nutrition Grants Monitoring System. Judy
Mahaffey (DMB/ASPS); Thomas VogI (OD). A system
has been designed for the NIH Nutrition Coordinating
Committee to assist them in monitoring and reporting
data on biomedical and behavioral nutrition research at
NIH and at other agencies within DHHS. The system is
operational and Dr. Vogl's office is currently using it to
answer inquiries from NIH directors' offices, the White
House, Congress, and the public as they relate to dollar
amounts and percentages of grant money being spent
in the area of nutrition. This is an ongoing project with
the data base being created each fiscal year. During
FY83 work was started to involve all government
(nutrition) grants under a new system that will be
developed by DMB/ASPS.

OHMO Health Delivery Registry. George Roberts
(DMB/SAS); Mike Mock (DHHS/OHMO). The Office of
Health Maintenance Organizations must watch the
financing needs of the prepaid health units it oversees
with the financing capabilities of investors such as
insurance companies. Mr. Roberts wrote programs to
combine capability and financing needs information,
and provided update, search, and report capabilities.

NCI, RAEB Grants/Contracts Information System
(GENIUS). Penny Brogan (DMB/ASPS); Harry Canter
(NCI). The Grants Elemental Network Internal Users
System (GENIUS), operated by the Research Analysis
and Evaluation Branch of DEA, NCI, is the official NCI
programmatic information system. The system, initiated

in 1973, has been enlarged and maintained in an
ongoing fashion. It provides both administrative and
scientific classifying information via five subsystems:
grants, contracts, intramural projects, unfunded grants,
and grant-supported literature. The grants and
contracts systems are "generalized" so they can
provide information for any NIH Institute. Most of the
work done this year involved modifying existing
software and expanding individual files to
accommodate new data elements. Enhancements
include: calculation of expenditure percentages by
subject area, simplification of query formulation with the
use of a WYLBUR command procedure, and interfacing
GENIUS with the NIH nutrition system.

NIAID Intramural Reporting System. Dennis George

(DMB/ASPS); Jeffrey Schriver (DMB/DBAS); K. Sells
(NIAID/IRP). This project, designed and implemented
this year, provides NIAID with a weekly analysis of
actual monies expended versus budgeted amounts. A
fiscal year master file is updated weekly using
obligations and commitment transactions posted to the
NIH Central Accounting System. Five reports display
data that includes CAN, Object Class, Cost Center, and
budgeted amounts.

Visiting international Scientists in America MIS
(VISA). Penny Brogan (DMB/ASPS); Libby Low (FIC). A
total revision has been made to the foreign scientists
management information system used by the Fogarty
International Center. This system provides information
on foreign scientists who are in the U. S. to perform
health research. Most of these scientists are working at
NIH. The revised system now provides more complete
current information on each scientist. It also provides
more accurate editing and updating capabilities at time
of data entry and produces new reports. Important new
features include:

1 . the use of microfiche to facilitate telephone inquiry
responses;

2. ad hoc querying of the data base, now expedited
by combining parameterized COBOL programs with
QUIKJOB;

3. 24-hour turnaround for producing annual reports
that formerly required two months to compile;

^ ' 75

4. automatic notification of such things as impending
terminations and expiration of 1-94 dates (which now
expedites FIC staff's ability to take appropriate
actions); and

5. the capability to post "across the board" pay
changes.

Employee Health System and Accident Reporting
System. Steve Soroka (DMB/ASPS); Julio Rivera, John
Leach (ORS/S). A system has been developed to
combine the employee health and accident reporting
systems. The system was implemented and turned over
to the users during FY83.

Committee on Academic Science and Engineering
(CASE) Reports. Darius Georg (DMB/ASPS); J. Bailey
(OD/OPPE). This project involves a broad spectrum of
data processing support required for the collection and
reporting of DHHS Obligations to institutes of higher
education, research and development centers, and
nonprofit institutions. This is an ongoing project.

Training Information System. John Parks (DMB/
ASPS); Ursula Lohman (0PM). This system was
developed to help the Training Management Branch
expedite data requests and management analysis of
data gathered on DHHS Form 350. Programming is
complete. The system test, documentation, and user
training are undenway.

System for Controlling and Monitoring Complaints
of Discrimination at NIH. Darius Georg (DMB/ASPS);
G. Yee, M. Williams (OD/DEO). This project establishes
and maintains a file that provides statistical data, on a
case-by-case basis, of formal and informal complaints
of discrimination at NIH. In the past year Mr. Georg
revised and simplified the retrieval process.

