symposium information science · vol. 29, 1965 automated handlingof chemical-biological data it is...

BACTERIOLOGICAL REVIEWS, Dec., 1965Copyright © 1965 American Society for Microbiology

Vol. 29, No. 4Printed in U.S.A.

Symposium on Information ScienceVIII. An Approach to the Automated Handling of Chemical-Biological Data

in a Pharmaceutical Firm'

C. W. DURACHTA, C. E. SCHENK, R. G. DICK, AND F. M. STURTEVANTMead Johnson & Company, Evansville, Indiana

INTRODUCTION

SYSTEMS AND DATA PROCESSING CENTER.561DATA-PROCESSING APPLICATIONS.561

Calculation of Mean and Standard Error, Standard Deviation, and Student's t Test. 561Calculation of ED5o or LD5o Via Berkson's Method.562Specialized Forms.563

Processing of data derived from scintillation counts and spectrophotometer read-ings.563

Processing of necropsy data; liver and carcass analysis.564Determination of curves based upon microbiological assay calculations. 564Product development work load analysis.564Automated weighing system (toxicity studies).564

Punched Paper Tape and Printed Digital Tape: Data Based upon Animal Weightand Food Calculations (Nutritional Research).564

Clinical Data.565INFORMATION STORAGE AND RETRIEVAL APPLICATIONS AND CLERICAL ROUTINES... 565Key Word in Context (KWIC): Application to Published Literature on Mead John-son Products and Other Technical Documents.565

Inventory Control System of Chemical Compounds, Biological Testing Requested,Work in Progress, and Work Completed.566

Systems for the Reporting of Biological Test Data Results.568COMBINED DATA-PROCESSING AND INFORMATION RETRIEVAL SYSTEM FOR PHARMA-COLOGICAL DATA (5) 568

Code Sheet and Card Layout.568Validity of the Code Deck.572Hypnotics and sedatives..................................................... 572Anticonvulsants............................................................ 572Centrally acting interneural muscle relaxants.572Narcoticsanalgetics.572Antipyretic/analgetics.572Tranquilizers............................................................... 572Anticholinergics.572Antihistamines............................................................. 573Adrenergics.573CNS stimulants 573

Method of Coding.574Problem of Ambiguity of Biological Terminology.575SUMMARY...................................................................... 575LITERATURE CITED.576

INTRODUCTION

The major activity and principal product of aresearch and development laboratory is thegeneration of technical data and information.Organizations engaged in work of a scientific

1 A contribution to the symposium "Informa-tion Science" held at the Annual Meeting of theAmerican Society for Microbiology, Washington,D.C., 4 May 1964, with H. W. Batchelor as con-vener, and G. H. Nelson, M. D. Nelson, and A. J.Shanahan as consultant editors.

nature find themselves in an increasingly com-petitive research environment at a time whenstringent government regulations, serious short-ages of technical manpower, rising costs, and aburgeoning scientific literature combine to reducethe total productivity of the research staff.Specialization in a given field may afford somerelief to these problems, but, because techno-logical advances frequently have interdisciplin-ary significance, the desire to remain technicallycompetent forces the research worker to scan theliterature from diverse scientific fields.

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VOL. 29, 1965 AUTOMATED HANDLING OF CHEMICAL-BIOLOGICAL DATA

It is evident that science and technology(government as well as industry) have been andcontinue to be confronted with an acute problemin screening, documenting, storing, retrieving,assimilating, and utilizing the vast quantity oftechnical data and information generated by thescientific community.

Obviously, scientific data and informationshould not be buried or ignored, since it is as-sumed generally that the success of any researchand development (R & D) effort is a result of theavailability of technical data and the intelligentuse to which it is put.To cope with these problems, some pharmaceu-

tical firms have established highly organizedtechnical information groups to handle allinformation problems confronting the R & Deffort. Others have elected to permit each de-partment to solve specific information problemsindependently, as they see fit.The Mead Johnson Research Center evaluated

its technical information problems relative to themethods in use and reached the decision thatelectronic data-processing (EDP) techniquesshould be initiated to process the large volumesof data generated within its R & D laboratories.A study team was appointed to evaluate theproblem. It became evident that, because of thediffuse nature of the problem and the confusionsurrounding the concepts implied by "dataprocessing" versus "information retrieval," acareful appraisal of the literature and the ex-periences of colleagues from other firms would bedesirable. One predominant opinion among thefirms contacted seemed to be that it would beimpractical for an R & D effort to rely on data-processing facilities outside its organization. Itwas stressed that conflicts of job priority wereinevitable, and, consequently, decentralizedmachine facilities were preferable despite theloss of sophisticated services afforded by theversatile but expensive computing equipmentin the accounting departments.

SYSTEMS AND DATA PROCESSING CENTERPerhaps we were more fortunate than our

colleagues. Our corporate Systems and DataProcessing (EDP) Center had been established asan independent unit in the company with theassigned function of serving all corporate divi-sions as the needs arose. Because of this central-ization and because of the willingness and abilityof the Systems personnel and the EDP Centerto assist the Research Center, it has been possibleto gain access to the corporate IBM 1410/1401computer-complex.

All contact with the EDP Center is conductedthrough one individual in the Department of

Technical Information, thus allowing all ResearchCenter requests to be coordinated and prioritiesto be assigned by the Department's CentralRecords Office. Members of this Department areresponsible too for all Research Center computerapplications and for the Research Library, forwriting and submitting Notices of ClaimedInvestigational Exemptions for New Drugs(IND) and New Drug Applications (NDA),plus their foreign equivalents, and for developingand maintaining various product and structureactivity files.

In the EDP Center, a programmer and asystems man are assigned to work on ResearchCenter problems. This arrangement has enabledus not only to approach our original objectives,but to perform many other routines that other-wise would be impossible. A few of these computerapplications are listed below under the threemain headings: Data Processing Applications,Information Storage and Retrieval Applicationsand Clerical Routines, and Combined DataProcessing and Information Retrieval Systemfor Pharmacological Data.

This listing outlines the approaches we havetaken in automating certain of our electronicdata-processing (EDP) and information re-trieval (IR) functions; its presentation as followsis intended not only to illustrate some of thedifferences surrounding concepts of EDP andIR, but also to suggest approaches which mayclarify or stimulate thinking on the use of com-puter equipment at other facilities.

DATA-PROCESSING APPLICATIONSCalculation ofMean and Standard Error, Standard

Deviation, and Student's t TestThis program forms one part of a general

purpose statistical program which computes:

so = / E X2N(N-1)

and

X1- X2

ZE(xii - )2 +E(X2i -X2)2 N2 + N1V N1+ N2-2 NN2/

The computer selects t (P = 0.05) for the ex-perimental group from a 30-position table andcalculates the Student t value for selected sets ofdata processed through the mean and standarderror program, if signaled by the user to do so.

Completed data input-forms, collected dailyin the Research Center Library, are transmittedto the EDP Center for processing. Computedresults are subsequently collected from the EDP

561

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DURACHTA ET AL.

1,ALCUIATIIIN OF THE ED,;) (orl- 5) PHONE EXTENSIONI 702?P~t7.Cj-'RI tNO- | Mt4NTH DAY YEAR| MJoAL&THOP S ;t*ys:[email protected]

.:2 1 4 " 6 818 9 10 11 11213 14 .115116 17 18 ;19 20 . I 21 22 24, 2S 27 r 2 Q311 ,12 O R,+4 . 'S4 17 L I0 ~ 0 JIGV 5 10 ooiI T01Cl zioTeoj- LXc 1w. D_ TS

PAE l 0ADD DPTA&O. EML NO U EDP LE06VEL-i

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1~~~~~~~~~~=1iI_KU_L-Z1~~~~imik/<,or f__ 2 c __11 / _ _ L0 I

_ _ 0_ _ 2

No_ A DAY YEAR, Kit No. SALT If METHOD NO0. RT. ISVESTICATOR'S NAME

2;6 N°" 0 19II1l1121213 1141 15 41 910 1212j 23j 12'_'_ 22_ i

Entreesp~rsE 1 A~l~lljQNfAL RF yC jl U EEL O XN.I DOSE LEVEL i SD GI Los1trvE ol

42 134 514614 14.ll5150 51|52|53, 54 15 81 5!6 61a61 63 6 6 67 68 69 |70 71 72i X73 t157 7181 7

8-Bek-.n J.: J. As. Sa.Asc48 565-99, (Sptebr 1953 t i i

FIG. la. Data input form for calculation of -D5o values (Berkson's method).

