PROPOSAL FOR

      STANFORD UN IVERS ITY

MEDICAL EXPERIMENTAL COMPmING FACILITY

         (SUMEX)

    Submitted to the

Biotechnology Resources Branch

       of the

National Institutes of Health

June 1, 1972

School of Medicine
Stanford University


TABLE OF CONTENTS

A.   INTRODUCTION
                   .......................................................... 1

   1.  Objectives and Long-Term Goals ..................................... 1
   2.  Background:  ACME Computer Facility Experience ................... ..Z

B.   SUMMARY  . . . . . . . . . . . . . . . e............. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

C.  JUSTIFICATION . . . . . . . . . . ..a............. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

1.  Demonstration of need.  ............................................. 6
2.  SUMEX Relationship to Institutional Plans .......................... 7

D.  RESOURCE OPE~TIONS....................................................9

1.  Adminstrative Structure ............................................ 9
2.  Operating procedures and Policies..................................1 1

E.  COMPUTER CONFIGURATION RATIONALE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...13

1.  Introduction.......................................................l 3
2.  Computing Environment .............................................. 13
3.  Technical Requirements ........................................... ..15
4.  Configuration Topologies...........................................~ 7
5.  Hardware Selection ................................................. 20
   a. Mainframe .................................................... ..2 0
   b.  Peripherals, Data Channels, and Satellite Computers............2 3
6.  Implementation Plan................................................Z 6

F.  RESOURCE PERSONNEL .................................................. ...2a

G.  RESOURCE ACTIVITIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..*....... 30

1.
2.

Services to be provided............................................3 0
Research ............................................................

a.  Core Research  ................................................. :t
  (1) Satellite Machine Support.................................3 1
     (a) problem Statement....................................3 1
         (1)  Limitations of standalone small computers ..... ..3 1
       (2) Attributes of large host systems................? 1
       (3) Anticipated direction of some technological
               innovations.  ......................
     (b) Background and Rationale           ............ ..3 2
                                           ............................. 35
        (1) Current environment for satellites in
              S.U. Medical Center  ........................... .35
       (2) Initial Approach in Software....................3 6
      (3) Incorporation of new hardware techniques........3 6
       (4) Resolution of specific goals with collaborators.37
    (c) Methods and Procedures...............................3 8
        (1) Satellite System Software Support
          (a) Assemblers.................................3 8
            (b)  High level language support ............. ...38
          (c) Realtime applications module library.......? 9
          (d) Extensions to manufacturers supplied
           operating systems..........................)! 0


      (2)  Computer to computer communications  ....... ..4 1
         (a)  Data transfers ....................... ..4 1
         (b)  Controlled interactions  .............. ..4 1
      (3)  Data manipulation  ........................... 42
         (a)  Data collection.. .................... ..4 2
         (b)  Data analysis ........................ ..4 3
     (4) Satellite performance, measurement and
           evaluation.. ................................ 44
  (d) Significance of satellite machine Support.........4 6
(2)  Extended Realtime Computing.. ....................... ..4 7
   (a)  Problem Statement and Objectives  ............... ..4 7
   (b)  Background ..................................... ..4 9
   (c)  Rationale  ........................................ 51
   (d)  Methods and Procedures ......................... ..5 3
   (e)  Significance ................................... ..5 8
  (f) Collaborative Arrangement.........................5 8
(3) PL/ACME on a PDP-10   .................................. 62

b.  Collaborative Research and Development......................6 5
(1) Predictive Modeling of Cardiovascular Function Utilizing
    X-Ray and Ultrasonic Imaging Techniques................6 5
     (a) Problem Statement.................................6 5
     (b)  Background ..................................... ..6 6
     (c)  Rationale ...................................... ..6 7
     (d)  Methods and Procedures ......................... ..6 8
           1.  X-ray Image Processing ..................... ..6 8
           2.  Ultrasonic Image Processing  .................. 69
           3.  Small Computer Integration. ............... ...7 0
     (e)  Significance .................................. ...7 0
     (f)  Relationships ........................... ..-.......7 1
  (2) Digital Computer   ..................................... 74
    Processing of Cineurographic Images of the Urinary Tract
     (a)  problem Statement .............................. ..7 4
    (b) &&ground .--...-...-............................7 5
     (c) Rationale  ........................................ 75
     (d)  Methods and Procedures ......................... ..7 6
     (e) Collaborative Affiliations .................... ...7 7
     (f)  Significance ................................... ..7 7
(3) Automated Gas Chromatography/Mass Spectrometry Analysis 78
     (a)  Introduction ................................... ..7 8
     (b) problem Statement.................................7 8
     (c) Background  ....................................... 80
     (d) Rationale   ....................................... 81
     (e)  Methods and Procedure .......................... ..8 5
    (f) ~~gn~f~can~e~..-.............................~...B 7
     (g)  Facilities Available.. ......................... ..8 7
    (h) Collaborative Arrangements .................... ...8 7
  (4)  Cell Separator Project .............................. ..9 0
     (a) Background .................................... ...9 2
     (b)  Rationale ...................................... ..9 3
     (c)  Methods and Procedures ......................... ..9 4
    (d) Significance .-----~----------..~-~...~....~......~ 4
    (e) Computer Interactio~.............................9 4


       (5)  Average Evoked Potentials and Perception  ............ ..9 7
          (a) Problem Statement ............................... ..9 7
          (b) Background and Rationale .......................... 97
          (c) Methods and Procedures  ........................... 98
        (d) Significance  ..................................... 99
          (e) Relationship to other work........................10 0
H.  BUDGET  ............................................................. iol
   1.  Detailed Budget for First 12-month Period ....................... 102
   2.  Budget Estimates for all years of Support.......................10 3
   3.  Explanation  .................................................... 105

I.  FUTURE PLANS  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109

J.  APPENDICES ........................................................ ..llO
   1.  ACME User Publications .......................................... 111
   2.  Biographical Sketches  .......................................... 120

FIGURES

E-l    ACME Configuration: May 1972  .................................. 16
E-2    General Characteristics of the Proposed System  ................. 19
E-3   Tentative Initial Machine Configuration for SUMEX...............2 2
E-4    Implementation Scheme for Remote Data Channels..................2 5
E-5    Implementation Phasing Plan  .................................... 27

G-l
G-2
G-3
G-4

Elements of Laboratory Instrumentation Data Systems.............5 2
Proposed topology for Central Processor and Peripherals.........5 4
Tentative Initial Machine Configuration for SUMEX...............5 6
Software ........................................................ 57

DENDRAL-1 Realtime Mass Spectrum Interpretation System.................8 3
DFNDRAL-2 Processing Time Interdependence  ............................. 84

Cell Separator-l  Simplified Blcok Diagram of Cell Separator............91



STANFORD UNIVERSITY MEDICAL EXPERIMENTAL COMPUTER RESOURCE

                      SUMEX              I

Proposal for a research resource in extension of the ACME project.

A.   INTRODUCTION

1.  Objectives and Long Term Goals

General purpose computer support of research at Stanford University
Medical School has reached substantial maturity under the impetus
of the ACME project (Advanced Computer for Medical Research)
funded since 1966 by NIH.  We have understood that our technical
success would be coupled with the gradual withdrawal of central-
ized agency support for a proven utility.  Hence,  June 1973 re-
presents the termination of the longstanding NIH subsidy for
ACME, which will thenceforth be operated as a fee-based service.

The present application seeks to establish a resource for a new
set of technical horizons, in keeping with the expending capability
and applications of computers in biomedical research.   SUMEX would

be a resource (1) to support a set of ongoing biomedical research
programs that exploit state-of-the-art computer techniques, and
help to shape further advances, and (2) the computer-science re-
search that is essential to expedite the creative uses of computers
in the laboratory, in the clinical research wards, and eventually
in patient care at every level.

The unifying theme of the SUMEX resource is the management of a
set of peripheral minicomputers by a powerful central facility.
The minicomputers in question are immediately situated in laboratory
and clinical-research environments.  They can perform some tasks
free-standing, but the selected projects require further backup
to sustain high-data-rate and closed-loop operations.   These
machines, together with others on less demanding projects, can be
enhanced by sharing peripherals, mutual backup, and higher level
language programming and debugging in the central processor. More
far-reaching in concept, and central to this proposal, is central
and "intelligent" management of the data-gathering process to meet
problem-oriented needs for information.  (This is no more than a
feeble emulation of the processes that higher organisms must have
evolved to modulate the flow of sensory data into the perceptual
mechanism.)

In the ideal situation this might entail a realtime closed-loop
control of a laboratory instrument or a patient-monitoring device.
Prior and currently updated information, related to partial solution
of a problem, would then selectively orient further data-taking
so as to expedite a complete solution.  A related example would be
a kind of triage-- allocating the time-shared partitions of a large

75


computer resource to concentrate on the patient with the most
problematical symptoms.  Even where realtime processing is
unrealistic, in the present state of the art, as in motion-picture
processing, the magnitude of computing requirements could be vastly
reduced by analyzing each frame to pose specific questions of the
next one, rather than prepare a digital core image of the entire
sequence.  Similar problems arise in every branch of spectrometry,
including mass-spectrometry, where costly instruments and samples
may be needlessly expended in conventionally serial acquisition of
the whole spectrum, followed by its analysis (which usually relies
upon a small part of the entire data set.)

The initial list of collaborating investigators is presented in
part C-l.  Others who are not yet prepared to commit themselves
to this enterprise will continue to be recruited as discussed in
part D.  The hardware requirements are detailed in part E and
further details of the operation of the SLJMEX resource, and its
relationship to service-computing at SUMC* are detailed in sub-
sequent sections.

*(Stanford University Medical Center)


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2.  Background:  ACME Computer Facility Experience

On August 1, 1966, the Biotechnology Research Resources Branch of NIH (then
known as the Research Resources Branch) awarded a grant to Stanford University
Medical School to support the establishment of ACME (Advanced Computer for
MEdical Research) facility.  The initial proposal included the following
paragraph concerning hardware selection and resource allocation:

"The IBM/360-50 has been selected for the initial realization of ACME
(1) as a machine technically appropriate to the immediate tasks in mind
and (2) for its system compatibility with the 360-67 already selected
for the eventual replacement of the 7090 by the Stanford Computation
Center.  The 360-50 will be installed in ACME May 1966 and will run on
three shifts under Operating System/360, subject to review by the policy
committee.  These will be dedicated respectively:

(A) A prompt access time-sharing mode - perhaps over most of
   the working day.

(B) A scheduled, full-use, on line mode - to service development
  work on high data rate and on line control applications, and
   for similar systems development.

(C) Job-shop, especially longer runs for which overnight turnaround
   is acceptable, and which cannot be serviced with comparable
  effectiveness by SCC."

The following aims were added to the ACME charter at the time of the Renewal
Proposal in the Spring of 1969:

(a) To improve hardware and software reliability for the benefit of
   the medical users.

(b) To provide small machine assemblers in PL/ACME so that code for
   small machines can be written from an ACME terminal.

(c) To achieve over time a state where income from user charges will
   match operational costs for the ACME system.  The target date for
   this has not yet been fixed by Stanford and NIH.

All of the original objectives have been achieved to varying degrees of
satisfaction.  Of special note is the development of PL/ACME as an interactive
timesharing system which can be easily learned and used by medical staff.
On the other hand, the realtime support offered is inadequate due to system
instabilities and data rate limitations.  Access to Campus facility is incon-
venient for ACME users.

In terms of the items added at renewal time, hardware and software reliability
have been markedly improved.  Small machine assemblers have been added, but the
user must write code in the assembly code for whatever satellite he intends
to run.  At present, assemblers of this type exist for PDP-11, PDP-8, and 1800.
The income of the facility has been rising steadily.  Economic overlaps with
NIH direct support for ACME have blurred the transition to totally non-subsidized

use.  A major rate increase was initiated in April, 1972.  With this change,


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income in the near term is expected to reach roughly 60% of direct operating
costs (exclusive of development efforts).  From the vantage point of hind-
sight one could well ask whether the selection of the 360150 hardware and
the decision to promote a large central time-sharing and data collection
resource were appropriate.  Given the availability of new third generation
hardware and the promises of IBM or expectations of its customers in 1966,
the 360/50 hardware selection is defensible.  However, the development of
low cost, fast, well-supported minicomputers was not anticipated to proceed
at the phenomenal pace that it has.  This major technological shift has
strongly influenced our present thinking for the future of computing in medicine
and related research.  The role of a large shared resource has by no means been
obviated by the minicomputer revolution.  We will continue to need powerful
facilities beyond the scope of current mini architecture.

The advantages of dedicated satellite processors make them mandatory for many
applications which require high reliability and availability.  A marriage of
of the two architectures is proposed.  The resultant synergism is designed to
solve identified problems in our research environment.


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B.   SUMMARY

The resource for which we are applying consists essentially of a Digital
Equipment Corporation PDP-10 system, to be procured on a lease-purchase plan
over the 5-year term of the grant.  The configuration has been designed for
flexibility in interfacing with numerous small machines )provided by the
collaborating investigators).  The rationale for this system, the associated
peripherals, and for the technical support staff, are detailed herein below.
The SUMEX machine will be scheduled for the sole use of the SUMEX collaborative
group, under the leadership of the principal investigator.  Other investigators
will, however, be recruited into the group if they qualify by virtue of their
interest in and competence for computer research relevant to the main themes
outlined here, and insofar as their theoretical and technical contributions
will enlarge our understanding of the application of computers for the manage-
ment of high-data-rate biomedical studies.  SUMEX will not be available for
routine computing that can be effectively purchased from existing utilities.
The initial group of coinvestigators includes all respondents at SUMC who
qualified by the stated criteria; however, several others are expected to
advance the sophistication of their computer applications so as to qualify
within the term of the grant.

SUMEX is expected to develop a number of applicatians that may become routine
once perfected.  These results would be transferred as appropriate to a service
utility which continues to meet the demand for conversational time-shared com-
puting as a legacy of the ACME project. For example, a number of workers at
SUMC have utility-level requirements for support of their minicomputers. We
believe this cognate requirement can be most efficaciously met if SUMC estab-
lishes a twin service facility based on a PDP-10, perhaps coupled with a small
IBM machine for fiscal data-processing with company-furnished software.  (These
decisions are outside the policy cognizance of the present applicants, and out-
side the funding hereby requested.  However, we are in good communication with
the SUMC computer service committee that is establishing those policies.)

These decisions need not be fixed at an early date; for example, the existing
IBM/360-50 ACME system might be retained for some time to provide feepaid
timesharing service, during a transition period at the establishment of SUMEX
as a research resource.  In any case, the existing ACME project, for the
remainder  of its term (Expires July 31, 1973) and to some extent the new SUMFX
program will have the responsibility of easing that transition for the com-
munity of users who have made large commitments to the ACME service.  Except
during an interim transition period and later on an emergency basis, SUMEX obli-
gations to the ACME community will be confined to providing technical advice for
conversion, and developing software that can be used interchangeably on the
SDMEX and on the SUMC service machines.  However, SUMEX developmental efforts
will be strongly biased by that requirement for compatibility, and indeed for
ready exportability to other biomedical computer groups.

The application of SUMEX could be summarized in terms of the scientific ob-
jectives of specific projects -- which are, however, detailed in section G.
These lend substance to the technical research on computers themselves which
is the unifying theme of our proposal.  The principal investigator's interest
in the DENDRAL project was, from the outset, motivated by the aim of broaden-
ing the application of machine intelligence to science generally (He is, after
all,a geneticist first, and entered into mass spectrometry only because the
latter was more amenable at the present level of the art.). While few other fields
of biomedical research are, at present, ready for the full-blown application


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of the techniques developed for DENDRAL as a problem in artifical intelligence,
there is a broader base of common concern for related problems in data manage-
ment.  Briefly, in as many ways as possible, we will be developing the means
to support small machines by a large central facility acting as an executive
manager for the minicomputers.  In addition, we will develop the technology of
programming the mini's in higher level languages compiled on the PDP-10; will
simulate minicomputer configurations as a way of designing new installations;
will provide buffering and communications among small machines, and between
them and various peripherals, including secondary storage, displays, and
(if the opportunity materializes) access to other nodes on national computer
networks.  Where control loops are to be closed back on the mini's, a great
deal of processing of the experimental data will presumably be done in the PDP-1(
We will also investigate the utility of small machines as auxiliary subroutine-
processors to increase the efficiency of a time-shared central device in some
long computations.

I.


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C.   JUSTIFICATION

1.  Demonstration of Need

The recruitment of an initial group of collaborators has made clear the need
for:

           .   dedicated large computing resources
           .   high data rate acquisition and control capabilities
           .   development of software and hardware techniques
           .   integration of host and satellite computing systems

The SUMEX Resource responds to needs identified by a number of research pro-
jects within the Medical Center.  Individually, their projects are unable to
avail themselves of resources as large as SUMEX.  Collectively, their
research objectives demand the capabilities designed into SUMEX in this pro-
posal.  The requested facility calls for a high degree of cooperation among
a small number of collaborators for their mutual benefit.

Five collaborative projects are described as part of this proposal.  They
are:

a.  Predictive modelling of cardiovascular function utilizing X-ray and
  ultrasonic imaging techniques, Dr. Donald C. Harrison, Cardiology.

b.  Development of computer based characterizations of radiographs of
  ureter, Drs. Thomas Stamey and Chris Constantinou, Urology.

c. DENDW -- Computer automation of the interpretation of mass spec-
  trum, Dr. Joshua Lederberg, Genetics; Dr. Carl Djerassi, Chemistry;
  and Dr. Edward Feigenbaum, Computer Science.

d.  Cell separator automation, Drs. L. Herzenberg and E. Levinthal,
   Genetics.

e.  Electroencephalogram Driven Stimulus/Response Studies of Drug
  Effects, Drs. B. Kopell, T. Roth, and Pfefferbaum, Psychiatry.


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2.  SUMEX Relationship to Institutional Plans.

Stanford University has relied extensively on IBM equipment; the decision to
procure a PDP-10 for SUMEX inevitably hinders compatibility and economy in
system effort.  Unfortunately, the IBM lines offer no cost-effective equiv-
alent to the PDP-10 for small machine interfacing.  An oversized and costly
IBM machine would offer few advantages of portability to other research pro-
grams interested in similar objectives. Furthermore, our experience with the
ACME IBM/360-50 suggests that one could easily overestimate the ease of retaining
compatibility, even within the IBM line, of programming systems that address
distinctive objectives.  (DOS systems differ from OS systems to a degree com-
parable to the barriers between machines from different manufacturers.)  The
best we can expect to do, in the face of conflicting objectives, is to strive
for the most efficacious compatibility we can achieve in higher level languages,
files systems, etc.  We do have the benefit of Dr. John McCarthy's long
experience with the PDP-line in the Artificial Intelligence Laboratory at the
edge of the Stanford Campus.

These decisions have been reviewed by Dr. Gene Franklin in his role as
University Associate Provost for Computing.

The SUMEX resource will divert its users from existing computer facilities
only to a limited degree.  Most of the uses intended for SUMEX require services
simply not available otherwise.  Some of the LISP programming of the DENDRAL
project would otherwise be run on one of the larger IBM machines.   This would
be at great cost, and in any case could not permit an approach to closed loop
management of the laboratory instruments.  The entire ACME machine, scheduled
with no shared users, lacks the computing power required for these applications.

We are recommending a twin PDP-10 for the SUMC service facility to optimize
the overall advantages of the SUMEX option.  IBM's performance in delivering
time-sharing and realtime software for the 360 line has been disappointing --
indeed this was an important crimp in the projected transfer of routine time-
sharing service from ACME to the SCC's 360-67 based service.  On the other
hand, DEC has done rather well with manufacturer-supplied software for these
users of the PDP line.

An important advantage to the Medical Center of the dual PDP-10 system would
be the availability of a back-up system.  The lack of redundant hardware has
precluded some applications; one user has opted to buy two mini-systems with
identical configurations in order to obtain maximum reliability.  The finan-
cial burden of this approach would be too great in most applications.   The
availability of redundant hardware facilities will be an important factor in
the Hospital's consideration of how to solve its computing problems.

The impact on the Medical Center of having shared data files for research,
service (research support), and administration can be significant.  Faculty mem-
bers in several disciplines are asking with increasing frequency for access to
data bases outside of their own department. Of course, the file system design
will provide file integrity, protection from catastrophic loss of data, and
security.  The availability of shared common files will (1) reduce the need for
duplicate files, (2) improve the visibility and availability of information
to faculty and staff, and (3) encourage placement of data on large, less e-en-
sive, rotating memories as opposed to smaller, more expensive hardware on
satellite systems.


Common communications support for research service, and administrative com-
puting systems is viewed as mandatory.  The proliferation of terminal types,
small machine types, etc.  will breed a foul nest of communications hardware and
software unless a sound, centralized, long-term plan is established. One
can envision users with multiple terminals in each office, ward, or laboratory
and multiple protocols needed by staff to use disparate systems unless the
trends toward decentralization are encompassed under some umbrella of sound
planning.  The use of a shared communication system may permit redundancy and
availability which would not be feasible in multiple independent systems.
However, the hardware choices of the SUMC service operation are perhaps less
important than the cooperative spirit that will be reinforced by the admin-
istrative arrangements for its coordination with SLMEX.


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D.  RESOURCE OPERATIONS

1.  Administrative Structure

Line authority for SUMEX is vested in the P.I., Dr. Joshua Lederberg, who was
also P.I. for the ACME system.  He also functions as Chairman of the Depart-
ment of Genetics, and, as a member of the Medical School's Executive Committee,
is in good communications with the other department chairmen.  In other roles
(e.g., University Committees on Research and Computing Facilities, the Human
Biology Program, etc.) he is also in frequent communication with general uni-
versity activities.  The Genetics Department includes the Instrumentation
Research Laboratory directed by Dr. E. C. Levinthal.

Dr. Clayton Rich, as Dean, is the principal administrative officer for the
Medical School, and Dr. Lederberg reports to him in several capacities.

    I        ,   Rich   . ..! . . . . . . . . . . . . .
                              .               .

                                             .
                              .               .
Assoc. De&
  John                       for Research
Wilson
   1

Dept.
Heads

Genetics
Dept.

Dept.
Heads

. . . . . . . . . . . . . . . . . . . . . . . .
                         .
                         .
           5               .

Dept.
Heads

J. Led&berg             Collaborative

cl
   ACME
TroJ ect

KEY:

. . . . . . . . . . . . .  Staff
            Line
-------  to be
      superseded


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With the phasing out of ACME, its service responsibilities will be the respon-
sibility of another organization reporting to the Dean independently of SUMEX.
One proposed arrangement is:

Dean and V. P.

Scope of this
Proposal

       I

Assoc. Dean
  for SDMC ___ _

Data Processing

k..............

. . . . . . . . . . . . . . . . .

(Computer Services)

The Associate Dean will assure the optimum exchange of information and
compatible policy development between computer research and computer
services.

The hatched area signifies that this proposed grant will support
(1) SUMEX operations and (2) liason with Stanford University Medical
Center Computer Facility (SUMCCF).  SUMEX will support development
efforts on its PDP-10 machine of a kind that should be readily trans-
ferable to the SDMCCF as well.  SUMEX will also assist the ACME community in
the transition to SUMCCF services.  However, operating expenses of the SUMCCF
will be met from the SUMC budget including user fees, and not from the SUMEX


grant.  SUMEX and SUMCCF may however, provide mutual back up, on mutually
advantageous terms, with respect to downtime emergencies and experiments
involving linked processors, on the basis of credits for demand availability
and use.  The functions of the existing ACME facility will then be parti-
tioned between SUMEX, for a limited number of computer-research oriented
collaborations, and a combined computer service facility for the S. U. Medical
Center, which we till label SUMCCF.

CURRENT

        o                                                                 ?
     ACME 360/50             Hospital Data Processing
                        360,' 40
              ?     ?
Computer         Utility               IJt,ilit;y
Science        Service Users                Service
Research       Time-Sharing &           _ Users
Users       Data Acquisition
                                   J

PROPOSED

              Assoc. Dean for SUMC Data Processing

P.I.  - SLJMEX
               *                 SUMC Service Computing Facility
SUMEX Facility _ _ _ _ _ _ _ _  (1. or more hdwe. systems)
                                               .

t    I
Small Number of
Collaborators
,

The SUMEX resource will operate under the direction of the Principal Inves-
tigator, who will be responsive to the research needs of the collaborators
in terms of scheduling, use of the resources, and relative priorities for the
programming staff.  He will also establish liaison with SUMCCF to maximize the
secondary gains of that relationship.

2.  Operating Procedures and Policies

SUMEX is primarily responsive to a designated set of investigators interested
in and competent to participate in major innovations in medical research appli-
cations of computers.  They will have the opportunity to develop these applica-
tions in SUMEX prior to mounting them as new services on the Service Facility.


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Authorized collaborators are limited and selected on the following grounds:

a.  The Research Facility must remain capable of being dedicated to one
  experimenter's efforts if the total resource is needed for his work.

b.  New hardware installation is likely to occur frequently on this
  facility.  It should not have to be performed at odd hours in order
  to avoid normal service interruptions.  The primary mission of this
  facility will be to service research users; routine service opera-
  tions will be available only on the Service Facility.

C.  Systems programmers will be testing new software concepts frequently.
  As a consequence, high system reliability and availability are not
   warranted.

d.  Experience gained at ACME indicates that as time passes,more and more
  users come to expect (and demand) routine, stable, highly available
   service.  Computer science related research cannot function effi-
  ciently in that environment.

e.  Opening the Research Facility to routine use by many would inhibit
  the evolution of a fee-based Service Facility.

f.  Management of the enterprise, including the selection of appropriate
  projects, will become increasingly difficult as the number of author-
  ized users grows.

g*  Their needs cannot be met on other local service facilities without
  undue disruption.

In the proposed grant period, no user service fees are contemplated for the
Research Facility.  As research concepts are developed and tested, it is
expected that the Service Facility will be able to add services to meet user
needs.  Thus, the research objectives, once met, will be replaced with new
research goals on the Research Facility.

Additional research collaborators will be recruited from the Stanford biomed-
ical research community as indicated in paragraphs a. through g., above. We
also contemplate cooperating with NIH grantees at other institutes via network
facilities.  During tne interim period, prior to the settling down of reliable
PDP-10 service on the SUMC facility, it may be desirable to coopt affiliated
                _- ~. _ ~-
investigators who do not meet the full range of criteria but who are developing
major projects in anticipation of the availability of the PDP-10 capabilities.
Arrangements for servicing such users  and for adding principal collaborators
will be coordinated with the Biotechnology Research Resources Branch at regular
intervals.  The principal investigator will be responsible for applying these
criteria for collaborating and affiliated projects, and for regular reporting
to the Branch.

The Service Facility could provide routine services to SUMEX systems staff at
times when the SUMEX was dedicated to a particular user's tasks.  In addition,
Service Facility usage would be needed to test newly transitioned packages from
the Research Facility.  The purchase of computer time on the SLJMCCF would enhance
the efficiency of SUMEX personnel.  For these reasons, some funds are being
requested to pay for services on the Service Facility.


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E.  COMPUTER CONFIGURATION RATIONALE


1.  Introduction

This section addresses the problems of system configuration design and
computer selection based on projected requirements and available
machines.  To summarize the discussions of these topics which follow,
we have arrived at the following conclusions and proposed course of

action:

   (a>

Separate machines for computer research and utility service
are required to provide simultaneously a continuous and
reliable computing utility service like the current ACME
system and support for new system developments.

(b)

The two machines, including required communications and future
data base interfaces, ideally should be as similar as possible
and geographically contiguous to allow redundancy for
reliability, ease of software transfer, and efficiency of
operation,

(4

The two machines will have some level of coordinated manage-
ment but with financing of the service machine derived from
fee for service funds and of the research machine from the
presently proposed grant funds.

Cd)

Based on evolving software requirements for time-shared and
realtime support as well as the capabilities and economics
of currently available systems, it is proposed that both
machines be Digital Equipment Corporation PDP-10 computers.

(4

A phased transition (Figure E-5) from the present single
IBM 360/50 configuration to the dual PDP-10 configuration
including necessary PL/ACME modifications is planned so as
to minimize the trauma of conversion.

2.  Computing Environment

The design of a medical experimental computing resource for research
on satellite machine interactions and extended realtime problems
interacts strongly with the overall design of computing support within
the Stanford Medical Center.  Based on past ACME experience, hospital
administration experience, and projected Medical Center needs, an
overall facility must be able to accommodate three main types of
computing simultaneously:


(14)

( a>

6)

(4

Medical Service Computing - A stable and reliable computing
utility service must be available which supports on-going
medical research and clinical needs in the sense that ACME
currently performs these functions.  The users of this type
of utility are presently largely within Stanford but can be
expected to extend outside of Stanford as network facilities
come more and more into use.  Such a utility must include in
its repertoire appropriate state-of-the-art services for
time-sharing and batch operation as well as satellite
machine programming and on-line data communications facilities.

Hospital Administrative Computing - A stable and reliable
computing support of hospital administrative computing must
be available for processing data related to patient
accountability, financial records, clinical laboratory
records, pharmacy records, etc.  This type of computing is
based to a considerable extent on software packages which
have been developed outside of Stanford for specific
computing systems.  In the future the system must be able to
support some level of integrated hospital information system.
A long term requirement exists for compatible file structures
accessible from various machines and software packages over
local and larger scale networks.

Medical Computing Research - Computing service must be
available to support the development of computer system
software and hardware capabilities as well as research
projects which require sporadic dedication of large amounts
of computing resources or which endanger system reliability.
Such a service must be tolerant of higher system volatility
than the utility services in order to allow evolutions in
system design and utilization without impacting essential
on-going computing functions.

There are reliability, capability, and priority conflicts in the
requirements which these three groups place on a computing facility.
'Ihe evolution of the present ACME system, while successful in making
powerful computing tools easily and broadly available to medical
researchers and clinicians, has also provided examples of such
conflicts between various users.  The ideal facility design must embed
support for these various computing functions in an overall configura-
tion which optimizes the desirable interactions of information and
technology while minimizing the fundamental conflicts.  As needs for
computing resources within the Stanford Medical Center and its
affiliates grow, the computing facility must be capable of economical
expansion based on these needs in ways which minimize conversion and
transition trauma.


(15)

3.  Technical Requirements

Estimates of requirements for future computing service in terms of
capacity,  response time, communications, etc. are based on past
experience with existing systems as well as projected new requirements.
In the following only the requirements related to this grant applica-
tion are considered.  The major non-administrative computing service
offered in the Medical Center has been the interactive, time-shared
PL/ACME system.  This type of system will continue to be the basic
environment for the proposed research in satellite machine support and
realtime systems.  Thus the evolution of the ACME system is an essential
element of this plan,

ACME Background - The PL/ACME system currently runs on an IBM 360/50
computer system shown functionally in Figure E-l.  The time-sharing
aspects of the system, developed under the previous ACME grant,
apportion memory resources to multiple users from a large fixed
reservoir (2.1 x 106 bytes).  Realtime support for on-line experiments
is provided by means of interfaces through either an IBM 1800 computer
or an IBM 2701 data adapter.  From a consideration of the loading
history of this machine and related usage data a number of conclusions
are drawn.

( a)

(b)

(4

(d)

W

The time-shared PL/ACME system has been of great benefit in
fostering the medical use of computers at Stanford.   It is
expected that the needs for these services will increase in
volume and sophistication.

The 360/50 processor does not have the through-put capacity
to provide adequate response service to existing heavy
loads and is inadequate for closure of sophisticated
realtime loops.

Even with the large core memory available, core limitations
impact perfo.rmance and accessibility.  A more sophisticated
allocation of resources based on swapping and hardware
relocation or on paging is required.

The allocation of priorities to running tasks is too
democratic with a resultant impact on applications with
critical response timing requirements.   Additional
sophistication in the hardware and software priority
hierarchy is necessary.

Satellite machine programming and communication as well as
real time needs will increase in terms of number of
machines, complexity of application, aggregate data rates,
and number of users.  The system must integrate more
flexible hardware and software satellite machine support
into its repertoire.


(16)

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(f) More sophisticated usage of the system requires access to
  additional languages (such as list processing languages),
  more flexibility in organizing programs in terms of overlays,
   and more flexibility in overlapping task functions.

Future Needs - Based on these considerations, existing benchmarks for
program through-put, and estimated new hardware and software requirements
in support of research goals, the following gross summary of facility
requirements is appropriate:

CPU:

2-4 times the through-put of the 360/50 with
address relocation or paging and an interrupt
hierarchy.

Memory:    Approximately lo6 bytes of memory.

Bulk Storage: 4-8 x lOa bytes.

User Load:    Research (this grant):  20-40 terminals
         (4 to 6 projects).

Service: 50 - 100 terminals.

Satellite Machine
Interfaces:    Satellite machines will be used both for remote
           instrument interfaces and for local multi-
         processing host support.  Capabilities for
         direct memory sharing as well as normal
           satellite interfaces to the host as terminals
         are required.

System Software:  The system software must allow effective
         scheduling and integration of conflicting time-
         sharing, batch and realtime computing loads.

4.  Configuration Topologies

The requirements and priorities for computing services within the Medical
Center place conflicting constraints on a computer facility.   Some
users require continuous, highly reliable service and others want access
to develop system hardware and software capabilities which have an
attendant risk of system crashes.  Still others want sporadic dedication
of sizable computing resources with response time constraints, and
administrative elements of the computing load utilize software packages
which require specific hardware and operating system characteristics
(e.g. IBM developed business systems).  One can consider a variety of
facility configurations to attempt to meet these needs ranging from a
large single processor to networks to completely distributed machines
satisfying specific local needs.


(18)

Single Central Machine - The single machine topology is not a satisfactory
solution because the conflicting priorities and reliability requirements
cannot be resolved simultaneously in an adequate fashion.  Serial scheduling
of the conflicting usage is not feasible either because of time constraints.
The duty cycle for reliable service support for medical research, clinical
service, and hospital administration can be expected to approach 24 hours
per day.  The requirement for reliability implies more than one machine
to guarantee minimum interruption in service.

Network Facilities -  Machines of adequate capacity and with applicable
software system capabilities exist at a number of nodes on established
networks such as the ARPANET.  Currently, however, because of the
developmental nature of specific facilities or operational constraints,
no known node or set of nodes can commit the needed capacity with suitable
response time and reliability to meet estimated Medical Center needs.
These factors rule out network facilities in the near term for providing
computing services.

Distributed Local Computers - The completely distributed system is
equally unsatisfactory at present because of gross inefficiency.  Rarely
can individual users keep a machine fully utilized for most research
work proceeds sporadically.  Whereas the cost of processors is decreasing
dramatically, the cost of peripherals and memory as well as small
machine prograrruning is still high.  Thus either gross inefficiency re-
sults or the individual researcher must make do with a machine of less
capability than required.  It is not feasible in the near future to
completely rely on distributed machines without the necessary ability
to synergize and focus large processing capability on specific problems
as required.

