SECS - Simulation and Evaluation of Chemical Synthesis— Section 9.2.2

9.2.2 SECS - Simulation and Evaluation of Chemical Synthesis

SECS - Simulation and Evaluation of Chemical Synthesis

PI: W. Todd Wipke
Board of Studies in Chemistry
University of California
Santa Cruz, CA. 95064

Coworkers:

D. Dolata (Grad student)
R. Lasater (Grad Student)
D. Rogers (Grad Student)
J. Chou (Postdoctoral)
P. Condran (Postdoctoral)
T. Moock (Postdoctoral)
T. Blume (Programmer)

I. Summary of Research Program

A. Technical Goals. The long range goal of this project is to
develop the logical principles of molecular construction and to use these
in developing practical computer programs to assist investigators in
designing stereospecific syntheses of complex bio-organic molecules. Our
specific goals this past year focused on basic research into representation
of strategies, facilities for user-defined transforms, revision of our
ALCHEM language for better debugging of transforms and extension of
capabilities for representing complex reactions. In addition we hoped to
improve capabilities for remote teletype usage of SECS and to initiate the.
formation of a world-wide SECS Users Group for sharing chemical transforms.

B. Medical Relevance and Cotlaboration.

The development of new drugs and the study of how drug structure is
related to biological activity depends upon the chemist's ability to
synthesize new molecules as well as his ability to modify existing
structures, e.g., incorporating isotopic labels or other substituents into
biomolecular substrates. The Simulation and Evaluation of Chemical
Synthesis (SECS) project aims at assisting the synthetic chemist in
designing stereospecific syntheses of biologically important molecules.
The advantages of this computer approach over normal manual approaches are
many: 1) greater speed in designing a synthesis; 2) freedom from bias of
past experience and past solutions; 3) thorough consideration of all
possible syntheses using a more extensive library of chemical reactions
than any individual person can remember; 4) greater capability of the
computer to deal with the many structures which result; and 6) capability
of computer to see molecules in graph theoretical sense, free from bias of.
2-D projection.

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Section 9.2.2 SECS - Simulation and Evaluation of Chemical Synthesis

The objective of using XENO (a spinoff of SECS) in metabolism is to
predict the plausible metabolites of a given xenobiotic in order that they
may be analyzed for possible carcinogenicity. Metabolism research may also
find this useful in the identification of metabolites in that it suggests
what to look for. Finally, it seems there may even be application of this
technique in problem domains where one wishes to alter molecules so certain
types of metabolism will be blocked.

C. Progress and Accomplishments.

RESEARCH ENVIRONMENT: At the University of California, Santa Cruz, we
have a GT40 and a GT46 graphics terminal connected to the SUMEX-AIM
resource by 1200 and 2400 baud leased lines (one leased line supported by
SUMEX). We also have a T1725, T1745, CDI-1030, DIABLO 1620, and an ADM-3A
terminal used over 300 baud leased lines to SUMEX. UCSC has only a small
IBM 370/145, a PDP-11/45, 11/70 and a VAX 11/780, (the 11's are restricted
to running small jobs for student time-sharing) all of which are unsuitable
for this research. The SECS laboratory is in the process of moving to a
newly renovated room with raised floor in the same building and same floor
as the synthetic organic laboratories at Santa Cruz so the environment is
excellent,

I, C. Highlights of Research Progress
1. SECS Program Developments

The Simulation and Evaluation of Chemical Synthesis (SECS) program
has undergone many additions to improve its capabilities and usefulness to
synthetic chemists. The CONGEN layout program of Carhart has been modified
and incorporated in SECS for clean teletype output and simplified teletype
input for users without graphics terminals.

The synthesis tree plotting program for hard copy has been rewritten
to give more compact trees which are faster to plot on the plotter. This
generates better plots in less time and can also be used with XENO.

The ALCHEM language which we developed for representing chemical
reactions has undergone extensive revision to make it easier to represent
absolute stereochemistry and some of the complex reactions in heterocyclic
chemistry. Part of this revision now enables SECS to explain to the
chemist which ALCHEM statements are being used and the results of their
interpretation via a new decompiler for ALCHEM. A complete manual on
ALCHEM and a manuscript on the revisions has been written.

A User Defined Transform (UDT) module has been added to bridge the
gap between program knowledge and user knowledge. This allows the chemist,
during a synthetic analysis, to graphically specify a reaction which SECS
doesn't know, and continue without interrupting the analysis. The SECS
database is also still expanding as a result of contributions from our
group and from the SECS Users Group.

A META-SECS top-level plan generator has been outlined to reason
using synthetic principles and conclude plans which will then be used to

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SECS - Simulation and Evaluation of Chemical Synthesis Section 9.2.2

guide the existing SECS program in synthetic analysis. The First Order
Predicate Calculus is being used to represent the synthetic Strategies and
an inference processor is currently in design stages. The explicit
representation of synthetic strategies will be an interesting exploration
which we feel other synthetic chemists will benefit from, even through
manual use of these strategies. Hand simulation of this program is in
progress.

2. XENO - A Program to Predict Plausible Metabolites

The XENO program was developed to assist metabolism researchers in
predicting plausible metabolites of compounds foreign to an organism, and
in evaluating the potential biological activity of the resulting
metabolites. The knowledge base of XENO has been revised completely and
now includes 110 types of metabolic processes. We have specialized on rat
and mouse systems to date. The XENO program takes graphical input of a
compound to be metabolized and stepwise generates a tree of metabolite
structures which might result. The program is operational, but both the
program and the data base need improvement for field use.

The teletype input and output has been improved by incorporating a
modified version of Carhart's teletype plot module from CONGEN so the
program can be accessed remotely via teletype or graphics terminal.

The second phase of XENO which evaluates potential biological
activity is currently being developed. Currently XENO can check each
metabolite generated by exact match against a library of compounds and thus
if a match is found, pull out the biological activities. Our plans however
are to allow extrapolations beyond known compounds and for that we are

pursuing several approaches using chemical pattern recognition and chemical
similarity.

Collaborations with experimental metabolism researchers have begun in
order that XENO can make predictions for compounds actively being studied
in the laboratory. We hope to get feedback regarding the usefulness of
this methodology and to accumulate a list of verified predictions for
publication. These collaborators include scientists from NIH, FDA, EPA,
ICI Pharmaceutical, Upjohn Co., and UCSF Medical School. This work is
sponsored by the National Cancer Institute.

D. List of Current Project Publications

M.L. Spann, K.C. Chu, W.T. Wipke, and G. Ouchi, "Use of Computerized
Methods to Predict Metabolic Pathways and Metabolites," J. of Env.
Pathology and Toxicology, 2, 123 (1978); also reprinted in “Hazards
from Toxic Chemicals," ed. M.A. Mehiman, R.E. Shapiro, M.F. Cranmer ‘and
M.J. Norvell, Pathotox Publishers, Inc., Park Forest South, I11., 1978,
pp. 123-121.

 

J.D. Andose, E.J.J. Grabowski, P. Gund, J.B. Rhodes, G.M. Smith, and W.T.
Wipke, "Computer-Assisted Synthetic Analysis: The Merck Experience,” in.
Computer-Assisted Drug Design, ed Olson and Christoffersen, ACS
Symposium Series 112, pp 527-552, 1979.

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Section 9.2.2 SECS - Simulation and Evaluation of Chemical Synthesis

S.A. Godleski, P.v.R. Schleyer, E. Osawa, and W.T. Wipke, "The Systematic
Prediction of the Most Stable Neutral Hydrocarbon Isomer," Progress in
Physical Organic Chemistry, in press.

Manuscripts describing our work on symmetry, similarity, and ALCHEM
are currently in the review process.

E. Funding Status

1. Resource~Related Research: Biomolecular Synthesis
PI: W. Todd Wipke, Associate Professor, UCSC
‘Agency: NIH, Research Resources
No: RRO1059-03S1
7/1/80-2/28/81 $ 36,949 TDC

2. Computer-Aided Prediction of Metabolites for Carcinogenicity Studies
PI: W. Todd Wipke
Agency: NIH, National Cancer Institute
No: NO1-CP-75816
1/1/80-12/31/80 $74,394 TDC

II. Interactions with SUMEX-AIM Resource

A. Medical Collaborations and Program Dissemination via SUMEX. SECS
is available in the GUEST area of SUMEX for casual users, and in the SECS
DEMO area for serious collaborators who plan to use a significant amount of
time and need to save the synthesis tree generated. Much of the access by
others has been through the terminal equipment at Santa Cruz because
graphic terminals make it so much more convenient for structure input and
output. A complete synthesis tree was generated for Prof. William Dauben,
UC Berkeley of isocomene which was analyzed in detail by his students.

They were impressed by the magnitude of the number of synthetic approaches
and that all known syntheses were found by the computer. Similarly an
analysis of several insect pheremones was done and sent to Prof. A.C.
OehIschlager, Dept of Chemistry, Simon Fraser University, British Columbia,
Canada. Other visitors for whom we have done analyses include Dr. M.
Onozuka, A. Tomonaga and H. Itoh, Kureha Chemical Co, Tokyo Japan, Dr.
Rhyner, Director of research, Ciba-Geigy, Basel. A synthesis of
vellerolactone, a substance found to be toxic and teratogenic was generated
for Prof. R.E. Carter, Univ. Lund Sweden. A conformational Study of
substituted hydroazulenes was performed for Clayton Heathcock, Berkeley
(Synthesis of Isoprenoid Antitumor Lactones, NIH CA 12617). The XENO
project is working on metabolism of diallylmelamine N-oxide, a hypotensive
compound in collaboration with Dr. John M. McCall of Cardiovascular
Diseases Research, The Upjohn Co.

Dr. Wipke has also used several SUMEX programs such as CONGEN in his
course on Computers and Information Processing in Chemistry. Testing and
collaboration on the XENO project with researchers at the NCI depend on
having access through SUMEX and TYMNET.

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SECS - Simulation and Evaluation of Chemical Synthesis Section 9.2.2

B. Examples of Sharing, Contacts and Cross-fertilization with other
.SUMEX-AIM projects: This year the SECS and XENO project have made use of
the teletype plot program which Ray Carhart of the CONGEN project wrote at
Stanford. We modified the program to fit the needs of our projects. This
was facilitated by being able to transfer the programs within areas on the
same computer system at SUMEX. We continue to have intellectual
interactions with the DENDRAL and MOLGEN project in areas where we have
common interests and have had people from those projects speak at our group
seminars. SUMEX also is used for discussions with others in the area of
artificial intelligence on the ARPANET.

We developed a local print capability through SUMEX with the help of
the SUMEX staff which has facilitated our work greatly.

C. Critique of Resource Services. We find the SUMEX-AIM network very
well human engineered and the staff very friendly and helpful. The SECS
project is probably one of the few on the AIM network which must depend
exclusively on remote computers, and we have been able to work rather
effectively via SUMEX. Basically we have found that SUMEX-AIM provides a
productive and scientifically stimulating environment and we are thankful
that we are able to access the resource and participate in its activities.

SUMEX-AIM gives us at UCSC, a small university, the advantages of a
larger group of colleagues, and interaction with people all over the
country. We especially thank SUMEX for support of the leased line for our
GT40, and for helping develop our remote print capability.

SUMEX however has fallen short of our goals and desires: the load
average on SUMEX has increased .and reduced my group's efficiency greatly--
the system is too overloaded. We also have not been able to utilize the
4800 baud high speed line we purchased because SUMEX limitations forced
running at 2400 baud. We had hoped to be able to write tapes locally with
the 4800 baud line, but at 2400 baud it is too slow to be practical. We
would like to see some of their local lines slowed down so those remote
people doing graphics can run at a higher speed. We have found that when a
FORTRAN program is overlayed, the symbol table is lost, making symbolic
debugging with DDT impossible, we wish that could be corrected. Lastly our
disk space (8000 pages) is too small for our current research projects and
staff.

D. Collaborations and Medical Use of Programs via Computers other
than SUMEX. Arrangements are currently being made to place SECS 2.7 on
several computer networks so anyone can access it without having to convert
code for their machine. This has proved very useful in the past as a
method of getting people to try this new technology. SECS 2.0 has resided
on the First Data network since 1974 and has been used extensively in the
US and abroad.

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Section 9.2.2 SECS - Simulation and Evaluation of Chemical Synthesis.

III. Research Plans (8/80-7/86)

A. Long Range Project Goals and Plans. The SECS project now
consists of two major efforts, computer synthesis and metabolism, the
latter being a very young project. Our plans for SECS for the next year
include adding a high level reasoning module for proposing strategies and
goals, and providing control which continues over several steps. This
reasoning module also will be able to trace the derivation of goals and
thus explain some of its reasoning. We also plan to focus on bringing the
transform library up in sophistication to improve the performance and
capabilities of SECS. In particular we plan to allow a transform to have
access to the precursors generated as well as the product, this will allow
much greater control and more natural transform writing, but it requires
extensive changes in the SECS control structure to permit this.

Currently the similarity module requires a special version of SECS.
We plan in the next year to incorporate this module into the standard
version of SECS so that the bonds that if broken could lead to identical or
similar fragments can be used to create a goal to guide SECS toward such
efficient syntheses, even though there may not be a reaction capable of
doing that rejoining step. ,

We will incorporate the Aldrich catalog of available chemicals, both
to recognize when a precursor is available and to explore strategies based
on available starting materials. The process must be efficient for the
library contains 20,000 compounds.

We have now a PDP-10, a Univac, and an IBM version of SECS. We hope
to compare these and create one version which will run on these and other
machines to facilitate sharing of new modules among collaborators.

The XENO metabolism project will be expanding the data base to cover
more metabolic transforms, including species differences, sequences of
transforms, and stereochemical specificities of enzymatic systems.
Development of the second phase which assesses the biological activity of
the metabolites will continue as will efforts to simulate excretion and
incorporation, the endpoints of metabolism. Finally, application of the
current program to the molecules actively being investigated by metabolism
researchers will occur concurrently to test and verify the work done to
date on XENO and provide examples for publication.

In the next five years we foresee the SECS and XENO projects reaching
a stage of maturity where they will find much application in other research
groups. Our research will continue in these areas, but turn to some new
programs that approach the problems from different viewpoints and allow us
an opportunity to begin fresh taking advantage of what we have learned from
the building of SECS and XENO,

B. Justification and Requirements for Continued use of SUMEX. The
SECS and XENO projects require a large interactive time-sharing capability
with high level languages and support programs. I am on the campus
computing advisory committee and am the campus representative to the UC

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SECS - Simulation and Evaluation of Chemical Synthesis Section 9.2.2.

Systemwide computing advisory committee and know that the UCSC campus is
not likely in the future to be able to provide this kind of resource.
Further there does not appear to be in the offing anywhere in the UC system
a computer which would be able to offer the capabilities we need. Thus
from a practical standpoint, the SECS and XENO projects still need access
to SUMEX for survival.

Scientifically, interaction with the SUMEX community is’ still
extremely important to my research, and will continue to be so because of
the direction and orientation of our projects. Collaborations on the
metabolism project and the synthesis project need the networking capability
of SUMEX-AIM, for we are and will continue to be interacting with synthetic
chemists at distant sites and metabolism experts at the National Cancer
Institute. Our requirements are for good support of FORTRAN. ,

Our needs for SUMEX include an expansion of our disk allocation from
8000 pages to 10000 pages for the growth of our programs, databases, and
personnel. We are currently tightly constrained spacewise and are hampered
in research because of inability to keep needed files. We also would like
to have the overlay loader fixed so that an overlaid program can retain its
symbol table and permit symbolic use of DDT. This is a serious problem we
hope can be fixed by SUMEX staff because without symbols, debugging is very
difficult and time-consuming, since we must run SECS and XENO overlaid.

C. Needs beyond SUMEX-AIM. We do plan to acquire a virtual memory
minicomputer like a VAX or PRIME in the future to offload some of our
processing from SUMEX. Such a machine would enable us to do some
production and development work locally and would explore the feasibility
of those types of machines as hosts for SECS and XENO. A local machine
would also free us from the problems we have experienced in the winter when
the telephone lines to Stanford get wet and are too noisy to use. Even if
we had such a machine we still need to use SUMEX because we plan to
continue to develop and maintain the PDP-10 version of SECS and we need
SUMEX for its networking capabilities. In the future if we had a mini at
UCSC, we would Tighten our load on SUMEX, but currently we see our load
increasing as our group grows and as we start new projects yet must
maintain existing large programs.

We especially need the local capabilities to read and write magnetic
tape because we receive and send many tapes between our collaborators.
Driving to SUMEX to write a tape is not efficient for our personnel and
hinders communication with collaborators via tape. The problem will worsen
because the SECS Users Group will be sending UCSC tapes of chemical
transforms on a regular basis.

D. Recommendations for Community and Resource Development. The AIM
Workshops have been excellent in the past and should be continued. We feel
the SUMEX resource is heavily utilized, too heavily utilized at times to
get any productive work done. SUMEX staff could Tighten the load on the
machine by reducing the speed of text terminals at Stanford from 2400 baud
and above down to 1200 baud which is plenty fast for humans to read, and

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Section 9.2.2 SECS - Simulation and Evaluation of Chemical Synthesis

giving remote users faster capabilities, say 4800 baud. We feel the
community would benefit if remote users such as we had a virtual
minicomputer so the toad could be distributed more and not have everything
go through Stanford which is highly congested and quite expensive for
multiple leased lines. We further feel that it would be worthwhile if
discussions regarding the future expansion of SUMEX and the community could
include the remote users who depend on SUMEX. SUMEX can not currently
handle additional people from the outside community using SECS or XENO for
testing. The response time guests and outside collaborators see is not a
good reflection on the actual efficiency of the programs.

A trivial suggestion but also important is that TV-EDIT be improved
to not leave null characters in files which cause problems with compilers
both at SUMEX and at other sites when the files are sent to another
machine. This suggestion has been made many times by many people but the
Situation still exists.

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Hierarchical Models of Human Cognition Section 9.2.3

9.2.3 Hierarchical Models of Human Cognition

 

Hierarchical Models of Human Cognition (CLIPR Project)
Walter Kintsch and Peter G. Polson

University of Colorado
Boulder, Colorado

I. Summary of Research Program

 

" The two CLIPR projects have made substantial progress in their
research in this past year. This progress is almost completely due to our
access to the SUMEX facility. The prose comprehension group has completed
one major project, and is currently interacting with other SUMEX projects
with the goal of building a prose comprehension model that reflects state-
of-the-art knowledge from psychology and artificial intelligence.

The main activity of the planning group during the last year has been
the detailed analysis of thinking-out-loud protocols collected from both
expert and novice software designers. SUMEX facilities have been used to
store, edit, and reformat the raw protocols to facilitate later analysis.
Results of successive analyses are then input to SUMEX, and SUMEX
facilities are used to collate the various results.

Technical Goals

The CLIPR project consists of two subprojects. The first, the text
comprehension project, is headed by Walter Kintsch and is a continuation of
work on understanding of connected discourse that has been underway in
Kintsch's laboratory for over seven years. The second, the planning
project, is headed by Peter Polson of the University of Colorado and
Michael Atwood of Science Applications Incorporated, Denver, and is
Studying the processes of planning using software design tasks.

The goal of the prose comprehension project is to develop a computer
System capable of the meaningful processing of prose. This work has been
generally guided by the prose comprehension model discussed by Kintsch and
van Dijk (1978), although our programming efforts have identified necessary
clarifications and modifications in that model (Miller & Kintsch, 1980a).
Our more recent research (Miller & Kintsch, 1980b) has emphasized the
importance of knowledge and knowledge-based processes in comprehension, and
we are accordingly working with the AGE and UNITS groups at SUMEX toward
the development of a knowledge-based, blackboard model of prose
comprehension. We hope to be able to merge the substantial artificial
intelligence research on these systems with psychological interpretations
of prose comprehension, resulting in a computational model that is also
psychologically respectable.

The primary goal of the planning project is the development of a

model of human performance on software design tasks. We intend to begin by
modeling protocols of experts on solving a particular problem, eventually

E. A. Feigenbaum 234 Privileged Communication
Section 9.2.3 Hierarchical Models of Human Cognition

extending the model to other levels of experience and problems. We propose
a two-pronged attack on the process of developing a model,

The first is to develop a deeper understanding of our protocol data,
to increase our knowledge of the details of the planning processes and the
knowledge structures that experts use in the process of planning. We have
developed a method of protocol analysis that essentially involves the
transforming of the protocol into a Tow level theoretical description of
the processes used to solve the design problem. We have assumed a very
simplified version of a blackboard model that is described in Atwood and
Jeffries (1980). We currently carry out our analysis by hand, developing a
form of this low level model for each protocol. However, much of the
activities involved in developing this model are clerical in nature and
involve the categorization of segments of a verbal protocol and then the
reorganization of the categorized information. Much of this work can be
automated, and we propose to develop a program that will facilitate our
protocol analysis and the development of the Tow level models that we use
to describe the behavior of individual subjects.

Our second and much longer term objective is the development of a
substantive model in AGE that can simulate the design processes. We feel
that the software tools that are being developed at SUMEX -- in particular
AGE and the UNITS package -- will dramatically facilitate our ability to
develop this substantive model. Furthermore, current theoretical ideas
about both the process of design and the representation of knowledge
involved in developing a design have been strongly influenced by the MOLGEN
project at SUMEX (Stefik, 1980).

Medical Relevance and Collaboration

The text comprehension project impacts indirectly on medicine, as the
medical profession is no stranger to the problems of the information glut.
By adding to the research on how computer systems might understand and
Summarize texts, and determining ways by which the readability of texts can
be improved, medicine can only be helped by research on how people
understand prose. Development of a more thorough understanding of the
various processes responsible for different types of learning problems in
children and the corresponding development of a successful remediation
Strategy would also be facilitated by an explicit theory of the normal
comprehension process.

Note that our goal of a blackboard model is particularly relevant to
the understanding of learning difficulties. One important aspect of a
blackboard model is the separation of cognitive processes into a set of
interacting subprocesses. Once such subprocesses have been identified and
constructed, it would be instructive to observe the model's performance
when certain of these processes are facilitated or inhibited. Many
researchers have shown that there are a variety of cognitive deficits
(insufficient short-term memory capacity, poor long-term memory retrieval,
and such) that can lead to reading problems. Having a blackboard model in
which the power of individual components could be manipulated would be a
Significant step in determining the nature of such reading problems.

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Hierarchical Models of Human Cognition Section 9.2.3

The planning project is attempting to gain understanding of the
cognitive mechanisms involved in design and planning tasks. The knowledge
gained in such research should be directly relevant to a better
understanding of the processes involved in medical policy making and in the
design of complex experiments. We are currently using the task of software
design to describe the processes underlying more general planning
mechanisms that are also used in a large number of task oriented
environments like policy making.

Both the text comprehension project and the planning project involve
the development of explicit models of complex cognitive processes;
cognitive modelling is a stated goal of both SUMEX and research supported
by NIMH.

The on-going development of the prose comprehension model would not
be possible without our collaboration with the AGE and UNITS research
groups. We look forward to a continued collaboration, with, we hope,
mutually beneficial results. Several other psychologists have either used
or shown an interest in using an early version of the prose comprehension
model; these people include Alan Lesgold of SUMEX's SCP project. Needless
to say, all of this interaction has been greatly facilitated by the local
and network-wide communication systems supported by SUMEX. There has been
considerable communication between members of the prose comprehension and
AGE/UNITS groups as program bugs have been discovered and corrected; the
presence of a mail system has made this process infinitely easier than if
telephone or surface mail messages were required.

Progress Summary

The prose comprehension project has completed an early version of a
comprehension model that has now been used by several different researchers
(Miller & Kintsch, 1980a). This model has been applied to twenty different
texts, and has yielded quite reasonable predictions of recall and
readability. We are currently expanding on the premises of this model
toward a system that can make use of world knowledge in its analyses,

The planning group has completed the detailed analysis of several
long thinking-out-loud protocols collected from both expert and novice
software designers. These analyses involved the development of a lower
level model for each of the protocols. See Atwood and Jeffries (1980) for
details and examples. We are about to start development of a program toa
partially automate this modelling process.

List of Relevant Publications

Atwood, M. E., & Jeffries, R. Studies in plan construction I: Analysis of
an extended protocol. Technical Report SAI-80-028-DEN, Science
Applications, Incorporated, Denver, Co. March, 1980.

Polson, P. G., Jeffries, R., Turner, A., & Atwood, M. E. The process of

designing software. To appear in J. R. Anderson (Ed.), Learning and
Cognition. Hillsdale, N.J.: Erlbaum.

E. A. Feigenbaum 236 . Privileged Communication
Section 9.2.3 Hierarchical Models of Human Cognition

Atwood, M. E., Polson, P. G., Jeffries, R., and Ramsey, H. R. Planning as
a process of synthesis. Technical Report SAI-78-144-DEN, Science
Applications, Incorporated, Denver, Co. December, 1978.

Kintsch, W. On modelling comprehension. Invited address at the American

Educational Research Association convention. San Francisco, April 10,
1979.

Kintsch, W. and van Dijk, T. A. Toward a model of text comprehension and
production. Psychological Review, 1978, 85, 363-394.

Miller, J. R., & Kintsch, W. Readability and recall of short prose
passages: A theoretical analysis. Journal of Experimental Psychology:
Human Learning and Memory, 1980, in press.

Miller, J. R., & Kintsch, W. Readability and recall of short prose
passages. Paper presented at the American Educational Research
Association meetings, April, 1980.

Funding Support Status

1. Readability and Comprehension.
Walter Kintsch, Professor, University of Colorado
National Institute of Education
NIE-G-78-0172
9/1/78 - 8/31/81: $96,627
9/1/79 - 8/31/80: $46,537

2. Text Comprehension and Memory
Walter Kintsch, Professor, University of Colorado
National Institute of Mental Health
5 Rol MH15872-9-13
6/1/76 - 5/31/81: $159,060
6/1/79 - 5/31/80: $32,880

3. Comprehension and Analysis of Information in Text
Walter Kintsch, Professor, University of Colorado, and
Lyle E. Bourne, Jr., Professor, University of Colorado
Office of Naval Research, Personnel and Training Programs
ONR N00014-78-C-0433
6/1/78 - 5/31/80: $68,315
6/1/80 - 5/31/81: $60,000

4, Procedural Net Theories of Human Planning and Problem Solving
Michael Atwood, Research Psychologist, Science Applications,
Incorporated; Denver, Colorado

Office of Naval Research, Personnel and Training Programs
ONR N0014-78-C-0165

1/25/78 ~ 12/31/80: $230,000
1/1/80 - 12/31/80: $85,000

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Hierarchical Models of Human Cognition Section 9.2.3

If. Interactions with the SUMEX-AIM Resource
Sharing and Interactions with other SUMEX-AIM Projects

Our primary interaction with the SUMEX community has been the work of
the prose comprehension group with the AGE and UNITS projects at SUMEX.
Feigenbaum and Nii have visited Colorado, and one of us (Miller) recently
attended the AGE workshop at SUMEX. Both of these meetings have been very
valuable in increasing our understanding of how our problems might best be
solved by the various systems available at SUMEX. We also hope that our
experiments with the AGE and UNITS packages have been helpful to the
development of those projects. We should also mention theoretical and
experimental insights that we have received from Alan Lesgold and other
members of the SUMEX SCP project. It is likely that the initial
comprehension model (Miller & Kintsch, 1980a) will be used by Dr. Lesgold
and other researchers at the University of Pittsburgh, as well as
researchers at Carnegie-Mellon University and the University of Manitoba.

Critique of Resource Management

The SUMEX-AIM resource is clearly suitable for the current and future
needs of our project. We have found the staff of SUMEX to be cooperative
and effective in dealing with special requirements and responding to our
questions. The facilities for communication on the ARPANET have also
facilitated collaborative work with investigators throughout the country.

III. Research Plans (8/79 - 7/81)
Long Range Projects Goals and Plans

The primary long-term goal of the prose comprehension group is the
development of a blackboard-based model of prose comprehension.
Correspondingly, we anticipate continued use of the AGE and UNITS packages.
These packages allow us to model the knowledge structures possessed by
people and the inferential processes that operate upon those structures,
and are essential to our work,

The primary goal of the planning project is the development of a
model, or a series of models, of human performance on the software design
task. We intend to begin by modeling the protocols of experts on a
particular task, eventually extending the model to other levels of
experience and other tasks. To do this we will have to become more
Familiar with AGE and work on articulating our theory in a way that is
compatible with the AGE framework. This will involve two parallel lines of
effort. One is a deeper analysis of our protocol data, to increase our
knowledge of the detailed planning processes and knowledge structures
experts are using to solve these problems. The second is the development of
a model in AGE that can simulate these processes. We have to date been
using SUMEX only for the latter activity, but we are beginning discover
that both objectives are so intertwined that it is counter-productive for
us to be using separate computer systems. We have transferred much of our
protocol analyses activities to SUMEX, making it easier for us to share
this very rich data source with other investigators.

E. A. Feigenbaum 238 Privileged Communication
Section 9.2.3 Hierarchical Models of Human Cognition

Justification and Requirements for Continued SUMEX Use

The research of the prose comprehension project is clearly tied to
continued access to the AGE and UNITS packages, which are simply not
available elsewhere, We hope that our continued use of these systems will
be offset by the input we have been and will continue to provide to those
projects: our relationship has been symbiotic, and we look forward to its
continuation.

Needs and Plans for Other Computational Resources

We currently use three other computing systems, two of which are
local to the University of Colorado. One is the Department of Psychology's
CLIPR system, which is a Xerox Sigma 3 used primarily for the real-time
running of experiments to be modeled on SUMEX. The second is the
University of Colorado's CDC 6400, which is used for various types of
statistical analysis. Thirdly, the planning group has been using a PRIME
computer located at Science Applications, Incorporated for the storage and
analysis of protocols. -

CLIPR is about to replace the Sigma 3 with a VAX 11/780. When the
ARPA-sponsored Vax/Interlisp project is completed, we would be most
interested in experimenting with becoming a remote AGE/UNITS site. It would
seem that this sort of development is the ultimate goal of the package
projects, and this type of interaction, once it becomes feasible, would be
a logical extension of our association with the SUMEX facility.

Recommendations for Future Community and Resource Development

Our primary recommendation for future development within SUMEX
involves (a) the continued support of INTERLISP, which is needed for AGE
and for other work we have underway on SUMEX and (b) the continued
development of the AGE and UNITS projects. In particular, we would like to
see an extension of AGE to include a wider variety of control structures so
that our psychological models would not be confined to one particular view
of knowledge-based processing.

Given our imminent acquisition of a VAX, we would particularly
Support the ongoing and continued development of INTERLISP for the VAX, so
that local use of AGE and UNITS would be possible. Since we, as well as
other psychologists, need the real-time capability of VAX/VMS to run on-
line experiments, we hope that the INTERLISP system to be developed will be
compatible with VMS. Note that this need for real-time work coincides with
real-world applications of SUMEX programs, in which a VAX might be devoted
to both real-time patient monitoring and diagnostic systems such as PUFF or
MYCIN.

Privileged Communication 239 E. A. Feigenbaum
HMF - Higher Mental Functions Section 9.2.4

9.2.4 HMF - Higher Mental Functions

Higher Mental Functions Project

Kenneth Mark Colby, M.D.
Professor of Psychiatry and Computer Science
Neuropsychiatric Institute
University of California at Los Angeles

I. Summary of Research Program
A. Project rationale

The rationale of this project is to contribute new knowledge and
instruments to the fields of psychiatry, neurology, and communication
disorders using the concepts and methods of artificial intelligence. The
project is involved in studies of paranoid conditions, psychiatric
taxonomy, intelligent speech prostheses, ideographics for language
generation, and computer enhancement of patient outcomes in large mental
hospitals.

B.. Medical relevance and collaboration.

As can be seen from the above description, the project has clear
medical relevance. The project collaborates with psychiatrists,
neurologists, speech pathologists and biomedical engineers. Besides
working at the UCLA Neuropsychiatric Institute, the project collaborates
with the Northridge Hospital Foundation, Northridge, California.

C. Highlights of research progress.

In collaboration with three psychiatrists and four psychologists we
are working out a new taxonomy for the "neuroses", a category which is
notoriously unreliable in the psychiatric classification scheme. In this
pilot study we are collecting data on 50 patients and 70 controls. One
segment of data is provided by the subjects’ self-accounts which are
analyzed by a large program run on the SUMEX facility. This program finds
the key ideas in the subject's account and assigns him a profile. The
profiles will be clustered into groups and the groups compared to those
formed on the basis of the other data-collections in the study. During the
past year, the project has developed intelligent speech prostheses (ISPs)
which (a) utilize a lexical-semantic word-finding algorithm for anomic
aphasias and (b) utilize ocular control for the generation of synthesized
Speech. These devices serve as aids to nonvocal patients handicapped by
Strokes, tumors, cerebral palsy, and tracheostomies.

The word-finding algorithm is dynamically re-organized by the user's
selection of words. It is currently being tested on a 54-year-old man with
an almost complete anomia due to a stroke in the left hemisphere. The
algorithm needs a larger memory to accommodate at least 5,000 English
words. The large dictionary on the SUMEX facility is of great help in
constructing the lexical-semantic memory,

E. A. Feigenbaum 240 Privileged Communication
Section 9.2.4 HMF - Higher Mental Functions

We have just begun to test the use of ocular control of an ISP. The
‘patient wears specially designed spectacles which can detect where the eye
is directed on a small TV screen. Thus the patient spells out words by
looking at letters on the screen. Signals from the spectacles are sent to
the ISP which generates the utterance of the words thus spelled.

Although we have ceased to work on the paranoid PARRY program, due to
Tack of funding, it is available for demonstration and study by those
interested in modelling psychiatric syndromes.

We are in the planning stages of developing a computer ideographic
writing system for language generation by nonspeaking patients who cannot
spell. If they can learn ideographic symbols which stand for certain
concepts and construct the symbols on a graphics terminal by pressing keys,
a translating program will convert the symbols into English words which in
turn will be spoken by an ISP. We are also beginning to design a type of
computerized “recreational-educative" therapy for patients in large mental
hospitals with such a shortage of professional manpower that the patients'
treatment is limited mainly to custodial care.

D. List of Relevant Publications.

Colby, K. M., Christinaz, D., Graham, S. 1978. A computer-driven personal,
portable, and intelligent speech prosthesis. Computers and Biomedical
Research, 11: 337-343,

Colby, K. M. 1979. Computer simulation and artificial intelligence in
psychiatry. In Methods of Biobehavioral Research E. A. Serafetinides,
(ed.), New York: Grune and Stratton.

Colby, K. M. 1980. Computer psychotherapists. In Technology in Mental
Health Care Delivery Systems, J. B. Sidowski, J. H. Johnson, T. A.
Williams (Eds.). Norwood, New Jersey: Ablex Publishing Corporation.

 

Heiser, J. F., Colby, K. M., Faught, W. S., Parkison, R. C. 1980. Can
psychiatrists distinguish a computer simulation of paranoia from the
real thing? The limitations of Turing-like tests as measures of the
adequacy of simulations. Journal of Psychiatric Research, Vol. 15, No.
3

Parkison, R. C. 1980. An effective computational approach to the

comprehension of purposeful English dialogue. Stanford University,
Ph.D. dissertation, (forthcoming).

Colby, K. M., Christinaz, D., Graham, S., Parkison, R. C. A word- finding

algorithm using a dynamic lexical- semantic memory for patients with
anomia. (In press)

Privileged Communication 241 E. A. Feigenbaum
HMF - Higher Mental Functions Section 9.2.4

E. Funding Support.
1. Titles of grants
a) Intelligent Speech Prosthesis
b) Ocular control of Intelligent Speech Prosthesis.
2. Principal Investigator
Kenneth Mark Colby, M.D.
Professor of Psychiatry and Computer Science
Neuropsychiatric Institute
University of California at Los Angeles
3. Funding agencies

a) Intelligent Systems Program, Division of Mathematics and
Computer Science, National Science Foundation.

b}) Science and Technology to Aid the Handicapped Program,
National Science Foundation.

4. Grant numbers
a) NSF-MCS 78-09900
b) NSF PFR - 17358
5. Total award period
a) 6/1/78 - 11/30/80 $135,260.
b) 10/1/79 - 3/31/81 $318,368.
6. Current period
(see 5. above)
II. Interactions with the SUMEX-AIM Resource

A. The project communicates and collaborates with the Communication
Enhancement Project at Michigan State University, John Eulenberg, Principal
Investigator.

B. The project communicates with the SUMEX project at the University
of Texas at Galveston, John F. Heiser, M.D., Principal Investigator, who
experiments with and demonstrates the PARRY program,

C. Critique of resource management. The SUMEX staff is still

excellent and responsive to our needs. Our only problems are with the
telephone company portion of our communications link with SUMEX.

E. A. Feigenbaum 242 Privileged Communication
Section 9.2.4 HMF - Higher Mental Functions

TII. Research Plans (8/80 - 7/86)
A. Project goals and plans
1. Near-term

We plan to continue to work on the problems described above. Further
clinical experience is necessary in testing and developing the word-finding
algorithm and the ocularly-controlled ISP. These efforts should be
completed in about two years.

2. Long-range

It will take years to solve the problems of psychiatric taxonomy,
computer ideographic writing systems, and computer enhancement of
hospitalized patient outcome. Our work in these areas will depend upon
obtaining the requisite funding.

B. Justification for continued SUMEX use,

All the problems we work on involve natural language in some form or
other. We analyze natural language input and generate natural language
output. These efforts require large dictionaries and large LISP programs
which run at SUMEX. No comparable facilities are available at UCLA. Hence
we are heavily dependent upon SUMEX for the continuation of this research.