PROG. PROJ. DATE MJ NO. SALT TEST NO. ROUTE INVESTIGATOR NOTEBOOK PAGE REF. CONTROL SET50 00 06/02/646 500 01 223B PO C.W.DURACHTA 2 255 MG/KG 900 001

DOSE D PRIME X N R R/N W NW NWX NWX2 WL NWL NWLX

5.00 1.00 .0000 10 .0500 .047500 .475000 .0000000 .0000000 .1398870- 1.3988700- .0000000-20.00 4.00 .6020 10 2 .2000 .160000 1.600000 .9632000 .5798464 .2218048- 2.2180480- 1.3352648-40.00 8.00 .9030 10 4 .4000 .240000 2.400000 2.1672000 1.9569816 .0973344- .9733440- .8789296-80.00 16.00 1.2040 15 4 .2666 .195524 2.932860 3.5311634 4.2515207 .1978624- 2.9679360- 3.5733949-160.00 32.00 1.5051 10 7 .7000 .210000 2.100000 3.1607100 4.7571846 .1779267 1.7792670 2.6779747320.00 64.00 1.8061 15 13 .8666 .115604 1.734060 3.1318857 5.6564987 .2163182 3.2447730 5.8603845

A C SUMNWX2 B SUMNWLX

11.241920 12.9541591 17.2020320 2.5341580- 2.7507699

XBAR 1.1523084

E 2.2748457 F 5.6709015

SLOPE 2.4928730 INTERCEPT 3.0979789-

1.24273 D50 87.4361

S2 X50 .0148923 _ D150 24.5686

FIG. lb. Computer printout of -DDO values (Berkson's method).

Center and distributed to respective users. Thetotal cycle usually takes 24 to 48 hr. We considerthis application to be highly successful since,during the first year of operation, approximately16,000 sets of data-representing the equivalentof 3.5 man-years of computational work-wereprocessed via this system.

Calculation.of ED5o or LD5o Via Berkson's MethodBased upon data for all-or-none responses,

this program (1) computes the theoretical doseand 95% confidence limits at which 50% of theanimals have been affected by some treatment.The computer program can accomodate a

maximum of 18 dose levels (Fig. la) with numer-ical values up to 99999.99 for each dose level. Aprintout of the processed data is shown in Fig. lb.Data sheets are collected and distributed dailyvia the Research Center Library as describedabove.

Additional computer programs, which havebeen or are being developed as a part of thegeneral-purpose statistical program, include thecalculation of: (i) chi-square, (ii) linear andcurvilinear regression, (iii) logarithmic con-versions, (iv) analysis of variance, and (v) ageneral-purpose algebraic formula containingmany options that can be specified by the user,

562 BACTERIOL. REV.


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including subsequent statistical analysis ofalgebraic results.

Specialized FormsIn conjunction with the computer statistical

programs, various data input-forms, some boundinto laboratory notebooks, have been developedthat render the statistical program more usefulfor both single-time jobs and for highly re-petitive work.The main objective in developing specialized

forms was to reduce the burden of transcribingdata and concurrently to prevent or reduce

Book 3C Page 1

errors of transcription; both objectives have beenachieved wherever this approach has beenimplemented. The following five systems exem-plify this approach.

Processing of data derived from scintillationcounts and spectrophotometer readings. A labora-tory notebook was designed in which the tearoutpages also serve as input-forms and code sheetsfor the key punch operator. Subsequent to keypunching, the original pages are returned to thebiologist for permanent storage. The data arecompiled according to a reduction formula and

Progroam No........ Program Page.....................

Book 3C Peg. 1 Program No.... ... ...........P.Progoom Page......................

Signoture

FIG. 2. Combined laboratory notebook and data input form for liver and carcass analysis.

563

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564 DURACH

processed via the mean and standard errorroutine.

Processing of necropsy data; liver and carcassanalysis. A laboratory notebook similar to thatdescribed above was designed for original re-cording and processing of necropsy data (Fig. 2).The computer tests the data for sufficient labora-tory processing, printing a warning when itdetects incomplete processing, rejects data ex-ceeding a predetermined tolerance, applies areduction formula, and then sends the data intothe mean and standard error program describedabove, providing full print-out.

Determination of curves based upon micro-biological assay calculations. This computer pro-gram calculates a standard curve based uponsubmitted turbidimetric data and then de-termines values for any number of assays basedupon the standard reference curve. The programincludes a table of over 40 commonly used con-version factors, with provision for additionalfactors to be included when needed.

Product development work load analysis. Theinput form for this program is shown in Fig. 3.Based upon work load estimates for current andanticipated development projects, this computerprogram calculates and prints a series of cumu-lative load tables which indicate work load and

'-aat"* ''-"PRODUCT DEVELOPMENT SCHEDULINGSHEETREQUESTED BY PHONE

SI.,I~~~~~~~~~~~~~I

_ _ n , |L N. | [REQUEST ATEY O.GR;0. 11G... , RG... V 'l

*-13 5 1-8 19-21 22-2. 25-271 28-30 31 321 33-SO

STI-T COishO M ONTHS REQUIRED-ROJECT DEPT _N~FE ROIYY.0- GA.RRP, G.P. 11 G.P .. GoRP,.1 G.". I

1F 9-1 1-3 1-5 1-7 819 20-23 2.-21 28-31 32-35 M,-39

-~-777 -7

:7-i71

FIG. 3. Data input form for the product develop-ment work load analysis.

ITA ET AL. BACTERIOL. REV.

"percentage of full load," based upon existingmanpower availability, by month, group, anddepartment. Since development projects areentered in a priority sequence, and a cumulative-load table is printed after each project is entered,the report yields a great amount of informationconcerning potential bottlenecks. It indicateswhen and where work-load bottlenecks willoccur, which projects can be completed on time,the effect of revising priorities on requestedcompletion dates, the impact of new projects,and related information.Automated weighing system (toxicity studies).

This system, presently undergoing development,is based upon the manual recording of data onsuitably designed laboratory-notebook input-forms. An automatic scale and recorder (ExactWeight) providing printed or punched digital-tape output has been evaluated and foundunsuitable for this application. A similar system,in use at the Lilly Toxicology Laboratories (12),however, does use a semiautomatic (Toledo)balance-apparently with satisfactory results.By use of this system, various parameters on

rats or other animals weighing 1 kg or less can beautomatically processed and tabulated by theEDP Center. Completed computer printouts ofdata are returned to the toxicity group formicrofilming and permanent storage. Numericaldata to be processed weekly or biweekly includebody weight changes, food consumption, andwater consumption. Computations include (i)mean and standard error calculations, (ii) de-termination of quantity of test compound to beincorporated into the food to maintain pre-determined concentrations of drug throughoutthe test period, (iii) analysis of variance on bodyweight changes, and food or water intake changes,and (iv) calculation of the actual quantity ofcompound ingested. A by-product of this systemis the accumulation, from all chronic experiments,of control-group data for normally occurringteratogenesis and other population statisticsstudies.

Punched Paper Tape and Printed Digital Tape;Data Based upon Animal Weight and Food

Calculations (Nutritional Research)Data pertaining to animal weight and food

and water consumption in nutritional studiesare entered directly onto punched paper tape,by use of a Friden Add-Punch; the printeddigital tape, produced as a by-product, is re-tained by the laboratory man as a file copy. Thepunched paper tape is automatically convertedto punched cards in the EDP Center precedinginput to the computer. A report is generatedonce weekly on experiments in progress, showing

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average body weight changes and averagefood-and-water intake.

Clinical Data

Case report forms (Fig. 4a and b), computerprograms, and code systems have been developedthat enable us to gather, analyze, and tabulatemedical and laboratory data, and print them outin a form suitable for use in New Drug Appli-cations (NDA). By use of this approach, an NDAfor the oral contraceptive/progestational agent,Dimethisterone (Oracon), was submitted to theFood and Drug Administration. Compilation ofthe data in this fashion (Fig. 5a and b) hasgreatly facilitated its organization and analysisfor the preparation of the NDA. Total duplica-tion time for 20 copies, each containing ap-proximately 1,600 pages of computer-generatedforms, required approximately 16 to 20 hr of

computer running-time on the IBM 1401; bycomparison, the former manual procedure re-

quired several weeks of intensive effort merelyto duplicate case report forms without any

tabulations of the clinical data.

INFORMATION STORAGE AND RETRIEVALAPPLICATIONS AND CLERICAL

ROUTINES

Key Word in Context (KWIC): Application toPublished Literature on Mead Johnson Products

and Other Technical DocumentsAll known published literature on Mead

Johnson products has been entered onto com-puter tape via the KWIC index program (8),made available to us through the IBM ProgramLibrary. The primary reason for having under-taken this task was to index this material indepth so that we would be better able to gain

MEAD JOHNSON RESEARCH CENTER

INVESTIUDATOR'S N550E DRUG ( INSTITUTION

DENTAL FLUORIDE

I D NO. ADDRESS (5!s068

GROUP CITY STATE d/

NAYS. OF PATIENT ( BIRTH DATE AGE(YRS - MONTHS)(16) SEX (CirclD) cl

BIRTH P!,5C RACE aCiaCID N g WEIGHT RHEIGHTI CaIcDAiDA NegRD DOthE-

PERSONAL SCHOOL GRADE (Circle) DATE STARTED ON PRODUCT(

DATA K 1 2 3 4 5 6 7 8

PARENT OR GUARDIAN'S NAME PHONE NO. 5) jADDRESS

LOCATION (

Rural Urban O Suburban

PPMF PPMF PPMF

PHYSICIAN'S SAME PHONE NO. ADDRESS (

DENTIST'S NA>ME ( @PHONE NO. ADDRES

ASSOCIATED MEDICAL AND/OR DENTAL CONDITIN(S)D)

DENTAL/1)

MEDICAL 2) SYMPTOMTSHI STORY

3) COMPLICATIONS

PREVIOUS SIGNIFICANT DENTAL OR MEDICAL THERAPY WITHIN PAST YEAR (Dates and results of extraction, drugs, etcR

FIG. 4a. Precoded dental study case report form. This form serves simultaneously for key punching.Front.

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566~~~~~DURACHTA ETAL.BCTRO.EV

-LIII- L-.I

UPPER ±~~..

9A~ ~ ~ ~

~10

EHF.t7h_1_~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~KL~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

19 - 20 21 23 2

FIG. 4b. Precoded dental study case report form. This form serves simultaneously for key punching.Back.

access to a large body of pertinent information.As a by-product of this application, we becamebetter equipped to conform to recently adoptedFederal Drug Regulations; specifically, para-graphs 130.3(a) (2) (6) (b), 130.35(b), 130.4(c)(iii) and 130.13 relating to published records andreports concerning experience on investigationaldrugs or those for which an approval is in effect.Until further experience with this system isgained, it is anticipated that the computer-gen-erated indices and bibliographies will be updatedquarterly, semiannually, and annually. Weeklyor monthly nonindexed supplements will also beprovided-depending upon volume of input.KWIC indexing can be adapted to the liter-

ature of many scientific disciplines as well as tocorrespondence and complaint files, specialtechnical reports, memoranda, legal documents,procedural manuals, etc. At the present time,all technical reports on programs and projectsin the Pharmaceutical Research Division areprepared for indexing and retrieval in this sys-tem; the chief mode of data entry is via theautomatic Friden Flexowriter.To produce the index, bibliographical entries

consisting of (i) title and subtitles, (ii) author,(iii) source (journal reference, address, etc.),(iv) additional descriptors or key words, and (v)summary or abstract are placed into a machine-readable medium such as punched cards orpunched paper tape. These subsequently areread and processed by the computer. Since allentries are made and stored in machine language,cumulative listings can be prepared periodicallyor updated and distributed as dictated by need.For example, in filing a supplementary IND orNDA, the bibliographical section on publishedliterature can be prepared and submitted, uponshort notice, either on tape or in the form ofhard copy (Fig. 6a and b).Inventory Control System of Chemical Compounds,Biological Testing Requested, Work in Progress,

and Work CompletedAll compounds submitted for biological testing

are catalogued in the Central Records Office viaa Mead Johnson reference number system. Byuse of a photo-reduction, offset-printing process,chemical structures and pertinent bookkeepingdata having legal or documentary importance

566 BACTERIOL. REV.


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VOL. 29,1965 AUTOMATED HANDLING OF CHEMICAL-BIOLOGICAL DATA

FIG. 5a. Computer tabulation of clinical datafor the oral contraceptive dimethisterone (Oracon).

* KEYWCRC PAG, 4~ELOCHERPAPFOCITE/1943E AMENOPRFEIC/EXCEPT-WHEN-UN-DRUCDS/ PS AC402UTERINE BLEEOING. PRIOR ANEMIA C NODULARITY IN CUL-TE-SAC. A0615

HYPERMENORRHEA, ANEMIA DUE-TO ANCVULATION SEX-F A27U 4SEVERE HYPERMENCRRHEA. ANEMIA WITP RECUCEC HEMATOCRITIHG A1610

DEC £ SEVERE ANEMIA. RENO/METRO /6-0ONTHS/ A2388.ELIVEREE-5-MCNTHS- ANEMIA-SECONDARY-TO-INTESTINAL-SPRUE A/175

DAY CYCLES. PT. ANEMIC PRE-RX . SEX-F MAR-STATF-G A1547RACE-U ANENCRRIEE ANOREXIA NERVOSA SEX-F RAR-STATE-U A2736

LOW BACK PAIN, ANOREXIA. A1056ICN. ANOREXIA-NERUOSA, DESIRES CONTRACEPT A0893CLIGOAMENTURRIEA DUE-TO ANOVULATION SEX-F MAR-STATE-U RACE- A27/3

ANEMIA TUE-TO ANOVULATION SEX-F MAR-STATE-U MACE- A276OMAR-STECLEUCAMENCRREEA ANOVULATION-8-MOS.-POSTPARTUM SEX-F A2762IRREGULAR MENSES-6-MOS. ANOVULATORY 88T SEX-F MAR-STATE-F A1529ARRIAGEI 8LEEOINGKIRREG ANOVULATORY NLEEDING/SHORTLY-AFTEE-M A20/1

ANEOVULATORY CYCLE, IRREGULAR MENSES A1493CPSY-N PRIM.-USE-AIO ANTI.GTH CRF PROO-504U-NA UT-R1 A0891CPSY-N PRIE.-USE-A10 ANTI.6TH CRF PROD-5048-AElUT-81 A0703

CPSY-Y PRIM.-USE-AIO ANTI.GTH CRf PREO-5048-ARCUT-61 £1101CPSY-N PRIP.-USE-AIO ANTI.GTH CRf TROO-50N8-DC UT-R1 R0519CPSY-Y PRtM.-USE-AIO ANTI.GTH CRF PROD-5048-DE UT-81 /0892CPSY-N PRIN.-USE-AIO ANTI.GTH CRF PROD-5048-SN UT-81 A1890CPSY-N PRIM.-USE-AlT ANTI.GTH CRF PROD-5048-SE UT-HI AN894CPSY-N PRIM.-USE-AIO ANTI.GTHC UT-El A1893

PREMENSTRUAL ECERA ANXIETY. SEX-F MAR-STATE-U RACE-A A0688CHOLECYSTECTMY AUSC APPENDECTOMY. SEX-F RAR-STATE-U A1962

PCS AGC/U 20 X 4 DTYS/ ARRFENCELASTCTA-L.-OVARY-ME TEO-5- A2118PREMENSTRUAL-TENSION, ARTHRITIS. SEX-F MAR-ST -A R0723STJ LI ACEKEP INCL. RTIFICIAL INSEREINATIE A2571

S5< A^MPS. PCSITS H<te DUNDEE. LAST ^A1588

FIG. 5b. Computer-generated index based on

clinical case reports. An application of the KWIC(key word in context) index program to clinicaldata.

are duplicated onto IBM cards as depicted inFig. 7a. These decks, some 40 in number, are

key punched, automatically sorted, and updatedweekly or biweekly. One master set is also codedand key punched for chemical structure. Non-steroids are coded according to a modifiedDerwent system (4); steroids are coded accordingto a code developed by the British Drug Houses(V. Petrow, unpublished data). Although theduplicating and sorting application may seem

trivial, it has saved approximately 250 hr per

year, has permitted the routine and timelydistribution of this form of information, and has

allowed us to apply the time to other equallypressing clerical routines. AMechanization hasenabled us to prepare weekly printouts andmonthly accumulations of tests requested; thus,the Records Office has been able to provideadditional service requiring no extra time fortheir personnel and concurrently to relieve

IN MAN FROMEARORAMOR ANIMAL STUDIES. CYTOXAN I/ CYCLOPHOSP OWENAJ-62-PATANTARLE AND PHONTANEOUS AN AL TUMORS. CYTORAN YICLDPOASPT MINEST-61-AEESODUTHLPEtCUDEiIDN G AILS O U OR. - PI R

