PROPOSAL FOR
STANFORD UNIVERSITY
MEDICAL EXPERIMENTAL COMPUTING 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
INTRODUCTION
enone e ene ees eee emer were cesar eee reset enwereesveesesccevevvedl
1. Objectives and Long-Term GoalSerecrneeseee Peer ee w es wenens eee ervceve 1
2. Background: ACME Computer Facility Experience.......ccceceeceseseed
SUMMARY 1... cece ccc s cece nce cere rtenesecvncace teen e ee eens sce e rev eaee 4
JUSTIFICATION ..... ce eee ete e cece cece nees pees et ee ees sees ssueaes 00028
1. Demonstration of need. or sec cesvercccccccvccercrcesuves Cece ene aceee .6
2. SUMEX Relationship to Institutional Plans ...+..ceeeeeeceeseceee osaol
RESOURCE OPERATIONS -- ees esc c secs cc scr cere enter eccrescecsseeeesttsnsves 29
1. Adminstrative Structure ---+-++-+-cces Cee ec cee eee ee eer e coer er sreereted
2. Operating Procedures and Policies --+---++-see. a ras 11
COMPUTER CONFIGURATION RATIONALE----- Cotte eee e neces ccons sence aeee coe el
1. IMtroduction «+--+ cece cece cece ec re www ee ee eet et nese nee rec enscaceaees 13
2. Computing Environment --+-++-.+++eeseoee tree ee eee etter eters er eevee ole
3. Technical Requirements -..-..... Ferenc ener owner eae receseeeresesseedly
4. Configuration Topologies .+-.. eee c cece cece ce cence cnn c eee eevanerenaes l7
5. Hardware Selection .-- ec ecc cee crccccvccrascccccseccacsccssvseseseces 20
a. Mainframe --.--scececevesrcee Ce i a a rr i rrr decease 22020
b. Peripherals, Data Channels, and Satellite Computers............ 23
6. Implementation Plan ..-- cece cece ccc a rent ceca esses secnrectetcvces 26
RESOURCE PERSONNEL «+--+ eececevecsecssceces ogee ese baeaeeseeeesesucse 222-28
RESOURCE ACTIVITIES «--cceccvccccevccvcucsscesses eect wenee cece nance 22 30
1. Services to be provided..... i i a rr 30
2. Research «e+e secre scceae ene eres coseee eee rr ews rae veesoe ee err ws eae eee JL
a. Core Research «cr-ccerccecccescesscouee seam e ee nweee seen teens eee DL
(1) Satellite Machine Support..-..... Pe i re teem ae veee 31
(a) Problem Statement--..--. Cer m erm e mere rnc ener sree eree 31
(1) Limitations of standalone small computers.-.....31
(2) Attributes of large host systems........... veeee DL
(3) Anticipated direction of some technological
innovations. ,............. ee beet e ec eceee 32
(b) Background and Rationale ..... cece cence cere cee r eens DD
(1) Current environment for satellites in
S.U. Medical Center <«-+-cessecereee eee er rar cesr ove 35
(2) Initial Approach in Software.....cscceeceeseceee DO
(3) Incorporation of new hardware techniques........ 36
(4) Resolution of specific goals with collaborators. 3/
(c) Methods and Procedures.-..-..ecessscccceccucse seve ences 38
(1) Satellite System Software Support
(a) Assemblers... ..- ccc sec e cer cece rs veesreeces 38
(b) High level language support.........-.++.4.. 38
(c) Realtime applications module library....... 39
(d) Extensions to manufacturers supplied
operating SysteMS ..----- ee ee cece reece ecees 10
(2) Computer to computer communications .........41
(4) Data transfers .......... ccc cece cuee Al
(b) Controlled interactions ................ Al
(3) Data manipulation ....... cc. ccc eee c cece ence ne 42
(a) Data collection .......... ccc cece eee eee 42
(b) Data analysis ........ cc ccc eee ce eee nee 43
(4) Satellite performance, measurement and
evaluation 1... cee cee ec eee cee eee enna 44
(d) Significance of satellite machine Support......... 46
(2) Extended Realtime Computing ...........cceceecceeceeees 47
(a) Problem Statement and Objectives ............0000. 47
(b) Background ..... 0... ccc eect c ne ce cece eeees 49
(c) Rationale ...... ccc ccc eect ee enc eceenane 51
(d) Methods and Procedures ........ccccccececacceccecs 53
(e) Significance ... ccc cece eee cece ce cee eee eens 58
(f) Collaborative Arrangement............. cee eceeeeues 58
(3) PL/ACME on a PDP-10 ......euues ee rr 62
b. Collaborative Research and Development...............0ee000- 65
(1) Predictive Modeling of Cardiovascular Function Utilizing
X-Ray and Ultrasonic Imaging Techniques.............6-. 65
(a) Problem Statement........... Cee mer wt nw ene ete 65
(b) Background ....... cc ccc cece cece ete c eee eececteeans 66
(c) Rationale ...... ccc ccc cece cece cece eee ees ee ae eens 67
(d) Methods and Procedures ..... sence ec eneseenes 210 68
l. X-ray Image Processing ..--- sss cece cece eacese 68
2. Ultrasonic Image Processing ............ee.00. 69
3. Small Computer Integration -.+..+.. ee seeeeeeee 70
(e) Significance -.- sce c cece c cence cece eee tater eee neee 70
(£) Relationships Cem ene eee eae eee reece anen ewe suss 71
(2) Digital Computer «-- eee c eee eee ccc ee ene eee tence tees 74
Processing of Cineurographic Images of the Urinary Tract
(a) Problem Statement --- +--+ cece cece ccc nce cn cusnscceevee 74
(b) Background Pee meer mmm mmr weer err ene nen ners ernvrseene 75
(c) Rationale «see e cere crn cccnsvvacrvvence Pew wn were ee ene 75
(d) Methods and Procedures «+--+ eccesserecnenccuscecae 76
(e) Collaborative Affiliations .--......e.. cesses eee 77
(£) Significance Hee ee meme ree ner emer ene creer nenesneezens 77
(3) Automated Gas Chromatography/Mass Spectrometry Analysis 78
(a) Tntroduction «cece cere rece cece erence nes a seen ceean 78
(b) Problem Statement-.---.. ccc cece cence nce ncevvcteuce 78
(c) Background Ca 80
(d) Rationale «----.. Cee ee eee cere ee ee te ete e eee eas 81
(e) Methods and Procedure «-.+-- eee wee e rece a rece neces 85
(£) Significan€e tee eee eee eee eee cece eee eee eect ees 87
(g) Facilities Available -+-- ese cece cece cece eee enaee 87
(h) Collaborative Arrangements ---++-+ eee eee eee eee ees 87
(4) Cell Separator Proj CCE cree ner e enc w errr evar nerves esccas 90
(a) Background «+--+ sees cece cee eee eee ete eee eee eeee 2
(b) Rationale Ca 93
(c) Methods and Procedures + ec c rece ren rene never cucve 94
(d) Significance «+++ eee e cece eee cece cee teen enaes 94
(e) Computer Tnteractions sss escent ener wenn ane ane vrece 94
(5) Average Evoked Potentials and Perception ...... cee eee IT
(a) Problem Statement........0. 0... ccc cece cece ecu ceues 97
(b) Background and Rationale.......... ccc cece ce ccc uee 97
(c) Methods and Procedures ...... seeeae see ncee swe nes 98
(d) Significance co.cc ccc cece nce ccc cece ence eenens 99
(e) Relationship to other work.........ccccceccccccses 100
H. BUDGET 2... ccc ccc ec cece nee e eee ceneeeeeeteeueeneueeeuans 101
1. Detailed Budget for First 12-month Period,,.... cece ne eeeee sees 102
2. Budget Estimates for all years of Support.........ccccecececeees 103
3. Explanation ........ seen eee eee eee ne anace Sasa ee eseenesensecsece 105
I. FUTURE PLANS 1... cece ccc ce ccc nce tence c ences euneteaternees 109
J. APPENDICES...... seme e rence scenes rr eee wer eee ee reat aee 110
1. ACME User Publications..... Bee eee eee eee eee ee eee eee wuss eseesaeun 111
2. Biographical Sketches .......... 0... cece ccc cece cece eee cceecaees 120
FIGURES
E-l ACME Configuration: May 1972 ....... cc cee ee eee sete cece eee 16
E-2 General Characteristics of the Proposed System ,................ 19
E~3 Tentative Initial Machine Configuration for SUMEX............... 22
E-4 Implementation Scheme for Remote Data Channels..... sce w ence eee 25
E-5 Implementation Phasing Plan ..... 0... ccc cece cc cece ccc ncnccrceuce 27
G-1 Elements of Laboratory Instrumentation Data Systems............. 52
G-2 Proposed topology for Central Processor and Peripherals........ 254
G-3 Tentative Initial Machine Configuration for SUMEX............... 56
G-4 Software..... Poe eee mene etme tee eee eet te eee ete e es eneneantesee 57
DENDRAL~1 Realtime Mass Spectrum Interpretation System... . ccc eee 83
DENDRAL-2 Processing Time Interdependence ...........cccccecccerceceaes 84
Cell Separator-1 Simplified Blcok Diagram of Cell Separator.....ees oe IL
(1)
STANFORD UNIVERSITY MEDICAL EXPERIMENTAL COMPUTER RESOURCE
Proposal for a research resource in extension of the ACME project.
SUMEX
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 solutions
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
(la)
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 SUMEX resource, and its
relationship to service-computing at SUMC* are detailed in sub-
Sequent sections.
*(Stanford University Medical Center)
(2)
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,
(3)
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 360/50 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.
(4)
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
TBM/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 SUMEX
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
SUMEX 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
(5)
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-10.
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.
(6)
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. DENDRAL -- 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.
(7)
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 exven-
sive, rotating memories as opposed to smaller, more expensive hardware on
satellite systems.
(8)
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 SUMEX.
(9)
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.
Dean
Rich ree grrttese ee eee
Assoc, Dean : Assoc. Dean
Jgohn : for Research
Wilson : hm. C. Levinthal
i
Executive Committee
. ACME
Dept. Genetics Dept. Dept. Advisory
Heads Dept. Heads Heads Committee
J. Lederberg Collaborative
Chairman P.T. ~ Investigators |
—,, .?
mt |
oo —
—,
—~ | ACME
Project
Kennedy Labs Instrum. UME
for Molecular Research Lab S x
Medicine B.C. Levinthal Project
KEY:
Sees ..e. otaff
Line
~ oot om om tn to be
superseded
(10)
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:
SUMC
Dean and V. P.
Assoc. Dean SUMCCF
Scope of this for SUMC Pk User Group
Freposat Data Processing
— <
XO \ \ \S
SONS ‘ NOS ‘
\ So -
eos ene oem eam ener ner weere eo wesr
SUMCCF
XComputer Research (Computer Services)
. SON,
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 SUMCCF 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.
and use,
(11)
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
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 will label SUMCCF.
SUMEX Facility
I
mall Number of
Collaborators
CURRENT
ACME 360/50 Hospital Data Processing
“ 360/40
Computer Utility Utility
Science Service Users Service
Research Time-Sharing & Users
Users Data Acquisition
PROPOSED
__-——"| Assoc. Dean for SUMC Data Processing
P.I. - SUMEX
SUMC Service Computing Facility
(1 or more hdwe. systems)
| utility Service Users |
|
|
Research
Support
Administrative
Support
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.
secondary gains of that relationship.
2. Operating Procedures and Policies
He will also establish liaison with SUMCCF to maximize the
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.
(12)
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.
£. Management of the enterprise, including the selection of appropriate
projects, will become increasingly difficult as the number of author-~
ized users grows.
&- 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. vuring 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 SUMCCF would enhance
the efficiency of SUMEX personnel. For these reasons, some funds are being
requested to pay for services on the Service Facility.
(13)
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.
(c) 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.
(d) 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.
(e) 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) Medical Service Computing - A stable and reliable comput ing
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.
(b) 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.
(c) 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.
The 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-1l. 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) 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.
(b) 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.
(c) Even with the large core memory available, core limitations
impact performance and accessibility. A more sophisticated
allocation of resources based on swapping and hardware
relocation or on paging is required.
(d) 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.
(e) 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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(23)
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 100K 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 MX10 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/0 bus. For this and
economy reasons the satellite PDP-11 is indicated. The hardware
connection is to the PDP-1l 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-10/11
interface is indicated. This is a powerful but expensive device. It
allows the PDP-1l1 to use segments of PDP-10 core. The segments allotted,
and the interrupt service between computers, is enabled by the PDP-10.
The PDP-10/11 interface also allows up to 8 PDP-11's; 4 are included
in the present configuration. Incremental PDP-1l'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-11/10 capability. The fourth PDP-11l
has been configured as a DEC disc operating system. It can be used as
a facility in a purely DEC fashion toassist other DEC users and the
SUMEX staff in their software and interfacing efforts.
(25)
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(26)
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 function wholely transferred 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.
(27)
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(28)
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
@ 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
(29)
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.
(30)
RESOURCE ACTIVITES
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 (rimarily in the form of a DEC PDP-~10
system with KI-10 processor, 192K words of main memory and }
satellite PDP-1l's connected via a PDP1O/11 interface. See figure
E-3.) for use in computer science related research in biomedicine
and development of new hardware interfaces to users' peripheral
minicomputers.
Development of software support under a core research program and
software support for collaborative research projects.
The resources will provide backup computing facilities for the
Stanford University Medical Center Computer Facility.
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.
2.
a.
(1)
(a)
(1)
(31)
Research
Core Research
Satellite Machine Support
Problem Statement
Limitations of stand-alone small computers. The primary limitations of
existing stand-alone systems are a) the economics of primary and secon-
dary storage 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
2¢ 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-ll costs approximately $3,000 for 4K words or 4.5¢ 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 development even in rather simple applications. Some additional
limitations are as follows:
(a) 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.
(b) The manufacturers tend to scale their system software to the smaller
end of the line.
(c) Owners of small machines lack easy access to one another's data
base because their planning has assumed dedicated use of the hardware.
(d) 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.
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,
(3)
(bd)
(32)
(5) availability of broader line of peripherals,
(6) shared access to common databases, and
(7) more extensive software support from the hardware manufacturer.
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 256K 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.
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 repidly
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 1/10 the cost of the current MOS sy s-
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.
(b)
(33)
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. Schwartz of Stanford University (SLAC)
is developing parallel processing hardware which can be attached
to a PDP-ll 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.
As 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.
(a)
(e)
(g)
(34)
Microprogramming technigues. 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.
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.
High speed remote links. High speed remote links will become
available as conventional communication industry services are
extended. Current networks such as APRANET 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-ll 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
(35)
highspeed communication over a single path and also requires
only one interconnecting wire rather than the number of wires
in a PDP-11 unibus.
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.
(h) 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.
(i) 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 mentioned attempts to 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-1l'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 Unit.
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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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.
(2) 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-1l
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~1l as the primary small system to be
supported under this program is the expectation that the PDP-ll 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-ll are
a) the ability to execute programs in PDP-10 core from a PDP-ll 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
* "C.mmp: The Multiminiprocessor Computer", C. G. Bell, W. Brody, W. Wulf,
and A. Newell, Dept. of Computer Science, Carnegie-Mellon University.
(4)
(37)
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, and processing large 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.
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.
(c)
(1)
(38)
Methods and Procedures
Satellite system software support
(a)
(b)
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-1ll,
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.
High level language support.
(i) 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/11. 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.
(39)
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.
(c) Realtime applications module library. Some of the items expected
to be provided are the following:
(i)
(11)
(i111)
(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.
(d)
(v)
(vi)
(40)
Communications protocol with host computer. User programs
would interface to the communications network via routines
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.
(2)
(41)
Computer to computer communications.
(a) Data transfers,
(i)
(ii)
(iii)
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.
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.
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)
(ii)
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.
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.
(iit)
(42)
Network management. 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
10° to 107 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 edditional 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.
(b)
(43)
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
assurance 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.
Date analysis.
(i) 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.
(4)
(44)
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 611 storage tube displays.
c) Calecomp and Houston incremental plotters.
a) 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
(45)
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.
(46)
(d) Significance 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.
(47)
(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.) ;
(48)
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.
(49)
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
Realtime 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 forward. 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.
(50)
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 such as bubble chamber 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.
(51)
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 G-1 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
(52)
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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 G-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 ,
(54)
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however, before this will be possible. The initial complement of
collaborative problems includes:
1. Harrison, et al.: Cineangiogram Analysis Automation.
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-10/PDP-1l 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
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(56)
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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.
10.
ll.
12.
13.
14.
15.
(59)
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Crouse, L. and G. Wiederhold, "An Advanced Computer System for Real-Time
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Henry, W., L. Crouse, R. Stenson, and D. Harrison, "Computer Analysis of
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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.
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.
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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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.
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Quan, L.H., R. Tucker, S. Liebes, M. Hannah, and B. G. Eross, "Computer Inter-
active Picture Processing", Stanford Artificial Intelligence
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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",
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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
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(62)
(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. Their software 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:
(a)
(b)
(c)
(d)
(63)
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.
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.
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).
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:
Ww ON nO EWN Pe
10.
System Function Man-Months
Statistical programs 2 mm
PL compiler 12
Error messages/processing 1
Execution time excluding 1/0 6
File System 6
Run time I/O and text editing 6
LISP compiler 0
Miscellaneous 1
SYSI. FORTLIB (FORTRAN library) 1
Plotting routines 2
Core management 1
Realtime support (configuration dependent) 3
System control 3
Terminal handling 1
Assembly utility 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.
17.
18.
System education (4-5 people @ 1.5 mo/person) 7 mm
Conversion planning 12 mm
User file conversion aids 4 mm
Sub Total: 23 mm
Grand Total 69 mm
(64)
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.
b.
(1)
(65)
Collaborative Research and Development
(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 catheteri-
zation and specific angiographic procedures must be performed. Data which are
obtained from these complex procedures are in many instances tnadequate 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 (1~4). 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 (1-3).
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
(b)
(66)
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 presenceof 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 sepmental 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, pressure 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
(c)
(67)
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.
(a)
(68)
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.
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.
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 and sophisticated
computer installations.
It is with these rationales in mind that the Cardiology Division desires to
participate in the development of the research computer facility at Stanford.
Methods and Procedures
Several specific procedures to improve definition and provide quantitation of
cardiac function are planned.
l.
X-ray Image Processing - New image processing techniques will be developed.
The
are:
a.
goals and methods for accomplishing this particular research project
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/sec. 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.
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.
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.
(69)
ad. Segmental analysis of various portions of the heart wall motion will be
possible using these computer techniques.
€. 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.
(70)
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 drug 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 evaiuate 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.
(71)
f. Relationships
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.
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.
(72)
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. 31).
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.
(73)
REFERENCES
1.
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.
2)
(a)
(74)
Digital Computer Processing of Cineurographic Images of the Urinary
Tract. - prepared by C. Constantinou and T. Stamey
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 same 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-ray 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.
(bd)
(c)
(75)
>. 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.
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 ealyceal
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 cine 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 cine fluoroscopic studies. The fact still
remains that this form of evaluation remains a visualization 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 cine should be sought and coded.
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
(a)
(76)
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.
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
(e)
(f)
(77)
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.
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.
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 parameters 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.
(78)
(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 requirements 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
(79)
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 10° samples of data collected every 5 to 10 seconds. Out of the
possible ensemble of 108 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 possibili-
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.
(80)
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.
DENDRAL 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 (7i). This program has also demonstrated
its ability to identify the components present in laboratory-made mixtures
of estrogens. At the present time work is progressing with crude estro-
genic 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 DENDRAL 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 DENDRAL 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
(81)
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 spectrum.
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 DENDRAL spectrum interpre-
(82)
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 ~1 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) 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.
(2) Reliable and fast methods must be developed for detecting and resol-
ving overlapping peaks in the gas chromatograph and mass spectro-
meter sensor outputs.
(3) The quality of extracted information must be evaluated based on
instrument performance parameters and ion statistics.
(4) 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.
(5) 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.
(6) 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.
(83)
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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 DENDRAL 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-10/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-
tion 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~10/satellite extended realtime system affording required
response without total commitment of the PDP-10 system.
(87)
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
@ spectrum predictor and the analytical capabilities of Heuristic DENDRAL
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.
Facilities Available. The research in this proposal will draw heavily
upon the PDP-10/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.
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.
(88)
REFERENCES
1. For pertinent reviews see: C. G. Hammar, B. Holmstedt, J. E. Lindgren
and R. Tham, Advan. Pharma Col. Chemother., 7, 53, (1969); J. A. Vollmin
and M. Muller, Enzymol. Biol. Clin., 10 , 458 (1969)
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H. J. Forster, H. S. Hertz, C. E. Hignite, R. C. Murphy, G. Petrie and
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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
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(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, O and N.
J. Am. Chem. Soc., 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. Soc., 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. Soc., 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. Soc., 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 CoH, 90:
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7g.
7h.
7i.
(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
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
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.
Applications of Artificial Intelligence forChemical Inference. VIII.
An Approach to the Computer Interpretation of the High Resolution Mass
Spectra of Complex Molecules. Structure Elucidation of Estrogenic Steroids.
J. Amer. Chem. Soc.,
By D. H. Smith, B. G. Buchanan, R. S. Englemore, A. M. Duffield,
A. Yeo, E. A. Feigenbaum, J. Lederberg and C. Djerassi
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.
D. H. Smith, A. M. Duffield - dC. Djerassi, Org. Mass Spectrom.,
Submitted for publication.
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
ULTRASONIC
TRANSDUCER
, PULSE
an SIGNAL w—IANALYZER &
ELECTRONICS COUNTER
| CHARGING
ni PULSE
PHOTODETECTOR
CELL
COLLECTOR
Figure Cell Separator-l1
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. ("Hemolab 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.
(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 behind 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.
CELL SEPARATOR LINC COMPUTER
OPERATOR@ — — — — —— J
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
Operator}- -~—| Display
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.,
1970b). 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.
(b) 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.,
1972). 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 EEG 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 analysis 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-10/12 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/0O capability of 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 4:1 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)
(a) 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-
chological changes 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.
(101)
BUDGET
1. Detailed Budget for First 12-Month Period
2. Budget Estimates for All Years of Support
3. Explanation
(102)
SECTION I — PRIVILEGED COMMUNICATION
FROM THROUGH
DETAILED BUDGET FOR FIRST 12-MONTH PERIOD 8-1 - 73 T- 31 - 74
DESCRIPTION (/temize) time on AMOUNT REQUESTED (Omit cents}
PERSONNEL “cMRS. | SALARY FRINGE TOTAL
NAME TITLE OF POSITION BENEFITS
Joshua Lederberg PRINCIPAL INVESTIGATOR LO 0 0 0
Edward Feigenbaum Associate Investigator 10 0 0 0
Thomas Rindfleisch SUMEX Facility Head 100
Ron Jamtgaard 50 (Details|of Salary [Budget
Gio Wiederhold 90 are submitted in qa separate
Lee Hundley 100 letter)
9 - Systems Programmers 900
il - Applied Mathematician 100
2 - Engineers 200
3 ~ Technicians 300
3 - Operations Staff 300
1 - Secretary 100
1 - Administrative Aide 100
e - Grad. Student RA.’s plps summer help 100
Total (24.(FTE) 375,000 63,750 438,750
CONSULTANT COSTS 2,500
EQUIPMENT.__Lease of PDP-10 System (Purchase Price--$1,744,750 less 10% assumed
Educational discount plus 5% Calif. Use Tax times DEC lease factor of 2.2% per
435 300%
month=$36,275/month plus miscellaneous features on hardware to be leased. 700
: Purchase graphics station--$8,000; small machine equipment peripherals
$26,000; communications hardware--$6, 000. 40,0005
suppiies Office Supplies 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
Engineering Supplies 15,000 15,000
Postage & Freight 2,500 2,500
DOMESTIC 5 East, 5 Midwest, 6 West Coast 4,400
TRAVEL
FOREIGN
PATIENT COSTS (See instructions}
ALTERATIONS AND RENOVATIONS
Air conditioning, false flooring, etc., needed for hardware installation. 45,000
OTHER EXPENSES (/temize) Computer service from SUMCCF 24,000
Maintenance: For PDP-10 System--$84,600; for service contracts on
aphics ripherals communications hardware-~$9 400. 94.000
Communications Costs (Transmission lines and modems) 12,000
—__Staff Treining 2,000
TOTAL DIRECT COST (Enter on Page 1, item 5) > 1,137,850
INDIRECT « sen DATE OF DHEW AGREEMENT: [J] walveo
cost _ . {_] UNDER NEGOTIATION WITH:
(See Instructions) —Hh __wtoc* d 4
*IF THIS 1S A SPECIAL RATE (e.g. off-site), SO INDICATE,
PHS 398
Ba: 2.70
SECTION Il — PRIVILEGED COMMUNICATION
(103)
BUDGET ESTIMATES FOR ALL YEARS OF SUPPORT REQUESTED FROM PUBLIC HEALTH SERVICE
DIRECT COSTS ONLY (Omit Cents)
1ST PERIOD
ADDITIONAL YEARS SUPPORT REQUESTED (This application only)
DESCRIPTION (SAME AS DE-
TAILED BUOGET) 2ND YEAR 3RD YEAR 4TH YEAR 5TH YEAR 6TH YEAR 7TH YEAR
coere et 438,750 | 464,630 | 491,990 | 520,930 | 551,530
CONSULTANT COSTS
(Include fees, travel, etc.) 2,500 25900 2,900 2500 2,200
Lease 436,000 | 436,000 | 436,000 | 436,000 | 436,000
EQUIPMENT Maint. 94,000 | 94,000 | 160,000 | 160,000 | 160,000
Purchase 40,000 | 40,000 54,000 | 64,000 64,000
suppiggemunications 12,000} 16,000 16,000 | 18,000 18,000
Supplies 39,200 |] 40,000 41,000 | 42,000 43,000
DOMESTIC 4,400 4400 4,000 4,200 4,200
TRAVEL
FOREIGN
PATIENT COSTS
ALTERATIONS AND
RENOVATIONS 45,000 --= = -~- -——
Computer Services 24,000 | 24,000 24,000 | 24,000 24,000
E
OTHER EXPENSES
Training 2,000 1,000 1,000 1,000 1,000
b
TOTAL FOR ENTIRE PROPOSED PROJECT PERIOD (Enter on Page 1, !tem 4)
$ 6,007 ,730
REMARKS: Justify aif costs for the first year for which the need may not be obvious. For future years, justify equipment costs, as well as any
significant increases 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.
and 1% per year greater in each subsequent year.
Staff benefits are 17% in Year 1
3. Alteration and renovation funds of $45,000 are requested for air conditioning and
false floors needed for hardware installation.
4, The PDP-1O maintenance contract will be changed from 12 hours, 5 days per week to
24 hours, 7 days per week in Year 3.
needed by the Service System, and
~versa,.
This will provide the backup capability
PHS-398
Rav. 32-70
(104)
BUDGET ESTIMATES FOR PDP-10 SYSTEM:
Purchase
Price
Central Processor $ 380,000
KI-10 incl. Operator's Console
Memory System 400,000
8 x MEO, 8 x 16k words
Auxillary Memory System 225,000
4 x ME1O and DTOLC
Keyboard Terminals(16) 48,000
Hardcopy & CET, to be selected (16x 3K)
Memory Bus Swapping Drum System 83,000
RM1LO B & Controller
Memory Bus Dise System 150,000
4 x RPO3 Dise & Controller
Input/Output Bus Peripheral System 64,850
Tape Systems, 3 x TU1O, (9x7 track)
& 1 DEC TU56 & Controllers
Asynchronous Communication System 37,500
DC1O System for Keyboard Terminals
Monthly Maint.
(2hrs 5 days)
$ 525
1,336
78%
320
265
826
338
110 (A)
SATELLITE COMPUTERS; Includes intercomputer communications and --
Multiplexed Memory System
PDP 11/45 #1: 8K 74 ,050*
#2: 4K 16,450
#3: 4K 16,450
#4: 8K (incl. RK11 and RF11 Disc, 56,450
& PC1ll Punch and tape)
10/11 Interface 70,000
MX1O Memory Multiplexor 4,500
Peripherals 118,000
LP1LOC Line Printer, CPLOA, CR1OD Card
Punch & Reader
Sub Totals 1,744,250
Assume 10% Educational Discount - 174 425
Net 1,569,825
Options:
1) Memory System(4 x ME10) 200,000
2) Terminal Communications(DP11DA's & DP11DC's) 7,900
3) Syne Communications System(DC-75) 50,000
257 5900
(Incl. Option 1) TOTAL $ 1,769,325
a) Added to A above.
b) Deletes $7,400 of B above.
547* (B)
195
195
LE4#
500*
15*
6o*
6,896
(Not including sales tax)
668 ’
115 3
250 b)
1,033
(Not incl. sales tax)
(105)
3. Explanation
a. Major Assumptions
The five-year budget request has been prepared with the following major
assumptions:
(1)
(2)
(5)
(6)
(7)
(8)
SUMEX will include a PDP-10 KI-10 Processor with 192K words of core
plus four PDP-1l 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. ») man-years will be devoted to the transition of a PL-type language
(2)
(3)
(106)
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.
Staff Benefits: The standard rate for the University's FY1974
is 17%.
Training, Consulting, Travel, and Publications: The training bud-
get of $2,000 will be used to make the staff better acquainted
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, and 6 on the west coase ($3,200
+ 900 + 400 = $4,400). The travel funds will be used to ex-
change information with other research centers, attend training
sessions, disseminate information, and investigate possible
network participation.
(4)
(5)
(6)
(107)
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
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 DENDRAL 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 40Okb
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.
Equipment 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.
(7)
(8).
(9)
(108)
Maintenance of Equipment: The primary hardware maintenance contract
will be with DEC. Using DEC's standard 5-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 SUMEX. 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.
Other 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.
(109)
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.
(110)
J. APPENDICES
1. ACME User Publications
2. Biographical Sketches
(111)
ACME Note APUB-9
Erica Baxter
Papers Written By ACME Users February 23, 1972
This list contains papers voluntarily reported to ACME.
Balikian, H., A. Brodie, S. Willoughby, A. Dowdy, G. Nokes, M. Weinberger, 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 Community," presented at the 28th Annual
Meeting of the Society for Applied Anthropology, Mexico City, Mexico, Apr. 1969.
Beatrice, E., 1. Harding-Barlow, and D. Glick, "Electric Spark Cross-Excitation in
Laser Microprobe-Emmission Spectroscopy for Samples of 10-25 Micron Diameter,"
APPLIED SPECTROSCOPY, vol. 23, pp. 257-259, 1969.
Beatrice, E. and D. Glick, "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 Microspectroscopic
Elemental Analysis," ANAL. CHEM., vol. 40, pp. 1178-1182, 1968.
Becker, J., Y.T. Thathachari, P.G. Simpson, “Molecular Conformation of
L-DOPA," BIOCHEM. BIOPHYS. RES. COMM., Vol. 41, pp. 444-449, 1970.
Beliville, J., J. Green, and W. Forrest, dJr., "Respiratory Effects of
Etomide and Codeine," CLIN. PHARM. THERAP., vol. 9, pp. 142-151, 1968.
Bellville, J. and W. Forrest Jr., “Respiratory and Subjective Effects of
d and 1 Pentazocine,” CLIN. PHARM. THERAP., vol. 9, pp. 142-151, 1968.
Bellville, J. and J. Seed, "A Comparison of the Respiratory Effects of
Dextropropoxyphene and Codeine in Man," CLIN. PHARM. THERAP., vol. 9,
pp. 428-434, 1968.
Bellville, J., W. Forrest, Jr., J. Stevens, and E. Beer, "The Hypnotic Effects
of Ethchlorvynol and Secobarbital in Man," CLIN. PHARM. THERAP., vol. 9,
pp. 625-530, 1968.
Bellville, J., L. Escarraga, S. Wallenstein, and R. Houd,
"The Respiratory Effects of Codeine and Morphine in Man,” CLIN. PHARM.
THERAP., vol. 9, pp. 435-441, 1968.
Bellville, J., G. Fleischit, and J. Defares, "A New Method of Study
Regulation of Respiration--The Response to Sinusoidally Varying C02
Inhalation,“ COMPUTERS FOR BIOMEDICAL RESEARCH, vol. 2, no. 4, pp. 329-349,
June 1969.
Bellville, J., G. Fleischl1, and G. Attura, "Servo Control of Inhaled Carbon
Dioxide," J. APPL. PHYSIOL., vol. 24, pp. 414-415, 1968.
Bernffeld, M. and P. Maenpaa, "Quantitative Variation in Serine Transfer
Ribonucleic Actd during Estrogen-Induced Phosphoprotein Synthesis in Rooster
Liver,” BIOCHEMISTRY, vol. 8, pp. 4926-4935, 1969.
Bernfield, M., "Chromatographic Properties 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 Orift," 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 Incompatibility, Reproductive Compensation,
and Heterozygote Advantage," AMER. J. HUMAN GENETICS, vol. 21, no. 2,
pp. 171-193, Mar. 1969.
Bodmer, W., J. Bodmer, D. Ihde, and S. Adler, "Genetic and Serological Associa-
tion Analysis of the HL-A Leukocyte System," COMPUTER APPLICATIONS IN GENETICS
(ed. N. Morton), Univ. Hawaif Press, pp. 117-127, 1969.
(112)
APUB-9
Page 2
Bodmer, W., V. Miggiano, and M. Nabholz, "Hybrids between Human Leukocytes and
a Mouse Cell Line: Production and Characterfzation," 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 Babinga 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 £. 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, duly 1970.
Bodmer, W., P. Mattiuz, D. 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/1," IFIP68 CONGRESS PROCEEDINGS, Edinburgh, Scotland, Aug. 1968.
Brown, B. and L. Soyka, “Survey of Drugs Administered to Nine-Hundred Hospitalized
Children: I. Relation to Age, Sex, and Diagnostic Category," submitted to JAMA,
Mar. 1970.
Bussien, R, "L‘informatique medicale aux Etats-Unis, MEDECINE et
HYGIENE, Nov 1970
MeCalvert, J. Lee and John H. Frenster, "Economics of Effectiveness and
Efficiency in Patient Care," CLINICAL RESEARCH, vol. 19 >» P. 501 , 1971
(abstract).
MCalvert, J. Lee and John H. Frenster, "Economics of Investment in Biomedical
fenearac ne Current Patient Care," CLINICAL RESEARCH, vol. 19, p. 499, 1971
abstract).
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 vivo,” J. MOL, BIOL., vol. 37, pp. 387-406, 1968.
Cohen, S. and C. Miller, "Multiple Molecular Species of Circular R-Factor DNA
Isolated from Escherichia coli,” 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
Escherichia coli,” J. MOL. BIOL., 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. CHEM., vol. 244,
pp. 1869-1877, Apr. 1969.
Collins, R., M. Weinberger, C. Gonzales, G. Nokes, and J. Luetscher,
"Catecholamine Excretion in Low Renin 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.
(113)
APUBS9
Page 3
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.
Constantinou, C., J. Sands, and D. Govan, "Computer Monitoring and Contro}
Instrumentation tn Urology Research,” PROCEEDINGS OF THE 6TH ANNUAL
BIOENGINEERING SYMPOSIUM, Fort Collins, Colo., May 1971.
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.
Crouse, L. and G. Wiederhold, “Interactive Use of Timesharing System for Medical
Laboratory Support," presented at the San Diego Biomedical Symposium,
San Diego, Calif., Apr. 1970.
Crouse, L., R. Stenson, W. Henry, and 0. Harrison, "A Time Shared Digital
Computer System for On-Line Analysis of Cardiac Catheterization Data,“
COMPUTERS AND BIOMEDICAL RESEARCH, vol. 1, no. 6, p. 605, Academic Press,
Inc., June 1968,
Doering, C., "Cholesterol Side Chain Cleavage Activity in the Adrenal Gland of
the Young Rat: Development and Responsiveness to Adrenocorticotropic Hormone,”
ENDOCRINOLOGY, vol. 85, pp. 500-511, 1969.
Doering, C., "A Microassay for the Enzymatic Cleavage of the Cholestero] Side
Chain," METHODS IN ENZYMOLOGY, (ed. R. Clayton), vol. 15, pp. 591-596,
Academic Press, 1969.
Dong, £., 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,
Englund, P., J. Huberman, T. Jovin, and A. Kornberg, “Enzymatic Synthesis of
Deoxyribonucleic Acid, XXX. Binding of Triphosphates to DNA Polymerase," submitted
to J. BIOL. CHEM., vol. 244, pp. 3038-3044, 1969.
Farber, E. and R. McClintock, Jr., "A Current Review of
Psoriasis," MEDICAL PROGRESS, vol. 108, pp. 440-457, June 1968.
Farber, E. and A. Cox, "The Biology of Psoriasis,” J. OF
INVESTIGATIVE DERMATOLOGY, vol. 49, no. 4, pp. 348-357, 1967.
Farber, E., R. Bright, and M. Nall, "Psoriasis -
A Questionnaire Survey of 2,144 Patients," ARCH. DERM., vol. 98, pp. 248-259,
Sept. 1968.
Forrest, W., Jr. and J. Bellville, "The Use of Computers in Clinical Trials,"
BRIT. J. ANESTH., vol. 39, pp. 311-319, 1967.
Forrest, W., dr. and J. Bellville, "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
Assoctation in Pittsburgh, Pa., Aug. 1968.
Fried, M. and K. Vosti, "The Importance of Underlying Disease fn Patients with
Gram-Negative Bacteremia," 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.
*H 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.
Gersch, W. and E. Dong, Jr., “A Note on Warner's Vagus Heart Rate Control
Model," CIRCULATION RESEARCH, 1970.
Gersch, W., D. Eddy, and E. Dong, Ur., "Cardiac Arrhythmia Classification:
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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APUR-*)
Page i
Glick, D. “Cytochemical Analysis by Laser Microprobe-Emission Spectroscopy,"
ANNALS N. ¥. ACAD. SCI., vol. 157, pp. 265-274, 1969.
a& Glick, D., "Cytochemical Analysis by Laser Microprobe ~ Emission Spectroscopy,”
RECENT ADVANCES IN QUANTITATIVE HISTO- AND CYTOCHEMISTRY, pp. 192-193, 1971.
& Glick, 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.
Glick, D., K. Marich, P. Carr, and £. 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-Thiocarbony] Ester Derivatives," TETRAHEDRON LETTERS, vol. 27,
p. 3119, 1968.
Harman, 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 Community 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 Myocardtal Infarction,"
CIRCULATION, vol. 28, Nov. 1968.
Harrison, D., M. Flamm, and &. Hancock, “Muscular Subaortic Stenosis: Preven-
tion of Outflow Obstruction with Propranolol," CIRCULATION, vol. 28, p. 846, 1968.
Harrison, 0., R. Gianelly, W. Angell, E. Stinson, and N. Shumway, “Homograft
Replacement of the Mitral Valve,” CIRCULATION, vol. 28, p. 664, 1968.
Harrison, D., &. Stinson, E. dong. Jr., and J. Schroeder, “Initial Clinical
Experience with Heart Transplantation,” AMER. J. OF CARDIOL., vol. 22,
p. 791, 1968.
Harrison, D., M. Robinson, and R. Kleiger, "The Role of Hypoxia in Digitalis
Toxicity," AMER. J. MED. SCI., vol. 256, p. 352, 1968.
Harrison, D. and R. Gianelly, "Studies on the Antiarrhythmic and Circulatory Ac-
tions of Lidocaine (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, “Orugs Used in the Treatment of Cardiac
Arrhythmias," DISEASE-A-MONTH, Jan. 1969.
Harrison, D., M. Klughaupt, M. Flamm, and £. 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, 0., 8. Treister, R. Gianelly, and R. Cohn, "The Circulatory Effects of
Isoproterenol, Acetylstrophanthidin and Volume Loading in Acute Pericardial
Tamponade," CARDIOVASC. RES., vol. 3, p. 299, 1969.
Harrison, D. and M. Pertroth, "Cardiogenic Shock: A Review,” CLIN. PHARMACOL.
AND THERAPEUT., vol. 10, p. 449, 1969.
Harrfson, D., R. Gtanelly, and B. Treister, "The Effect of Propranolol on Exercise-
Induced Ischemtc ST egment Depression," AMER. J. CARDIOL., vol. 24, p. 161, 1969.
Harrison, D., d. 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., B. Wintroub, J. Schroeder, M. Schroll, and S. Robison, "The Hemo-
dynamic Response to Dopamine in Experimental Myocardial Infarction,” AMER. J.
PHYSIOL., vol. 217, pp. 1716-1720, Dec. 1969.
Harrison, D., B. 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 Atrial Septal Defect," AMER. HEART J., Vol. 80, p.575, 1970.
Harrison, D., R. Stenson, W. Henry, and L. Crouse, "Analysis of Hemodynamic Data
from Cardiac Catheterization with a Digital Computer," OPTICS TECHN. REVIEW, 1969,
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.
Hillman, R., “The Teaching of Psychotherapy Problems by Computer," to be
presented at the American Psychiatric Association Convention, San Francisco,
Calif., May 1970.
Hillman, R., “The Teaching of Psychotherapy Problems by Computer," ARCHIVES
OF GENERAL PSYCHIATRY, in press.
Hodgson, G., E. Petterson, K. Kvenvolden, E. Bunnenberg, B. Halpern, and C. Ponnam-
peruma, "Search for Porphyrins in Lunar Dust,” SCIENCE, vol. 167, pp. 763-765,
Jan, 1970.° .
Huberman, J. and A. Kornberg, “Enzymatic Synthests of Deoxyribonucleic Acid, XXXV.
A 3 -Hydroxy] ribonucleotide Binding Site of Escherichia colf Deoxyribonucleic Acid
Polymerase," J. BIOL. CHEM., Vol. 245, p. 5326, 1970.
Ingels, N., S. Rush, and N. Thompson, "Analytic Stop Motion Stereo Photogrammetry,"
THE REVIEW OF SCIENTIFIC INSTRUMENTS, vol. 40, no. 3, pp. 487-492, Mar. 1969.
Kakthana, R., J. Butte, and E. Noble, "Effects of Goldthioglucose on Alcohol
Consumption in CS7BL 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, Pp. 360, 1968.
Kessler, S., “Speed of Mating and Sexual Isolation in Drosophila," NATURE,
vol. 220, pp. 1044-1045, 1968.
Kessler, S., "The Genetics of Drosophila Mating Behavior I - Organizations of
Mating Speed in Drosophila pseudoobscura," AN. BEHAV., vol. 16, pp. 485-491, 1968.
Kessler, S., "The Genetics of Drosophila Mating 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
silogreft Recipfents by Leukocyte and Kidney Cell Phenotyping," presented at
the 31st Annual Meeting of the Society of University Surgeons, Pittsburgh,
Pennsylvania, Feb. 1970.
Kriss, J., 8. Kountz, S. Yeh, J. Wood, and R. Cohn, "99m 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,"
ADVANCES IN METABOLIC DISORDERS, (eds. K. Levine and R. Luft), vol. 3, pp. 209-
230, 1968.
Kriss, 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.
Kriss, J., T. Mori, and J. Fisher, "Studies of an in vitro Binding Reaction
between Thyroid Microsomes and Long-Acting Thyroid Stimulator Globulin (LATS):
1. Development of Solid-State Competitive Binding Radioassay Methods for
Measurement of Anti-Microsomal and Anti-Thyroglobulin Antibodies, "
J. CLIN. ENDOCR. AND METAB., 1970.
Kriss, J. and S. McHardy-Young, "Simplified Technique for the Radioimmunoassay
of Human TSH," J. NUCLEAR MED., vol. 10, p. 356, 1969, (abstract).
Kriss, J., S. McHardy-Young, and H. Kaplan, “Serum Tsh Levels Following Megavol tage
Radiotherapy for Hodgkin's Disease," PROGRAM, 45TH AMERICAN THYROID ASSOCIATION,
Pp. 83, July 1969, (abstract).
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APUB-9
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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)
rs feces 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 Lymphoma," CLINICAL RESEARCH,
vol. 18, p. 168, 1970, (abstract).
Kriss, J. and T. Mori, "Rapid Competitive Binding Radioassay of Serum Anti-
Microsomal and Anti-Thyroglobulin Antibodies: Measurements in Graves' Disease,"
CLINICAL RESEARCH, vol. 18, p. 170, 1970, (abstract).
Kriss, J. and T. Mori, “Rapid Competitive Binding Radioassay of Serum Anti-
Microsomal 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 Carbamy]l Phosphate to Hydroxyurea:
An Assay for Carbamy? Phosphate Synthetase, " ANALYTICAL BIOCHEMISTRY, vol. 42,
no. 2, pp. 324-337, August 1971.
3k 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.
je Levine, R., N. Hoogenroad, and N. Kretchmer, “Regulation of Activity of Carbamoy]
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.
Luzzatti, L., R. Greenstein, D. Harris, and H. Cann, “Cytogenetic Analysis of a
Boy with the XXXY¥ Syndrome: Origin of the X-Chromosomes,” PEDIATRICS, Apr. 1970.
Luzzatti, L. and H. Pryor, "Body Proportions and Dermatoglyphic Patterns in
Children with Cleft Lip and/or Palate," submitted to PEDIATRICS.
Luzzatti, 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, S., Jr., JT. Weisshaar, 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,
Loulsfana, Apr. 1969.
Marich, K., Carr, P., Treyt], 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.£., 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 Intoxfcation,” ARCH GEN
PSYCHIAT., Vol. 23, pp. 204-210, 1970.
Melges, F.1., Anderson, R.E., Kraemer, H.C., Tinklenberg, J.R., and Weisz, A.E.,
THE PERSONAL FUTURE AND SELF-ESTEEM, in press.
Mesel, &., "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 Septal Defects," J. APPLIED PHYSIOL., Vol. 28, No. 3, March 1970.
(117)
APUB+9
Page 7
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.
Morris, 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., S. 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.
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Forms of Aspartate Transcarbamylase in Rat Liver," BIOCHEM. BIOPHYS.
RSCH. COMMUN., vol. 37, pp. 505-511, 1969.
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a Cooperative Study," presented at the 31st Annual meeting of the Committee
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 Sensitivity 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 Committee E-14),
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, —. 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 Waller), 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, 0. Cummins, J. Flexer, K. Holtz, J. Miller,
and G. Wiederhold, “An Advanced Computer System for Medical Research,"
AFIPS CONFERENCE PROCEEDINGS, vol. 31, 1967.
Sanders, W.J. and A. Silvers, "Digital On-Line Computer Display to
Investigate the Structure of Metabolic Systems," COMPUTERS AND BIOMED.
RES., Vol. 3, pp. 133-145, April 1970.
Schneiderman, L., W. Sampson, W. Schoene, and G. Haydon, "Genetic Studies of a
Family with Two Autosocial Dominant Conditions," AM. J. MED., vol. 46, p. 380,
1969.
Schneiderman, L., L. DeSalvo, S. Baylor, and P. Wolf, "The ‘Abnormal’ Screening
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1970, (abstract).
(118)
APUB-9
Page 8
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., "Discussion 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 Communication 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 Immunity,”
NATURE, vol. 220, p. 821, Nov. 1968.
Solomon, G., "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,” AM. J. CARDIOLOGY, vol. 22, no. 5, pp. 696-705,
Nov. 1968.
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. Coste], and D. Cummins, "Computer Administered Psychiatric
Inventory," 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,
Apri? 1971,
Thathachari, Y., “X-Ray Diffraction Studies on Melanins,” PROCEEDINGS OF THE
VII INTERNATIONAL PIGMENT CELL CONFERENCE, Seattle, Wash., 1969.
Thathachari, Y. and M. Blots, "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 Biophysical 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 Mammals, sponsored by the International Union of
Biological Science, July 1969.
Thoman, £., S. Levine, and R. Conner, “Lactation Suppresses Adrenal
Conticosteroid Activity and Aggressiveness in Rats," J. COMP. PHYSIOL. PSYCHOL.,
Vol. 3, pp. 364-369, 1970.
Thoman, E., A. Turner, P. Leiderman, and C. Barnett, "Neonate-Mother Interaction:
Effects of Parity on Feeding Behavior,” CHILD DEVELOPMENT, Vol. 40, pp. 1103-1111, 1970.
Thoman, E., and S. 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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APUB-9
Page 9
Thoman, E. and A. Korner, "Effects of Vestibular Stimulation on Behavior ana
Development in Infant Rats," DEVELOPMENTAL PSYCHOLOGY, in press.
Tinklenberg, J.R., Melges, F.T., Hollister, L.E., and H.K. Gillespie,
"Marthuana and Immediate Memory,” NATURE, Vol. 226, pp. 1171-1172, 1970.
Weinberger, M., R. Collins, A. Dowdy, G. Nokes, and J. Luetscher, "Hypertension
Induced by Oral Contraceptive Containing Estrogen and Gestagen - Effects on
Plasma Renin Activity and Aldosterone Excretion,” ANN. INTERN. MED,, vol. 71,
p. 891, 1969.
Weinberger, M., A. Dowdy, G. Nokes, and J. Luetscher, “Stimulation of
Plasmas Renin Activity without Increased Aldosterone Production after
Administration of Chlorothtazide to Hypertensive Patients," J. CLIN. INVEST.,
vol. 46, p. 1130, 1967.
Weinberger, M., A. Dowdy, G. Nokes, and J. Luetscher, "Plasma Renin
Activity and Aldosterone Secretion in Hypertensive Patients during High
and Low Sodium Intake and Administration of Diuretic," J. CLIN. ENDOCR.,
vol. 28, p. 359, 1968.
Weinberger, M., A. Dowdy, G. Nokes, and J. Luetscher, "Reversible
Increases in Plasma Renin Activity, Aldosterone Secretion and Blood
Pressure in Women Taking Oral Contraceptive Preparations," CLIN. RES.,
vol. 16, p. 150, 1968.
Westley, J. and B. Halpern, "The Use of (-)Menthyl Chloroformate in the
Optical Analysis of Asymmetric Amino and Hydroxy? Compounds by Gas
Chromatography," J. ORG. CHEM., vol. 33, p. 3978, 1968.
Westley, J., V. Close, D. Nitecki, 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 Summary of the ACME System," PROCEEDINGS OF THE ONR
COMPUTER AND PSYCHOBIOLOGY CONFERENCE, Monterey, Calif., May 1966.
Wiederhold, G., "A Summary 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 COMPUTERS
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.
Wiederhold, G., "An Advanced Computer System for Medica] Research,"
PROCEEDINGS OF THE IBM JAPAN COMPUTER SCIENCE SYMPOSIUM -- RESEARCH
AND DEVELOPMENT AND COMPUTER SYSTEMS, Tokyo, Japan, pp. B1-B15, Nov. 1969.
Wiederhold, G., "Setting Up a General-Purpose Data~Acquisition System,”
PROCEEDINGS OF THE I8M SCIENTIFIC COMPUTING SYMPOSIUM ON COMPUTERS
IN CHEMISTRY, Data Processing Division, White Plains, New York,
pp. 249-264, Aug. 1969.
Wiederhold, 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 (lst ed.), Sept. 1968 (2nd ed.).
Wolf, P., T. Durbridge, and D. Enlander, “An Evaluation of SNOP Coding of Pathologic
Data for Computer Retrieval," LABORATORY MEDICINE - THE BULLETIN OF PATHOLOGY,
pp. 400-401, Dec. 1969.
* New Iintry Since Last APUB.
Revision of APUB-8 dated August 12, 1971
Diet: Stelf/AlL
HLL ED Aas (120)
BIOGRAPHICAL SKETCH
(Give the following information for all protessioral personnel listed on page 3, beginning with the Principal Investigator.
Use continuation pages and follaw the same genera/ format for each person. |
NAMS TITLE BIRTHDATE (Ma, Day, Yr.)
Professor and Executive Head,
LEDERBERG, JOSHUA Department of Genetics 5-23-25
PLACE OF BIRTH (City, State, Country) PRESENT NATIONALITY (/f non-US citizen, SEX
: indicate kind of visa and expiration date)
Montclair, New Jersey U.S.A. CiMate _T] Female
EDUCATION (8egin with baccalaureate training and include postdoctoral)
YEAR SCIENTIFIC
INSTITUTION AND LOCATION DEGREE CONFERRED FIELD
Columbia College, New York B.A. 1944
College of Physicians & Surgeons,
Columbia University, New York (1944-46)
Yale University Ph.D. 194] Microbiology
HONORS
1957 - National Academy of Sciences
1958 - Nobel Prize in Medicine
MAJOR RESEARCH INTEREST : ROLE iN PROPOSED PROJECT
Molecular
Genetics; Artificial Intelligenc PRINCIPAL INVESTIGATOR
RESEARCH SUPPORT (See instructions)
SEE ATTACHMENTS:
RESEARCH AND/OR PROFESSIONAL E XPERIENCE (Starting with present position, list training and experience relevant to araa of project List all
or most representative publications, Oo not exceed 3 pages for each individual.)
1961-
1959-
Stanford University
Director, Kennedy Laboratories for Molecular Medicine
Professor, Genetics and Biology, and Executive Head, Department of
Genetics, Stanford University
1957-1959 University of Wisconsin
1957
1950
Chairman, Department of Medical Genetics
Melbourne University, Australia
Fullbright Visiting Professor of Bacteriology
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)
RHS-398
Rev. 3-70
81.
182.
186.
192.
194,
(121)
LIST OF PUBLICATIONS
Lederberg, J., 1959
A View of Genetics.
Les Prix Nobel en 1958: 170-89.
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.
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. 165-190.
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.
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 Projects: Ff
JPL Contract Extended Mission of 9/1/69 - 6/30/72 $185,000 16%
952489 Mariner Mars
NASA Viking Biology Team -6/30/72 $ 9,608
NAS-19692
NIH RRO311 Advanced Computer for 1966 - 7/31/73 $ 25%
Med. Research
NIH Genetics of Bacteria 9/1/71 - 8/31/72 $ 58,000
Al 05160-14
Managerial:
NIH Training Program in 7/1/71 - 6/30/72 $130,609
GM 295-13 Genetics
NSF Exchange Program 5/1/72 - 4/30/73 $ 60,000 (Applied
GB 29094 in Genetics and for)
Molecular Biology
between Universities
of Stanford and
Pavia (Italy)
NASA Cytochemical 9/1/71 - 8/30/72 $240,000 05%
NGR 05-020-004 Studies of
Planetary Micro-
organisms
SECTION Il — PRIVILEGED COMMUNICATION (123)
BIOGRAPHICAL SKETCH
(Give the following information for aft professional personnel listed on page 3, beginning with the Principal Investigator.
Use continuation pages and follow the same general format for each person. }
NAME TITLE BIRTHDATE (Mo., Day, Yr.)
Edward A. Feigenbaum Professor of Computer Science |1-20-36
PLACE OF SIRTH (City, State, Country) PRESENT NATIONALITY (If non-U.S. citizen, SEX
indicate kind of visa and expiration date}
Weehawken, New Jersey U. S.A. (mate (Female
EDUCATION (8egin with baccalaureate training and include postdoctoral}
YEAR SCIENTIFIC
INSTITUTION AND LOCATION DEGREE CONFERRED FIELD
Carnegie Institute of Technology B. S. 1956 Electrical Engineering
Carnegie Institute of Technology Ph.D. 1959 Industrial Administration
HONORS
Fulbright Research Scholar, Great Britain, National Physics Laboratory,
Teddington, England, 1959-60.
MAJOR RESEARCH INTEREST ROLE IN PROPOSED PROJECT
Artificial Intelligence Research
Heuristic Programming Associate Investigator
RESEARCH SUPPORT (See instructions) Current Total, Proj. % Source of
Contract/Grant No. Title Year Period Effort Support
ARPA SD~183 The Heuristic Programming $200,000 $700,548 2% ARPA
Project of the Stanford
Artificial Intelligence
Project
5 R24 RROO612-02 Resourcé-Related 214,093 722,062 27% NIH
_ 88S Research; Computers and
Chemistry
RESEARCH AND/OR PROFESSIONAL EXPERIENCE (Starting with present position, list training and experience relevant to area of project. List aff
or most representative publications, Do not exceed 3 pages for each individual.)
1965- Stanford University, Computer Science Department Faculty
1965-68 Stanford University, Director, Computation Center
1968-72 National Institutes of Health, Member, Computer and Biomathematical
Sciences Study Section
1965- Editor, Computer Science Series, McGraw-Hill Book Company, New York
1960-64 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
1963 National Science Foundation. Summer Research Training Institute in
Computer Simulation of Cognitive Processes. Faculty member.
1962 Carnegie Corporation. Summer Research Training Institute in Heuristic
Programming. Faculty member.
1956 IBM Scientific Computing Center, New York
RHS-398
Rev. 3-70
(124)
Recent Publications
Smith, Q. H., 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,
O 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, ©. 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)
(125)
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 IFIP68 International
Congress, Edinburgh, August 1968. (Also Stanford Artificial Intelligence
Project Memo No. 67, August 1967)
Lederberg, J. and Feigenbaum, Es A., "Mechanization of Inductive Inference
in Organic Chemistry", in Formal Representations for Human Judgment,
B. Kleinmuntz, ed., Wiley, 1968. (Also Stanford Artificial Intelligence
Project Memo No. 54, August 1967.)
(126)
SECTION II — PRIVILEGED COMMUNICATION
BIOGRAPHICAL SKETCH
(Give the following informatien 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.}
NAME TITLE BIRTHDATE (Mo., Day, Yr.)
Thomas C. Rindfleisch Research Associate 12-10-41
PLACE OF BIRTH (City, State, Country) PRESENT NATIONALITY f/f non-U.S&. citizen, SEX
indicate kind of visa and expiration date)
Oshkosh, Wisconsin, USA USA % Male ClFemate
EDUCATION /[8egin with baccalaureate training and include postdoctoral)
YEAR SCIENTIFIC
INSTITUTION AND LOCATION DEGREE CONFERRED FIELD
Purdue University, Lafayette, Ind. B.S 1962 Physics
California Institute of Technology, M.S 1965 Physics
Pasadena, CA Ph.D Thesis to ba completed. All
course work land examinations
completed.
HONORS
Purdue University, Graduated with Highest Honors, Sigma
Xi.
MAJOR RESEARCH INTEREST ROLE iN PROPOSED PROJECT
Space sciences, computer science and
image processing Technical Support
RESEARCH SUPPORT (See instructions)
RESEARCH AND/OR PROFESSIONAL EXPERIENCE (Starting with present position, list training and experience relevant to area of project, List all
or most representative publications, Do not exceed 3 pages for each 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
~~. aan
(127)
Thomas C. Rindfleisch
PUBLICATIONS (cont'd)
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.
2
Rindfleisch, T., "Digital Image Processing," To be published, IEEE
Special Issue, July 1972.
SECTION i! — PRIVILEGED COMMUNICATION (128)
BIOGRAPHICAL SKETCH
(Give the foltowing 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, }
NAME TITLE BIRTHDATE {Mo., Day, Yr.)
Donald C. Harrison Professor of Medicine 2/24/34
PLACE OF BIRTH (City, State, Country) PRESENT NATIONALITY (/f non-U.S. citizen, SEX
i indicate kind of visa and expiration date)
u.S.
Blount County, Alabama Ss C5 Mate C] Female
EDUCATION (Begin with baccalaureate training and include postdoctoral)
YEAR SCIENTIFIC
INSTITUTION AND LOCATION DEGREE CONFERRED FIELD
Birmingham Southern College, Ala. B.S. 1954 Chemistry
Medical College of Alabama M.D. 1958 Medicine
HONORS
Omicron Delta Kappa, Phi Beta Kappa, Alpha Omega Alpha
MAJOR RESEARCH INTEREST ROLE IN PROPOSED PROJECT
Computer applications in Cardiology Collaborator
RESEARCH SUPPORT (See instructions] Medical Cardiology, HE-5866, NIH, 7/70-6/71, $50,149
15% effort. Evaluation of Cardiovascular System During Various Circulatory
Stresses, NGR-05-020-305, NASA, 9/70-8/71, $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, 9/67-8472, $174,080, 17.5% effort.
RESEARCH AND/OR PROFESSIONAL E XPERIENCE (Starting with present position, list training and experience relevant to area of project. List all
or most representative publications, Do not exceed 3 pages for each individual.)
1972-. Professor of Medicine, Stanford Univ. School of Med., Stanford, Ca.
1968-72 Associate Prof. of Medicine, Stanford Univ, School of Med.
1967- Chief, Division of Cardiology, Stanford Univ. School of Med.
1965-68 Asst. Prof. of Medicine, Stanford Univ. School of Med.
1964-69 Asst. Program Director, Clinical Research Center, Stanford Univ.
1963-64 Instructor in Medicine and Chief Resident in Medicine, Stanford
Univ. School of Med.
1961-63 Clinical Research Associate, National Heart Institute, NIH,
Bethesda, Md.
1960-61 Research Fellow, Harvard Medical School, Boston, Mass.
1958-60 Intern and Asst. Resident in Medicine, Peter Bent Brigham
Hospital, Boston, Mass.
RHS-398
Rev. 3-70
(129)
Donald C. Harrison, M.D. Bibliography
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., 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 Il — PRIVILEGED COMMUNICATION (130)
BIOGRAPHICAL SKETCH
{Give the foliowing information for all protessional personnet listed on page 3, beginning with the Principal Investigator.
Use continuation pages and fellow the same general format for each person.}
NAME TITLE BIRTHDATE (Mo,, Day, Yr]
Stenson, Robert E. Asst. Prof. of Medicine 6/1/38
PLACE OF BIRTH (City, State, Country} PRESENT NATIONALITY (If non-US, citizen, SEX
. indicate kind of visa and expiration date)
Pennsylvania U.S.
3 Male [_} Female
EDUCATION (Begin with baccalaureate training and include postdoctoral)
YEAR SCIENTIFIC
INSTITUTION AND LOCATION DEGREE CONFERRED FIELD
Massachusetts Institute of Tech. M.S. 1960 Elec. Engr.
Harvard School of Medicine M.D. 1965
HONORS
Eta Kappu Nu-Honorary Society of Electrical Engineers
Tau Beta Pi-Honorary Society of Engineers
Sigma Xi-Honorary Scientific Society
MAJOR RESEARCH INTEREST ROLE IN PROPOSED PROJECT
Computer Applications in Cardio- Collaborator
logy
RESEARCH SUPPORT (See instructions)
RESEARCH AND/OR PROFESSIONAL EXPERIENCE (Starting with present position, list training and experiance refevant to area of project. List alt
or mast representative publications, Do not exceed 3 pages for each individual.)
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
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 I — PRIVILEGED CO!AMUNICATION .
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.}
NAME TITLE BIRTHDATE (Mo., Day, Yr.)
Professor of Surgery
Chairman, Division of Urology April 26, 1928
Thomas A. Stamey, M. D.
PLACE OF BIRTH (City, State, Country) PRESENT NATIONALITY (/f non-US. citizen, SEX
indicate kind of visa and expiration date}
Rutherfordton, N.C. USA [iMate (Cl Female
EDUCATION (Begin with baccalaureate training and include postdoctorat)
YEAR SCIENTIFIC
INSTITUTION AND LOCATION OEGREE CONFERRED FIELD
Vanderbilt University, Nashville, Tenn. A.B. 1948
Johns Hopkins University School of Medicite M.D. 1952 Medicine
Johns Hopkins University School of
Med tine, Brady Urological House
Staff Residency 8 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
Scientific Advisory Board, National Kidney Foundation; Member, Scientific Advisory
Council, No. Calif. Kidney Foundation; Member, Research Comm.; No. Calif. Kidney Fndtn;
Editor, Urology Digest; Member, Editorial] Board. Jovest, Urol; Member Editorial Boch,
MAJOR RESEARCH INTEREST ROLE IN PROPOSED PROJECT KIDNEY
Renal Physiology. Infectious Diseases, Collaborator
RESEARCH SUPPORT (See instructions)
2 TO1 AM 05513 -- Training Grant in Urology
Period 7/1/71-6/30/76
5 RO] AI 09366 -- Urinary Infection Grant
Period 1/1/70-12/31/72
RESEARCH AND/OR PROFESSIONAL EXPERIENCE (Starting with present position, list training and 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
RHS-398
(133)
THOMAS A, STAMEY, M.D.
PUBLICATIONS
Books.
Renovascular Hypertension. Baltimore: Williams & Wilkins Co., 1963.
lst reprinting, Mar. 1967.
Urinary Infections. Baltimore: Williams & 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 & Febiger, 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 - Festschrift,
Baltimore: Williams & Wilkins Co. (in press).
Scientific Papers
Stamey, T.A.: The pathogenesis and implications of the electrolyte imbalance
in ureterosigmoidostomy, S&.G. & 0., 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., Schwentker, 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 pyelonephritis in man.
(two articles: PartI 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.
SECTION Ul — PRIVILEGED COMMUNICATION
(134)
BIOGRAPHICAL SKETCH :
(Give the following information for all professionat personnel listed on page 3, beginning with the Principal Investigator.
Use continuation pages and follow the same general format for each person.}
NAME TITLE BIRTHDATE (Mo., Day, Yr}
Constantinou, Christos E. Research Associate July 21, 1939
PLACE OF BIRTH (City, State, Country} PRESENT NATIONALITY (/f non-U,S. citizen, SEX
Limassol, Cyprus
indicate kind of visa and expiration date)
United Kingdom (TI)
(4 Male (_] Femaie
EDUCATION (Begin with baccalaureate training and include postdoctoral}
YEAR SCIENTIFIC
INSTITUTION AND LOCATION DEGREE CONFERRED FIELD
Borough Polytechnic, London, England HNC 1964 Elect. Engineering
Stanford University, Stanford, Calif. M.Sc. 1968 Biomedical Engineering
Ph.D. Expected
1972 Biomechanics
HORGHE
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 (See instructions) ;
NIH Training Grant in Urology - 2 TO1 AM 05513
July 1, 1971 - June 30, 1973
RESEARCH AND/OR PROFESSIONAL EXPERIENCE (Starting with present position, list training and experience relevant to erea of project. List alf
Or most representative publications, Do not exceed 3 pages for each individual.)
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 transducers 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.
RHS-398
Od mae
am
Christos Constantinou (135)
Research Associate
Bibliography
Chapters in Books
Constantinou, C.E., Dale, R.L., Briggs, E.M., and Govan, D.E.: Electro-
physiological methods in the study of 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: IT. System for
data collection and evaluation. Invest. Urol., 8:645-654, 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. Urol., 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. 39th Annual Meeting of
American Academy of Pediatrics, San Francisco, Oct. 1970.
Friedland, G.W., Kohatsu, S., and Constantinou, C.E.: Relationship between motility
of gastric sling fibers and distal esophagus. Proc. of 18th AUR Symposium.
Invest. Radiol., p. 272 5(4)1970.
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 radiopaque
contrast media on the ureter. Western Section, American Urological Association,
Inc. July 2-7, 1972.
(136)
SECTION 1) — PRIVILEGED COMMUNICATION
BIOGRAPHICAL SKETCH
(Give the foliowing information for all professional personnel listed on page 3, beginning with the Principal investigator.
Use continuation pages and follow the same general format for eech person, |
NAME TITLE oc. Dean for Research, BIRTHDATE (Mo, Oay, Yr.)
Elliott C, Levinthal SU Med School, Director of IRL April 13, 1922
PLACE OF BIRTH (City, State, Country} PRESENT NATIONALITY (/f non-U.S. citizen, SEX
indicate kind of visa and expiration date}
Brooklyn, New York
id USA (Cd Mate ([} Femate
EDUCATION (Begin with baccalaureate training and include postdoctoral)
YEAR SCIENTIFIC
INSTITUTION AND LOCATION OEGREE CONFERRED FIELD
Columbia College BLA. 19h2 Physics
Massachusetts Institute of Technology M.S. 1943 Physies and Math
Stanford University Ph.d. 1949 Physics and Math
HONORS
MAJOR RESEARCH INTEREST ROLE IN PROPOSED PROJECT
Medical Instrumentaion Research Collaborator
RESEARCH SUPPORT (See instructional
Contract 952489 Mariner 71 Photo Interpretation, Current Year $71,000 Total $5, 000
Jet Propulsion Lab, 25% time
Contract NAS~1-9687 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 GM17 367-03 Automatic Cell Separation - Clinical and Riological Uses,
$364, 455, 10% time, no salary (cont'd below)
RESEARCH AND/OR PROFESSIONAL EXPERIENCE (Starting with present positon, list training and experience relevant to erea of project. List all
or most representative publications, Do not exceed 3 pages for each individual.)
1970-present Associate Dean for Research Affairs, Stanford University School of Medicine
1961-present Senior Scientist, Director of Instrumentation Research Laboratory,
Dept. of Genetics, Stanford University School of Medicine
1953-1961 President, Levinthal Flectronic Products
1952-1953 Chief Engineer, Century Electronics
1950-1952 Research Director, Member of Board of Directors, Varian Associates
1949-1950 Research Physicist, Varian Associates ©
1946-1948 Research Associate, Nuclear Physics, Stanford University
1943-1946 Project Engineer, Sperry Gyroscope Co., New York
1943 Teaching Fellow in Physics, Massachusetts Institute of Technology
Research Support (cont'd)
Stanford Medical School Associate Dean for Research 25% time
Relevant Publications
and Papers:
(137)
E. C. Levinthal,"Detection of Extraterrestrial Life",
Professional and Technical Group of Instrumentation
and Measurements of I.F.E.E., April, 1963.
E. C. Levinthal,"The Detection of Life Within Our
Planetary System", Presented at WESCON, August, 1963.
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: Exobiology.
E. C. Levinthal, J. Lederberg and L. Hundley, "Multivator -
A Biochemical Laboratory for Martian Experiments”, Life
Sciences and Space Research II, COSPAR (Committee on
Space Research) 1964.
B. Halpern, J. W. Westley, E. C. Levinthal, J. Lederberg,
"The Pasteur Probe: An Assay for Molecular Asymmetry",
Life Sciences and 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. Sei.,
National Research Council.
E. C. Levinthal, "Prospects for Manned Mars Missions",
in: Biology and the Exploration of Mars, Nat. Acad. Sci.,
National Research Council,
O. Reynolds, E. Levinthal, G. Soffen, "The Role of the
Scientist in Automated Laboratory Systems", AIAA’ Paper
No. 67-632, (1967).
E. C. Levinthal, J. Lederberg 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. Levinthal and J. Lederberg, “Contamination
of Mars*", Science, 159: 1191-1196 (1968)
E. C. Levinthal, "The Role of Molecular Asymmetry in
Planetary Biological Exploration", Gordon Research Conferences,
Nuclear Chemistry Section, 1968. (Paper)
Relevant Publications
(continued)
(138)
J. P. Kriss, W. A. Bonner, E. C. Levinthal. ‘Variable
Time-Lapse Videoscintiscope: A Modification of the Scinti-
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 System’ 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, 10-45 (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" Science, 175 (4019)
294 (1972).
(139)
SECTION I — PRIVILEGED COMMUNICATION
BIOGRAPHICAL SKETCH
(Give the following information for all professional personnel listed on page 3, beginning with the Principal Investigator.
Use cantinuation pages and follow the same general format for each person, }
NAME TITLE BIRTHDATE {Ma Day, ¥r)
Leonard A. Herzenberg Professor of Genetics Nov. 5, 1931
PLACE OF BIRTH (City, State, Country] PRESENT NATIONALITY (If non-US citizen, SEX
indicate kind of visa and expiration date)
Brooklyn, New York U.S. EXMale C] Female
EDUCATION (Begin with baccalaureate training and include postdoc torat}
. YEAR SCIENTIFIC
‘NS !
NSTITUTION AND LOCATION DEGREE CONFERRED FIELD
Brooklyn College, Brooklyn, New York A.B. 1952 Biology, Chemistry
California Institute of Technology , Pasadend Ph.D. 1955 Biochemistry,
Pasteur Insti fute, Paris, Postdoctoral fel low Immunology
HONORS
Phi Beta Kappa, Sigma Xi, .
Distinguished Alumnus Award, Brooklyn College, 1970
Genetics Study Section, National Institutes of Health
MAJOR RESEARCH INTEREST ROLE iN PROPOSED PROJECT
Immunogenetics, somatic cell genetics Collaborator
|
RESEARCH SUPPORT (See instructions)
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, $44,044 current year, $240,893 total
funds for project period
RESEARCH AND/OR PROFESSIONAL EXPERIENCE (Starting with present position, fist training and experience relevant to area of project: List alf
or most representative publications. Oo not exceed 3 Pages for each individual. }
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. Qwen)
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 8. 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 immunoglobulin production in radiation
chimeras. Proc. of Sec. of Exp. Biol. & Med. 1161-1163.
RHS-398 een —
Rev, 3-70
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Continuation page
nO.
in
12.
13.
14,
15.
16.
17.
18.
9.
20.
21.
Klein, J., J. Martinkova & L. A. Herzenberg. 1967. Analysis of the histo- |
compatibility-2 (H-2) locus of NZB mice. Transplantation 5: 1335-1337.
Klein, J. & L. A. Herzenberg. 1967. Congenic mouse strains with different
immunoglobulins allotypes. 1. Breeding scheme, histocompatibility tests and
kinetics of ¥G globulin production by transferred cells for C3H. S.W. and
its congenic paftner CWB/5. Transpl. 5:1484-1495.
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. Immunoglobulin isoantigens
(allotypes) in the mouse. IV. Allotypic specificities common to two distinct
immunoglobulin classes. J of Immunol. 99:675-678.
Minna, J. D., G, M. Iverson & L. A. Herzenberg. 1967. Identification of a
gene locus for 6G, immunoglobulin H chains and its linkage to the H chain
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 liver cells: a source
of specific immunoglobulin production in radiation chimeras, pp. 87-89. In
J. Dausett, J. Hambruger, G. Mathe (Eds.) Advance in transplantation. Proc.
Ist Intl. Cong. Transpl. Soc., Paris, June 27-30 (Munksgaard, Publisher).
Herzenberg, L. A., Leonore A. Herzenberg, R. C. Goodlin & 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. 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: 181-186.
Herzenberg, L. A. H. O. McDevitt & Leonore A. Herzenberg. 1968. Genetics of
antibodies. Ann. Rev. of Genetics 2:209-244.
Tyan, M. L. & L. A. Herzenberg. 1968. Ontogeny of the mouse immune system.
If. Immunoglobulin-producing cells. J. of Immunol. 101:446-450.
Tyan, M. L., H. O. 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. Tyan. 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. Immunoglobulin production by embryonic
tissues: thymus independent. Proc. of Soc. for Exp. Biol. & Med. 128;952-954
Heraenberg, L. A. 1969. Rabbit Aa locus allotypes: quantitative comparisons
in IgG, IgA, and IgM by inhibition of precipitation. Fed. Proc., p. 435 (abstract)
Hulett, H. R., W. A. Bonner, J. Barrett and L. A. Herzenberg. 1969. Cell
sorting: automated separation of mammalian cells as a function of intracellular
fluorescence. Science 1663747.
Tyan, M. L., L. A. Herzenberg-& P. R. Gibbs. 1969. Lympoid precurosors:
thymus independent antibody production. J. of Immunol. 10331283.
L'age=Stehr, J. and L. A. Herzenberg. 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.
Jacobson, E. B., J. L'age-Stehr & 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 with clinical applications. Laboratorv
Investigations (abstract in press) Presented at 5¥th Annual Meeting of
International Academy of Pathology, St. Louis, Missouri, March, 1970.
Fru s avo A870 — 78-895
DO NOT TYPE IN THIS SPACE-BINDING MARGIN
(141)
Continuation page
p2. Riblet, Roy J. and L. A. Herzenberg. 1970. Mouse lysozyme: production by
a monocytoma, isolation, an comparisons with other lysozyme. Science 168:1595
23. Herzenberg, L. A. Gene interactions in immunoglobulins (in press).
Presented at Symposium on Anti-Human Gamma Globulins, Lund, Sweden, Oct. 1969.
24. Herzenberg, L. A. 1970. From cell biology to immunology -- a short trip.
J. of Cellular Physiology 76: 303-310.
1971. The antibody response to (T,G) -A--L in tetraparental mice. Federation
Proceedings, p. 1531 (abstract).
27. Riblet, R. J., L. A. Herzenberg & L. A. Herzenberg. 1971. Active allotype
28. Bonner, W. A., H. R. Hulett & L. A. Herzenberg. 1971. Highspeed sorting
of fluorescence labelled cells. Federation Proceedings, p. EIO. (abstract)
29. Mitchell, G. F., E. 0. Chan, M. S. Noble, I. L. WEissman, R. I. Mishell and
in both T-cell and B-cell populations and requirement for T-cell in expression
of B-cell memory. Evidence using Anti 6 and anti-allotype sera with congenic
mice, J. Exp. Med., in press.
of T-cells in antibody production. Presented at the lst International Congres
of Immunology, Washington D.C., August, 1971.
31. 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.
32. Herzenberg, L. A. 1971. Immunoglobulin genetics in cellular immunology.
New York Academy of Sciences. In press.
Selected publications before 1967:
1. Herzenberg, L. A. and Leonore A. Herzenberg. 1959. Adaptationto lactose.
Nutrition Review 17:65-87.
2. Herzenberg, L. A. 1959. Studies on the induction of beta-galactosidase in
a cryptic strain of escherichia coli. Biochimica et Biophysica Acta 31:525-538.
3. Herzenberg, L. A. and Leonore A. Herzenberg. 1961. Association of H-2 antigens
with the cell membrane fraction of mouse liver. Proc. of Natl. Acad. of Sci.
47:762-767.
4. Herzenberg, Leonard A. 1962. Part I. Steps toward a gentics of somatic cells
5. CAnn, H. M. and L. A. Herzenberg. 1963. In vitro studies of mammalian somatic
cell variation II. Isoimmune cytotoxicity y with a cultured mouse lymphoma and
selection of resistant variants. J. of Exp. Med. 117: 267-284.
6. Wunderlich, J. and L. A. Herzenberg. 1963. Genetics of a gamma globulin iso=
antigen (allotype) in themuse. Proc. of Natl. Acad. of Sci. 49 3592-598,
7. Erickson, R. P., D. K. Tachibana, L. A. Herzenberg and L. T. Rosenberg. 1964.
J. of Immunol. 92:611-615.
8. Hereenberg, L. A. 1964. A chromosome region for gamma 2, and beta 2, globulin H
chain isoantigens in th mouse~ Cold Spring Harbor Symposium of Quantitative
Biology 29:455-464.
Total number of publications: 75.
25. Merrill, J. T., N. Veizades, H. R. Hulett, P. L. Wolf and L. A. Herzenberg. 1971.
An improved cell-volume analyzer. Review of Scientific Instruments 42:1157-1163.
26. Bechtol, K. B., T. G. Wegmann, B. W. Chesebro, L. A. Herzenberg & H. 0. McDevitt.
Suppression in a cell transfer system. Federation Proceedings, p. 2552. (abstract)
L. A. Herzenberg. 1971. Specific immunological memory to heterologous erythrocyt 3
in culture. Part II. Maternal isoimmunization as a result of breeding in the mous
A single gene controlling hemolytic complement and a serum antigen in the amouse.
ru SHPO. 1470 — 370-408
30. Mitchell, %, F. R. I. Mishell and L. A. Herzenberg. 1971. Studies on the influence
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BIOGRAPHICAL SKETCH
(Give the following information for alt professional personnel listed on page 3, beginning with the Principal Investigator.
Use continuation pages and foliow the same general format for each person.)
SECTION !f — PRIVILEGED COMMUNICATION
NAME TITLE Chiet, Psyt. Research & BIRTHDATE (Mo, Day, Yr.)
Bert S. Kopell, M. D. Training Division, VA Hospital
Palo Aito, California 2/11/31
PLACE OF BIRTH (City, State, Country) PRESENT NATIONALITY (/f non-U.S. citizen, SEX
New York N ew York indicate kind of visa and expiration date}
>
USA 4 Male (] Female
EDUCATION (Begin with baccalaureate training and include postdoctoral}
YEAR SCIENTIFIC
INSTITUTION AND LOCATION DEGREE CONFERRED FIELD
Univ. of Geneva, Geheva, Switzerland Medical
Baccalaureate 1953 Medical Sctence
Univ. of Geneva, Geneva, Switzerland M. OD. 1958
Maimonides Hospital, New York Rotating 1958-59
lotern
ONO chiatry Career Teaching Award--July, 1966 - June, 1968
Diplomate of American Board of Psychiatry & Neurology in Psychiatry, 1966
MAJOR RESEARCH INTEREST ROLE tN PROPOSED PROJECT
Electrophysiological Studies of Drugs Collaborator
RESEARCH SUPPORT (See instructions)
}. 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 Apri
30, 1972--$115,062.
2. Pending Applications .
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 (Starting with present position, list training and experience relevant to area of project. List ail
or most representative publications. Do not 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., Stanford Univ. 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 Applications (continued)
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.
RHS-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-
209-221, 1964.
Kopell, B. S., Noble, E. P. and Silverman, J. The effect of thiamytal and
methamphetamine on the two-flash fusion threshold. Life Sciences, 4: 2211-14, 1965.
Stilson, D. W., Kopell, B. 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., 6: 159-167, 1968.
Kopell, B. 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. § Non-contingent reinforcement and certainty.
Psychonomic Science, 1]: 211-213, 1968.
Macpherson, L. and Kopell, B. S. Systems approach to the measurement of
Slow evoked potential changes. Med. Biol. Eng., 6: 673-65, 1968.
Kopell, B. 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, R. B., and Hamburg, D. A. Fluctuations in symptoms and mood during the
menstrual cycle. J. Psychosom. Res., 13 37-44, 1969.
Kopell, B. S., Wittner, W. K. and Warrick, G. The effects of stimulus differ-
ences, light intensity and selective attention on the amplitude of the visual
averaged 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, B. S., Wittner, W. K., Lunde, D. T., Warrick, G., and Edwards, D.
Cortisol effects on the averaged evoked potential, alpha rhythm, time estimation,
and the two-flash fusion threshold. Psychosom. Med., 32: 39-49, 1970.
Roth, W. T. and Kopell, B S$. The auditory evoked response to repeated
stimuli during a vigilance task. Psychophysiology, 6: 301-309, 1969.
Hilf, F. D., Wittner, W. K., 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.
(144)
Bert S. Kopell, M. D.
Publications Continued
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., 32: 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, B. S. An electrically operated
skin resistance switch. Psychophysiology, 8: 673-675, 1971.
Macpherson, L. and Kopell, 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, 8. S$. Blink and eye movement EEG artifacts. Psycho-~
pyhsiology, in press. (1972).
Kopell, B. S., Maxim, P., and Koran, L. Influence of lithium on selective
attention as measured by the averaged evoked potential in man. Submitted and
accepted for publication by Psychopharmacologia.
Kopell, B. S., Wittner, W. K., Lunde, D. T., and Wolcott, L. L. Effect of
amphetamines and barbiturates on selective attention as measured by the averaged
evoked response. In preparation.
Kopell, B. S , Tinklenberg, J. R and Hollister, L. E. Effects of marijuana
and alcohol on the contingent negative variation. In preparation. To be sub-
mitted to Archives of General Psychiatry.
Kopell, B. S., Wittner, W. K., and Lunde, D. T. Influence of amphetamines
and barbiturates on contingent negative variation. In preparation. To be sub-
mitted to Psychopharmacologia.
Corby, J. C. and Kopell, B. S. Effect of predictability on evoked response
enhancement in selective attention. In preparation.
Lunde, D. T., Costell, R., Wittner, W. K. and Kopell, B. S. The electro-
corticol expression of sexual object preference in non-deviant male and female
subjects. In preparation. To be submitted to Science.
Moos, R., Clayton, R., Kopell, B. S$. and Hamburg, D. A. Progesterone and
menstrual cycle symptomatology. In preparation.
SECTION f! — PRIVILEGED COMMUNICATION (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 sarne general format for each person,}
NAME TITLE . . BIRTHDATE [Mo., Day, Yr)
Chief of Psychiatric
Walton T. Roth, M.D. Consultation Services 2/23/39
PLACE OF BIRTH (City, State, Country] PRESENT NATIONALITY (if non-US citizen, SEX
L indicate kind of visa and expiration date)
Topeka
peka, Kansas USA {xl Mate 1} Female
EDUCATION (Begin with baccalaureate training and include postdoctoral)
YEAR SCIENTIFIC
INSTITUTION AND LOCATION DEGREE CONFERRED FIELD
Harvard College B.A. 196] Biochemistry
New York University School of Medicine M.D. 1965
HONORS
Harvard National Scholar, 1957-196]
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 Collaborator
RESEARCH SUPPORT (See instructions)
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 3-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 AND/OR PROFESSIONAL E XPERIENCE (Starting with present position, list training and experience retevant to area of project, List all
or mast representative publications, Do not exceed 3 pages for each individual. }
1971 - Present Chief of Psychiatric Consultation Services, V.A. Hospital, Palo Alto, Ca.
