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Related Efforts - Much effort has gone into, designing fast computers
by overlapping the micro-execution of program elements. Simultaneous
-operations on various elements of a computing load have been achieved
through the design of special peripheral devices such as correlation
processors and Fast Fourier Transform boxes. More flexible hardware
devices may be designed using Clark's macromodules (ref. 15) or
microprogrammed machines (ref. 16).

The coordinated use of clusters of small machines sharing memory and
peripheral devices is being investigated by Bell (ref. 17, 18).
This approach offers considerable long term potential when coupled to
appropriate software capability.  Software support must be available
to effectively focus and manage such an array in a multi-user environment.

The proposed research in this grant does not have as its aim extensive
research into computer architecture.  Rather we will draw upon related
developments in these areas (commercial and academic) as available for
our specific medical applications.

Efforts are being made to provide support of remote computers by larger
host systems.  A number of manufacturers have available Assembly
Language processors for minicomputers which run on larger hosts.   IBM
is developing a Distributed System Programming (DSP) system (ref. 19-20)
which provides for communication of programs, data, and control
information between a number of remote System 7 machines and a host.
The announced capability of DSP is a 134 baud communication rate and
no usable realtime priority structure in the host.  The data rates of
interest to this proposal are 3 to 4 orders of magnitudes higher.

(c) Rationale

The underlying rationale of our approach to extended realtime problems
in medicine is based on the concepts:

1.  For problems involving large volumes of data or complex
  instrumentation and analysis procedures, the computer becomes
  a more powerful tool the more reliably,adaptively, and
  accurately it can perform necessary tasks without need of
  human supervision.

2.  The integration of coordinated satellite machine capabilities
  with time-shared host facilities offers an effective and
  economical method for providing required computing resources
  among intensive users.

Automation - Most laboratory instrumentation data systems consist of
the elements shown in Figure Gl or some subset of those elements. In
many cases human beings perform some of these functions directly in
order to introduce adaptability and reliability.  Inherent in the
human performance of these tasks is a feedback situation where the
results of an operation are evaluated in terms of "reasonableness" to
verify the degree of success with which the task is performed and to


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,
r


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modify the operation as required to optimize the result.  Without this
model for what constitutes an appropriate range for the process outcome,
the human being would be no more reliable than the blind computer.

In situations where the human being cannot directly perform these
functions, methods for automating the computer performance of such tasks
must be developed.  Such methods depend upon extending the underlying
processing algorithms to include methods for adaptation, performance
evaluation, and feedback optimization of processing parameters.  Models
by which the computer can judge and modify its performance can be based
on physical models of the instrument or data source, heuristic models
of the environment, or guidance from previously developed problem
solutions.  In the near term these models are defined by human control.
In the longer term more autonomous computer organization of its problem
domain will be required.

Computing Support - The use of remote and local satellite processors
about a large host system with shared large core and peripheral equipment
allows the economical expansion of parallel processing capacity and the
efficiency benefit of sharing costly system resources.  The general
topology which we plan to use is shown in Figure C-2.  This type of
system can be constructed from available hardware and can take advantage
of new developments underway at other locations.  The satellite machines
can be thought of as flexible building block processors which can be
organized and programmed to support critical realtime projects while the
main system acts to coordinate overall operation and provide less
critical time-share, batch, and realtime service.   These machines can
be readily reconfigured by software to support various realtime tasks
as needed and thereby are more efficiently shared among sporadic users.
As necessary dedicated use of a satellite processor in a particular
application such as a special instrument interface, is encouraged.
Incompletely used and sharable resources are spread across a broader
set of users.

(d) Methods and Procedures

Our approach to investigating extended realtime problems will be to
set up a computing resource configured to meet anticipated extended
realtime requirements and to select a set of problems in conjunction
with a collaborator community with which to experiment with specific
solutions.  These problems will be selected to draw upon the expertise
available in the Stanford medical and computing communities and to
offer significant promise for application of these methods.   It can
be expected that the complement of problems under attack will evolve
as successes and failures are encountered.  In the longer term, attempts
to generalize analogous solutions will be made.  Significant progress
remains to be made in the exposition of particular solutions,


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I   Sn


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however,  before this will be possible. The initial complement of
collaboratPve problems includes:

1.  Harrison, et al.:  Cineangiogram Analysis Automation.

2.  Constantinou:  Cineradiogram Studies of the Ureter.

3.  Lederberg, Feigenbaum, Djerassi, Buchanan, Duffield,
   Smith:  DENDRAL - Automated Mass Spectrum Interpretation.

4.  Herzenberg and Levinthal:  Cell Separator Automation.

5.  Kopell, Roth and Pfefferbaum:  Electroencephalogram Driven
  Stimulus/Response Studies of Drug Effects.

The backgrounds and proposed approaches to these research applications
are contained in corresponding succeeding sections of this proposal.

The computing resource will be built around a PDP-10 computer with a
derivative of the PL/ACME time-share software system.  The PDP-10 hardware
configuration will be as shown in Figure G-3,"with the following signi-
ficant features:

1.  The host computer allows state-of-the-art time-shared computing
  for system and program development as well as dedicated
  application to developmental realtime problems as required.

2.  The direct memory access of the array of satellite PDP-11/45
  processors provides for the experimental parallel processing
  support of intensive realtime applications in the time-shared
   environment.

The system will utilize the converted PL/ACME system as a base together
with the developed satellite machine programming and communication
system described in an earlier section of this proposal.  Additional
system software will be developed for interfacing and coordinating the
satellite PDP-11/45 machines,  It is expected that this software will
evolve as application requirements dictate (see Figure G-4).