XA 0;A18 ~

FDE# UK NARINU NTAS LYOOXN I 10PM UtRAM :>:LHOSPHAMIDI COLONI CAND ANORECTAL FUNCTION AND DISEASEg PUV TUREEO-61.-CAFEd THE USE OF SEROTOMIN ANTAGONISTS IN THE TREA TMENT 0* THE WEAVE A-61_USA

PHOSPRAMIDE. CYTUDAN /CYCLOPUOSPHA.RIOEA A PRELUIMINARM CLIN HOSTRE-60-PCSPIOSPRATTIDE. CYTUOXAN /CCLOOOSPF O IDE A PUELUS UE CLINIC EREGSD-6O-PCT

ANIMUE YTOXAN CLUPOOSPRAKIOER A TOTICLO AN A- -DEERTHEARMIA. LYTOTAN I CLUUSRM AE* UOG1. LIUI h-.WbREMOTHERAPT. CMTAN ICYCLOPUOSPHARIOE AAROMRINAL PERFUSED SRINGA-60-APCHEMOLECL U.E CTOUN /CYCLOPMOSPHARDEA ARSORPOTON, DIFFUS RITFRUAO

IDEA DCLOY OPANTE/CMTDN N ACUTE LEKEERIA. CYT OXAN UUGOA-UI-LCAIDACCLOYSPAC E DTDN N ACUTE LEUKEEMIA. PRELIME UGAU-C

SOF CMCY RSR1EkLM DTA E OTTAL MIIE ANBIRIC ~'~DUS-IDE CCMOSAIE/CYTOXAN/ TERAPM DF CMILDHOODR NEURON EONTRS-61UCCTO O C'CLO.PHOSPRARIT /YCTOAN/ 1PUINt ORE RENA TOPOIETIC SYST NIERMHE-6U-ECCLOPHOUDRRIER LIICAL EVALUATION, OF A NEW ALKYL DING AGENT COGGIP-UU-CENRANICDCLUPHOSPRARIDEO RUALUATU UP ANTIL EUKAERMIC AGENTS U GOLDIASEA

OL ION OFCDCLAOAPR0SPUARIDE /CYTUJ AREELA-6ZLO UOSPRARIDER PHASE VIRALUATION OP CYCLTPRUSPURO: ETHTEF-UEACULOGY AND PRELIRINAN RUALUATIUN OP CYTOXAN ICDCLOPHOSPDAN COGGIP-59-CPP

UAN /CYCLGJPHOSPHAMREDE EXPERIRENTAL AND CLINICAL RESULTS IN DUBOIR-61-ECRRAN /CYCLOPHOSPUAMIDEA EXPERIMENTAL AND CLINICAL RESULTS AI GERUAU-60-ECR

DAN /CMCLOPMOSPMADIE: E MEIENTAL EVALUATION, OP POTTENTA SP-UEPDNICYCLOPHOSPHARIDER EXPERIETLEA LUATIDN OP PDTENTIAL SCRAFJ-U1-EEP

CE THERAPM UP MALIGNANT HERANLASTORAS. CYTOXAN I CYCLOPHOSPR KUEROJ-60:CMTFROM CHENECALLY INDUCED HERATOOEPRESSION. CYTOUAN / CYCLDPHODNIERMR-61--RCIX!CAAUU LPOUT AI RHEMATOLOGI EDLAINIF DIDRS AU, EL -XIONE;CA, IC Eo EMATTLOGTCJ D EFFECTS UPYCLOPR40SP r SLGENA -RSE

CORPARI 00 BETAEEN THE RENATDOCOGICAL SiDEEFFECTS OP CVCLOP NISSRO-U60-CBHRIDE ESTER IENDOXAN/ UN RERATOPOTESIS IN TUE THERAPM UP RUALE PETRIP-58-EGEACID DI AMREOE1ENOOUAN.I TOUICITTMOFYN,N-RIS-/NB-CHLDOREMRL/- N RUYASY:63:TPASA OF NTROENFEUALEAGENITAL CRATYFOLL TOINANTENECOPLUSPUICTRE KLM60A

P n r~~~~~~~~~~~~~SO MI-U-N

OF THE GASTROINTESTINAL TRACT WITH ANTITUMOR AGENTS. CYTOXAN

KEYWORD

3yR I4c-i1-R"FHURLEJ- L- TAC

MACHINEGENERATEDCODE

FIG. 6a. KWIC (key word in context) index topublished literature on Cytoxan.

WHRELA-61-TPC WHEELENR A.G. DANSAM. . HNAUINS, C.H.TODICOLOGIC P'RO'PERTIES OP CYCLOPHDSPRARIDE /CMDDDAN/.CYTDXANI CYCLOPHOSPHARIDE

FED. PROC. 20.- 434 PART MARCH RU96E. ACDCLTPNRSPUARI1DE /N,N-NEL/B-CNLDRETHML/-R D-PRDPYLENEPHOSPHORIC ACID DIANIDE RONOHYDRATE/ RAS TROODCED AD APOTENT CYTOSTATIC AGE;Ti WHICH S THOUGHT TO NE INACTI VE INITS TCAGSPORTFOAMT CT RATED INTO A POWERFUL ALKYLATllG ACENT BY ENZYME ICTIVITY AROO . ET AL, NATURWISSENICHAFTEN 45.6-R66E. 1958-. IN RICE 1ND &ATS TH °ORAL LDSARALUESEAERE 35 AND9RNGRU/E RESPECTIVELM. DOGS SURVIVEDREPEATEDORAL DOSES OF 5N RUKG 5 DADS A REEK FOR 6 WEEKS. ONA SIRILAR SCHEDULE RATS TOLERATED 6 RG/KG. ALL PATHOLODICALLESIONS - PETECHIAL HERORRHAGES, SPLENIC CONGESTION WITHREACTIVE HERATOPOIETIC TISSUE AND NONE MARROD CHANGES-WEREREVDESINLj WITHIN 2-N REEKS. ADMINISTRATION NY PARENTERALEDO DE A S NLL TDLERAT ED. * INTRADERRAL RRITATION AAS VENDMUCH LESS THAN AITH NITRODEN MUSTARD. FOLLDWING A SINGLESUELETHAL ROSE THE PERIPHERAL ALOO EXOHNBIDTER LEUKOCYTE RE-PRE SION WITHE AECOVERY IN 3 WEEK S AND ERYTHROIO DEPRESSIONETHN CORPLETE RECOVERY RETHIN ED bUMS. ON REPEATED DOSES THELEDEOPENIA EATS RWA ACCDMPANIED BY A REVERSAL Of THE NORMALN UTROPHIL- YMP OCYTE RATIO. DEVELOPMENT OF LEUKOPENIA INDOGS CORNELATED AITH ROTH DOSE LEVEL AND TOTD DOSE ADMINIS-TERED. IT RAS EVIDENT THAT TOSAUE COULD BE TI RATED USING

IL-* ANHEELER. A.G. DANSBY. D. HARKINS, N.C.A TOXICOLOGIC AND HEMATOLOGIC ADALUJRCYCLOOPANIDE/CPHOSPYTOARN/ IN EXPERIMENTAL ANIMALS.

TOXIOT . AND APPL. PHARMACOL. 4.- 324-343. /NAY/ 196E. A2HMNARYOHE ACUTE TOXIC TM OF CYCLOPHOSPHAMIDE RAS DETERMINED INRICE. RATS, AND DOGC. THE LETHAL EFFECTS WERE DELAYED AFTEREITTOR ORAL OK INTRAVENOUS ADRIN ISTRATTON. THE 14-DAM ORALMEDIAN LETHAL ROSES TO RICE. RATS, ANDENOUNSCERE 350 RU/KGR94M/GADAPPROOTRATEL aNGREEE EPETDAD 121STAAT102,OF ODAL DOSES OF 6/C5K. WERE IELL .ERAT5EM

RATS DEREDOSES OF 3 NG/KG EY DOOS. LARGER DOSESCAUSED PROCRESSIVE DEBILITATION ANM DEATHN OE PREDOMINANTHEMATOLOGIC EFFECT OP CYCLDPRRSPHNAIDK NAbLEUCOCYTICDEPOEE

NEON. CONSIDEGRALY LENS DEPRESSION OP THE NOE ARROW OR

THRONNOCTE S RANOOED ONE REITANCY POTENTIAL OPCYCLOPH-OSPHANRIE AS REASONED NM TNTARERMAL IKE ITA N AND EFFECTSMAONCILIAR TILIO MAN LOW.ESPECIALLY AS RELAYED TO NIT-ITEOOFTHELKYLATIN AGENTS UPON IN VEI N COFMAC EEC ACIDS OF CYTOXAN-SENSITIEAND, YOXAN-RENI OCAMMOAN /ASI HMTES

CANCER RE PROC. 3.. /NARCN/ 1962D MD. D92. /AASTR./ ADIDM NIOTTANONSOPCMRDDANOTINO EN OR O-TEPA TO

ARNST NEARING EILATERALLY IRPLAATEDO I OOEAN-SENS ITIE ANNCYTOOAN-EENESTANT PLASRACYTORAS CRSED REGRESSION OPTOE SENDITIE TUMOR1 WAILE ONE RESISTANT TUMORCONTINUER DO GROW.INCRONDORATIUNDOFPDRMATE-CI4 INTO ORE PARINES OP ERNA ANDDNA WAS INHERITED RD THESE AGENTS IN THE SENSIT TOE TUMOR EATNOD IN OR REISTANT TUMRD. ONE INCORPORATION OP ADENINE-N-CAN INTO THE DNA-ADENINK OP ONE SENSITIVE TUMOR WAS INNER-TED MM THESE AGENTS.,* LENS OR NDOIRA RO ON O THE INCOR-PORATION INTO DNA-GUANINE, RNA-DN N DR RA-GUAN IRE DCCURREE. OC ISTENT INNINITINOPHEI NCORPORADTEON INTOONE DNA DR NRANOPF HE RESISTANT TRADE OCCURRED. CHRENATO-UNR PRIC-RA2IDAUTOUAAPHIC KUAMIMATION OP EXTRAC STSOP THENTED~SU isNDLCAEDETHT SYNTH SIS OP PURINE NUCLEDOIDES OKMAS:IJIT2 BS HATFTHEE MAR LITTLE EPPF CO UPON TNT; POE-

MAI IN DlGNUkETIDE PRMPEORD RNN- N TREATMENTCUSRA KE~AL EKCEAsE EM TM K RANDITY ArcENPERO FOR-

FIG. 6b.Cytoxan.

Abstract section of the KWIC index on

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9332 3 4 5 lo I b 9 10 11 Id 13 is 5 16 I' lit i9 21

25


MILFORMULAOJMo.rwn. J. No.

l ~~~~Ci12B32U23 25

NAME PHENOWBRITAL; 5-3THYL-5-PHENrLBARBITRIC ACID (STJ W REFERENCE)

MOL. WfT. | %ACTIVE INBE"D. AMOUNT N f 0 o9ouz COPON -7a boo COMPOUND

232.2 100 1 stookPREPARED BY MOT9-O.0 O.

Mallinckrodt (Welikel) HDATE APPEAR^FlCE

October 31, 1962 white solidSOLUBILITY Cg

Welr HC+ mg. H O toI 1WC2H5|

Ad)^a~di _ 1.. O/Be' ppS. pH WF.AH_._S.I .Alcohol to 125 .S. He. ppd. _ _ " H N

ST erILITYAND HALINe EiTp

CLOSE RELATIVE OF

LT. REP. Mrck Index, 7th Edition, p. 74IeVC I 'a I." zC' 10XA I

21 22 23 24 25 26 27 X8 29 30 3l 32 33 :- IS 3b 31 38 39 40 *1 4? 43 4!: 45 *D 41 48 49 50 51 52 53 54 SS %4 57 is 59 60 61 62 F3 64 65 66i 67 68l 69 70 71 12 73 14 15 76 77 78 79 03

FIG. 7a. Mead Johnson chemical structure card.QTRLY BY TEST METHOL NO. APRIL 9, 1964

M.J. NO. LOTNO.RETEST TESTNO SP. COL. CODE COMP DATE REQ. DATE CO4ENT

587 DL LOT 2

663 DL

697707 LOT 2

735735

x 735

737 1

x 740

x 740742742742 1

743

06DA 0SD 03/05/64860A K 01 02/25/64860A M 01 01/23/64860A C 01 02/25/64860A K 01 02/25/64860A K 01 01/23/6436CA K 01 03/05/64860A K 01 01/23/6406DA K 01 02/25/64'960A C: 01 02/25/64860A : 01 02/25/64860A K 01 03/05/64860A K 01 03/05/64960A M 01 03/05/64

02/04/6401/10/6410/30/6302/04/6410/30/6310/30/6311/04/6311/15/6312/13/6312/13/6312/30/63oa/08/6401/08/6401/29/64

GROUP TOTAL 26

RETEST 6CRB u 01 02/25/64 02/14/64

860B U 01 02/25/64 02/14/64

FIG. 7b. Sample page of an inventory controlsystem of biological testing requested, work in prog-ress, and testing completed.

laboratory personnel of a time-consuming clericalburden.As a by-product of this record-keeping

function, other data are key punched into sup-plementary cards and are accumulated for an

inventory control system (Fig. 7b). This systemhas replaced a manual operation that wasessential but very time-consuming. Data in thefile are used for the preparation of quarterly andannual reports, requiring not more than 1 hr ofclerical time quarterly. Manually, this reportrequired 1 week per quarter to compile, type, andduplicate. Similar records had been maintained

by various laboratory personnel.It is anticipated that future expansion of this

system will enable us to improve our method forpredicting fiscal budgetary requirements.

Systems for the Reporting of Biological Test DataResults

This system and the preceding chemicalstructure card system are intended to form anintegrated approach to the routine and timelydistribution of data issuing from the researchlaboratories. Subsequent to the completion andcompilation of biological data, summarizedresults for each compound are reported to allinterested members of the research staff via testdata sheets distributed from the Central RecordsOffice.

This system, however, is presently beingconverted to an IBM card format (Fig. 8a) tofacilitate the distribution of test results; a flowchart depicting this system is shown in Fig. 8b.

COMBINED DATA PROCESSING AND INFORMATIONRETRIEVAL SYSTEM FOR PHARMACOLOGICAL

DATA (5)One area of biological coding, in which we have

conducted extensive experiments, is that con-cerned with the initial screening in animals ofpotentially useful medicinal agents. This codesystem, referred to as a "side-effects code," wasdesigned for the storage, retrieval, and cor-relation of gross signs of pharmacological activityin animals. This concept will become meaningfulas the code sheet (Fig. 9a and b; see also Fig. 10-12) is examined.

Code Sheet and Card LayoutThe broad areas of biological response, relating

primarily to anatomical systems, are located on

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VOL. 29, 1965 AUTOMATED HANDLING OF CHEMICAL-BIOLOGICAL DATA 569

the far left side (labeled A) of the code sheet columns (columns 29-75) on the same card. This(Fig. 9b). Specific pharmacological signs are was accomplished by employing an alpha-numericlocated in the adjacent column to the right coding system and arbitrarily dividing overt(labeled B). Because of space limitations on the pharmacological signs into "adrenergic" andIBM card, a procedure had to be developed "cholinergic" categories. Although this divisionwhereby a multiplicity of doses, as well as the occasionally does not make pharmacologicalside effects, could be coded simultaneously in 47 sense, two important objectives were achieved:

FIG. 8a. Summary biological test data card.

A. CHEMIST B. CENTRAL RECORDS OFFICE C. BIOLOGIST

PhysicalData

1) Ch.i.1 s.bhits Mood JohbsonCb.mical submission sbeet toC...rl Recoods Offic. fe-ca

b.scempo .d at bicb time

biologicol testing is mequeste.d

D. RESEARCH CENTER

C2H50HPhpsic..Data

2) C*.tse I

phstoAd

IC2H5

~~~~~~~~~~~~~~~~~SIo L<1 B. tes|

| ~~~~~~~~~~~~~~~Data Sheet |Dot. Sh ...t

Recoods Office p*pms 41 Ce.r Recods Office processes 5) Biologist completI.ctien of top half. biologio.l test daH shoot on.d stsco pletee

f/hro-.,s to biologist togethe, sheet to Recodos C/ith copy of Chbeio.l strct.ue processing onddis

S.,f co.nsei.. ofse.

/ CDa Sheet

BAA Core

C*o.I Recods Offic.prop..s IBM coeds aodf.-.,drs thes. t. Dot.P .c5s0ing CaN.e,k.y-punchi.g.

/ C2H50H |Su~ery Bio

I Test Det.a

7) Fooed to EDP C.e.,fo, k.y-p..chi.g e.dSoH2ing.

6) Caoal Radods Offic.p2Sp.r.s mi.ofilmo.dmultilith mesters fremcombi..d ch-icol onobiological test doo.o

o) M.ltilith pbotoreeuction.f s..aay act..

b) 8'i 11tl.t do. sh..t.

/

tes #.St eneIfst<touOffic. foristriution.

DISTRIBUTION

FCIt.l R .cFldsOffi fil ol o 9ica l d at ..d forsodIUXJ. M.o .nd Tws Aittho N.. moD C ,e for keey-punhing

FIG. 8b. Flow chart for processing of chemicallbiological data.


/ 500 4014 Clo1oN40S RX-75L11-iN2:TYLINDOLE-2, 3-DIONE 3-THIOECARBAZONE (STANDARD REFEMRENCT)

I.LClY -EC 1.tlZ4. i0 ..O.., 2 ...COOC.. 0N ou~

234.3 100 1 5 g.

2Nut. Biochem. Corp. (Harrison)

April 29, 1964 yello powderTD-TAr;fa _ DATE CCoVrF7 D S ;4 ICH3

'-'''-D-'i 4f -(C..vDY P 1 m =~ ~ A

2 0 MAY 1934 =N-NH-C-NH2ar>M MINIMAL INHIBENRY

T-ST 3ACT-=RLA REACTION CC Z (-cg/.I)Staphybco~cusau-eus P-siti-e 7 {OD

__ ____

Homnaarutl os NgatHve _ v M p. 239-24C°(dec., (Corr..Salmlon- 11a typhl n urlu Negat2l 7/00

FD -CR. ANTIBACTERIAL ACTIVITY IN VITRO (H±nl1 IShbIt0ry Co-.otrtlon)

AzV.IaACVIAL RHATIrm E ..OisOtmOodert. M slight E I

s cti-eRECOMMENDATIOH NNoFutheH T..Etig Purther T.ting W.nted

EB.tt Tha- Better h

COMPARATIVE ANIBACTERIAL ACTIVISTY EEqa TSo Eql T.

I...s Th-n L... Th-n

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f=Hl- LIST |PROG./PRO MOL FORMULA '! J. NO.

RI1rEUC LIST *]r~o. O C12HN203 R- 25NAME PHENOBARBITAL; 5-ET YL-5-PHENYLBARBITURIC ACID (STANDARD REFERENCE)

MOL. WT. ACTIVE IN.RE. N NEW COMPON|NN COMPOUND

232.2 100 1 stock .PREPARED BY NO mo 0

Mallinckrodt (Weikel) HDATE APPEARANCE

October 31, 1962 white solid NDATE STARTSD]4A./ DATECOMPF1TED91rxsC5l

NOTEBOOK C OMPLE!TED BC 5:DI: LIse maAAPPROVED BYr7m.1 DATE

/ S

SPECIES h104/5 E6 SEX& ROUTE 0

DOSE LE'VELS (mg/kg ,SALT) ,

Ro /9 t, 3oASY 5~6- ____,/19 ID5_ 3SN_ _;2_ 7./k9

LD5C--ZL0-* Q° /kg Dso mg/kgTESTES FORt ACUTE TCXICITYSUIVAhRY OF DRUG, ACTION:

Standard Reference Agent, Phenobarbital.Initial excitement followed by sedation,hypnosis and death.

M. J. No. SALT MSSESD I3p. Seo Rt I ASY *TD50 *LDo><L'NE S 2 S 4 5 -7 A 9 10 11 12 13 I4 1511617|18|19|20 21 22 23 25R 26271/ooNo.z/oo 113143.45Oo (SERper; ^H | 0 00l; | l_*0, OloM3I 2| | l l | VE)

REVISUE:U E -_Active Component

FIG. 9a. Biological test data sheet; also used as a code sheet for key punching of data. Front.

(i) the definition is consistent, and (ii) thealpha-numeric coding system expands the spaceavailable on the cards.The remaining columns (columns 76-79) were

dedicated to rarely observed side effects; theseare punched without regard to dose level. By use

of this direct punch field, 48 additional numericalcard positions were provided for future expansion.Column 80 is a control column and is alwayspunched "4" in this deck. Initial studies sug-

gested that rarely did a drug simultaneouslycause "adrenergic" and "cholinergic" effects inthe same animal, although, for example, bimodalactions such as miosis (column 57) and mydriasis(column 58) might occur at different timesduring the test period. It was therefore assumedthat judicious pairing of "side effects" would

reduce or circumvent widespread conflicts incoding, and simultaneously conserve space. Thisassumption was partially incorrect; in practice,code conflicts were encountered, and it there-fore became necessary to evalute the magnitudeand significance of this code defect.

Analysis of the master file indicated thepresence, in four of the "side effects" codecolumns, of conflicts. It was apparent that thesehad occurred because the code structure hadbeen based upon the assumption that a given doseof a specific drug would affect all animals in thesame test group in a similar way although,perhaps, not to the same degree.

In practice it was found that supposed"mutually exclusive" events occurred simul-taneously or alternately; that is, in the same

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YRHETl / c '

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DOSE CODE (Adrenergic) o A B C D E T TO H1

DOSE LEVEIS (mg/kg.) 3 51

5-201 20 1-1 5010 2000 1 5<.C 5-221--It1--0-CllIJ DOSE CODE (Chollnergic)

-Nystag-Edema)

-Reap .R

-Reap.I-Eurhyt

-Hypothq-Periph

-Enophtl

l R

-Chromodacryorrhea(C)-i.uI.Hvperfunction(C-Saliva, Watery( C)-Lacrimation( C)-Rhinorrhea(C)-Polyhidross(aC)-Anuria( C )

7I _13

=

_=-2-=

.Refers to mInnum lethal dose.

CODING INSTRUCCTIONS: Indicate the lowest dose at which response occurs in any animal.Biphaslc response Is indicated by the letter X at all doses where seen.

FIG. 9b. Combined biological test data sheet and code sheet. Back.

test animals at different times during the testperiod or in different animals of the same testgroup at the same time. Conflicting eventsincluded: (i) analgesia versus pain/writhing(column 38), 4.9% (21/425 conflicts); (ii) res-piratory rate decrease versus respiratory depthdecrease (column 48), 1.2% (10/851 conflicts);(iii) hypothermia versus hyperthermia (column53), 6.7% (3/45 conflicts); (iv) hematuria versusmelana (column 71), 9.1% (2/22 conflicts). Itwas found, too, that code conflicts were impos-

sible in three columns [column 29: "Side effectsunspecified" versus "Ataxia"; column 42:"Bizarre behavior" versus "No drug effects";column 64: "Vomiting" versus "Chromodacryor-rhea" (only rodents exhibit the latter action androdents do not vomit)] because they were truly"mutually exclusive"; i.e., one pharmacologicaleffect excluded the possibility of the occurenceof the other.Although some of these conflicts could have

occurred through mistakes in recording or re-

A SIGNS

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FIEID

A - emical

NJ slrber prefixF: compoeid derived from outside sourceR: rcfcrence standardl

'J numberNsbetbs fran 1000 through 9999 occupysolumns 3-6; higher numbers utilize 2-6.

Drug combinations are nct coded.

Salt nuaeberPlace nssmber as far to the right in these3 solaunns as possibie. For hydrated salts,omit the hydrate designation.

B - ill Melthod

Tcst "'ethod number providing the side effectsdata

Suffix, if any. Disregard Test 100 suffixes

C-

Specsies

tM mouseraiL

R ribb itC cat

D dog N chickenG guinea pig P pigeonH hamster K manF frog A Rhesus monkey

Q squirrel nonkey

F female B both (or notstated)

Rckit e

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P i.p. T topical0 p.(,. A istiter-srteriaI1. lymph sac R intra.' s-lsslSi aer.osol J contissti,;isl ;a5

FIG. 10. Partial key to the side effects code (cardcolumns 1 to 16).

porting of test data, it was apparent that neitherthe magnitude nor the significance of the conflictslimited the utility of this code; therefore, no

corrective action was required. Were we tostart anew, however, some attempt would bemade to eliminate this situation entirely.

Validity of the Code Deck

Because intelligent retrievals can be conductedonly if the composition of the file (i.e., code deck)is known, the frequency of occurrence of sideeffects and other items of information was

analyzed; the results of this study are shown inTable 1.The most frequently observed and reported

signs relate to the central nervous (ataxia/hypo-activity) and respiratory systems (dyspnea). Itis noteworthy that the majority of assays (83.1 %)were conducted in mice, that the primary route(65.4%) of administration was oral, and thatacute deaths (i.e., within 24 hr or less) occurredin more than half (56.6 %) of the animals.However, the most critical phase in determin-

ing the validity of the code system was to compareand evaluate manual versus machine retrievalsbased on real data compiled from our labora-tories. This was done manually with data basedon bioassays in mice for the 10 classes of stand-ard reference drugs; results were as follows.

Hypnotics and sedatives. This category ofagents, representing 46 bioassays on 12 known

reference drugs, was characterized by the pre-sence of ataxia, hypoactivity, and hypnosis, andby the absence, in general, of central stimulatoryeffects. An exception to the latter was hyper-activity, which had a frequency of 56%. Ataxia,hypoactivity, and hyperactivity generally tendedto occur in the same dose range, which, however,was lower than the range in which hypnosis,dyspnea, and respiratory depression occurred.This disparity was significant but not unex-pected.

Anticonvulsants. The 14 tests on four knowndrugs in this category revealed the presence ofhypoactivity and the general absence of centralnervous system (CNS) stimulation and convul-sions.

