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Common Statistical
Methods for
Clinical Research:
with SAS® Examples
Glenn A. Walker
SAS Publishing
More praise for this new edition
“This book is an extension and improvement to the excellent first edition, which appeared
in 1996. Each chapter has an introduction covering a specific statistical method and gives
examples of where the method is used. The introduction is followed by a synopsis
presenting the necessary and significant information for the reader to get a good
understanding of the statistical method. Excellent examples are given, followed by the
SAS code for the example. Detailed annotations make the SAS output easy to understand.
The book also gives numerous extensions for the methods.
Dr. Walker has certainly used his many years of consulting experience, his teaching
experience, and his understanding of SAS to produce an even better book that is equally
understandable and helpful to the novice as well as the experienced statistician. Each will
benefit from this insightful journey into statistics and the use of SAS, whether as a
teaching tool or a refresher. I can recommend this book wholeheartedly.”
CommonStatistical Methods
for Clinical Research
with SAS Examples
®
Glenn A. Walker
58086
The correct bibliographic citation for this manual is as follows: Walker, Glenn A. 2002. Common Statistical Methods
®
for Clinical Research with SAS Examples, Second Edition. Cary, NC: SAS Institute Inc.
®
Common Statistical Methods for Clinical Research with SAS Examples, Second Edition
SAS Institute Inc., SAS Campus Drive, Cary, North Carolina 27513.
SAS Publishing provides a complete selection of books and electronic products to help customers use SAS software to
its fullest potential. For more information about our e-books, e-learning products, CDs, and hardcopy books, visit the
SAS Publishing Web site at www.sas.com/pubs or call 1-800-727-3228.
®
SAS and all other SAS Institute Inc. product or service names are registered trademarks or trademarks of SAS
Institute Inc. in the USA and other countries. ® indicates USA registration.
Other brand and product names are trademarks of their respective companies.
Table of Contents
Chapter 23 – Exercises
23.1 Introduction............................................................................................................................. 381
23.2 Exercises .................................................................................................................................. 381
23.3 Appropriateness of the Methods ........................................................................................... 383
23.4 Summary.................................................................................................................................. 387
This second edition expands the first edition with the inclusion of new sections,
examples, and extensions of statistical methods described in the first edition only
in their most elementary forms. New methods sections include analysis of
crossover designs (Chapter 9) and multiple comparison methods (Appendix D).
Chapters that present repeated measures analysis (Chapter 8), linear regression
(Chapter 10), analysis of covariance (Chapter 11), the chi-square test (Chapter 16),
and logistic regression (Chapter 20) have been notably expanded, and 50% more
examples have been added throughout the book. A new chapter of exercises has
also been added to give the reader practice in applying the various methods
presented. Also new in this edition is an introduction to α-adjustments for interim
analyses (Chapter 2).
Although many of the new features will have wide appeal, some are targeted to the
more experienced data analyst. These include discussion of the proportional odds
model, the clustered binomial problem, collinearity in multiple regression, the use
of time-dependent covariates with Cox regression, and the use of generalized
estimating equations in repeated measures analysis. These methods, which are
based on more advanced concepts than those found in most of the book, are
routinely encountered in data analysis applications of clinical investigations and, as
such, fit the description of ‘common statistical methods for clinical research’.
However, so as not to overwhelm the less experienced reader, these concepts are
presented only briefly, usually by example, along with references for further
reading.
The examples have been updated to Version 8 of SAS, however, the programming
statements used have been kept ‘portable’, meaning that most can be used in earlier
versions of SAS as they appear in the examples, unless otherwise noted. This
includes the use of portable variable and data set names, despite accommodation
for use of long names beginning with Version 8. Because SAS is
xii Common Statistical Methods for Clinical Research with SAS Examples
not the main focus of this book but is key to efficient data analysis, programming
details are not included here, but they can be found in numerous references cited
throughout the book. Many of these references are other books in the Books by
Users program at SAS, which provide the details, including procedure options, use
of ODS, and the naming standards that are new in Version 8. For statistical
programming, my favorites include Categorical Data Analysis Using the SAS
System, Second Edition, by Stokes, Davis, and Koch (2000) and Survival
Analysis Using the SAS System, A Practical Guide, by Paul Allison (1995).
I welcome and appreciate reader comments and feedback through the SAS
Publications Web site.
Glenn A. Walker
July 2002
Preface xiii
This book was written for those involved in clinical research and who may, from
time to time, need a guide to help demystify some of the most commonly used
statistical methods encountered in our profession.
All too often, I have heard medical directors of clinical research departments
express frustration at seemingly cryptic statistical methods sections of protocols
which they are responsible for approving. Other nonstatisticians, including medical
monitors, investigators, clinical project managers, medical writers and regulatory
personnel, often voice similar sentiment when it comes to statistics, despite the
profound reliance upon statistical methods in the success of the clinical program.
For these people, I offer this book (sans technical details) as a reference guide to
better understand statistical methods as applied to clinical investigation and the
conditions and assumptions under which they are applied.
