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 CLUSTER
RANDOMISED
TRIALS

C8164_C000.indd i 11/17/08 10:04:03 AM

 CHAPMAN & HALL/CRC
Interdisciplinar y Statistics Series
Series editors: N. Keiding, B.J.T. Morgan, C.K. Wikle, P. van der Heijden

Published titles

AN INVARIANT APPROACH TO S. Lele and J. Richtsmeier

STATISTICAL ANALYSIS OF SHAPES

ASTROSTATISTICS G. Babu and E. Feigelson

BAYESIAN DISEASE MAPPING: Andrew B. Lawson

HIERARCHICAL MODELING IN SPATIAL
EPIDEMIOLOGY

BIOEQUIVALENCE AND S. Patterson and

STATISTICS IN CLINICAL B. Jones
PHARMACOLOGY

CLINICAL TRIALS IN ONCOLOGY J. Crowley, S. Green,

SECOND EDITION and J. Benedetti

CLUSTER RANDOMISED TRIALS R.J. Hayes and L.H. Moulton

CORRESPONDENCE ANALYSIS M. Greenacre

IN PRACTICE, SECOND EDITION

DESIGN AND ANALYSIS OF D.L. Fairclough

QUALITY OF LIFE STUDIES
IN CLINICAL TRIALS

DYNAMICAL SEARCH L. Pronzato, H. Wynn,

and A. Zhigljavsky

GENERALIZED LATENT VARIABLE A. Skrondal and

MODELING: MULTILEVEL, S. Rabe-Hesketh
LONGITUDINAL, AND STRUCTURAL
EQUATION MODELS

GRAPHICAL ANALYSIS OF K. Basford and J. Tukey

MULTI-RESPONSE DATA

INTRODUCTION TO M. Waterman
COMPUTATIONAL BIOLOGY:
MAPS, SEQUENCES, AND GENOMES

MARKOV CHAIN MONTE CARLO W. Gilks, S. Richardson,

IN PRACTICE and D. Spiegelhalter

C8164_C000.indd ii 11/17/08 10:04:04 AM

 Published titles

MEASUREMENT ERROR AND P. Gustafson

MISCLASSIFICATION IN STATISTICS
AND EPIDEMIOLOGY: IMPACTS AND
BAYESIAN ADJUSTMENTS

META-ANALYSIS OF BINARY DATA D. Böhning, R. Kuhnert,

USING PROFILE LIKELIHOOD and S. Rattanasiri

STATISTICAL ANALYSIS OF GENE T. Speed

EXPRESSION MICROARRAY DATA

STATISTICAL AND COMPUTATIONAL R. Wu and M. Lin

PHARMACOGENOMICS

STATISTICS IN MUSICOLOGY J. Beran

STATISTICAL CONCEPTS J. Aitchison, J.W. Kay,

AND APPLICATIONS IN and I.J. Lauder
CLINICAL MEDICINE

STATISTICAL AND PROBABILISTIC P.J. Boland

METHODS IN ACTUARIAL SCIENCE

STATISTICAL DETECTION AND P. Rogerson and I.Yamada

SURVEILLANCE OF GEOGRAPHIC
CLUSTERS

STATISTICS FOR ENVIRONMENTAL A. Bailer and W. Piegorsch

BIOLOGY AND TOXICOLOGY

STATISTICS FOR FISSION R.F. Galbraith

TRACK ANALYSIS

C8164_C000.indd iii 11/17/08 10:04:04 AM

 C h ap man & Hall/CRC
I n t e rd i s c i p l i nar y Statistics Series

CLUSTER
RANDOMISED
TRIALS

Richard J. Hayes
Lawrence H. Moulton

C8164_C000.indd v 11/17/08 10:04:05 AM

 Chapman & Hall/CRC
Taylor & Francis Group
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Library of Congress Cataloging-in-Publication Data

Hayes, Richard J., DSc.

Cluster randomised trials / authors, Richard J. Hayes and Lawrence H. Moulton.
p. ; cm. -- (Interdisciplinary statistics)
“A CRC title.”
Includes bibliographical references and index.
ISBN 978-1-58488-816-1 (hardcover : alk. paper)
1. Clinical trials. 2. Cluster analysis. I. Moulton, Lawrence H. II. Title. III. Series.
[DNLM: 1. Cluster Analysis. 2. Randomized Controlled Trials as Topic--methods. 3.
Data Interpretation, Statistical. WA 950 H418c 2009]

R853.C55H39 2009
615.5072’4--dc22 2008035804

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C8164_C000.indd vi 11/17/08 10:04:05 AM

 To our families:

Anne, Clare and Emma; Ann, Carine and Tyler.