Centrally acting interneural muscle relaxants.This category, comprising 18 bioassays on 10standard drugs, was characterized by the pre-sence of ataxia and hypoactivity and the generalabsence of CNS stimulation. At this level ofevaluation, specificity of action could not bemade on the basis of reports of muscular hypo-tonia or the separation of depression of mono-synaptic and polysynaptic reflexes. As might beexpected, this category merged with the seda-tives.

Narcotics/analgetics. Ten tests on five standardnarcotics failed to show a high frequency of anyone sign; three frequently observed and reportedsigns were hyperactivity, ataxia, and Straubtail. Hyperactivity always preceded Straub tailas the dose was increased. Although analgesia wasreported only 40% of the time, analgesia orStraub tail was reported 100% of the time.

Antipyretic/analgetics. Nineteen tests on fivestandard reference agents revealed mixed stim-ulatory and depressant signs; notably absentwere effects such as alteration of muscle tone,piloerection, and respiratory stimulation. Asexpected, these drugs were relatively nontoxicand failed to show marked analgetic activity ina gross screening procedure of this type.

Tranquilizers. Six drugs had been screened in17 tests. Sedation and ataxia were the mostprominent signs in terms of frequency; reportingof ptosis was frequent in comparison with othercategories. As dosage increased, sedation ap-peared before ptosis. Miosis was absent.

Anticholinergics. This class, comprised of 16assays on 10 drugs, was characterized by thepresence of ataxia and sedation and by theabsence of hypnosis, diarrhea, salivation, andlacrimation. Interestingly, mydriasis had a fre-quency of only 25% and constipation or xe-rostomia were not reported at all. The absenceof the latter signs, no doubt, is related to theacute nature of the test procedure.

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TABLE 1. Frequency of occurrence of pharmacological effects based on more than 5,000 bioassays

Sign ~~~Fre- Per SinFre- PerSign | quency cent Sign quency cent

Ataxia.............................Hypoactivity ......................Dyspnea...........................Convulsions, clonic.................Hyperactivity......................Hypnosis ..........................Convulsions, tonic.................Respiratory rate decrease...........Tremors ............................Respiratory rate increase...........Straub tail.........................Salivation, watery.................Analgesia ..........................Convulsions, asphyxial.............Hypotonia .........................Ptosis..............................Simple polysynaptic reflex..........Exophthalmos ......................Mydriasis ..........................Hypertonia.........................Hostility...........................Coordinated polysynaptic reflex....Lacrimation........................Diarrhea...........................Respiratory depth increase.........Vomiting ..........................Piloerection........................Vasodilation .......................Monosyn reflex.....................Writhing...........................Salivation..........................Bizarre behavior...................Respiratory depth decrease.........Tachycardia .......................Ascending paralysis................Vocalization .......................Xerostomia ........................Polyuria ...........................

3,2653,2141,9061,4141,2269708177907477297113843543323172762471951671621501481401381281111058983716261615443383332

69.468.440.530.126.120.617.416.815.915.515.18.27.57.16.75.95.24.13.63.43.23.13.02.92.72.42.21.91.81.51.31.31.31.10.90.80.70.7

Scratching.........................Hypothermia.....................Pupillary reflex....................Vasoconstriction ..Miosis.............................Descending paralysis..............Priapism...........................Arrhythmia........................Hyperthermia......................Hematuria.........................Bradyeardia.......................Local irritation....................Rales..............................Chromodacryorrhea ....Nictitating membrane relaxed.Algesic response in hypnosis.......Grooming .........................Epistaxis ..........................Eurhythmia .......................Bloody stools......................Anorexia...........................Enophthalmos .....................Local analgesia or edema...........Bloody vomitus....................Nystagmus........................Edema ............................Coughing..........................Constipation ......................Sneezing...........................Anuria.............................Rhinorrhea........................Hyperphagia ......................Xerodermosis.....................Xerophthalmia ....................Polyhidrosis......................Generalyzed edema................Flatus.............................

Anthihistamines. In this category, five stand-ard drugs had been subjected to 10 tests. Char-acteristically present were ataxia and hyper-activity, with frequent reporting of Straub tailbut no piloerection. Ptosis and diarrhea wereabsent.

Adrenergics. Seventeen assays had been runon 11 drugs in this class. Separation of alphaand beta mimetics did not affect the results.This category was mainly characterized by thepresence of CNS stimulation, although no onesign was reported with a very high frequency.CNS stimulants. In this test category, the

results of 27 tests on 14 standard compoundswere reviewed. This class of standard referencedrugs was characterized mainly by the presenceof hyperactivity and the absence of hynosis.

Reports of ataxia were reported infrequently,whereas convulsions (usually clonic) were re-ported frequently in comparison with othercategories of standard reference drugs.Based upon this study, machine retrieval

programs were written for the 10 categories ofdrugs listed above.The percentage error in selection that would

have occurred had these drugs been screenedaccording to the machine programs is shown inTable 2. Some explanation regarding the in-cidence of false drops may be in order. Forexample, in the sedative/hypnotic class, con-tributing to false negative errors were data frombioassays in which inadequate (e.g., hypnotic)dose levels had been used, the false positiveerror appeared to be due to the arbitrary clas-

3027242120201818181716141110108777554333322111110000

0.60.60.50.40.40.40.40.40.40.40.30.30.20.20.20.20.10.10.10.10.10.10.10.10.10.1

0000

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sification of muscle relaxants as nonsedatives,whichlin general may be incorrect.

It is difficult, if not impossible, to programsatisfactorily for the retrieval of anticonvulsants.There appears to be no satisfactory substitutefor the antimetrazol, antistrychnine, or electro-shock screening procedures. The large falsepositive error, however, can be greatly reducedif the barbiturates are included in this class.

Referring to the antipyretic/analgetics, wefind the poorest differentiation of all. This servesto emphasize that drugs in this class do notreadily lend themselves to detection in pre-liminary screening procedures or, for that matter,in highly sophisticated techniques.The large false-negative error for tranquilizers

was due to the absence of reports of ptosis in fourrecords. Other sources of error for some of theremaining compounds could be traced to theinclusion of monoamine oxidase (MAO) in-hibitors as CNS stimulants and the arbitraryand perhaps incorrect assumption that anti-histamines and adrenergic agents were notCNS stimulants.The following conclusions were derived from

the foregoing study. (i) Classification of newcompounds could not be based upon the "text-book profile" of different categories of drugs, butrather upon what the biologist really observesand actually reports under routine laboratoryconditions. The two are definitely not the sameand to assume so is to risk grave errors. (ii)Pharmacological classification of drugs is oftenbetter predicted by the absence rather than thepresence of certain signs. (iii) Experiencedpharmacologists are needed "at the bench"

TABLE 2. Per cent errors in machine retrieval bydevised programs based on manual retrieval

and evaluation of the data

Pharmacological class Total False Falsebioassays positive* negativet

Hypnotic/sedative. 46 7 17Anticonvulsant .. . 14 31 0Anticonvulsant includ-

ing barbiturates 18 0Muscle relaxant....... 18 19 6Narcotic analgetic.... 10 8 0Antipyretic/analgetic 19 26 21Tranquilizer........... 17 2 24CNS stimulant........ 27 13 12Anticholinergic ..... . 16 23 6Antihistamine......... 10 8 10Adrenergic ............ 17 11 12

* False drop of cards not of interest.t Failure of cards of interest to drop.

COLUMNS 17, 21, 25

CODE MEANING

A

I

C

D

I3

K

L

N

<1

<2<3

<4

<9

>1

>2>3

>4

COLUMNS 20, 24, 28

CODE MEANING

0 xlO1 - x11 X 101 . X 10

2 xlo' - looO3 x 103 - x 1000