Dual Central Machine Compromise - This leads to a compromise dual machine
topology for the Medical Center computer facility which meets the
simultaneous needs of conflicting users.  The general characteristics
of such a system are shown in Figure E-2.This system allows the maintenance
of reliable computing service by shifting system element commitments
at the expense of lower priority uses in the event of some failure.
Conflicting requirements are resolved through the scheduling of separate
processors.  The Research and Service subsystems should be of similar
configuration allowing interchangeability to achieve reliability for
service support.  In addition the symmetry of this configuration provides
for software interchange in the evolution of the fruits of computing
research to a more routine service environment.  Economy is advanced
by geographic contiguity implyin g shared operations as well as peripheral
and communications equipment.

The service computing subsystem has as its basic design goals the
distribution of reliable computing support for PL/ACME time-share users,
realtime computing as it develops, small machine support, and admini-
strative computing.  This system will be funded on a fee for service
basis using the currently projected ACME customer base as well as
anticipated network users.


(19)

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The research computing subsystem has as its basic design goals the
support of work under this grant proposal.  These needs include an
evolving PL/ACME based system to develop satellite computing support
(remote and local) and extended realtime systems in an environment
tolerant of developmental system volatility.  This system also provides
back-up to the service machine in case of failure and allows service
system modification without impacting on-going service.   The research
system will be funded out of this grant if approved and will include
provision for documenting and passing developed capabilities into the
service domain as they become available.

5.  Hardware Selection

a.  Main Frame

The selection of hardware elements to carry out the facility plan shown
in Figure E-Z requires consideration of several issues:

(a) The current configuration and its suitability or adaptability
   for future goals.

(b) Alternative hardware systems including capability and
   reliability.

(c) Alternative software systems including capability and
   reliability.

(d) User community contributions to software developments.

Current System - As indicated previously, the ACME system is an inter-
active time-sharing concept implemented on a large memory IBM 360/50
computer.  The system as it exists supplies a powerful service to the
Stanford community and could supply that service to a broader community
given expanded through-put capacity.  Such expansion in capacity is
possible by incorporating a faster processor with more memory or a
faster processor with a swapping relocation core sharing scheme.   IBM
will eventually make such features available on the more reliable 370
computer line.  The current 512K byte memory limitation on the 370/145,
however, is not contemplated to be expanded.  This would force an
expanded implementation in the much more expensive 370/155 or in an old
machine, the 360/65-67.

Future Needs - The proposed research in this grant application, based
on the PL/ACME system, places several additional requirements on the
future system.  First, the system must allow interfacing other languages
(such as LISP, Assembly language, etc.) in addition to PL-1 and permit
a more sophisticated hierarchical structuring of programs and their
interfaces to on-going realtime events.  This implies a system which
at one level is as easy to use as the present PL/ACME system but which
affords, when desired, the opportunity for deeper control of computer
functions without having to convert to an entirely new system
environment.  It is recognized that these levels of user control may
endanger system reliability through user-caused software crashes.


(21)

Secondly, the original system design did not foresee the proliferation
of small machines which has occurred.  Our research goals in the
present plan include developing effective means for supporting and
incorporating such systems in the distribution of computing services.
This implies a requirement for more flexible ways of interfacing large
and small machines in the form of memory to memory and CPU to
external memory linkages.  These go beyond the simple terminal or I/O
device data forwarding roles currently in use.

Thirdly the design of realtime systems which allow "intelligent" loop
closure commitments within time-sharing environments requires in
addition to satellite machine interface flexibility, internal machine
priority hierarchies, basically hardware implemented but with software
control and extension.

Manufacturer Considerations - The size limitations of the 370/145, the
high cost of the 370/155, the design age of the 360/65, and design goal
considerations, suggest a reassessment of the selection of IBM hardware.
This suggestion is enhanced by IBM's currently loose commitments to
future time-sharing and realtime system support.  The IBM systems
provide a primitive priority and interrupt hierarchy and little flexi-
bility in satellite processor interfaces.

From cost, hardware, and software points of view DEC equipment appears
attractive.  The PDP-10 hardware system (in particular-the KI-10
processor) is of moderate capacity approximately comparable to the
360/65 and costs 30% less than the 370/155. The system is expandable
to a multi-processor configuration to increase capacity at relatively
low cost and has features comparable to those available on IBM
hardware.  These include soft fail machine check, hardware address
relocation and paging (IBM will announce these shortly), and instruc-
tion look-ahead.  In addition to these features, however, are a
hierarchical interrupt structure and direct memory interfaces to
satellite machines including other PDP-10's as well as PDP-11, and
PDP-15 minicomputers.  The software system is efficient and is designed
around the integration of time-sharing, batch processing, and realtime
computing taking advantage of appropriate hardware features.   The
PDP-10 community includes many research facilities working on aspects
of machine architecture, system development, language support, arti-
ficial intelligence graphics, etc.  These features of the PDP-10 and
the computer science user community appear to be more in line with
projected research and service requirements.

Other manufacturers offer hardware which incorporates many similar
advantages but these systems lack the evolved software systems and
applications packages as well as the large, actively working community
of contributers which the DEC system has.  Whereas IBM has a large
community of users, the present impetus in the directions appropriate
to this research are questionable.  Thus, based on current information,
it is felt that the PDP-10 offers a better technical and more


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economical long term posture for the experimental computing facility.
This decision implies the judgment that the cost of converting the ACME
software to run on a PDP-10 is offset by the longer term advantages
expected to accrue from the more sophisticated system hardware and
software support.  The conversion effort is estimated to take 5.5 man
years.  A hardware change is painful but is less so the earlier it is
made.

Hardware Configuration - The computer configuration as currently planned
for the research subsystem is shown in Figure E-3. The service machine
could appear as a symmetrical system.

b.  Peripherals, Data Channels, and Satellite Computers

Attention is given here to the balance of the proposed hardware system.
The RMlOB drum is essential to DEC core swapping software.   Certain
other facilities are standard:  The card reader and punch, line printer
and operator's console need no explanation.  The TD-10 controller and
DEC tape units are necessary for maintenance of the PDP-10 system, hence
a minimum configuration is included.  9 track tapes are selected for
archive dumps, and some job entry or data interfaces with other computer
facilities.  A 7 track unit is included as experience has taught us
that this tape format is still in use and a research facility must cope
with this format from time-to-time.

Data Channels - This computer will quite literally exist for the
processing of data from and to distant sites. Thus the remote data
channels are of utmost interest.  It is not intended to make a research
project out of the communication aspects.  On the contrary, it is
proposed to have a set of solutions that can be implemented promptly
and predictably in any laboratory, observing the due constraints of
distance, cable, and rates.  This service is to include diagnostic
means for verification or troubleshooting.

Four classes of external communications are provided for:

1.  Asynchronous character.  100 to approximately 400 baud.
  Suitable for TTY and other keyboard devices, many CRT
   terminals.

2.  Synchronous character.  Nominally up to 40,000 baud.
  Communication is suitable for telephone lines and will use
  nationally recognized standards.  The modems used will be
  of standard commercial design,the proposed system uses
  exclusively DEC modems on the central computer end.

The user may use commercial equipment of his choice on his
end; however, there will be a unit available that incorporates
a small remote satellite computer that is capable of running
diagnostic programs to verify data communication to any


(24)

remote location.  Also this unit will be a "preferred" design
for standardization.

3.  Binary data channels.  Up to 1OOK words/second.  This would
  be restricted to on-campus connections that have multi-pair
   cable connections.  Probably there would be a 3 pair, 11 pair
  and 19 pair version with somewhat different maximum speeds.

The Binary Data Adaptors will be locally built. A characteristic
is that both ends will plug into a PDP-11, or identical Unibus
Models for this exist at Stanford in two versions, the IRL
Chemistry-Medical Center connection, and the ACME small computer
interface.

Experience with many versions of these interfaces have taught
the necessity of having standard service and connections to
avoid the repetition of special engineering and resulting
difficulty in maintaining service. The configuration of
Figure E-4 provides standard service and is a configuration
that may be checked by diagnostic software.

4.  The need may arise for a superspeed data interface. None has
  been standardized for this purpose, but provision is being
  made to access Memory Bus #4 through the MXlO multiplexer for
  this purpose.

Alternate Ports for Types 1, 2, or 3 Channels - It is proposed currently
to bring type 2 and type 3 channels into a local satellite computer. A
trade-off exists here between hardware and software costs which will
require further investigation.  There is no commercial standard DEC
service for type 2 to the memory bus or the I/O bus.  For this and
economy reasons the satellite PDP-11 is indicated.  The hardware
connection is to the PDP-11 bus, hence the configuration allows flexi-
bility in moving any type 2 or type 3 channel to any of the local
satellite computers.

Satellite Computers - To connect a PDP-11 to the PDP-10, the PDP-lO/ll
interface is indicated.  This is a powerful but expensive device. It
allows the PDP-11 to use segments of PDP-10 core.  The segments allotted,
and the interrupt service between computers, is enabled by the PDP-10.
The PDP-lo/11 interface also allows up to 8 PDP-11's; 4 are included
in the present configuration.  Incremental PDP-11's are economical and
this allows exciting possibilities of small computer arrays for
pipeline and parallel processing.  This extra usefulness is thus a
low priced expansion of the PDP-ll/lO capability.  The fourth PDP-11
has been configured as a DEC disc operating system.   It can be used as
a facility in a purely DEC fashion toassistother DEC users and the
SUMEX staff in their software and interfacing efforts.


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General Options - One of the most perplexing dilemmas confronting configu-
ration planning today is the evolving technology and economy of memories.
We have shown our planned configuration incorporating strictly DEC equip-
ment including memory for simplicity.  We are well aware, however, that
DEC memory is not currently economically competitive and as indicated
earlier in the small machine support proposal,  the cost of large elec-
tronic memories in general is precarious and likely to drop significantly
in the next few years.  Whereas we must obtain sufficient memory immedi-
ately with our machine to allow initial developments, we will carefully
consider a variety of manufacturers, incremental expansion, and leasing
so as to optimize our posture for taking advantage of these new memory
developments as they become available.  A corollary problem exists in the
peripheral equipment field such as disk drives.

In addition to these component problems several options exist in the de-
sign of terminal interfaces and synchronous data interfaces with the PDP-10.
These trade-offs involve the relative cost and technical desirability of
using a minicomputer interface which could require system software modifi-
cation as opposed to standard DEC interface systems,

In general, the specification of a particular approach here does not pre-
clude the lease or purchase of an alternate as long as system performance
is optimized, the cost is attractive, and the agencies and regulations
permit.  In fact every effort will be made to search the market for the
most effective and economical alternates, consistent with design goals.

6. Implementation Plan

The implementation of the proposed dual machine facility must proceed so
as to minimize the impact on on-going service computing.  The phased con-
version effort is shown schematically in Figure 5.  Under this grant, the
first PDP-10 machine will be procured and the PL/ACME software converted
to run utilizing the PDP-10 time-share monitor functions and relocation
features.  When this system is checked out, the 360/50 will be removed
with the service computing functionwholelytransferred to a second PDP-10
installed to take its place.

The facility accommodations for the two machines can be made within a
straightforward modification of the current 360/50 facility.  This modi-
fication is consistent with currently approved building plans for a cor-
responding arcade in the Medical Center; no formal commitment to these
modifications has yet been requested from the University.


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F.  RESOURCE PERSONNEL

The senior personnel associated with this grant's core research activity will
include Dr. Joshua Lederberg, Principal Investigator, Dr. Edward Feigenbaum
Associate Investigator, and the technical staff with considerable experience
in the development of computing techniques.

Among the technical staff currently employed in biomedical computing is Thomas
Rindfleisch who supervised image processing development in an applications
group in the Jet Propulsion Laboratory prior to coming to Stanford. He played
a central role in developing the image processing for the Mariner Mars 1969
Space Photographic missions, which has also been extended to the realtime
analysis of Mars photographs in the current (1971-72) Mariner program.  These
studies have also led to on-going advances at JPL in image enhancement of X-ray
images, light microscope images, and other biomedical applications.   At Stan-
ford he has been engaged in the design of extended realtime systems for the
DENDRAL Project and in planning activities for Medical Center computing in gen-
eral.  His nine years of experience in digital image processing at JPL provide
a solid base of capability with which to undertake the imaging portions of the
collaborator's projects.

Another member of the technical staff is Gio Wiederhold who led the design and
implementation of the ACME time-sharing system. After directing the ACME
facility for its initial five years, he participated in the design of a new com-
puter architecture and consulted regularly with biomedical computer users. In
the recent past he has assisted a number of new realtime users on the ACME system
with their data acquisition problems.

Another senior member of the technical staff is Lee Hundley, who implemented
much of the realtime data collection system under ACME.  In addition, Lee Hundley
has written the assemblers for PDP-8's and PDP-11's which are currently available
to ACME users and has supervised the systems development group during the past
three years.

Dr. Walter Reynolds has been working in the Instrumentation Research Laboratory
for several years and has authored a number of publications on realtime connec-
tions of laboratory instruments to computers.

Other members of the ACME computing facility have significant experience in com-
munications, file handling, compiler improvement, graphics, small machine
assemblers and simulators,and related fields.  Important contributions to the
proposed goals can be made by a number of well-experienced staff members.

One member of the systems programming staff will serve as a, point of contact
on each collaborator's project.  We would expect these programmers' loyalties
to rest with the collaborator's objectives.  It is felt that such an assignment
would help to produce good communication and cooperation.

The collaborators who will perform the research for this proposed grant are a
group of sophisticated, experienced computer users.  Both the medical staff and
the programming staff have achieved notable success in the past.  The program-
ming staff in the Division of Cardiology, led by William J. Sanders (formerly
of the ACME staff), has achieved notable success in realtime monitoring of
cardiac catheterization procedures and video image analysis.  Chris Constantinou
in Urology has spent the past three years studying the movement of the ureter
using animal subjects connected in realtime to the ACME system.  The Instrumen-
tation Research Laboratory in the Department of Genetics has made major contri-
butions to the DENDRAL and cell separation projects.  Included in the IRL


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engineering and programming staff are Dr. Walter Reynolds and Mark Stefik.
Additional examples of accomplishments by current staff are briefly described
in the collaborators' research statements and the lists of publications
attached to the biographical sketches.

Another example of highly significant computer related research at Stanford
is DENDRAL.  This project has achieved acclaim as an artificial intelligence
project performing automated interpretation of mass spectra.  A number of
publications authored by this group are cited in the collaborative project
description and the individual biographical sketches. This research team
adds considerable depth to the measure of technical talent affiliated with
the proposed resource.

Over these past six years, ACME has had a number of outstanding successes.
The initial implementation of a time-shared interactive complex in eighteen
months was a feat of some magnitude.  The accomplishment of a medium data
rate, realtime data acquisition and control system in the framework of a time-
shared system is impressive.  ACME's major accomplishment, the education of
the user community, can best be appreciated by noting that over 1000 people
have attended ACME courses in the past five years. These accomplishments
are attributable to the excellence,  dedication and motivation of the ACME
staff.


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G.  RESOURCE ACTIVITES

1.  Services to be Provided

This proposal calls for the creations of a research resource called SUMEX.
SUMEX will offer services of four types:

a.  Central computing hardware (primarily in the form of a DEC PDP-10
  system with KI-10 processor, 192K words of main memory and 4
  satellite PDP-11's connected via a PDPlO/ll interface.  See figure
E-3.) for use in computer science related research in biomedicine
and development of new hardware interfaces to users' peripheral
  minicomputers.

b.  Development of software support under a core research program and
  software support for collaborative research projects.

C.  The resources will provide backup computing facilities for the
  Stanford University Medical Center Computer Facility.

d.  The resource will include a group of people with strong technical
  skill to support computer-science type research in the biomedical
  community.  Some additional personnel resources which can be shared
  among several collaborators are planned; the applied mathematician
  in the budget is one such position.

The SUMEX resource will support research on advanced computer applications.
Specific examples of support anticipated are listed in the core research
and collaborative projects described below.


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2.  Research

a.  Core Research

(1) Satellite Machine Support

(a) Problem Statement

(1) Limitations of stand-alone small computers.  The primary limitations of
  existing stand-alone systems are  a) the economics of primary and secon-
  dary stor.age and b) the lack of highly sophisticated software.  Secondary
  storage costs for small stand-alone systems tend to run twice the corres-
  ponding costs on large systems.  Primary storage (core) costs approximately
  24 per bit for Ampex bulk core memory (i.e., for the 360/50) capable of
  running at approximately 2.4 microseconds.  DEC supplied 1.8 microsecond
  memory for the PDP-11 costs approximately $3,000 for 4K words or 4.54 per
   bit.  The second major limitation of stand-alone small systems is the
  limited support for sophisticated programming languages and interactive
   capabilities.  This implies that large amounts of effort are spent for
  software develoment even in rather simple applications.  Some additional
   limitations are as follows:

(a>

(b)

(cl

(d)

Because the hardware investment is low, users seem to have difficulty
justifying significant programming effort. Only users with a large
number of similar machines can justify a substantial software sys-
tems effort.

The manufacturers tend to scale their system software to the smaller
end of the line.

Owners of small machines lack easy access to one another's data
base because their planning has assumed dedicated use of the hardware.

Finally, the software systems do not provide the ability to concur-
rently utilize a variety of system capabilities.  For example, one
cannot be performing realtime data acquisition and editing programs
simultaneously.

(2

Attributes of large host systems.

(a) Needs not met by satellite systems.  A large host computer can pro-
  vide an array of services not available to stand-alone small
  machines in today's technology.  Among such services are:

(1)  access to large volumes of source programs,

(2) ability to edit them efficiently,

(3) ability to concurrently use multiple system capabilities,

(4)  availability of highly sophisticated programming languages and
  interactive capabilities,


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(3)

(5)  availability of broader

(6) shared access to common

(7)  more extensive software

line of peripherals,

databases, and

support from the hardware manufacturer.

(b) Special attributes of larger systems.  Larger systems such as the
  PDP-10 can directly address large quantities of memory (the PDP-10
  can address directory up to 256~ words).  The large system has more
  input/output ports which can operate concurrently.  Large machines
  provide a standard capability for handling scientific calculations
  (floating point hardware, etc.).  Hardware and software systems are
  currently available for measuring performance on large systems; this
   cannot be said for most small systems.

(4

Impact on users.  The objective of this part of the proposal is to
provide to the small stand-alone user a link to a larger system.
The link will make available to the satellite system services which
can be obtained today on larger systems but cannot be obtained today
on smaller systems.  Thus, the satellite user will have available
more sophisticated programming languages, access to cheaper primary
and secondary storage, shared database, shared communications sys-
tems, backup support for large computational problems, and an overall
significant degree of labor saving.  In today's computer environment,
most users can expect to spend two or more times their hardware in-
vestment for software development.  The trend of this curve is to
increase software costs relative to hardware (some say geometrically).

Small machine users have adopted patterns of thought which were appro-
priate to dedicated stand-alone systems. Part of the mission of this
grant will be to demonstrate the feasibility of broader services
which could be available in satellite mode and to expand their deci-
sion-making analysis to include more flexible and sophisticated com-
puting services.  If successful, the program should also enable the
medical user community to save a considerable cost in hardware and
software.  Most satellites would no longer require an extensive col-
lection of peripheral hardware.

Anticipated direction of some technological innovations. Given the rapidly
expanding market for computer-based applications and cost-effective hard-
ware systems, major development effort is being expanded in the industry
for the development of new techniques.  Intelligent planning requires cog-
nizance of the most likely near-term advances in relevant technology, in-
volving the following:

(a>

Primary storage.  Very low cost primary storage will become available
quite soon.  The costs associated with integrated circuit memory can
be expected to reach less than l/10 the cost of the current MOS sys-
tems.  The primary reason for this significant drop in cost is the
removal of the high labor content of current core technologies.   Cur-
rently, MOS costs are close to those of core memories, despite the
fact that it is a very recent development and still heavily burdened
with development costs.


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Secondary storage.  Secondary storage systems are being
developed which will have faster access times and transfer
rates and higher density on the storage media.  Current
secondary storage technology involves physically rotating
memories with inherent mechanical complexity and high costs
of achieving the tolerances required and of maintaining the
the system once installed.  Major breakthroughs in the cur-
rent technology bottleneck appear possible through develop-
ment of magnetic bubble memories and charge coupled devices.
In terms of information made public to date, Bell Telephone
Laboratories seems to be spending the largest effort in both
of these new non-mechanical approaches to large data storage
devices.  Corollary efforts on the parts of other manufac-
turers have a very low profile at this time.

Low cost general purpose processors. The recent development
of large scale integrated circuitry makes possible today the
building of general purpose processors at very low costs.
For example, ITEL Corporation now has an 8 bit central pro-
cessor (designed with MOS technology) available on a single
chip.  The cost of such a component is expected to drop below
$50 within the next year.  It is of greater sophistication
than a PDP-8, although 10 times slower. We anticipate that
such developments will lead to new small computer organizations
incorporating large numbers of such central processing units
dedicated to a variety of applications. Of course this is but
one element in a system, the balance of which includes signi-
ficant cost components.  The impact of this change cannot be
postponement of solutions needed now. We can cite two recent
examples of the development of special purpose processors
which support applications on a general purpose computer.  The
Berkeley Computer Corporation, BCC-1, incorporated a number of
micro-processors which were assigned tasks such as:

(1) file management,

(2) drum scheduling for a large swapping drum,

(3) terminal input/output and control of remote communication
   links.

In order to process large volumes of experimental data in
realtime, Professor M. Schwa&a of Stanford University (SLAC)
is developing parallel processing hardware which can be attached
to a PDP-11 processor via the unibus.  This hardware allows
multiple operations to be performed at a high speed.  One can
add two 16-element vectors together as one parallel operation.
AB well, one can compare 256 data points with one common value
and determine which of these 256 entries is greater than this
common value.  This special purpose processor is extremely in-
expensive and compact.  Yet it provides high speed execution of
many parallel operators such as those found in the APL language.


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(d)

Microprogramming techniques.  Currently, several small computers
permit the modification of their instruction set utilizing micro-
programming techniques.  For example, the Hewlett-Packard 2100
permits the extension of its instruction set by reloading alternate
or modified versions of the basic micro-program.  We visualize
many applications in the area of data processing, communication
control, and data compression which would gain substantially
from new instructions specifically designed to improve the through-
put of these operations.  Previous studies of the implementation
of microprogram techniques have indicated one to two orders of
magnitude improvement in the handling of special problem areas
such as communications control.

(e) Interactive graphics hardware.  The development of low-cost inter-
  active graphic hardware is anticipated in the near term.  Today,
   a display scope, vector generator and keyboard costs on the order
  of $6,000.  We would expect this cost level to be reduced to the

$1,000 to $2,000 range in roughly three years.  The primary reason
for the price reduction is mass production coupled with lower
component cost.

(f)

k)

High speed remote links.  High speed remote links will become
available as conventional communication industry services are
extended.  Current networks such as APBANET and TYMNET are initial
entries into this general utility field.  The Bell Telephone Sys-
tem is currently testing a 500,000 bit per second line and will
offer experimental lines at this rate,  We do not contemplate
early connection to such networks, but are watching their evolution
closely as a future option.

Time multiplexed ring, The introduction of a commercial time
multiplexed ring for digital communication started approximately
three years ago in the form of the Collins C-System. This concept
carries the potential of offering very high data rates at very
low costs for inter-device communication. The data rates are
sufficiently high that one could consider sharing memory among
several satellite processors.  It also provides a framework in
which a number of satellite systems can be assigned selected
portions of a common task.  This concept may provide a redundant
communications path among a large number of instruments and sat-
ellite machines throughout the Medical Center.  A related devel-
opment could well be a simple integrated circuit interface making
it possible to inexpensively connect devices to the ring.

Perhaps, smaller subrings could be installed to individual labora-
tories.  This ring would interconnect many experimental devices
to one or several of the satellite computers. We believe that
such a system would greatly reduce the problem inherent in inter-
facing large numbers of individual experiments to small satellite
computers.  The time division multiplexed ring may be compared to
the PDP-11 unibus.  The control features and inter-device communi-
cation paths are quite similar,  The major difference is in the
time division nature of the proposed ring which simplifies multiple


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highspeed communication over a single path and also requires
only one interconnecting wire rather than the number of wires
in a PDP-11 unibus.

(h)

(i>

A time multiplexed ring on coaxial cable would have desirable
characteristics for connecting satellite computers.  This would
provide a daisy chain in which very high data rates could be
accepted.  It would also provide a very reliable hardwire con-
nection.  In addition to the possibility of replacing fixed head
disks with core on a ring, one can hope to replace small expen-
sive fixed head disks with a few large moving head disks.

Reliability.  One general result of technological innovation will
be substantial improvements in hardware reliability.  This is a
key point relating the use of satellite systems to the medical
environment.  Improved reliability can significantly impact the
architecture of future medical systems.

Satellite software.  As the problems of inter-device communications
approach solution, we could expect to see satellite processing
units designed to handle higher level languages efficiently.
There are several examples of powerful high level language process-
ors currently available from computer manufacturers.  The Burroughs
B 1500 provides specialized micro-computer support for COBOL, ALGOL,
and systems programming applications.  The SYMBOL machine developed
by Fairchild utilized many cooperating processors to provide a
high level language environment.  These processors were dedicated
to the tasks of syntax analysis, storage management, garbage col-
lection, and input/output handling.  Also, commercially available
is the Hewlett-Packard System 3000.  It too provides a machine
organization optimized to support a higher level language processor.
A processor for APL is under development at the University of Calif-
ornia at Berkeley.  This system utilizes special microprogram tech-
niques on a Digital Scientific Corporation META 4 computer.*  Each
of the systems we have mentionedattemptsto reduce overall software
costs by incorporating special features and language oriented archi-
tecture within a satellite computer.

(b) Background and Rationale

(1) Current environment for satellites in S. U. Medical Center.   Stanford
   Medical Center today has approximately two dozen small stand-alone computing
   systems.  They range in size from PDP-8's with 4K of core to a Sigma 3
   with 32K of core,  Some systems are being established to provide routine
    service.  Examples of this include a Sigma 3 in the Clinical Laboratory,
  PDP-11's for Drug Interaction service in the Hospital Pharmacy, and an
  HP 2116 for physiological monitoring in the Catheterization Laboratory,
   and an HP 2100 being prepared for monitoring in the Cardiac Care [init.
   Some of the research applications which currently use mini systems in-
   clude PDP-11's for control of data acquisition and mass spectroscopy,

* "A Firmware APL Time-Sharing System", AFIPS-Spring 1971, R. Zaks, D. Stien-
gart and J. Moore, U. C. Berkeley.


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(2)

two PDP-12's for realtime data acquisition research in Cardiovascular
Surgery and Psychophysiology, a number of PDP-8's and an HP 2116 for
research in Psychiatry and Cardiology, and an HP 2100 for realtime data
acquisition from nuclear cameras  for the Division of Nuclear Medicine.
A number of these systems will be connected to the ACME system during
the summer of 1972 via a new small machine multiplexor interfaced to
the 360/50 by a 16 bit PDA port on the 2701.  A few have been connected
to ACME in the past via the IBM 2701 and 270X. Research groups in the
Medical Center have hired approximately 20 scientific programmers (ex-
clusive of the ACME facility staff) to work primarily on new applications.
In addition the ACME Computing facility has a number of programmers well
versed in small machines.  ACME is used as a consulting source by a
number of the small machine users in the Medical School.

Initial approach in software.  The small machine support development
effort will initially be concerned with providing sophisticated soft-
ware support for existing hardware in the Medical School.  Specifically,
it is our intention to provide a large number of new services for PDP-11
users and HP 2100 users.  The new services will be software extensions
to the systems currently provided by DEC and HP.  For example, satellite
machines will be given the ability to read and write files on the disk
attached to the large host system, to communicate with other satellites
in the network, and to prepare most of their software from a terminal
connected to the host.

(3) Incorporation of new hardware techniques.  In addition to the task of
  adding software to better serve existing satellite computers, it is
  our intent to integrate the new hardware technologies listed above
   within the Stanford medical environment.  One possibility would be the
  modification of the HP 2100 system using micro-programming techniques.

Historically, the manufacturers of small computing systems have been
slow to provide software support for new hardware technologies. Al-
though DEC has announced its PDP-11/45 with memory segmentation hard-
ware, no operating system has been announced to make use of this new
feature.

One-reason for selecting the PDP-11 as the primary small system to be
supported under this program is the expectation that the PDP-11 family
will continue to be the primary focus of DEC support over the next
several years in the minicomputer market and that it will have broad
acceptance.  This market acceptance in turn will lead to new technolo-
gical innovations being made compatible with this particular line of
hardware.  Two examples of hardware support needed for the PDP-11 are
a) the ability to execute programs in PDP-10 core from a PDP-11 and
b) the ability to utilize PDP-11's as links in a network.

C. G. Bell of Carnegie-Mellon is currently developing a computer net-
work utilizing a large number of interconnected PDP-11's which share
one common  extremely large primary store.*  This system is being

* "Cmulp:  The Multiminiprocessor Computer", C. G. Bell, W. Brody, W. Wulf,
and A. Newell, Dept. of Computer Science, Carnegie-Mellon University.


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constructed in order to provide an appropriate computer system for the
realtime processing and recognition of human speech.  Their proposed
system appears extremely economical and well thought out.  It provides
a highly reliable environment in which a large number of small processors
can intercommunicate and cooperate in the processing of a realtime
analysis.  The results of their research may have a significant impact
in understanding the benefits or problems in interconnecting large num-
bers of small satellite processors.

Finally, the overall goal of intelligently managing large volumes of
source data in a realtime environment, andprocessinglarge bursts of
data with highly variable content and significance, will require coordin-
ated and sophisticated use of small computers operating as satellites
to the large host machine.  No major computer manufacturer appears to
place the solution to this problem high among the list of software sup-
port goals.  For example, much of the realtime support being developed
in the computing industry today is designed to support industrial manu-
facturing processes which do not in general have high burst data rates
and sophisticated computational requirements.

(4) Resolution of specific goals with collaborators. Early in the process
  of scheduling specific small machine support tasks, we will engage our-
  selves in extensive discussions with collaborators to determine which
  of their needs carry highest priorities and which of our proposed ser-
  vices should receive highest priority.  A firm understanding of the
  user's environment is essential to the small machine support team. It
  is our intent to avoid the common pitfall of finding the solutions for
  which no known medical problem exists.  This can only be done by close
  cooperation and collaboration with our prospective users.  No large
  research tasks will be undertaken in the area of small machine support
  until a collaborator has been identified with a specific set of require-
  ments to be met. This position does not prevent the development team
  from attempting to raise the horizons or expectations of the potential
     users.


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(c) Methods and Procedures

(1) Satellite system software support

(a>

Assemblers.  The advantage of providing assemblers on the large
host machine is that satellite users are permitted to flexibly
save, edit, and assemble source programs for new applications.
In addition, they have the advantage of better error diagnostics
in far less time than is the case on their dedicated systems.
At present the ACME system supports assemblers for the PDP-11,
PDP-8 and the IBM 1800.  (This will be extended to include the
HP 2100.) The existing assemblers will be updated from time to
time to take advantage of the extensions to the manufacturer-sup-
plied operating systems as described below.

(b) High level language support.

0)

Machine dependent.  We can simplify the code generation process
while maintaining highly efficient execution on the satellite
processors by introducing new languages modelled after PL/360
or BLISS.  The applications programmer will be able to obtain
optimal machine code without the need to be concerned with all
details of architecture of the hardware upon which he will be
running.  The programmer is not prevented from inserting
machine language where he feels he can improve upon the facil-
ities provided.  Over a five-year period, we would expect to
spend roughly two man-years on this effort.  Carnegie Mellon
has produced a BLISS-11 and CERN Laboratory in Switzerland is
producing a PL/ll.  We will select the best support from among
several such development efforts and make them available at
the Stanford Medical Center.  We will not concern ourselves
with the provision of standard language support in small
machines as this is already being undertaken by manufacturers
and others.

(ii) Machine transparent.  The second class of non-machine-oriented
   language support deals with non-standard languages such as
   APL, SNOBOL, and LISP.  Providing a subset of APL is highly
   appropriate for satellite machines.  We intend to define new
   APL-like primitives and couple then with a subset of existing
   APL primitives to provide a high level language support for
   realtime medical computing.  We want to make available an
   interactive language with user-oriented runtime diagnostics,
   simple language structure, and the ability to modify programs
   without complete recompilation or assembly, coupled with
   graphic output.  Some examples of such primitives are:

a.  Smoothing primitive.  This primitive would employ a number of
  arguments such as window size, resolution, convolution
  function, or other user-supplied arguments.   The second
  parameter would be the new data.  The primitive would
   return smoothed data as its value.


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(cl

b.  Peak Extraction Primitive.  This would return the coordi-
  nates of all peaks found above a threshold provided as a
  parameter by the user.  If the data provided is a vector,
  the primitive would return the set of index values at
  which the function attains its peaks.  If the data are
  paired coordinates (the first being the data point and
  the second being, for instance, time) then the primitive
  would return the peaks and times, possibly interpolated
  between two time values.

C.  Curve Fitting Primitive.  The parameters associated with
  this primitive would be data and name of a system or user
  function which would provide the shape of the curve to be
   fitted.  The primitive would search for the parameters to
  the function which provide the best fit among the user
  supplied data points.  The user function will automati-
  cally handle fitting of overlapping peaks as a natural
  outgrowth of the nature of the APL language.

Some of the current APL operators which would be very
useful in a realtime environment include matrix manipu-
lation, sorting, bit manipulation,  and conversion of raw
BCD data to binary by using the encode operator.

Realtime applications module library.  Some of the items expected
to be provided are the following:

(0

(iii>

(iv>

Data collection routines.  These would include automatic
sampling of selected data channels at user specified breaks,
interrupt driven data collection, and automatic scheduling
of resources on the inter-computer communication network.

Data compression routines such as the Aztec procedure devel-
oped by Dr. Jerry Cox for compression of EEG data at
Washington University in St. Louis.

Input/Output buffering routines.  These routines would auto-
mate core management since, due to the great variability of
data rates, a sophisticated scheme is necessary.   Extensive
effort will be needed in this area because manufacturer-sup-
plied operating systems have not addressed themselves to the
high data rate, burst mode, realtime data collection problem.
The intelligent management of such data streams will require
innovative techniques in core management.

Peripheral handlers.  We wish to provide a standardized
approach to unique peripherals similar to that currently
provided by the manufacturers for standard peripherals.
The newly developed peripheral handlers (for instruments
such as mass spectrometers and gas chromatographs) can
then utilize a standard interface to the operating system.


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Cd)

(VI






(vi>

Communications protocol with host computer.  User programs
would interface to the communications network via roT:tInss
present in the applications library.  The detailed operation
of the communications system need be no more apparent to the
user than the details of a disk or tape controller would be.

Debugging packages.  Along with all the new facilities out-
lined above, we must provide the user with a complete set of
debugging packages for realtime control systems. This func-
tion is essential in any realtime environment, where any one
of several links in the total chain may prevent satisfactory
operation.  The ACME facility has consistently found it
difficult to identify just which link in the chain is defec-
tive (despite the best efforts of good engineers and program-
ming talent!).

Extensions to manufacturers supplied operating systems.  Handling
realtime functions and using multiple processor configurations are
two examples of activities contemplated here which are not covered
by current operating systems but are needed in our labs.
Our computing objectives cannot be met without extensions to what
exists.  For example, DEC permits several PDP-11's to be connected
via Unibus links, but no multiprocessor software is provided for
this (marketed) configuration.  The particular problem areas where
extensions are required have already been described above.


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(2)

Computer to computer communications,

(a) Data transfers,

(i)

To share peripheral equipment.  Software support should exist
to make possible the sharing of peripheral devices on a host
computer with all satellite processors.  For example, high
speed printers on the host should be accessible to data
collections or data analysis programs on satellite systems.
Similarly, results of data analysis on host machines should
be available at printers connected to satellite systems. It
is hoped that our commitment to software support for shared
peripheral equipment will reduce the overall number of
peripherals required in the Medical Center.

(ii) To move data to other systems.  Data transfer software
  support will facilitate transfer of data collected on mini-
  computers to the host system and vice versa.  In some cases,
  an intermediate system will serve as a store and forward
   device.  In this way users will not be dependent upon the
  availability of the large host machine for long term data
  collection problems,  A specific example of data transfer
  among satellite systems is the need for sharing of informa-
  tion between Clinical Laboratory and Pharmacy systems.   The
  interpretation of a certain laboratory result could be
  influenced by the knowledge that a given drug had been
  administered prior to collecting the laboratory specimen.

(iii) Loading of Object Modules.  Software support will be
  developed so that object modules can be loaded to satellite
   machines from the host machine.  In this manner, satellite
  machines avoid the necessity of loading object modules from
  paper tape or other more expensive peripherals.

(b) Controlled interactions.

(i) Start satellite machine (IPL) remotely. Code will be
  developed to permit the startup of a satellite by a program
   in the host machine.  The satellite in turn could be
  programmed to start up various laboratory instruments. The
  benefits of such a procedure are to permit control of
  experiments from one terminal and to enforce a common chain
  of events in the Startup of each day's operation in the
   laboratory.

(ii) Detect failure of other systems. The host machine can be
  programmed to detect failure of satellite systems and
  satellite systems in turn can be instructed to detect
   failure of instrumentation.  In the case of communications
  systems, failure detection is essential so that control of
  the communication system can be passed to an alternate
     source.  The same will be true for some physiological moni-
   toring systems.


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(iii) Network mananement.  Comtec, Honeywell, CDC, and Tymshare
  have devoted considerable effort to programming intelligent
  machines to handle network management tasks.  It is not our
  intention to duplicate this effort.  However, we may wish
  to supplement the existing network management programs by
   adding  realtime SUppOrt functions. One possible step in
  networking will entail the installation of a long-distance
   attachment for the ARPANET IMP.   An IMP exists on the
  Stanford campus at the Artificial Intelligence Laboratory
  directed by Dr. John McCarthy.  The long-distance attachment
  for an IMP is being designed at U. C. Santa Barbara.
  Assuming that the design will work, it may provide a rel-
  atively inexpensive connection to the ARPA Network.  The
  Hardware costs exclusive of "lease" line will be approxi-
mately $15,000. At this time, we have elected to study the
  networking opportunities without further commitment.

(3) Data manipulation.

(a) Data collection

(i) Feedback to local controllers of realtime data flow. Intel-
  ligent management of large volumes of data implies an inter-
  action between the initial data received, the long term goal,
  and feedback to the experimental apparatus.  The closed loop
  situation is one in which special benefits should accrue as
  a result of the small machine support effort.  Development of
  heuristic processors in models should permit increasing
   amounts of feedback to local controllers for instrument
   adjustment, calibration, and data management.

New predictive techniques could aid in image processing. In
classical digital image processing, an image is first
digitized to be in a machine readable form. This requires
lo5 to 10' bits, depending on the requirements for resolution
and grey scale.  At this point, data compression methods are
often applied to reduce storage and computational requirements.
This may result in compression factors of two to ten,
These actions require    a&Xition.al   computation and only
serve to make the data manageable, rather than to extract
information from it.

Another approach is to record only those elements of an image
which differ from the previous image.  This reduces the amount
of data but still does not recognize the fact that for a
large class of images (e.g., a beating heart) the position of
the elements in a new image can be predicted with a high de-
gree of accuracy, knowing the time between images, scale
factor, and direction over the past few images.  Since this
is true, a significantly reduced number of data points need
be taken to refine both the prediction and the model used
to make the prediction.  Gross deviation from a well estab-
lished model might be used to indicate a pathological condition.


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(b)

It is felt that this approach to image processing helps to
reduce the gross data handling requirements to a manageable
level.  It concentrates required complex image analysis
algorithms on that subset of the raw data worthy of atten-
tion.  By using such methods, we feel that significant
results can be drawn for a class of problems of biological
interest.

(ii) Multiple paths to large files.  We plan to provide multiple
  paths to large files from satellite computing systems. In
  this way, we can guarantee access to the large files for a
24 hour day, seven days a week period. Only by providing
  assuance on this point can satellite machine owners be
  convinced to assume the risk of minimizing their local
  dedicated configurations and depending upon shared use of
  larger resources.

(iii) Store and forward system.  One satellite in the system may
  be dedicated to realtime communications management and
  interim storage of realtime data.  The primary rationale for
  having such a facility is  a) to guarantee better response
  time, b) to provide larger storage capacity than would be
  feasible for each of the experimenters connected to the
   system, and c) to assure continuous availability either from
  the host or from the store and forward processor.

Data analysis.

(3.1 Multiple processor allocation.  Optimal use of the resources
  available in a large system implies that repetitive tasks
  should be handed to less expensive processors dedicated to a
  more limited range of tasks.  It is our intent to demonstrate
  that selected subroutines which are frequently used in a
  realtime environment can be passed to a satellite processor
  for execution, thus freeing the host machine for other tasks.

(ii) Software support for special hardware.  Special purpose
  devices such as Fast Fourier Transform hardware, matrix
  multipliers, and graphics aids canbe supportedfor satellite
   systems.  One can make a specialized device available to
  more than one user's laboratory while at the same time
  limiting the software investment for its use.

(iii) Interactive graphics.  Graphic interactions with realtime
  data streams is essential in the rapid interpretation by man
  of "what's going on".  The objective of this effort will be
  to provide a smooth human interaction with graphics devices
  in both directions (man-to-machine and machine-to-man).  The
  anticipated decrease in cost of graphics stations is likely
  to increase significantly the demand for this service.
  Common generalized software for support of such instruments
  can provide an important savings in programming manpower.


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(4)

ACME currently supports a variety of graphics devices in a
flexible manner.  All graphics devices are treated as real-
time output devices.  Associated with the description of
output devices on a realtime line are the programs that
convert a graphic description into the detailed control
sequences required for device operation.  The user needs
only to change the destination number parameter in his
graphic output calls and the identical user program will
drive any of the graphics devices available at ACME.

The devices currently supported are:

a) The ACME TV display (high precision, refreshed by an
  auxiliary core memory).

b) Tektronix 61.1 storage tube displays.

c) Calcomp and Houston incremental plotters.

d) General Purpose Graphics Terminals.

In addition to supporting other display types as they become
available, ACME is planning to extend support for graphics
activities in the following ways:

a) Development of interactive generation of display programs.
  The abstraction of a planned visual image into display-
  driving statements is not always obvious or easy for
   medical researchers.  Computer languages such as PL/ACME,
  while providing all the required capabilities, do not
  express the two dimensional nature of graphs very clearly.
  A question and answer communication between computer and
  user is being prototyped which will generate the required
  instructions using decision trees which systematically
   reduce the alternatives of choice.  The resulting protocols
  can be saved and subsequently modified as desired.

b) Current display support has been mainly oriented toward
  graphics.  The General Purpose Graphics Terminal has the
  capability to handle text.  This facility has been made
  available now to General Purpose Graphics Terminals
   users, but it should be made equally available on the
  other devices supported in graphics mode, which now have
  only limited text capability.

Satellite performance measurement and evaluation. Very little has been
done in the area of performance measurements for small computers. We
feel that there is much to be gained from activity in this area.   Both
hardware and software monitors will be investigated.

It is known that most programs spend a large amount of time executing
a small percentage of their total code.  The classic approach to
increasing a program's efficiency is to locate the most used code and


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recode it in the most efficient manner available.  If a program is to
be written in a higher level language, the ability to "tune" with
performance measurement tools may make code generated by a sub-
optimal compiler (which many small-machine compilers are) acceptable.

Such monitors are also valuable debugging aides. The sorting out of
a sequence of randomly occuring realtime events can be an almost
impossible task without some monitoring ability,  Excess time spent
in error recovery can be located and corrected.  Inadvertent loops
may be detected by monitoring.

It is felt that this type of support for the satellite machine falls
into that class of activity which needs very much to be done, but
which the individual mini user cannot afford to do.


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(d) Signifi cance of satellite machine support.

(1)









(2)









(3)









(4)

Remove the limitations in users' laboratories: Current
satellite machine users continuously encounter physical
limitations in their hardware, such as lack of core, lack of
disk space, lack of registers, inadequate cycles, lack of
generalized data acquisition, reduction and analysis subroutines,
and problems associated with interfacing hardware to experimental
apparatus.  The proposed research program and satellite machine
support will help to overcome most of these limitations.

Reduce effort required of experimentalists: The application of
standard interface hardware to the extent possible will reduce
the amount of active involvement of the experimentalist in this
problem.  Furthermore, availability of tried and tested software
for handling many of the problems frequently encountered in data
acquisition situations will allow him to select from a library
those elements which he needs.  Additionally, the local satellite
machine group will be aware of routines developed elsewhere in
the country through DECUS and other user groups. As the relative
investment in software becomes far greater than hardware, the
impact on the user of extensive satellite machine support will be
great.

Effective easy access to shared data: Computers can truly be
used as a means of sharing knowledge when the large volumes of
machine readable data can be shared with trivial effort on the
part of the user and at acceptable costs. Sharing of data among
Clinical Pharmacology, Hospital Pharmacy, Infectious Disease
Laboratory, other clinical laboratories, and physicians is
currently being requested but has not been provided other than
through manual transport of magnetic tape. In the research area
it is felt that new algorithms, models, new graphics techniques,
and other developments will be shared throughout the community
more quickly with improved communicaticns and file access systems.

Integrate benefits of small and large systems: Both the small
and the large systems offer unique benefits.  The objective is
to realize the synergism believed possible through the marriage
of small and large systems.


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(2) Extended Realtime Computing

(a) Problem Statement and Objectives

State-of-the-Art - Applications of computers have developed over the
past ten years which involve the interaction of computer systems with
various aspects of medical research.  Computers are used in a broad
spectrum of ways in support of the acquisition of raw instrument data,
the reduction and standardization of data quality, the interpretation
of experimental information and building of models, and finally the
design of new experiments to test the models. Historically computers
have performed simple supporting tasks such as prescribed data logging
procedures and reduction computations with human investigators carrying
out the higher level processes of adaptive system control as well as
theory building and testing.  In most cases errors arising from
simplistic computer processing of the data are detected and corrected
by human intervention.  Typically the computer does not have access to
a model of what it is doing to evaluate its success or failure. In
applications involving relatively small amounts of data which can be
collected simply and analyzed without severe time constraints, this
division of labor is satisfactory and economical.   Indeed this
separation is to some extent necessary because computer programs are
currently incapable of many of the complex reasoning and creative problem
solving processes necessary for medical research.

Limitations and Future Needs - There is an increasing number of
situations, however, for which this type of open loop or loosely closed
loop solution is infeasible or unacceptable. The requirements for more
automated loop closure may grow from a variety of circumstances such
as:

(1) Human boredom with making large quantities of precise,
   detailed measurements.

(2) Experiment time constants allowing the collection of only
   a subset of possible types of available information requiring
   judicious on-line selection.

(3) Economy of extracting small sets of significant information
   from large quantities of raw data.

(4) Adaptive experiment optimization and control requirements too
   complex or rapid for human response.

(5) Large and complex information bases or models difficult for
   human manipulation and analysis.

A variety of examples can be listed of applications facing these problems
today and most certainly increasing demands on computing capabilities
of this kind will arise in the future.  Such fields include image
processing and perception (microscopy, radiology, ultrasonics, etc.);


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stimulus/response experimentation (neurophysiology, anesthesiology,
etc.); analytical instrumentation (gas chromatography/mass spectroscopy,
x-ray diffractometry, etc.); and interactive system and data modelling.

Intelligence Requirements - Characteristic of these problem areas is
a requirement for more and more "intelligent" handling of information
within appropriate time constraints.  The term "intelligent" is used
to imply autonomous and adaptive performance of necessary operations.
In becoming autonomous the computer must take advantage of the dynamic
characteristics of the input data and extracted information as well as
previous or evolving problem solutions to economically produce accurate
and reliable results.  In the simplest form, the computer has a model
of its environment relative to the task it is performing and uses derived
measures of success or failure to optimize performance.  In the longer
term more sophisticated reasoning and inductive processes are applied
to an information base.

Difficult conceptual and implementation problems exist in designing
intelligent information handling programs for computers. Beginnings
have been made in developing such capabilities in a few applications.
Much more work is necessary to improve program capabilities and reliability
as well as to explore wider application areas in medicine.

Computing Requirements - As the sophistication of computer processing of
information increases, so does the requirement for intensive usage of
large computing resources.  These requirements are typically applied
over relatively short or sporadic periods of time.   In effect each such
application requires a large dedicated capability for high demand on-line
work and a less responsive time-sharing or batch support for off-line or
developmental work.  Thus the extended realtime user is faced with the
dilemma of needing to control for short periods of time a machine of a
capacity that does his job but which he cannot afford or justify having
totally dedicated to his work.  Methods for providing this type of service
economically must be developed.

Research Objectives -  The overall objectives of this portion of the
proposal are to develop a computer resource to investigate a range of
problems associated with extended realtime computer applications in
medicine including:

(1) The utilization of intelligent methods of information handling
   to increase system effectiveness and reliability and to
   allow the solution of problems which are unmanageable by
   brute force techniques.

(2) Methods for organizing and delivering large capacity computing
   power to extended realtime users within required time
   constraints and within the context of complementary time-
   sharing and batch machine utilization.


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The short term objectives will be to fashion solutions to specific problems
among a small set of collaborators.  In the longer term more general
methods for dealing with larger communities of users may become apparent.
Experience has shown that progress with automated computer systems is
difficult with success depending on the careful selection of problems as
well as techniques.  It is recognized that considerable differences exist
and indeed must exist in hardware and software needed to solve specific
problems.  It is not our goal to attempt to force the solution to all
problems within a rigid framework but rather to exploit the aspects of
commonality between applications while explicitly allowing for necessary
differences.

(b) Background

Bealtime Experience - Many laboratories are working on developing on-line
experiment support.  At Stanford the ACME computing resource has had
as one of its objectives the development of on-line, realtime instrument
support capabilities in a time-shared environment (ref. 4,5).  This
system has had success in servicing laboratory instrumentation primarily
as a store and &zwti,data logging service followed by near realtime
reduction processing.  Experience has been gained in a variety of on-line
applications including the measurement of heart function parameters
(refs 6, 9-12), respiratory function parameters and interactions (refs 1,14),
electroencephalogram correlations (refs 7-8), urinary function parameters
(refs 2-3), and the design and application of gas chromatograph/mass
spectrometer data systems (ref. 14).

Automated Systems - A number of application problems have arisen in the
course of this work where significant autonomy in the computer handling
of information is required.  Specific examples include the quantitative
analysis of cineradiograms (cardiology and urology), electroencephalograms,
and mass spectograms (see the succeeding collaborative experiment descriptions).
Without computers the quantitative utilization of these sources of
information would be infeasible.  Our experience in the design of automated
mass spectrogram interpretation systems (see Section G.2.b.3. for Dendral
references), and image processing systems (refs. 21-22, 31-32) indicate
two types of problems will be important:  First the design of algorithms
to accomplish the required information extraction and second the design
of algorithms to assess system performance to optimize information quality.
Most such systems are complex and display highly abstracted versions of
the source information as results.  Unless models are available to check
the quality of intermediate processing stages, subtle losses or distortions
of the information may result leading to misinterpretations.  Both types
of problems are difficult, application specific, and require intensive
computing resources.


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Closed loop problems are under consideration in a variety of applications
either with largely dedicated computer systems or with shared machines
where loop closure time constants are flexible.  Examples include image
processing and pattern recognition systems, analytical instrumentation
systems, robot systems, spacecraft operations, and military systems.

The DENDRAL programs at Stanford are able to infer the structures of
complex biological molecules from mass spectra without human aid.   Further
work is under way to automate the computer extension of the domain of
mass spectral problems it can solve.  Highly autonomous robot systems
such as SRI's SHAKEY (ref. 23) and the Stanford Artificial Intelligence
Hand-Eye Project (ref. 24) are able to completely solve "simple" problems
based on initial goal selection within geometrically structured
environments (such as stocks of cubes).  Pattern recognition systems
dealing with more amorphous environments suchas bubblechamber tracks
(ref. 25), karyograms (refs, 26-28), or radiograms (refs. 29-30) must
either carefully select samples for processing or rely on manual
intervention.  Much work remains to be done in automating computer
applications to medical problems.  We will draw upon related research
as appropriate in our work.

Impact of Small Machines - Closed loop experiments on ACME have been
limited to relatively low rate interactions or non-real time closure
because of capacity constraints and usage priority conflicts. These
difficulties with central machine support have led to an increased use
of "mini" computers dedicated to each particular laboratory environment.
For a variety of economic and technical reasons this experience is common
as witness the tremendous market which has built up around small computers
over the past few years,  The trend of servicing laboratory instrumentation
with local minicomputers is unmistakable and numerous self-contained
instruments with supporting data systems are available commercially.

Small Machine Limitations - Small dedicated computer systems provide
highly flexible data logging devices and perform straightforward data
reduction tasks as well.  A machine restricted in memory, peripherals,
and instruction flexibility, however, must exercise many short-cuts to
achieve results.  These short-cuts restrict system adaptability and limit
the domain of data-interpretation algorithms which can be employed.

Such limitations are offset by incrementally expanding "small" systems
by adding special features such as floating point instructions or
relatively expensive memory, disk, and other peripherals. The result
is an increasingly expensive piece of general purpose equipment dedicated
to a task, and inefficiently used.

Our experience has shown that such data systems, built around small
machines, are adequate if limited realtime demands exist.  The presence
of a human being in the loop to make control decisions and adaptive
adjustments is essential in many situations.  More demanding applications,
however, require the examination of more parallel system hardware and
software configurations designed to balance the economy and capacity
of central and distributed machines.


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

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

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

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

(c) Rationale

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

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

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

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


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,
r

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

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

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

(d) Methods and Procedures

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


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I   Sn

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

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

2.  Constantinou:  Cineradiogram Studies of the Ureter.

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

4.  Herzenberg and Levinthal:  Cell Separator Automation.

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

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

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

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

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

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

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

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

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

I

Figure G-3


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                      .
.                       .
.                       *
.


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computers will have similar support and responsibilities.

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

(e) Significance

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

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

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

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

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

(f) Collaborative Arrangement

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


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References

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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


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16.

17.

18.

19.



20.



21.

22.

23.

24.

25.

26.

27.

28.

29.

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

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

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

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

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

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

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

Nilsson, N. J., "A Mobile Automaton:  An Application of Artificial Intelli-
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Feldman, J. A., et al., "The Stanford Hand-Eye Project", Proceedings of the
      International Joint Conference on Artificial Intelligence, pp 521-
       526, 1969.

Strand, R. C., "Man-Machine Cooperation in Digital Pattern Recognition of
      Bubble Chamber Tracks", ANNALS OF NEW YORK ACADEMY OF SCIENCES,
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Neurath, P.W., Gallus, G., Selles, W. D., "Interactive Computer Aided Chromo-
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       Course, 1969.

Mendelsohn, M.L. et al., "Computer Oriented Analysis of Human Chromosomes II,
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      Art. 1, p 376, 1969.

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

Selzer, R. H., "Recent Advances in Computer Processing of X-ray and Radio-
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Brooks, S. H., Selzer, R. H., Crawford, D. H., and Blankenhorn, D. H.,
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31. Levinthal, E. C., "Mariner 9 - Image Processing and Products", COSPAR Proceed-
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(3) PL/ACME on a PDP-10

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

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

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

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

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

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

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

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

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

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

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

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

The following assumptions were made in arriving at the estimate:

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

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

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

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

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

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

System Function

Man-Months

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

1

Sub Total            46 mm

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

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

                               Sub Total:            23 mm

                               Grand Total           69 mm

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

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


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b. Follaborative Research and Developent

(1)

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

(a) Problem Statement

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

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

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

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


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b)

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

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

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

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

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

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

Background

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

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

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

Rationale

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

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

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

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

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

analyze from that transducer will require large
computer installations.

and sophisticated

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

.(a) Method s and Procedures

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

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

are:

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

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

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

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

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

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

2.  Ultrasonic Image Processing

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

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

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


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3. Small Computer Integration

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

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

e. Significance

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

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

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

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

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

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


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f.  Relati.onships

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

1.

2.









3.








4.

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

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

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

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


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5.

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

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

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


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REFERENCES

1.

2.

3.

4.

5.

6.

7.





8.

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

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

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

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

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

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

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

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

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

(a) Problem Statement

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

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

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

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

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

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

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

(b) Background.

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

(c) Rationale.

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



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methods for the first time in the extraction of dynamic information
from pyelograms.  In this way, governing parameters determining the
stability of a unidirectional flow towards the bladder and the
prevention of ureteral reflux can be studied and properly evaluated.
Furthermore, reliable quantitative documentation for developing
disease states will be possible by the integration of the measure-
ments of the outlines and significant features of radiographs with
other archival medical records,  In this way, it will be possible to
document reliably the time dependent changes in the upper urinary
tract dynamics of patients with spinal cord injuries, recurrent
urinary tract infections, congenital abnormalities, stones, etc.
The direct result of this classification is to reduce to a manageable
level the amount of repetitive work and provide the urologist with a
direct method of realizing the diagnostic information asked without
having to handle massive loads of films and data,

(d) Methods and Procedures.

A great effort has been devoted during the last few years to image
evaluation and enhancement.  The group at the Jet Propulsion
Laboratory has continued its work on image enhancement with application
to space television and biomedical imagery. For the purposes of this
study, it is not our desire to repeat any of this pioneering work.  The
field would obviously provide us with newer, better, and more efficient
algorithms for picture encoding, computer processing, and pictorial
pattern recognition.  Philosophically, our approach will be in the
domain of feature extraction algorithms which will outline the renal,
ureteral, and bladder projections from each frame in the most
economical way, avoiding brute force methods.

Additional features of interest will include video densitometry within
outlined structures related to the concentration and thickness of
radiopaque material.  This information can be combined with peripheral
boundary measurements to infer relative cross-section information.

The time evolution of pyelograms includes considerable redundancy and
correlation from frame to frame.  This information can be used to
model local system dynamics (frame to frame variations) and hence
direct the data processing.  In this way the relatively sophisticated
pattern analysis algorithms for edge detection, structure skeletonizing,
and densitometry can concentrate on small important subsets of the
large amount of raw data involved.  We can minimize computing and time
resources required by utilizing these solution guided processing
schemes.

The initial orientation of the computer to an image sequence may require
human interaction as well as to assist in processing difficult frames,
We expect the application of these results to succeeding frames as
described above to minimize the need for human interactions.

Algorithms which may be used for automated computer analysis of the
images include dynamic threshold and maximum gradient techniques for
edge detection.  Continuity conditions can be imposed for sequential


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edge following.  Techniques similar to these are being successfully
developed for karyo typing and arterioangiogram analysis. Relative
video densitometric information can be used to determine ureter size
by measuring variations in density about a local mean and relating
these to cross sectional area.  This is accomplished by correlating
mean density to mean boundary separation and assuming vessel
symmetries.

Time evolutions of extracted information will be studied through
various on-line graphical presentations.  Deviations from predicted
local model behavior may be used to identify time dependent
anomalies which could be of interest.

The pyelogram information is collected on 35 mm film and significant
archives of patient histories exist and will be studied.  Initially,
to develop techniques, we will use existing video scanning equipment
at Stanford (SLAC) to digitize the entire frame sequences of interest.
In order to conveniently store this large volume of data for computer
processing we may use data compression techniques which take into
account intraframe as well as interframe correlations.  A scheme
requiring relatively little computational effort to encode and
reconstruct the video information would be a Huffman code built around
picture element difference statistics.

In the longer term we want to obtain resources to build a computer
directed scanner so that only the pertinent information need be
measured from the film.

(e) Collaborative Affiliations.

A continuing dialogue and exchange of ideas in both the experimental
and theoretical aspects of image processing will be maintained with
Dr. Harrison's group.  Although the contrast and time constants of
cardiac catheterization is very different from pyelography, it is
hoped that this cooperation would prove economically and scientifically
beneficial.

(f) Significance.

The development of computer based characterizations of radiographs
would be of practical significance to the present and future need of
urologists and radiologists.  The information accrued from such a
system would span a broad range of benefits in specific areas of
quantification, standardization, and information storage of otherwise
neglected parsmeters in pyelography.

The potential future development of pattern recognition methodologies
which can be realized from these evaluations, can handle more variability
and allow the consideration of biomedical applications.  It is realized
however, by other workers and us that instead of trying for completely
automated systems, we would use an interactive man-machine system that
would allow human intervention in questions and tasks not easily
automated.  Thus, a number of interesting and difficult applications
for computer assisted analysis of radiographs can become technically
feasible.


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(3) Automated Gas Chromatography/Mass Spectrometry Analysis
  Prepared by Tom Rindfleisch

(a) Introduction

This section of the proposal is concerned with the design and development
of the computer hardware and software components necessary for a fully auto-
mated gas chromatography/mass spectrometry (GC/MS) system.  This work repre-
sents an extension of a portion of the existing DENDRAL research grant
(NIH grant RR-00612).  Significant progress is being made in all phases of
the DENDRAL research as summarized in the succeeding sections.  We have
gained a greater experience with the data system requirements for the auto-
mated collection and analysis of mass spectrometry data as well as the
limitations of the existing ACME system for developing such system. Because
of the critical reqtirements for information integrity throughout an automated
GC/MS system for medical applications and because the DENDRAL project is a
natural environment in which to explore "intelligent" information handling and
instrument control problems, we are proposing this more extensive automation
effort.  This work complements the on-going DENDRAL artificial intelligence,
chemistry. and instrumentation research as explained in subsequent paragraphs.

(b) Problem Statement

The combination of gas chromatography with mass spectrometry (GC/MS) has had
a tremendous impact on analytical problems in organic chemistry and bio-
chemistry over the past decade (1).  Increasingly GC/MS is being used as a
tool in clinical and medical research applications to identify metabolites
and other materials contained in body fluids.  For example, Biemann and
collaborators (2) describe a dramatic series of events following the admis-
sion of an unconscious patient to a hospital following a drug overdose.
GC/MS analysis provided an identification of the drug used in this suicide
attempt.  Fales and Milne have been active in the identification of abused
drugs.  They describe (3) the use of GC/MS for the analysis of drugs separa-
ted from the stomach contents of 45 would-be suicides, and the resulting aid
to proper treatment of the patients involved.

Medical research applications of computerized GC/MS have included the detec-
tion of metabolic disorders of genetic origin from an analysis of the organic
chemical constituents of a patient's body fluids (usually blood or urine).
Jellum and his associates (4) in Norway have been active in this field and
through largely manual methods have been able to identify four previously
undescribed metabolic diseases of genetic origin based on urine analysis.

These examples serve to illustrate the potential of GC/MS analysis as a
tool in medical research and clinical applications.  The basic power of the
techniques lies in the ability of the gas chromatograph to physically separ-
ate and pass the components of a complex mixture into a mass spectrometer.
The spectrometer makes measurements leading to a "fingerprint" for identi-
fying each component of the mixture.  In urine samples such as studied by
Jellum, et al., such a mixture may contain several hundred components and
may be subjected to fractionation prior to GC/MS analysis.  The amount of


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data contained in the output of such a GC/MS experiment is very large and
the procedures for extracting significant information including interpre-
tation are complex.  An experiment may last for 2 hours with a spectrum
containing lo5 samples of data collected every 5 to 10 seconds.  Out of the
possible ensemble of lo8 data points must come an identification of all
components with as little ambiguity as possible.  Computer based data systems
are essential for any effective utilization of this powerful technique.

Several computer-based approaches have been utilized to aid in the analysis
of low resolution mass spectral data, whether or not collected by GC/MS (5)
systems.  For materials to be identified within a known class of possiblli-
ties, the potentials of library search routines have been explored (6). These
procedures are frequently ambiguous as they use only a subset (low resolu-
tion spectra) of the information which a mass spectrometer can provide.
Furthermore, in many medical research situations it is precisely the unexpec-
ted or previously unknown materials which are of greatest interest (4).
Such problems cannot be solved within the domain of a library and currently
fall back on human intervention to resolve ambiguities or synthesize new
solutions.  This limitation restricts considerably the utility of GC/MS
systems because of the effort and time delays required to explore new situ-
ations.

The on-going DENDRAL work (7a-i) at Stanford (RR-00612) offers a far-reaching
solution to this problem by designing into computer programs the ability to
construct explanations for mass spectra in terms of chemical structure.
Recently, these efforts in the context of high resolution mass spectra, have
had considerable success in dealing with estrogenic steroids (7h). Future
work will expand these capabilities to more classes of compounds as well as
generalize the heuristic rule-forming processes to allow automatic computer
extensions.

Manual, as well as automated interpretive procedures (7c,d,h) can utilize a vari-
ety of ancillary information (e.g., high resolution, low ionizing voltage, met-
astable data, and NMR data) to produce reliable and unambiguous results.   Present
low resolution GC/MS systems, because of limitations in system and/or instrument
designs, are generally incapable of collecting all possible information on
which to base an analysis during the finite interval of a gas chromatograph
effluent peak.  A realtime selection of instrument mode and information optimi-
zation  type and quality is required.

Acquisition and reduction of mass spectral data in realtime have progressed
to the stage where automation and closed-loop control are feasible and desir-
able.  Closed loop automation of data extraction and instrument control pro-
cesses places additional burdens for capability, integrity, and reliability
on the overall data system.  Because of the complexity of data reduction and
interpretive processing, great care must be taken throughout the system to
avoid the destruction of or artifactual invention of information.

The objectives of this portion of the proposal are to develop and demonstrate
a fully automated gas chromatograph/mass spectrometer system in collaboration
with on-going DENDRAL chemistry, artificial intelligence, and instrumentation
research.


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Specific objectives of the research include:

1.  The development of autonomous and reliable instrument control and
  information extraction programs capable of reacting to a hierarchy
  of GC/MS response requirements within the context of a time-shared
  computer system.

2.  The integration of evolving DENDRAL artificial intelligence programs
  to interpret extracted information and to provide feedback within
  the system specifying information requirements to insure optimal
  sample management.

3.  The application of the developed system in cooperation with
  collaborating chemists and medical researchers to problems in the
  analysis of steroids and other metabolites found in biological
   fluids.

(c) Background

The elucidation of the systematics by which chemical compounds fragment under
electron bombardment has a large literature with very significant contribu-
tions from the laboratory of Professor Carl Djerassi at Stanford.   These
systematics form the basis for computer automation of the interpretation of
mass spectra - the DENDRAL project.

DENDPAL is a set of computer programs which have developed over a period of
several years, initially for the interpretation of the low resolution mass
spectra of specified classes (ketones, ethers, amines, alcohols, thiols, and
thioethers) of alicyclic compounds (7b-7h). Subsequently, this theory was
extended to include the high resolution mass spectra of the estrogen class
(female sex hormones) of steroids (71).  This program has also demonstrated
its ability to identify the components present in laboratory-de mixtures
of estrogens.  At the present time work is progressing with crude estro-
genie mixtures obtained from biological sources.  The successful completion
of this project will represent a new, rapid approach for the identification
of estrogenic steroids without the necessity of first derivatizing and then
analysing the mixture by gas chromatography.  Heuristic DENTIRAL is also
being enlarged to accommodate a theory of mass spectrometric fragmentation
of other classes of steroids and alkaloids, utilizing high resolution mass
spectra.

Metastable ions formed in the first field-free region of a double focussing
mass spectrometer (so called defocussed metastable ions) have been used by
mass spectroscopists for the identification of parent-daughter ion relation-
ships.  As part of its spectrometry theory, Heuristic DENDBAL will use this
additional type of experimental data.  A recent paper (8) described a new
use of defocussed metastable ions for the unraveling of competing fragmen-
tation pathways.

Meta-DENDRAL research efforts are aimed at the computer formulation of
scientific theories based on the examination of related sets of data.   Such


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a capability will allow the automatic extension of computer capabilities for
mass spectrum interpretation by the inference of new rules.  To date these
programs are capable of writing primitive rules about fragmentations and
the influences of molecular parameters (e.g. substituent effects).

Work of others in the field.  Data systems which can cope with
the large accumulation of spectral information generated during a
low resolution GC/MS run have been developed in a number of loca-
tions including Stanford (9).  These systems run open loop in that
they systematically collect data from sequential low resolution
spectrometer scans, reduce the data based on instrument calibra-
tions, and provide the chemist with the ability to retrieve parti-
cular spectra corresponding to gas chromatograph effluent activity.
However, even when coupled with library search procedures  (6))
there systems make few, if any, intelligent decisions about the
data, and provide the chemist with few clues about the validity of
his results.  Our approach will be to develop techniques to
validate results under closed loop control based on instrument
performance parameters and ancillary information such as the
routine use of high resolution data.  We will make use of the work
by others in the development of suitable library search routines.

(d) Rationale

The power of the gas chromatograph/mass spectrometer data system as a medical
research tool derives from the ability of the gas chromatograph to physically
separate microgram quantities of complex mixtures followed by the mass
spectrometer to identify each constituent from its "fingerprint" mass spertrum.

For each of the gas chromatographic peaks, the basic function of the mass
spectrometer is to ionize sample molecules which then fragment and, through
electromagnetic separation, to measure the abundance of fragments with
different masses.  At high resolution the elemental composition of the
various fragments can be determined.  These abundances are related to the
molecular structure of the sample material and these relationships can be
used by inference to derive the structures for unknown sample materials from
their mass spectra.  There are numerous modes of operation of a mass spectro-
meter which allow the measurement of ion abundances with varying time,  mass,
resolution, and ionization energy, as well as enable the observation of
delayed or metastable ion fragmentation pathways. Not all information in all
modes of operation can be collected during a gas chromatographic peak because
of limitations in data rates, instrument sensitivity, and sample flow into
the ion source.  Conversely not all collectable information is necessary for
the identification of an unknown.  The optimum experimental conditions pro-
ducing the most relevant information in the shortest time are not predictable
a priori for an unknown material.  Thus closed loop computer analysis of the
spectrometer with subsequent feedback control of its operation could maximize
collected data quality and ensure the collection of needed information for
the interpretation of an unknown structure.

The essence of our proposal is to design the necessary information handling
and system control intelligence to complement the DFNDRAL spectrum interpre-


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tation intelligence and to integrate these elements into a reliable, auto-
nomous GC/MS system.  The core of this work will be to design programs at
the various processing stages shown in Figure 1 which allow the system to
perform the required functions.  The time constants and data rates involved
in the various aspects of a typical GC/MS experiment range from-l msec to
-10 seconds.  These requirements are based on the typical 5 - 30 second
duration of sample uniformity in gas chromatographic peaks. The logical
sequencing of the loop element operations of Figure 1 is dependent upon the
sequence with which information becomes available and the degree of overlap
possible between successive operations.  Figure 2 shows conceptually how
this sequence takes place.

The GC/MS data systems existing today run almost entirely open loop in that
there is no attempt to modify experiment execution based on extracted
results.  The processes involved are implemented with inadaptive algorithms
so that if instrument performance, or data quality do not fall within para-
meter specifications, information may be destroyed, ineffective filtering may
occur, or catastrophic system failures may result.  Specific examples of
where added intelligence is required  exist throughout the system:

(1)

(2)

(3)

(4)

(5)

(6)

Failsafe data collection and management capabilities must be built
into the system to accommodate the inherently variable data length
and peak arrival rate statistics of the spectrometer output.

Reliable and fast methods must be developed for detecting and resol-
ving overlapping peaks in the gas chromatograph and mass spectro-
meter sensor outputs.

The quality of extracted information must be evaluated based on
instrument performance parameters and ion statistics.

The characterization of instrument performance parameters must
be continually updated and evaluated to allow optimum control of
parameter settings for scan, focus, resolution, source and reference
pressures, etc.

The successive operations on extracted information must adapt
their behavior based on the character and quality of their input
information and must add their effect on uncertainties at their
output.

The overall management of resource allocation must be based on pri-
orities derived from the on-going problem solving and interpretative
processing to maximize the effectiveness of applied resources, to
decrease processing time, and to minimize computing cycle
consumption.

The evolution and collaborative application of this system will be complemen-
tary in nature.  The conception, design, and implementation of the system
benefit from experimenting with its applications.  Conversely the power of
the automated system allows the systematic exploration of new areas in medical
and chemical research.































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(85)

(e) Methods and Procedure

The implementation of the proposed automated gas chromatograph/mass spectro-
meter system will be a highly collaborative effort drawing as much as possible
upon capabilities existing in laboratories at Stanford and elsewhere.
Specifically we will use:

(1) The GC/MS-computer instrumentation and data system interfaces
  existing and being developed at Stanford under DENDBAL and NASA
   grants.

(2) Appropriate modifications of existing library search algorithms and
  data bases to effectively utilize (3) below.

(3) The artificial intelligence programs for mass spectrum interpreta-
  tion being developed under the DENDRAL and ARPA grants.

In addition to these collaborative interactions, we will draw heavily on the
satellite machine support capabilities, extended realtime system functions,
and PDP-lo/satellite hardware and software systems being developed under
other sections of this grant application.

The various elements required in an automated GC/MS system are shown in
Figure 1.  These elements perform a variety of functions including:

(1) Data acquisition and detection. This element accepts the raw spectro-
  meter output and detects peak information above a dynamic background
   threshold.  Based on peak arrival statistics, control of the spec-
   trometer scan may be used to increase ion collection efficiency
   (this would be based on similar work being done by McLafferty,
  private communication).

(2) Information extraction and reduction.  This element extracts separ-
  ated peak amplitude and position information from raw data.
   Instrument calibration data are used and resulting data quality is
   estimated.  These quality measures can optimize instrument para-
    meters.

(3) Information analysis and interpretation. This element computes
  elemental compositions as required and applies library search routine
   with appropriate verifications based on spectrum predictor routines.
   If no solution is found more basic DENDRAL theory construction rou-
   tines are used to identify the unknown.

(4) Analysis performance evaluation and control. This element directs
   the search for an explanation of the sample spectrum using avail-
   able a priori information.  When ambiguities arise, control infor-
  mation is directed to obtain appropriate additional data.


(86)

(5) Analysis upgrade and extension. When new solutions outside of
  existing system capabilities are encountered this loop element
  incorporates these extensions into the system.  Such extensions may
  come from META-DENDRAL analysis or from chemists.

(6) Result and system status display.  This loop element provides
  the system user with rapid volatile plots and displays of on-going
   experiment results and status.  Hard copy is available off-line.

(7) Instrument control.  This loop element coordinates and implements
  control requests on instrument performance such as parameter
  adjustment or mode change by planning and issuing the appropriate
   electronic commands.

(8) System coordination and control.  This loop element receives and
  maintains status and performance data relating to various system
  elements and guarantees the appropriate sequencing of interde-
  pendent operations.  This element also coordinates system opera-
  tion changes commanded from the outside.

(9) Command interface.  This loop element decodes commands and control
  information received through the instrument operator or chemist
   user interface.

(10) Information storage and management. This element includes the
  organization and storage of spectral information and the ability
   to access this data on demand.

Models by which the computer can assess and optimize its performance will
be developed based on physical principles for instrument performance and
heuristic schemes for control and interpretation protocols.

Instrument control functions will be implemented as appropriate for parame-
ters such as gas chromatograph temperature programming and mass spectrometer
scan control, mode selection, resolution control, scan dwell, etc.  The
coordination of these parameters in terms of automated setting determination
and sequences for control implementation will be developed heuristically from
models of instrument performance and operator procedures.

Our concept of overall software organization follows the functional informa-
t1on flow shown in Figure 1 coupled with the timing interactions shown in
Figure 2.  The shortest term response requirements (-1 msec.) exist for the
data acquisition functions and will be implemented in a dedicated machine
interfaced to the GC/MS.  This machine also allows open loop operation of the
instruments in the existing modes during development of the integrated closed
loop system.  The other elements of the system will be implemented as sub-
processors in the PDP-lo/satellite extended realtime system affording required
response without total commitment of the PDP-10 system.


(87)

(f) Significance.  Low resolution GC/MS has become one of the most widely used
  and most powerful techniques available to the organic or biochemist (1).
  The potential applications of these techniques in medical research and
  practically in the clinic have just begun to be explored (4). Closed-
  loop control of this instrumentation would permit rapid exhaustive analysis
  of tissue extracts across large populations of individuals in various medi-
  cal contexts and may provide new discoveries important to public health.

Extension of GC/MS to routine operation of the mass spectrometer at high
resolving power would be an important breakthrough in terms of the speci-
ficity of information available per microgram of sample, compared to low
resolution techniques.

The integration of library search techniques with the screening power of
a spectrum predictor and the analytical capabilities of Heuristic DJXNDRAL
would provide a powerful data analysis capability which would exploit the
advantages of each approach.

These techniques are of unique importance to medical science since they
alone of the current physical methods have sufficient sensitivity and
analytical precision to study human biochemistry at the molecular level.

(g) Facilities Available.  The research in this proposal will draw heavily
  upon the PDP-lo/satellite computing resource we are proposing to estab-
   lish.  We have available two gas chromatograph/mass spectrometer systems
  which will be involved in this research including a Finnigan quadrupole
   instrument in the Department of Genetics and a Varian-MAT 711 instrument
   in the Department of Chemistry.  Also available in the Department of
  Chemistry are MS-9 and Varian-MAT CH-4 instruments.

(h) Collaborative Arrangements.  The proposed research project is a highly
   interdisciplinary effort involving collaboration between Professor J.
  Lederberg (Department of Genetics), Professor C. Djerassi (Department
  of Chemistry), Professor E. Feigenbaum (Department of Computer Science),
  Dr. B. Buchanan (Computer Science), Dr. A. Duffield (Genetics and Chem-
  istry), Dr. D. Smith (Chemistry), and the Instrumentation Research Lab-
   oratory.  The proximity of these people and facilities offers a highly
  unique opportunity for collaborative interaction.


REFERENCES

1.  For pertinent reviews see:  C. G. Hammar, B. Holmstedt, J. E. Lindgren
  and R. Tham, Advan. Pharma Col. Chemother., L, 53, (1969); J. A. Vollmin
  and M. Muller, Enzymol. Biol. Clin., lc, 458 (1969)

2.  J. R. Althans, K. Biemann, J. Biller, P. F. Donaghue, D. A. Evans,
   H. J. Forster, H. S. Hertz, C. E. Hignite, R. C. Murphy, G. Petrie and
  V. Reinhold, Experientia, 26, 714 (1970).

3.  H. Fales, G. Milne and N. Law, reported in Medical World News, February
   19, 1971.

4.  E. Jellum, 0. Stokke and L. Eldjarn,  The Scandinavian Journal of Clinical
  and Laboratory Investigation, 27, 273 (1971).

5.  A. L. Burlingame and G. A. Johanson, Anal. Chem., 44, 337R (1972).

6.  H. S. Hertz, R. A. Hites and K. Biemann, Analytical Chemistry, 43, 681
  (1971), S. L. Grotch, ibid., 43, 1362 (1971).

7a.  Applications of Artificial Intelligence for Chemical Inference. I. The
   Number of Possible Organic Compounds:  Acyclic Structures Containing C,
   H, 0 and N.

J. Am. Chem. Sot., 91, 2973 (1969)
By J. Lederberg, G. L. Sutherland, B. G. Buchanan, E. A. Feigenbaum,
A. V. Robertson, A. M. Duffield and C. Djerassi.

7b.  Applications of Artificial Intelligence for Chemical Inference. II.
   Interpretation of Low Resolution Mas Spectra of Ketones
     J. Am. Chem. Sot., 91, 2977 (1969)
      By A. M. Duffield, A.V. Robertson, C. Djerassi, B. G. Buchanan,
      G. L. Sutherland, E. A. Feigenbaum and J. Lederberg

7c.  Applications of ARtificial Intelligence for Chemical Inference. III. Al-
   iphatic Ethers Diagnosed by Their Low Resolution Mass Spectra and NMR
     Data.

J. Am. Chem. Sot., 91, 7440 (1969)
By G. Schroll, A. M. Duffield, C. Djerassi, B. G. Buchanan,
G. L. Sutherland, E. A. Feigenbaum and J. Lederberg

7d.  Applications of Artificial Intelligence for Chemical Inference. IV.
   Saturated Amines Diagnosed by Their Low Resolution Mass Spectra and
   Nuclear Magnetic Resonance Spectra.
     J. Am. Chem. Sot., 92, 6831 (1970)
      By A. Buchs, A. M. Duffield, G. Schroll, C. Djerassi, A. B. Delfino,
      B. G. Buchanan, G. L. Sutherland, E. A. Feigenbaum and J. Lederberg

7e.  Applications of Artificial Intelligence for Chemical Inference. V. An
   Approach to the Computer Generation of Cyclic Structures.   Differentiation
  between all the Possible Isomeric Ketones of Composition C6H100.


                       (89)



      Org. Mass Spectr., 4, 493 (1970)
      By Y. M. Sheikh, A. Buchs, A. B. Delfino, G. Schroll, A. M. Duffield,
      C. Djerassi, B. G. Buchanan, G. L. Sutherland, E. A. Feigenbaum and
      J. Lederberg

7f.  Applications of Artificial Intelligence for Chemical Inference. VI. An
   Approach to a General Method of Interpreting Low Resolution Mass Spectra
   with a Computer.
      Helv. Chim. Acta., 53, 1394 (1970)
      By A. Buchs, A. B. Delfino, A. M. Duffield, C. Djerassi, B. G. Buch-
      anan, E. A. Feigenbaum and J. Lederberg

7g-  The Application of Artificial Intelligence in the Interpretation of Low
   Resolution Mass Spectra.
      Advances in Mass Spectrometry, 5, 314, (1970)
       By A. Buchs, A. B. Delfino, C. Djerassi, A. M. Duffield, B. G. Buch-
      anan, E. A. Feigenbaum, J. Lederberg, G. Schroll and G. L. Sutherland.


7h.  Applications of Artificial Intelligence forchemical Inference.   VIII.
   An Approach to the Computer Interpretation of the High Resolution Nass
   Spectra of Complex Molecules.  Structure Elucidation of Estrogenic Steroids.
       J. Amer. Chem. Sot.,
      By D. H. Smith, B. G. Buchanan, R. S. Englemore, A. M. Duffield,
      A. Yeo, E. A. Feigenbaum, J. Lederberg and C. Djerassi

7i.  An Application of Artificial Intelligence to the Interpretation of
   Mass Spectrometry.
      By B. G. Buchanan, A. M. Duffield and A. V. Robertson,
       Mass Spectrometry, B. W. G. Milne, Editor, John Wiley and Sons,
      New York, 1971. pp. 121-178.

8.  D. H. Smith, A. M. Duffield - d C. Djerassi, Org. Mass Spectrom.,
      Submitted for publication.

9.  Anal. Chem., 42, 1122 (1970); W. E. Reynolds, V. A. Bacon, J. C. Bridges,
      T. C. Cobum, B. Halpern, J. Lederberg, E. Levinthal, E. C. Steed,
         and R. B. Tucker.


(90)

(4) Cell Separator Project.  Prepared by L. A. Herzenberg and E. Levinthal.

The Cell Separator Project, currently in its third year, is developing the
equipment and techniques for automated high speed sorting of functionally
different human and other mammalian cells. This project involves an
interdisciplinary group of biologists under the direction of Dr. Leonard
Herzenberg, Professor of Genetics as well as a staff of engineers and
supporting technicians located in the Instrumentation Research Laboratory
under the direction of Dr. Elliott Levinthal, Senior Research Scientist.
The biomedical objectives include:

(a) Separation of the various cells involved in the humoral (antibody)
  and cell mediated (hypersensitivity) immune response.  Antigen
  binding cells, thymus derived cells, bone-marrow derived cells,
  cells with specific immunoglobulins on their surface will be
  detected and viably separated after appropriate immunofluorescent
  surface staining.

(b) Study the binding kinetics and affinities of cell surface molecular
  probes like Concanavalin A, other phytoagglutinins, and aniline
  napthalene sulfonate (ANS) with the aim of distinguishing and
  separating different cell types including perhaps malignant from
   normal cells.

(c) Select somatic cell intra or interspecific hybrids after Sendai
  virus fusion by nondestructive positive immunoselection.

(d) Detection of fetal red blood cells in maternal circulation.

(e) Differentiating leucocytes and other cell types in normal and
  pathological body fluids.

(f) Detection of tumors by reaction of circulating tumor cells with
  fluorescent labelled tumor specific antigens.

(g) Other related applications on an opportunistic basis, as it
  becomes apparent that such work is worthwhile.

The instrumentation effort involves the development of the optical flow
system and separator components as well as the control electronics and
software, for the cell separator.  The instrument consists of a nozzle
assembly designed to provide examination of single particles flowing in
a narrow stream and a pulsing and deflection assembly designed to
physically separate particles of interest from other constituents of the
stream.


(91)

PRESSURIZED CELL
  RESERVOIR

ELECTFKINNX

PRESSURIZED OUTER FLOW
   RESERWIR

CELL
COLLECTOR

Figure Cell Separator-l

Simplified Block Diagram of
     Cell Sorter


(92)

(a) Background

In the same way that many of the spectacular advances in molecular biology
were impossible until it became possible to separate functionally different
molecules by such techniques as electrophoresis and ultracentrifugation,
advances in cell biology have awaited development of instrumentation
able to separate large numbers of functionally different cell types.
Many have attempted to do this by bulk methods, but the resolution of such
methods is limited.  It appeared to us that the best approach to the
problem was to inspect the cells individually and sort them on the basis
of these individually measured characteristics.  We have found that a
number of separations of biomedical interest could be accomplished using
fluorescent markers on the desired cells and electronically deflecting
drops containing the various types of cells into separate containers.
The only other workers with a similar approach are Fulwyler, et al., who
have demonstrated electronic cell sorters operating on volume (1) and are
now building a unit able to operate on both volume and fluorescence
(personal communication).  Several workers have described cell analysis
systems based on flow techniques similar to those used in our equipment
(Van Dilla, et al. (2), and Kamentsky et al. (3).

Biophysics, Inc., ("Cytograph" and "Cytofluorograph") and Technicon
Instruments Corp.  ('Y-I emolab D") now market cell analysis instruments
using flow techniques but these instruments do not have separation capability.

(1) Fulwyler, M. J., Glascock, R. B., and Hiebert, R. D. "Device
  Which Separates Minute Particles According to Electronically
   Sensed Volume".  Rev. Sci. Inst. 40: 42, 1969.
                        --  -n
(2) Van Dilla, M. A., Trujillo, T. T., Mullaney, P. F. and Coulter,
    J. R. "Cell Microfluorometry: A Method for Rapid Fluorescence
   Measurement".  Science 163: 1213, 1969.
(3) Kamentsky, L. A., Melamed, M. R., and Derman, H. "Spectropho-
    tometer:  New Instrument for Ultrarapid Cell Analysis".   Science
   150: 630 (1965).

Since starting the major effort on this project in 1968 a number of
significant successes have been achieved in both the technical development
as well as the biological applications.  The following bibliography
provides a summary of these results:

(1) W. A. Bonner, H. R. Hulett, and L. A. Herzenberg.  "Highspeed
  Sorting of Fluorescence Labeled Cells", Fed. Proc. 30, 699
                                                 --
   Abs. 1971.

(2) L. A. Herzenberg. Chairman, Conference Session, "Fluid
  Transport Methods", Engineering Foundation Research Conference
  on Automatic Cytology, New England College, Henniker, New
  Hampshire, July 26-30, 1971.


(93)

(3) L. A. Herzenberg and R. G. Sweet. "Fluorescence Activated
  Cell Sorting", presented at Engineering Foundation Research
  Conference on Automatic Cytology, New England College,
  Henniker, New Hampshire, July 26-30, 1971.

(4) L. A. Herzenberg, T. Masuda, and M. Julius.  Invited paper
   on Symposium on Thymus and Bone Marrow Cells in the Immune
  Response, Annual Meeting of the American Society for
  Hematology, San Francisco, Dec. 4, 1971.

(5) L. A. Herzenberg.  Invited participant in symposium on Cell
  Purification by Use of Surface Antigens and Receptors,
  Midwinter Conference of Immunologists, Asilomar, California,
   Jan. 22, 1972.

(6) L. A. Herzenberg, R. G. Sweet, M. Julius, T. Masuda, and
   R. A. Merker.  Invited paper,  "Fluorescent Activated
  Electronic Cell Sorting in Immunology", to be presented at
   Biophysical Society Annual Meeting, Toronto, Canada, Feb.
   19, 1972.

(7) W. A. Bonner, H. R. Hulett, R. G. Sweet, and L. A. Herzenberg.
  "Fluorescence Activated Cell Sorting", Rev. Sci. Inst. 43,
                                                ---
   404, 1972.

(8) L. A. Herzenberg in "Immunological Intervention", Jonathan
   Uhr and Maurice Landy, eds.  Academic Press.  (In press, 1971).

(9) M. Julius, T. Masuda and L. A. Herzenberg.  "Isolation of Functional
  Antibody Forming Cell Precursors Using a Fluorescence Activated
   Cell Sorter".  (In preparation).

(b) Rationale

The rationale behin.d our approach was simply that separation of large
numbers of functionally different cells would make it possible to conduct
many important studies on specific cell functions.  In order to acquire
large numbers of cells in a reasonable time, rapid observation was
necessary.  This effectively eliminated scanning systems and limited us
to use of only a few parameters.  A flow system was a logical way to
look at the cells rapidly and sequentially.  Use of fluorescent techniques
provided readily available means of differentiating between many
funtionally different types of cells, but required incorporation of a
laser light source in order to provide sufficient signal-to-noise ratio
to detect the cells.  Electronic sorting techniques originated by Sweet
and adapted by Fulwyler (see Background) provided us with a basis for
developing a rapid, accurate method of sorting desired cell types as a
function of fluorescent information.


(94)

(c) Methods and Procedures

The procedure involved in the use of the cell separator presently
involves three steps:

A.  Preparation of cells occurs over a period of hours or days
  depending on the experiment.  Cells of interest, immunologically
  sensitive cells for example, are collected and tagged with a
   fluorescent marker.

B.

This single cell suspension is then brought to the instrument
and analyzed and/or divided into fractions.  This latter
procedure involves a certain amount of subjective decision
making by the experimentor and machine operator.   Data on the
cells, e.g.  distribution of several fluorescent and low and
wide angle light scattering amplitudes is acquired before
separation for analysis and then thresholds and/or windows
for the various parameters are set for separation.   Data on the
cells, usually the distribution of their fluorescent signal
amplitudes, is acquired before or during separation. The
resulting fractions are sometimes reexamined via the cell
separator or by microscope.  More frequently the fractions are
tested by the Jerne plaqueing technique or reinjection into
irradiated hosts.

C.  Finally, the data collected from the cell separator (stored
  on the computer) and resulting biological procedures are
  correlated statistically.

The scientific gains to be made by collaboration with SUMEX are both
improved operations under B by on-line coupling of the instrument to a
computer to allow interactive decisions to be made during separations
and under C by more sophisticated statistical analysis of the data.

(d)

Significance

Separations of functionally different, viable cells permit their
characterization and studies of their function and interactions. It
is as crucial a step in cell biology as precise methods for protein and
nucleic acid separations in molecular biology.  Progress in understanding
the immune system is being speeded by separation of functional cells
of the lymphoid system.

Development of rapid machine assisted hematological, and cell pathological
diagnostic methods will increase clinical laboratory capability and
decrease the cost of current manual methods.

(e) Computer Interaction

As mentioned, in the background section, there are only one or two other
groups successfully pursuing this approach to cell characterization and
separation.  This is due to the requirement for success of a juxtaposition
of skilled biological and engineering personnel.   Stanford is also
especially fortunate in having a very active program in computer development.


(95)

The cell separator project is currently using a dedicated small computer
on-line (LINC) as well as the ACME system on a less regular, off-line
basis.

There are two levels of interaction between the cell separator(s) and
general purpose computers.

A.  The on-line, hook-up of each instrument to a small computer
  provides a data collection and analyzer system for preliminary
   results.  This is currently in use full time.  It allows 4 to
  8 hour experiments with assurance that the data is meaningful
  at each step of the experiment.  The human operator is
  presently the primary link in the feedback loop from the data
  collection system and the experimental equipment.

OPERATOR* - - - - ---I

Such interaction requires feedback times in the range of a few
minutes.  More rapid feedback between the small computer and
cell separator is envisioned as the characteristics and uses
of the instrument become better understood.

B.  The second level of interaction, based on the capabilities
  of a larger computer system, will provide more sophisticated
  analysis of results.

C.  A third level would use the larger computer to enhance the
  functioning and software developments necessary for the
  optimimum use of the small computer.

Cell Separator

Small Computer

Large System

Multiparameter analysis of cell distributions is one of the features
which would be of immediate benefit to the project.


(96)

Implicit in our need for multiparameter analysis, is a feedback time
scale which allows modification of experimental procedures.   For
example, a three-dimensional display of 2 or 3 minutes of data offers
the opportunity of more precise manual adjustment of separation
parameters.  Also, a numericalintegration of areas under three-dimensional
curves could actually be used to automatically, and continuously readjust
these separation controls.  The result of such feedback will be more
consistent and more precise definition of the cell populations separated
and studied.  The large system's language capability can dramatically
increase the feasibility of "programming" the instrument to carry out
various experimental regimes.  At present,  the effort involved in
programming the small computer has forced the project to use a standard
set of software routines and tailor the experiment to fit these.
Increasing the coupling between the small computer and cell separator
has received limited emphasis because of the software developments
required.

After some years of experience with realtime use of computing facilities,
we feel that the above uses are not only possible, but feasible without
our taking on the role of a major computer development project ourselves.


(97)

(5) Average  Evoked Potentials and Perception - prepared by Bert S. Kopell
   and Walton T. Roth

(a) Problem Statement

The Laboratory of Psychophysiology at the Palo Alto VAH has been studying human
neurophysiology as related to psychiatric disturbance and the action of medi-
cations for about eight years.  We have even been able to measure drug effects
neurophysiologically at doses below the threshold for subjective effects in
the cases of cortisol (Kopell et al., 1970a) and thyroid hormone (Kopell et al.,
????? ? o  A major emphasis has been on finding neurophysiological measures of
perceptual processes,  Very little is known about the realtionship between
subjective perception and its neurophysiological counterpart, but there is
some indication that the average cortical evoked response afford an objective
index of perceptual process and attention (Satterfield, 1965).  Various percep-
tual processes are known to be disturbed or altered in psychiatric disorders
and by psychoactive drugs.  Objective neurophysiological measurements of sub-
jective perceptual processes may have the potential for giving prognostic in-
dicators regarding psychiatric decompensation or the predilection for alcohol
or drug addiction.

(bl Background and Rationale

Our primary interest is in the electrocortical activity in response to sensory
stimulation.  The averaged cortical evoked response has been shown to be af-
fected by various physiological and psychological parameters including medica-
tions, alcohol, attention, and psychiatric disturbances.  A small electrocorti-
cal response is generated with any sensory stimulation but this cannot be seen
in the EEG as measured directly from the scalp.  Computer averaging of the EEG
over several stimulations, however,  can be utilized to enhance the size of the
signal and make it available for study.  Recently various members of our lab-
oratory have used the classic LINC and the PDP-12 for this purpose (Gips et al.,
???? ? o  While these computers are an advance on the technology of 10 years ago,
they do have limitations.  Just as these computers have provided for more sophis-
ticated experimentation as compared to the special purpose computers, the pro-
posed system will allow us to make a qualitative and quantitative advance in the
complexity and sophistication of our investigations.

A particular problem in studying perception in this manner is presented by the
fact that perception is an evanescent and continuous process and the evoked
response is the stochastic result of an accumulation of this process over time.
Very rapid on-line statistical manipulations of the BEG are needed if one is
going to achieve a better understanding of the perceptual process utilizing
this technique.  With this proposed computation power, one can obtain a closer
estimate of the perceptual process from second to second rather than only being
able to talk about the "average" process over time.  Indeed, further knowledge
of the nature of the second to second variations is crucial in understanding the
perceptual process.


(98)

(c) Methods and Procedures

The data acquisition methods that are needed in our experiments are in the order
of 10 KHz and above sampling rate over a period of up to an hour.  Though the
PDP-12 can acquire data at this rate, it cannot either store or perform suffi-
cient analytic operations on data at this rate.  A solution to this problem is
to use the PDP-12 as a peripheral to a larger computer (PDP-10) and perform the
sampling and analog to digital conversion with the PDP-12 and the analysis
and storage with the PDP-10.

An example would be the recording of the EEG from several locations on the
scalp of a subject while he is viewing a given set of stimuli.  By comparing suc-
cessive responses to the cumulative response of previous experiments or a given
segment of the current experiment, one can determine if he has been able to dis-
criminate a change in stimulus intensity or if his attentional state with regard
to the stimuli is changing.  The comparison might require doing a statistical
procedure  such as the Pearson Product Moment Correlation or Fourier Analysis
between the digitized EEG for the last second recorded and a previous similar
sample for each of the six or eight electrode placements being used.   The re-
sults of this on-line statistical snalysis might then be used to determine cer-
tain qualities of the next stimulus to be presented.  In this way we can have
an on-line feedback controlled perceptual experiment based on a statistical
analysis of the EEG.  This is not possible with the PDP-12 alone because of the
time and data storage requirements.

The major need for the PDP-lo/12 configuration is to provide for adequate com-
puter ability to perform on-line analytic procedures of high rate physiological
samples and then use these results to alter the stimulus properties.  This
computer configuration will also allow us to produce complex visual stimuli
(such as animated figures) on a computer driven cathode ray tube and simul-
taneously measure the neurophysiological responses.

The configuration needed includes a PDP-12 which we have from other funding
sources.  All interfacing with the PDP-10 must be provided for by this grant.
This is to include anI/O capabilityof 10 KHz 12 bits wide (10,000 12 bit
PDP-12 words per second) probably implemented via the PDP-12 accumulator and
a single I/O command.  In addition, a parallel remote graphic display terminal
with CRT, keyboard, and hardcopy, which can be used to access the PDP-10 in-
dependent of the PDP-12 at least 110 baud is needed. Since our laboratory is
physically about two miles from the proposed location of the PDP-10, adequate
and reliable transmission facilities must also be provided.

These facilities will include 40K baud telephone lines and a remote PDP-11/05
data concentrator.  If a 4:l data compression is possible (a likely case), a
single telephone line with synchronous modems will suffice.  Otherwise one,
up to an unlikely three, additional units will be needed.  The CRT keyboard
would be standard.


(99)

(d) Significance

The experiments that are being performed in our laboratory are designed to in-
crease our knowledge of the action of drugs such as marihuana, alcohol, heroin,
and methadone.  Electrophysiological data correlates with central nervous system
processes that are independent of language and other social response variables.
Thus, such data can be generalized to drug users from different backgrounds.
In addition, information obtained by physiological methods is appreciated by the
general public as being objective and trustworthy, and can be used to reduce the
credibility gaps between the scientific community and drug users.

In the case of marihuana little is known about its effects on attentional pro-
cesses, which are of obvious relevance to such activities as driving an auto-
mobile.  Many users claim that they can control their mental state while intox-
icated with marihuana and perform normally if need be.  With neurophysiologic
measures of attention the claims can be objectively tested.

Addictive drugs such as heroin or alcohol raise other questions. For example,
why do some persons become heavily dependent after experimenting with these
drugs, while others do not, despite equivalent experimentation? Obviously
socioeconomic and environmental factors play a role, but there also may be
physiological differences in susceptibility.  Another question is what is the
most useful treatment program for a given individual?  The individual dif-
ferences we are looking for may allow rational decisions to be made as to
whether a heroin addict should be put on a program of abstinence or methadone
replacement, or whether neither of these alternatives is likely to succeed.
Since there is a center for the treatment of heroin addicts here at Palo Alto
Veterans Administration Hospital, we have a readily available source of experi-
mental subjects that can be followed long enough to test prognostic predictions.
Another ward specializes in the treatment of alcoholics, and it has provided
a place for us to study an experimental cycle of intoxication and withdrawal
under controlled conditions.  In the case of alcoholics there are many pressing
questions that may be approached neurophysiologically.  As in the case of
heroin addicts, there is the problem of differences of susceptibility with its
implication for prognosis and the choice of treatment.  Also there is the
question of whether occult brain damage from chronic abuse of alcohol is present
in a given patient.  The determination of an alcoholic deficit has important
medico-legal implications, as well as an implication as to how much rehabili-
tation is possible.

Thus, the investigations that we are undertaking are very important in view
of the expanding use of drugs of all kinds.  Aside from the obvious theoreti-
cal yield from studying the neurophysiological actions of psychoactive com-
pounds, there are immediate social and treatment implications.


(100)

(e) Relationship to Other Work

Our work involving alcohol and heroin addicts is being performed in conjunc-
tion with Dr. Zarcone and Dr. Dement, members of the faculty of the Depart-
ment of Psychiatry.  They are especially interested in mechanisms of sleep
dysfunction and hallucinosis in alcoholics in relation to serotonin metabol-
ism.  Our marihuana work has enjoyed the collaboration of Dr. Tinklenberg,
also of the Department of Psychiatry, who is interested in measuring psy-
chologicalchanges simultaneously with neurophysiological. ones.  He has de-
veloped some special techniques for measuring memory and attention in drug
states.

There are very few centers in the world which do work of a nature similar
to ours.  Dr. M. Buchsbaum at NIMH has been investigating evoked response
correlates of perceptual process for several years, and has provided us with
some valuable techniques.  Dr. C. Shagass of the University of Pennsylvania
Medical School has been a leader in studying aspects of the evoked responses
that are relatively independent of attention and memory in patients with
mental disease and patients under the influence of drugs.  The design of some
of our studies on alcoholism is based on work being done at St. Elizabeth's
Hospital in Washington, D.C., by Dr. N. Mello under the direction of Dr.
Morris Chavetz.



H.   BUDGET


   1.  Detailed Budget for First 12-Month Period

   2.  Budget Estimates for All Years of Support

   3.  Explanation


(102)

SECTION II -PRIVILEGED COMMUNICATION

IFROM        ITHROUGH

DETAILED BUDGET FOR FIRST 12MONTH PERIOD  I   8 - 1 - 73  I   7 - 31 - 74

                                                                           I
                DESCR lPTlON (Itemize)                         AMOUNT REQUESTED (Omit cents)
PERSONNEL                                                    TIME OR
                                                            EFFORT
           NAME                                            %/HRS.    SALARY      FRINGE
                                TITLE OF POSITION                          BENEFITS     TOTAL

  Joshua Lederberg        PRINCIPAL INVESTIGATOR         10     0         0         0
   Edward Feinenbaum      Associate Investinator      10     0         0          0

2 - Engineers           I                     I 2001

3 - Operations Staff                  1 300 1

l- Administrative Aide  I                        100
2  - Grad. Student RA.'s pips  summer help            100
     Total (24.bFTE) 1                       375,000   63,750   438,750

CONSULTANT COSTS                                               2,500
                                                                  I

EQUIPMENT Lease of PDP-10 System (Purchase Price--$1,744,750 less 10% assumed
Educational discount nlus 5% Calif. Use Tax times DEC lease factor of 2.2% per 435,3OCQ&
month=$36.275/month ~1~s miscellaneous features on hardware to be leased.         700
     Purchase aranhics station--$8.000; small machine eauipment peripherals
     $26,000; communications hardware--$6,000.                  40,000*

SUPPLIES  Off ice SURPlieS      4.000      Computer Supplies   6,000          10.000
     Books & Publications     200      Office Telephone    7,000           7,200
     Reproduction Expense   2,500      Technical Services   2,000         4,500
     Enaineerinu Sunplies   15,000                                   15.000
     Postaae & Freight      2.500                                    2.500

     DOMESTIC 5 East,  5 Midwest,  6 West Coast                 4,400
TRAVEL
         FOREIGN

             I
PATIENT COSTS (See instructions)

ALTERATIONS AND RENOVATIONS

Air conditioning, false flooring, etc.,  needed for hardware installation.      45,000

                                                                           I
OTHER EXPENSES flfemizel  Computer service from SUMCCF                   I   24,000

TOTAL DIRECT COST (En&w on hge I, /tern 6)                 ))1,137,850

INDIRECT
   COST
(See lnstruc tionsl

                                                                 I
               DATE OF DHEW AGREEMENT:

       % S&W*                      0 WAIVED
                              0 UNDER NEGOTIATION WITH:
,&2&lTDC*  omdiot,

PHS 398
Pm.* 1.-m

*IF THIS IS A SPECIAL RATE (84 off-sire), SO INDICATE.