The satellite computers are considered to be available on call for a
class of realtime users.  The machines contain supervisory software
which formalizes the PDP-lO/PDP-11 interface by providing interrupt
handling, intermemory transfers, program loading, program termination,
and intermachine status and control monitoring functions.  The satellites
are allocated when not busy on the basis of a task list accumulated
in the host machine posting requested user activity by sequence, type
and priority.  Each user application with access to extended realtime
service will have available a set of routines which allow communication
with the host monitor for posting of satellite tasks, priority control,
on-going processing control and interruption, error and exception
handling, input/output processing, and debugging facilities based on
host and satellite language capabilities.  Remote laboratory satellite
*Identical to figure E-3.  Repeated here for ease of reference.


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o ??? ?????? ?? ?? ? ?????
70 BE ANUWNCED   I--

TIY - /o,
s-l-i    r---------------7
            I          cfr */
  TU f0       I  4-l
                  3-c/45

I

Figure G-3


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                      .
.                       .
.                       *
.


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computers will have similar support and responsibilities.

In general each realtime user has a supervisory driver which is
responsible for job organization, synchronization,and coordination
as well as outside user interactions.  As each satellite performs
specified tasks to completion it maintains updated status information
on progress with the host system and upon completion of the task
returns a completion status and frees itself for reallocation to the
next highest priority task in the queue.  The ability to service a
community of users depends on providing enough satellites to accommodate
scheduled loading within the adaptation constraints of each user.

(e) Significance

The development of reliable automated computer systems for dealing with
complex and voluminous information in specific medical applications is
important for a number of reasons:

1.  Such tools augment capabilities for analysis and interpretation
  of increasingly complex measurements on biological systems.

2.  Such tools provide a means for collecting quantitative data
  from large populations establishing statistically sound
  baselines for testing research hypotheses.

2.  Such tools are an essential element to the routine delivery
  of preventative health care to large populations.

The significance of the associated research applications we have chosen
speaks for itself.   Clearly one must not expect the computer to
replace human capabilities but to augment and extend them.  Progress
has been made on a few problems to date and progress must be made on
many more fronts.

(f) Collaborative Arrangement

The essence of the proposed approach to extended realtime research is
to select a specific set of significant problems to provide a basis
for more general solutions.  These specific applications draw upon
the expertise of the collaborators named above.


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References

1.  Bellville, J., G. Fleischli, and G. Attura,  "Servo Control of Inhaled Carbon
        Dioxide," J. APPL. PHYSIOL., vol. 24, pp 414-415, 1968.

2.  Constantinou, C., E. Briggs, R. Dale, and D. Govan, "Real-Time Digital Computer
        System for Ureteral Physiology Investigation," URODYNAMICS, Chap.
        33, Academic Press, New York, in press.

3.  Constantinou, C., J. Sands, and D. Govan, "Computer Monitoring and Control
        Instrumentation in Urology Research," PROCEEDINGS OF THE 6TH
         ANNUAL BIOENGINEERING SYMPOSIUM, Fort Collins, Colorado, May 1971.

4.  Crouse, L. and G. Wiederhold, "An Advanced Computer System for Real-Time
        Medical Applications," COMPUTERS AND BIOMEDICAL RESEARCH, vol. 2,
        no. 6, pp 582-598, Dec. 1969.

5.  Crouse, L. and G. Wiederhold, "Interactive Use of Timesharing System for
        Medical Laboratory Support," presented at the San Diego Biomedical
        Symposium, San Diego, Calif., April 1970.

6.  Dong, E., Jr. and B. A. Reitz, "Effect of Timing of Vagal Stimulation on Heart
        Rate in the Dog," CIRCULATION RES., Vol. 27, No. 5, Nov. 1970.

7.  Gersch, W. and G. Goddard, "Epileptic Focus Location: Spectral Analysis Method,"
        SCIENCE, vol. 169, pp 701-702, 1970.

8.  Gersch, W., "Spectral Analysis of EEG's by Autoregressive Decomposition of
        Time Series," MATHEMATICAL BIOSCIENCES, vol. 7, pp 205-222, 1970.

9.  Harrison, D., W. Henry, C. Ploeg, and S. Kountz, "An Improved Hydraulic Vas-
        cular Occluder for Chronic Electromagnetic Blood Flow Measurements,"
        J. APPL. PHYSIOL., vol. 25, P. 790, 1968.

10.  Harrison, D., R. Stenson, W. Henry, and L. Crouse, "Analysis of Hemodynamic
        Data from Cardiac Catheterization with a Digital Computer," OPTICS
         TECHN. REVIEW, 1969.

11. Henry, W., L. Crouse, R. Stenson, and D. Harrison, "Computer Analysis of
         Cardiac Catheterization Data," AM. J. OF CARDIOLOGY, vol. 22, no. 5,
         pp. 696-705, Nov. 1968.

12. Mesel, E. and M. J. Gelfand, "An Automated Data Analysis and Acquisition Sys-
        tem for a Cardiac Catheterization Laboratory," COMPUTERS IN BIOLOGY
         AND MEDICINE, in press.

13. Reynolds, W., V. Bacon, J. Bridges, T. Coburn, B. Halpem, J. Lederberg, E.
         Levinthal, E. Steed, and R. Tucker, "A Computer Operated Mass Spec-
        trometer System" submitted to ANALYTICAL CHEMISTRY, 1970.

14. Swanson, G., T. Carpenter, D. Snider, and J. Bellville, "An On-Line Hybrid
        Computing System for Dynamic Respiratory Response Studies,"
        COMPUTERS AND BIOMEDICAL RESEARCH, vol. 4, pp 205-215, April 1971.

15. Clark, W. A., "Macromodular Computer Systems", Spring Joint Computer Conference
         Proceedings, vol. 30, p 335, 1967.  (See also the succeeding 6 papers
         pp 337-401.)