9 x109

A x 10 1_ x 0.1-23 x 10 2. x 0.01

-3C xl10 3 x 0.001

-4D x 10x_0.0001

R >9 x 109

FIG. 11. Conventional dose notation.

during initial screening of compounds when, infact, the opposite frequently occurs. (iv) Manyobservations are not recorded. (v) Despite thevariability and scarcity of certain facets of data,machine retrieval can be a practical solution tothis type of information problem.

Method of CodingThe dose notation (Fig. 11), suggested by

Abbott Laboratories, enabled us to code a largerange of doses in four card columns. For example,in the four-column field representing the asymp-tomatic dose (ASY, columns 17 to 20, Fig. 9a), wewould express a dose of 1,000 mg/kg by enteringthe first three significant figures into the first threecolumns (columns 17 to 19) of the field. The lastcolumn (column 20) is used for an exponent toconvert the 1-0 to 1,000. In this example, theexponent would be 10 to the first power (101);the exponent 1 is written in the last column(column 20). Thus, 1,000 is coded 1J-1J;10,000 is coded 1-0-0-2, etc. Negative expo-nents are coded alphabetically; thus, 10-1 = Aand the number 10 is coded 1-0-0-A; 10-2 = Band the number 1 is coded as 1-0--B, etc.The lowest dose range in which a pharma-

cological sign is observed is coded either byletter or by number. For example, in an acutetoxicity study, if ataxia first appears at 10 mg/kg,column 29 is coded with the number 2. Thenhyperactivity may appear as 5.0 mg/kg, andcolumn 31 is coded with the letter B. This pro-cedure is followed until all side effects have beencoded as shown in Fig. 9a and 9b. Also notethat: (i) the lowest dose level at which any signpersisted for more than 24 hr is coded in columns72 and 73; (ii) the dose range for lethality duringthe first 24 hr is coded in column 74; (iii) theminimal dose causing deaths after 24 hr is codedin column 75; (iv) if no deaths occurred, then thehighest dose administered is coded in columns 74or 75, or both. As mentioned previously, the

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remaining columns (columns 76 to 79) arededicated to rarely observed side effects via adirect punch procedure.

After completion of coding by Records OfficePersonnel, the sheet is forwarded to the EDPCenter for key punching of a specially designedIBM card and for verifying and incorporationof the card into the master file.

Problem of Ambiguity of Biological Terminology

The process of coding test data sheets served toemphasize that definitions of biological activity,particularly those relating to behavior, are oftenvague or variable.

It was therefore believed that a subjectauthority list or Dictionary of Biological Terms(Fig. 12) would be helpful, not only for codingpurposes but also for reference use by laboratorypersonnel. Consequently, a dictionary wasprepared for use in conjunction with the sideeffects code. Its contents were based upon de-scriptions of biological activity obtained fromnumerous published and unpublished reports,other dictionaries, and well over 5,000 biologicaltest data reports. Laboratory jargon was includedand defined, whenever possible with assistancefrom laboratory personnel. In certain instances,

AHS:NCE ,I E --acuat> r., wels.const ipaF;.io

ABSL!:LE of pain. A ,-X. a

ABSETCE Af a-r1 . ria.

As'CTI L;E .N l , oeoi zedd, inboyj, cavi t E 5 s: An~asdrca.

ACC-.'LAT10N, do loalized, inbodyIv cdvitics r t:FF'S. T.poedema.

AT-?ATSIA. B0 V strezngth, loss of;Asthenia.

ACROCYANOSIS. Extrenities, bluenessof.

ACHROHYPCYTHFRMY. Extremities, coldnessof, dAte to imrs;.oad irculation,

ACTION, cardiac, excessive rapidityof.

ACTION, cardiac, xcessive slownessof.

ACTIVITY, locouootor, abnormal disin-clination toward. Lethargy; hvpo-dynamia.

ACTIVITY, o xcessive,Hyperdynaria.

FIG. 12. One page from thefor the Mead Johnson "side eff

where terminology derived from test data reportswas vague, activities and definitions had to beevaluated and interpreted from associated bio-logical signs; in such instances, arbitrary cate-gorizations were sometimes necessary.The alphabetical arrangement of descriptions

was designed to simplify the use of the dictionaryby directing the coder or user to a generic termvia the biological activity or activities, all ofwhich were alphabetically arranged and widelycross-indexed. However, since all permutationswere not possible or practical, it was found thatmore than one search or line of thought wasoccasionally required to pinpoint a desiredaction or Key Word.Although the authority list was prepared

primarily as a coding tool, it was felt that itmight be useful to laboratory personnel as areference manual. To date, we find its use in thisarea very limited; for coding purposes, however,it has proven invaluable.

In view of the many arbitrary decisions thathad to be made and on the basis of small quan-tities of data that had been accumulated byvarious biologists, employing different methodsover the years, we were indeed encouraged bythe relatively good selectivity of the code system,and we have continued our efforts.

SUMMARY

KEY WORD &CODF We should like to reiterate that the precedingCONSTIPATION 65 A review covers but a limited number of the ap-

proaches we have taken in attempting to copeANALGESIA 38 A with our information problems. No doubt many

convergent lines of thought will emerge asXEROPHTHAULMIA 67 A similar information and data-processing problemsGEMCENE.RALIZED 46 C are identified by the scientific community. We

7t -5 have attempted, through illustration, to demon-EDMA LOCALIZE 46 C strate the difference between data-processing

'0-4 applications, those concerned with informationlYPOTONIAPARLALYSIS 33 C retrieval, and, finally, a method (the "side effectsFLACCID GENERALIZED code") that encompasses both IR and EDPAPNEA-DYSP\FA- 47 C concepts, depending upon the objectives of theRESPIRATORY FAILURE user. Clearly, the greatest number of difficultiesPERIPHERAL 5,4 A have been found in areas dealing with infor-VASOCONSTR'CTICN mation-retrieval, doubtless because of the sub-TACHYCARDIA 52 A jective manner in which information is inter-

preted, stored, and used. In our experience,BRADYCA.RDIA 51 C computing equipment has been helpful in dealing

with problems of this nature, but even thisHYPOREACTIVIT- 30 C wonderous hardware cannot rectify erroneousHYPOACTIVITY data, clarify ambiguity, or replace sound judge-

ment. If, in the final analysis, there is generalHYPERACTIVIT`Y- 31 A agreement and concern regarding the existenceEXCITEMENT of an "information crisis," then we must char-subject authority list acterize the nature of the problems before aMcts" code. solution can be attempted.

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Perhaps improved communication of ideas isthe answer; if so, then let us attempt to expressour ideas more clearly and logically. It may bethat a more intimate knowledge of computercapabilities is required to translate data andideas into a machine-usable form; thus, edu-cational programs related to machine capa-bilities may offer a solution, Shall the approachbe "prophylactic or therapeutic"? Considerationof these and other facets of the problem willultimately play an important role in the solutionof our communications and data-processingproblems.

LITERATURE CITED

1. BERKSON, J. 1953. A statistically precise andrelatively simple method of estimating thebioassay with quantal response, based onthe logistic function. J. Am. Stat. Assoc.48.565-599.

2. BooTH, A. D. 1962. Some applications of digi-tal computers in medicine. Phys. Med. Biol.6:377-388.

3. BRowNsoN, H. L. 1960. Research on handlingscientific information. Science 132:1922-1931.

4. DERWENT INFORMATION SERVICE. 1963. Phar-maceuticals patents punch-card code. Der-went Information Service, London.

5. DIETRICH, E. V. 1960. Machine retrieval of

pharmacological data. Science 132:1556-1557.

6. FROME, J., AND P. T. O'DAY. 1962. A generalchemical compound code sheet format. Un-published manuscript, U.S. Department ofCommerce Patent Office.

7. GRAY, D. E. 1962. Information and research-blood relatives or in-laws? Science 137:263-266.

8. INTERNATIONAL BUSINESS MACHINES. 1962.General information manual (KWIC) index-ing. International Business Machines Pro-gram Information Department, WhitePlains, N.Y.

9. MOYER, J. H. 1962. Applications of computersin cardiovascular disease. American HeartAssociation Monograph, No. 5, p. 485-647,The American Heart Association, Inc. NewYork.

10. SKAGGS, B., AND M. SPANGLER. 1963. Easingthe route to retrieval with permuted in-dexes. Business Automation 9:26-29.

11. SKOLNIK, H. 1956. Planning an R & D infor-mation center. Research and Engineering11(7):26-29.

12. SMALL, R. M. 1964. A semiautomatic weightrecording system for chronic rat toxicitystudies. Unpublished Report. The Lilly Toxi-cology Laboratories, Eli Lilly & Co., Green-field, Ind.

13. YATES, F. 1962. Computers in research-promise and performance. Computer J. 4:273-279.

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