Section 6.4.1 COMMUNICATION ENHANCEMENT PROJECT

converting our major software programs for speech generation and
adaptive inputs to the SUMEX AIM system in part so that they can be used
by Dr. Colby and his group. ,

2. Mr. Douglas Appelt, a doctoral student at SU-AI was our principal
systems programmer last summer. He is currently doing research in the
same area as ours with Dr. Gary Hendrix of SRI. We have used his
knowledge of your system (via the message sending routines) to assist us
in starting our project. Mr. Appelt will be working with us at MSU

again this summer (June-Sept.,1977), and he will be using the SUMEX-AIM
system.

C) Critique of resource services.

We have found the HELP files to be a lot of help. We are beginning to
understand our own needs and your services to the extent that it may be helpful
to meet with one of your staff. Dr. Eulenberg will be in California in early
June and plans to visit your facility. However, we have found that your system

is easy to use and do not feel more distant from you than from other computer
installations on our own campus.

III) Follow-on SUMEX grant period (8/73-7/83).

A) Long-range user project goals and plans.

We want to do fundamental research in artificial intelligence in the
context of the generation of speech from very minimal amounts of input. This
problem seems closely related to the understanding of speech. It seems that the
methods of representation of knowledge used for speech or vision understanding
can be used in a natural way for fluent generation of speech. Our area seems
almost unique in AI in that it is socially desirable (without question). Even

relatively primitive systems can improve the quality of life for hundreds of
thousands of people.

Major long range goals are:

1) To do research in transposing the vocal tract to another region of the
body in which an individual has suitable myoelectric control for the
generation of speech.

2) To define a suitable system of semantics and to encode world knowledge
in that system that would be useful for the generation of speech
fluently.

3) To discover primitive operations on semantics which allow new and
appropriate combinations of speech to be generated. (Using other sources
of knowledge.)

J. Lederberg 176 Privileged Communication
COMMUNICATION ENHANCEMENT PROJECT section 6.4.1

4)

5)

6)

7)

8)

9)

10)

11)

To develop means for individuals who are physically unable to use
standard input devices to program and personalize their own speech and
environmental control system.

To study means of using speech output to aid blind persons both throuzh
experiments with simplified text to speech devices and through means of
training blind persons to write in cursive and manuscript.

To study the educational consequences of communication aid systems for
individuals who, because of previous misdiagnoses as mentally impaired,
have been excluded for the mainstream education system.

To improve the prosodic qualities of generated speech, using its
semantic aspects.

To design portable speech prostheses which allow maximum use of state of
the art knowledge in speech generation.

To develop an experimental base for studing how the concepts which are

articulated in speech are manipulated by individuals at differing states
of mental organization

To study the potential for speech generation systems as a means of
stimulating autistic children,

To develop voice recognition systems which will aid individuals with
limited speech to develop their full potential.

(We don’t expect to finish all of these by 1983. )

B) Justification for continued use of SUMEX by your project.

1)

2)

3)

4)

5)

6)

Privileged Communication 177

we need to use many sources of knowledge represented in computers to do
our work, similar to many SUMEX users.

We know kindred spirits in the AI community for many of our long range
goals.

We have substantial hardware and software expertise which we are willing
to share.

We are making a substantial effort in the practical application of such
research and would expect to benefit society.

This area does not have a traditional means of support for research
separate from development which makes your support vital at this time.

Qur area is very interdisciplinary and the communication aspects of
SUMEX-AIM will be increasing valuable to us.

J. Lederberg
Section 6.4.1 COMMUNICATION ENHANCEMENT PROJECT

C) Comments and suggestions for future resource goals, ete.

In view of the fact that we are new members of the community, we do not
have any special suggestions for new resource goals at this time.

J. Lederberg ivi
Privileged Communication
AI IN PSYCHOPHARMACOLOGY Section 6.4.2

6.4.2

AL IN PSYCHOPHARMACOLOGY

Artificial Intelligence in Psychopharmacology

Jon F. deiser, M.D.
Dept. of Psychiatry and Human Benavior
University of California at Irvine

I. Summary Research Program

A. Technical Goals

1.

Privileged Communication 179

We propose to construct a computer based system embodying some of the
knowledge of an expert in clinical psychopharmacology. Such a system
could greatly assist physicians and students who are not specialists
in the chemotherapy of mental disorders in choosing the best
psychopharmacological treatment for patients for whom such treatment
is indicated. The system could also serve as a teaching source of
psychodiagnostic and psychopharmacological knowledge.

The specific aims of this project are:

Oo To develop a set of MYCIN type rules which are a model of expert
clinical teaching, consulting and decision-making for clinical
psychopharmacology.

o To implement this set of rules in the MYCIN system, and

o To evaluate the performance of the resulting system as a teaching
and consulting aid.

No system currently available or under development approaches the
goals of the project in the field of clinical osychopharmacology.

It is anticipated that the research will .fall into two distinet
phases each of approximately 138 months duration. The first and
current phase involves evaluating the relevance of the structure of
the HYCIN system for use in clinical psychopharmacology by replacing
the current infectious disease diagnosis and therapy rules and
parameters with psychopharmacology rules and parameters. The second
phase will involve accumulating a large body of rules and entering
them into the MYCIN system and evaluating their performance. Toward
the end of this phase, the behavior of the system will be compared
with the behavior of recognized experts workinz on the Adult
Inpatient Psychiatric Service of the UCI Medical Center. This
evaluation will focus on the adequacy of the system for representing
the knowledge of a skilled psychopharmacolozist rather than an actual
system performance in the clinical framework.

J. Lederberg
Section 6.4.2

J.

AI IN PSYCHOPHARMACOLOGY

B. Medical Relevance and Collaboration

1.

Lederberg

Medical Relevance

a.