For the clinical data analyst and statistician new to clinical applications, the
examples from a clinical trials setting may help in making the transition from other
statistical fields to that of clinical trials. The discussions of 'Least-Squares' means,
distinguishing features of the various SAS® types of sums-of-squares, and
relationships among various tests (such as the Chi-Square Test, the Cochran-
Mantel-Haenszel Test and the Log-Rank Test) may help crystalize the analyst's
understanding of these methods. Analysts with no prior SAS experience should
benefit by the simplifed SAS programming statements provided with each example
as an introduction to SAS analyses.
This book may also aid the SAS programmer with limited statistical knowledge in
better grasping an overall picture of the clinical trials process. Many times
knowledge of the hypotheses being tested and appropriate interpretation of the
SAS output relative to those hypotheses will help the programmer become more
efficient in responding to the requests of other clinical project team members.
Finally, the medical student will find the focused presentation on the specific
methods presented to be of value while proceeding through a first course in
biostatistics.
For all readers, my goal was to provide a unique approach to the description of
commonly used statistical methods by integrating both manual and computerized
solutions to a wide variety of examples taken from clinical research. Those who
learn best by example should find this approach rewarding. I have found no other
book which demonstrates that the SAS output actually does have the same results
as the manual solution of a problem using the calculating formulas. So ever
reassuring this is for the student of clinical data analysis!
xiv Common Statistical Methods for Clinical Research with SAS Examples
Each statistical test is presented in a separate chapter, and includes a brief, non-
technical introduction, a synopsis of the test, one or two examples worked
manually followed by an appropriate solution using the SAS statistical package,
and finally, a discussion with details and relevant notes.
Chapters 1 and 2 are introductory in nature, and should be carefully read by all
with no prior formal exposure to statistics. Chapter 1 provides an introduction to
statistics and some of the basic concepts involved in inference-making. Chapter 2
goes into more detail with regard to the main aspects of hypothesis testing,
including significance levels, power and sample size determination. For those who
use analysis-of-variance, Appendix C provides a non-technical introduction to
ANOVA methods. The remainder of the book may be used as a text or reference.
As a reference, the reader should keep in mind that many of the tests discussed in
later chapters rely on concepts presented earlier in the book, strongly suggesting
prerequisite review.
Many of the examples are based on actual clinical trials which I have analyzed. In
all cases, the data are contrived, and in many cases fictitious names are used for
different treatments or research facilities. Any resemblence of the data or the tests'
results to actual cases is purely coincidental.
Glenn A. Walker
May 1996
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moarne yette in stadige Easterkoelte, ta to setten, it waeide, det it
lille en de wyn roan al heger en heger ta ’t fiere Noard-Easten ta.
Do lichte in swierladene Noardlânskoffe fol hout it anker en
stevene, al de seils op en sêft soeijende as in skuitsjeseas yn syn
riemmen op ’e weagen, op ’e fiere igge fen Grinzerlân oan. En Ryklef
Ripperda stie foarenoan by de boech. Under’t mom fen in ienfâldich
houtfrachtersfeint sloech syn hert mei heftiger slaggen, do-t se al
skipperjende en lavearjende, de hiele koffe oer en oer wyt en de
seils as planken sa hird, ta de haven fen Delfsyl ynsylden en it paed
nei de greate sted fen Grins sochten.
Mar gjin healûre letter lei de greate trijemester stil. De froast wie
machtiger as hy en stie him.
It wintere fûl.—
VII.
Dy-t preekje woe, koe wol in lokael hiere en dy-t sjonge en bidde
woene, diene det mar yn hjar eigen hûs. Den koste it neat en scoe
wol like folle helpe,—hie hy laeitsjend sei. „Wy dogge it der ek wol
sûnder, nou?” Poppéus hie flau oandraeid nikt, hy siet mei niget to
lêzen yn ’e Decamerone en biseach de moaije printsjes en liet heit
mar skrippe en wrotte.
It hie me in opskûr jown yn Fryslân fen hwer bin jo my, do-t it
earste jild ynfoardere waerd en op heite oanstean hie Poppéus in
skoft yn Brussel tahâlden. Hy woe syn jonge, de thesaurier général,
net dea ha.... in rút ef hwet stikken yn ’e hûs, det mocht noch hinne
bruije.
Mar einliks bilune de stoarm en bigoan it jild moai dripkjende wei
binnen to kommen. It gyng stadich, mar de bêste saden binne de
bûrrelders, net de spuiters, den is ’t gau dien en de tsjerkfâlden en
de gasthús- en weesfâlden hingen oan ’t jild as tiken oan ’e wolle. It
mes waerd hjar sa op ’e kiel set, det hja moasten einliks wol en hy
wreau him yn ’e hânnen, dizze útfining bisloech boppest bêst,
Ljouwert wie for gâns in set út ’e jildkrapte en hy soarge wol, det
Poppéus eard waerde as de gnappe rekkenmaster, dy-t dit plan
úttocht hie. Hy sels bleau efter de skermen en hie syn wille.