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16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

wu, Y. s., "Architectural Considerations of a Signal Processor under Micro-
      program Control", SPRING JOINT COMPUTER CONFERENCE PROCEEDINGS,
       vol. 40, p 675, 1972.

Bell, C. G. and Newell, A., "Possibilities for Computer Structure", FALL
      JOINT COMPUTER CONFERENCE PROCEEDINGS, vol. 39, p 387, 1971.

Bell, C. G., W. Broadley, W. Wult, and A. Newell, "C.mmp:  The CMU Multi-
      miniprocessor Computer", CMU-CS-72-112, 1971.

IBM, "System/370 Distributed System Program (DSP)", Program Number 360A-TX-
       032, Brochure G520-2539.

IBM, "Real Time Monitor (RTM), Program Number 360A-SV-001, Program Descrip-
        tion GH20-0876-0.

Quan, L.H., R. Tucker, S. Liebes, M. Hannah, and B. G. Eross, "Computer Inter-
      active Picture Processing", Stanford Artificial Intelligence
      Project Memo AIM-166, STAN-CS-72-281, April 1972.

Rindfleisch, T. C., J. A. Dunne, H. J. Frieden, W. D. Stromberg, and R. M.
       Ruiz, "Digital Processing of the Mariner 6 and 7 Pictures",
       J. GEOPHYS. RES., vol. 76, no. 2, pp 394-417, January 1971.

Nilsson, N. J., "A Mobile Automaton:  An Application of Artificial Intelli-
      gence Techniques", Proceedings of the International Joint Confer-
      ence on Artificial Intelligence, pp 509-520, 1969.

Feldman, J. A., et al., "The Stanford Hand-Eye Project", Proceedings of the
      International Joint Conference on Artificial Intelligence, pp 521-
       526, 1969.

Strand, R. C., "Man-Machine Cooperation in Digital Pattern Recognition of
      Bubble Chamber Tracks", ANNALS OF NEW YORK ACADEMY OF SCIENCES,
      vol. 157, Art. 1, p 65, 1969.

Neurath, P.W., Gallus, G., Selles, W. D., "Interactive Computer Aided Chromo-
      some Analysis", Lecture Notes, Engineering 871.S, UCLA Short
       Course, 1969.

Mendelsohn, M.L. et al., "Computer Oriented Analysis of Human Chromosomes II,
      Integrated Optical Density as a Single Parameter for Karyotype
      Analysis", ANNALS OF NEW YORK ACADEMY OF SCIENCES, vol. 157,
      Art. 1, p 376, 1969.

Castleman, K. R. and R. J. Wall, "The Analysis of Human Chromosomes", to be
       published.

Selzer, R. H., "Recent Advances in Computer Processing of X-ray and Radio-
      isotope Scanner Images", Biomedical Sciences Instrumentation,
      vol. 6, p 225, 1969.

Brooks, S. H., Selzer, R. H., Crawford, D. H., and Blankenhorn, D. H.,
      "Computer Image Processing of Peripheral Vascular Angiograms",
       to be published.


31. Levinthal, E. C., "Mariner 9 - Image Processing and Products", COSPAR Proceed-
       ings, May 1972 (to be published, ICARUS).

32. Green, W. B. and D. A. O'Handley, "Recent Developments in Digital Image Process-
       ing at the Jet Propulsion Laboratory", to be published, IEEE Special
          Issue, July 1972.


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(3) PL/ACME on a PDP-10

The PDP-10 systems as provided by DEC contain an excellent timesharing system
with its memory allocation, support a variety of languages and have an ade-
quate file system.

A service that ACME has provided is a language and a support system that has
a number of features not included in the DEC processors:

(a) A language that conveniently handles both numeric and string data.

(b) The capability to alter programs in terms of source statements at
   any time, including execution.

(c) The capability to carry out all debugging, including interruption,
  inquiry into state of variables or system change of variables,
   and continuation from such points, in source program formats.

These points have made ACME a useful tool for non-computer specialists in
medical research.

Most of these features are part of the compiler and the execution time support
provided through availability of symbol table, controlled linkages, etc.

We therefore would like to put a PL/ACME language processor on the PDP-10
if such a machine is obtained for Stanford.  Before starting this project,
we will look for other options to provide PL-type language support on the
PDP-10.  The language processor should be useable on other machines of
similar type and configuration.  We will seek other PDP-10 users of PL and
form sharing efforts on language extension.

The work is simplified by the fact that major portions of PL/ACME are written
in FORTRAN and that the compiler does not generate directly 360 machine
language.  It generates specification to a macro assembler which produces the
detailed code.

It is DEC's impression that their new FORTRAN compiler will materially assist
this conversion effort.

A number of decisions will have to be made regarding byte size and other
parameters, ACME's byte size is 8 bits, determined by the IBM hardware;
DEC hardware is flexible,  Theirsoftware normally prefers 7, but their COBOL
uses 6, as do their peripheral devices in standard mode.

The estimate of the required conversion effort that follows was made by the
ACME staff members based on discussions with DEC to clarify PDP-10 system
capabilities and services.  DEC made no direct examination of ACME code in
responding to our general queries.

The following assumptions were made in arriving at the estimate:


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(a) Indicated man month requirements assume uniform concentration on
   the problems of conversion.  Competing demands on personnel time
  will introduce inefficiencies and increase calendar time required.

(b) The staff will consist of qualified systems programmers familiar
  with the PL/ACME system augmented by member(s) previously familiar
   with the PDP-10 system.

(c) No attempt will be made to extend PL/ACME capabilities in the
   conversion effort.  Reprogramming will include taking advantage
  of existing PDP-10 capabilities including monitor control of time-
   share allocations, core swapping/hardware relocation or paging,
  and a file system which on the surface is similar to that currently
  used by ACME (there may be differences in security and integrity
  provisions).