For many years it has been well recognized that potent, effective
psychopharmacological agents are frequently used in an
unsystematic and irrational manner. The most prescribed
medication in the United States today is diazepam (Valium), a
minor tranguilizer. The first six most prescribed medications
are all psychoactive agents. In California, instances of
repetitive use of psychotropic drugs have been reported by 70% of
a random sample of adults. About 30% of the sample had used
psychotropic drugs in the preceding twelve months. Another study
showed that 20% of a medical population was taking psychoactive
agents at any given time. These figures do not include alcoholic
beverages or non-prescription and illicit drugs with psychoactive
properties. Many persons are advised to ingest a daily
pharmacologic stew consisting of one or more neuroleptic agents,
an antidepressant, an anti-parkinsonian agent, one or more
tranquilizers, a hypnotic and possibly a psychostimulant. These
regimens are often complicated by non-prescription remedies,
alcoholic beverages and illicit drugs. The inevitable drug-drug
interactions affect absorption, distribution, binding metabolism
and excretion of many drugs.

Each year Americans spend over $700,000,000 for psychotropic
drugs. In a recent year $150,000,009 was spent on the anti-
anxiety agent chlordiazepoxide (Librium). Between 20 and 25
million prescriptions are written each year for diazepam. It is
estimated that 170,000,000 prescriptions for psychotropic drugs
were written in 1967, and that 202,000,000 prescriptions were
written in 1970, more than one for every person in the United
States. About 17% of all orescriptions written are for
psychoactive drugs. If we include medications in which a
psychotropic drug is combined with an antispasmodic vasodialator,
or other agent, probably 25% of all prescriptions contain
psychotropic drugs. The vast majority of these prescriptions are
written by physicians who are not psychiatrists.

Many physicians, including psychiatrists, who are practicing
today, completed their formal medical training prior to the
1950°s when modern psychopharnacological agents first became
available. Their training typically includes no instruction in
modern clinical psychopnarmacolosy. Even physicians trained
since the mid~1950°s cannot be expected to keep abreast of the
expanding and changing field of psychopharmacology. The
principles and practices recommended a few years azo are rapidly
becoming obsolete. A recent study showed that the general
knowledge of the pharmacology, physiology, and side effects of
psycnoactive medications was low in both psychiatrists and non-
psychiatrists: less than 29% of the physician subjects were able
to devise a psychopharmacologically rational dosage schedule for
benzodiazepines. Fifty percent of the non-psychiatrist medical

185 Privileged Communication
AI IN PSYCHOPHARMACOLOGY Section 6.4.2

2.

a

1.

Privileged Communication 181

staff felt that doses up to one gram per day of a tricyclic
antidepressant, more than three times the recommended maximum and
a potentially fatal amount, might be prescribed for depressive
symptoms.

d. We estimate that there are at least 25 diserete syndromes
currently identified in clinical psychiatry, each of which has a
unique hierarchy of pharmacological treatment. Each treatment in
each section has its own set of potential side effects, adverse
reactions and drug-drug, drug-host, drug-age and drug-state of
health interaction. In addition, for each therapeutic regimen in
each hierarchy, there are several classes of drugs which
typically consist of more than one agent or combination of agents
which are potentially beneficial and which can be preferentially
ranked dependent on several other factors in the clinical
situation.

Medical Collaboration

1. The principal investigator, Jon F. Heiser, 4.D., is a physician
who is board certified in psychiatry and in full time teaching,
research and University service.

2. Three medical students have participated in this project to date:
Clifford Risk, Dana W. Ludwig, and Sue A. Clear. 3. Two
resident physicians have participated in this project: Bronco R.
Rnadisavljevic, M.D., and Steven J. Smith, M.D.

4. A Doctor of Pharmacy participates in the research: Pierre J.
Menard, Pnarm. D.

C. Progress Summary

Our initial endeavors to extend a MYCIN-like system to clinical
psychopharmacology have been successful. None of the envisioned or
predicted problems related to the vagaries of psychiatric terninology
and diagnosis have materialized. The system apoears to work promptly
and accurately to diagnose psychiatric conditions, and in a very
rudimentary form, to suggest appropriate pharmacological treatment.

The current system consists of about 20 clinical parameters and about

50 decision rules aimed chiefly at a small number of diagnosed
psychiatric conditions.

J. Lederberg
section 6.4.2 AI IN PSYCHOPHARMACOLOGY

The following is an example of a sanple consultation but realistic
case:

sample Consultation with HEADMED, a Psychopoharmacology Advisory Systea

Patient History

A 37 year old man was brought into the emergency room by his distraught
family members. They described how the patient, a well-liked, successful
and cheerful but reserved history professor, had become increasingly
outspoken, short-tempered, and inattentive to accepted norms of social
behavior over the preceding three weeks. An unprovoked argument and physical

assault upon a long-time friend motivated the family to seek professional
nelp.

Results of a physical exam and routine laboratory studies were within
normal limits. Consultation with the psychiatric service was requested.
A first year psychiatric resident re-interviewed the patient and his
family, and completed a formal mental status exam prior to obtaining the
following consultation from the system.

{Questions are generated by the system and appear in mixed upper and lower
case, user responses are in boldface capitals and follow a double asterisk.
Added commentary is indented in italics.]

HHA RARE REAR

Special options (type for help):

#* AFB

Hello, Dr. Bowen

Do you wish to run the consultation progran
# EYES

29-OCT-76 00:47:26

wee enn PATIENT~1--~------
1) PATIENT’S NAME [The consultation begins with a few standard
questions. ]

*8 JOHN DOE

2) PATIENT’S AGE IN YEARS

#8 37

3) SEX:

#* MALE

4) IS John Doe ORIENTED

Re N
[Since the patient is disoriented, the system begins to
Probe a little deeper .]