                        (103)
SECTION II -PRIVILEGED COMMUNICATION

    BUDGET ESTIMATES FOR ALL YEARS OF SUPPORT REQUESTED FROM PUBLIC HEALTH SERVICE
                     DIRECT COSTS ONLY (Omit Cents)

                         IST PERIOD
     DESCRIPTION         (SAME AS DE-  ADDITIONAL YEARS SUPPORT REQUESTED lThis application only)
                       TAILED BUDGET1   2ND YEAR    3RD YEAR    4TH YEAR    5TH YEAR    6TH YEAR    7TH YEAR


PERSONNEL
COSTS 438,750  464,630  491,990  520,930   551,530

CONSULTANT COSTS
(Include fees, travel, etc.) 2,500   2,500    2,500   2,500    2,500

     Lease 436,000  436,000  436,000  436,000  436,000
EQUIPMENT mint. 94,000  94,000  160,000  160,000  160,000
     Purchase 40,000  40,000   54,000  64,000   64,000
supp~~~unications 12,000  16,000   16,000  18,000   18,000

      Supplies 39,200  40,000   41,000  42,000   43,000

            DOMESTIC
TRAVEL 4,400   4,koo   4,000   4,200   4,200

            FOREIGN

PATIENT COSTS

ALTERATIONS AND
RENOVATIONS 45,000     ---        ---       ---         ---

Corn uter Services 24,000
w               24,000   24,000  24,000   24,000
OTHE EXPENSES
      Training 2,000   1,000    1,000   1,000    1,000


TOTAL DIRECT COSTS   1~37,850 .-&22,530 1,230,4gO .1,272,630 .1304,230

                                           ii
TOTAL FOR ENTIRE PROPOSED PROJECT PERIOD (Enter on Page 1, /rem 41  -  5 6,0$7,730

REMARKS: Justify all costs for the first year for which the need may not be obvious For futura yaers, justify equipment costs, es well as any
significant increacts in any other category. If a recurring annual increase in personnel costs is requested, give percentage,  (Use continuation
page if needed.)

1.  Lease of equipment covers a PDP-10 Computer System.

2.  Personnel salaries are increased at 5% per year. Staff benefits are 17% in Year1
  and 1% per year greater in each subsequent year.

3.  Alteration  and renovation funds of $45,000 are requested for air conditioningand
   false floors needed for hardware installation.

4. The PDP-10 maintenance contract will be changed from 12 hours, 5 days per week to
  24 hours, 7 days per week in Year 3.  This will provide the backup capability
  needed by the Service System, and      -versa.


BUDGET ESTIMATES FOR PDP-10 SYSTEM:

Central Processor
KI-10 incl. Operator's Console

v x 16k words

Auxiliary Memory System
4 x ME10 and DT04C

Keyboard Terminals(l6)
Hardcopy & CET, to be selected (16~3K)

Memory Bus Swapping Drum System
RMlO B & Controller

Memory Bus Disc System
4 x RP03 Disc & Controller

Input/Output Bus Peripheral System
Tape Systems, 3 x TUlO, (gx7track)
& 1 DEC TU56 & Controllers

Asynchronous Communication System
DC10 System for Keyboard Terminals

Purchase
Price

Monthly Maint.
h2hrs 5days)

$ 380,000     $

400,000

225,000

48,000

83,000

150,000

64,850

37,500

SATELLITE COMPUTER& Includes intercomputer co~~ice;tions and --
Multiplexed Memory System
PDP 11/45 #l: 8~
       #2: 4K                  74,050"

       #3: 4K                  16,450
     #4: 8K (incl. RKll and RF11 Disc,    16,450
                           56,450
          & PC11 Punch and tape)
lo/11 Interface                     70,000
MXlO Memory Multiplexor              4,500

Peripherals                     118,000
LPlOC Line Printer, CPlOA, CRlOD Card
Punch & Reader

                Sub Totals   1,744,250
Assume 10% Educational Discount - 174,425

555

1,336

748"

320

265

826

338

110 (A)

547" (B)
195
195
484"

500*
15"
462* '

6,896

Net   1,569,825 (Not including sales tax)

Options:
1) Memory System(4 x MElO)               200,000          668
2) Terminal Commnications(DPllDAS &DPllDC's)    7,900       115 a)
3) Sync Communications System(DC-75)         50,000       250*b)

                              257,900         1,033
  (Incl. Option 1)         TOTAL $ 1,769?325 (Not incl. sales tax)
a) Added to A above.
b) Deletes $7,400 of B above.


(105)

3.  Explanation

a. Major Assumptions

The five-year budget request has been prepared with the following major
assumptions:

(1)

(2)

(3)

(4)

(5)

(6)

(7)

(8)

SUMEX will include a PDP-10 KI-10 Processor with 192K words of core
plus four PDP-11 satellite processors. Additional "user owned" re-
mote satellites will be attached by collaborators.

It is assumed that the Medical Center will opt to replace the 360/50
with a PDP-10 for the Service Facility.  SUMEX personnel will mount
a PL-type language on the PDP-10 in order to provide a transition
from the 360/50 for current software.

A 10% education discount from list price on the PDP-10 has been
assumed.  A higher discount may be negotiable.

The staff of SUMEX will evolve from the existing groups which have
demonstrated competence in tackling and solving biomedical computing
problems.

University authorization and funding of modifications to existing
machine room space are assumed.  Detailed and formal proposals will
not be available for consideration by the University prior to sub-
mission of this proposal.

We expect that the full lease costs associated with the SUMEX PDP-10
System will be covered by the proposed grant. A full pay-out, 5-year
lease is proposed.

In general, collaborators will provide their own laboratory hardware
and applications programming.  SUMEX will provide host computer ser-
vices, system software support, and some assistance in interfacing
to the host.

A beginning date of August 1, 1973, is proposed. This coincides with
the end of the current ACME grant.

b.  Notes on Budget Elements -- Year 1

The explanation of each budget element requested for Year 1 is presented below.

Salaries:  The salaries included in the budget are based upon the following
manpower assumptions:

(1) SUMEX will have a Facility Director, a senior technical project leader,
   and a one-half time administrative manager on its management team.   It
   is assumed that one project leader might be given the small machine
   support task while the other would handle the extended realtime support
    tasks.  A total of 10 systems programming personnel are included in
   the budget.  This will make a tight fit in Year 1 when an estimated
   5.5 man-years will be devoted to the transition of a PL-type language


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to the PDP-10.  The number of programmers covered by the budget
reflects our concern with becoming "too large" to be manageable
as a research team, as well as recognition of the large effort
required to achieve our goals.

Five man-years of engineering and technician effort are budgeted.
Their primary efforts will involve design, fabrication, installa-
tion, and maintenance of special interfaces and communications
lines.  Much of the collaborators' work described in the proposal
will be dependent upon interfacing new hardware to computing sys-
tems.  For example, two scanning devices are to be acquired by col-
laborative projects and will be interfaced to machines in the
Resource.  Detailed planning for this group will be dependent upon
future decisions in the participating projects.

The Operations staff will operate, by assumption, both the SUMEX
and SUMCCF systems.  Since the SUMEX operation will involve only
a few research groups, the operations tasks should be relatively
light during most hours of operation.  If the SUMCCF budgets four
full time equivalents and the SUMEX budgets three, then it is
feasible to cover all 21 shifts per week. The operations staff
figure includes an Operations Manager who would be shared by the
two facilities.  All of these estimates are based upon the assump-
tions that SUMEX and SUMCCF will be situated in a common area and
that shared operating staffs are desired by computing coordinators
in the Center.

The balance of the staff will be comprised of an applied mathe-
matician, one administrative aide, one secretary, plus occasional
part time help, including graduate student  research assistants.
The applied mathematician is requested in order to assist colla-
borators and core research efforts.  Such assistance should prove
especially valuable in developing new algorithms, appraising new
techniques for image processing, etc.

(2) Staff Benefits:
  is 17%.      The standard rate for the University's FY1974

(3) Training, Consulting, Travel, and Publications: The training bud-
  get of $2,000 will be used to make the staff better acauainted
  with PDP-10's, various satellite processors, and new software
   techniques.  The consulting item of $2,500 is an estimate of the
   first year's needs.  It is double the current year budget for
  ACME outside consulting due to the complexity of tasks to be
   undertaken.  The travel time should provide eight trips to the
  east coast, 3 to the midwest,
  + go0 + 400 = $4,400).     and 6 on the west cease ($3,200
                   The travel funds will be used to ex-
  change information with other research centers, attend training
   sessions, disseminate information, and investigate possible
  network participation.


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(4) Materials and Supplies:  These estimates are based entirely upon
  the experience,. gained in the ACME Grant. The items are as follows:

Item

Est. Cost

Office Supplies           $  4,000
Computer Operations Supplies     6,000
Publications                 2,500
Postage and Freight            2,500
Books and Periodicals              200
Office Telephone              7,000
Technical Services             2,000
Engineering Supplies           15,000

Total

$ 39,200

(5) Communications Costs:  Collaborators in this proposal are situated
  from 100 feet to 2.5 miles from the existing machine room. This
  budget element will be used to provide high data rate communications
  lines as required by each research project. Dr. Kopell's group is
  located in the Palo Alto Veterans Hospital which is about 2.5 miles
   distant.  The mass spectrometer used by the DENDBAL group is situated
  in the Chemistry Building which is more than 1,000 feet from the
   machine room.  Communications will be handled by a combination of
  Telephone Company lines and local hardwire connections.  Specific
  transmission requirements must precede detailed estimates. A 4Okb
  telephone line connecting VA Hospital and the machine room has
  been priced at $596 per month plus an installation fee of $950.
  This budget element will also include some modem rentals. We anti-
  cipate the announcement of a number of commercially available modems
  which will accommodate bandwidths and data rates of interest.

(6)

Equiment Lease:  The hardware described in Section E of the proposal
is a KI-10 System with a list purchase price of $1,744,750. A full
payout lease has been offered by DEC at 2.2% of the purchase price
per month.  A 10% educational discount has been assumed; no negotia-
tion has been held with DEC on this point.  To this net price, the
5% California Use Tax must be added. The lease rate is calculated
as $1,744,750 less 10% plus 5% tax at 2.2% per month giving a monthly
rate of $36,274.  At the end of five years, the equipment will be

owned.  The lease rate does not include maintenance. Additional
equipment was presented in Section E as "options".  The options in-
cluded additional core, terminal communications add-ons, and a syn-
chronous communications system.  In view of the competing demands
for funding, these items have been excluded from the budget. If
future arrangements with DEC permit the acquisition of more equip-
ment within the budgeted dollars, then optional items will be added
to the configuration.  The optional items were initially part of
the required configuration but were set aside in order to obtain a
balance between hardware and personnel within an overall budget
which was deemed feasible.


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(7) Maintenance of Equipment:  The primary hardware maintenance contract
    will be with DEC.  Using DEC's standard s-day 12-hour maintenance

contract for all items in the budgeted configuration results in
monthly charges of $7,053.  This figure includes estimates for six
hardware items on which standard maintenance charges have not been
announced.  This level of maintenance may be adequate for the re-
search activity of SUMFX.  If more hours are needed in order to
provide better backup support for the SUMCCF, the 5-day 12-hour
assumption will be re-evaluated.  In addition to the $84,600 for
PDP-10 system maintenance, the budget includes $9,400 for mainten-
ance contracts covering graphics stations, additional small machine
peripherals, communications hardware, etc.

( 8 ).. .

(9)

Olher Equipment:  In addition to the items identified in the PDP-10
system, SUMEX will require equipment for its engineering group,
communications hardware, and graphics support.   In a research and
development program of the type proposed, equipment needs will arise
which cannot be specified today.  A few examples of the types of
hardware which are likely to be required include: complete graphics
station:for $8,000; special hardware interfaces for small machines
for $10,000;  expansions to the small machine equipment pool for
$16,000; and communications hardware for $6,000.

Alterations and Renovations:  $45,000 are included in the budget
in order to provide adequate facilities in which to house the
SUMEX hardware.  Extension of the existing space occupied by the
ACME Machine Room will be needed.  The University is being asked
to provide structural modifications,  This proposal includes the
funds to provide necessary air conditioning, false floors, cable
tray access, and some special electrical provision for the com-
puting facilities.  The cost estimate is rough at this time.
Efforts will be made in the near term to obtain requisite approvals
from the University plus the funding for the building modifications.
Also, more detailed estimates of special facilities associated with
the hardware will be prepared.


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I.  FUTURE PLANS

Our plans beyond the requested five-year period of support call for hard-
ware dedicated to the types of user projects listed in our proposal. We
expect that the central hardware will continue to be available as a research
resource for a limited number of users.  New projects presumably will emerge
calling for development of new computing techniques.  The current talents
of the staff will be deepened and new skills will be developed which we assume
will prove highly useful in solution of some of tomorrow's problems.

A lesson from the ACME experience is that technological change, as evidenced
by the minicomputer revolution, must be carefully monitored.  We hope to
anticipate major changes more accurately so that new developments will inte-
grate well with local research efforts.  We would expect, based upon current
trends, to involve ourselves with computer architectures other than the
initial selection for this research resource.


J. APPENDICES


   1. ACME User Publications

   2. Biographical Sketches


ACME Note

Papers Written By ACKE Users

       AFfJB-9
   Eric8 Baxter
Februsry 2% 1972

Thls list contains papers voluntarily reported to ACME.

Ballkian, H., A. Brodie, S. Willoughby, A. Dowdy, G. Nokes. M. Wefnberger. and
  J. Luetscher, "Response of Plasma Aldosterone Concentration in Hypertensive
  Patients to Changes In Posture and Sodium Intake," CLIN. RES.. vol. 17. p. 141,
  Jan. 1969, (abstract).

Barnett, C., J. Jackson, and H. Cann, "Child Spacing and Its Implications for
  Population Control in Highland Guatemala Cotmnunity," presented at the 28th Annual
  Meeting of the Society for Applied Anthropology, Mexico City. Mexico, Apr. 1969.

Beatrice, E., I. Harding-Barlow, and D. Glick, "Electric Spark Cross-Excitation in
  Laser Microprobe-Enanisslon Spectroscopy for Samples of lo-25 Micron Diameter,"
  APPLIED SPECTROSCOPY, vol. 23, pp. 257-259. 1969.

Beatrice, E. and D. Gltck, "A Direct Reading Polychromator for Emission
  Spectroscopy," APPLIED SPECTROSCOPY, vol. 23, pp. 260-263, 1969.

Beatrice, E., 0. Glick, E. Scribner, L. Alterton. R. Honey, I. Harding-Barlow.
  N. Peppers, and R. Rosan, "Q-Switched Ruby Laser for Emission Mlcrcspectroscopic
  Elemental Analysis," ANAL. CHEM., vol. 40. pp. 1178-1182, 1968.

Becker, J.. Y.T. Thathachari, P.G. Simpson. "Molecular Conformation of
  L-DDPA," BIOCHEM. BIOPHYS. RES. COW.. Vol. 41, pp. 444-449. 1970.

Eellville, J., J. Green, and W. Forrest, Jr., "Respiratory Effects of
  Etomide and Codeine." CLIN. PHARH. THERAP.. vol. 9, pp. 142-151, 1968.

Eellville, J. and W. Forrest Jr., "Respiratory and Subjective Effects of
  d and 1 Pentarocine," CLIN. PHARM. THERAP., vol. 9. pp. 142-151. 1968.

Bellville. J. and J. Seed, "A Comparlson of the Resplratory Effects of
  Dextropropoxyphene and Codeine in Man." CLIN. PHARM. THERAP.. vol. 9.
  pp. 428-434, 1968.

Eellvllle, J., W. Forrest, Jr., J. Stevens, and E. Beer, "The Hypnotic Effects
  of Ethchlorvynol and Secobarbltal in Man," CLIN. PHARM. THERAP., vol. 9,
  pp. 625-530, 1968.

Bellville, J.. L. Escarraga, S. Wallensteln, and R. Houd.
  "The Respiratory Effects of Codeine and Morphine In Man," CLIN. PHARM.
  THERAP., vol. 9, pp. 435-441, 1968.

Bellville, J., G. Flelschli, and J. Defares. "A New Method of Study
  Regulation of Respiration--The Response to Sinusoidally Varying CO2
  Inhalation," COMPUTERS FOR BIOMEDICAL RESEARCH, vol. 2. no. 4. pp. 329-349.
  June 1969.

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

BernfIeld. M. and P. Maenpaa, "Quantitatfve Variation in Serine Transfer
  Ribonucleic Acid during Estrogen-Induced Phosphoprotein Synthesis in Rooster
  Liver." BIOCHEMISTRY, vol. 8, pp. 4926-4935. 1969.

Bernfield, M., "Chromatographic Propertles of Pyrrolidone Carboxylate-tRNA,"
  submitted to J BIOLOGICAL CHEM.

Bernfield, M., "Characterization of Pyrrolidone Carboxylate-RNA from Rat Liver,"
  in preparation.

Bodmer, W. and L. Cavalli-Sforza, "A Migration Matrix Model for the Study of
  Random Genetic Drift," GENETICS, vol. 59, pp. 565-592, 1968.

Bodmer, W., M. Feldman, and M. Nabholz, "The Evolution of the Rh Polymorphism:
  A Model for the Interaction of Incompatlbllity, Reproductive Compensation,
  and Heterorygote Advantage," AMER. J. HUMAN GENETICS, vol. 21. no. 2.
  pp. 171-193, Mar. 1969.

Bodmer, W., 3. Bodmer, 0. Ihde, and S. Adler, "Genetic and Serologlcal Associa-
  tion Analysis of the HL-A Leukocyte System," CORUTER APPLICATIONS IN GENETICS
  (ed. N. Morton), Univ. Hawaii Press, pp, 117-127, 1969.


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AFJB-3
Page 2

Bodmer, W., V. Miggiano. and H. Nabholz. "Hybrids between Human Leukocytes and
  a Mouse Cell Line:  Production and Characterization." WISTAR INSTITUTE SYMPOSIUM,
  monograph no. 9. "Heterospecific Genome Interaction." (ed. V. Defendi), THE
  WISTAR INSTITUTE PRESS, 1969.

Bodmer, W., M. Nabholz, V. Miggiano. "Genetic Analysis Using Human-Mouse Somatic
  Cell Hybrids," NATURE, vol. 223, pp. 348-363, 1969.

Bodmer, W. and L. Cavalli-Sforza, "The Genetics of Human Populations." FREEMAN
  AND COMPANY, in press.

Bodmer, W. and J. Bodmer, "Studies on African Pygmies IV: A Comparative Study
  of the HL-A Polymorphism in the Babfnga Pygmies and Other African and Caucasian
  Populations," AM. JOUR. HUM. GENET., July 1970.

Bodmer, W. and B. Gabb, "A Micro Complement Fixation Test for Platelet Antibodies,"
  HISTOCOMPATIBILITY TESTING, July 1970

Bodmer, W., J. Bodmer, A. Coukell. R. Payne, and E. Shanbrom, "A New Allele for
  the LA Series of HL-A Antigens:  The Analysis of a Complex Serum." HISTOCOM-
  PATIBILITY TESTING, July 1970.

Bodmer, W., J. Bodmer. and M. Tripp.  "Recombination between the LA and 4 Loci
  of the HL-A System." HISTOCOMPATIBILITY TESTING, July 1970.

Bodmer. W.. P. Mattiuz, 0. Ihde, A. Piazza, and R. Ceppellini, "New Approaches
  to the Population Genetic and Segregation Analysis of the HL-A System."
  HISTOCOMPATIBILITY TESTING, July 1970.

Breitbard. G. and G. Wiederhold. "PL/ACME: An Incremental Compiler for a
  Subset of PL/l," IFIP6B CONGRESS PROCEEDINGS, Edinburgh, Scotland, Aug. 1968.

Brown, 8. and L. Soyka.
  Children: I.    "Survey of Drugs Administered to Nine-Hundred Hospitalized
          Relation to Age, Sex, and Diagnostic Category," submitted to JAMA.
  Mar. 1970.

Butsien, R, "L'informatique medicale aux Etats-Unis, MEDECINE et
  HYGIENE, Nov 1970

*Calvert, J. Lee and John H. Frenster, "Economics of Effectiveness and
   Efficient
   (abstract . 3 in Patient Care," CLINICAL RESEARCH, vol. 19 , p. 501 , 1971

ffcalvert, J. Lee and John H. Frenster.  "Economics of Investment in Biomedical
   Research and Current Patient Care,"
   (abstract).              CLINICAL RESEARCH, vol. 19, p. 499, 1971

Cann, H., B. Van West, and C. Barnett, "Genetics of Diego Blood Groups in Guatemalan
  Indians:  Use of Antiserums to Diego a and Diego b Antigens," SCIENCE, vol. 162.
  pp. 1391-1392. Dec. 1968.

Clayton, R., "Methods in Enzymology," STEROIDS AND TERPENOIDS, vol. 15,
  Academic Press, 1969.

Cohen, S. and J. Hurwitz, "Genetic Transcription in Bacteriophage   : Studies
  of   mRNA Synthesis in viva." J. m)L. BIOL.. vol. 37. pp. 387-406, 1968.

Cohen, 5. and C. Miller, "Multiple Molecular Species of Circular R-Factor DNA
  Isolated from Escherichia calf." NATURE, vol. 224, pp. 1273-1277, 1969.

Cohen, S. and C. Miller,  "Non-Chromosomal Antibiotic Resistance in Bacteria:
  II. Molecular Nature of R-Factors Isolated from Proteus mirabilis and
  Escherlchia coli." J. MOL. VIOL., vol. 50, No. 3, pp.671-687, June 1970.

Cohen, S. and A. Chang, "Genetic Expression in Bacteriophage   . III. In-
hibition of E. coli Nucleic Acid and Protein Synthesis during   Develop-
  ment," J. MOL. BIOL.. Vol. 49, No. 3. pp. 557-575, May 1970.

Collins, K. and G. Stark, "Aspartate Transcarbamylase: Studies of the Catalytic
  Subumt by Ultraviolet Difference Spectroscopy," J. BIOL. CHEW.. vol. 244.
  pp. 1869-1877, Apr. 1969.

Collins, R., M. Weinberger, C. Gonzales, G. Nokes. and J. Luetscher.
  "Catecholamine Excretion in Low Renfn Hypertension," CLIN. RES.,
  vol. 18, p. 167, 1970, (abstract).

Constantinou, C., and E. Butler. "Medical Application of Computer Displays
  in the Rapid Examination of Developing Abnormality Patterns in the
  Kidney," PROCEEDINGS OF THE INTERNATIONAL SYMPOSIUM OF THE SOCIETY OF
  INFORMATION DISPLAY, Philadelphia, May 1971.


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Constantinou, C.. E. Brfggs, R. Dale, and 0. Govan. "Real-Time Digital
Computer System for Ureteral Physiology Investigation."
URODYNAMICS, Chap. 33, Academic Press. New York, in press.

Constantfnou. C., J. Sands, and 0. Govan, "Computer Monitoring and Control
Instrumentation in Urology Research," PROCEEDINGS OF THE 6TH ANNUAL
BIOENGINEERING SYMPOSIUM, Fort Collins, Colo.. May 1971.

Crouse, L. and G. Wfederhold,
  Medical Applications,"   "An Advanced Computer System for Real-Time

  pp. 582-598, Dec. 1969. COMPUTERS AND BIOMEDICAL RESEARCH, vol. 2, no. 6,

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

Crouse, L.. R. Stenson, W. Henry, and D. Harrison, "A Time Shared Digital
Computer System for On-Line Analysis of Cardiac Catheterization Data,"
ft!PUTERS AND BIOMEDICAL RESEARCH, vol. 1, no. 6, p. 605, Academic Press,
    ., June 1968.

Doerfng, C., "Cholesterol Side Chain Cleavage Actlvfty in the Adrenal Gland of
the Young Rat:  Davelopment and Responsiveness to Adrenocorticotropfc Hormone."
ENDOCRINOLOGY. vol. 85, pp. 500-511, 1969.

Doering, C., "A Microassay for the Enzymatic Cleavage of the Cholesterol Side
Chatn," METHODS IN ENZYMOLOGY, (ed. R. Clayton), vol. 15, pp. 591-596.
  Academic Press, 1969.

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

Englund. P., J. Huberman. T. Jovfn, and A. Kornberg. "Enzymatic Synthesfs of
Deoxyribonucleic Acid, XXX. Binding of Trfphosphates to WA Polymerase," submitted
  to J. BIOL. CHEM., vol. 244. pp. 3038-3044. 1969.

Farber, E. and R. McClfntock. Jr., "A Current Review of
Psoriasis." MEDICAL PROGRESS, vol. 108, pp. 440-457, June 1968.

Farber, E. and A. Cox, "The Biolo y of Psoriasis.' J. OF
  INVESTIGATIVE DERMATOLOGY, vo 3 . 49, no. 4, pp. 348-357, 1967.

Farber, E., R. Bright, and M. Nail, "Psoriasis -
A Questionnaire Survey of 2,144 Patients,"
  Sept. 1968.                 ARCH. DERM.. vol. 98. pp. 248-259,

Forrest, W., Jr. and J. Bellvflle, "The Use of Computers in Clfnfcal Trials,"
BRIT. J. ANESTM., vol. 39, pp. 311-319, 1967.

Forrest, W., Jr. and J. Bellvflle, "Respiratory Effects of Alphaprodine in
Man," OBST. AND GYN., vol. 31, pp. 61-68, 1968.

Forrest, W., Jr., B. Brown, and J. Peters, "Management of Cooperative Clinical
Trials," Paper presented at the Annual Meeting of the American Statistical
Association in Pittsburgh, Pa., Aug. 1968.

Fried, M. and K. Vosti, "The Importance of Underlying Disease in Patients with
Gram-Negative Bacteremfa," ARCH. INT. MED., vol. 121, pp. 418-423, 1968.

Fries, J., "Experience Counting in Sequential Computer Diagnosis,"
ARCHIVES OF INTERNAL MEDICINE, Vol. 126, Oct. 1970.

#Fries. J., "The Effect of Ice Water on Esophageal Rewarming in Connective
   Tissue Diseases (CTD)," abstract submitted to GASTROENTEROLOGY.
Gersch, W. and G. Goddard, "Epileptic Focus Location: Spectral Analysis Method,"
   SCIENCE, Vol. 169, pp.701-702. 1970.

Gers;i;le;. and E. Dong, Jr., "A Note on Warner's Vagus Heart Rate Control
    1" CIRCULATION RESEARCH, 1970.

Gersch, W., D. Eddy, and E. Dong, Jr., "Cardiac Arrhythmia Classiffcatfon:
A Heart Beat Interval-Markov Chain Approach," COMPUTERS AND
BIOMEDICAL RESEARCH, Aug. 1970.

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

Gersch, W., "Estimation of the Autoregressive Parameters of a Mixed
Autoregressive-Moving Average Time Series," IEEE TRANS. AUTOMATIC CONTROL,
Aug. 1970.


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Glick, D. "Cytochemical Analysis by Laser Microprobe-Emission Spectroscopy,"
   ANNALS N. Y. ACAD. SCI.. vol. 157. pp. 265-274, 1969.

24 Glick. D., "Cytochemical Analysis by Laser Microprobe - Emission Spectroscopy."
   RECENT ADVANCES IN QUANTITATIVE HISTO- AND CYTOCHEMISTRY, pp. 192-193, 1971.

%Gllck. D., K. Marich. J. Orenberg, P. Carr, and D. Miller, "Effect of Atmosphere
   on Spectral Emission from Plasmas Generated by the Laser Microprobe," ANALYTICAL
   CHEMISTRY, vol. 43, pp. 1452-1456, September 1971.

Gllck, 0.. K. Marich. P. Carr, and E. Beatrice, "Laser Microprobe-Emission
  Spectroscopy," ANNALS N. Y. ACAD. SCI., vol. 168. pp. 507-509, 1970.

Halpern. 8.. V. Close, A. Wegmann. and J. Westley, "Gas Chromatography of
  Amino Acids as N-Thiocarbonyl Ester Derivatives," TETRAHEDRON LETTERS, vol. 27,
  p. 3119. 1968.

Hat-man. C.E. and C.S. Raymond, "Computer Prediction of Chronic
  Psychiatric Patients." J. NERV. and MENTAL DIS., Vol. 150, pp. 490-503,
  1970.

Harman, C.E. and K. Meinhardt. "A Computer System for Treatment Evalua-
  tion at the Cotmaunity Mental Health Center." presented at the 2nd Bay
  Area Regional Conference on Program Evaluation In San Francisco, Calif.,
  January 7, 1971.

Harrison, D., R. Goldman, M. Klughaupt. T. Metcalf, and A. Spivack, "Central
  Venous Oxygen Saturation Measurements in Patients with Myocardial Infarction,"
  CIRCULATION, vol. 28, Nov. 1968.

Harrlson, D., M. Flansn. and E. Hancock,  "Muscular Subaortic Stenosis: Preven-
  tion of Outflow Obstruction with Propranolol," CIRCULATION, vol. 28, p. 846, 1968.

Harrison, D., R. Gianelly, W. Angell, E. Stinson, and N. Shumray, "Homograft
  Replacement of the Mltral Valve." CIRCULATION, vol. 28, p. 664, 1968.

Harrison, 0.. E. Stinson. E. Don 3' Jr., and J. Schroeder, "Initial Clinical
  Experience wlth Heart Transp antation." AMER. J. OF CARDIDL., vol. 22,
  p. 791, 1968.

Harrlson, D., M. Robinson, and R. Kleiger. "The Role of Hypoxia in Dlgitalis
  Toxiclty," AMER. J. MED. SCI.. vol. 256, p. 352, 1968.

Harrison, D. and R. Gianelly, "Studies on the Antiarrhythmic and Circulatory Ac-
  tions of Lldocaine (Xylocaine(R))," ALA. J. MED. SCI., vol. 6, p. 74, 1969.

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

Harrison, 0. and R. Gianelly, "Drugs Used in the Treatment of Cardiac
  Arrhythmias," DISEASE-A-MONTH, Jan. 1969.

Harrison, D., M. Klughaupt, M. Flatmn, and E. Hancock. "Non-Rheumatic Mitral In-
  sufficiency:  Determination of Operability and Prognosis," CIRCULATION, vol. 39,
  p. 307, 1969.

Harrison, D.. W. Henry, S. Kountz, R. Cohn, and S. Robison, "Changes in Pulsatile
  Blood Flow in Autograft and Homograft Kidneys during Rejection." TRANSPLANTATION,
  vol. 7, p. 545. 1969.

Harrison, D., B. Treister. R. Gianelly, and R. Cohn, "The Circulatory Effects of
  Isoproterenol, Acetylstrophanthldin and Volume Loading in Acute Pericardial
  Tamponade." CARDIOVASC. RES.. vol. 3, p. 299, 1969.

Harrison, D. and M. Perlroth, "Cardiogenic Shock: A Review," CLIN. PHARMACOL.
  AND THERAPEUT., vol. 10, p. 449, 1969.

Harrison, D.  R. Gianell , and B. Treister,
Induced fschemlc ST r           "The Effect of Propranolol on Exercise-
            egment Depreslion," AMER. J. CARDIDL., ~01.~24, p. 161, 1969.

Harrison, D., J. Schroeder, R. Popp, E. Stinson, E. Dong, Jr., and N. Shumway.
"Acute Rejection Following Cardiac Transplantation: Phonocardiographic and
  Ultrasound Observations," CIRCULATION, vol. 40. p. 155, 1969.

Harrison, D., 8. Wintroub, J. Schroeder, M. Schroll, and S. Robison, "The Herno-
$;;i$ Response to Dopamine in Experimental Myocardial Infarction." AMER. J
        .I vol. 217, pp. 1716-1720, Dec. 1969.

Harrison, D., 8. Wintroub, S. Robison, and S. Pirages, "The Pulmonary and Systemic
Circulatory Response to Dopamine Infusion," BRIT. J. PHARMACOL.. Vol. 37. p. 618. 1969.


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Harrison, D., S. Robison, and M. Schroll, "The Circulatory Response to Lidocaine
  In Experimental Myocardial Infarction," AM. J. MED. SCI., Vol. 258, p. 260, 1969.

Harrison, 0. and J. Ridges, "Nomograms for Determination of Mixed Venous 02
  Content and 02 Stepup in Atria1 Septal Defect," AMER. HEART J.. Vol. 80. p.575. 1970.

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

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

Hillman, R., "The Teaching of
  presented at the American
  Calif., May 1970.

Psychotherapy Problems by Canputer," to be
Psychiatrfc Association Convention, San Francisco,

hillman, R., "The Teaching of Psychotherapy Problems by Computer," ARCHIVES
  OF GENERAL PSYCHIATRY, in press.

Hodgson, G., E. Petterson, K. Kvenvolden, E. Bunnenberg, 8. Halpern, and C. Ponnam-
  peruma, "Search for Porphyrlns In Lunar Dust," SCIENCE, vol. 167. pp. 763-765.
  Jan. 1970.'

Huberman. J. and A. Kornberg, "Enzymatic Synthesis of Deoxyribonucleic Acid, XXXV.
A 3'-Hydrox$ribonucleotide Blndin Site of Escherichia colt Deoxyribonucleic Acid
  Polymerase, J. BIOL. CHEM., Vol. 145, p. 5326, 1970.

Ingels, N.. S. Rush, and N. Thompson, "Analytic Stop Motion Stereo Photogransaetry."
  THE REVIEW OF SCIENTIFIC INSTRUMENTS. vol. 40, no. 3, pp. 487-492. Mar. 1969.

Kaklhana, R., J. Butte, and E. Noble, "Effects of Goldthloglucose on Alcohol
  Consumption in C57BL Mice," LIFE SCIENCES, vol. 7, p, 825, 1968.

Kakihana, R.. E. Noble, and J. Butte, "Corticosterone Response to Ethanol in
  Inbred Strains of Mice," NATURE, vol. 218, p. 360, 1968.

Kessler, S., "Speed of Mating and Sexual Isolation in Drosophila," NATURE,
  vol. 220, pp. 1044-1045, 1968.

Kessler, S.. "The Genetlcs of Drosophfla Mating Behavior I - Organizations of
  Mating Speed In Drosophila pseudoobscura." AN. BEHAV., vol. 16, pp. 485-491, 1968.

Kessler, S., "The Genetics of Drosophila Nating Behavior II - The Genetic
  Architecture of Mating Speed In Drosophila pseudoobscura," GENETICS,
  vol. 62. pp. 421-433. 1969.

Kessler, S. and R.H. Moos, "The XYY Karyotype and Criminality: A Review,"
  J. PSYCHIATRIC RES., Vol. 7, pp. 153-170, 1970.

Kountz, S., K. Cochrum, H. Perkins, K. Douglas, and F. Belzer, "Selection of
Al10 raft Rectptents by Leukocyte and Kidney Cell Phenotyping," presented at
  the s 1st Annual Meeting of the Society of University Surgeons, Pittsburgh,
  Pennsylvanta, Feb. 1970.

Kriss, J., S. Kountz, S. Yeh, J. Wood, and R. Cohn, "9% Tc (V)-Citrate Complex
  for Estimation of Glomerular Filtration Rate," NATURE, vol. 215, p. 1937, 1967.

Kriss, J., "The Nature and Significance of the Long-Acting Thyroid Stimulator,"
AI;;AN;E;~IN METABOLIC DISORDERS, (eds. K. Levine and R. Luft), vol. 3, pp. 209-
     I .

Krlss, J., "The Long-Acting Thyroid Stimulator," CALIF. MED., vol. 109, p. 202.
  1968.

Kriss. J., "The Long-Acting Thyroid Stimulator and Thyroid Disease,"
  ADVANCES IN INTERNAL MEDICINE, 1970.

Krlss, J.. T. Mori, and J. Fisher, "Studies of an in vitro Binding Reaction
Fetween Thyroid Microsomes and Long-Acting Thyroid Stimulator Globulin (LATS):
    Development of Solid-State Competitive Binding Radioassay Methods for
Measurement of Anti-Microsomal and Anti-Thyroglobulin Antibodies."
  J. CLIN. ENDDCR. AND METAB., 1970.