System for Classifying NIH Research and
Development Awards. Darius Georg (DMB/ASPS);
William Rhode (OPPE/RA). The objective of this
ongoing project is to test the feasibility of using CRISP
index terms for categorizing NIH research projects into
basic, applied, or developmental research and then to
develop a computer system to show percentage
distribution of dollars associated with each category.
New methods were tested this year to index the CRISP
terms in order to develop a more precise percentage of

distribution for each area of research. Once a feasible
system is developed, the data collected, analyzed, and
compiled by the system will be used to prepare annual
reports to the Office of Management and Budget
(0MB) and the National Science Foundation (NSF).

DCRT Computerized Bibliography. Richard Baxter
(DMB/OC); Karen Griffin, Patricia Miller (DCRT/OD).
This project, complete this year, was begun in FY79 to
create a file of citations for all papers published by
DCRT authors. It is now possible to retrieve
bibliographic reports from the file.

Interferon Production lUlonitoring System. Dennis
George (DMB/ASPS); Hilton Levy (NIAID/LVD). The
purpose of this project is to develop a system to
monitor the production and subsequent use of
interferon on an experimental basis. Various production
techniques and use protocols are to be monitored in
both human and animal subjects. Analysis and design
have been completed and implementation of the
system has been started.

Information System of Extramural Scientists. Darius
Georg (DMB/ASPS); William Rhode (OD/OPPE). This
project involves the creation of a data base drawn from
various sources to perform analysis of patterns of
involvement in NIH science review activities by
extramural scientists. The data base has been created
and reports are being run as requested. During FY83
the system was modified to provide online editing and
also to create history files for data from 1950 through
1978.

IMedical Records Auditing System. Judy Mahaffey
(DMB/ASPS); Gloria Burich (CC/MRD). The purpose of
this system is to assist the Medical Records
Department in the monitoring and reporting of the
status of medical records from the time they enter the
department until they leave. The audit segment of the
system was completed during the past year. Now being
explored is the possible further automating of data
transmissions directly from their data transcription
contractor in Florida. Also being considered is more
sophisticated scanner equipment.

AIRS Personnel System. Steve Soroka (DMB/ASPS);
L Lee Manuel (DCRT/OD). This project involves a

complete revision of the system due to the availability
of the new TAPS file. Analysis, design, and
implementation were completed during the last year.

Biomedical Communications
Applications

Selective Dissemination of information. Sigurd
Knisley (DMB/SAS). The Scientific Applications Section
has continued its support of the current awareness
search for both Chemical Biological Activities (CBAC)
and Biosciences Information System (BIOSIS).
Retrospective searches are referred to the NIH Library
staff. In the spring of 1983 a study was done to
determine the utility of this service at NIH and to
explore a personal computer-based system as an
alternative.

Bibliographic Data Base. Sigurd Knisley (DMB/SAS);
Curtis Harris (NCI/DCCP). Bibliographic information and
l<eywords drawn from Dr. Harris' reprints of scientific
articles were entered into the computer files. A system
for searching this information and printing it for direct
inclusion into book and journal bibliographies was set
up using the powerful new tools available in WYLBUR.

Computer Research and Technique
Development

SFOR (Structured FORTRAN) Compiler. Bob

Magnuson (DMB/OC). The SFOR compiler, which
generates block-structured IBM FORTRAN source
code, was further enhanced to assist programmers
writing structured programs. There are six different
kinds of blocks available to the FORTRAN
programmer-CASENTRY, FOR, IF, LOOP, REPEAT,
and WHILE.

RMAG Products Support. Bob Magnuson (DMB/OC).
Necessary support is provided for RMAG, SLR, Logic
Subroutines, Arithmetic Subroutine, SLANG, Voice
Input, PDOC, CP Tools, and SFOR. This ongoing
support includes software maintenance, customer
assistance, and the teaching of formal DCRT courses
on the use of these products. In particular, a special
effort had to be mounted to change over to the new
WYLBUR format data sets.