C8164_C000d.indd vii 11/17/08 9:59:26 AM

 Contents

Preface ...................................................................................................... xvii

Authors .......................................................................................................xix
Glossary of Notation .................................................................................xxi

Part A: Basic Concepts

1 Introduction ........................................................................................ 3
1.1 Randomised Trials................................................................................ 3
1.1.1 Randomising Clusters ..............................................................4
1.1.2 Some Case Studies ....................................................................6
1.1.3 Overview of Book ..................................................................... 8

2 Variability between Clusters .......................................................... 11

2.1 Introduction ......................................................................................... 11
2.2 The Implications of Between-cluster Variability:
Some Examples .................................................................................... 12
2.3 Measures of Between-cluster Variability ........................................ 15
2.3.1 Introduction ............................................................................. 15
2.3.1.1 Binary Outcomes and Proportions ......................... 15
2.3.1.2 Event Data and Person-years Rates......................... 15
2.3.1.3 Quantitative Outcomes and Means ........................ 16
2.3.2 Coefficient of Variation, k ....................................................... 16
2.3.3 Intracluster Correlation Coefficient, ρ .................................. 17
2.3.3.1 Quantitative Outcomes ............................................. 17
2.3.3.2 Binary Outcomes ....................................................... 18
2.3.3.3 Estimation of ρ ........................................................... 18
2.3.4 Relationship between k and ρ ............................................... 18
2.4 The Design Effect................................................................................ 19
2.4.1 Binary Outcomes ..................................................................... 19
2.4.2 Quantitative Outcomes .......................................................... 21
2.5 Sources of Within-cluster Correlation .............................................22
2.5.1 Clustering of Population Characteristics.............................22
2.5.2 Variations in Response to Intervention ...............................22
2.5.3 Correlation Due to Interaction between Individuals......... 23

3 Choosing Whether to Randomise by Cluster ............................... 25

3.1 Introduction ......................................................................................... 25
3.2 Rationale for Cluster Randomisation .............................................. 25
3.2.1 Type of Intervention ............................................................... 25

ix

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 x Contents

3.2.2 Logistical Convenience and Acceptability .......................... 26

3.2.3 Contamination ......................................................................... 27
3.3 Using Cluster Randomisation to Capture Indirect
Effects of Intervention ........................................................................ 28
3.3.1 Introduction ............................................................................. 28
3.3.2 Effects of an Intervention on Infectiousness ....................... 29
3.3.3 Mass Effects of Intervention .................................................. 31
3.3.4 Direct, Indirect, Total and Overall Effects........................... 33
3.4 Disadvantages and Limitations of Cluster
Randomisation .................................................................................... 37
3.4.1 Efficiency .................................................................................. 37
3.4.2 Selection Bias ........................................................................... 37
3.4.3 Imbalances between Study Arms ......................................... 39
3.4.4 Generalisability ....................................................................... 40

Part B: Design Issues

4 Choice of Clusters ............................................................................ 45

4.1 Introduction ......................................................................................... 45
4.2 Types of Cluster .................................................................................. 45
4.2.1 Geographical Clusters ............................................................ 45
4.2.1.1 Communities .............................................................. 46
4.2.1.2 Administrative Units ................................................ 47
4.2.1.3 Arbitrary Geographical Zones ................................ 48
4.2.2 Institutional Clusters .............................................................. 49
4.2.2.1 Schools ........................................................................ 49
4.2.2.2 Health Units ............................................................... 50
4.2.2.3 Workplaces ................................................................. 50
4.2.3 Smaller Clusters ...................................................................... 51
4.2.3.1 Households and Other Small Groups .................... 52
4.2.3.2 Individuals as Clusters ............................................. 52
4.3 Size of Clusters .................................................................................... 53
4.3.1 Introduction ............................................................................. 53
4.3.2 Statistical Considerations ....................................................... 53
4.3.3 Logistical Issues ......................................................................54
4.3.4 Contamination ......................................................................... 55
4.3.4.1 Contacts between Intervention and
Control Clusters ......................................................... 55
4.3.4.2 Contacts between Intervention Clusters and
the Wider Population ................................................ 55
4.3.4.3 Contacts between Control Clusters
and the Wider Population ........................................ 56
4.3.4.4 Effects of Cluster Size on Contamination .............. 56
4.3.5 Transmission Zones of Infectious Diseases ........................ 56

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 Contents xi

4.4 Strategies to Reduce Contamination................................................ 58

4.4.1 Separation of Clusters............................................................. 58
4.4.2 Buffer Zones ............................................................................. 60
4.4.3 The Fried Egg Design ............................................................. 62
4.5 Levels of Randomisation, Intervention, Data Collection
and Inference .......................................................................................64

5 Matching and Stratification ............................................................ 65

5.1 Introduction .........................................................................................65
5.2 Rationale for Matching ......................................................................65
5.2.1 Avoiding Imbalance between Treatment Arms ................. 66
5.2.2 Improving Study Power and Precision ................................ 68
5.3 Disadvantages of Matching............................................................... 70
5.3.1 Loss of Degrees of Freedom .................................................. 70
5.3.2 Drop-out of Clusters ............................................................... 72
5.3.3 Limitations in Statistical Inference for Matched Trials ..... 74
5.3.3.1 Adjustment for Covariates ....................................... 74
5.3.3.2 Testing for Variation in Intervention Effect ........... 74
5.3.3.3 Estimation of Intracluster Correlation
Coefficient and Coefficient of Variation ................. 75
5.4 Stratification as an Alternative to Matching ................................... 75
5.5 Choice of Matching Variables ...........................................................77
5.5.1 Estimating the Matching Correlation ..................................77
5.5.2 Matching on Baseline Values of Endpoint of Interest........ 78
5.5.3 Matching on Surrogate Variables ......................................... 79
5.5.4 Matching on Multiple Variables............................................ 79
5.5.5 Matching on Location.............................................................80
5.6 Choosing Whether to Match or Stratify .......................................... 81
5.6.1 Introduction ............................................................................. 81
5.6.2 Trials with a Small Number of Clusters .............................. 81
5.6.3 Trials with a Larger Number of Clusters.............................83

6 Randomisation Procedures ............................................................. 85

6.1 Introduction .........................................................................................85
6.2 Restricted Randomisation ................................................................. 86
6.2.1 Basic Principles ........................................................................ 86
6.2.2 Using Restricted Randomisation to Achieve Overall
Balance ...................................................................................... 87
6.2.3 Balance Criteria ....................................................................... 89
6.2.4 Validity of Restricted Randomisation .................................. 94
6.2.5 Restricted Randomisation with More than Two
Treatment Arms ...................................................................... 99
6.3 Some Practical Aspects of Randomisation ..................................... 99
6.3.1 Concealment of Allocation .................................................... 99
6.3.2 Public Randomisation ............................................................ 99

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 xii Contents

7 Sample Size ..................................................................................... 105

7.1 Introduction ....................................................................................... 105
7.2 Sample Size for Unmatched Trials ................................................. 106
7.2.1 Event Rates ............................................................................. 107
7.2.2 Proportions ............................................................................ 109
7.2.3 Means ...................................................................................... 110
7.2.4 Variable Sample Size per Cluster ........................................ 111
7.2.5 Sample Size Calculations Based on Intracluster
Correlation Coefficient ......................................................... 111
7.3 Sample Size for Matched and Stratified Trials ............................. 113
7.3.1 Matched Trials ....................................................................... 113
7.3.1.1 Event Rates ............................................................... 114
7.3.1.2 Proportions ............................................................... 114
7.3.1.3 Means ........................................................................ 114
7.3.2 Stratified Trials ...................................................................... 116
7.4 Estimating the Between-cluster Coefficient
of Variation ........................................................................................ 117
7.4.1 Unmatched Trials .................................................................. 117
7.4.1.1 Event Rates ............................................................... 118
7.4.1.2 Proportions ............................................................... 119
7.4.1.3 Means ........................................................................ 120
7.4.2 Matched and Stratified Trials .............................................. 120
7.4.2.1 Event Rates ............................................................... 120
7.4.2.2 Proportions and Means .......................................... 121
7.5 Choice of Sample Size in each Cluster ........................................... 121
7.6 Further Issues in Sample Size Calculation.................................... 124
7.6.1 Trials with More than Two Treatment Arms .................... 124
7.6.2 Trials with Treatment Arms of Unequal Size ................... 124
7.6.3 Equivalence Trials ................................................................. 125
7.6.4 Power and Precision ............................................................. 126
7.6.5 Assumptions about Intervention Effects ........................... 127

8 Alternative Study Designs ............................................................ 129

8.1 Introduction ....................................................................................... 129
8.2 Design Choices for Treatment Arms.............................................. 129
8.2.1 Trials with Several Treatment Arms .................................. 129
8.2.2 Factorial Trials ....................................................................... 130
8.2.2.1 Independent Effects ................................................ 130
8.2.2.2 Non-independent Effects........................................ 132
8.2.3 Crossover Design .................................................................. 135
8.2.4 Stepped Wedge Design ........................................................ 136
8.3 Design Choices for Impact Evaluation .......................................... 141
8.3.1 Introduction ........................................................................... 141
8.3.2 Repeated Cross-sectional Samples ..................................... 142
8.3.3 Cohort Follow-up .................................................................. 143