5) IS John DOE DISORIENTED-TO-PERSON

RE y

6) IS Jonn Doe DISORIENTED-TO-PLACE

#2 N

7) IS John Doe DISORIENTED-TO-TIME
KR Y

J. Lederberg 182 Privileged Communication
AI IN PSYCHOPHARMACOLOGY Section 6.4.2

8) PLEASE TYPE IN THE ONE WORD WHICH BEST DESCRIBES THE THOUGHT PATTERNS
OR THOUGHT DISORDER OF John Doe
** CONFUSED
CONFUSED not a recognized response
What is THE THOUGHT PATTERN OR THOUGHT DISORDER OF John Doe
Expected responses are: NORMAL PROLIXIC TANGENTIAL CONFABULATION ETC>
Enter HELP for list of user options.

[The initial response was incorrect, so the user was reminded of
some of the correct responses. He then requests a display of the
entire list. Note that both of these capabilities are part of the
core of MYCIN itself. Applying it to this new domain required
more than supplying the relevant list of acceptable answers. ]

RX 9

Expected responses are: NORMAL PROLIXIC TANGENTIAL CONF ABULATION

RETARDED LOOSE CONCRETE AUTISTIC DELUSIONAL WORD-SALAD MANICY MUTE

Enter HELP for list of user options.

®* TANGENTIAL

9) Has any biological relative of John Doe been evaluated or treated
for a mental or psychiatric problem

#8 N

10) What is the single word which best describes John Doe’s behavior
He
What is the best single word description of John Doe’s behavior

Expected responses are: NORMAL AVERAGE UNREMARKABLE CATATONIC-EXCITEMENT
ete.

Enter HELP for list of user options.

®* HYPERACTIVE

11) What is the single word which best describes John Doe’s mood

** LABILE

12) WHAT IS THE SINGLE WORD WHICH BEST DESCRIBES THE EMOTIONS OR FEELINGS
OF John Doe

#* SLATED

13) Does John Doe tend to feel worse or be more symptomatic for the

first several hours after awakening for the day
*& WHY

i.e. WHY is it important to determine whether or not PATIENT-1 tends

to feel worse or be more symptomatic for the first several hours
after awakening for the day}

[4.0] This will aid in determining the DIAGNOSIS OF PATIENT-1.
if
[4.1] John Doe tends to feel worse or be more symptomatic for
the first several hours after awakening for the day
then
there is weakly suggestive evidence (.45) that THS DIAGNOSIS OF
john doe is depression
[ RULEO 17 ]

[All the standard explanatory capabilities of tne core system extend
to the new domain without additional programming effort.]

Privileged Communication 183 J. Lederberg
Section 6.4.2 AI IN PSYCHOPHARMACOLOGY

[back to question 13...]

¥# N

14) Does John Doe have early morning insomnia

#e W

15) Please specify the number of pounds that John Doe lost or gained
in the 2 months prior to seeking medical or psycniatric help.
Estimate if necessary. Precede weight LOSS with a MINUS sign (for
example: -~8 ~ a weight loss of (approximately) 8 pounds within the
2 month period prior to seeking professional help)

EHS
16) Has psychological testing been ordered on John Doe
¥% N

17) ARE THE PERCEPTIONS OF John Doe NORMAL, i.e., NEITHER DISTORTED
NOR DISORDERED

#% N

18) DOES John Doe HAVE DEPERSONALIZATION

eH ON

19) DOES John Doe HAVE EXPERIENCES OF ALIENATION and/or EXPERIENCES OF
INFLUENCE

#2 N

20) DOES John Doe HAVE INCOMPLETE AUDITORY HALLUCINATIONS and/or OTHER
HALLUCINATIONS

#2 Y

21) DOES John Doe HAVE COMPLETE AUDITORY HALLUCINATIONS and/or THOUGHT
BROADCASTING

#4 N :

22) what is John Doe’s level of consciousness

Hx

What is THE LEVEL OF CONSCIOUSNESS OF John Doe

Expected responses are: HYPERALERT VIGILANT ALERT NORMAL etc.

Enter HELP for list of user options.

#2 VIGILANT

23) Is this the first episode of significant mental disturbance that
john doe has had

**% WHY

fi.e. WHY is it important to determine whether or not this is PATIENT-1’s
first episode of significant mental disturbance}

[8.0] This will aid in determining THE TREATMENT NAME OF PATIENT-1.

if
[8.1] THE DIAGNOSIS OF John Doe is mania, and
[8.2] this is not John Doe’s first episode of significant mental

disturbance

then
there is strongly suggestive evidence (.9) that THE TREATMENT
NAME OF John Doe is lithium

{ RULEO71]

[back to question 23...]
[The system has finished with the diagnostic phase, and asks a

question to help determine the appropriate therapy.]
a% Y

J. Lederberg 184 Privileged Communication
AI IN PSYCHOPHARMACOLOGY Seetion 6.4.2

{And finally the system presents its diagnosis and therapy recommendations.

The numbers are used to give relative weightings to the conelusions:
negative numbers indicate that the evidence tends to rule out that
possibility.]

Tne diagnosis for patient 1 is:

ORGANIC-BRAIN-SYNDROME (.84)

DEPRESSION (.37)
MANTA (.35)
SCHIZOPHRENIA (.2)
PERSONALITY-DISORDER (-.4)
NEUROSIS (-.4)

So the treatment should be

D. Up

1.

2.

Privileged

EVALUATION ( .84)
ANTIDEPRESSANT (.3)
NEUROLEPTIC (.28)

Recently work has been directed toward expanding the system and
revising the representation of psychiatric diagnosis and treatment
recommendation.

