Clinical Trials Dictionary

Clinical Trials DictionaryTERMINOLOGY AND USAGERECOMMENDATIONS

Second Edition

Curtis L. MeinertBloomberg School of Public HealthThe Johns Hopkins UniversityBaltimore, Maryland

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Library of Congress Cataloging-in-Publication Data:

Meinert, Curtis L.Clinical trials dictionary : terminology and usage recommendations / Curtis L.

Meinert. – 2nd ed.p. ; cm.

Includes bibliographical references and index.ISBN 978-1-118-29515-1 (cloth)I. Title.[DNLM: 1. Clinical Trials as Topic–Dictionary–English. QV 13]610.72′403–dc23

2011051093

Printed in the United States of America

10 9 8 7 6 5 4 3 2 1

In memory of Chris Klimt,the man who started me on the trail of trials.

When ideas fail, words come in very handy

JW Goethe: I Faust, i, 1808

A flaw in a piece of white jade may be ground away, but a word spoken amiss may not be calledback

Confucius: The Book of Poetry, circa 500 b.c.

To make dictionaries is dull work

Samuel Johnson [1755]121

Preface to A Dictionary of the English Language

Contents

FOREWORD 1ST EDITION ix

PREFACE xi

CONTRIBUTORS xiii

EXPLANATORY NOTES xv

Domain of coverage xv

Order and place of entries xv

Synonyms, antonyms, and related terms xv

Language and usage conventions xv

Sources and references xvi

Adages xvi

Usage notes xvi

Etymologies xvi

Abbreviations xvii

Index xvii

USAGE PRACTICES, CAUTIONS,AND RECOMMENDATIONS xix

Recommended and preferred usages xx

Comparative and relative terms xxii

Redundancies, repetitions, and unnecessarywords xxiii

Not saying what we mean xxv

Humanizing the inanimate xxv

Pre-, post-, non-, and un- words xxvi

Small troublesome words xxvi

The language of praise, implied valuejudgment, and presumption xxvii

Euphemisms xxix

Currency words xxix

The language of criticism xxx

The language of exception xxxi

The language of intimidation, implication,and position xxxii

The language of division xxxiii

Usurpative language xxxiii

The language of positivity andnegativity xxxiv

Pronouns xxxvii

The language of equivocation andweaseling xxxvii

Vacuous language and claims xxxviii

Jargon xxxviii

Truth by declaration and repetition xxxix

ABBREVIATIONS xli

LISTING OF ENTRIES xlvii

Dictionary

A 1

B 15

C 27

D 63

E 79

F 93

G 107

H 113

I 119

J and K 137

L 141

M 151

N 165

vii

viii Contents

O 175

P 185

Q 217

R 221

S 241

T 273

U 291

V 297

W 301

X, Y, and Z 305

REFERENCES 307

INDEX 317

EQUATIONS AND FUNCTIONS

Bayes’ theorem 18

Binomial distribution 22

Binomial theorem 22

Bivariate normal distribution 23

Exponential distribution 90

F-test statistic 93

Gamma distribution 107

Gamma function 107

Geometric distribution 108

Gompertz’s curve 108

Greco-Latin square 110

Hypergeometric distribution 117

Inverse sine transformation 133

Kappa statistic 138

Kendall’s tau 139

Latin square 141

Normal distribution 172

Poisson distribution 199

Square root transformation 256

t distribution 273

GRAPHIC ILLUSTRATIONS

Figure 1. Bar Diagram 16

Figure 2. Bell-Shaped Curve 18

Figure 3. Bimodal Distribution 21

Figure 4. Box Plot 25

Figure 5. Chi-square Distribution 31

Figure 6. Circle Graph 32

Figure 7. Closed Sequential Design 37

Figure 8. CONSORT Chart 52

Figure 9. Cumulative FrequencyDistribution 60

Figure 10. Exponential Distribution 90

Figure 11. F Distribution 93

Figure 12. Flowchart 99

Figure 13. Forest Plot 101

Figure 14. Frequency Polygon 103

Figure 15. Gantt Chart 107

Figure 16. Histogram 116

Figure 17. Isometric Graph 136

Figure 18. J-shaped Curve 137

Figure 19. Left Skew Distribution 143

Figure 20. Logistic Curve 147

Figure 21. Normal Distribution 172

Figure 22. Open Sequential Design 180

Figure 23. Poisson Distribution 199

Figure 24. Right Skew Distribution 239

Figure 25. s-shaped Curve 241

Figure 26. Scatter Diagram 243

Figure 27. Survival Curve 270

Figure 28. t Distribution 273

Figure 29. Uniform Distribution 294

Figure 30. Venn Diagram 299

Foreword 1st Edition

In writing an essay that celebrates the skills ofthe great German composer Johannes Brahms,Arnold Schonberg coined a pithy phrase ofadvice intended for other composers butrelevant as well to writers: Say what you have tosay with ‘‘precision and brevity’’. For authorsreporting clinical trials, taking this advice couldmake the difference in getting your reportpublished or not. If you take it, you are morelikely to convince a journal’s editor that yourtrial merits attention. If you ignore it, yourun the risk of conveying an impression thatyou don’t know the science of designing andrunning a first-rate trial. ‘‘Precision’’ lies inusing terms that convey to others reading a trialreport exactly how the trial was designed andexactly how it was carried out. ‘‘Brevity’’ lies inusing terms and phrases that are succinct andeffectively replacing wordy descriptions.

Giving writers, and their readers, preciseterms with clear definitions is a main goalof compilers of dictionaries. An effectivedictionary establishes an ample vocabulary ofwords and phrases that will leave no questionas to what they stand for. Dr. Meinert hasproduced in this dictionary a treasure for thoseof you who aim to write about clinical trials withprecision and brevity. It goes well beyond thegeneral dictionaries of medicine in representing

in detail and great accuracy the large andcomplex vocabulary needed to describe clearlythe methods and results of clinical trials. Italso provides a thorough index to the entriesof its main section that facilitates the findingsof terms associated with particular conceptsand practical steps in trials. But perhaps itsmost extraordinary and admirable section isthat on usage. Here Dr. Meinert gives us adeeply perceptive and strongly illuminatingdiscourse on nuances in the rhetoric of scientificspeech and writing as seen by him through hislong and fruitful engagement with designing,running, reporting, and interpreting clinicaltrials.