Kriss, J. and S. McHardy-Young. "Simplified Technique for the Radioimeunoassay
  of Human TSH," J. NUCLEAR MED., vol. 10. p. 356. 1969, (abstract).

Kriss, J., 5. McHardy-Young, and H. Kaplan, "Serum Tsh Levels Following Megavoltage
  Radiotherapy for Hodgkfn's Disease," PROGRAM, 45TH AMERICAN THYROID ASSOCIATION,
  p. 83, July 1969, (abstract).


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Kriss, J. and T. Mori, "Studies of a Rapid, in vitro. Binding Reaction between
Human Thyroid Microsomes and Radioiodinated Long-Acting Thyroid Stimulator (LATS)
  IgG Globulin," PROGRAM, 45TH AMERICAN THYROID ASSOCIATION, p. 28, July 1969,
  (abstract).

Kriss. J., E. Glatstein. and J. Eltringham. "Serum TSH and Thyroid Function
Following X-Ray Therapy in Patients with Malignant Lymphomd," CLINICAL RESEARCH,
vol. 18, p. 168. 1970, (abstract).

Kriss, J. and T. Mori, "Rapid Competitive Binding Radioassay of Serum Anti-
  Microsomal and Anti-Thyro lobulin Antibodies:  Measurements in Graves' Disease,"
  CLINICAL RESEARCH, vol. 1 , p. 170, 1970, (abstract).
         !

Kriss, J. and T. Mori, "Rapid Competitive Bindlng Radioassay of Serum Anti-
Microsomsl and Anti-Thyroglobulin Antibodies:  Measurements in Graves' Disease,"
submitted to 6TH INTERNATIONAL THYROID CONFERENCE. June 1970, (abstract).

Laipis, P., B. Olivera. and A. Ganesan, "Enzymatic Cleavage and Repair of
Transforming DNA," P.N.A.S., vol. 62, p. 289, 1969.

Levine, R. and N. Kretchmer, "Conversion of Carbamyl Phosphate to Hydroxyurea:
  An Assay for Carbamyl Phosphate Synthetase, ' ANALYTICAL BIOCHEMISTRY, vol. 42,
  no. 2, pp. 324-337, August 1971.

3? Levine, R., N. Hoogenroad, and N. Kretchmer, "Copurification of Carbamoyl Phosphate
  Synthetase and Aspartate Transcarbamoylase from Mouse Spleen," BIOCHEMICAL AND
   BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 44, pp. 981-988, 1971.

&Levine. R.. N. Hoogenroad, and N. Kretchmer, "Regulation of Activity of Carbamoyl
   Phosphate Synthetase from Mouse Spleen," BIOCHEMISTRY, vol. 10, no. 20, pp. 3694-
   3699. 1971.

Luetscher, J., M. Weinberger. and R. Collins, "Oral Contraceptives and
  Hypertension:  Clinical and Laboratory Observations," METABOLIC EFFECTS
OF GONADAL HORMONES AND CONTRACEPTIVE STEROIDS, edited by D. Kipnis. et al,
  Plenum Publishing Corp., 1969.

Luetscher, J., M. Weinberger, A. Dowdy, and G. Nokes, "Effects of
Sodium Loading, Sodium Depletion and Posture on Plasma Aldosterone Concen-
tration and Renin Activity In Hypertensive Patients," J. CLIN. ENDOCR.,
  vol. 29, p. 1310, 1969.

Luzzattl, L., R. Greenstein, D. Harris, and H. Cann, "Cytogenetlc Analysis of a
  Boy with the XXXY Syndrome:  Origin of the X-Chromosomes," PEDIATRICS, Apr. 1970.

Lurzatti, L. and H. Pryor, "Body Proportions and Dermatoglyphic Patterns in
Children with Cleft Lip and/or Palate," submitted to PEDIATRICS.

Lutzatti, L. and L. Knight. "Synchronization of Human Lymphocyte Cultures with
  FuDR," In preparation.

Luzzatti, L. and L. Knight. "Morphologic and Labeling Characteristics of the
Late Replicating X Chromosome In Man." in preparation.

Luzzatti, L. and L. Knight, "Intrapair and Interpair Chromosome Distance at
Metaphase in Human Lymphocytes," in preparation.

McIntosh, 5.. Jr., T. Welsshaar, and H. Ashley, "Progress in Aeroelastic Opti-
  mization - Analytical Versus Numerical Approaches," SUDAAR, no. 383, July 1969.

McIntosh, S.. Jr., T. Weisshaar, and H. Ashley. "Progress in Aeroelastic Opti-
  mization - Analytical Versus Numerical Approaches," presented at the AIAA
Structural Dynamics and Aeroelasticity Specialist Conference, New Orleans,
  Louisiana, Apr. 1969.

Marich, K., Carr, P., Treytl, W., and D. Glick, "Effect of Matrix Material
on Laser-Induced Elemental Spectral Emission," ANALYTICAL CHEMISTRY, Vol. 42
  Dec. 1970.

Melges, F.T., Tinklenberg, J.R.. Hollister, L.E., and H.K. Gillespie, "Marihuana
  and Temporal Disintegration." SCIENCE, Vol. 168, pp. 1118-1120, 1970.

Melges, F.T., Tinklenberg, J.R., Hollister, L.E., and H.K. Gillespie, "Temporal
Disintegration and Depersonalization During Marihuana Intoxication,"'ARCH GEN
  PSYCHIAT.. Vol. 23, pp. 204-210, 1970.

Melges F.T.  Anderson R.E. Kraemer, H.C., Tinklenberg, J.R., and Weisz. A.E..
THI PERSbNAL FUTURE AND SELF-ESTEEM. in press.

Mesel, E., "Direct Measurement of Intracardiac Blood Flow in Dogs with Experi-
mental Ventricular Septal Defects," CIRCULATION RES., Vol. 27, Dec. 1970.

Mesel, E., "Transducer for Direct Measurement of Shunts In Experimental
  Ventricular Seotal Defects," J. APPLIED PHYSIOL.. Vol. 28. No. 3. March 1970.


017)

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

Morrell, F., "Neural Coding," NEUROSCIENCES RESEARCH PROGRAM BULLETIN, 1969.

Morrls, S.. "Metabolism of Mouse Brain Synaptosome Proteins," Ph.D. Dissertation,
  Stanford University, 1969.

Morris, S. and L. Shooter, "Half-Lives of Mouse Brain Synaptosomes." J. NEUROCHEM..
  in press.

Murray, G., F. Offensend, D. Silva, E. Sondik, and L. Klainer. "A Medical Service
  Requirements Model for Health System Design." special issue of the PROCEEDINGS
  OF THE IEEE ON HEALTH SYSTEMS, vol. 57. pp. 1880-1887, Nov. 1969.

Noble, E., 5. Silbergeld, B. Kopell, W. McKinney, W. Wittner, and J. Butte,
  "The Effects of Physiologic Doses of Corticosteroid on Catecholamine Metabolism
  in Man," J. PSYCHIAT. RES., vol. 6, p. 159, 1968.

Oliver, I., 0. Koskimies, R. Hurwitz, and N. Kretchmer, "Macromolecular
  Forms of Aspartate Transcarbamylase in Rat Liver." BIOCHEM. BIOPHYS.
  RSCH. COf+lUN., vol. 37, pp. 505-511. 1969.

Peters, J.. W. Forrest, Jr., and B. Brown. "Use of Computers in Management of
  a Cooperative Study," presented at the 31st Annual meeting of the Comnittee
on Problems of Drug Dependence, Palo Alto, Calif.. Feb. 1969.

Peters, J., "Using a Time-Shared Computer to Manage a Cooperative Study," Stanford
  University, May , 1969.

Petralli, J., S. Wallis, and T. Merigan, "A Computer Method for Improvement
of Antibiotic Sensitivity Data and Guidance in Therapy," CLINICAL RESEARCH
  JOURNAL, 1968.

Petralli. J.. Russell, E., Katooka. A., and T.C. Merigan, "On-Line
Computer Quality Control of Antibiotic Sensitivlty Testing." NEW
  ENGLAND J. OF MEDICINE, Vol. 283, pp. 735-738. Oct. 1970.

Porter, R., M. Modebe, and G. Stark, "Aspartate Transcarbamylase:
  Kinetic Studies of the Catalytic Subunit." J. OF BIOL. CHEM.,
  vol. 244, pp. 1046-1057. April 1969.

Reynolds, W., "Computer Control of Mass Analyzers," PROCEEDINGS OF THE SIXTEENTH
ANNUAL CONFERENCE ON MASS SPECTROMETRY AND APPLIED TOPICS, (ASTM Comnittee E-141,
  Pittsburgh, Pa., May 1968.

Reynolds, W., "A Small Computer Approach to Low Resolution Mass Spectrometry."
presented at the Pacific Conference on Chemistry and Spectroscopy, Anaheim,
  Calif., Nov. 1967.

Reynolds, W., "Instrumentation in a Time Shared Computer Environment,"
  RESEARCH AND DEVELOPMENT, Vol. 21, No. 4, pp. 20-26, Apr. 1970.

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

Reynolds, W., "Biochemical Applications of Mass Spectrometry," Chapter III,
(ed. by Wailer), to be published by John Wiley & Sons, New York.

Rousseau, W.. "A Method for Computing Probabilities in Complex Situations,"
Doctoral Dissertation, Stanford University, 1968.

Sachs, D., E. Jellum, and B. Halpern, "Determination of the Stereospecific
Hydrolytic Action of Pepsin by Nuclear Magnetic Resonance Spectroscopy."
BIOCHEM. BIOPHYS. ACTA.. vol. 198, pp. 88-92, 1970.

Sanders, W., G. Breitbard, D. Cuennins, J. Flexer, K. Holtz. J. Miller,
  and G. Wlederhold, "An Advanced Computer System for Medical Research."
  AFIPS CONFERENCE PROCEEDINGS, vol. 31, 1967.

Sanders, W.J. and A. Slivers, "Digital On-Line Computer Display to
  Investigate the Structure of Metabolic Systems," COMPUTERS AND BIOMED.
  RES., Vol. 3, pp. 133-145. April 1970.

Schneidenan, L., W. Sampson, W. Schoene. and G. Haydon, "Genetic Studies of a
Family with Two Autosoclal Dominant Conditions," AM. J. MEO., vol. 46, p. 380,
  1969.

Schneiderman, L., L. DeSalvo, S. Baylor, and P. Wolf, "The 'Abnormal' Screening
  Laboratory Result: Its Effect on Physician and Patient." AM. FED. CLIN. RES.,
  1970, (abstract).


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Sibergeld, S., N. Brast. and E. Noble, "The Menstrual Cycle: A Double-Blind
  Study with Enovid and Placebo," PSYCHOSOMATIC MEDICINE, in press.

Smallwood, R., E. Sondik, and F. Offensend, "Toward an Integrated Methodology
  for the Analysis of Health Care Systems." in preparation, to be presented at
the 37th National Meeting of the Operation Research Society of America,
  Washington, 0. C.. Apr. 1970.

Smith, R., "Discusslon Tasks as a Measure of Family Role Structure: Implications
  for the Study of Pathological Families." submitted for publication in J.
  PSYCHIAT. RESEARCH.

Smith, R., "Discussion Versus Ccimnunication Network Tasks in the Study of Family
Role Structure," submitted for publication in J. NERV. MENTAL DISEASES.

Solomon, G., S. Levine, and J. Kraft, "Early Experience and Iaznunity,"
  NATURE, vol. 220, p. 821, Nov. 1968.

Solomon. 6.. "Stress and Antibody Response in Rats," INT. ARCH. ALLERGY AND
APPLIED IMMUNOLOGY, vol. 35, pp. 97-104. 1969.

Starr, A. and J. Wernick, "Olivocochlear Bundle Stimulation: Effects on
Spontaneous and Tone-Evoked Activities of Single Units in Cat Cochlear
  Nucleus," J. NEUROPHYSIOL., vol. 31, pp. 549-564. 1968.

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

Stillman, R., W. Roth, K. Colby, and P. Rosenbaum, "An On-Line Computer
System for Initial Psychiatric Inventory." AMER. J. PSYCHIAT., vol. 125.
  p. 7, Jan. 1969.

Stillman, R., R. Costell, and D. Cuasnins,
  Inventory,"               "Computer Administered Psychiatric
       presented at the Annual Meeting of the American Psychiatric Association,
Miami, Florida, May. 1969.

Strickland, R., "The Effect of Prednisolone on Gastric Function and Structure in
Man," GASTROENTEROLOGY. vol. 56, pp. 675-686, 1969.

Swanson. G., D. Snider, T. Carpenter. and J. Bellville. "A Hybrid Computing
System for On-Line Respiratory Studies," published in the PROCEEDINGS OF THE
  SEVENTH ANNUAL ROCKY MOUNTAIN BIOENGINEERING SYMPOSIUM AND EIGHTH INTERNATIONAL
ISA BIOMEDICAL SCIENCES INSTRUMENTATION SYMPOSIUM, Denver, Colorado, May 1970.

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

Thathachari, Y., "X-Ray Diffraction Studies on Melanins," PROCEEDINGS OF THE
VII INTERNATIONAL PIGMENT CELL CONFERENCE, Seattle, Wash.. 1969.

Thathachari. Y. and M. 8101s. "Physical Studies on Melanins: X-Ray Diffraction."
BIOPHYSICAL JOURNAL, vol. 9, no. 1, pp. 77-89, 1969.

Thathachari, Y., "X-Ray Diffraction Studies on Melanins," presented at the
Annual Conference of the Biophysics1 Society, Los Angeles, Calif.. Feb. 1969.

Thathachari, Y., "Radial Distribution Studies on Melanins," PROCEEDINGS OF THE
THIRD INTERNATIONAL BIOPHYSICS CONGRESS, Cambridge. Mass., Aug.-Sept. 1969.

Thoman, E. and S. Levine, "Hormonal and Behavioral Responsiveness to Foster
Pups as a Function of Prior Maternal Experience." presented at the Symposium
of Maternal Behavior in Marmaals. sponsored by the International Union of
  Biological Science, July 1969.

Thoman, E.. S. Levine, and R. Conner, "Lactation Suppresses Adrenal
Contlcosteroid Activity and Aggressiveness in Rats," J. COMP. PHYSIOL. PSYCHOL.,
  Vol. 3, pp. 364-369, 1970.

Thoman, E., A. Turner, P. Leidenaan, and C. Barnett. "Neonate-Mother Interaction:
  Effects of Parity on Feeding Behavior," CHILD DEVELOPMENT, Vol. 40, pp. 1103-1111, 1970.

Thoman, E.. and 5. Levine, "Effects of Adrenalectomy on Maternal Behavior
  in Rats," DEVELOPMENTAL PSYCHOLOGY, in press.

Thoman, E., C. Barnett, and P. Leiderman, "Neonate-Mother Interaction: Oevelop-
ment of Earliest Feeding Patterns as a Function of Parity," CHILD DEVELOPMENT.

Thoman, E.. J. Olson, and P. Leiderman, "Behavior Patterns of Breast-Feeding
Mothers and Neonates as a Function of Parity of the Mother and Sex of the
  Infant," in preparation.


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Thoman. E. and A. Korner. "Effects of Vestibular Stimulation on aenavlor ana
  Development in Infant Rats," DEVELOPMENTAL PSYCHOLOGY. in press.

Tinklenberg, J.R., Melges, F.T., Hollister, L.E., and H.K. Gillespie,
  "Marlhuana and Imnedlate Memory," NATURE, Vol. 226, pp. 1171-1172, 1970.

Welnberger. M., R. Colllns, A. Dowdy. G. Nokes, and J. Luetscher, "Hypertension
  Induced by Oral Contraceptive Containing Estrogen and Gestagen - Effects on
  Plasma Renln Activity and Aldosterone Excretion," ANN. INTERN. MED.. vol. 71,
  p. 891, 1969.

Welnberger, M., A. Dowdy, G. Nokes, and J. Luetscher, "Stimulation of
  Plasmas Renin Activity without Increased Aldosterone Production after
  Admlnistratlon of Chlorothlaride to Hypertensive Patients," J. CLIN. INVEST.,
  vol. 46, p. 1130, 1%7.

Weinberger, M., A. Dowdy, G. Nokes. and J. Luetscher, "Plasma Renin
  Activity and Aldosterone Secretlon in Hypertensive Patients during High
  and Low Sodium Intake and Administration of Diuretic." J. CLIN. ENDOCR..
  vol. 28, p. 359, 1968.

Welnberger. M., A. Dowdy, G. Nokes, and J. Luetscher, "Reversible
  Increases in Plasma Renin Activity. Aldosterone Secretion and Blood
  Pressure In Women Taklng Oral Contraceptive Preparations." CLIN. RES.,
  vol. 16, p, 150, 1968.

Westley, J. and 8. Halpern, "The Use of (-)Menthyl Chloroformate in the
  Optical Analysis of Asyaanetric Amino and Hydroxyl Compounds by Gas
  Chromatography," J. ORG. CHEM., vol. 33, p. 3978, 1968.

Westley, J., V. Close. D. Nftecki, and B. Halpern. "Determination of
  Steric Purity and Configuration of Diketopiperazines by Gas-Liquid
  Chromatography, Thin-Layer Chromatography and Nuclear Magnetic
  Resonance Spectrometry," ANAL. CHEM., vol. 40, p. 1888, 1968.

Wiederhold, G., "A Stanaary of the ACME System," PROCEEDINGS OF THE ONR
  COMPUTER AND PSYCHOBIOLOGY CONFERENCE, Monterey, Calif., May 1966.

Wiederhold, G., "A Sumnary of the ACME System," PROCEEDINGS OF THE CONVERSA-
  TION WITH A 50 CONFERENCE, Argonne National Laboratory, Chicago, Illinois,
  Oct.-Nov. 1966.

Wiederhold, G.. "Setting up a General Purpose Data-Acquisition System,"
  PROCEEDINGS OF THE IBM SCIENTIFIC COMPUTING SYMPOSIUM ON CONPUTERS
  IN CHEMISTRY, Yorktown Heights, New York. pp. 249-264, Oct. 1968.

Wiederhold, G. and L. Hundley, "A Timeshared Data-Acquisition System."
  published in the PROCEEDINGS OF THE IEEE COMPUTER GROUP CONFERENCE ON REAL-TIME
  SYSTEMS, Minneapolis, Minnesota, June 1969.

Wiederhald, G., "An Advanced Computer System for Medical Research,"
  PROCEEDINGS OF THE IBM JAPAN COMPUTER SCIENCE SYMPOSIUM -- RESEARCH
  AND DEVELOPMENT AND COMPUTER SYSTEMS, Tokyo. Japan, pp. 81-815, Nov. 1969.

Wiederhold, G., "Setting Up a General-Purpose Data-Acquisition System,"
  PROCEEDINGS OF THE IBM SCIENTIFIC COMPUTING SYMPOSIUM ON COMPUTERS
  IN CHEMISTRY, Data Processing Division, White Plains, New York,
  pp. 249-264, Aug. 1969.

Wlederhold. G.. R. Frey, and S. Girardi. "A Filing System for Medical Research,"
  presented at Journees Internationales d'Informatique Medicale de Toulouse,
  France, Mar. 1970.

Wiederhold, G., R. Frey, and S. Girardi. "A Filing System for Medical Research,"
  presented at the Eighth Annual Symposium on Biomathematics and Computer Science
  in the Life Sciences, Houston, Texas, Mar. 1970.

Wiederhold, G. and G. Breitbard, "A Method for Increasing the Modularity of
  of Large Systems," IEEE COMPUTER GROUP NEWS, vol. 3. no. 2, p. 30,
  Mar./Apr. 1970.

Wiederhold, V., "How to Use PL/ACME," Document No. 80-50-00, Stanford
  Computation Center, Stanford University, July 1967 (1st ed.), Sept. 1968 (2nd ed.).

Wolf. P., T. Durbridge, and D. Enlander,
  Data for Computer Retrieval,"     "An Evaluation of SNOP Coding of Pathaloglc
                  LABORATORY MEDICINE - THE BULLETIN OF PATHOLOGY,
  pp. 400-401, Dec. 1969.

* New Kntry Glnce Last AFUR.

H~rfiaion of ARIB- dated August 12, lyll
Did:  Utul.L/iu


--_- _             . ~. .     ", . , ,- . -.
i.Z-! . . -,.I ,' `-.::J ~_,. ,- ,..-`-,..J"         /I 7n-l
                 613GRAPH~CAi SKETCH                                    -.- _

NAM5

/Give the fol/oknq informabon for a/lpro%=ssk~ra~ ormmmel listed on p+e 3, bqininninq with the Principal tnvertiqator.
         Use continuation pages and follow the same general format for each person I
               1 TITLE                 (BIRTHDATE (Ma, by, vf.1

I Professor and Executive Head, I  5-31-35      ----

1 Department of Genetics             2 . . u.2
PRESENT NATIONALITY l/f non-US citizen,    SEX
indicate kind of visa and expiration date)

    LEDERBERG, JOSHUA
PLACE OF GIRTH (City. Stare, Country)

Monte air,
  i    New Jersey         U.S.A.                    a Male   g Female
           EDUCATION i&gin with baccalaureate training dnd include postdoctoral)

INSTITUTION AND LOCATION              DEGREE        YEAR            SCIENTIFIC
                                            CONFERRED            FIELD

Columbia College, New York   I  B.A.        1944
College of Physicians & Surgeons,
Columbia University, New York (1944-46

Yale University
HONORS

1 Ph.D.    I 1947

1957 - National Academy of Sciences
1958 - Nobel Prize in Medicine

MAJOR RESEARCH INTEREST                     ROLE IN PROPOSED PROJECT

Molecular Genetics; Artificial Intelligent    PRINCIPAL INVESTIGATOR
RESEARCH SUPPORT Bee instructions)

SEE ATTACHMENTS:

RESEARCH AND/OR PROFESSIONAL EXPERIENCE {Starting tirh present position, Jist trainiuand experience relevant to area of project  List all
of most rspresen*ltive publicationr  00 not exceed 3 pages for each individual.)
1961-     Stanford University
       Director, Kennedy Laboratories for Molecular Medicine
1959-    Professor, Genetics and Biology, and Executive Head, Department of
         Genetics, Stanford University
1957-1959  University of Wisconsin
        Chairman, Department of Medical Genetics
1957     Melbourne University, Australia
       Fullbright Visiting Professor of Bacteriology
1950     University of California, Berkeley
       Visiting Professor of Bacteriology
1947-1959  University of Wisconsin
          Professor of Genetics
1946-1947  Yale University.  Research Fellow of the Jane Coffin Childs Fund for
           Medical Research
1945-1946  Columbia University.  Research Assistant in Zoology
Professional Activities:

1967-      NIMH:  National Mental Health Advisory Council
1961-1962  President (Kennedy)'s Panel on Mental Retardation
1960-      NASA Committees:  Lunar and Planetary Missions Board
1958--   National Academy of Sciences:  Committees on Space Biology
1950-    President's Science Advisory Committee panels.  National Institutes
       of Health, National Science Foundation study sections (genetics)
tlHS-398
Rav. 3-70


LIST OF PUBLICATIONS

81.  Lederberg, J., 1959
   A View of Genetics.
   Les Prix Nobel en 1958:  170-89.

182.  Buchs, A., A.B. Delfino, A.M. Duffield, C. Djerassi, B.G. Buchanan,
   E.A. Feigenbaum, and J. Lederberg, 1970.
   Applications of Artificial Intelligence for Chemical Inference. VI.
   Approach to a general method of interpreting low resolution mass spectra
   with a computer.

Helvitia Chimica Acta 53 (6): 1394-1417.

186.  Feigenbaum, E. A., B. G. Buchanan, J. Lederberg, 1971
   On generality and problem solving: a case study using the DENDRAL program
   in Machine Intelligence 6, (B. Meltzer and D. Michie, eds.),
   Edinburgh University Press, P. X5-190.

192.  Reynolds, W.E., V.A. Bacon, J.C. Bridges, T.C. Coburn, B. Halpern,
   J. Lederberg, E.C. Levinthal, E. Steed, R.B. Tucker, 1970
   A computer operated mass spectrometer system.
   Analytical Chem. 42:1122-1129, September 1970.

194.  Lederberg, J.
   "Use of Computer to Identify Unknown Compounds: The Automation of Scientific
    Inference" in Biochemical Applications of Mass Spectrometry (G.R. Waller,
    ed.).  John Wiley & Sons, New York (in press)


(122)

RESEARCH SUPPORT:                                    Budgeted
                                                           Amt. of
   Grant           Project Title          Dates        Amt.     Salary __

Research Proiects:
------ -----------------_-----~~~---~-~-~

JPL Contract      Extended Mission of   9/l/69 - 6/30/72 $185,000       16%
952489           Mariner Mars

NASA
NAS-19692

Viking Biology Team

-6130172   $ 9,608

NIH RR0311

Advanced Computer for 1966  - 7/31/73 $
Med. Research

25%

NIH
Al 05160-14

Managerial:
-- ----

NIH
GM 295-13

NSF
GB 29094

NASA
NGR 05-020-004

--

Genetics of Bacteria 9/l/71 - a/31/72 $ 58,000

Training Program in  7/l/71 - 6130172 $130,609
Genetics

Exchange Program    5/l/72 - 4/30/73 $ 60,000     (Applied
in Genetics and                             for)
Molecular Biology
between Universities
of Stanford and
Pavia (Italy)

Cytochemical
Studies of
Planetary Micro-
organisms

9/l/71 - a/30/72 $240,000       05%


SECTION II - PRIVtLEGED COIL!MUNICATlON      (123)
                        BIOGRAPHICAL SKETCH

      IGive the following information for sll professional personnel listed on page 3, beginning with the Principal InvgFtigator.
                 use continuation pages 8nd follow the same general format for each person.]

NAME                                 TITLE                        BIRTHDATE (Ma, Day, Yr.1
   Edward A. Feigenbaum        Professor of Computer Science l-20-36

PLACE OF BIRTH (City, State, Counayl          PRESENT NATIONALITY IIf non-US citizen,    SEX
                             indicete kind of viaa and expiration date)
   Weehawken, New Jersey         U. S. A.                @j Mate   a Female
                E DIJCATI ON (Bqln with baccalauraata training 8nd include postdoctorall

INSTITUTION AN0 LOCATION    I    DEGREE        YEAR             SCIENTIFIC
                                            CONFERRED            FIELD

Carnegie Institute of Technology      B. S.     19%
Carnegie Institute of Technology      Ph.D.      1959

lectrical Engineering

       Administration

Nbright Research Scholar, Great Britain, National Physics Laboratory,
Tedding-ton, England, 1959-60.

MAJOR RESEARCH INTEREST                     ROLE IN PROPOSED PROJECT
   Artificial Intelligence Research
   Heuristic Programming          Associate Investigator

                                               I
RESEARCH SUPPORT (See insmuztiona)                    Current Total, Proj.   $ Source of
   Contract/Grant No.        Title                Year    Period   Effort Support
   ARPA SD-183     The Heuxc Programming  $200,000 '$700,548 -w ARPA

             Project of the Stanford
             Artificial Intelligence
             Project
5 R24 RR00612-02   Resour&-Related        214,093  722,062  27%    NIH
sss           Research; Computers and
             Chemistry

RESEARCH ANDIDR PROFESSIONAL EXPERIENCE (Stating tithprerentposition,~8ndexpetiencor~event to 8m8 ofproject  List all
or moat repmsentative publication+  Do not exceed 3 pages for eech individual. I

196s
1965-68
1968-72

1965-
1960-64

1963

1962

19%

Stanford University, Computer Science Department Faculty
Stanford University, Director, Computation Center
National Institutes of Health, Member, Computer and Biomathematical
Sciences Study Section
Editor, Computer Science Series, McGraw-Hill Book Company, New York
University of California, Berkeley
Research-Center for Research in Management Science, 1960-64
Research-Center for Human Learning, 1961-64
Assistant and Associate Professor, School of Business Administration,
  1960-64
National Science Foundation.  Summer Research Training Institute in
Computer Simulation of Cognitive Processes. Faculty member.
Carnegie Corporation.  Summer Research Training Institute in Heuristic
Programming.  Faculty member.
IBM Scientific Computing Center, New York

RI-is-398
Rev. 3-70


(124)

Recent Publications

Smith, R. II., Buchanan, B. G., Engelmore, R. S., Duffield, A. M.,
  Yeo, A., Feigenbaum, E. A., Lederberg, J., and Djerassi, Carl,
  "Applications of Artificial Intelligence for Chemical Inference
   VIII.  An Approach to the Computer Interpretation of the High
  Resolution Mass Spectra of Complex Molecules.   Structure
  Elucidation of Estrogenic Steroids," December, 1971.

Buchanan, B. G., Feigenbaum, E. A., and Lederberg, J., "A Heuristic
  Programming Study of Theory Formation in Science." In proceedings
   of the Second International Joint Conference on Artificial
  Intelligence, Imperial College, London (September 1971).  (Also
  Stanford Artificial Intelligence Project Memo No. 145.)

Buchs, Armand, Delfino, Allan B., Djerassi, Carl, Duffield, A. M.,
  Buchanan, B. G., Feigenbaum, E. A., Lederberg, J., Schroll, Gustav,
  and Sutherland, G, L., "The Application of Artificial Intelligence
  in the Interpretation of Low-Resolution Mass Spectra", Advances
  in Mass Spectrometry Volume 5, 314-318.

Feigenbaum, E. A., Buchanan, B. G., and Lederberg, J., "On Generality
  and Problem Solving:  A Case Study Using the DENDRAL Program",
  Machine Intelligence 6, B. Meltzer and D. Michie, eds., Edinburgh
  University Press, 1971.

Lederberg, J., Sutherland, G. L., Buchanan, B. G., Feigenbaum, E. A.,
  Robertson, A. V., Duffield$ A. M. and Djerassi, C., "Applications
  of Artificial Intelligence for Chemical Inference I.  The Number
  of Possible Organic Compounds.  Acyclic Structures Containing C, H,
  0 and N", Journal of the American Chemical Society, 91, 2973, 1969.

Duffield, A. M., Robertson, A. V., Djerassi, C., Buchanan, B. G.,
  Sutherland, G. L., Feigenbaum, 5. A. and Lederberg, J., "Applications
  of Artificial Intelligence for Chemical Inference II.  Interpretation
  of Low Resolution Mass Spectra of Ketones", Journal of the American
  Chemical Society, 91, 2977, 1969.

Schroll, G., Duffield, A. M., Djerassi, C., Buchanan, B. G., Sutherland,
  G. L., Feigenbaum, E. A. and Lederberg, J., "Applications of Artificial
  Intelligence for Chemical Inference III.  Aliphatic Ethers Diagnosed
  by Their Low Resolution Mass Spectra and Nuclear Magnetic Resonance",
  Journal of the American Chemical Society, 91, 7440, 1969.

Lederberg, J., Sutherland, G. L., Buchanan, B. G. and Feigenbaum, E. A.,
  "A Heuristic Program for Solving a Scientific Inference Problem:
  Summary of Motivation and Implementation", Stanford Artificial
  Intelligence Project Memo No. 104, November 1969.

Buchanan, B. G., Sutherland, G. L. and Feigenbaum, E. A., "Toward an
  Understanding of Information Processes of Scientific Inference in
  the Context of Organic Chemistry", in Machine Intelligence 5,
  B. Meltzer and D. Michie, eds., Edinburgh University Press, 1970.
  (Also Stanford Artificial Intelligence Project Memo No. 99,
  September 1969)


Publications
Page 2

Buchanan, B. G., Sutherland, G. L., and Feigenbaum, E. A., "Heuristic DENDRAL:
  A Program for Generating Explanatory Hypotheses in Organic Chemistry",
in Machine Intelligence 4, B. Meltzer and D. Michie, eds., Edinburgh
  University Press, 1969.  (Also Stanford Artificial Intelligence
  Project Memo No. 62, July 1968.)

Feigenbaum, E. A., "Artificial. Intelligence:  Themes in the Second Decade",
  in Final Supplement to Proceedings of the 1~1~68 International
  Congress, Edinburgh, August 1968.  (Also Stanford Artificial Intelligence
  Project Memo No. 67, August 1967)

Lederberg, J. and Feigenbaum, $3; A., "Mechanization of Inductive Inference
  in Organic Chemistry", in Formal Representations for Human Judgment,
  B. Kleinmuntz, ed., Wiiey, 1968.  (Also Stanford Artificial Intelligence
Project Memo No. 54, August 1967.)



                         (126)
SECTION II - PRIVILEGED COMMUNICATION
                      BIOGRAPHICAL SKETCH

     (Give the following information for all professional personnel listed on pege 3, beginning tith rhe Principal Invrstigeror.
               Use continuation psges and follow the mme gene& format for each person.)
NAME                                  TITLE                       BIRTHDATE (MO., Dsy, Yr.)

Thomas C. Rindfleisch              Research Associate           12-10-41
PLACE OF BIRTH (Civ, State, Country)         PRESENT NATIONALITY f/f non-US citizen,    SEX
                            indicate kind of visa and expiration date)
Oshkosh, Wisconsin, USA               USA              [Ifr Male   0 Female
               EDUCATION (Begin with baccalaureete training and include postdoctoral)

INSTITUTION AND LOCATION               DEGREE        YEAR             SCIENTIFIC
                                             CONFERRED            FIELD

Purdue University, Lafayette, Ind.        B.S         1962     Physics
California Institute of Technology,        M.S         1965     Physics
Pasadena, CA                           Ph.D     Thesis to be completed.  All
                                         course work and examinations
                                   completed.
HONORS
Purdue University, Graduated with Highest Honors, Sigma
Xi.

MAJOR RESEARCH INTEREST
Space sciences, computer science and
image processing
RESEARCH SUPPORT &e instrucdons)

ROLE IN PROPOSED PROJECT

Technical Support

RESEARCH ANDKIR PROFESSIONAL EXPERIENCE (Sterting with present position,~andexperience relevant to erea ofproject  List all
or most representative publications  Do not WCC& 3 pees for eech individual.)
1971-Present Stanford University Medical School, Department of Genetics,
         Stanford, CA.
        Research Associate - Mass Spectrometry, Instrumentation research.
1962-1971   Jet Propulsion Laboratory, California Institute of Technology,
         Pasadena, CA.
         Relevant Experience:
           1969-1971:  Supervisor of Image Processing Development and
                Applications Group.
           1968-1969:  Mariner Mars 1969 Cognizant Engineer for Image
                 Processing
         1962-1968: Engineer - design and implement image processing
                 computer software.

1.  Rindfleisch, T. and Willingham, D., "A Figure of Merit Measuring Picture
  Resolution," JPL Technical Report 32-666, September 1, 1965.

2.  Rindfleisch, T. and Willingham, D., "A Figure of Merit Measuring Picture
  Resolution," Advances in Electronics and Electron Physics, Volume 22A,
  Photo-Electronic Image Devices, Academic Press, 1966.

RHS-398
". -.-.I


(127)

Thomas C. Rindfleisch
PUBLICATIONS (cont'd)

3.

4.

5.

6.

7.





8.





9.