(d) The new FORTRAN compiler being designed by DEC will be efficient,
   compatible with language standards, and allow efficient provision
  for extended capabilities such as logical operators, byte manipu-
   lation, and binary shifting.

The following are the conversion estimates for a PDP-10:

1.  Statistical programs
2.  PL compiler
3.  Error messages/processing
4.  Execution time excluding I/O
5.  File System
6.  Run time I/O and text editing
7.  LISP compiler
8.  Miscellaneous
9.  SYSI. FORTLIB (FORTRAN library)
10.  Plotting routines
11.  Core management
12.  Realtime support (configuration dependent)
13.  System control
14.  Terminal handling
15.  Assembly utility

System Function

Man-Months

2mm
12
1
6
6
6
0
1
1
2
1
3
3
1

1

Sub Total            46 mm

In addition to converting program code, provision must be made for planning
the conversion details, learning the new computer and monitor system, and
assistance to users in file conversion:

16.  System education (4-5 people @ 1.5 ma/person)             7lNn
17.   Conversion planning                                  12  mm
18.  User file conversion aids                             4mIn

                               Sub Total:            23 mm

                               Grand Total           69 mm


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In the above estimates no provision was made for project management, project
service, or operations personnel time as well as hardware costs.  Additional
software effort will be involved in building accounting routines for a new
machine/environment.  More significant and user dependent will be some user
effort to convert data files to a new word length system.  For files of uni-
form format (numeric or alphameric (text)), conversion can be automated.
For mixed files the user must be involved to define the formats of the data.
Provision is made in the above estimate to generate file conversion program
aids based on user format specifications.

The LISP conversion problem is in essence ignored above based on the follow-
ing.  No adequate LISP capability currently exists on ACME.  The LISP 1.5
batch processor currently used on the 360/67 has a counterpart on the PDP-10
which requires minimal conversion of programs using conventional LISP func-
tions.  According to B. Buchanan, some DENDRAL LISP code includes special
functions written in LAP (a LISP assembly language) which will require
conversion.  This code is not voluminous and some will benefit from conver-
sion and/or redesign.


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b. Follaborative Research and Developent

(1)

ve w Of Car-ion TJt .   . .
                          -X-RavandUltra-
Imaging Techniques - prepared by Donald C. Harrison

(a) Problem Statement

Cardiovascular disease continues to be the leading cause of death in the United
States and in most developed countries, even though significant research into
the prevention, diagnosis, and treatment of cardiac conditions have provided
much insight during the past several decades.  Coronary artery disease (CAD)
accounts for more than 50% of all deaths in the United States and between eight
and ten million people are estimated to have symptomatic CAD at the present
time.  Untold more millions have latent CAD which has not yet been detected.   CAD
frequently does not involve the muscle of the heart wall symmetrically and in
fact, typically, is segmental in nature leading to localized areas of dysfunction
with areas which are dyskinetic, akinetic, or dyssynchronous in their contraction
patterns.  All of these abnormalities may occur in the same heart and in general,
can be correlated with a decrease in coronary blood flow to the specific segment
of myocardium.  In order to determine which patient should receive medical or
surgical therapy for CAD, and whether or not segments of wall should be removed
in specific patients, it is important to define in quantitative terms the areas
of abnormal contractility and their severity.

Patients with valvular heart disease also may have localized abnormalities of
muscle contraction in their heart wall.  In determining whether or not the valve
damage is primary, thereby requiring surgical therapy, or whether it is secondary
to the abnormal muscle function, sophisticated studies such as cardiac cathcteri-
zation and specific angiographic procedures must be performed.   Data which are
obtained from these complex procedures are in many instances inadequate to make
a precise assessment of muscle function.  Thus, our overall desire is to develop
techniques which will permit a better assessment of ventricular performance,
first by using the invasive techniques of cardiac catheterization and angiog-
raphy now available, but providing improvements for analyzing signals.  Secondly,
we wish to develop new techniques, primarily using ultrasound, which will not
require cardiac catheterization and angiocardiographic procedures for defining
precisely cardiac muscle function.

Computer technology has been applied successfully in order to permit more accurate
assessment of cardiac function in recent years.  Computer techniques for monitor-
ing the electrical and mechanical performance of the heart in a number of disease
states have been developed in the Cardiology Division at Stanford (l-4). Dedi-
cated small computers have been used for these purposes and the programs for
determining pressure and flow relationships in patients undergoing cardiac
catheterization have been developed by the Cardiology Group at Stanford (l-3).
These functions are now performed by a dedicated mini-computer operating in a
real-time mode during much of the day.  In addition, the software for monitoring
electrical and pressure-flow relationships in patients following acute heart
attacks is presently being developed by the Cardiology Group.  The basic soft-
ware package for this dedicated mini-computer has been developed, and validation
of these computer programs is now in progress.

A technique for video image analysis obtained when patients are undergoing
angiocardiographic procedures has also been developed by the Cardiology Group
(4-6).  Furthermore, techniques for monitoring the coronary blood flow as it is
partitioned to various muscle segments in the heart has been developed using a
gamma camera for counting radioisotopes after the injection of gamma emitting
isotopes into the coronary arteries.  Individual patients undergoing cardiac


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b)

evaluation or treatment at Stanford may well have tests or procedures which are
analyzed by all three dedicated mini-computers now operative in Cardiology.
Since all calculations are now being carried out by mini-computers which are not
tied together in any network, the special calculation and integration of data
from any specific given patient is not possible without the use of a larger
computer system.  The Cardiology Division desires to utilize the proposed research
computer system in order to develop more sophisticated techniques for studying
the function of the heart, and to develop techniques which can be applied widely
for choosing the appropriate diagnosis or treatment of specific patients with
cardiac disorders.  The specific problems which we wish to solve are as follows:

1.  To diagnose the presence of disease of the cardiovascular system and to
  quantitate its severity utilizing data being generated by the several
  dedicated mini-computers monitoring cardiovascular performance. The
  ability to perform multiple sophisticated calculations on these data
  which can be integrated from several dedicated mini-computers in Cardiology
  will provide a basis on which to define heart muscle and hydraulic pump
  function in a more precise manner.