We have also begun development of a small system to score the
Minnesota Multiphasic Personality Inventory (MMPI) psychological test
using empirically well established rules easily coded into the MYCIN
system.

to date list of publications.
No reports of this work have been published to date.
Heiser, J.F. Computer-Aided Diagnosis of Psychiatric Patients.
Presented to the Research Meeting, Sehool of Engineering, University

of California, Irvine, 7 October 1976.

Brooks, R. E. and Heiser, J.F. An Application of Artificial
Intelligence to Psychiatry. Presented to:

(a) Indian Institute of Technology, Madris, India,
28 September 1976, and

(b) Madris Christian College, Madris, India, 3 October 1976.
Heiser, J.F. and Brooks, R. E. Artificial Intelligence in

Psycnopharmacology. Accepted for presentation at the VI World
Congress of Psychiatry, Honolulu, Hawaii, 23 August - 3 October 1976.

Communication 185 J. Lederberg
Section 6.4.2

J.

AL IN PS¥CHOPHARMACOLOGY

E. Funding Status

1.

2.

Lederberg

Current Funding

a.

Personnel

x. The principal investigator, Jon F. Heiser, M.D., co-
investigator Ruven E. Brooks, Ph.=., and Pharmacist, Pierre
J. Menard, Pharm. D., are full time employees of the
University of California, Irvine.

ii. Resident pnysicians are employees of the University of
California Irvine and the Long Beach Veterans Administration
Hospital and have worked on this project during elective
periods of their psychiatric residency for which they
received training credit.

iii. Medical students working on this project either participated

for academic credit during elective periods or were supported
by National Institute for Mental Health fellowshios for
medical student research.

iv. Two undergraduate students (Tnomas E. Holthus, and Darryl
Hansen) are also working on this project for academic credit
during elective periods.)

v. Additional supporting staff such as secretaries are supplied
by the University of California Irvine.

Office space, supplies and equipment ineluding several data
terminals with acoustic couplers, are supplied by the University
of California Irvine.

lo other sources of funds are currently being used.

Pending applications and renewals

a.

A joint grant application (in collaboration with Dr. Bruce
Buchanan, Stanford University) has been submitted to the
Department of Health, Education, and Welfare; Public Health
Service. The University of California, Irvine (Dr. Jon Heiser,
Principal Investigator) part of the application requests a total
budget of $147,655 over three years to begin July 1, 1977, with
$46,423 requested for the first year.

An additional financial support for undergraduate student Thomas
E. Holthus has been requested through funds allocated to
University of California Irvine by tne National Science
Foundation (NSF) to assist in the development of new research
workers.

136 Privileged Communication
AL IN PSYCHOPHARMACOLOGY Section 6.4.2

Ii. Interactions with the SUMEY-AIM resource
A. Examples of collaboration and medical use of programs via SUMEX

1. As explained fully in the attached research grant application, the
MYCIN group has been working informally with Dr. Heiser on the
development of a knowledge base of decision criteria for
psychopharmacology over the past two years.

B. Examples of sharing, contacts, and cross-fertilization with other
SUMEX-AIM projects (via workshops, system facilities, personal
contacts, ete.)

1. Dr. Heiser’s introduction to the SUMEX-AIM project first occurred
at the first AIM workshop held at Rutgers in June 1975.

2. Although Dr. Heiser had previously neard of the MYCIN project, his
official collaboration with MYCIN resulted from discussions
originating at the first AIM Worksnop.

3. A collaborative experiment with Kenneth Mark Colby, M.D., and
members of the PARRY project was developed, implemented and
analyzed completely on SUMEX-~AIM. Enclosed is a rouzh draft of a
paper reporting this "Turing Test" which was performed on-line on
SUMEX, with the psychiatrist-judges located at Irvine, the patient-
person at UCLA and PARRY at SUMEX.

4. Much technical support has been received freely and continuously
from the SUMEX staff and members of the MYCIN team, including basic
instruction in the use of SUMEX, TENEX, and MYCIN, principles of
knowledge representation in MYCIN, and on-going consultation for
details of implementing HEADMED in MYCIN.

Much information has been obtained during three visits to to SUMRYX
and NYCIN, but daily work in this project would be impossible
without the ability to converse via links, messages, and telephone
conversations with members of the SUMEX and MYCIN staffs.
C. Critique of User Services

It is difficult for naive users to acquire the necessary Knowledge and

Skills to function effectively in SUMEX without making a site visit to

SUHEX.

Ill. Follow on SUMEX grant period (8/78 ~ 7/83)

A. Longs range user project goals and plans.

It will probably take at least five years to achieve the aims mentioned
in "IT.A." above. If limiting conditions in the application of MYCIN to

Privileged Communication 187 J. Lederberg
Section 6.4.2 AI IN PSYCHOPHARMACOLOGY

the domain of clinical psychopharmacology are encountered, alternative
systems for achieving the same goals may be developed. If progress is
straight forward and completed in less than five years, attempts will
be made to enrich the system with deeper models of the nature of
psychiatric disorders and the action of psychopharmacological
substances. Also, if the system works well using UCI psychiatrists and
patients, consultation with a panel of national experts will be
developed to increase the generality and power of the rule base.

B. Justification for continued use of SUMEX by your project.

We believe that this collaboration between the Stanford University
MYCIN group, the University of Arizona infectious disease group, and
the University of California at Irvine psychopharmacology group offers
a unique opportunity to study the decision-making process in two
domains: the chemotherapy of infectious diseases and the chemotherapy
of psychiatric disorders. We believe that this methodological approach

will markedly increase the potential range of applicability of our
work,

C. Comments and Suggestions for Future Resource Goals, and
Development Effort.

For those not geographically located at the SUMEX site, a stress on
additional aid to users in the form of increasing the staff of user
consultants, documentation writers, ete., would be preferable to an
exclusive stress on additional hardware acquisition.