PDOC: Program Documentation System. Bob

Magnuson (DMB/OC). PDOC is a tool used to
document programs. It is a front end to the WYLBUR
Document Formatter, allowing the users to employ all
of the Document Formatter's powerful features while
adding several useful enhancements of its own. PDOC
was enhanced during the past year in order to better
produce the large and complex MLAB Beginners Guide.
A number of PDOC commands have been revised and
new ones have been added to enable the author of a
document to customize formatting and to make
insertions, deletions, or rearrangements of screen lines
at will with the references in the author's text being
automatically revised by PDOC. Another new feature of
the system enables the author to "reproduce" in the
document a boxed version of a CRT screen display and
then to reference each line within the box symbolically
in text discussion.

CP Tools. Bob Magnuson (DMB/OC). CP Tools is an
integrated set of WYLBUR command procedures that
permits the user to issue single user-defined
commands to expedite text entry/editing and running
jobs while on the NIH7000 terminal. Among the new
tools developed during the year are: "token editing" for
changing variables or keywords without affecting other
parts having identical substnngs; JCL generators for
microfiching any number of hold jobs and for running
SLANG and SFOR; and getting PF keys on the
NIH7000 to do whatever the user wants.

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Computer Center Branch

Joseph D. Naughton, Chief

New Facilities

A policy decision to facilitate microcomputer access to
resources and services available on the Computer
Utility led to the implementation of two functions:
terminal emulation, a means to allow microcomputers
to be used as terminals to access the mainframe
computers; and file transfer, a system for transferring
programs and data from the microcomputer to the
mainframe computer (called "uploading") and from the
mainframe computer to the microcomputer
("downloading").

Microcomputer-based devices that are ASCII (American
Standard Code for Information Interchange) teletype-
compatible can access both the IBM System 370 and
the DECsystem-10 over the switched telephone
network using the ASCII communications code. The file
transfer function required the use of a packet-based
protocol with companion programs that run
simultaneously on both the mainframe computer and
the microcomputer. Extensive testing was done to
ensure that the communications packages selected
would provide reliable and accurate data transfer
services on both the IBM System 370 and the
DECsystem-10, while meeting the specific requirements
of the Utility's user community.

An entirely new communications service was
implemented on the IBM System 370 to provide
switched network access to users with 3270-type
display devices or microcomputers. The new service,
called System Network Architecture (SNA)
Synchronous Data Link Control (SDLC), allows users of
microcomputers that can emulate the 3270 protocol to
use IMS, TSO, or WYBLUR under TSO without
incurring the cost of a leased telephone line.

Up-to-date status information about online data sets,
migrated data sets, and dedicated volumes has been
placed online, and users now receive this information at
their convenience through the terminal. This capability
frees Computer Center personnel from the
responsibility of creating quickly-outdated paper reports,
and allows them to devote more of their time to more
critical user needs.

The Tektronix graphics package was added to
SPEAKEASY, greatly increasing the usefulness of this
language. Users can use the package to obtain high
quality plots of data in a matter of seconds. Ease of
use is a major feature of the SPEAKEASY graphics
package. Once results have been calculated, a plot
may be generated on a Tektronix terminal using as few
as two SPEAKEASY commands.

Full color graphics capabilities were made available
through OMNIGRAPH on the DECsystem-10. Eight
standard colors and as many as 256 user-defined color
combinations can be used for producing multicolor
graphs or colorful visuals in MLAB or POSTER.

Because TELL-A-GRAF and DISSPLA have replaced
the Integrated Plotting Package (IPP), and maintenance
and support for the system were discontinued by the
original author, plans were developed to phase IPP out
of sen/ice. A function to allow users to produce pnnter
plots directly using DISSPLA is being implemented so
that IPP can be retired without inconvenience to users.

Customer Assistance and Systems
Maintenance

Customer assistance continued to be an important
priority for the Computer Center during FY83. The
Programmer Assistance and Liaison Unit, which has
continued to operate under restricted hours for
telephone and drop-in help, recorded 20,100 calls or
visits from customers needing assistance this year. In
addtion, 2,800 Programmer Trouble Reports were
researched and answered.

SYSGENS installed during the past year numbered 75.
Nearly 9,000 "fixes," both preventive and corrective,
were tested and applied to the system, and 12 new
releases of current software packages were installed.

User Training

Alternative training opportunities were emphasized this
year in order to meet the challenge of providing
adequate user training. 5,214 requests for training were
received this year and 2,939 students were
accommodated in 150 sessions of 57 different courses.

Two distinct means of individual self-study were
available for those who could not be accommodated in
the formal training program:

• Multimedia self-study courses, available on a loan
basis on a variety of topics and a wide range of
levels, allow students to learn from texts, workbooks,
and audio or video cassettes. A new self-study
course, "Creating an OS/VS Program," was acquired
and introduced this year, bringing the total number of
courses available to 27. Over 750 students utilized
these multimedia courses during FY83.