For these reasons this new dictionary is goingto be a classic at birth. It merits an audience farwider than just authors reporting clinical trials.That audience should include authors’ editors,journal editors and their manuscript editors,indexers of clinical-trials papers, meta-analysts,teachers of clinical epidemiology, and anyoneelse who reads reports of trials and assesses theirscientific strength and clinical value. I believe itwill get that wide audience.

Edward J. HuthEditor EmeritusAnnals of Internal Medicine

ix

Preface

It is the fate of those who toil at the lower employments of life, to be rather driven by the fearof evil, than attracted by the prospect of good; to be exposed to censure, without hope of praise;to be disgraced by miscarriage, or punished for neglect, where success would have been withoutapplause, and diligence without reward.

Among these unhappy mortals is the writer of dictionaries; whom mankind have considered, notas the pupil, but the slave of science, the pioneer of literature, doomed only to remove rubbishand clear obstructions from the paths of Learning and Genius, who press forward to conquest andglory, without bestowing a smile on the humble drudge that facilitates their progress. Every otherauthor may aspire to praise; the lexicographer can only hope to escape reproach, and even thisnegative recompense has been yet granted to very few.

Preface to A Dictionaryof the English LanguageSamuel Johnson [1755]121

I was born with a literalist gene. From youngon I took delight arguing with my father aboutwhatever and ‘‘winning’’ on technicalities. Hedid not have much book learning but he waspretty smart and adept at arguing and not easyto corner. My mother was smart enough aswell, but technicalities were of no relevancewhen trying to talk myself out of trouble.

The gene has its advantages. It is an asset asa trialist methodologist when writing protocolsand checking out data collection forms. Butthere are downsides. My literalism drives mywife crazy and I have run out of people at workwho are willing to wager in arguments. Mynickel versus theirs; too many instances wherethey have been had on ‘‘technicalities’’.

But even with the gene one does not wakeup one morning and start writing a dictionary.It happens insidiously, in bits and starts until,like Murray, the editor of the Oxford EnglishDictionary, you are caught in a web of words.185

Recognition of the need for languageconventions emerged with the CoordinatingCenter Models Project (CCMP), a studystarted in 1976 that involved the comparisonof different trials with regard to design and

operating features.45 The establishment ofthe journal Controlled Clinical Trials (nowClinical Trials), along with assumption ofeditorial responsibilities for it, reinforced thatrecognition.173

The creation of a dictionary began with aglossary developed for CCMP.46 That glossarywas refined and expanded for inclusion as anappendix in my textbook on clinical trials.172

It, in turn, served as a starting point for a printedition of the dictionary in 1996 (now out ofprint).

The fires for a 2nd edition got blazing againwhen writing the 2nd edition of my textbookon clinical trials published in 2012.

The language of clinical trials is the productof a dynamic process. It was evolving on boardthe Salisbury at sea in 1747 when Lind155

did his scurvy experiment and continues today.It is a mixture of the languages of medicine,biostatistics, epidemiology, computer science,and bioethics. The focus is on clinicaltrials with selected terms from biostatisticsand epidemiology considered relevant to thelanguage of trials.

xi

xii Preface

The entries contained in this dictionary arethe product of three related aims:

1. To produce a document having sufficientgenerality and coverage to satisfy therequirements of trialists concerned with thedesign, conduct, and analysis of trials.

2. To introduce a vocabulary for thecharacterization and description of featuresand activities associated with trials.

3. To provide a dictionary reflective of currentusage practices and conventions in the field.

Achieving the first aim required thecompilation of a dictionary overlapping thedomains of medicine, statistics, epidemiology,computer science, and bioethics. Achievingthe second aim required the developmentof nomenclature for features, elements, and

activities of trials not described by existingvocabulary. Achieving the third aim requireda review of books and journals to identifyterms for inclusion and to note differentuses of similar terms. Journals screenedincluded the British Medical Journal, Journalof the American Medical Association, Lancet,New England Journal of Medicine, Biometrics,Journal of the American Statistical Association,and Controlled Clinical Trials (now ClinicalTrials).

But alas, work of this kind is never finished.The swamp is endless. There is no escape fromit. The only recourse is to declare this iterationdone and struggle on. I so declare!

Curtis L. MeinertTowson, Maryland29 May 2012

Contributors

EditorsKatheleen Bates The Johns Hopkins University, BaltimoreJoan Bossert Oxford University Press, New YorkSandra Bryant American Journal of Epidemiology, BaltimoreKaren Collins The Johns Hopkins University, BaltimoreBetty Collison The Johns Hopkins University, BaltimoreRachael Courduff The Johns Hopkins University, BaltimoreJill Meinert The Johns Hopkins University, BaltimoreSusan Meinert Towson, MarylandSusan Murray American Journal of Epidemiology, BaltimoreSusan Tonascia The Johns Hopkins University, BaltimoreSusan Vaupel American Journal of Epidemiology, BaltimoreAnnette Wagona The Johns Hopkins University, Baltimore

Graphics and ProductionMichele Donithan The Johns Hopkins University, BaltimoreJill Meinert The Johns Hopkins University, BaltimoreDeborah Nowakowski The Johns Hopkins University, BaltimoreMark Van Natta The Johns Hopkins University, Baltimore

DefinitionsPatricia Belt The Johns Hopkins University, BaltimoreRonald Brookmeyer The Johns Hopkins University, BaltimoreJoseph Canner Blantyre, Malawi (International Eye Foundation)Iain Chalmers United Kingdom Cochrane Centre, OxfordBetty Collison The Johns Hopkins University, BaltimoreChristopher Dawson The Johns Hopkins University, BaltimoreKay Dickersin University of Maryland, BaltimoreAdele Gilpin The Johns Hopkins University, BaltimoreSteven Goodman The Johns Hopkins University, BaltimoreBarbara S Hawkins The Johns Hopkins University, BaltimoreJanet Holbrook The Johns Hopkins University, BaltimoreMilana Isaacson The Johns Hopkins University, BaltimoreLisa Jacobson The Johns Hopkins University, BaltimoreHelena Kraemer Stanford University, Stanford, CaliforniaHarry Marks The Johns Hopkins University, BaltimoreLee McCaffrey The Johns Hopkins University, BaltimoreElinor Miller Memorial Sloan-Kettering Cancer Center, New YorkClaudia Moy The Johns Hopkins University, BaltimoreSteven Piantadosi The Johns Hopkins University, BaltimoreSuresh C Rastogi Food and Drug Administration, Rockville, Maryland

xiii

xiv Contr ibutors

Evan B Siegel Astra Pharmaceutical Products, Inc, Westborough, MassachusettsStephen Singer Dedicated Response, BaltimoreJames Tonascia The Johns Hopkins University, BaltimoreSusan Tonascia The Johns Hopkins University, BaltimoreMark Van Natta The Johns Hopkins University, BaltimoreIna Wallace University of North Carolina, Chapel Hill, North CarolinaO Dale Williams University of Alabama, BirminghamMarcelle Winget The Johns Hopkins University, BaltimoreScott Zeger The Johns Hopkins University, Baltimore

Explanatory Notes

DOMAIN OF COVERAGE

Anyone foolish enough to venture intoproducing a dictionary is soon faced withthe need for ‘‘rules’’ to limit the domain ofinclusion, leastwise one end up Caught inthe Web of Words.185 A difficulty in anyspecialized dictionary is the extent to which it isconstructed to include everyday terms found inany desk dictionary. The construction principlefollowed in the first edition to this work wasto provide dictionary definitions for each wordappearing in compound terms such as for theterm activities of daily living adding to thelength of the dictionary without adding muchof substance. The number of base terms hasbeen limited in this edition to those considerednecessary. Definitions of those terms may bemore or less than those found in ordinary deskdictionaries, depending on need.

The language of trials, for the most part,is universal. Type I error is type I error,randomization is randomization, stratificationis stratification, subgroup analysis is subgroupanalysis, and data dredging is data dredgingwherever you are in the world. Most of the2,800+ entries in the dictionary are of this type.Exceptions are entries relevant to the languageof regulations and controls underlying trials.

The bodies responsible for review andapproval of trials as a prelude to initiation goby a variety of names, depending on location.The generic name for such bodies in theUnited States is ‘‘institutional review board’’and variously, ethics committee, ethics reviewboard, Helsinki committee, and reserach ethicscommittee in other parts of the world. Thelayers and levels of review depend on fundingsources, locales where conducted, and whetherthe review body is empowered to act on behalfof a trial or simply for centers participating intrials.

Another area of difference is in the languageof control and approval for licensure of drugs,biologics, and medical devices. The UnitedStates has a centralized structure vested inthe Food and Drug Administration. TheEuropean Union, with its formation, hasmoved toward harmonizing differences incontrol and approval of medicinal productsin member states with the establishment of theEuropean Medicines Agency (initially whenestablished in 1995 the European Agency forthe Evaluation of Medicinal Products).

The default language for structures,controls, and regulations having differentnames depending on locale is as establishedand used in the United States. Efforts havebeen made to indicate like terminology in otherparts of the world when known.

ORDER AND PLACE OF ENTRIES

Entries are arranged alphabetically. Hence,entries having base terms such as bias,mask/masked, or random/randomized arescattered throughout the Dictionary. The listof terms having common base terms can befound in the index under those base terms.

SYNONYMS, ANTONYMS, ANDRELATED TERMS

Terms in boldface following definitions,denoting synonyms (syn), antonyms (ant), andrelated terms (rt), are defined elsewhere in thedictionary.

LANGUAGE AND USAGECONVENTIONS

The default language of the Dictionary is thatof clinical trials. Hence, the designation for a

xv

xvi Explanatory Notes

person enrolled in a trial is generally patient.Medically neutral terms such as person, humanbeing, or individual are used when theconnotation of illness is inappropriate.

The term treatment is used throughout torefer to the experimental variable in a trial.

The modifier clinical is routinely dropped,except in usages where there is need toemphasize the clinical or medical nature ofa trial or class of trials.

Study is used in definitions with broaderuse or applicability than for trials alone.

Definitions are written assuming that aperson is the treatment unit—the unit to whichtreatment is applied. However, users need to bemindful that, in certain contexts, the unit canbe part of a person (e.g., eye in trials with eye asthe randomization unit) or a group of persons,e.g., as represented in a household, census tract,village, or community.

SOURCES AND REFERENCES

Webster’s New Collegiate Dictionary (9th, 10th,and 11th editions)257–259 served as the basedictionaries for this work. Other dictionariesused include those represented by citations 4,22, 54, 170, 181, 184, 238, and an occa-sional pinch of 21. Medical dictionaries usedinclude those represented by citations 66, 177,240, 247, and 256. Specialty dictionaries andglossaries in research, mathematics, statistics,epidemiology, and computer science includethose represented by citations 9, 22, 41, 53, 94,98, 113, 119, 128, 134, 141, 143–145, 165,167, 234, 241, 262, the Cochrane Collab-oration (http://www.cochrane.org/glossary/5),and Wikipedia. The dictionaries by Freundand Williams in statistics, by James and Jamesin mathematics, and by Last in epidemiologywere invaluable as reference sources and asguides for domains of coverage (citations 94,119, and 144, respectively).

Texts used in statistics, epidemiology, andrelated fields include those denoted by citations

10, 28, 43, 72, 74, 96, 99, 111, 127, 132,147, 150, 154, 179, and 227. Texts in clini-cal trials include those by Buyse, Staquet, andSylvester,33 Friedman, Furberg, and DeMets,96

Leventhal and Wittes,148 Meinert andTonascia,172 and Pocock.210 The Encyclopediaof Statistical Sciences137 and the InternationalEncyclopedia of Statistics138 were also used.

Numbers following citations in referencelistings correspond to pages where the citationappear.

ADAGES

Adages appearing as headers to pages ofthe Dictionary are admixtures of ‘‘everyday’’utterances of fellow trialists, colleagues,and acquaintances from various fields anddisciplines. A few have elements traceable toMuench’s Postulates, Laws, and Corollaries (JEBearman, RB Loewenson, and W Gullen,Biometrics Note, No 4, April 1974; Officeof Biometry and Epidemiology, National EyeInstitute, Bethesda MD). Laws ascribed toMuench (Hugo, 1894–1972; professor ofBiostatistics, Harvard University) are:

No full-scale study confirms the leadprovided by a pilot study.

Results can always be improved by omittingcontrols.

In order to be realistic, the number ofcases promised in any clinical study mustbe divided by a factor of at least 10.

USAGE NOTES

The usage notes affixed to various terms inthe Dictionary are provided to expand ondefinitions and to provide recommendationsconcerning usage. The list of definitions withusage notes can be found under the index entryusage note.

ETYMOLOGIES

Etymologies included for a few selected termsare from Webster’s.257–259

Explanatory Notes xvii

ABBREVIATIONS

Pages xli through xlv provide a listing ofabbreviations and designations used in theDictionary.

INDEX

The Dictionary contains a combined subjectand author index.

All authors listed in references appearing onpages 307 through 316 are indexed. Only theauthors listed in text citations are indexed. Forexample, only Jones is indexed in a text citationof the form [Jones et al., 1990].

Studies cited are indexed under the headingstudy index. Page numbers cited correspond tomentions of those names or shortened forms ofthose names in citations in definitions or usagenotes.

Usage Practices, Cautions, andRecommendations

When I use a word, Humpty Dumpty said, in a rather a scornful tone, it means just what I chooseit to mean—neither more nor less.

Lewis Carroll’s Through the Looking-Glass (1872)

We use different words to mean the same thing.We vary our verbiage to reduce monotony andadd zest and color to what we say or write. Weexpect variation and are taught to deal with it.A child learns that 10:45, quarter to eleven,15 minutes to eleven, 15 minutes till eleven,and forty-five minutes after ten are the same.As adults, we understand when an announcertells us that the Yankees trounced the Red Sox,the Athletics pummelled the Angels, the Indianssqueaked by the Tigers, and the Orioles weretriumphant over the Twins, though we wouldhave learned as much if the announcer had usedbeat in place of trounced, pummeled, squeakedby, and were triumphant over.

We not only tolerate the variation but insome measure are enriched by it. Imagine MarkTwain or Robert Frost with the staid writingstyle of a scientist.

As in ordinary discourse, we accept minorvariations in the discourse of a researcherwithout difficulty. We accept that an authoris using the same basic trick as the sportsannouncer when discussing the work of othersby referring to Smith’s findings and the work ofHarrison and coworkers, or by indicating thatJones found, Franklin indicates, and Green et al.concluded .

However, our tolerance for variationdiminishes as we move up the scale of requiredprecision. Lawyers, responsible for draftingwills or contracts, are more interested inproducing documents that will stand up tocourt challenges than in interesting reading.

Variation of language in the discourse ofresearch, even if not ‘‘fatal’’ in the samesense as for legal documents, is, nonetheless,undesirable to the extent that it confuses orobscures. For example, a reader is more likelyto be confused than entertained by referencein one place to baseline examinations, inanother to screening examinations, and in stillanother to eligibility examinations, when thethree terms all refer to the same examinations.The emphasis should be on uniformity andprecision, even if to the disadvantage of styleand prose.

No self-respecting researcher sets aboutproducing documents that are vague orconfusing, although much of what we writeis vague and confusing. Why? In part, becauseof haste and failure to refine, reiterate, andedit, ad nauseam, and, in part, because thelanguage for a single project, even if carriedout over a relatively short period of time,evolves—changes that may go unnoticed inthe same way that most other gradual changesescape our notice. Most of the research effortsinvolving trials, even if followup is of shortduration, measured in days or weeks, willextend over a period of months, if notyears. Hence, thought must be given at theoutset to terminology. Conventions should beestablished and maintained over the life ofthe project. The careful worker will establish aglossary of accepted terms and their definitions,including lists of accepted synonyms where

xix

xx Usage Pract ices, Caut ions, and Recommendat ions

applicable, and maintain and update the listover the course of the activity.

RECOMMENDED AND PREFERREDUSAGES

Terms in the table below are classified asfollows:

R RecommendedNR Not recommendedP PreferredNP Not preferredA AvoidCC Caution, may be confusing or

contradictory in some settingsCR Caution, may be redundant or

unnecessaryCP Caution, presumptiveCW Caution, weasel term

Preferred is a weaker categorization thanRecommended and is used when there arereasons for the preference but when they are notconvincing enough to warrant a Recommendedcategorization. Most of the categorizations aresupported in usage notes for listed terms ortheir complements (see index heading usagenote for list). The categorization Avoid is usedfor terms with contradictory definitions orhaving high potential for confusion. Termsin the category Caution, redundant are likely tobe redundant or unnecessary in most usages.The categorization Caution, presumptive isused for terms usually implying underlyingfacts, conditions, or assumptions. Those facts,conditions, or assumptions should be madeexplicit if terms in this class are used. Thecategory Caution, weasel is used for terms usedprimarily for qualification or weaseling (seeweasel term, page 301, for note).

Word or Term Category Comment

allocation (defn 2) NP Use assignment; see assignment for usage note (page 11)allocation ratio NP Use assignment ratioanalysis by intention to treat NP Use analysis by treatment assignmentassignment Rarm NP Use groupaverage NP Use meanbaseline CCbi- (meaning twice) A Use twice or semi-biannual A Dual meaning; twice a year or once every other yearbias CPbimonthly A Dual meaning; twice monthly or once every other

monthbiweekly A Dual meaning; twice weekly or once every other weekblind, blinded NP Use mask or maskedcareful CR See careful for usage note (page 27)case-comparison study NP Use case-control studycase-compeer study NP Use case-control studyco- (prefix) CC co-principal investigator; contradictory meanings in

certain usages; see usage note for co-.co-principal investigator A Dual meaning; see usage note for co- and co-principalcollaborative CR collaborative trial; not a suitable synonym for

multicenterconfounded CP See usage note for confounded (page 47)cooperative CR Not a suitable synonym for multicenterdouble-blind, double-blinded NP Use double-mask or double-masked

Usage Pract ices, Caut ions, and Recommendat ions xxi

Word or Term Category Comment

double-mask, double-masked Pdrop-in A Subject to confusionearly stopping CP See usage note for early adjendpoint NR; CC See usage note for endpointexperimental trial CR See usage note experimental trial (page 89)fraud CP See usage note (page 102)informed consent CP Use consent; see usage note for informed consent (page

126)intention to treat CP Use more informative terminology such as analysis by

original treatment assignment; see usage note (page 129)intervention NP Use treatment; see page xvimask, masked Pmeta-analysis Rmonthly CC See usage note for month (page 159) and time measure

(page 276)multicenter R See usage note for multicenter (page 161)open CW Not informative when used as an adjective in relation to

trial (e.g., open trial) or treatment administration (e.g.,open label); see usage note for open (page 179)

open label A Uninformative and subject to confusion with open trial;use unmasked

open label trial NR Use unmasked trialopen trial A Subject to confusion; avoid; see usage note for open

trial (page 180)optimum CP See usage note for optimum (page 181)oral consent R Use in conjunction with consents obtained without

benefit of a written statement; not a synonym for verbalconsent

outcome P See usage note for endpoint n (page 83)overmatch CW; CP See usage note for overmatch (page 183)overrepresent CP See usage note for underrepresent (page 293)overstudy CP See usage note for understudy (page 293)overview analysis A Synonym for meta-analysis; avoid, use meta-analysispopulation-based trial A See usage note (page 200)pre- (prefix) CC Use sparingly and with caution; see usage note for pre-

(page 202)preclinical CC Meaning dependent on context; use with caution; see

usage note for preclinical (page 203)principal investigator NP Often not a useful designation, especially in multicenter

settings; see usage note for principal investigator (page208); use only as an administrative label

randomness CP See usage note (page 224)run-in NP Use lead-insemi- (prefix) P semiannual, semimonthly, semiweekly; preferred to bi-;

see usage notes for semi- (page 247) and bi- (page 20)

xxii Usage Pract ices, Caut ions, and Recommendat ions

Word or Term Category Comment

side effect CP See usage notes for side effect (page 250) and drugreaction (page 77)

single-blind, single-blinded NP See usage note for mask, masked adj (page 152)single-mask, single-masked P See mask, maskedsubject NP See usage note for subject (page 268) for reasons to

avoid or limit usetoxic drug reaction CP See usage note for drug reaction (page 77)toxic side effect CP See usage notes for side effect (page 250) and drug

reaction (page 77)treatment P Preferred label for the experimental variable in a trial;

see usage notes for treatment (page 279) and forintervention (page 132)

treatment arm NP Use treatment group or regimen; see usage note fortreatment arm (page 279)

treatment failure CP See usage note for treatment failure (page 283)triple-blind, triple-blinded NP See defn for blind and usage note for mask, masked adj

(pages 24 and 152)triple-mask, triple-masked P See usage note for mask, masked adj (page 152)undermatch CW; CP See usage note for overmatch (page 183)underrepresent CP See usage note for underrepresent (page 293)understudy CP See usage note for understudy (page 293)verbal consent NP Use oral consent or written consentwithdrawal CP See usage note for withdrawal (page 303)

COMPARATIVE AND RELATIVE TERMS

Clinical trials, by definition, are comparativeand concerned with ascertaining relative truth.As a consequence, the language of trials is ladenwith the language of relativity and comparison.

Comparative terms such as large, early, orlong have meaning only in relation to explicitlydefined or implied standards. The tendencies ineveryday discourse to use such terms as if theyhave intrinsic meanings of their own are notacceptable in scientific discourse. The carefuluser will take care to be explicit as to themeaning of comparative terms.

Words such as more or less are in and ofthemselves comparative terms. They should notbe used in relation to states or conditions notamenable to such quantifications. For example,one is either pregnant or not pregnant; thereare no other states. Similarly, it is pointless tothink of or characterize one position or stand

as more ethical than another. If one is ethical,there is no way to be more ethical.

For the most part, the language ofcomparison is symmetrical and should bethought of and used in that way. Hence, oneshould not use early, as in early stopping , unlessthere is a notion of what it means to stop ontime or to be late in stopping. Similarly, thenotion of big or bigger should have counterpartsrelated to small or smaller, and the notion ofeasy has meaning only in contrast with difficultor hard .

Our everyday usage abounds in the use ofrelative terms as absolutes. To be convinced,one need only count the number of timesone is expected to make a decision or choicewithout the information needed for doing so.For example, at the fast food lunch counter,one is expected to answer the question: Small,medium, or large? without any idea of the sizesinvolved. Merchants are adept at wooing us

Usage Pract ices, Caut ions, and Recommendat ions xxiii

into their stores by notice of sale or discount orby announcing Everything 30% off . We rushto spend to ‘‘save’’.

Often the norm or standard for comparisonis implicit, as in tall or short, fat or thin, andearly or late. We usually know what is meantwhen somebody tells us that Johnny is tall,Darlene is fat, or Henry is late. The standardimplied for Johnny is the average height ofother boys about the same age and generalheritage as Johnny.

Our everyday language is laced with termsindicative of change, such as more or less, upor down, high or low, and better or worse.To make an assessment of change, one has tohave observations of the condition or variableof interest at two or more points in time.Ordinarily, one is careful to indicate the pointof comparison, e.g., We are better off financiallynow than we were a year ago. Exceptions arisewhen the previous time point is implied, e.g.,the patient is worse today, or where there is adesire or value to being vague as to the actualpoint of comparison, e.g., advertising claimssuch as better than ever, new and improved, savemore than ever, or Now, more than ever (NBCtelevision former voiceover boast followingtheir evening news show).

Change measures are the result ofdifferencing operations and, hence, are signed.The direction of the comparison must bemade explicit for proper interpretation ofthe measure. Typically, changes are measuredrelative to baseline or relative to a specifiedstudy treatment (usually a control treatment)in the case of trials. Changes relative to baselineare presented as a signed difference (e.g., themean weight loss after 6 months of treatmentwas + 8.9 lb) or with sufficient information toallow the reader to do the differencing (e.g., themean body weight was 156.5 lb at baseline and147.6 lb after 6 months of treatment). Changesrelative to a specified treatment are presentedin similar fashion (e.g., the 6-month mortalityrates were 17.6/100 and 22.8/100, for the testand control treatment groups, respectively, or thetest-control difference in mortality was −5.2%).

Some changes will involve changes ofchanges (e.g., laser treatment produced a netintraocular pressure (IOP) drop of 3.1 mmHgrelative to baseline and the control treatment asmeasured at the 6-month followup visit). Netchanges (defn 2) are differences of differences.The value, in the example, 3.1 mmHg, is infact the result of two different differencingoperations. The first one involves derivingthe net IOP change for the two treatmentgroups being compared, done by subtractingthe 6-month value for a patient from thepatient’s baseline value and deriving the meanof those differences for the eyes represented inthe two treatment groups. The value for thelaser-treated eyes is then subtracted from thecorresponding value for control-treated eyes toyield the net laser treatment effect, (16.5 −22.1)−(19.4 − 21.9) = − 5.6 − (−2.5) = −3.1.

The potential for confusion is great in alldifferencing operations. Confusion as to theway in which the differences were obtained,when they are large, has the potential of causingreaders to indict the wrong treatment. Hence,signed differences, such as the +8.9 or −3.1 inthe paragraphs above should be accompaniedby sufficient detail (via example or definitionalverbiage) to minimize the chance of readersbeing confused about meaning of the sign inrelation to treatment.

REDUNDANCIES, REPETITIONS, ANDUNNECESSARY WORDS

The habit of repeating what we say for emphasisor ‘‘clarity’’ carries into what we write. Incase of doubt, delete every other sentence in aprized draft. Most of the message survives withhalf the words. Early drafts of most things arelong and wordy because of repetition and poororganization. The amount of redundant andrepetitious material provided may go unnoticeduntil one is faced with the need to shorten oredit by edict of editors. It is sobering, at suchtimes, to note the number of awkward or wordyparses or sentences that can be ‘‘fixed’’ simplyby deletion. Usually the editor’s requirement

xxiv Usage Pract ices, Caut ions, and Recommendat ions

to cut the length, sometimes by as much as50%, though painful, results in a better, moreinformative document.

Our spoken language, by the same token, iswordy, repetitious, and redundant. We repeatbecause we seemingly abhor silence and becausewe want to make certain we are ‘‘gettingthrough’’. We use throwaway declaratives suchas you know in place of pauses, and we askfor reassurance in the form of questions suchas OK ? or Understand ?—questions we ask,usually without any pause for an answer.Though our written word is devoid of suchannoying fillers, it is certainly not free ofredundancies and needless repetition.

The emphasis in scientific writing should beon conciseness and on word economy. Sayingthe same thing with different words in differentplaces in the manuscript can cause readers toassume that difference in language is purposefuland intended to convey difference. Considerthe following sentences, intended by the writerto be equivalent: Baseline data were collectedat baseline visits and Entry data were collectedduring screening examinations. The only waythey will be recognized as being equivalent is ifreaders are clever enough to equate baseline dataand entry data and baseline visits and screeningexaminations.

Ralph Waldo Emerson reminds us thatA foolish consistency is the hobgoblin of littleminds, and indeed it may be so. However, theconsistency of nomenclature and terminologywithin a manuscript and across relatedmanuscripts is neither foolish nor likely tobe the product of small minds.

Redundant words or phases should beavoided, if for no other reason than for wordeconomy. Some words are unnecessary simplybecause they are obvious or implied in thecontext of usage, e.g., human in human subject,prospective in prospective followup, and oftenclinical in clinical trial . Other examples areprimary in primary purpose and overall in overallaim.

Other words, though technically unneces-sary, are nonetheless required—for example,female in pregnant female.

Most ly words are unnecessary. Many canbe deleted simply because they are implied inthe context of usage—for example, carefullyin carefully measure. One assumes care onthe part of the researcher, hence, there isnothing to be gained by its use. If the writerbelieves it is important for the reader to knowhow something was done, then details shouldbe provided and the writer should leave thecharacterization to the reader. Other examplesinclude extremely as in extremely high (use high),highly as in highly important (use important)or as in highly significant (use significant andstate the p-value), really as in really low (uselow), or actually as in actually determined (usedetermined ).

Words expressing desire, such as want orlike, are also unnecessary. For example, ratherthan writing we want to point out write we pointout. Similarly, rather than writing we wouldlike to thank, write we thank. As a reader, oneis more interested in what authors do than inwhat they would like to do.

Many of the words or phrases of transition,deduction, conclusion, or exception, suchas however, generally, moreover, therefore, ingeneral, in summary, or nonetheless, can beeliminated from the finished written product.Use should be limited to places where theyare needed to warn of (a) breaks in flow,(b) exceptions to what is being said, or (c)a conclusion or deduction. Avoid redundantusage, as in therefore, we conclude . . . (usetherefore or conclude) or as in In general, usually. . . (usually serves the same function as ingeneral ; use usually—one word and fewerletters than for in general).

Various other excesses are:

actively reinforce (use reinforce)

careful monitoring (use monitoring)

careful review (use review, one assumes allreviews are carefully done)

comprehensive system (use system; let thereader judge as to comprehensiveness)

effective solution (use solution, all solutionsare effective in the literal sense of that term)

Usage Pract ices, Caut ions, and Recommendat ions xxv

formal system (use system, one assumes asystem has structure and, hence, is formal inthat sense)

further clarification (use clarification, let thereader decide if it is ‘‘further’’)

overcomplier (jargon; avoid; it is not possibleto ‘‘overcomply’’)

planned schedule (use schedule, the termimplies planned )

quite good (jargon; avoid; describe and letthe reader judge as to ‘‘goodness’’)

regularly review (use review and indicate theschedule of review)

strict method (use method and let the readerdecide if it is ‘‘strict’’)

NOT SAYING WHAT WE MEAN

Often we do not mean what we say or ask. Thepractice arises from our desire not to offendand from carelessness in the way we talk andwrite. Often the questions we are asked are notto be interpreted as asked, such as the May Ihelp you? question of a building sentry (usuallybetter interpreted as Halt, who goes there? orWhat do you want?) or May I bother you for thetime? (properly answered yes or no).

As a literalist, I find a certain mischievoussatisfaction in answering questions as askedrather than as intended. My usual answer tosentries at my institution is Yes to Do you havean ID? and a likewise Yes on the phone whenasked by the person on the other end: May Iask who is calling?

One need merely read such childhoodfavorites as Amelia Bedelia to appreciate thatwhat we say is not what we mean, especiallywhen it comes to instruction. The adage wheneverything else fails read the instructions is asmuch a reflection of the usefulness of mostinstructions as of our own impatience in dealingwith them. Any parent who has had to assemblea child’s toy can attest to the ‘‘usefulness’’of instructions. Often, it is after one hasmanaged to assemble the toy, largely by trialand error, that one comes to understand the

instructions—an understanding by no meansenhanced by the desire of manufacturers tomake one set of instructions work for 17versions of the toy and by the fact that yourversion is the ‘‘new and improved’’ version notmentioned in the instructions.

Amelia Bedelia’s only ‘‘failing’’ was that shefollowed Mrs. Rogers’ instructions to a T. Sowhen she was told to dust the furniture shedid—with powder—and when she was told tochange the towels in the bathroom she did—bycutting them in half. The problem was in theinstruction, not with Amelia. Nevertheless, itwas Amelia who suffered the embarrassment of‘‘her’’ mistakes, not Mrs. Rogers for hers.

One need merely read the instructions in theprotocols and manuals we write to discover thatwe are not necessarily any better at instructingthan Mrs. Rogers. Similarly, we have the samepotential as the sentry or the person on the otherend of the phone for asking the wrong questionwhen it comes to designing our data collectionforms. It is certain that our instructions anddata forms will be vague, confusing, and evenmisleading unless they are written and rewrittenand tested and retested before being put to use.

HUMANIZING THE INANIMATE

We learn as children to attribute humanqualities to inanimate objects. Children’s storiessuch as the Little Engine That Could andTV shows such as Sesame Street are filledwith objects that have human qualities. Aschildren we are thrilled by fantasies of dancingsugarplums, steam engines with personalities,and scarecrows that come alive. As adultswe come to realize that there are no talkingscarecrows or engines that can, while at thesame time offering encouragement to Betsy,the family car, as she struggles up a hill orcursing our computer for being so obstinate.We speak of Mother Nature, Father Time, OldMan River, winds that are calm or restless,stock markets that react, and economies thatrecover.

Some of the attributions are useful. It ismore efficient (and colorful) to say that the

xxvi Usage Pract ices, Caut ions, and Recommendat ions

wind is calm than to say that the wind velocityis 0 or that the computer tells us instead of ouranalysis indicates.

We are likely to write that the trial found, thestudy concluded , and the results tell us. However,it is people who find, conclude, and tell us, nottrials, studies, and results. Those processes aredistinctly human and should not be attributedto the object of interest in what we write.

PRE-, POST-, NON-, AND UN- WORDS

The prefixes pre- and post- are used as modifiersto denote order or sequence in relation tosome event or action, e.g., pre- or post-war. Of the two, pre- is the more common(and more objectionable). There is no doubtthat if the Big Dictionary Writer in the Skysuddenly banned all pre- words, a few wouldbe missed, such as preview and preamble, butoverall there would be more celebrations thanwakes. Would anyone miss those vacuouscongratulatory salutations of letters fromcredit card companies notifying you thatyour applications—applications never madeor desired—have been pre-approved ? Wouldanyone be upset if the airlines simply offeredearly boarding instead of the opportunity topreboard ? Would we care if cooks suddenlystopped pre-heating their ovens and werecontent to simply heat them?

The creation of a pre- or post- word byaffixing the prefix to a verb creates somelinguistic oxymorons, for example, as withpreboarding a plane or watching a prerecordedshow. How is it possible? What is the stateof being preboarded ? Does it involve beingbeamed aboard in the ‘‘Star Trek’’ sense? Ordoes it involve boarding the plane on the tarmacbefore it has arrived at the gate? Similarly, whatare we to make of the claim prerecorded before alive audience? How does a TV network manageto do that? Does it mean they recorded theshow before the audience arrived and are thereany other audiences other than live?

The best practice is to avoid pre- and post-words, except those found in ordinary deskdictionaries. Use beyond the ordinary should

be limited to instances in which such termsare used as forms of shorthand expressionsfor more complicated phrases, if at all. Thefinished written product should be scanned forjargonistic usages, undefined uses, and usagesin which the terms can be avoided by useof other words or modifying phrases. In fact,most uses can be avoided with before or after asin before randomization, after randomization,before screening, after screening (instead ofpre-randomization, post-randomization, pre-screening, and post-screening).

The prefix non- means other than, reverseof, or absence of. When modifying a nounor verb, it serves to negate or indicate theopposite of what is conveyed by the baseterm, like nonmask meaning not masked ornonrandomized meaning not randomized.

The prefix un- means opposite of, in reverseof, deprived of, or removed from. Un- wordsinclude such terms as uncontrolled, unadjusted,and unbalanced.

Before we entered the electronic age, theopportunities to undo were limited. Now wewould be severely handicapped if suddenly theundo function on our computers disappeared.However, beyond question the most annoyinguse of the prefix is unsubscribe. In theold days subscribing was an active process.Now if you merely launch a website youhave unwittingly subscribed and good luckunsubscribing.

SMALL TROUBLESOME WORDS

Prepositions such as by, for, from, on, to,and through are often used in relation tomeasurements or time designations. Hence,we may read that all patients were seen by themiddle of the year, measurements cover a rangeof values from 42 to 89, all patients are to beseen on the 1st of the month, the last intervalincludes values through 423, or patients wereinstructed to take their medication for a periodof 10 days. All of the words have varied usages,as is readily seen by the number of definitionsand the length of the entries for those terms inany standard desk dictionary.

Usage Pract ices, Caut ions, and Recommendat ions xxvii

By in relation to time means up to, upto and beyond, close to, past, in the periodof, and not later than. On in the samecontext means occurrence at a given time orat an exact moment in time. Hence, the twowords have different connotations and are notinterchangeable, though they are often used asif they are. Perhaps the best example of suchpresumed interchangeability is in the 1990National Census. Instructions on the outsideof the packet mailed to every household in theUnited States prior to April 1, 1990 were tocomplete your form and return it by April 1,1990; but the first item on the form asked therecipient to list on the numbered lines below thenames of each person living here on Sunday, April1. Clearly, no one at the Census Bureau hadany concern regarding the logical inconsistencyinvolved in expecting recipients to completeand return the form by April 1 while at thesame time asking them to report the numberof people living in the household on April 1.Clearly, as a literalist, I had to either guess as tomy whereabouts on April 1 and comply withthe instruction on the outside of the packet orignore the instruction and wait until after April1 to fill out the form. For all we know, some ofthe undercounting was due to literalists beingdriven to inaction by contradictory instruction.

On in relation to time should refer to a pointin time and for to an interval of time. On issometimes confused with for and used insteadof for. For example, baseball announcers, forreasons that remain a mystery to me, invariablyspeak of batting average on the year, e.g., CalRipken is batting 287 on the year. Why not forthe year?

To means reaching or extending as far as,reaching or extending to some point or limit.Through means from the beginning to the end,in or during an entire period or interval, to, andincluding. For is a function word for indicatingamount, extent, or duration. To, in relation to atime point or continuous measure, may includethe point indicated or may be inclusive of allpoints or measures up to but not includingthat point. Hence, its use leaves room forconfusion. For example, does the statement

applications accepted up to January 15 meanthat the 14th is the last day they will be takenor will they be accepted through the 15th?The situation is not helped much by using byin place of to. A reasonable operational ruleis to assume, unless one is told or otherwiseindicated, that the use of to excludes the pointof reference, and, hence, in the example above,plan on being done with the application bythe 14th. The IRS avoids use of by or on withan instruction telling us that our tax returnsmust be filed not later than April 15. Does itmean we must file before April 15 or do wehave until the midnight separating April 15thand 16th? Even a casual observer of activitieson April 15 learns the answer. We shouldavoid such confusions by being explicit aboutwhether the designated time point is includedor excluded from permissible time points, e.g.,by indicating that applications will be acceptedthrough January 15th or that applications will beaccepted up to and including January 15th andthat we have through April 15 to file our taxreturn.

From is used as a function word to indicatea starting point, e.g., from this day forward orfrom January 16th on. The word is subject toconfusion when used as a reference point, e.g.,people having weights from 150 lb and greater.The reader is in doubt about whether thestatement is intended to include or excludethe value of 150. The problem is avoided bywriting people with a weight of 150 lb or greater.

THE LANGUAGE OF PRAISE, IMPLIEDVALUE JUDGMENT, ANDPRESUMPTION

We have a variety of words and terms forexpressing or intimating praise or expressingvalue judgment. They are useful in everydaydiscourse but have a limited role in the discourseof science, where emphasis is on fact rather thanon praise or value. The responsibility of thewriter is to convey the necessary information toenable readers to reach their own conclusions.It is pointless, if not bad form, to coach readersas to the values they should adopt, except on

xxviii Usage Pract ices, Caut ions, and Recommendat ions

editorial pages of journals or perhaps on thediscussion pages of a manuscript.

A dispassionate writer avoids use ofqualitative labels or characterizations such asgood, careful, accurate, or precise in relation tohis or her methods or procedures. They are,what they are and laudatory characterizationsdo not make them better.

The use of self-laudatory language inrelation to one’s own work is foolhardy. Itis presumptuous, pompous, and short-sightedto label one’s own work as original, unique, orinnovative; likewise, it is a sign of consummatenaivete to characterize work still in planning orexecution as definitive, e.g., we are carrying out atrial to provide a definitive answer to the question.Typically, definitive is a characterization appliedin retrospect by others, years hence. By thesame token, one should avoid characterizationssuch as modern, as in we used modern methodsto determine concentrations of the compound .Modern is in the eye of the beholder, and themere application of a label does not serve tomake a method modern nor does absence ofthe term imply antiquation. Ditto for easy orsimple.

Implied praise by use of laudatory languagein relation to the work of others should begenuine. Avoid as fluff or as a prelude to awilting attack or criticism.

The clinical trialist should take pains toavoid implied conclusions or presumptionsin the nomenclature used for key measures,variables, or phenomena. One reason for doingso has to do with the need to avoid confusionwhen doing the trial, for example, as discussedin a usage note for endpoint (page 83) as asynonym for outcome. Reaching an endpointimplies cessation or completion. Its use as asynonym for outcome may be justified when theevent being referenced is death or some otherevent that, when it occurs, means the end oftreatment or followup, but not in other uses.

Another reason has to do with the needfor avoiding implied conclusions, for example,as in most usages of treatment failure whenapplied to individual patients, e.g., the patientwas considered to be a treatment failure because

of the side effects associated with the treatmentor patients having an MI were consideredto be treatment failures (see usage note forthe term, page 283). Both uses imply causeand effect relationships. For the first use tobe justified, one should be convinced thatthe side effects being referenced are uniqueto the indicated treatment. The second useimplies that the treatment is known to preventMI—an implication, which in all probability,presupposes more knowledge of the drug andits mode of action than actually exists.

Most uses of treatment failure are as impliedindictments of a treatment arising because ofthe ‘‘failure’’ of the treatment to have preventedor delayed some adverse health event oroutcome. Study personnel should be taught touse operationally neutral language (e.g., eventor outcome) in place of the characterization. Inaddition, they should be taught to avoid useas a collective label for an aggregate of eventsor outcomes having various explanations (as ina table entitled Treatment failures by treatmentgroup with counts of a heterogeneous collectionof events or outcomes observed in the differenttreatment groups). The term is meaningless insettings where used without regard to treatmentassignment.

It is meaningless as well in settings whereone of the study treatments is a placebo or nulltreatment. Use in such settings is indicative ofa certain sloppiness of language and will likelycause discerning readers mild befuddlement asto ways in which placebo or null treatmentscould ‘‘fail’’.

The term drug reaction carries a cause andeffect connotation. Similarly, many uses ofside effect in relation to drugs imply such arelationship. Both terms should be avoidedwhen the relationship is in question, or whenthey are used in settings where only some of theuses are justified (e.g., a placebo-controlled trialwhere some of the ‘‘drug reactions’’ are due toplacebo or in which some of the ‘‘reactions’’occur in the absence of any drug).

Qualitative labels such as mild, moderate,or severe carry implied judgments that shouldbe made explicit. Except when obvious, the