J. Lederberg 188 Privileged Communication
ORGAN CULTURE PROJECT Section 6.4.3

6.4.3 ORGAN CULTURE PROJ#CT

 

Application of Computer Science to Organ Culture

Professor Robert K. Lindsay and Dr. Maija “ibens
The University of Michigan, Ann Arbor

I) Summary of research program

The goal of this research project is to develop new methods for the design
and analysis of organ culture experiments, using techniques of artificial
intelligence,

The cultivation of organ fragments is an important method for the study of
disease processes. In contrast to cell culture, organ culture is designed to.
lahibit outgrowth of cells and to deal with normal tissue relationships as they
exist in the body, divorced from the complexities or organ interaction. The
technique involves the maintenance of differentiated cells as a group within
their normally associated tissues. With an ability to maintain differentiated
tissues in culture, a direct histologic and biochemical assessnent of factors
influencing an organ is possible. Such a biologic model would permit
investigation of the structural and functional effects of various substances
directly on the target organ. With a chemically defined medium, the technique
would allow a simultaneous evaluation of metabolites or hormones released by the
organ fragments.

The research is being done in collaboration with Professors Raymond Kahn,
Theodore Fischer, and William Burkel of the Department of Anatomy, the University
of Michigan Medical School.

We have been working on methods of image analysis of microscope slides.
This has been approached from two directions. On the one hand we are writing
programs for special image analysis hardware. These programs will calculate
various indices of the condition of the cultivated organ fragments based upon
measured morphological features. The second approach is to translate the
biologist’s verbal descriptions of microscope slides into computer data
structures which encode conditions not detectable by our inage analysis programs,
though readily seen and reported by trained human observers. We have developed a
dictionary of anatomical terms and programs for morphological analysis. At
present we are working on the syntactic analysis of the scientist’s verbal
descriptions.

A grant application titled "Application of Computer Science to Organ
Culture" has been written and will be submitted to the National Institutes of

Health on June 1, 1977. Current support is from the University of Michigan with
computer services supplied by SUMEX-AIM.

Privileged Communication 189 J. Lederberg
Section 6.4.3 ORGAN CULTURE PROJECT

It) Interactions with the SUMEX-AIM resource

We have had valuable contacts with memoers of the DENDRAL project and the
MOLGEN project, which share certain goals and methods with our own work.

The resource services received from SUMEX-AIM continue to be excellent. The
staff is very helpful, and the system is well-maintained and reliable. The only

serious difficulties which arise are due to system saturation and limited file
space.

IIIf) Follow-on SUMEX grant period

Our proposal, if funded, would commit us to expanding our efforts to
develop a histology knowledge base and methods to rationalize the design of organ
culture experiments. This would involve heavier use by a larger group of the
SUMEX-AIM resource. Our work to date, though of limited scope, is encouraging.
The work is dependent upon continued availability of the SUMEX-AIM system, which
we would like to see expanded not only to provide more services for present
projects, but to include a wider range of relevant bio-medical and artificial
intelligence research. The commonality of resource and the opportunities for
communication which SUMEX-~AIM provides are extremely valuable in our view. Given
the community of resource consumers attracted py SUMEX-AIM, we think it would be
an excellent focus for the encouragement of new techniques, new ideas in
prograuming languages, and increased variety of input and output media.

J. Lederberg 199 Privilesed Communication
NEUROPROSTHESES PROJECT Section 6.4.4

6.4.4 NEUROPROSTHESES PROJECT

 

Neuroprostheses Project

M. G. Mladejovsky, Ph.D., Director
Division of Artificial Organs
University of Utah Medical Center
Salt Lake City, Utah 34112

I. Research Summary

Qur research involves the investigation of artificial vision by electrical
Stimulation of visual cortex and artificial hearing by electrical stimulation of
the cochlea. This effort has involved the collaboration of several people from
many disciplines, not only from the University of Utah, but also from the Ear
Research Institute, Los Angeles; University of Western Ontario, London, Ontario;
and Columbia University, New York.

The instrumentation involved is controlled by a minicomputer system
consisting of a PDP-8 and a PDP-11/05. Experimental protocols are implemented by
programs running. in the PDP-~11. We sought access to SUMEX in order to use the
BLISS~11 compiler which runs on the PDP-10. We are using BLISS-11 as the
implementation language for an interactive programming system which will enable
more flexible control and variation of our experiments.

The base language we are using is BALM (Malcolm Harrison, "BALM
Programmer’s Manual", Courant Institute, NYU, 1974). This language is defined in
terms of an abstract machine called the MBALM machine. The plan of attack is as
follows:

1) implement the MBALM machine in BLISS-11

2) bring up BALM, using a dummy garbage collector and no
virtual menory

3) implement garbage collection and virtual memory

4) add floating point operations

5) add a graphics package

5) add real~time capabilities

7) provide an interface to PDP-11 machine language

The project has progressed to the point that step 2 is almost complete.
This has involved installing a new version of BLISS-11 at SUMEX, writing software
to allow file transfers between SUMEX and our PDP-11 (which is connected to the
Utan-TIP as a terminal), writing MBALM and various support routines in BLISS-11,
implementing an I/0 package for BALM in assembly language, and performing a
bootstrapping process with the BALM self-definition. Our schedule calls for
completing steps 3, 4, and 5 by 1 July 1977. Steps 6 and 7 have not been planned
in detail at this time.

Privileged Communication 191 J. Lederberg
Section 6.4.4 NEUROPROSTHESES PROJECT

We are planning to run the resulting programming system on our PDP-11/05
with 28K core, GT-40 graphics system, and running the RT-11 operating system.
Modifying the system to run under a different operating system should be
straightforward. However, whether the system will run efficiently on a machine
with less than 20K core is questionable. It is too early now to say.

There have been no new publications by our group since our application was
filed last year. Currently several papers are in progress but have not yet been
submitted for publication. A partial list of previous publications is attached.

When the BALM system has reached a stable state, we will be happy to
provide documentation. and sources for it to anyone who requests them.

The support for our human experiments is provided by a grant from the Max
C. Fleischmann Foundation. This grant expires 30 June 1977, and a renewal
proposal is now being prepared.

If. Interactions with SUMEX

We have been perfectly satisfied with our use of SUMEX. By far our greatest
use of the system has been of text editors and the BLISS~11 compiler.

We nave also become acquainted through SUMEX with the OMNIGRAPH graphics
package available from NIH and have obtained a copy of the OMNIGRAPH manual. We
nave not used OMNIGRAPH yet but may wish to in the future. We are considering the

features of OMNIGRAPH in the design of the graphics package for our interactive
system.

We are quite interested in using the MAINSAIL system being developed at
SUMEX and have been told that RT-11 is one of the first operating systems under
which it will be available.

IIIf. Long-rance Plans

Our plans for the period beyond July 1978 will depend to a large extent on
results of experiments which have not yet been performed. Our use of SUMEX for
the purpose of developing an interactive programming system will presumably be
complete sometime in 1977. It is possible that future needs will require non.

real-time access to a machine of greater capabilities than our PDP-11/05 and PDP-
8.

IV. Publications

Dobelle, W. H., Mladejovsky, M. G., and Girvin, J.P. Artificial vision for the
Dlind: electrical stimulation of visual cortex offers hope for a functional
prosthesis. Science, 183, 1 February 1978, 440-444.

Dobelle, W. H., and Mladejovsky, H. G. Phosohenes produced by electrical
stimulation of human occipital cortex and their application to the
development of a prosthesis for the blind. J. Phsiol., 243, 1974, 553-576.

J. Lederbere 192 Privileged Communication
NEUROPROSTHESES PROJECT Section 65.4.4

Dobelle, W. H., Mladejovsky, M. G., Evans, J. R., Roberts, T. S., and Girvin, J.
P. “Braille” reading by a blind volunteer by visual cortex stimulation.
Nature, 259, 15 January 1976, 111-112.

MlLadejovsky, M. G., Eddington, D. K., Evans, J. R., and Dobelle, W. H. A
computer-based brain stimulation system to investigate sensory prostheses
for the blind and deaf. IEEE Trans. Biomed. Eng., BMZ+-23, 4 July 1976, 286-
296.

Mladejovsky, M. G., Eddington, D. K., Dobelle, W. H., and Brackmann, D. E.
Artificial hearing for the deaf by cochlear stimulation: pitch modulation
and some parametric thresholds. Transactions of ASAIO, 21, 1975, 1-6.

Privileged Communication 193 J. Lederberg
e we can}
r

Section 6.4.5 MATHEMATICAL MODELING OF PHYSIOLOGICAL SYSTEMS
6.4.5 MATHEMATICAL MODELING OCF PHYSIOLOGICAL SYSTEMS

Mathematical Modeling of Physiological Systems

John J. Osborn, M.D., Director
Research Data Facility
The Institutes of Medical Sciences
San Francisco, California 94115

The overall goal of the Institutes of Medical Sciences’s collaboration with
SUMEX is the application of computer technology to clinical medicine. Our
efforts during the past year have been in the fields of knowledge based
engineering and mathematical modeling.

We are using our available computer based physiological measurement systens
to provide the basis on which physiological interpretation is being developed
using knowledge engineering, and to provide the data with which mathematical
models are being developed using the SUMEX modeling facility.

Project support:

Granting Agency: NIH

Grant Number: MB00134

Total period of the award: 3 years
Current year: 3

Current funding: $45,570

Granting agency: NIH

Grant Number: HR42917

Total period of the award: 3 years
Current year: 3

Current funding: $198,839

BIOMEDICAL KNOWLEDGE ENGINEERING IN CLINICAL MEDICINE (KEMED)

The KEMED system is conceived as an application of the discipline of
heuristic based programming to the interpretation of measurements made in
clinical medicine. The long range goal of the project is to do research on a
biomedical knowledge-based system for interpreting the clincal significance of
Physiological data. This interpretation will be used to aid in diagnostic
decision making and the selection of therapeutic action. Even the best
measurements often go unused because of the reasonable reluctance of clinical
staff to make measurements whose results they only poorly understand and whose
relation to clinical management is ambiguous. We will use techniques of
biomedical knowledge engineering to extract and systematize the heuristic
knowledge used by experts in the practice of their clinical art. These
techniques will be used to construct and utilize a knowledge base to guide
inference making by computer programs.

J. Lederberg 194 Privileged Communication
MATHEMATICAL MODELING OF PHYSIOLOGICAL SYSTEMS Section 6.4.5

The first program in the KEMED system is designed for interpretation of
standard pulmonary function laboratory test data. A knowledge base was developed
for interpreting the relationship between measured flows, lung volumes, pulmonary
diffusion capacity and pulmonary mechanics and the standard diagnoses of
pulmonary function. The knowledge base includes interpretation of measured test
results and diagnosis of the type and severity of any pulmonary disease which may
be present. The program is being developed as an extension to the MYCIN
formalism, and it makes extensive use of the MYCIN structures and programming
system. Funding has been requested to continue this work.

MATHEMATICAL MODELING OF PHYSIOLOGICAL SYSTEMS

Mathematical models of the cardio-pulmonary system are being developed to
extract clinical physiological information from data acquired by the patient
monitoring system. two approaches are being taken: 1) parsimonious models of the
dynamic behavior of CO, following an increase in inspired oxygen concentration
are being developed for automated patient monitoring application, and 2) a
detailed model of the regional behavior of radioactive tracers in the lung is
being used as a standard for evaluation of the previous models. The MLAB
(Modelling Laboratory) program, available on SUMEX is being used extensively for
model development by simulating hypothesized models and for data analysis, i.e.,
identification of model parameters from experimental data. The CO. dilution
method has been applied successfully in the ICU and additional funding requested.
Two new methods for measuring regional lung function with radioactive tracers
have been developed where MLAB was essential and further funding has been
requested. MLAB was used to perform an error analysis of the method for
measuring regional pulmonary shunt fraction. Also, using MLAB model simulation
to understand the complex dynamics of 133-~Xenon in the lung-tissue systen, a
method for measuring intraregional ventilation/perfusion ratio maldistribution
has been developed which significantly extends the sensitivity of previous
methods. A model of the oculatory system is presently being developed on MLAB in
collaboration with the Smith-Kettlewell Institute of the Visual Sciences. We
anticipate that their model will be used in the future for treatment of patients
witn strabismus,

Interface with SUMEX

We use SUMEX through the Tymshare network using a terminal. The text
editing facilities of SUMEX, including both text editing and message sending, are
excellent additions to our in-house facilities (PDP-11 based system). The
message system is particularily useful for communicating ideas and questions with
other colleagues using the SUMEX system. Our principal difficulty with SUMEX is
turn-around time. Both the MYCIN amd MLAB systems are interactive, and the 30-59

second time response times associated with MYCIN and MLAB jobs are at best
discouraging.

We have a strong desire to develop in-house capabilities in artificial
intelligence. We have already invested significant numbers of hours in
developing competence with the MYCIN system, and we are confident of developing
an extremely capable staff in heuristic programming. An in-house ATI
computational capability is a more difficult capability to conceive. Developing

Privileged Communication 195 J. Lederbers
Section 6.4.5 MATHEMATICAL MODELING OF PHYSIOLOGICAL SYSTEMS

artificial intelligence programming facility on a PDP-11 based system remains a
Significant long-term interest. The satellite capability offers both the
potential of not continuing to provide additional load on SUMEX, and it offers
tne potential of more rapid interaction with the user.

The SUMEX facility contributed to the following grant applications and
articles:

Requested Funding:

1) Biomedical Knowledge Engineering in Clinical Medicine (NIH)
2) Pulmonary Function in Acute Illness (NIBH)

3) Computer Laboratory for Clinical Support (NIH)

4) Improvement in Regional VA/Q Resolution (NIH, USAF, USN)

thy

Bibliography

1) Simulation to Relate Measured Gas Concentrations at the Mouth to Pulmonary

Mechanics and Perfusion. J.C. Kunz, R.R. Mitchell, D.H. McClung, J.J.
Osborn, Submitted to the 1977 ACEMB.

2) Identifiability of Pulmonary and Recirculation Parameters Fol~lLowing

sequential Bolus Inputs of 133 Xe. R.R. Mitchell, R.J. Fallat. Submitted
to the 1977 ACEMB.

3) Simulation of Intraregional Ventilation-Perfusion Ratio Mal-distribution.
J.C. Glaub, R.R. Mitchell, R.J. Fallat. Submitted to the 1977 ACEMB.

4) Measurement of Residual Volume and Ventilation Distribution Using Helium and a
Five Vital Capacity Breath Maneuver. R.R. Mitchell, Technical Report 32,
Institutes of Medical Sciences, Feb. 1977.

5) Identification of Human Oculomotor System Parameters with Application to
Strabismus. N.K. Gupta, A.V. Phatak, Systems Control; R.R. Mitchell, Heart
Research Institute and Carter Collins, Smith-Xettlewell Institute, Institutes
of Medical Sciences. Submitted to Joint Automatic Control Conference, 197..

J. Lederberg ivi
o Privileged Communication
PUFF/VM PROJECT Section 6.4.6
6.4.6 PUFF/VM PROJECT

PUFF/VM ~ Pulmonary Function and Ventilator Management Project

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

and

BE. A. Feigenbaum
Computer Science Department, Stanford University

Note: The PUFF/VM project is the outgrowth of the efforts of Prof. Feigenbaum’s
group at Stanford to establish new applications areas for AI in medical research.
It represents a collaboration with Dr. Osborn’s group which has been working on
another AIM pilot project titled "Mathematical Modeling of Physiological
Systems". A PUFF/VM proposal is currently pending with NIH and and PUPFF/YM is

being reviewed in parallel by the AIM Executive Committee for separate pilot
status.

1. General Problem

Measurements of patient physiology have become universally accepted as
important parts of the delivery of clinical medicine. Good, useful measurements
often go unused, however, because of the legitimate resistance of attending staff

to using measurements which they poorly Understand. Thus, technology contributes
to clinical medicine if:

~- It’s so useful, economical and easy to use that everyone can use it (e.¢
SHA-12, Brain scanner, Paps)

-- It’s so useful, economical and has been around long enough that many people
have been trained to use it (e.g.: ECG in ICU).

The dissemination of new technology in clinical medicine is limited by the
ability of the system of medical care delivery to accept and assimilate the
interpretation of the results of the technology. Given that the technology is
useful in knowledgeable hands, this rate of assimilation is related somewhat to
cost, but more to the rate at which education progresses. The new computer axial
tomography systems have been accepted rapidly (two neighboring hospitals near San
Francisco made headlines when each tried to purchase $209,900 devices) because
the measurements they make are useful, and they are readily interpreted by staff.
A system of medical technology should:

-- Hake clinically important physiological measurements;
-~- Get data automatically, accurately [done often];

-- Recognize irrelevant data, poor data and artifact [rarely done];

Privileged Communication (197
Section 6.4.6 PUFF/VM PROJECT

~~ Interpret clinical significance of data in light of limitations of the data
collection and analysis [almost never done];

-- Operate economically.