• Independent Training Assisted by Computer (ABC)~a
hands-on, computer-assisted approach-was
implemented this year to supplement the multimedia
self-study program that was introduced in past years.

ABC allows students to study at their own pace, using
a printed text or the computer terminal. Interactive
review lessons and practice exercises encourage
hands-on experience. ABC courses are an ideal
alternative for students who need to review a topic or
who cannot travel to NIH for classroom training.

"Introduction to WYLBUR" was the first ABC course
made available this year, because a knowledge of
WYLBUR is fundamental to the effective use of the NIH
Computer Utility and there is always a backlog of
students for basic WYLBUR courses. ABC
"Introduction to WYLBUR" consists of 40 short lessons
that cover the same information as two elementary
WYLBUR classroom courses. Over 3,000 students
utilized the course this year.

Documentation and Publications

INTERFACE continued to be a particularly important
source of up-to-date documentation on new hardware
installations, system enhancements, and software
developments. Seven issues, including the annual
index, were published during the past year.

The publication won second prize in the 1 982
newsletter contest conducted by the Association for
Computer Machinery (ACM) Special Interest Group on
University and College Computing Services. The
competition involved newsletter entries from 57
academic, commercial, and research organizations,

which were evaluated based on quality of articles,
organization, content, graphic design, and typography.

Five updates of the Computer Center's User's Guide
were issued during the year. Eight new technical
documents were published and 1 1 others were either
revised or updated during the year.

Research Projects

NOTICE OF INTRAMURAL RESEARCH PROJECT

ZOl CT00113-01 CCB

October 1, 1982 to September 30, 1983 |

Design and Development of an Advanced Molecular Graphic

Facility

Richard J. Feldmann, Computer Specialist, COB, DCRT

^^■l

. V,.iSi

Computer Center Branch

SECTION

DCRT, NIH, Bethesda, Maryland 20205

0.9 1 0.5 1

Design and Development of an Advanced Molecular
Graphics Facility

This research work deals with advances in computer
technology that offer new, surprising, and powerful
opportunities for improving the ability to model the
structure of macromolecules. Molecular modeling can
be roughly divided into three parts: getting the pieces
together, getting the correct shape of the molecule, and
producing pictures of the resulting molecule.

We have used centralized timesharing machines for the
past fifteen years to do the first function. The evolution
of desk-top work stations makes it possible to bring this
molecule construction process closer to the scientist-
user. The evolution of powerful array processors makes
it possible to speed up and enhance the process of
finding the optimal shape of the molecule being
modeled. The evolution of new displays makes it
possible to make representations of complex molecular
assemblies, viruses, cellular components, and cells.

We have begun the design and implementation of a begin to consider the question of the design of

molecular graphics facility that will hopefully allow us to macromolecules.

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Office of the Director

Arnold W. Pratt, M.D., Director

Research Projects

NOTICE OF INTRAMURAL RESEARCH PROJECT

ZOl CTOOl 10-01 00

nrtober I. 1982 to September 30. 1983

al Computer Workgtatlo:

Arnold W. Pr,

DCRT: B. McLaughlin, CD

P.E. Burke, 00
D. Sonftco, CSL

J. Dickson .
R. Kagnuaon,
J. Oberthale

DC«T. ma, BetheaJa. MaryUml 2020S

Personal Computer Workstations

This project will apply personal computers to a variety
of problems in offices and laboratories throughout NIH.
The goal of this project is to determine how effectively
programmable workstations can be used to perform a
number of functions, including text processing,
production of business and scientific graphics,
maintenance and inquiry of small data files, and so
forth. Use of commercial software and communications
with the central NIH computer facility are being
stressed.

In the first phase of the project, begun in FY83, a
number of workstations, based on the IBM Personal
Computer, are being installed in DCRT branches and
laboratories. These computers are being used by DCRT
technical and administrative personnel to evaluate the
workstations from both systems and application
viewpoints. A byproduct of this early evaluation will be
to define the best use of available DCRT resources in
promoting effective use of personal computers
throughout NIH.

Multi-function Microprocessor Interface. A. Pratt
(OD); D. Songco (CSL). Begun in FY80, this project
seeks to adapt a variety of information acquisition
techniques on a single microcomputer as a versatile
data input/output interface for biomedical scientists and
clinicians.