1969 - 197] National Institutes of Mental Health, Clinical Associate
1966 - 1969 Resident in Psychiatry, Stanford Hospital
1965 - 1966 Intern in Medicine, North Carolina Memorial Hospital
1964
National Science Foundation Summer Fellowship, The Worcester Foundation
for Experimental Biology
1960 National Science Foundation Summer Fellowship, Harvard
See Representative Publications
RHS-398
Rev. 3-70
(146)
Publications, Walton T. Roth, M.D.
Roth, W.T. The effect of LSD, mescaline, and d-amphetamine on the evoked
‘'secondary discharge’. Psychopharmacologia (Berl.), 9: 253-258, 1966.
Roth, W.T. and Kopell, B.S. The auditory evoked response to repeated stimuli
during a vigilance task. Psychophysiology, 6: 301-309, 1969.
Roth, W.T., Kopell, B.S., and Bertozzi, P.E. The effect of attention on the
average evoked response to speech sounds. Electroenceph. clin. Neurophysiol.,
29: 38-46, 1970.
Stillman, R., Roth, W.T., Colby, K.M., and Rosenbaum, C.P. An on-line computer
system for initial psychiatric inventory. Amer. J. Psychiat., 125: 7, Jan. 1969
suppl., 8-11.
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
publication, 1972b.
(147)
SECTION I! — PRIVILEGED COMMUNICATION
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.)
NAME TITLE BIRTHDATE (Mo., Day, Yr.}
Ronald D. Jamtgaard Facility Director (ACME) May 2, 1933
PLACE OF BIRTH (City, State, Country) PRESENT NATIONALITY (f/f non-U.S citizen, SEX
indicate kind of visa and expiration date)
Sioux Falls, South Dakota
USA EXMate (] Female
EDUCATION (Begin with baccalaureate training and include postdoctoral)
YEAR SCIENTIFIC
INSTITUTION AND LOCATION DEGREE CONFERRED FIELD
Augustana College, Sioux Falls, S.D.
University of Minnesota A.B. 1957
University of Minnesota coursework for M.A.
in Pub. Admin.
HONORS
MAJOR RESEARCH INTEREST ROLE IN PROPOSED PROJECT
Biomedical computing, communications
systems Management Support
RESEARCH SUPPORT (See instructions)
ACME Computing Facility, Stanford School of Medicine 95% time RROO411
S.U. Medical Center Computer Planning Funds 5%
RESEARCH AND/OR PROFESSIONAL EXPERIENCE (Starting with present position, list training and experience relevant to area of project, List all
or most representative publications, Do not exceed 3 pages for each individual.)
1970-present Director, Advanced Computer for MEdical Research (ACME) Stanford
Medical School, Stanford Computation Center, Stanford University.
1969-1970 Manager of Administrative Services, Radiation Division, Varian
Associates, Palo Alto, California.
1967 -1969 Inter-Facility Associate Director, Stanford Computation Center,
Stanford University.
1966- Executive Assistant to Director (Dr. W.K.H. Panofsky) Stanford
Linear Accelerator Center, Stanford University.
1961-1966 Budget Officer, Stanford Linear Accelerator Center, Stanford
University.
1958-1961 Management Trainee, Field Office Liaison Officer and Pudget Analyst
U.S. Atomic Energy Commission at Germantown, Maryland, and Idaho
Falls, Idaho.
RHS-398
Rev. 3-70
(148)
St -_ “thy LEGED COMMUNICATION
BIOGRAPHICAL SKETCH
{Give tha follawing information for all professional personnel listed on page 3, beginning with the Principal Investigator.
Use continuation pages and follow the same general format far each person. |
NAME THTLE BIRTHDATE (Ma, Day, ¥r.)
. . Lecturer, Consultant, and June 2h, 1936
Gio C.M. Wiederhold le ~ .? , 3
wernior Systems Designer
PLACE OF BIRTH {City, State, Country} PRESENT NATIONALITY (/f non-U.S citizen, SEX
indicate kind of visa and expiration date}
Varese, [taly Permanent Resident Alien
CJ Male () Femaie
EDUCATION (Begin with baccalaureate training and include postdoctoral}
YEAR SCIENTIFIC
INSTITUTION AND LOCATION OEGREE CONFERRED FIELD
IMS Technicum, Rotterdam, Holland B.S. 1957 Aeronautical Eng.
U.C. Berkeley, Calif. 1960-64 Coursework in heu-
risti ropramming
Comp! Ter destin, Bte.
HONORS
Graduated cum laude from TMS Technicun.
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 medil- Technical Staff
cal applications of computers.
RESEARCH SUPPORT (See instructions)
ACME Computing Facility, Computation Center, Stanford University. Supported
under the Biotechnology Resources Branch of NIH, Grant No. RROO311-06.(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 eer ’
(60% time
RESEARCH AND/OR PROFESSIONAL EXPERIENCE (Starting with present position, list training end experience relevant to area of project. List all
or most representative publications, Do not exceed 3 pages for each individual.)
1970-present: User Services Manager, ACME and consultant to Director, SU. Hospital, ADP.
1965-70: Director, ACME Facility, Stanford Computation Center.
1965-present: Lecturer, Computer Science Dept., Stanford University.
1964-65: Visiting Professor, Indian Inst. of Technology, Kanpur, India under USAID.
1961-64: Head of Programming, U.C. Berkeley, Calif.
1958-61: IBM Service Bureau Corp., New York and San Jose, Programmer.
1958: 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 (1969-70), 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. SBC Corp., 1959.
2) Wiederhold, G. and Tsao, 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. American Cyanamid Co., Stamford, Conn., 1962.
4) Wiederhold, G.: Control language for an interactive time-sharing system. SHARE
TSS/67 Control Language Comm., 1966.
(continued)
RHS395
Rew. 3-70
(149)
Gio C. M. Wiederhold, B.S. 2
Bibliography (continued)
5)
6)
10)
11)
12)
13)
14)
15)
16)
17)
18)
19)
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.
Wiederhold, G.: A Summary of the ACME System. ONR Computer and Psychobiology
Conference Proceedings, Monterey, Calif., May 17, 1966.
Wiederhold, G.: A Summary of the ACME System. Conversation with a 50 Conference
Proceedings, Chicago, Ill., October 31 ~ November 1, 1966.
Sanders, W.J., and Wiederhold, G., et al.: An Advanced Computer System for Medi-
cal Research. AFIPS Conference Proceedings 31, Anaheim, Calif., 1967.
Brietbard, G.Y., and Wiederhold, G.: PL/ACME: An Incremental Compiler for a Sub-
set of PL/1. IFIP68 Congress Proceedings, Edinburgh, Scotland, August 1968.
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.
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.
Wiederhold, G.: An Advanced Computer System for Medical Research. Proceedings
of IBM Japan Computer Science Symposium, Research and Computer System, Tokyo,
Japan, pp. Bl-B15, November 1969.
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.
Wiederhold, G.: Internal Documentation (ACME Notes), Stanford Computation Center,
ACME Computer Facility, Stanford, Calif., November 1965 - present.
Wiederhold, G.: Medical Uses of Computer (in Japanese) presented in Tokyo, Japan,
November 1969, published in IBM Review No. 27, February 1970.
Wiederhold, G., Brietbard, G.: A Method for Increasing the Modularity of Large
Systems. IEEE Computer Group News, vol. 3, 2, March-April 1970.
Girardi, S., Frey, R., Wiederhold, G.: A Filing System for Medical Research. Pre-
sented at Journees Internationales d'Informatique 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.
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.
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.
(150)
SECTIC . 1, — PRIVILEGED COMMUNICATION
BIOGRAPHICAL SKETCH
(Give ths 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, }
NAME TITLE BIRTHDATE (Ma, Day, Yr.)
Hundley, Lee Assistant Director, ACME danuary 31, 1941
PLACE OF BIRTH (City, State, Country) PRESENT NATIONALITY (/f non-U.S. citizen, SEX
indicate kind of visa and expiration date}
Dallas, Texas USA Mate ()Femate
EDUCATION (Begin with baccalaureate training and include postdoctorat)
YEAR SCIENTIFIC
INSTITUTION AND LOCATION DEGREE CONFERRED FIELD
Southern Methodist University, Dallas, Té¢x. B.S. 1960 Electrical Engineer
San Jose State College, S.J., Calif.
coursework for MA
HONORS
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 Technical Staff
RESEARCH SUPPORT (See Instructions)
ACME Computing Facility, Stanford School of Medicine 100% time RROO411
RESEARCH AND/OR PROFESSIONAL EXPERIENCE (Starting with present position, list training and experience relevent to srea of project, List all
or most representative publications. Do not exceed 3 pages for each individual.)
1967-present Assistant Director ACME Computing Facility, Stanford University
1966-67 Manager, Systems Engineering-Programming Manager, Data Pathing,
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.
Re, DP,
(151)
Publications:
Montgomery, P. O'B. and liundley, L. L.: "The Use of
Television in Scanning Techniques for Ultraviolet
Irradiation of Cells." Digest of Technical Papers,
12th Annual Conference on Electrical Teconiques in
. Med. and Biol. November 10-12, 1959, 19.
Hundley, L. L. and Montgomery, 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'B. and Hundley, L. L.: "The Use of
Television and Scanning Techniques for Ultraviolet
Irradiation Studies of Living Cells." IRE Trans.
Med. Electr. ME 7:135-138 July 1960.
Montgomery, P. O'B. and Hiundley, L. L.: "The Effects
of Selective Ultraviolet Irradiation of the
Cytoplasm of Living Cells." Proc. Soc. Exp. Bio. &
Med. 105:117-120, Oct. 1960.
Montgomery, P. O'B., Bonner, Wm. A. and Hundley, 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. Vv.
Irradiation in Chaos Chaos." Royal Microscopical
Society. 80:19-24 (PT I) April 1961.
Montgomery, P. O'B. and Hundley, L.L.: "A Flying Spot
Interference Television Microscope." Nature.
192:4807, 1059-1060, December 1961.
Montgomery, P. O'B., Van Orden, F., Hundley, L. L.,
Chapman, C. L. and Cook, 3. E.: "Effects of
Selective Ultraviolet Irradiation of the Nuclei
of Living Cells." Proc. Soc. 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 IEEE. Computer Group Conference, March 1970
SECTION I — PRIVILEGED COMMUNICATION
(152)
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 sech person}
NAME
Regina Frey
TITLE
BIRTHDATE (Ma, Day, Yr.)
Systems Programmer September , 1937
PLACE OF BIRTH (City, State, Country)
Newton County, Indiana
PRESENT NATIONALITY (ff non-U.S citizen, SEX
indicate kind of visa and expiration date)
USA Oj Male _fiFemasie
EDUCATION (Begin with baccalaureste training and include postdoctoral)
YEAR SCIENTIFIC
INSTITUTION ANDO LOCATION DEGREE CONFERRED FIELD
Purdue University, Lafayette, Indiana B.S. 1959 Mathematics
HONORS
General Motors and Purdue University Alumni Association Scholarships
MAJOR RESEARCH INTEREST
Biomedical systems computing
RESEARCH SURPORT (See instructions)
ROLE IN PROPOSED PROJECT
Technical Staff
ACME Computing Facility, Stanford University School of Medicine 100% time
NIH BRR Grant RROO311
RESEARCH AND/OR PROFESSIONAL E XPERIENCE (Starting with present position, list training end experience relevant to area of project, List ail
or most representative publications, Da not exceed 3 pages for each individual.)
1968-present Systems programmer, ACME Facility, Stanford Computation Center,
c Stanford University .
1964-1967 Programmer, University of California at Berkeley, Linguistics Dept.
1959-1964 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, 1971, Elsenier Publishing Company, Ltd., England.
HS-355
Rev. 3-70