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 Contents xiii

Part C: Analytical Methods

9 Basic Principles of Analysis .......................................................... 149
9.1 Introduction ....................................................................................... 149
9.2 Experimental and Observational Units......................................... 149
9.3 Parameters of Interest ...................................................................... 151
9.3.1 Event Rates ............................................................................. 151
9.3.2 Proportions ............................................................................ 153
9.3.2.1 Cluster-specific Odds Ratio ................................... 154
9.3.2.2 Population-average Odds Ratio ............................. 155
9.3.3 Means ...................................................................................... 156
9.3.4 More Complex Parameters .................................................. 157
9.4 Approaches to Analysis ................................................................... 159
9.4.1 Cluster-level Analysis........................................................... 159
9.4.2 Individual-level Analysis ..................................................... 159
9.5 Baseline Analysis .............................................................................. 160

10 Analysis Based on Cluster-level Summaries .............................. 163

10.1 Introduction ..................................................................................... 163
10.2 Point Estimates of Intervention Effects ........................................ 164
10.2.1 Point Estimates Based on Cluster Summaries .............. 164
10.2.2 Point Estimates Based on Individual Values ................. 165
10.2.3 Using the Logarithmic Transformation ......................... 167
10.2.4 Case Studies ....................................................................... 168
10.3 Statistical Inference Based on the t Distribution ........................ 172
10.3.1 Unpaired t-test ................................................................... 172
10.3.2 Confidence Intervals Based on Cluster Summaries ..... 173
10.3.2.1 Rate Difference .................................................. 173
10.3.2.2 Rate Ratio ........................................................... 174
10.3.3 Case Studies ....................................................................... 174
10.3.4 Using the Logarithmic Transformation ......................... 177
10.3.5 The Weighted t-test ........................................................... 178
10.4 Statistical Inference Based on a Quasi-likelihood Approach ... 179
10.5 Adjusting for Covariates ................................................................ 182
10.5.1 Stage 1: Obtaining Covariate-adjusted Residuals ......... 182
10.5.1.1 Event Rates ......................................................... 183
10.5.1.2 Proportions ........................................................ 183
10.5.1.3 Means .................................................................. 184
10.5.2 Stage 2: Using the Covariate-adjusted Residuals .......... 184
10.5.2.1 Ratio Measures of Effect .................................. 184
10.5.2.2 Difference Measures of Effect ......................... 185
10.5.3 Case Study .......................................................................... 186
10.6 Nonparametric Methods................................................................ 189
10.6.1 Introduction........................................................................ 189
10.6.2 Rank Sum Test ................................................................... 189
10.6.3 Permutation Tests .............................................................. 190
10.7 Analysing for Effect Modification ................................................ 194

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 xiv Contents

11 Regression Analysis Based on Individual-level Data ............... 199

11.1 Introduction ..................................................................................... 199
11.2 Random Effects Models .................................................................200
11.2.1 Poisson and Cox Regressions with Random Effects......201
11.2.1.1 Poisson Regression with Random Effects ..... 201
11.2.1.2 Cox Regression with Random Effects ............ 207
11.2.2 Mixed Effects Linear Regression .................................... 208
11.2.3 Logistic Regression with Random Effects ..................... 213
11.3 Generalised Estimating Equations ............................................... 219
11.3.1 GEE Models for Binary Data............................................ 219
11.3.2 GEE for Other Types of Outcome.................................... 221
11.4 Choice of Analytical Method ........................................................223
11.4.1 Small Numbers of Clusters ..............................................223
11.4.2 Larger Numbers of Clusters ............................................ 224
11.5 Analysing for Effect Modification ................................................225
11.6 More Complex Analyses ................................................................ 226
11.6.1 Controlling for Baseline Values ....................................... 226
11.6.2 Repeated Measures during Follow-up ........................... 227
11.6.3 Repeated Episodes............................................................. 229

12 Analysis of Trials with More Complex Designs ........................ 233

12.1 Introduction ..................................................................................... 233
12.2 Analysis of Pair-matched Trials .................................................... 233
12.2.1 Introduction........................................................................ 233
12.2.2 Analysis Based on Cluster-level Summaries .................234
12.2.3 Adjusting for Covariates .................................................. 237
12.2.4 Regression Analysis Based on Individual-level
Data...................................................................................... 241
12.3 Analysis of Stratified Trials ........................................................... 242
12.3.1 Introduction........................................................................ 242
12.3.2 Analysis Based on Cluster-level Summaries ................. 243
12.3.3 Regression Analysis Based on Individual-level
Data...................................................................................... 250
12.4 Analysis of Other Study Designs ................................................. 251
12.4.1 Trials with More than Two Treatment Arms ................ 251
12.4.2 Factorial Trials.................................................................... 252
12.4.3 Stepped Wedge Trials ....................................................... 253

Part D: Miscellaneous Topics

13 Ethical Considerations ................................................................... 257

13.1 Introduction ..................................................................................... 257
13.2 General Principles ........................................................................... 257
13.2.1 Beneficence ......................................................................... 258

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 Contents xv

13.2.2 Equity .................................................................................. 258

13.2.3 Autonomy ........................................................................... 259
13.3 Ethical Issues in Group Allocation ............................................... 259
13.4 Informed Consent in Cluster Randomised Trials ...................... 260
13.4.1 Consent for Randomisation ............................................. 261
13.4.1.1 Political Authorities .......................................... 262
13.4.1.2 Village Heads ..................................................... 262
13.4.1.3 Community Representatives ........................... 263
13.4.1.4 Medical Practitioners ........................................ 263
13.4.2 Consent for Participation.................................................. 264
13.5 Other Ethical Issues ........................................................................ 266
13.5.1 Scientific Validity ............................................................... 266
13.5.2 Phased Intervention Designs ........................................... 266
13.5.3 Trial Monitoring ................................................................ 267
13.6 Conclusion........................................................................................ 267

14 Data Monitoring ............................................................................. 269

14.1 Introduction ..................................................................................... 269
14.2 Data Monitoring Committees ....................................................... 270
14.2.1 Review of DMC Responsibilities ..................................... 270
14.2.2 When Are DMCs Necessary for CRTs? .......................... 271
14.2.2.1 Likelihood of Adverse Events ......................... 271
14.2.2.2 Seriousness or Severity of Outcome
Measures ............................................................ 271
14.2.2.3 Timing of Data Collection................................ 272
14.2.3 Monitoring for Adverse Events ....................................... 273
14.2.4 Monitoring for Efficacy ..................................................... 274
14.2.5 Monitoring Adequacy of Sample Size ............................ 274
14.2.6 Assessing Comparability of Treatment Arms ............... 275
14.2.7 Approving the Analytical Plan ....................................... 275
14.2.8 Presentation of Data to the DMC .................................... 276
14.3 Interim Analyses ............................................................................. 277
14.3.1 Introduction........................................................................ 277
14.3.2 Timing of Interim Analyses ............................................. 277
14.3.3 Stopping Rules ................................................................... 278
14.3.3.1 Event Rates ......................................................... 280
14.3.3.2 Proportions ........................................................ 280
14.3.3.3 Means .................................................................. 280
14.3.4 Disadvantages of Premature Stopping........................... 282

15 Reporting and Interpretation ....................................................... 285

15.1 Introduction ..................................................................................... 285
15.2 Reporting of Cluster Randomised Trials..................................... 285
15.2.1 Overview ............................................................................ 285
15.2.1.1 Extended CONSORT Statement ...................... 286
15.2.1.2 Publication Bias ................................................. 286

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 xvi Contents

15.2.2 Reporting of Methods ....................................................... 289

15.2.2.1 Rationale for Cluster Randomisation ............. 289
15.2.2.2 Description of Clusters and Interventions .... 289
15.2.2.3 Sample Size ........................................................ 290
15.2.2.4 Matching, Stratification and
Randomisation .................................................. 291
15.2.2.5 Blinding and Allocation Concealment........... 291
15.2.2.6 Definition of Primary Endpoints .................... 292
15.2.2.7 Statistical Methods............................................ 293
15.2.3 Reporting of Results.......................................................... 294
15.2.3.1 Flow Diagram .................................................... 294
15.2.3.2 Baseline Comparisons ...................................... 294
15.2.3.3 Analysis of Endpoints ...................................... 295
15.2.3.4 Subgroup Analyses ........................................... 296
15.2.3.5 Contamination ................................................... 297
15.2.3.6 Estimates of Between-cluster Variability....... 297
15.3 Interpretation and Generalisability.............................................. 298
15.3.1 Interpretation ..................................................................... 298
15.3.2 Generalisability.................................................................. 299
15.3.3 Systematic Reviews ...........................................................300

References ................................................................................................. 303

Index .......................................................................................................... 309

C8164_C000toc.indd xvi 12/3/08 1:00:49 PM

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