This work has led to an outgrowth of related
developments in DCRT: an Office of the Director
project on Personal Computer Workstations, and two
Computer Systems Laboratory projects, the Medical
Information Technology Project and the Personal
Computers in Laboratory Applications project (both
reported elsewhere in this volume).

Medical Linguistics. A. Pratt (OD), et al. This is a long-
term project to define a set of semantic and syntactic
forms that can aid in the analysis and interpretation of
written medical statements.

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October 1. m2 to Septaabar JO, ■«•)

Concordance Tro^rm

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Concordance Program

A concordance is an index in which the words
appearing in a document are entered with quotations of
context. The reader who looks up a word in a
concordance can use the quotations of context to
decide which occurrences of the word might be of
interest.

A program to produce concordances has been made
available. It can produce the following types of output:
a concordance in KWIC (Key-Word-ln-Context) format;
a concordance in KWOC (Key-Word-Out-of-Context)
format; a word index; or a word frequency list. The
program can accept an input data set consisting of
lines entered with a text editor, each line containing a
text fragment to be operated upon by the program in
order to construct text fields or records. The input data
can represent a continuous stream of text, like a book
or journal article, or it can represent a collection of
discrete text items, like those in a catalog or

bibliography. The program also can accept as input a
pre-existing file of formatted records.

A number of program options have been provided:
concordance lines may be sorted within indexed words;
a format may be defined for KWOC output; keys may
be constructed from multiple fields; words may be
specified for exclusion (or inclusion); word definition
may be modified, etc.

The description of input data and the specification of
program parameters are made with problem-oriented
statements and do not require changes to the
concordance program.

NOTICE OF INTRAMURAL RESEARCH PROJECT

ZOl CT00106-01 OD

October 1,1982 to September 30, 1983

I Program for Finding Moun Phrases in English '

Paul J. Kalkowski, Computer Speclali

Office of the Dlrecto

T, HIH, Bethesda, Maryland 20205

A Program for Finding Noun Phrases in English
Text

A pilot program has been written to find noun phrases
in English text. Potentially, such a program might be
useful as a step in automatically indexing text or in
performing information retrieval from English language
data bases.

In general, the program executes as follows: Each word
of text is looked up in a dictionary containing at present
about 27,000 words and phrases. If found, part of
speech possibilities are taken from the the dictionary
entry. If not found, the word is examined for prefixes,
suffixes, and inflectional endings, and an attempt is
made to derive the word from a word in the dictionary.
A part of speech may be deduced from a suffix, an
inflectional ending, and/or properties of a base word.
Othenwise, an unknown word is assumed to be a noun.
Each word of text is then considered in its context and

with its possible parts of speech, and rules of syntax
are applied to determine an actual part of speech, or
else to reduce the part of speech possibilities. When a
sentence is complete, the program scans it for possible
noun phrases.

The program is not based upon any mathematical
model of language, and it does not produce a complete
parse of a sentence showing all relationships between
words. Problems encountered by conventional parsers
are avoided (e.g., resolving ambiguity, determining
antecedents of pronouns), and indeed are considered
irrelevant to the program's goal of finding noun
phrases.

Because the program cannot always determine a
word's part of speech, the program cannot find noun
phrases exactly, and it is designed to err on the side of
finding noun phrases that are too long. In any system
that employs the program, it is anticipated that
subsequent steps could be taken to refine the noun
phrases that are produced.

E OF INTRAMURAL RESEARCH

ZOl 0100040-05 OD

October 1, 1982 to September 30. 1983

Actln Assembly in Nonmuscle Cells

Stephen L. Brenner, Research Chemist, OD, DCRT

Laboratory of Cell Biology, NHLBI

Office of the Direct'

DCRT, HIH, Bethesda. Maryland 20205

Actin Assembly In Nonmuscle Cells

The protein actin is a major cytoskeletal component of
all eukaryotic cells, serving both structural and motility-
related roles. In the cell, assembly and disassembly of
actin microfilaments are temporally and spacially
regulated. This project is aimed at understanding the
mechanism of G-actin assembly into F-actin, the role of
the hydrolysis of actin-bound ATP, and the cellular
control mechanisms for actin assembly.