2.  Utilizing the X-ray image processing techniques to improve analysis
  of the hydraulic function of the heart, it should be possible to estimate
  and detect segmental  abnormalities in function.  Clearly,  much can be
  learned from studying the geometric changes in the heart wall during
  contraction which can supplement the pressure-flow relationships which
  we are now using for analyzing function.

3.  To integrate the pressure-flow-volume and geometric changes for the entire
  heart and for the small segments of the wall representing small areas
  of muscle dysfunction or necrosis which may be important for overall
   cardiac function.

4.  To develop non-invasive methods utilizing ultrasound techniques as a
  substitute for angiography which will permit screening of patients with
  suspected cardiac function abnormalities without subjecting them to the
  considerable risk of cardiac catheterization and angiographic techniques.
  It is also possible that these ultrasonic techniques can be applied in
  non-hospitalized patients, thereby decreasing the cost of screening
  significantly.

5.  To follow the course of cardiac disease by studying in quantitative
  fashion the changes in function in relationship to pressure flow,
  volume, and geometry as a natural history of a disease process unfolds.

Background

During the past two decades,  p ressure measurements in the various chambers
within the heart have been the primary method for determining  dysfunction.
Transducer systems for analyzing the cyclic changes in pressure have been
available for several decades , and abnormalities of valve function and muscle
function are reflected in changes in systolic pressures, diastolic pressures,
and the rate at which pressures are developing.  During the past two decades
measures of total flow during the cardiac cycle have been developed and used
together with pressure measurements to provide a more sophisticated technique
to analyze the overall hydraulic pumping function of the heart.  Recently
techniques for measuring volume changes throughout the course of a cardiac


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cycle have been developed at Stanford.  Video images are stored on a video
disc after the injection of radio-opaque media into the cardiovascular chambers.
Then utilizing a light-pen for drawing the images on a video screen and trans-
mitting the coordinants from the light-pen to a computer, has provided a basis
upon which ventricular volumes could be determined throughout the cardiac
cycle once geometric formulae for the changing ventricular shapes were developed.
This technique is tedious, requires a human interface and does not provide high
resolution.  In an attempt to improve these methods of determining ventricular
volume, techniques for videodensitometry which have been developed at the Mayo
Clinic (7) and in Dr. Heintzen's laboratory in Germany (8) are now being
planned for cardiology laboratories.  Videodensitometry requires that computer
processing techniques be developed to recognize borders and that the movement
of these various borders be followed throughout several cardiac cycles while
the ventricular chamber is filled with radio contrast material. These techniques
offer great promise for studying the geometric changes which occur during
cardiac contraction and for defining the changes which occur segmentally in
patients with CAD.  However, even these sophisticated techniques require
cardiac catheterization and angiography.

Recently the use of reflected ultrasonic waves from the moving wall of the
heart has been accomplished in a number of centers throughout the United States.
These techniques offer promise for a non-invasive method to study heart function.
Using these reflected ultrasound techniques, it is possible to determine
specific patterns of wall motion for a given area of the heart.  Unfortunately,
it is difficult to locate precisely these areas and to make certain that one
can focus the ultrasonic beams on a specific area throughout the course of a
cardiac cycle or throughout several cardiac cycles.  The development of new
and multiple ultrasonic transducer systems may provide an opportunity to look
at more than one area of movement in the heart wall.  With multiple trans-
ducers, computer processing of ultrasonic data becomes essential.   In the
Cardiology Division at Stanford we have developed a rapid A-D conversion
technique for computer processing these ultrasonic signals, and have developed
tracking programs and pattern recognition techniques.  At present our progress
is limited without access to a large computer which can receive high data
input, store it for later calculations and then display it graphically.  Multiple
transducers are now being developed and with them it should be possible to
analyze more than one area of wall motion in a particular cardiac cycle.   Such
transducer systems are available now, but their use is delayed due to the
general inability to process the accumulated data.  Computer techniques for
handling the large volume of data are now being considered and will require
access to a large computer with extensive core, disc storage, and sophisticated
graphic outputs.

Rationale

The specific rationale for proposing the use of the large research computer
facility at Stanford at this time is as follows:

1.  The Cardiology Division has made a step-wise approach, utilizing
  dedicated small computers to measure cardiovascular functions and
  follow them in quantitative terms.  Computer techniques for analyzing
  pressure and flow signals have already been developed and initial
  applications utilizing a human interface have also been made for
  video image processing.


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2.  Analysis of cardiac contraction patterns , segmentally, necessitates
  high video frame rates with video image processing of each frame.   It
  appears that videodensitometric methods utilizing techniques for deter-
  mining border movement for various segments of muscle throughout a
  cardiac chamber are essential to provide quantitative data.

3.  Sequential analysis of discrete areas of ventricular wall motion so
  that disease which alters the function of a particular segmental area
   of the heart can be detected.  The nature of coronary artery disease
  is that segmental wall damage is almost always the way in which ventricu-
   lar function is altered.