C. Needs and plans for other computer resources.

An ISP consists of a microprocessor interfaced with a speech
Synthesizre. We have constructed 3 ISPs, building two of the
microprocessors ourselves. We expect to purchase another microprocessor
and a graphics terminal.

D. Recommendations for future development.

The SUMEX system is often heavily loaded during daytime hours. The
batch facility permits us to run some large production jobs overnight
unattended, but the daytime loading is often so great that it discourages
even small interactive jobs, such as text editing. It would be very
helpful to have more computing power during the daytime, if funding is
available.

Privileged Communication 243 E. A. Feigenbaum
INTERNIST Project Section 9.2.5
9.2.5 INTERNIST Project

INTERNIST Project

J. D. Myers, M.D. and H. Pople, Ph.D.
University of Pittsburgh
Pittsburgh, Pennsylvania

I. Summary of Research Program
A. Medical Rationale

The principal objective of this project is the development of a high-
level computer diagnostic program in the broad field of internal medicine
as an aid in the solution of complex and complicated diagnostic problems.
To be effective, the program must be capable of multiple diagnoses (related
or independent) in.a given patient.

A major achievement of this research undertaking has been the design
of a program called INTERNIST, along with an extensive medical data base
now encompassing almost 500 diseases and more than 3,000 manifestations of
disease.

Although this consultative program is designed primarily to aid
skilled internists in complicated medical problems, the program may have
spin-off as a diagnostic and triage aid to physicians assistants, rural
heaith clinics, military medicine and space travel.

Development of the system which we now call INTERNIST-I was begun
about eight years ago. The system was successfully demonstrated for the
first time in 1974 and has been used since that time in the analysis of
hundreds of clinical problems. ;

; A major point of departure for the design of the original INTERNIST
program was the realization that the task of clinical decision making in
internal medicine is an ill-structured problem. In other domains, the task
of diagnosis is often viewed as one of pattern recognition or
discrimination: there is available a predefined collection of possible
classifications (characterizing disease entities or clinical states), one
and only one of which is considered possible in the case being studied. A
diagnostic problem solver dealing with such a well structured domain has
the fairly straightforward task of selecting that one of this fixed set of
alternatives which best fits the facts of the case. Many statistical,
pattern recognition, and algorithmic techniques have been employed
successfully in performing computer aided diagnosis in these well
Structured clinical problem domains.

Primarily because complex cases often involve two or more
concurrently active disease processes, no set of exhaustive and mutually
exclusive classifications can be developed to structure the diagnostic
problem in internal medicine. In principle, it might be argued that this

E. A. Feigenbaum 244 Privileged Communication
Section 9,2.5 INTERNIST Project

more complex problem domain could be reduced to a simple discrimination -
task if, in addition to the individual disease entities, one includes
appropriate multiple disease complexes in the set of allowable patient
descriptors. However, since our experience indicates that as many as ten
or twelve individual descriptors may apply in a complex clinical problem,
and considering that there are a thousand or more individual descriptors of
interest in Internal Medicine, the prospect of recording explicitly ail
possible multiple disease classifications is clearly infeasible.

Our thesis is that, in the absence of explicit structure derived from
the problem domain, the successful clinician engages in heuristic
imposition of structure so that effective problem solving strategies might
be selected and employed for decision making relative to the postulated
problem structure.

In INTERNIST-I, this concept of heuristic imposition of structure is
expressed primarily by means of a novel "problem-formation" heuristic. In
effect, the program composes dynamically, on the basis of evidence
provided, what in context constitutes a presumed exhaustive and mutually
exclusive subset of disease entities that can explain, more or less equally
well, some significant subset of the observed findings in a clinical case.
This heuristic problem structuring procedure is invoked repeatedly during
the course of a diagnostic consultation in order to deal sequentially with
the component parts of a complex clinical problem.

Because INTERNIST is intended to serve a consulting role in medical
diagnosis, it has been challenged with a wide variety of difficult clinical
problems: cases published in the medical journals, coc's, and other
interesting and unusual problems arising in the local teaching hospitals.
In the great majority of these test cases, the problem-formation strategy
of INTERNIST has proved to be effective in sorting out the pieces of the
puzzle and coming to a correct diagnosis, involving in some cases as many
as a dozen disease entities.

On the basis of this extensive test of the initial INTERNIST system,
it has become clear that many aspects of the system's performance could be
significantly enhanced if it would be possible to deal with the various
component problems and their interrelationships simultaneously. This has
led to the design of INTERNIST-II, a system embodying strategies of
concurrent problem-formation which we expect will yield more rapid
convergence to the correct diagnosis in many cases, and in at least some
cases provide more acceptable diagnostic behavior.

B. Medical relevance and collaboration
The program inherently has direct and substantial medical relevance.
The institution of collaborative studies with other institutions has

been deferred pending completion of the programs and knowledge base
enhancements required for INTERNIST-II,

Privileged Communication 245 E. A. Feigenbaum
INTERNIST Project . Section 9.2.5.

C. Highlights of research progress
Accomplishments this past year

During the past year, the R & D activities of the INTERNIST project
have concentrated on three major problem areas associated with the original
implementation of INTERNIST. These areas are:

a) restructuring of the underlying diagnostic logic of INTERNIST to
conform more closely to the expectations of clinician users of the
System. The primary goal in developing a new model of diagnostic
reasoning is to achieve a concurrent problem formation capability in
order that improved scoring methods and attention to the principle
of parsimony might be exploited in focusing the attention of
INTERNIST on regions of the problem space having the greatest
potential for yielding a solution. Moreover, the new approach has
the potential for improved modes of interaction with the user, as it
can reveal at any point in its analysis the multiple partial
characterizations that have been postulated, and expose the space of
alternative complex descriptions that can be generated by combining
these partial characterizations. The potential for providing
justification and explanation of the system's behavior is thereby
greatly enhanced.

b) development of a friendlier user interface, enabling use of the
system by clinicians unfamiliar with the specifics of the INTERNIST
vocabulary. One of the barriers to successful implementation of the
original INTERNIST system in a ward setting is the language of
discourse used in that system for specifying the positive and
negative findings in a clinical case. The number of possible
findings that might be entered now numbers more than three thousand;
thus some means for convenient browsing among these possible
entries, and some convenient means for communicating the selected
items to INTERNIST had to be found. We have developed for this
purpose a menu-selection front end system, that comprises a network
of approximately 1000 frames designed to permit selection of
pertinent facts that might be revealed by any of a host of
information acquisition procedures. Convenient escape mechanisms
have been provided to permit the user to alternate between the
interactive data entry and analytical components of the system.

c) incorporation of additional disease profiles and related medical
information in the INTERNIST knowledge base, to approach the
critical mass required for effective field tests of the system.

Research in Progress ©

There are five major components to the continuation of this research
project:

1) The completion, continued updating, refinement and testing of the
extensive medical knowledge base required for the operation of
INTERNIST.

E. A. Feigenbaum 246 Privileged Communication
Section 9.2.5 INTERNIST Project

2) The completion and implementation of the improved diagnostic
consulting program, which has been designed to overcome certain
performance problems identified during the past four years'
experience with the original INTERNIST program.

3) Institution of field trials of INTERNIST on the clinical services in
internal medicine at the Health Center of the University of
Pittsburgh.

4) Expansion of the clinical field trials to other university health
centers which have expressed interest in working with the system.

5) Adaptation of the diagnostic program and data base of INTERNIST to
subserve educational purposes and the evaluation of clinical
performance and competence.

D. List of relevant publications

1. Pople, H.E. "The Formation of Composite Hypotheses in Diagnostic
Problem Solving: An Exercise in Synthetic Reasoning", Proceedings of
the Fifth International Joint Conference on Artificial Intelligence,
Boston, August 1977.

2. Pople, H.E. "On the Knowledge Acquisition Process in Applied A.1I.
Systems", Report of Panel on Applications of A.I., Proceedings of Fifth
International Joint Conference on Artificial Intelligence, 1977.

3. Pople, H.E., Myers, J. D. & Miller, R.A. “The DIALOG Model of
Diagnostic Logic and its Use in Internal Medicine, Proceedings of the

Fourth International Joint Conference on Artificial Intelligence,
Tbilisi, USSR, September 1975.

4. Pople, H.E. "Artificial Intelligence Approaches to Computer-Based
Medical Consultation, Proceeding IEEE Intercon, New York, 1975.
E. Funding support

1. Title of grant.
Clinical Decision Systems Research Resource.

2. Harry E. Pople, Jr., Ph.D.
- Associate Professor of Business

Jack D. Myers, M.D.
University Professor (Medicine)
University of Pittsburgh

3. Division of Research Resources
National Institutes of Health

4. 5 R24 RRO1101-03

Privileged Communication 247 E. A. Feigenbaum
INTERNIST Project Section 9.2.5

5. 07/01/77-06/30/78
$160,414

07/01/78-06/30/79
$178,414

6. 07/01/79-06/30/80
$200,414

II. Interactions with the SUMEX-AIM Resource
A, B. Collaborations and Medical Use of Program Via SUMEX

INTERNIST remains in a stage of research and development. As noted
above, we are continuing to develop better computer programs to operate the
diagnostic system, and the knowledge base cannot be used very effectively
for collaborative purposes until it has reached a critical stage of
completion. These factors have stifled collaboration via SUMEX up to this
point and will continue to do so for the next year or two. In the
meanwhile, through the SUMEX community there continues to be an exchange of
information and states of progress. Such interactions particularly take
place at the annual AIM Workshop.

C. Critique of Resource Management

SUMEX has been an excellent resource for the development of
INTERNIST. Our large program is handled efficiently, effectively and
accurately. The staff at SUMEX have been uniformly supportive,
cooperative, and innovative in connection with our project's needs.

III. Research Plans (8/80-7/86)
A. Project Goals and Plans

We expect that the conversion of INTERNIST knowledge structures to
the form required by INTERNIST-II will be reasonably complete by the next
fiscal year (June 30, 1981). Shortly thereafter, provided adequate
hardware resources are available, we intend to commence formal field trials
of INTERNIST at the Presbyterian-University Hospital of Pittsburgh. This

local phase of the clinical evaluation will continue for approximately one
year,

Beginning in July 1982, we intend to extend the clinical trials to

collaborating institutions, with the addition of one additional user group
approximately every six months through June 1984.

E. A. Feigenbaum 248 Privileged Communication
Section 9.2.5 | INTERNIST Project

B. Justification and Requirements for Continued SUMEX Use

In order to provide the level of computer services required by the
expanded level of R & D activity in the near term, and to support the
schedule of field trial studies envisioned during the current five year
planning horizon, we have requested NIH support for a dedicated INTERNIST
machine to be acquired during the next fiscal year.

If this hardware support becomes available, we would not expect to
make additional demands on SUMEX-AIM for computing services. However, we
would continue to look to SUMEX for software support and for the
communications network that so effectively bridges the far-flung AIM
community.

Until such dedicated resources are in place, we would expect to make
use of the SUMEX-AIM facilities at a moderately increased level of
utilization.

Privileged Communication 249 E. A. Feigenbaum
PUFF/VM Project Section 9.2.6
9.2.6 PUFF/VM Project

PUFF/VM: Biomedical Knowledge Engineering in Clinical Medicine

John J. Osborn, M.D.
The Institutes of Medical Sciences (San Francisco)
Pacific Medical Center

and

Edward A. Feigenbaum, Ph.D.
Computer Science Department
Stanford University

The immediate goal of this project is the development of knowledge-
based programs to interpret physiological measurements made in clinical
medicine. The interpretations are intended to be used to aid in diagnostic
decision making and in therapeutic actions. The programs will operate
within medical domains which have well developed measurement technologies
and reasonably well understood procedures for interpretation of measured
resuits. The programs are:

(1) PUFF: the interpretation of standard pulmonary function
laboratory data which include measured flows, lung volumes,
pulmonary diffusion capacity and pulmonary mechanics, and

(2) VM: management of respiratory insufficiency in the intensive care
unit.

The second, but equally important, goal of this project is the
dissemination of Artificial Intelligence techniques and methodologies to
medical communities that are involved in computer aided medical diagnosis
and interpretation of patient data.

Funding support:

PUFF/VM is supported by NIH grant GM24669 for $164,000 from 1
September 1978 - 30 August 1981. Some indirect costs are included in this

total. A proposal for supplemental funding, submitted 1 February 1979, is
pending.

I. Summary Of Research Program

PUFF

A. Technical Goals

The task of PUFF program is to interpret standard measures of
pulmonary function. It is intended that PUFF produce a report for the |
patient record, explaining the clinical significance of measured test
results. PUFF also must provide a diagnosis of the presence and severity

E. A. Feigenbaum 250 Privileged Communication