Rindfleisch, T., "A Photometric Method for Deriving Lunar Topographic
Information," JPL Technical Report 32-786, September 15, 1965.

Rindfleisch, T., "Photometric Method for Lunar Topography," Photo-
grammetric Engineering, March 1966.

Rindfleisch, T., "Generalizations and Limitations of Photoclinometry,"
JPL Space Science Summary Volume III, 1967.

Rindfleisch, T., "The Digital Removal of Noise from Imagery," JPL Space
Science Summary 37-62 Volume III, 1970.

Rindfleisch, T., "Digital Image Processing for the Rectification of
Television Camera Distortions," Astronomical Use of Television-Type
Image Sensors, NASA Special Publication SP-256, 1971.

Rindfleisch, T., Dunne, J., Frieden, H., Stromberg, W., and Ruiz, R.,
"Digital Processing of the Mariner 6 and 7 Pictures," Journal of
Geophysical Research, Volume 76, Number 2, January 1971.

Rindfleisch, T., "Digital Image Processing," To be published, IEEE
Special Issue, July 1972.


SECTION It - PRIVILEGED COhlMUNICATION       (178)
                       BiOGRAPHICAL SKETCH

     (Dive the following information for811 professional personnel listed on page 3, beginning with the Principal lnvestigaror.
               Use continuation purges and follow the Same general format for each person.]
NAME                                  TITLE                      BIRTHDATE (MO., Day, Yr.)
Donald C. Harrison             Professor of Medicine    2/24/34

PLACE OF BIRTH (City, State, Country)          PRESENT NATIONALITY f/f non-US citizen,    SEX
Blount County,               indicare kind of visa and expiration date)
              Alabama             U.S.             ?!I Male   0 Female
                EDUCATION /Begin with baccalaureate training and include postdoctoral)

        INSTITUTION AND LOCATION               DEGREE         YEAR             SCIENTIFIC
                                                        CONFERRED             FIELD

Birmingham Southern College, Ala. B.S.      1954      Chemistry
Medical College of Alabama           M.D.       1958       Medicine

HUNOHS

Omicron Delta K-pa, Phi Beta Kappa, Alpha Omega Alpha

MAJOR RESEARCH INTEREST                     ROLE IN PROPOSED PROJECT
Computer applications in Cardiolog!T    Collaborator
REsEARCHSUPPoRT~~i~~~~~~J~Medical Cardiology, HE-5866, NIH, 7/70-6/71, $50,149
15% effort.
Stresses,   Evaluation of Cardiovascular System During Various Circulatory
      NGR-05-020-305, NASA, g/70-8/71, $66,431, 6% effort.   Under-
graduate-clinical, HE-5107, NIH, 3/71-2/72, $25,000, 5% effort.  Investiga-
tive Cardiovascular Physiology & Pharmacology, HE-5709, NIH, 7/68-6/73,
$497,835,  17.5% effort.  Cardiovascular Adrenergic Receptors-Effects of
Drugs, HE-9058, NIH, g/67-8/72, $174,080, 17.5% effort.

RESEARCH ANDKIR PROFESSIONAL EXPERIENCE (Starting 4th present position.lig traininqand expen'ance relevant to erea ofproject  List all
or most wnasntativa publications,  Do not axceed 3 pages for each individual.)

1972-
1968-72
1967-
1965-68
1964-69
1963-64

1961-63

1960-61
1958-60

Professor of Medicine, Stanford Univ. School of Med., Stanford, Ca.
Associate Prof. of Medicine, Stanford Univ, School of Med.
Chief, Division of Cardiology, Stanford Univ. School of Med.
Asst.  Prof. of Medicine, Stanford Univ. School of Med.
Asst.  Program Director, Clinical Research Center, Stanford Univ.
InStrUCtOr in Medicine and Chief Resident in Medicine, Stanford
Univ.  School of Med.
Clinical Research Associate, National Heart Institute, NIH,
Bethesda, Md.
Research Fellow, Harvard Medical school, Boston, Mass.
Intern and Asst. Resident in Medicine, Peter Bent Brigham
Hospital, Boston, Mass.

RH.s-398
Rovv. 3-M


(129)

Donald C. Harrison, M.D.                     Bibliography

1.






2.





3.






4.

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

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

Harrison, D.C., and Miller, H.A.:  The expansion of a con-
ventional cardiac catheterization laboratory to a computer-
assisted laboratory.  Measurements for Medicine (Hewlett-
Packard).  1971 (Booklet)

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


SECTION II -PRIVILEGED COMMUNICATION         (130 j
                      BIOGRAPHICAL SKETCH

(Give the forloiving information for allprotessional personnel listed on page 3, beginning with the Pfincipai Invnr~garor.
          Use continuation -es and fellow the same aenetal format for each oerson. I

                                    -                                                              -
NAME                                  TITLE                       BIRTHDATE (MO., Day, Yr.1

Stenson,  Robert E.           Asst.  Prof.  of Medicine    6/l/38

PLACE OF BIRTH ICity, State, Country)                                                                       -
                            PRESENT NATIONALITY f/f non-US citizen,     SEX
Pennsylvania                indicate kind of visa and expiration date)
                                      U.S.             & Male   c] Female
               EDUCATION IBqin with baccalaureate training and include postdoctoral)

        INSTITUTION AND LOCATION               DEGREE         YEAR             SCIENTIFIC
                                                       CONFERRED            FIELD

Massachusetts Institute of Tech.      M.S.      1960      Elec. Engr.
Harvard School of Medicine            M.D.      1965

Eta Kappu Nu-Honorary Society of Electrical Engineers
Tau Beta Pi-Honorary Society of Engineers
Sigma Xi-Honorary Scientific Societv
MAJOR RESEARCH INTEREST                      ROLE IN PROPOSED PROJECT
Computer Applications in Cardio-        Collaborator
W3Y
RESEARCH SUPPORT &e instmctions)

RESEARCH AND/OR PROFESSIONAL EXPERIENCE (Startiw with present position,&st treininpsndexperiance relevant toarea ofpro/ect  Listall
or most repmsentau've publications.  Do nor exceed 3 pages for eech individual. I

1972-   Assistant Professor of Medicine,  Stanford University School of
      Medicine, Stanford, Cal.
1971-   Clinical Instructor of Medicine, University of California,
      Davis, Cal.
1970-72 Major USAF, MC, Staff Cardiologist, Travis AFB, Cal.
1969-70 Sr. Resident, Stanford University Hospital, Stanford, Cal.
1967-69 Postdoctoral Fellow, Cardiology Division, Stanford University
      School of Medicine, Stanford, Cal.
1966-67 Resident, Beth Israel Hospital, Boston, Mass.
1965-66 Intern, Beth Israel Hospital, Boston, Mass.

RHS-398
Rev. 3-70


(131)

Robert E. Stenson, M.D.                    Bibliography

1.






2.





3.




4.

Stenson, R.E., Crouse, L., Henry, W.L., Harrison, D.C.: A
Time-Shared Digital Computer System for on-Line Analysis of
Cardiac Catheterization Data:  Computers and Biomedical
Research 1:605, June 1968.

Henry, W.L., Crouse, L., Stenson, R.E., Harrison, D.C.:
Computer Analysis of Cardiac Catheterization Data:   Am. J.
Cardiology, 22:696, Nov. 1968.
                -

Stenson, R.E., Constantino, R., Harrison, D.C.:   Interrelation-
ships of Hepatic Blood Flow, Cardiac Output and Blood Levels
of Lidocaine in Man:  Circulation 43:205, Feb. 1971.
                                             -

Stenson, R-E., Harrison, D.C.:  Cardiac Output:  Computer,
Dow and Fick.  (In press)  Cardiovasc. Res., 1972.


(132)

SECTION II -PRIVILEGED COf~MUNlCATlON  BIOGRAPHICAL &ETCH

       (Give the following information for all professional personnel listed on page 3, beginning with the Principal Irivest.`gator.
                  Use continuation p8ges and follow the same general format for EdCh person.1

NAME                                  TITLE                         BIRTHDATE (MO., Day, Yr.)
Thomas A. Stamey, M. D.          Professor of Surgery
                        Chairman, Division of Urology   April 26, 1928
PLACE OF BIRTH (City, State, Country)           PRESENT NATIONALITY (/f non4.S citizen,     SEX
                              indicate kind of visa and expiration dateJ

Rutherfordton, N.C.       I    USA          I   a Male   0 Female
                ED lJ CATI ON (Segin with bdccalaurw te training and include postdoc torall

INSTITUTION AN0 LOCATION              OEGREE         YEAR             SCIENTIFIC
                                             CONFERRED             FIELD

Vanderbilt University, Nashville, Tenn.      A.B.       1948
Johns Hopkins University School of Medici e M.D.       1952             Medicine
Johns Hopkins University School of
  Medjcine,Brady Urological  House
  Staff Residency                              1952-1956       Urology
HONORS Chairman, Comm. Renal Disease and Urology Training Grants, NIAMD, NIH; Member,
Advisory Board, USPHS/Coop Study on Renal Disease and Pyelonephritis; Member, National
                                 ion; Member, Scientific Advisory
                              earth Comm., No. Calif. Kidney Fndtn;
                                                                           . .

Renal Physiology, Infectious Diseases.

   rives t lJrn1 _ * Me&r Frl? tnru
   POSED PROJECT '             KIDNE\      Y-


Collaborator

RESEARCH SUPPORT /See instructions)

2  TO1 AM 05513  -- Training Grant in Urology
           Period 7/l/71-6/30/76
5 ROl AI 09366  -- Urinary-Infection  Grant
           Period l/1/70-12/31/72

RESEARCH AND/OR PROFESSIONAL EXPERIENCE (Starting with present position,jist traininqand experience relevant to area of project  List all
or most representative publications.  Do not exceed 3 pages for each individual.)
Professor of Surgery, Chairman, Division of Urology
Stanford University School of Medicine                1964-present

Sabbatical year with Prof. Paul Beeson,
Nuffield Dept. of Medicine

Radcliffe Infirmary, Oxford, England                       1967-1968

Assoc. Professor of Surgery, Chairman, Division of Urology
Stanford University School of Medicine                     1961-1964

Assoc. Professor of Urology
Johns Hopkins University School of Medicine

1960-1961

Asst. Professor of Urology
Johns Hopkins University School of Medicine

1958-1960

U. S. Armed Forces, United Kingdom-Urological Consultant      1956-1958

PUBLICATIONS:

       See list attached

Ii Iis


                       (133)
THOMAS A. STAMEY, M.7).

                            PUBLICATIONS
                                                  _.-

Books
I_-.-
Renovascular Hypertension.  Ealtimore:  Williams & Wilkins Co., 1963.
   1st reprinting, Mar. 1967.
Urinary Infections.  Baltimore: Williams Fr Wilkins Co. (in press).

Chapters in Books
       ____-
Stamey, T.A. and Good, P.H.:  Diagnostic tools in the evaluation of renal
    vascular disease. In:  Hypertension, Recent Advances.  Philadelphia:
   Lea 6 Pebiger, 1961, pp. 189-203.
Stamey, T.A.:  Differential renal function studies. In:  Diagnostic Urology:
   A Handbook of Urologic Diagnostic Technique.  Edited by J. Glenn.
   New York: Harper & Row, Chapt. 9, 1964.
Stamey, T.A.:  Some observations on the filtration fraction, on the transport
   of sodium and water in the ischemic kidney, and on the prognostic
   importance of R.P.F. to the contralateral kidney in renovascular
   hypertension. In:  Ciba Foundation Symposium on Antihypertensive Therapy.
   Edited by F. Gross,  Heidelberg, Germany: Springer-Verlag, 1966, pp. 555-579.
Stamey, T.A.:  The diagnosis of urinary tract disease in the patient with
   gastrointestinal symptoms.  In: Gastroenterologic Medicine.  Edited by
   M. Paulson, Philadelphia: Lea & Febiger, Chapt. 49, 1969.
Palmer, J.M. and Stamey, T.A.:  History of differential renal function studies.
   In: History of Urology.  Baltimore: Williams & Wilkins Co. (in press).
Meares, E.M. and Stamey, T.A.:  Bacterial prostatitis and recurrent urinary
   tract infection. In:  Infectious Diseases.  Edited by P.D. Hoeprich.
   New York: Harper & Row (in press).
Stamey, T.A.:  Renal vein renins or differential renal function studies in the
   diagnosis of curable, renovascular hypertension?  W.W. Scott - Fcstschrift,
   Baltimore: Williams & Wilkins Co. (in press).

Scientific Papers
--
Stamey, T.A.:  The pathogenesis and implications of the electrolyte imbalance
   in ureterosigmoidostomy. S.G. & O., 103:736-758, 1956.
Stamey, T.A. and Scott, W.W.:  Ureteroileal anastomosis.  S.G. & 0. 104:11-24,
    1957.

Stamey, T.A., Nudelman, I.J., Good, P.H., Schwcntker, F.N. and Hendricks, F.:
   Functional characteristics of renovascular hypertension. Medicine.
   40:347-394, 1961.
Stamey, T.A.:  The diagnosis of curable unilateral renal hypertension by
   ureteral catheterization.  Postgraduate Medicine, 29:496-504, 1961.
Spencer, F.C.; Stamey, T.A., Bahnson, H.T. and Cohen, A.:  The diagnosis and
   treatment of hypertension due to occlusive disease of the renal artery.
   Ann. Surg., 154:674-697, 1961.
Stamey, T.A.:  Functional characteristics of renovascular hypertension with
   emphasis on the relationship of renal blood flow to hypertension.   Circ.
   Res., 11:209-219, 1962.
Stamey, T.A. and Pfau, A.:  Some functional, pathological, bacteriological,
   and chemotherapeutic characteristics of unilateral pyeloncphritis in man.
   (two articles: Part1 and II).  Invest. Urol. 1:134-172, 1963.
Pfau, A. and Stamey, T.A.:  Some functional characteristics of polycystic
   renal disease.  Invest. Urol., 1:593-603, 1964.

-7-


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SECTION II - PRIVILEGED COwlMUNICATION
                         BIOGRAPHICAL SKETCH
       (Give the followifrg information for all professional personnel lisred on page 3, beginning with the Principal Investigator.
                  Use continuation pages and foNow the same general format for each person.1
NAME                                  TITLE                         BIRTHDATE (MO., Day, Yr.1
Constantinou, Christos E.           Research Associate          July 21, 1939

PLACE OF BIRTH (City, State, Country]           PRESENT NATIONALITY I/f non-U.S citizen,     SEX
Limassol, Cyprus                   indicate kind of visa and expiration date)
                      United Kingdom (TI)             a Male   0 Female
                     EDUCATION (Baoin with baccalaureate training and include postdoctorall

INSTITUTION AND LOCATION

I    DEGREE         YEAR
               CONFERRED I

SCIENTIFIC
FIELD

Borough Polytechnic, London, England
Stanford University, Stanford, Calif.




#l!a#taa

HNC
M.Sc.
Ph.D.

   1964    Elect. Engineering
   1968    Biomedical Engineering
Expected
   1972     Biomechanics

Member, Institute of Electrical and Electronic Engineers

MAJOR RESEARCH INTEREST                       ROLE IN PROPOSED PROJECT
Electrophysiology and biomechanics of the    Collaborator
upper urinary tract.

RESEARCH SUPPORT he instructions)
NIH Training Grant in Urology - 2 TO1 AM 05513
   July 1, 1971 - June 30, 1973

RESEARCH AND/OR PROFESSIONAL EXPERIENCE (Starting wirhpresentposition, JisttrainiClgendexperiencerelevant toarea ofproject Lisr all
or most represen ta rive publica Cons,  Do not exceed 3 pages for each individual. I
  1969-    Research Associate, Department of Surgery (Urology), Stanford University
  1966-1969 Research Assistant, Department of Surgery (Urology), Stanford University
Development of computer based system for the real time collection and analysis
  of experimental data from the surgical laboratory.  Integration and construction
of physiological monitoring devices in the study of the dynamics of transport
  in the ureter.  Incorporation of new electrophysiological techniques with bio-
mechanical t,ransducers to evaluate static and dynamic parameters of the peristaltis.

Cooperation with the Radiology Department in the assessment of contrast media and
other methods of visualizing the ureter, in vivo, using the technique described
in the list of publications enclosed.
Participate in the training of research residents in the quantification of
experimental data and teaching in biophysical and biostatistical techniques
using the time shared computer.

Ph.D. candidate.  Biomedical Engineering.

1965-1966 Research Assistant, Microwave Laboratory, Department of Radiotherapy,
      Laser research on parametric oscillators.


Christos Constantinou
Research Associate

(135)

Bibliography

Chapters in Books

Constantinou, C.E., Dale, R.L., Briggs, E.M., and Govan, D.E.: Electro-
  physiological methods in the study bf ureteral dynamics.  In URODYNAMICS,
  ed. Boyarsky, S., Chapter 12, Academic Press, New York, 1971.
Constantinou, C.E., Briggs, E.M., Dale, R.L., and Govan, D.E.:  Real time
  digital computer system for ureteral physiology investigation. In
  URODYNAMICS, ed. Boyarsky, S., Chapter 33, Academic Press, New York,
   1971.

Scientific Papers

Constantinou, C.E. and Briggs, E.M.:  Precision electrostatic urine flowmeter.
  J. Appl. Physiol., 29:396-397, 1970.

Constantinou, C.E., Dale, R.L., Briggs, E.M., Perkash, I., Engelsgjerd, G.L.,
   and Govan, D.E.:  Dynamics of the upper urinary tract:  I. System for
  data collection and evaluation. Invest. Urol., 8:645-6547 1971.
Dale, R.L., Constantinou, C.E., Briggs, E.M., and Govan, D.E.: Dynamics of
  the upper urinary tract:  II. The effects of an indwelling ureteral
  catheter on ureteral peristalsis.  Invest. Urol., 8:655-672, 1971.
Constantinou, C.E., Sands, J.P., and Govan, D.E.: Computer monitoring and
  control instrumentation in urology research.  Proceedings of the
  8th Annual Rocky Mountain Bioengineering Symposium. pp. 147-151, 1971.
Constantinou, C.E. and Butler, E.D.:  Medical application of computer displays
  in the rapid examination of developing abnormality patterns in the kidney.
  Digest of Society of Information Display International Symposium, pp. 72-74,
   1971.
Rosen, D.I., Constantinou, C.E., Sands, J.P., and Govan, D.E.: Dynamics of the
   upper urinary tract:  III. The effects of changes in bladder pressure and
  volume on ureteral peristalsis.  J. Urol., 106:209-213, 1971.
Sands, J.P., Constantinou, C.E., and Govan, D.E.: Bladder pressure and its
  effect on mean arterial blood pressure.  Invest. Ural., 10:6-17, 1972.
Briggs, E.M., Constantinou, C.E., and Govan, D.E.:  Dynamics of the upper urinary
    tract:  IV. The relationship of urine flow rate and rate of ureteral
  -peristalsis. Invest. Urol., 10:18-23, 1972,

Abstracts and Demonstrations

Butler, E.D. and Constantinou, C.E.:  The application of computers to urology.
  64th Annual Meeting of the A.U.A., San Francisco, May 1969.
Constantinou, C.E., Butler, E.D., and Govan, D.E.:  Computer graphic techniques in
  urologic follow-up of myelodysplasia in children.  39 th Annual Meeting of
  American Academy of Pediatrics, San Francisco, Oct. 1970.
Friedland, G.W., Rohatsu, S., and Constantinou, C.E.:
  of gastric sling fibers and distal esophagus.    Relationship Between motility

  Invest. Radiol., p. 272 5(4)1970.         Proc. of 18th AUR Symposium.

Dale, R.L., Constantinou, C.E., and Govan, D.E.:  Dynamics of the upper urinary
    tract:  The effects of acute and chronic obstruction on peristalsis.
  Presented at the Society of University Urologists - Residents Meeting,
  New Haven, Conn., May 6-9, 1970.

Granato, J.J., Constantinou, C.E., and Govan, D.E.: The effect of radiopaaue
   contrast media on the ureter.  Western Section, American Urological Association,
    Inc.  July 2-7, 1972.


                          (136)
SECTION II -PRIVILEGED COMMUNICATION
                       BIOGRAPHICAL SKETCH

       (Glva the following information for all professional personnel listed on pope 3, beginning with rhe PrincitM Invtutigstor.
                 Use continuation pagar and follow the seme general format for wch person I
NAME                 T' Fsoc
                   1   . Dean for Research,      BIRTHOATE (MO., Oay, Yr.)

Elliott C. Levinthal             SU Med School, Director of IRL   April 13, 192;:

PLACE OF BIRTH (City, state, Count&          PRESENT NATIONALITY iIf non-US citiran,    SEX
                              indicate kind of vise and expiration &te)
Brooklyn, New York                         USA                 a Mats   0 Femala
                  EDUCATION (Sag/n with baccalaurwte traininp nd include postdoctoral

          INSTITUTION AND LOCATION


Columbia College
Massachusetts Institute of Technology
Stanford University


HONORS

DEGREE



B.A.
M.S.
Ph.D.

  YEAP            SCIENTIFIC
CONFERREO            FIELD

1942      Physics
1943     Physics and Math
1949     Physics and Kath

MAJOR RESEARCH INTEREST                     ROLE IN PROPOSE0 PROJECT

Medical Instrumentaion Research             Collaborator

Contract 952489 Mariner 71 Photo Interpretation,  Current Year $/l,OOO Total $445,000
Jet Propulsion Lab, 25% time
Contract NAS-l-9681 Viking 75 Imaging, Current Year $31,658 'Total $297,805

Langley Res. Center, 20% time

Grant NGR 05-020-064-513 Cytochemical Studies in Planetary Microorganisms,
  Current Year $240,000 Total to date $3, 800,000, 25% time
NIH Contract Proposed, Cell Separator Construction, Total $240,000 10% time, no salary
Grant GMl7367-03 Automatic Cell Separation - Clinical and Biological Uses,
                      455. 10s time. no sal rv   (cont'd below)
                            rtiw wfth pmont positfon, IM and exp&u~ &event to am of pro/ccc L&t ON
01 mat npm8nbtive publiclrtlonr,  00 m t urcmd 3 m for uch In&ldu81)

lgO-present
1961-present

1953-1961
1952-1953
1950-1952
1949-1950
1946-1948
1943-1946
1943

Associate Dean for Research Affairs,  Stanford University School of Medicine
Senior Scientist, Director of Instrumentation Research Laboratory,
Dept. of Genetics, Stanford University School of Medicine
President, Levinthal 'Electronic Products
Chief Engineer, Century Electronics
Research Director, Member of Board of Directors, Varian Associates
Research Physicist, Varian Associates
Research Associate, Nuclear Physics, Stanford TJniversity
Project Engineer, Sperry Gyroscope Co., New York
Teaching Fellow in Physics,  Massachusetts Institute of Technology

Research Support (cont'd)

Stanford Medical School Associate Dean for Research 25s time


(137)

Relevant Publications
and Papers:      E. C. Levinthal,"Detection of Extraterrestrial Life",
             Professional and Technical Group of Instrumentation
             and Measurements of I.E.E.E., April, 1963.

E. C. Levinthal,"The Detection of Life Within Our
Planetary System", Presented at WESCON, August, 1463.

E. C. Levinthal, "The Biological Exploration of Mars",
Presented at the Space Technology Laboratory's Invited
Lecture Series, November 6, 1963.

E. C. Levinthal, "The Biological Exploration of Mars",
Presented at Moffet Field, Fullerton, Los Angles
and San Diego, April 27-30, 1964, as part of the University
of California Extension Series Lectures - Horizons in
Space Biosciences: Ex&biology.

E. C. Levinthal, J. Lederberg and L. Hundley, "Multivator -
A Biochemical Laboratory for Martian Experiments", Life
Sciences and Space Research II, COSPAR (Committee or
Space Research) 1964.

B. Halpern, J. W. Westley, E. 6. Levinthal, J. Lederberg,
"The Pasteur Probe:  An Assay for Molecular Asymmetry",
Life Sciencesand Space Research, COSPAR (Committee on
Space Research) 1966.

E. C. Levinthal, "Space Vehicles for Planetary Missions",
in:  Biology and the Exploration of Mars, Nat. Acad. Scl.,
National Research Council.

E. C. Levinthal, "Prospects for Manned Mars Missions",
in:  Biology and the Exploration of Mars, Nat. Acad. Sci.,
National Research Council.

0. Reynolds, E. Levinthal, G, Soffen, "The Role of the
Scientist in Automated Laboratory Systems", AIAA'i Paper
No. 67-632, (1967).

E. C. Levinthal, J. Lederherg and C. Sagan, "Relationship
of Planetary Quarantine to Biological Search Strategy",
Presented at COSPAR Meeting (Committee on Space Research),
London, (1967)

C. Sagan, E. C. Levlnthal and J. Lederberg, "Contamination
of Mars7", Science, lS9: 1191-1196 (1968)

E. C. Levlnthal, "The Role of Molecular Asymmetry in
Planetary Biological Exploration:', Gordon Research Cpnferences,
Nuclear Chemistry Section, 1968. (Paper)


(138)

Relevant Publications
(continued)       J. P. Kriss, W. A. Bonner, E. C. Levinthal.  "Variable
             Time-Lapse Videoscintlscope: A Modification of the Sclnti-
            llation Camera Designed for Rapid Flow Studies."
           J. Nuclear Med. 10, 249 (1969).
                             --- -

W. E. Reynolds, V. A. Bacon, J. C. Bridges,
T. C. Coburn, B. Halpern, J. Lederberg, E. C.
Levinthal and E. Steed, "A Computer Operated Mass
Spectrometer Systed'  Anal. Chem. 42, 1122 (1970).
                         --

H. Masursky, R. Batson, W. Borgeson, M. Carr, J. McCauley,
D. Milton, R. Wildey, and D. Wilhelms, B. Murray,
N. Horowitz, R. Leighton, and R. Sharp, W. Thompson,
G. Briggs, P. Chandeysson, and E. Shipley, C. Sagan and
J. Pollack, J. Lederberg, E. Levinthal, W. Hartmann,
T. McCord, B. Smith, M. Davies, G. DeVaucouleurs,
C. Leovy.  "Television Experiment for Mariner Mars 1971"
Icarus 12, lo-45 (1970).

H. Masursky, R. M. Batson, J. F. McCauley, L. A. Soderblom
R. L. Wildey, M. H. Carr, D. J. Milton, D. E. Wilhelms
B. A. Smith, T. B. Kirby, J. C. Robinson, C. B. Leovy
G. A. Briggs, T. C. Duxbury, C. H. Acton, Jr., B. C. Murray, J.
A. Cutts, R. P. Sharp, Susan Smith, R. B. Leighton, C. Sagan,
J. Veverka, M. Noland, J. Lederberg, E. Levinthal, J. B. Pollack,
J. T. Moore, Jr., W. K. Hartmann, E. N. Shipley, G. de Vaucouleurs
M. E. Davies.  "Mariner 9 Television Reconnaissance of Mars
and Its Satellites: Preliminary Results"  Sci.ence, 175 (4019)
294 (1972).


                        (139)
SECTION II -PRIVILEGED COMMUNICATION
                     BIOGRAPHICAL SKETCH

     /Give fhe following informer/on forallprof65sionol personnel Irsc& on pegs 3, brgfnnrng with rhe Prrncipal Investryror.
                Usa cottbnuation paga and follow the umo gener.4 format for each person. J
NAME                                  TITLE                         BIRTHDATE IMa, Dey, Yr.)

  Leonard A. Herzenberg           Professor of Genetics         Nov. 5, 1931
PLACE OF BIRTH (Ctrr, Srere. Caunrryl          PRESENT NATIONALITY I/f non-U.S crrtzen,     SEX
                            indkme kind of visa and expiration dare/

Brooklyn, New York

EDUCATION (Begin wirh baccalaureate rramrng and include postdoctoral)

;NSTITUTION AND LOCATION                DEGREE

Brooklyn College, Brooklyn, New York         A.B.

California Institute of Technology,Pasadenz.   Ph.D.

                         .

   PllT- ht1tut.p ParIn Pnstdnrtnral fpl'nw
HONORS

Phi Beta Kappa, Sigma Xi,.
Distinguished Alumnus Award, Brooklyn College, 1970
Genetics Study Section, National'Institutes of Health

  YEAR
CONFERRED


1952

1955

   SCIENTIFIC
     FIELD


Biology, Chemistry
Biochemistry,
Immunology

MAJOR RESEARCH INTEREST                       ROLE IN PROPOSED PROJECT

-

Immunogenetics, somatic cell genetics       Collaborator
                              I
RESEARCH SUPPORT l&a insrrucrrons/

N.I.H. GM-17367, Automated Cell Sorting-Clinical and Biological Uses, $115,072 current
  year, total funds for project $364,355.
N.I.H. AI-08917, Genetics of Immunoglobulins, $4=4,044 current year, $240,893 total
  funds for project period

RESEARCH AND/OR PROFESSIONALEXPERIENCE (Srening~rhpr~enrposi~on,~andexpe~encarrlevan;roareaofprojec~ L~sfa//
or m-t representative pubhcarionr  Do nor exceed 3 pages for each individual. 1
1969:  present Stanford University School of Medicine, Stanford, California,
      Professor of Genetics
1964-1969:  Stanford University School of Medicine, Stanford, California,
    Associate Professor of Genetics
1959-1964:  Stanford University School of Medicine, Stanford, California,
    Assistant Professor of Genetics

1957-1959:` National Institutes of Health, Bethesda, Maryland. Officer, USPHS
   (Dr. Harry Eagle)
1955-1957:  Pasteur Institute, Paris, France (Prof. Jacques Monod, American Cancer
   Society Postdoctoral Fellow)
1952-1955:  Ph.D. California Institute of Technology, Pasadena, California.
   (Major:  Biochemistry, Prof. H. K. Mitchell;  Minor:  Immunology, Prof. R. D. Owen)
1948-1952: A.B.  Brooklyn College, New York

Publications since 1967:

1.  Herzenberg, L. A. and N. L. Warner.  1967.Genetic control of mouse immunoglobulins,
  P* -
   In B. Cinader (Ed.), Regulation of the antibody response, Chapter Xv.
  C; C. Thomas, Springfield, Illinois.
2.  Tyan, M. L., L. J. Cole and L. A. Herzenberg.  1967.  Fetal liver cells:
  a source of thymus-dependent specific lmmunoglobulin production in radiation
   chimeras.  Proc. of Sec. of Exp.  Biol. & Med. 1161-1163.


1





1


1
`I





1




1


1

5.


5.


7.

1:



II


1





21



2







L-

3.


9.





0.



1.

040)
Continuotlon po(j0

3.


6.

5.

5.

7.

3.

3.

I.

1


2.


3.

5.

Klein, J., J. Martinkova & L. A. Herzenberg.   1967.  Analysis of the histo-
compatibility-2 (H-2) locus of NZB mice.  Transplantation 2: 1335-1337.
Klein, J. & L. A. Herzenberg.  1967.  Congenic mouse strains with different
immunoglobulins allotypes. I.
kinetics of KG           Breeding scheme, histocompatibility tests and
         globulin production by transferred cells for C3H.

its congenic p%tner CWB/5.                                  S.W. and
                Transpl. >:1484-1495.

Welton, J., S. R. Walker, G. C. Sharp, L. A. Herzenberg, R. Wistar and W. P. Creger
1968.  Macroglobulinemia with bone destruction.  Difficulty of distinguishing
between macroglobulinemia and myeloma. Amer. J. of Med. 44:280-288.
Warner, Noel L.  and L. A. Herzenberg.  1967.  Immunoglobxin isoantigens
(allotypes) in the mouse. IV.  Allotypic specificities common to two distinct
immunoglobulin classes.  J of Immunol. 99:675-678.
Minna, J. D.,  G
gene locus for Gl immunoglobulin H chains and its linkage to the H chain
      i M. Iverson 6 L. A. HerGnberg.   1967.  Identification of a

chromosome region in the mouse.   Proc.  of Natl. Acad. of Sci. 58:188-194.
Tyan, M. L., L. J. Cole & L. A. Herzenberg.  1967.  Fetal 1iveFcells:   a source
of specific immunoglobulin production in radiation chimeras, pp. 87-89. In
J. Dausett, J. Hambruger, G. Mathe (Eds.) Advance in transplantation.  Proc.
1st Intl. Cong. Transpl. Sot., Paris, June 27-30 (Munksgaard, Publisher).
Herzenberg, L. A., Leonore A. Herzenberg,  R. C. Goodlin 6 E. C. Rivera.   1967,
Immunoglobulin syntehsis in mice:  suppression by anti-allotype antibody. J.
Exp. Med. 126:701.

Herzenberg, L. A. J. D. Minna & Leonore A. Herzenberg.                       i
                                            1967.  The chromosome
region for immunoglobulin heavy chains in the mouse:  allelic electrophoretic
mobility differences and allotype suppression.  Cold Spring Harbor Symposia
on Quantitative Biology 32: 18.1-186.

Herzenberg, L. A. H. 0. EDevitt & Leonore A. Herzenberg.  1968.  Genetics of
antibodies.  Ann. Rev. of Genetics 2:209-244.
Tyan, M. L. & L. A. Herzenberg.  19a8.  Ontogeny of the mouse immune system.
ELn Immunoglobulin-producing cells.  J. of Immunol. 101:446-450.
  , M. L., H. 0. McDevitt & L. A. Herzenberg.   1968.  Genetic control of the
antibody response to a synthetic polypeptide:  transfer of response with spleen
cells or lymphoid precursors.  Abstract and paper submitted to 2nd Intl. Transpl.
Cong. N.Y., Sept. 1968.
Herzenberg, L. A. and M. L. "@an. 1968. Genetics of antibody formation:   role of
thymus in the evolution of the immune response.  12th Intl. Cong. of Genetics,
Tokyo, Japan, Aug. 19-28.
Tyan, M. L. & L. A. Herzenberg.  1968.  Irununoglobulin production by embryonic
tissues:  thymus independent.  Proc. of Sot. for Exp. Biol. & Med. 128;952-954

                                                                           I
                                                       !
Heraenberg, L. A. 1969.  Rabbit Aa locus allotypes:  quantitative comparisons        1

                                                    _ _
in IgG, IgA, and IgM by inhibition of precipitation.
Hule'tt, H. R., W. A. Bonner,            'Fed. Proc., p. 435 (abstract)
                 J. Barrett and L. A. Herzenberg.  1969. Cell
sorting:  automated separation of mammalian cells as a function of intracellular
fluorescence.  Science m;747.
Tyan, M. L., L. A. Herzenberg-& P. R. Gibbs.  1969.  Lympoid precurosors:
thymus independent antibody production.
L'age=Stehr, J. and L. A. Herzenberg.   J. of Immunol. =;1283.
                                1970.  Immunological memory in mice:
I.  Physical separation and partial characterizationof memory cells for different
Ig classes from each other and from antibody producing cells.  J. of Exp. Med.
131:1093-1108.
cobson, E. B., J. L'age-Stehr 6 L. A. Herzenberg.  1970.  Immunological
memory in mice: II.  Cell interactions in the secondary immune response studied
by means of Ig allotype markers.  J. of Exp. Med.' 131:1109-1120.
Hulett, H. R., L. A, Herzenberg, W. A. Bonner, and P. L. Wolf.  Rapid cell-
sorter -- a new tool for cell study :Jith clinical applications.  Laboratory
Investigations (abstract in pressj   :' resented at 55th Llnnual Meeting of
International Academy of Pathology, St. Louis, Missouri, March, 1970.