4.  Advanced technology in ultrasonic transducers is now being developed.
  Dr. Richard Popp of the Cardiology Division at Stanford and Dr. James Meindl
  of the Integrated Circuits Laboratories in the Stanford Electrical
  Engineering Department have been working on such multiple transducer
  systems.  Clearly the ability to sense the signal from these transducers
  and to activate one transducer at a particular time during the cycle and

analyze from that transducer will require large
computer installations.

and sophisticated

It is with these rationales in mind that the Cardiology Division desires to
participate in the development of the research computer facility at Stanford.

.(a) Method s and Procedures

Several specific procedures to improve definition and provide quantitation of
cardiac function are planned.

1.  X-ray Image Processing - New image processing techniques will be developed.
  The goals and methods for accomplishing this particular research project

are:

a.  To outline the opacified heart chamber after the images are recorded
  on either X-ray film or on a video disc.  Recording will generally be
  made at 30 frames/set. for delayed analysis.  Several techniques for
  border definition will be attempted.  Gray Scale analysis techniques
  utilizing scan methods for digitizing data alonglines on the film or
  video scan will be one of the methods attempted.  A film scanner will
  be necessary and will need direct computer control.

b.  Since biplane opacified images will be processed, three dimensional
  geometric displays of ventricular contraction will be developed. A
  promising technique of cartooning video images in three dimension
  has been developed by the Cardiology Division in association with
   Dr. Harold Sandler at NASA Ames Research Center.

C.  Models of the normal contractile patterns for ventricles will be
  developed.  Changes expected during various parts of the cardiac cycle
  can then be predicted by the computer and only those areas in which the
  contractile pattern differs significantly from normal will be studied
   in detail.  This ability for the computer to focus the analysis on
  areas of abnormality by feed-back mechanism excludes extraneous data from
  being digitized and analyzed.  This technique will permit a much more
  adequate use of the sophisticated computer technology and a great
  reduction in the volume of data handling necessary when high frame rates
  over many cardiac cycles are examined.


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d.  Segmental analysis of various portions of the heart wall motion will be
possible using these computer techniques.

e. Data on pressure and flow accumulated simultaneously will allow precise
calculation of muscle function in terms of force-load-velocity of
contraction and will permit pressure-volume loop displays.  Graphic
  display of the computed data will be essential for these calculations.

In the understanding of isolated muscle segment function it is important to
ascertain the relationship between force developed and velocity of wall motion
in a specific segment.  This should provide a basis for understanding the
hydraulic relationships developed in the pumping heart as a whole on the basis
of individual segment analysis.  Thus, it will be possible to develop pressure-
volume loops for the analysis of overall cardiac function.  The quantitative
determinations of overall function can then be related to normal expected
patterns.  Predictions of change in cardiac performance, based on removal or
alteration of contractility of a given segment, can then be made with precision.
This will perhaps lead to a better understanding of the function of isolated
segments of ventricular muscle and how these are affected by disease and the
treatment of that disease by either medical or surgical means.

2.  Ultrasonic Image Processing

It is the developmental plan of the Cardiology Division to utilize informa-
tion concerning cardiac function obtained by contrast angiography to validate
and provide a data base for the newer techniques of ultrasonic image gen-
eration and processing.  Detailed measures of ventricular contraction
utilizing ultrasonic image processing techniques appear  possible in more
than one dimension.  Several transducers may be used to reflect the movement
of the heart wall in three dimensions.

During the first year of the proposed grant we plan to develop better
techniques for digitizing ultrasonic data and to improve our methods for
tracking ultrasonic signals in real-time utilizing digital computer techniques.
In addition, during this period of time the development of multiple trans-
ducers on a hemispherical array will be completed in collaboration with
Dr. James Meindl in the Integrated Circuits Laboratory at Stanford.  Computer
software for activating one transducer and recording from it for a short
period of time and then sequentially activating other transducers so that
three dimensional ultrasonic display of ventricular wall motion can be made
will be developed utilizing the PDP-10 computer system proposed.

Border definition recognition, and sequential motion analysis can be pre-
dicted for normal hearts and deviations from normal can be highlighted by
activating the appropriate transducer in the hemispherical array for systema-
tic data accumulation throughout cardiac cycles.  This should permit the
development of non-invasive techniques for studying wall motion in patients
who have only latent heart disease and are not yet symptomatic.   Mass screen-
ing techniques with physiological documentation will be required once these
ultrasonic scanning techniques have been validated.  It seems likely that
ultrasonic techniques can replace the invasive radiographic methods now
required to analyze wall motion in quantitative terms and relate this to
pressure and flow data.


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3. Small Computer Integration

The Cardiology Division wishes to transfer the data analyzed by the small
dedicated computer systems in the cardiac catheterization laboratory, in the
monitoring unit, from the gamma camera, from the electrocardiographic lab-
oratory and from a gas chromatograph into the large research computer file
automatically.  Currently the integration of these data and performing
calculations with interrelated data from the several systems can only be
done manually.  To this data pool for sophisticated analysis we plan to
enter the X-ray image processed data, the clinical data, and the data from
the operating rooms.  Once these data can be analyzed in detail, highly
sophisticated diagnoses, prognoses, and predictative estimates for specific
patients with a variety of cardiovascular diseases can be made.

From the monitoring unit on the cardiology ward specific cardiac arrhythmias
can be detected and their frequency quantitated.  These arrhythmias are
treated with drugs which can be measured precisely  by gas chromatography.
The level of the drug can be related to its effect in many patients. Control
of its administration can be achieved by relating the frequency of arrhythmia
to blood level of the drvlg used for treatment.  We wish to experiment with
computer control of drug administration in these specific circumstances.

e. Significance

The significance of the above proposed analyses of cardiac function is as
follows:

1.  To understand better the physiologic interrelationships between changes
  in coronary blood flow, segmental muscle dysfunction and overall
  hydraulic pumping abnormalities in the heart of patients with significant
   cardiac disease.  It will be essential to study isolated muscle function
  in a segmental distribution and to integrate the pressure-flow-volume and
  geometric measures of ventricular performance.