Systematic interpretation of test data is both possible (if the problem has a

restricted domain) and desirable (because interpretation will be consistent for
all and usable without direct supervision of a specialist).

2. Objectives

2.1. Overall Objectives:

Our immediate objective is to develop a computer programming system for
interpreting the clinical significance of measures of pulmonary function. We
hope to develop this system for diagnostic use in the pulmonary function
laboratory and to aid diagnosis and ventilator management of respiratory
insufficiency in the intensive care unit. We hope to demonstrate the clinical

effectiveness of such a system for improving the accuracy and timeliness of
diagnosis.

Our long range goal is to develop an integrated system for making and
interpreting measures of pulmonary function. We believe that this is possible
because of the present and potential contribution of instrumentation and data
analysis systems to the diagnosis and clinical management of pulmonary distress.
We believe, in addition, that the discipline of knowledge-based heuristic
programming is potentially the best basis on which to develop a system for
automaticaly interpreting the results of the measures of pulmonary function.

We aim, in the long run, to develop an inexpensive enoush implementation
that the system will find wide acceptability in the delivery of clinical care.

2.2. Pulmonary Laboratory:

Our objective for this project is to develop a heuristic program for
interpreting the results of standard pulmonary function tests. The program will
identify the need for repeated measurements because of poor patient effort;
identify the need for additional information in order to make a more definitive
diagnosis; report and explain the reasons for primary and secondary diagnoses and
severity of any disease state; identify the relation between diagnosis and any
referral diagnosis; interpret any chanze from previous tests or limitations on
the interpretation because of the test methodology and the patient effort. We
propose to: implement the system using a significant extension of an existing
system of heuristic methods; extend the existing system to add new pulmonary
disease diagnosis decision rules; develoo models for directing program execution,
achieving faster performance, and detecting and interoreting the clinical
situation in terms of any inconsistent data; facilitate model acquisition.

J. Lederberg 198 Privileged Communication
PUFF/Vil PROJECT Section 6.4.6

2.3. Intensive Care Unit (ICU):

Gur objective for this project is to develop computer programs ror a system
to interpret results of tests of pulmonary function in the hospital Intensive
Care Unit. The program will interpret and explain the results of test
measurements used to diagnose respiratory insufficiency; suggest initial settings
for a ventilator for the patient with respiratory insufficiency; diagnose need
for change in ventilation for the patient on a mechanical ventilator; and
diagnose appropriateness of moving forward or back in the process of weaning the
patient from the ventilator. We will implement the system using a new heuristic
based interpretation system capable of interpreting continuous data from the
changing patient situation. The system will allow goal-oriented and data-driven
invocation of interpretation rules from the knowledge base.

2.4. Progress Evaluation:

Our objective for this project is to conduct major evaluations of the
direction and schedule of the above projects. These evaluations will be
conducted near the end of the first and second years of the project. The
evaluations will help assure the soundness of the computer science and the
clinical investigations. Outside experts in clinical medicine and computer
science will participate in the evaluation process.

2.5. Advantages of Collaborative Effort between IMS and the Stanford Heuristic
Programming Project

The collaboration offers a complementary blend of medical and computer
science knowledge:

~- Clinically important problems: Interpretation of pulmonary measurements,
both in lab and ICU.

-- Auto data collection and analysis in pulmonary lab and in ICU using
computer. Data has demonstrated value in clinical medicine; Well understood
procedures for collection, interpretation, use of data.

-- Having computer data collection, automated interpretation is logical next
step.

-- Use all power computer science has available; discard excess in application
specific implementation after designing into implementation the important
features.

-- The SUMEX charter from NIH includes exporting artificial intelligence
techniques (AI) to a larger community, and IMS is an excellent potential
colleague. IMS has real clinical problems which can use AI effectively;
biomedical engineering, statistics, and mathematical formulation of problems
to contribute to AT; strong clinical orientation to give AI practical use.

Privileged Communication 199 J. Lederberg
Section 6.4.6 PUFF/VM PROJECT

3.

A.

Specific Aims

Develop an integrated knowledge-based system for interpreting standard
pulmonary function test results.

Develop an integrated knowledge-based system for interpreting tests and
observations used for diagnosis and treatment of respiratory insufficiency
in the ICU.

Conduct major project evaluations, using outside experts in clinical
medicine and computer science, to review progress to date and to help
identify promising directions for continuing research.

To these ends, we will:

1.

J. Lederberg 209

Develop a knowledge base for pulmonary function laboratory test
interpretation, including rules to:

~- Interpret results from spirometry
of diffusion capacity for CO;

, body plethosmography and measurement

~-~- Diagnose the presence and severity of obstruction, restriction and
diffusion defects;

-- Diagnose the presence and severity of obstructive subtypes (asthma,
bronchitis, emphysema); and

-- Identify poor test results and the need for new information to make a
more definitive diagnosis.

Implement rules for pulmonary function test interpretation using a
significant extension of the existing MYCIN formalism. Heuristic and

mathematical models of "prototype" disease states will be used to:

-~ Identify the presence of supporting and conflicting evidence for a
primary interpretation;

~~ Interpret the clinical significance of measured data both in terms of
measured data , the patient history, and expected values for the typical

case;

-- Recognize and interpret the significance of inconsistent data; and --
Direct the invocation of rules, thereby speeding program operation.

Develop a knowledge base for interpreting tests and observations relevant
to diagnosis and ventilator management of respiratory insufficiency:

-- Interpret results of measurements of vital capacity, blood gases,
respiratory pressures, volumes, Zas concentrations; hemodynamics;

-~- Recommend procedure for setting up a ventilator for a patient;

Privileged Communication