*ucl-m 1.7" - ,7.-b*


6


7

8









TI


b

                        (141)
                         Continuotlon pcqjo                                          1
2.  Riblet, Roy J. and L. A. Herzenberg.  1970.  Mouse lysozyme:  production by       I

  a monocytoma, isolation, an comparisons with other lysozyme.  Science 168:1595
3.  Herzenberg, L. A.  Gene interactions in itnmunoglobulins (in press).      J
  Presented at Symposium on Anti-Human Gamma Globulins, Lund, Sweden, Oct. 1969.       '

c.  Herzenberg, L. A.  1970.  From cell biology to immunology -- a short trip.
  J. of Cellular Physiology 76: 303-310.
5.  Merrill, J. T., N. Veizadec H. R. Hulett, P. L. Wolf and L. A. Herzenberg. 1971. i

  An improved cell-volume analyzer.                          1
                              Review of Scientific Instruments 42:1157-1163. I
6.  Bechtol, K. B., T. G. Wegmann, B. W. Chesebro, L. A. Herzenberg & H.O. McDcvitt.
  1971.  The antibody response to (T,G) -A--L in tetraparental mice.   Federation
  Proceedings, p. 1531 (abstract).
7.  Riblet, R. J., L. A. Herzenberg 6 L. A. Herzenberg.   1971.  Active allotype
  suppression in a cell transfer system.  Federation Proceedings, p. 2552. (abstract)
8.  Bonner, W. A., H. R. Hulett & L. A. Herzenberg.  1971.  Highspeed sorting
  of fluorescence labelled cells,  Federation Proceedings, p. EIO.  (abstract)
3.  Mitchell, G. F., E. 0. Chan, M. S. Noble, I. L. WEissman, R. I. Mishell and
  L. A. Herzenberg.  1971.  Specific immunological memory to heterologous erythrocyt
  in both T-cell and B-cell populations and requirement for T-cell in expression
  of B-cell memory.  Evidence using Anti 8 and anti-allotype sera with congenic
   mice.  J. Exp. Med., in press.

3.  Mitchell, ?. F. R. I. Mishell and L. A. Herzenberg.  1971.   Studies on the influenc
  of T-cells in antibody production.  Presented at the 1st International Congres
  of Immunology, Washington D-C., August, 1971.
1.  Herzenberg, Leonore, E. B. Jacobson, L. A. Herzenberg, and R. J. Riblet. 1971.
  Chronic allotype suppression in mice:  an active regulatory process. New York
  Academy of Sciences.  In press.
2.  Herzenberg, L. A.  1971.  Immunoglobulin genetics in cellular immunology.
  New York Academy of Sciences.  In press.

elected publications before 1967:

3
I

e

.  Herzenberg, L. A. and Leonore A. Herzenberg. 1959.  Adaptationto lactose.
  Nutrition Review 17:65-87.

.  Herzenberg, L. A. 1959.  Studies on the induction of beta-galactosidase in
  a cryptic strain of escherichia coli.  Biochimica et Biophysics Acta 31:525-538.
.  Herzenberg, L. A. and Leonore A. Herzenberg. 1961.  Association of H-2antigens
  with the cell membrane fraction of mouse liver.   Proc.  of Natl. Acad. of Sci.
  47:762-767.

.  HEzenberg, Leonard A.  1962.   Part I.  Steps toward a gentics of somatic cells

  in culture.  Part II.  Maternal isoinununization as a result of breeding in rile muus~
.  CAnn,`H. M. and L. A. Herzenberg.  1963.   In vitro studies of mammalian somatic       I
                                                  --
   cell variation II.  Isoimmune cytotoxicity with a cultured mouse lymphoma and        ,

  selection of resistant variants.  J. of Emxp. Med. 117:267-284.
.  Wunderlich, J. and L. A. Herzenberg.  1963.  Genetirof a gamma globulin iso=
  antigen (allotype) in thenouse.  Proc. of Natl. Acad. of Sci. 49:592-598.

.  Erickson, R. P., D. K. Tachibana, L. A. Herzenberg and L. T. Rosenberg. 1964.
  A single gene controlling hemolytir complement and a serum antigen in the amouse.
  J. of Immunol. 92:611-615.

.  Hereenberg, L. AFl964.  A chromosome region for gamma 2A and beta 2A globulin H
  chain isoantigens in th mouse.-  Cold Spring Harbor Symposium of Quantitative
  Biology 29:455-464.
             -

i

otal number of publications: 75.


SEC-I-ION !I - PRIVILEGE@ COS'YUNICATION       (142)
                       BIOGRAPHICAL SKETCH
      &iv8 the following information for all professional personnel listed on page 3, bwinning with the Principal Invest& tar.
               Use continuation pages and follow the Same general format for each person.)
NAME                     TITLE Chlet, Psyt. Research &    BIRTHDATE IMo., Day, Yr.)
Bert S. Kopell, M. D.         Training Division, VA Hospital
                      Palo Al to, Cal ifornia          2/l l/31
PUKE OF BIRTH (City. State. Country/           PRESENT NATIONALITY l/f non4J.S citizen,     SEX
New York, Mew York              indicate kind of visa and expiration date)

                                     USA               I3 Male   0 Female
                EDUCATION (Begin with baccalaureate training dnd include postdoctoral)

       INSTITUTION AND LOCATION


Univ. of Geneva, Geheva, Switzerland

Univ. of Geneva, Geneva, Switzerland

  DEGREE         YEAR
             CONFERRED

Medical
Baccalaureat? 1953
M. 0.      1958

     SCIENTIFIC
       FIELD



Medical Science

Mairnonides Hospital, New York         Rotating    1 W-59
                                               I ntet-n
HOTRS
sychiatry Career Teaching Award--July, 1966 - June, 1968
Diplomate of American Board of Psychiatry & Neurology in Psychiatry, 1966

MAJOR RESEARCH INTEREST                      ROLE IN PROPOSED PROJECT
Electrophysiological Studies of Drugs      Co1 1 aborator

RESEARCH SUPPORT (See instructions)
  1.  Current Research Support
       a.  20% effort VA Part 1 funds "Electrocortical'Measurement of Set and Attention
      in Psychiatric Patients".  Grant terminates 6/20/72, $15,000 for F. Y. 1972.
     b.  10% effort to:  MH 19918; total direct costs for May 1, 1971 to April
      30, 1972--$115,o62.
  2.  Pending Appl icat ions
     a.  40% effort "Brain Responses, Behavior and Drug States in Man:  A General
      Research Proposal".  Total amount requested for current year $154,134.  Total
     requested for a 5-yr. period $635,801.  To NIMH and the VA (See Below)
RESEARCH AND/OR PROFESSIONAL EXPERIENCE (Starring withpresentposition, list traininqandexpen'encerelevant roared ofproject  List all
or mast representative publice tions  Do nor exceed 3 pages for each individual. )
1970-Present Chief, Psychiatry Research & Training Div., VA Hospital, Palo Alto, CA.
1970-Present Assoc. Professor, Stanford University Sch. of Medicine, Dept. Psychiatry
1969-Present Director, Medical Student Training Program in Psych., Stanford Univ.
1968-Present Director, Human Perception Lab., S.tanford UnTv. Sch. of Med., Dept. Psychi.
1965-1970     Assist. Professor, Stanford Univ. Sch. of Med., Dept. Psychiatry
1964-1966   Research Associate, Palo Alto Veterans Administration Hospital
1964-1965   Instructor, Stanford Univ. Sch. of Medicine, Dept. of Psychiatry
1962-1964   Chief, Psychiatric Services, Westover Air Force Base, Massachusetts
1959-1962   Resident, University of Colorado, Denver, Colorado
1958-1959    Rotating intern, Maimondes Hospital, New York

See representative publications

2.  Pending Appl icat ions (cant inued)
   b.  20% effort "Brain Responses in Alcoholics During Drinking Cycle".  Total
    amount requested for current year $73,607.  Total requested for a 3-yr.
    period $222,699.  Submitted to NIMH.

kHS-398
Rev. 3-70


Bert S. Kopell, M. D.

  (143)


PUBLICATIONS

  Stilson, D. W. and Kopell, B. S.  The recognition of visual signals in the
presence of visual noise by psychiatric patients.  J. Ner. Ment. Dis., 139.
zag-221, 1964.

  Kopell, B. S., Noble, E. P. and Silverman, J.  The effect of thiamytal and
methamphetamine on the two-flash fusion threshold.  Life Sciences, 2:2211-14, 1965.

  Stilson, D. W., Kopell, 6. S., Vandenbergh, R., and Downs, M P. Perceptual
recognition in the presence of noise by psychiatric patients.  J. Nerv. Ment. Dis.,
142:  235-247, 1966.

  Noble, E. P., Silbergeld, S., Kopell, B. S., McKinney, W., Wittner, W. K.,
and Butte, J. C.  The effects of physiologic doses of corticosteroid on catechola-
mine metabolism in man.  J. Psychiat. Res., 5:  159-167, 1968.

  Kopell,  6. S. and Wittner, W. K.  The effects of chlorpromazine and methampheta-
mine on visual signal from noise detection.  J. Nerv. Ment. Dis., 147:418-24, 1968.

  Hilf, F. and Kopell, B. S   Non-contingent reinforcement and certainty.
Psychonomic Science, 11:  211-213, 1968.

  Macpherson, L. and Kopell, B. S.  Systems approach to the measurement of
slow evoked potential changes.  Med. Biol. Et-q., 5: 673-65, 1968.

  Kopell, 8. S., Lunde, D. T., Clayton, R. B., and Moos, R. H.  Variations in
some measures of arousal during the menstrual cycle.  J. Nerv. Ment. Dis., 148:
180-187, 1969.

Moos, R. H., Kopell, B. S., Melges, F. T., Yalom, I. D., Lunde, D. T.,

Clayton,
menst rua 1


  Kope
ences, 1
averaged

R. B., and Hamburg, D. A.  Fluctuations in symptoms and mood during the
cycle.  J. Psychosom. Res., 13   37-44, 1969.
                                -

1, B. S., Wittner, W. K. and Warrick, G.  The effects of stimulus differ-
ght intensity and selective attention on the amplitude of the visual
evoked potential in man.  Electroenceph. Clin. Neurophysiol., 26:619-22, 1969.
                                                                     -

  Kopell, B. S.  The role of progestins and progesterone in brain function and be-
havior.  In The Metabolic Effects of Gonadal Hormones and Contraceptive Steroids,
Hilton A. Salhanick (ed.), New York,  Plenum Press, 1969.

Kopell, 6. S., Wittner, W. K., Lunde, D. T., Warrick, G., and Edwards, D.

Cortisol effects on the averaged
and the two-flash fusion thresh01

      Roth, W. T. and Kopell
stimuli during a vigilance task.

Hilf, F. D., Wittner, W. K.,

evoked potential, alpha rhythm, time estimation,
d.  Psychosom. Med., 32: 39-49, 1970.
                       -

B S.  The auditory evoked response to repeated
Psychophysiology, 6: 301-309, 1969.

Kopell, B. S.  Feedback utilization styles of

paranoid patients.  J. Nerv. Ment. Dis., 149:  491~495, 1969.

  Roth, W T., Kopell, B. S., and Bertozzi, P. E.  Effects of attention on
averaged evoked response to speech sounds.  Electroenceph. Clin. Neurophysiol.,
29:  38-46, 1970.


Bert S. Kopell, M. D.
Pub1 ications Continued

(144)

  Kopell, B. S , Wittner, W. K., Lunde, D. T., Warrick, G. and Edwards, D.
Influence of triiodothyronine on selective attention as measured by the averaged
evoked potential in man.  Psychosom. Med., 2: 495-502, 1970.

  Zarcone, V., de la Pena, A., Kopell, B. S., and Dement, W.  Visual evoked
response following REM deprivation.  Psychophysiology, 7:  301, 1970.

  Kopell, B. S., Zarcone, V., de la Pena, A., and Dement, W. C   Changes in
selective attention as measured by the visual averaged evoked potential following
REM deprivation in man.  Electroenceph. Clin. Neurophysiol., 32: 322-325, 1972.

  Macpherson, L., Hutchings, M. D., and Kopell, 8. S.  An electrically operated
skin resistance switch.  Psychophysiology, 8:  673-675, 1971.
                                               -

  Macpherson, L. and Kopel 1 , B. S.  A zero-setter and voltage reference unit
for EEG amplifier systems. Psychophysiology, in press. (1972).

  Tinklenberg, J. R., Kopell, B. S., Hollister, L. E., and Melges, F. T. A
comparison of the effects of marihuana and ethanol on memory, evoked potential, and
contingent negative variation.  Psychopharmacology Bulletin, in press. (1972).

  Corby, J. C. and Kopell, B. S.  Blink and eye movement EEG artifacts.
pyhsiology, in press. (1972).                           Psycho-

  Kopell, B. S., Maxim, P., and Koran, L.   Influence of lithium on selective
attention as measured by the averaged evoked potential in man.   Submitted and
accepted for publication by Psychopharmacologia.

  Kopell, B. S., Wittner, W. K., Lunde, D. T., and Wolcott, L, L.   Effect of
amphetamines and barbiturates on selective attention as measured by the averaged
evoked response.  I n preparation.

  Kopell, B. S , Tinklenberg, J. R and Hollister, L. E.  Effects of mari juana
and alcohol on the contingent negative variation.  I n preparation.  To be sub-
mitted to Archives of General Psychiatry.

  Kopell, B. S., Wittner, W. K., and Lunde, D. T.  I nf luence of amphetamines
and barbiturates on contingent negative variation.  In preparation.  To be sub-
mitted to Psychopharmacologia.

  Corby, J. C. and Kopell, B. S.  Effect of predictability on evoked response
enhancement in selective attention.  In preparation.

  Lunde, D. T., Costell, R., Wittner, W. K. and Kopell, B. S. The electro-
cortical expression of sexual object preference in non-deviant male and female
subjects.  In preparation.  To be submitted to Science.

  MOOS, R., Clayton, R., Kopell, B. S. and Hamburg, D. A.  Progesterone and
menstrual cycle symptomatology.  I n preparation.


SECTION I\ -PRIVILEGED COMMlJNtCATION      (145)
                         BIOGRAPHICAL SKETCH

       (Give the following information for all professional personnel listed on page 3, beginning with the Principal Investigator.
                Use continuation pages and follow the same general format for each person.1
NAME                                  TITLE Chief of Psychiatric       BIRTHDATE f&do., Day, Yr.1

Walton T. Roth, M.D.            Consul tation Services         2/23/39
PLACE OF BIRTH (City, State, Counayl           PRESENT NATIONALITY IIf non-US citizen,    SEX
Topeka, Kansas                  indicate kind of visa and expiration data)
                                       USA                Q Male   D Female
                EDUCATION (Begin tith bJCCa/JUr63Jte training and include pOStdoCtOrJl~

       INSTITUTION AND LOCATION

Harvard Co1 lege
New York University School of Medicine

DEGREE


B.A.
M.D.

  YEAR
CONFERRED

1961
1965

    SCIENTIFIC
      FIELD

Biochemistry

HONORS

Harvard National Scholar, 1957-1961          Diplomate of American Board of
N.Y.U. Merit Scholar, 1961-1965              Psychiatry and Neurology in
AOA Medical Honor Society, elected 1965         Psychiatry, 1972
MAJOR RESEARCH INTEREST                     ROLE IN PROPOSED PROJECT

Human Electrophysiology                     Co1 1 aborator

RESEARCH SUPPORT &a instructionsl
  1.  Current Research
         None
  2.  Pending Applications
   a. 50% effort "Brain responses in alcoholics during drinking cycle".  Total amount
     requested for current year $73,607.  Total requested for a j-year period $222,699.
       Submitted to NIMH.
    b. 50% effort "Brain responses, behavior and drug states in man: a general research
     proposal".  Total amount requested for current year $154,134. Total requested
     for a 5-year period $635,801. To NIMH and VA.
RESEARCH ANDK)R PROFESSIONAL EXPERIENCE /Startim with present position, list train& end experience relevant to area of projet  List all
or must reprassnmtive pubticationr  Do not exceed 3 peges for each individua1.l

  1971  - Present  Chief of Psychiatric Consultation Services, V.A. Hospital, Palo Alto, Ca.
  1969 - 1971     National Institutes of Mental Health, Clinical Associate

1366 - 1969   Resident in Psychiatry, Stanford Hospital.

1965 - 1966
1964

1960

Intern in Medicine, North C
National Science Foundation
for Experimental Biology
National Science Foundation

       See Representat

rol ina
Summer

Memorial Hospital
Fe1 lowsh ip, The Worcester Foundation

Summer

Fe1 lowsh ip, Harvard

ve Pub 1 ications

fi S-3 8
R:. 3%J


(146)

Publications, Walton T. Roth, M.D.

  Roth, W.T.  The effect of LSD, mescal ine, and d-amphetamine on the evoked
"seconda ry d i scha rge" .  Psychopharmacologia (Berl .), 9: 253-258, 1966.
                                                   --

  Roth, W.T. and Kopell, B.S.  The auditory evoked response to repeated stimul i
during a vigilance task.  Psychophysiology, 6: 301-309, 1969.

  Roth, W.T., Kopell, B.S., and Bertozzi
average evoked response to speech sounds,
29: 38-46, 1970.
-

  Stillman, R., Roth, W.T., Colby, K.M.,
system for initial psychiatric inventory.
suppl., 8-11.

, P.E.  The effect of attention on the
Electroenceph. cl in. Neurophysiol.,

and Rosenbaum, C. P.  An on-l ine computer
Amer. J. Psychiat., 125: 7, Jan. 1969

  Roth, W.T. and Cannon, E.H.  Some features of the auditory evoked response in
schizophrenics.  Arch. Gen. Psychiat., in press, 1972.

  Roth, W.T., Galanter, M., Weingartner, H., Vaughan, T., and Wyatt, R.  The effect
of marijuana and synthetic delta-9-THC on the auditory evoked response and background
EEG in humans.  Submitted for publication, 1972a.

  Roth. W,T.  Auditory evoked responses to unpredictable stimuli.   Submitted for
pub1 ication, 1972b.


(147)

SECTION II -PRIVILEGED COMMUNICATION
                      BIOGRAPHICAL SKETCH

      (Give the foJlowing information for all professionel personnel listed on pege 3, bsginniw with the Principal Invsrtigetor.
               ihe continuation peges and follow the seme general former for eech person. j
NAME                                TITLE                      BIRTHDATE (Ma. Day. Yr.1
Ronald D. Jamtgaard          Facility Director (ACME)       May 2, 1-933

PLACE OF BIRTH ICity, Sate, Country1

PRESENT NATIONALITY I/f non-US citizen,
indiwte kind of vise and expiration date)

SEX

Sioux Falls, South Dakota                  USA
               EDUCATION &g/n wfth biuxelaurmte treining end includepostdoctorel)

!$%Male   0 Female

INSTITUTION AND LOCATION               DEGREE        YEAR             SCIENTIFIC
                                         CONFERRED            FIELD

Augustana College, Sioux Falls, S.D.
University of Minnesota
University of Minnesota


HONORS

A.B.

1957

coursework for M.A.
in Pub. Admin.

MAJOR RESEARCH INTEREST
Biomedical computing, communications
systems
RESEARCH SUPPORT iSee instructions)

ROLE IN PROPOSED PROJECT

Management Support

ACME Computing Facility, Stanford School of Medicine 95% time RR00311
S.U. Medical Center Computer Planning Funds       5$

RESEARCH ANDmA PROFESSIONAL EXPERIENCE (Starting withpresentposition,~andexperiencerelevent toareeofproject Listall
or most nvpnsentative publiwtiont  Do not exceed 3 pages for eech individual.l

1gO-present

1969-1970

1967-1969

1966-

1961-1966

1958-1961

Director, Advanced Computer for MEdical Research (ACME) Stanford
Medical School, Stanford Computation Center, Stanford University.

Manager of Administrative Services, Radiation Division, Varian
Associates, Palo Alto, California.

Inter-Facility Associate Director,  Stanford Computation Center,
Stanford University.

Executive Assistant to Director (Dr. W.K.H. Psnofsky) Stanford
Linear Accelerator Center, Stanford University.

Budget Officer, Stanford Linear Accelerator Center, Stanford
University.

Management Trainee, Field Office Liaison Officer and qudget Analyst
U.S. Atomic Energy Commission at Germantown, Maryland, and Idaho
Falls, Idaho.

f? S-398
A:. 3-70


(148)

> .
sr:. .,      : F:l'.. I.cGED COMMUNICATION
,m-,. -.      - -- ..L              BIOGRAPHICAL SKETCH

NrlME

&is0 the following information for JllprOfmSiOnJl personnel listed on psge 3, beginning with the b%imipJl hwxtigstor.
         Use continuation pagas end follow the same general format for such person 1
                            TITLE                        BIRTHDATE IMa, by. Yd

Gio C.N. Wiederhold            Lecturer, Consultwt, and      tJu:t: ?)A , 1936
                          :ler!ior Systems Designer
PLACE OF BIRTH Kity, Stats, Country)           PRESENT NATIONALITY (If non-U.S citizen.    SEX
                               indicsh kind of vin and expiration date)
Varese,  -1 t sly                    E'e2`ma~ent Resident Alier,         m Msls   [II Female
                 EOUCATlON [Begin 4th baXal@urmte training md Include postdoctoral/

INSTITUTION AN0 LOCATION               OEGREE         YEAR             SCIENTIFIC
                                           CONFERRED            FIELD

TMS 'Technicum, Rotterdq Holland
!J.C. Berkeley, Calif.  1960-64




HONORS

B.S.

1957

Graduated cum laude from TMS Technicum.
Listed in WHO's WHO IN AMERICA, vol . 35, 1968-69.

MAJOR RESEARCH INTEREST                     ROLE IN PROPOSED PROJECT
Use of computers in data reduction and medi-          Technical Staff
cal applications of computers.
-RCH SUi'PORT &oo ituttvcdwl

ACME Computing Facility, Computation Center, Stanford University.  Supported
under the Biotechnology Resources Branch of NIH, Grant No. RR00311-06.(30%time)

Department of Surgery, Div. of Cariovascular Surgery, S.U. Medical Center,
Stanford University, consultant. (10% time)

Hospital Data Processing, S.U. Hospital, Stanford University, technical assistant.
                                             (60% time)

RESEARCH ANDX)R PROFESSIONAL EXPERIENCE (Smrting withprrmtpositioq&&&&g and uporimuw r&want to arsa of project List &II
or mat np~ntrdvopubihtioonr  00 not oxcmd 3pqes for each IndM&mL)

1970-present: User Services Manager,
1965-70 :                ACME and consultant to Director,Su. Hospital, ADP.
        Director, ACME Facility, Stanford Computation Center.

1965-present: Lecturer, Computer Science Dept., Stanford University.
1964-65 :     Visiting Professor, Indian Inst.
1961-64 :                         of Technology,Kanpur, India under USAID.
        Head of Programming, U.C. Berkeley, Calif.
1958-61:    IBM Service Bureau Corp.,
1958:                      New York and San Jose, Programmer.
        SHAPE Air Defense Technical Center, Europe - technical assistant.

Consultant to American Cyanamid Co. (1961-date); Optimum Systems Inc. (1967-date);
Syntex Corp. (1968); U.C. Berkeley Center for Research and Management Science (1968-69);
Reeves Telecom Corp., N.Y. and Detroit (196g-70).  Consultant, National Center for
Health Services, USPHS.  Consultant, Polymorphic Corp., Palo Alto, Calif.

Bibliography:

1) Wiederhold, G., Loewner, P. et al.: CSI/CSO Insurance Rate Tables.
2) Wiederhold, G. and Tsao,                             SBC Corp., 1959.
                 C. C.: A program for evaluation equilibrium combustion.
   Kinetics, Equilibrium and Performance of High-Temperture Systems, 1962.
3) Wiederhold, G. and Potter, R.L.: Computation of the equilibrium composition of
   multi-component chemical systems.
4) Wiederhold, G.:            American Cyanamid Co., Stamford, Conn., 1962.
            Control language for an interactive time-sharing system. SHARE
  TSS/67 Control Language Comm., 1966.
                     (continued)


Gio C. M. Wiederhold, B.S.

(149)

2

Bibliography (continued)

5) Wiederhold, G.: Internal Documentation, U.C. Computer Center, Berkeley, Calif'.,1962-65.
  FORFOR: A timesharing compiler system design; programming using Assembly Macros;
  FXMS: An error traceback procedure for FORTRAN IV and MAP Programs; MORT: A col-
  lection of Text Manipulating Procedures; Proposal for simple system allowing
  direct access to the computer;  STUDENT: A Fast FORTRAN IV Compiler.

6) Wiederhold, G.:  A Summary of the ACME System.  ONR Computer and Psychobiology
  Conference Proceedings, Monterey, Calif., May 17, 1966.

7) Wiederhold, G.:  A Summary of the ACME System.  Conversation with a 50 Conference
  Proceedings, Chicago, Ill., October 31 - November 1, 1966.

8) Sanders, W.J., and Wiederhold, G., et al.:  An Advanced Computer System for Medi-
    cal Research.  AFIPS Conference Proceedings 31, Anaheim, Calif., 1967.

9) Brietbard, G.Y., and Wiederhold, G.:  PL/ACME: An Incremental Compiler for a Sub-
   set of PL/l.  1~1~68 Congress Proceedings, Edinburgh, Scotland, August 1968.

10) Wiederhold, G. and Hundley, L.:  A Time-Shared Data Acquisition System.  Digest
  1969 IEEE Computer Group Conf. on Real-Time Systems, IEEE, Minneapolis, Minn.,
   pp. 190-196, June 1969.

11) Wiederhold, G.:  Setting Up a General Purpose Data Acquisition System. Proceedings
   of IBM Scientific Computing Symposium on Computers in Chemistry, Data Processing
   Division, White Plains, New York, August 1969.

12) Wiederhold, G.:  An Advanced Computer System for Medical Research. Proceedings
   of IBM Japan Computer Science Symposium, Research and Computer System, Tokyo,
   Japan, pp. Bl-Bl5, November 1969.

13) Crouse, L. and Wiederhold, G.:  An Advanced Computer System for Real-Time Medical
   Applications.  Computer in Biomedical Research (Academic Press), vol. 2, 6,
   December 1969.

14) Wiederhold, G.:  Internal Documentation (ACME Notes), Stanford Computation Center,
   ACME Computer Facility, Stanford, Calif., November 1965 - present.

15) Wiederhold, G.:  Medical Uses of Computer (in Japanese) presented in Tokyo, Japan,
   November 1969, published in IBM Review No. 27, February 1970.

16) Wiederhold, G., Brietbard, G.:  A Method for Increasing the Modularity of Large
    systems.  IEEE Computer Group News, vol. 3, 2, March-April 1970.

17) Girardi, S., Frey, R., Wiederhold, G.:  A Filing System for Medical Research. Pre-
   sented at Journees Internationales d'lnformatique Medicale de Toulouse, France,
   March 4-6, 1970, and at The Eighth Annual Symposium on Biomathematics and Computer
   Science in the Life Sciences, Houston, Texas, March 23-24, 1970.

18) Crouse, L. and Wiederhold, G.:  Interactive Use of a Timesharing System for Medical
   Laboratory Supports, San Diego Biomedical Symposium Computing On-Line, April 6-8,
    1970.

19) Wiederhold, G., and Ehrman, J.:  An inferred syntax and semantics of PL/S.   Sub-
   mitted to Sigplan Notices, A Journal of the ACM, September 1971.


                         (l50)
SEC'1 ;c
-.=- :; - PRIWLEGED COMMUNICATION
                     BIOGRAPHICAL SKETCH

     (Give the following informsdon forellprofessional personnel listed on pege 3, beginning with the Princtppsl Invatigetor.
              Use continuation pegts and follow the rame generel form8t for each person)
NAME                                 TITLE                       BIRTHDATE iMa. 08V, Yr.)
Hundley, Lee               Assistant Director, ACM?       2 aimary 31, 1931
PLACE OF BIRTH (City. Sbt8, Country)          PRESENT NATIONALITY f/f non-U.S citjzen,    SEX
                              indic8te kind of Via 8nd eXpir8tiOn d8t8)

Dallas, Texas

    I          US.4

EDUCATION (Begin with b8ccekure8m trrinlng end include paStdoHor8/)
                     1              I

lNSTlTUTlON AND LOCATION               DEGREE         YEAR            SCIENTIFIC
                                             CONFERRED            FlELD

Southern Methodist University, Dallas, T      B.S.     1960  I  Electrical Engineer
San Jose State College, S.J., Calif.                          coursework for MA

Sigma Tau - Engineering Honorary Fraternity
Eta Kappa Nu - Electrical Engineering Honorary Fraternity
Graduated second in a class of 92 from Southern Methodist University
MAJOR RESEARCH INTEREST                    ROLE IN PROPOSED PROJECT

Biomedical Computing Applications
RCH SUPPORT lsm hmtwriona)

I    Technical Staff

ACME Computing Facility, Stanford School of Medicine 100% time RR00311

RESEARCH ANOFDR PROFESSIONAL EXPERIENCE (St8rHw wlthprrpsntpodtion, &U&&g 8nd UpNfMOr &-nt t0 8tV8 Of p@OCt  L&t 811
or most nprmentadve publiutionr  Do not wce8d 3 pagas for nch Indlvi&sL)

1967 -present  Assistant Director ACME Computing Facility, Stanford University
1966-67     Manager, Systems Engineering-Programming Manager, Data Pathing, Inc.
         Los Altos, Calif.
1961-1966    Research Engineer, Instrumentation Research Laboratory, Genetics
         Department,  Stanford School of Medicine.
1959-1961    Research Scientist, University of Texas Southwestern Medical School.
  ' ,


Publications:
Montgomery, P. O'E. and iiundley, L. L.: "The USC of
   Television in Scanning Techniques for Ultraviolet
   Irradiation of Cells."  Digest of Technical ,Papers,
   12th Annual Conference on Electrical T!>c;lniqucs in
         7
    Me cl .  and Biol.  November 10-12, 1959, 19.
Hundley, L. L.  and Montgorrlery, P. O'B:  "Flying Spot
   Techniques in Microscopy."  *Digest-of Technical
   Papers, 12th Annual Conference on Electrical
   Techniques in Med. & Biol.  November 10-12, 1959, 20-21.
Montgomery, P. O'E. and Hundley, L. L.: "The Use of
  Television and Scanning Techniques for Ultraviolet
   Irradiation Studies of Living Cells.v   IRE Trans.
    Med.  Electr. ME 7r;35-138  July 1960.
,Montgomery, P. O'B. and tiundley, L. L.: "The Effects
   of Selective Ultraviolet Irradiation of the
   Cytoplasm of Living Cells."  Proc. Sot. Exp. Bio. 6
    LMCd.  105:117-120, Oct. 1960.
Montyomery, P. O'B., Bonner, Wm. A. and IIundley, L. L.:
  "Flying Spot Microscopy."  Encyclopedia of Microscopy,
   Edited by George L. Clark,  Reinhold Publishing Corp.
    PP.  334-338, 1961.
Montgomery, P. O'B. and Hundley, L. L.: "Ultraviolet
  Microbeam Irradiation of the Nucleoli of Living
    Cells."  Exp.  Cell Res. 24:1-5, 1961.
Montgomery, P. O'B., Bonner, W. A., Hundley, L. L. and
   Ashworth, C. T.:  "Biological Effects of U. V.
   Irradiation in Chaos Chaos."  Royal Microscopical
   Society.  8O:i9-24 (PT I) April 1961.
Montgomery, P. O'B. and Hundley, L.L.:  "A Flying Spot
    Interference Te levision Microscope."   Nature..
   192:4807,  1059-1060, December 1961.
Montgomery, P. O'B., Van Orden, F., Hundley, L. L.,
   Chapman, C. L. and Cook, J. E.:   "Effects of
   Selective Ultraviolet Irradiation of the Nuclei
   of Living Cells."  Proc. Sot. Exp.- Biol. and Med.
   108:2,  372-375, Nov. 1961.
Hundley, L. L.:  "A Flying Spot Interference Microscope."
   Annals of the New York Academy of Sciences, Vol. 97,
    Art.  2, pages 514-515, June 5, 1962.
Levinthal, E., Hundley, L. L., and Lederberg, J.: Life
, /  Sciences and Space Research II:   "Multivator - A
  Biochemical Laboratory for Martian Experiments,"
   North Holland Publishing Company, June 3-12, 1963.
Hundley, Coburn, Garwin and Stryer: "A Nanosecond
    Fluorimeter."  Review of Scientific Instruments,
    38-488-1967.
Wiederhold, Gio, Lee Hundley: "A Time-Shared Data Aquisition System"
   Proceedings of the IEEEComputer Group Conference, March 1970


SECT'!ON II -PRIVILEGED COMMUNICATION       (152)
- -, -w^.",--.                  BIOGRAPHiCAL SKETCH
      @ivy the following information for all profession61 personnel listed on pa@ 3, beginning na'th the Principal Invartlgstor.
                 use continwtion page% and follow the same gen~-#I format for arch person.)
NAME                                  TITLE                      BIRTHDATE (Ma, Day. Yr.)

Regina Frey                  Systems Programmer        September 4, 1-97
PLACE OF BIRTH (City, State, Country)           PRESENT NATIONALITY I/f non-US citiren,    SEX
                               indicate kind of viaa and o xplmdon date)
Newton County, Indiana                    USA                  0 Male   ES o oo???
                 EDUCATION (Bqfn 4th bealaurrte tdnlng and In&dopost&ctorwl)

       INSTITUTION AND LOCATION              DEGREE


Purdue University, Lafayette, Indiana      R. s.

  YEAR             SCIENTIFIC
CONFERRED            FIELD


1959      Mathematics

             I    I    I
HONORS

General Motors and Purdue University Alumni Association Scholarships

MAJOR RESEARCH INTEREST

Biomedical systems computing

ROLE IN PROPOSED PROJECT

  Technical Staff

ACME Computing Facility, Stanford University School of Medicine 100% time
  NIH BRR Grant RR00311

RESEARCH AND#R PROFESSIONAL EXPERIENCE IStmi~ wfthpmontposi(lon. &g&&l& and experience rdevmt to orea of pro/rt L&t alI
01 mat nprumntatiw publimionr  Do not oxcad 3 m for rch indivl&mLl

1968-present  Systems programmer, ACME Facility, Stanford Computation Center,
1964-196;    Stanford University

1959-1964   Programmer, University of California at Berkeley, Linguistics Dept.
        Programmer-Analyst, Systems Development Corporation, Santa Monica,
           Calif.

Education

1959. Programmers Training School,  System Development Corporation
1970. Systems Science II, IBM Education

Papers

A Filing System for,Medical Research, coauthored, BIOMEDICAL COMPUTING,
     vol. 2, lgl, Elsenier Publishing Company, Ltd., England.

Rw. 3-30