2.  To choose appropriate medical or surgical therapy for the large numbers
  of patients presenting with cardiac disease based on quantitative
   determinations of abnormalities in cardiac function.

3.  To evaluate sequentially in quantitative terms the results to either
  medical or surgical therapy in these patients.

4.  To develop and improve non-invasive techniques which will provide all
  of the information necessary to analyze heart function in quantitative
   terms.  These approaches may later lead to mass screening techniques
   for latent disease.

Clearly, if the objectives outlined above are met successfully by the research
computer facility, they will become daily operational activities for cardiolo-
gists.  In this instance the programs developed could be moved to the utility
machine or to small dedicated computers of this type now used by the Cardiology
Division.  Specifically, it is planned after each of these techniques are
developed and validated they will be moved to the Medical Center utility machine.


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f.  Relati.onships

The Cardiology Division works with a number of other units within the Medical
School and in the Undergraduate University.  In order to utilize the proposed
computer facility as has been described, it is essential that these relationships
be maintained and increased.  Presently the following interrelationships are
maintained by the Cardiology Division as they are operative in relationship to
this proposed computer grant.

1.

2.

3.

4.

Cardiology Division is directed by Dr. Donald C. Harrison, Professor of
Medicine, Stanford University School of Medicine, who has during the last
five years emphasized research for adapting computer techniques for
cardiologic diagnosis and treatment.  Dr. Robert Stenson will be joining
the Cardiology Division as Assistant Professor of Medicine.  He has an
extensive background in computer sciences and in cardiology and will direct
the computer research operations for the Division.  Dr. Edwin Alderman and
Dr. Richard Popp are both working with video image processing--Dr. Alderman
with angiographic methods and Dr. Popp with ultrasonic techniques.  They
both are working with a number of collaborators and postdoctoral trainees
on projects which will relate closely with this computer technique develop-
ment.  Mr. William Sanders, who has worked with the Cardiology Division for
two and one-half years as the Chief Programmer, will direct the programming
efforts and will work as a liaison man with the overall computer staff of
the proposed central computer facility.  During the past year two graduate
students from Electrical Engineering,  Mr. Michael Hirsh and Mr. Patrick
McClure, have worked in association with Mr. Sanders.  At the present time
in Cardiology two Hewlett-Packard computer systems are operational on a day-
to-day basis.  The Cardiology Division has also been approved for an M.D.
training program in computer sciences.  This will be carried out in associ-
ation with Dr. Edwin Parker of the Communications Department and the
Computer Sciences Department in the Undergraduate School at Stanford.   Further-
more, the Cardiology Division is presently negotiating with Hewlett-Packard
for another 2100 computer system which would then give the Cardiology Division
three small dedicated computer systems to be integrated into the larger
proposed Research Computer network.

NASA Relationships - Dr. Harold Sandler, Head of the Biotechnology Group
at NASA-Ames Research Center is one of the pioneers in angiographic methods
in studying ventricular geometry and cardiac function. The Cardiology
Division has worked closely with Dr. Sandler and at present all of his
clinical work is performed in our cardiology laboratories at Stanford.  NASA
has also supported an ongoing project for the past five years at Stanford
to develop better methods for analyzing ventricular performance.

Integrated Circuits Laboratory - Dr. Richard Popp is working closely with
Dr. James Meindl in designing new arrays of ultrasonic transducers.   This
work is at an early phase at the present, but plans are being made for
more than one transducer mounting so that several segments of wall motion
may be studied in the same heart.

Communication, Department - Dr. Edwin Parker of the Communication Department
has agreed to work with the Cardiology Division in a training program for
medical scientists in the application of computer techniques for data handling
and analysis.  Such a program has been approved by the Study Section of the
National Library of Medicine and should be activated in the year 1972.


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5.

Artificial Intelligence Group - Numbers of individuals working in
the Artificial Intelligence Group have worked with image processing
techniques which will be complementary to the plans in Cardiology.
Tom Rindfleisch, Dr. Elliott Levinthal, and Dr. Bruce Buchanan of
this group have participated with the Cardiology Division in plan-
ning the image processing techniques to be utilized.  Professor
Lederberg and Dr. Levinthal are on the Mariner 9 TV Experimenter
Team.  In this capacity, Dr. Levinthal has headed the Data Processing
Task Group which has had the team scientific and policy responsibili-
ty for the very large image processing computer requirements for
this mission (ref. 3).

Mr. Thomas Rindfleisch, when he was at the Jet Propulsion Laboratory
had the responsibility for the implementation of this system. There
is thus the opportunity to benefit from these space-related experi-
ences in image-processing.

In addition, Dr. Buchanan is closely related to the M.D. Computer
Science training program of the Division of Cardiology. These inter-
relationships will provide high level computer consultation for the
Division of Cardiology as the step-wise plan to utilize the proposed
research computer facility above unfolds.


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REFERENCES

1.

2.

3.

4.

5.

6.

7.

8.

Stenson, R.E., Crouse, L., Henry, W.L., and Harrison, D.C.: A time-shared
digital computer system for on-line analysis of cardiac catheterization
data.  Comput. Biomed. Res. 1:605-614, 1968.

Henry, W.L., Crouse, L., Stenson, R., and Harrison, D.C.:  Computer analysis
of cardiac catheterization data.  Amer. J. Cardiol. 22:696-705, 1968.

Harrison, D.C., Ridges, J.D., Sanders, W.J., Alderman, E.L., and Fanton, J.A.:
Real-time analysis of cardiac catheterization data using a computer system.
Circulation 44:709-718, 1971.

Sanders, W.J., Alderman, E.L. and Harrison, D.C:  An interactive computer-
based technique for left ventricular volume measurement. Jour. Assoc. Adv.
of Med. Instr. 6:188, 1972.

Alderman, E.L., Sandler, H., Brooker, J.Z., Sanders, W.J., Simpson, C. and
Harrison, D.C.: Light-pen computer processing of video image for the determi-
nation of LV volume.  Submitted to Circulation.

Brooker, J.Z., Alderman, E.L. and Harrison, D.C.: Abstract.  Angiographic
documentation of changes in ventricular volumes during Valsalva maneuver.
Accepted for presentation at the American College of Chest Physicians,
October 1972.

Wood, E.H., Strum, R.E. and Sanders, J.J.:  Data processing in cardiovascular
physiology with particular reference to roentgen videodesitometry. Proc. Mayo
Clin. 39:849, 1964.

Heintzen, P.H.:  Roentgen-Cine-and Videodensitometry.  Georg Thieme Verlag,
Stuttgart, 1971.


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2) Digital Computer Processing of Cineurographic Images of the Urinary
  Tract.  - prepared by C. Constantinou and T. Stamey

(a) Problem Statement

Due to the expanding sophistication and specialization of the clinical
urologist, the specific need for computer aided quantification and
documentation of X-ray images is becoming increasingly urgent.  Thus,
with the routine introduction of cinefluoroscopy as a dynamic mode of
visualization of the urinary tract, the quantity and quality of
information available to every day diagnostic procedures has greatly
increased.  At the same time, the objective evaluation and quantifica-
tion of this information remained in the cognitive mind of the
radiologist who is asked to provide a larger volume, accurate measure-
ments, and at the s&me time, maintain a consistent diagnosis.  To this
end, some information is available to the urologist from static X-ray
films as measured by the radiologist. This information includes renal
size , parenchymal thickness, calyceal geometry, pelvic and ureteral
dimensions and can be reasonably abstracted and documented manually by
measurement,  But a living system is not static and therefore dynamic
studies, using cinefluoroscopy, have been organized to view the
kinetics of peristaltic flow, retrograde reflux, and dilation, in the
ureter on film.  This effort has proven very useful for first order
visual evaluation by the urologist but has inherent limitations in
terms of quantitative data that can be abstracted in a manner analogous
to the static X-my measurement,

The broader application and objective use of these dynamic studies is
therefore limited due to the vast amount of work and calculations
required for the determination of even the most basic parameterization
of any of the kinematic constants.  It is in this area of dynamic
interpretation of extended cinefluoroscopic studies with its plethora
of potentially valuable information that this program addresses itself
now.

The overall objectives of this proposed program is the development of
the computational capability to greatly increase the informational
content of intravenous pyelographic film.  It is expected in this way
that an extensive determination of the dynamics of flow of the upper
urinary tract under physiological and pathological conditions can be
made.  Specifically, the following parameters will, for the first time,
become available in a simultaneous measurement from the computer
processed film:

1.  Volume, dimensions, and direction of propagation of the discrete
  urine bolus.
2.  Speed of peristaltic transmission and frequency characteristics of
  a group of contractile waves.
3.  Spatial separation of retrograde peristalsis and reflux under
  various conditions of flow.

4. Accurate documentation of time varying changes of above in disease
  situations where there is known progressive deterioration in the
  lower ureteral tract.


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5.  Correlation of these changes with the geometry of the upper tract
  and kidney.

The direct benefits of this integration and quantification of parameters
would significantly enhance the informational content of pyelography
for the urologist and radiologist.  At the same time the underlying
mechanisms of obstructive uropathy would be quantitatively evaluated
and compared to normal physiological pressures.

(b) Background.

In clinical urology, the transport of urine from the kidney to the
bladder is visualized radiographically by the injection of radiopaque
contrast media into a vein and observing the outline of the calyceal
walls and the excretion patterns of the ureter during peristalsis.
This diagnostic procedure is termed intravenous pyelography and
frequently performed in most hospitals.  The dynamic nature of the
transport of urine in the ureter is enhanced when observations are
made continuously through a fluoroscope to visually trace the path of
the contrast labelled urine along the entire length of urinary tract.
Thus, the anatomical outline, from kidney to bladder, is illuminated
and obstructive or restrictive pathways can be observed.  The amount
of information thus extracted is substantially increased when a per-
manent record of the flow patterns is documented on tine film or
video tape, and subsequently examined at slower speeds.  At that time,
retrograde flows can be seen together with a host of other physical
phenomena characteristic of a diseased kidney, ureter, or bladder.
The informational content of this visual examination is presently
limited to a qualitative description of size, shape, position, and
primitive motion of the ureters.  Films or tapes resulting from these
studies are stored and subsequently used for comparison.  Thus, it is
possible to evaluate and correlate current visualization of a given
patient with his previous tine fluoroscopic studies. The fact still
remains that this form of evaluation remains a tiisualization and
progressive anatomical changes are thus not easily documented. Some
attempts have been made in grading the morphological appearance of
these organs and following the changes of the grading as a function
of time and disease.  This has proven very unsatisfactory due to the
variability of grading between different observers.  In our earlier
attempts in this area, a complex library of shapes of each anatomical
landmark was constructed and stored on a computer.  Thus, a review
could be made on any patients by asking the computer graphics program
to reconstruct a primitive image from the interpretive codes.  This
proved very unsatisfactory except in the simplest cases due to a lack
of quantitative and dynamically obtained data.  At that point, it
becomes clear that other avenues approximating more closely the
realities of the X-ray tine should be sought and coded.

(c) Rationale.

The capability and flexibility of a high data rate computer in the
processing of urologically significant radiographic film would
provide a medium for the application of sophisticated quantification