This past year we have shown that monomer-polymer
subunit exchange in steady state F-actin solutions
occurs by a diffusion mechanism and not by opposite-
end assembly-disassembly (treadmilling). We have also
discovered that F-actin alone possesses ATPase
activity independent of monomer-polymer interaction;
exchange of F-actin-bound ADP for ATP in solution can
occur directly by a "breathing" of the polymer structure.

The assembly of F-actin with bound ADP has been
studied. Even though no nucleotide hydrolysis occurs,
the kinetics of assembly are consistent with a rate-
limiting nucleation step followed by elongation. We
have begun to measure absolute rate constant for the
assembly reaction by using a chemically cross-linked
actin trimer to bypass the nucleation step.

A study has begun to determine the mechanism for
control of actin filament assembly in human platelets. A
1:1 complex of actin and a 90,000-dalton protein has
been purified from platelets. The modulation of actin
assembly by this complex is currently being
investigated.

Publications:

Brenner, S.L., and Korn, ED.: On the mechanism of actin monomer-polymer
subunit exchange at steady slate, J. Biol. Chem. 258: 5013. 1983.

Brenner, S.L. Tobacman. L.S., and Korn. E.D.: The kinetics o( actin polymeriza-
tion and monomer-polymer subunit exchange at steady state In Dos Re-
medios. D. (Ed.): Actin (In press).

Tobacman. L.S.. Brenner. S L.. and Korn, ED.: Eflects of Acanthamoeba prod-
lin on the pre-steady state kinetics of actin polymenzation and on the
concentration of F-actin at steady state. J. Biol. Chem. (In press).

Harrli 1. |1H1 tn .Ipn'— l-.r 10, Hill

NOTICE OF INTBAMUH»L flESEARCH PROJECT

ZOI CTOOIlt-01 OD

■ irf fif CflrhohYririitff

Dr, Michael Levlct, Dept. Chemical Phys

ur. nicnaei lcvill, fc|/i. 1-...^.^ = . .../-..

Dr J. David Ravm. Dept. Chem., To»80n State Univ.. Towson. KD

Dr. David H. Bing, Cambridge Research Laboratories, Cambridte.

Scl., Rehovot, larael

DCRT, NIH. Bethesda. Maryland 20205

Molecular modeling of the structure of
carbohydrates

Many variations of the basic carbohydrate ring structure
are to be found in biological systems in the form of
chain and branched structures. These structures are to
be found on the surfaces of cells where they serve as
the elements of recognition between cells and other
processes. Crystallography has been done on some of
the variational units and on a few small chains. We
have begun a graphics project to construct as many of
the naturally occurring structures as have been
reported in the literature. In order to produce realistic
structures, an energy minimization program is being
used to find energy-minimum and therefore stable
conformations. Data from Nuclear Magnetic Resonance
(NMR) experiments also will be used to help determine
the shape of the carbohydrate structures. Preliminary
model construction and minimization indicates that
carbohydrates are rather more ngid than amino or
nucleic acids. If this proves to be true in general, the
shape of a complex structure will be simply, and
perhaps uniquely, determined by the type and
connection of the components.

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Reprint File Index

This is an experimental project to determine the
potenial usefulness of WYLBUR Command Procedures
in building, maintaining, and searching an index of
journal article reprints. A command procedure called
REPFILE allows the user to enter certain information
about each journal article or book chapter he or she
wishes to index. This information is retained in an
online WYLBUR data set for later inquiry. The index

' " 85

can be searched and selected references can be
displayed in tabular or bibliographic citation format.

DISCRIMINATION PROHIBITED: Under provisions of
applicable public laws enacted by Congress since
1964, no person in the United States shall, on the
grounds of race, color, national origin, handicap, or
age, be excluded from participation in, be denied
the benefits of, or be subjected to discrimination
under any program or activity (or, on the basis of
sex, with respect to any education program or
activity) receiving Federal financial assistance. In
addition, Executive Order 11141 prohibits
discrimination on the basis of age by contractors
and subcontractors in the performance of Federal
contracts, and Executive Order 11246 states that
no federally funded contractor may discriminate
against any employee or applicant for employment
because of race, color, religion, sex, or national
origin. Therefore, the Division of Computer
Research and Technology must be operated in
compliance with these laws and Executive Orders.

KRT

Division of Computer Research and Technology
National Institutes of Health
Bethesda. Ivlaryland 20205

iiiiMtt

tMm

• LIBRARY

l|^ Amazing Research.
Amulng Help-

http://nihlibrary.nih.gov

10 Center Drive

Bethesda,MD 20892-1150

301-496-1080

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