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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.”

Stephan Ogenstad, Ph.D.

Senior Director, Biometrics
Vertex Pharmaceuticals Incorporated
 SECOND EDITION

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

Copyright © 2002 by SAS Institute Inc., Cary, NC, USA

ISBN 1-59047-040-0
All rights reserved. Printed in the United States of America. No part of this publication may be reproduced, stored in a
retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise,
without the prior written permission of the publisher, SAS Institute Inc.
U.S. Government Restricted Rights Notice: Use, duplication, or disclosure of this software and related
documentation by the U.S. government is subject to the Agreement with SAS Institute and the restrictions set forth in
FAR 52.227-19, Commercial Computer Software-Restricted Rights (June 1987).

SAS Institute Inc., SAS Campus Drive, Cary, North Carolina 27513.

1st printing, July 2002

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
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®
SAS and all other SAS Institute Inc. product or service names are registered trademarks or trademarks of SAS
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Other brand and product names are trademarks of their respective companies.
 Table of Contents

Preface to the Second Edition .........................................................................................................xi

Preface to the First Edition ............................................................................................................xiii

Chapter 1 - Introduction & Basics

1.1 Statistics—the Field .................................................................................................................... 1
1.2 Probability Distributions ........................................................................................................... 4
1.3 Study Design Features ............................................................................................................... 9
1.4 Descriptive Statistics ................................................................................................................ 13
1.5 Inferential Statistics ................................................................................................................. 16
1.6 Summary ................................................................................................................................... 21

Chapter 2 – Topics in Hypothesis Testing

2.1 Significance Levels .................................................................................................................... 23
2.2 Power ......................................................................................................................................... 25
2.3 One-Tailed and Two-Tailed Tests ............................................................................................ 26
2.4 p-Values ..................................................................................................................................... 27
2.5 Sample Size Determination ..................................................................................................... 27
2.6 Multiple Testing ........................................................................................................................ 30
2.7 Summary ................................................................................................................................... 38

Chapter 3 – The Data Set TRIAL

3.1 Introduction............................................................................................................................... 39
3.2 Data Collection ......................................................................................................................... 39
3.3 Creating the Data Set TRIAL.................................................................................................. 42
3.4 Statistical Summarization ....................................................................................................... 45
3.5 Summary.................................................................................................................................... 54

Chapter 4 – The One-Sample t-Test

4.1 Introduction............................................................................................................................... 55
4.2 Synopsis ..................................................................................................................................... 55
4.3 Examples ................................................................................................................................... 56
4.4 Details & Notes ......................................................................................................................... 64

Chapter 5 – The Two-Sample t-Test

5.1 Introduction............................................................................................................................... 67
5.2 Synopsis ..................................................................................................................................... 67
5.3 Examples ................................................................................................................................... 68
5.4 Details & Notes ......................................................................................................................... 73
 iv Table of Contents

Chapter 6 – One-Way ANOVA

6.1 Introduction............................................................................................................................... 77
6.2 Synopsis ..................................................................................................................................... 77
6.3 Examples ................................................................................................................................... 80
6.4 Details & Notes ......................................................................................................................... 86

Chapter 7 – Two-Way ANOVA

7.1 Introduction............................................................................................................................... 91
7.2 Synopsis ..................................................................................................................................... 91
7.3 Examples ................................................................................................................................... 94
7.4 Details & Notes ....................................................................................................................... 107

Chapter 8 – Repeated Measures Analysis

8.1 Introduction............................................................................................................................. 111
8.2 Synopsis ................................................................................................................................... 111
8.3 Examples ................................................................................................................................. 115
8.4 Details & Notes ....................................................................................................................... 148

Chapter 9 – The Crossover Design

9.1 Introduction............................................................................................................................. 157
9.2 Synopsis ................................................................................................................................... 158
9.3 Examples ................................................................................................................................. 160
9.4 Details & Notes ....................................................................................................................... 171

Chapter 10 – Linear Regression

10.1 Introduction............................................................................................................................. 175
10.2 Synopsis ................................................................................................................................... 175
10.3 Examples ................................................................................................................................. 178
10.4 Details & Notes ....................................................................................................................... 193

Chapter 11 – Analysis of Covariance

11.1 Introduction............................................................................................................................. 199
11.2 Synopsis ................................................................................................................................... 200
11.3 Examples ................................................................................................................................. 203
11.4 Details & Notes ....................................................................................................................... 221

Chapter 12 – The Wilcoxon Signed-Rank Test

12.1 Introduction............................................................................................................................. 227
12.2 Synopsis ................................................................................................................................... 227
12.3 Examples ................................................................................................................................. 228
12.4 Details & Notes ....................................................................................................................... 234

Chapter 13 – The Wilcoxon Rank-Sum Test

13.1 Introduction............................................................................................................................. 237
13.2 Synopsis ................................................................................................................................... 237
13.3 Examples ................................................................................................................................. 239
13.4 Details & Notes ....................................................................................................................... 244
 Table of Contents v

Chapter 14 – The Kruskal-Wallis Test

14.1 Introduction............................................................................................................................. 247
14.2 Synopsis ................................................................................................................................... 247
14.3 Examples ................................................................................................................................. 249
14.4 Details & Notes ....................................................................................................................... 253

Chapter 15 – The Binomial Test

15.1 Introduction............................................................................................................................. 257
15.2 Synopsis ................................................................................................................................... 257
15.3 Examples ................................................................................................................................. 259
14.4 Details & Notes ....................................................................................................................... 261

Chapter 16 – The Chi-Square Test

16.1 Introduction............................................................................................................................. 265
16.2 Synopsis ................................................................................................................................... 265
16.3 Examples ................................................................................................................................. 267
16.4 Details & Notes........................................................................................................................ 279

Chapter 17 – Fisher’s Exact Test

17.1 Introduction............................................................................................................................. 285
17.2 Synopsis ................................................................................................................................... 285
17.3 Examples ................................................................................................................................. 286
17.4 Details & Notes........................................................................................................................ 289

Chapter 18 – McNemar’s Test

18.1 Introduction............................................................................................................................. 293
18.2 Synopsis ................................................................................................................................... 293
18.3 Examples ................................................................................................................................. 294
18.4 Details & Notes........................................................................................................................ 301

Chapter 19 – The Cochran-Mantel-Haenszel Test

19.1 Introduction............................................................................................................................. 305
19.2 Synopsis ................................................................................................................................... 305
19.3 Examples ................................................................................................................................. 307
19.4 Details & Notes........................................................................................................................ 313

Chapter 20 – Logistic Regression

20.1 Introduction............................................................................................................................. 317
20.2 Synopsis ................................................................................................................................... 318
20.3 Examples ................................................................................................................................. 322
20.4 Details & Notes........................................................................................................................ 340

Chapter 21 – The Log-Rank Test

21.1 Introduction............................................................................................................................. 349
21.2 Synopsis ................................................................................................................................... 350
21.3 Examples.................................................................................................................................. 351
21.4 Details & Notes........................................................................................................................ 359
 vi Table of Contents

Chapter 22 – The Cox Proportional Hazards Model

22.1 Introduction............................................................................................................................. 365
22.2 Synopsis ................................................................................................................................... 366
22.3 Examples.................................................................................................................................. 367
22.4 Details & Notes........................................................................................................................ 376

Chapter 23 – Exercises
23.1 Introduction............................................................................................................................. 381
23.2 Exercises .................................................................................................................................. 381
23.3 Appropriateness of the Methods ........................................................................................... 383
23.4 Summary.................................................................................................................................. 387

Appendix A – Probability Tables

A.1 Probabilities of the Standard Normal Distribution............................................................. 390
A.2 Critical Values of the Student t-Distribution....................................................................... 391
A.3 Critical Values of the Chi-Square Distribution ................................................................... 392

Appendix B – Common Distributions Used in Statistical Inference

B.1 Notation.................................................................................................................................... 393
B.2 Properties................................................................................................................................. 394
B.3 Results ...................................................................................................................................... 395
B.4 Distributional Shapes.............................................................................................................. 397

Appendix C – Basic ANOVA Concepts

C.1 Within- vs. Between-Group Variation.................................................................................. 399
C.2 Noise Reduction by Blocking ................................................................................................. 401
C.3 Least Squares Mean (LS-mean) ............................................................................................ 405

Appendix D – SS Types I, II, III, and IV Methods for an Unbalanced

Two-Way Layout
D.1 SS Types Computed by SAS .................................................................................................. 409
D.2 How to Determine the Hypotheses Tested ........................................................................... 411
D.3 Empty Cells.............................................................................................................................. 416
D.4 More Than Two Treatment Groups..................................................................................... 417
D.5 Summary.................................................................................................................................. 419

Appendix E – Multiple Comparison Methods

E.1 Multiple Comparisons of Means ........................................................................................... 421
E.2 Multiple Comparisons of Binomial Proportions.................................................................. 432
E.3 Summary.................................................................................................................................. 436

Appendix F – Data Transformations

F.1 Introduction............................................................................................................................. 437
F.2 The Log Transformation........................................................................................................ 438

Appendix G – SAS Code for Exercises in Chapter 23.................................................... 441

References .............................................................................................................................................. 447

Index ................................................................................................................................................... 453