Mar ’t is net lang sinneskyn, as der komt wer in bui en nou siet ’r
wer yn noed en soarch om dy jonge. Dit woe ’r net en det woe ’r net
en as ’r al hwet diich, roan ’t altyd op skea út ef hy sette himsels op
in nuvere menear fêst. Krekt as wierne syn tinsen altyd op ’e doele.
—
Sá tocht d’ âld man en koe syn soan der hast om hate. It hekke al
gau ris mei hjar yn ’e lêste tiid, sa ’s nou hjoed ek wer. En den socht
’r syn hael by Anne en de lytse poppe. It moaije wiif fen syn soan,
hjar ljeaf antlit mei syn sêftreade wangen en blierkjende heldere
eagen, de gutigens fen it mûltsje en ’e dertenens fen de dobkes yn
dy wangen, it wie him in eachweiding, as hy it ris wer seach, de
ginaemd spinfoetsjend op ’e skoat en syn lytse fingerkes lûkend oan
’e krollen fen hjar glanzich hier.
Hy forstie hjar better as syn soan it eigen wiif en Anne, o hja roan
heech mei pake! sa ’s se him altyd, it ljeave sêfte lûd ien strieling,
neamde. Pake wie hjar bounnoat, hjar help en hjar stipe yn mennich
ding. Mem stie ’r alhiel bûten, foaral nou se hjar yn in twadde trou
bijown hie mei hjar fâld. En as Anne om dy dagen tochte, den
suchte se. Hja hie hjar it libben ek oars winske, as it kaem wie. It
wie allegear sa deagewoan, it libben in forfeelsum karwei, om
trochhinne to arbeidzjen nei de ein. Hiel djip yn hjar hert fielde se
hjar altyd noch de aristocrate, dy-t hjar delbûgt nei de boargerman,
al is ’r ek noch sa ryk en yn oansjen as de fen Rhé’s en by tiiden, as
se in min sin hie, liet se it net, om him ris in gefoelige ealjebij’s prip
to jaen. Den glimke hy fyntsjes en liet it by him delglide as wetter by
in iel. Ljeaver sa ’n ien ta skoandochter, der fjûr yn siet as in sleau
tutsje, dy der net iens in eigen oardiel op neihâlde.
Ynienen krige hy der sin oan, nou foartdaedlik ris efkes by hjar to
sjen. Poppéus syn stúmjend selskip wie net folle oan.
„Giest mei nei ús jongfolk?” frege ’r, wylt ’r de piip delsette yn ’e
stander.
Poppéus bromde hwet. It sinnige him net, hearde ’r wol. Hy loek
de jas rjucht, sprinkele hwet lodderein op ’e klean en skouwde de
prûk in bytsje út de eagen. Efkes riboske ’r, do-t ’r út de waerme
keamer kaem, it loek kâld yn ’e gong, al skynde de sinne
maitiidseftich en wierne de dagen moai oan ’t winnen.
Der bigoan me ynienen de âlde spylklok yn ’e gong to spyljen,
skel, gekjeijende wei mei hege trillerige lûdtsjes en syn âld wyske
brocht yn in omsjoch in libben fen fleur en ljocht yn ’t healtsjuster
fen ’e brede gong. Tra.... lá!.... tra.... lá!.... tra.... lá! gyng it, in âld
ruterkeliet foar hûndert jier nij en neisongen troch in jonkheit fen do.
De popkes boppe yn ’e wizerplaet niichden en bûgden, de boatsjes
op ’e frjemdblaue wetters skommelen, de triedtsjes fen it touwirk
trillen en wynderen, suver as blies der in wyntwirre fen ’t forline yn
’e seilen. Heech en skel song de klok troch, ta twa kear ta itselde
âlde, wufte, ljeave, dertene deuntsje. Do waerde it ynienen
deastil.... de klok sloech fol, fjouwer ûre.
De hânnen yn ’e bûs, de skrandere eagen heal tichtknypt, sa stie
âlde fen Rhé der nei to sjen en formakke him der mei, ho-t de
boatsjes noch altyd skommelen en it wiiske fen ’e klok noch itselde
wie, as do hy him as lytse jonge for ’t earst hearde yn syn heite hûs.
En nou hearde syn bernsbern him al sa, lytse Henricus fen Rhé. Mei
hasten stapte ’r nei de túnkeamer ta en diich sunich de doar op.
Hwet ’r do seach, wie suver in skilderij.
Foar ’t finster yn ’t grille ljocht stie de lytse boi, in hege steek op
fen swart sitspompier, in kwast fen útraffele en útpluze fjûrread sajet
der foar op, in lange jageline fen pypstallen en reade lapkes om ’e
mil oer ’e liebân, in great swird fen goudpompier op ’e side. En Anne
yn hjar sidene staesjejurk der efteroan en dy mende him en hja
songene it heechste liet togearre fen „De Peerdeman”: