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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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and the CRC Press Web site at

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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

 Preface

Randomised controlled trials are the accepted gold standard for evaluating
the effects of interventions to improve health, and the advantages of this
study design are widely recognised. In the great majority of such trials, indi-
vidual patients or participants are randomly allocated to the experimental
conditions under study, for example to treatment and control groups. Some-
times, however, it is more appropriate to randomise groups of individuals
to the different treatment arms. Trials of this kind are known as cluster ran-
domised trials, and this book aims to discuss the design, conduct and analysis
of such trials.
Few cluster randomised trials were carried out before the 1980s, but since
then the design has become more widely known and many such trials are
carried out and reported every year. In the early years, the special design
and analysis requirements of these trials were not always understood, and
there were many examples of trials that were designed, analysed or reported
inappropriately. Over the past two decades, much work has been done on
methods for cluster randomised trials, and the quality of reported trials has
gradually improved.
This is still a relatively new study design, and methods for such trials are
an active area of statistical research. A large number of alternative methods
have been proposed and published, and their relative merits have not always
been definitively established. We have reached the stage, however, where it is
possible to present a set of core methods of design and analysis. In this book,
we have not attempted to provide a comprehensive review of all possible
methods. Rather we have aimed to select a more limited range of methods
that are simple to understand, easy to apply with readily available statistical
software and perform well under the conditions experienced in most cluster
randomised trials.
The book has grown out of the personal involvement of the authors in a
wide range of cluster randomised trials, mostly in the field of international
public health. We hope it will provide a useful practical resource for inves-
tigators carrying out such trials. Toward this end, we have provided more
material on study design options than is usually found in statistical texts.
While some equations are needed to describe and present the methods
adequately, we have tried to avoid unnecessary mathematical detail. We
have also worked hard to use consistent notation throughout the book, and
this is set out in the Glossary of Notation.
We were particularly keen that readers should be able to apply the methods
to their own trials. There is therefore a heavy emphasis on practical examples,
many of them based on our own research. We have tried to include exam-
ples from a wide variety of settings, including both developing and indus-
trialised countries. Cluster randomisation may confer particular advantages
xvii

C8164_C000a.indd xvii 11/17/08 10:00:17 AM

 xviii Preface

when evaluating the effects of interventions against infectious diseases. We feel

that this aspect of the design has received insufficient emphasis in the litera-
ture, and have ensured that our examples cover such applications as well as
studies of non-communicable diseases. To illustrate the application of ana-
lytical methods, we have provided several datasets from actual trials. These
datasets can be downloaded from the “Downloads & Updates” section of the
publisher’s website at http://www.crcpress.com/e_products/downloads/.
Computer output is displayed in text boxes to show how these data can be
analysed using the Stata® statistical package. The reader is encouraged to
reproduce these analyses and to explore alternative approaches. Equivalent
analyses can usually be carried out using other packages such as SAS®.
While our examples focus on medical applications, the cluster randomised
trial design is of equal relevance for the evaluation of other types of interven-
tion, for example in the fields of education or social welfare. We hope that the
book will be of value to practitioners working in these and other fields. We
think that the rigorous evidence of intervention effects provided by cluster
randomised trials has the potential to inform public policy in a wide range
of areas.
This book could not have been written without the help of many friends,
colleagues and collaborators. We have benefited from valuable discussions
on methodology and applications with many colleagues. We are particularly
grateful to Simon Cousens, Steve Bennett and Andrew Thomson for sharing
their insights, and to the many statisticians and other colleagues who have
worked with us on specific trials over the years. We would like to thank
Fred Binka, John Changalucha, Heiner Grosskurth, Linda Morison, Kate
O’Brien, Gillian Raab, Ray Reid, David Ross, Mathuram Santosham, Helen
Weiss and Danny Wight for making available datasets from their studies.
The first author was able to work on the first draft of this book during a
sabbatical from his work as head of the Tropical Epidemiology Group, and
wishes to thank Helen Weiss and Paul Milligan for looking after the group
in his absence. The support and inspiration provided by the Consortium to
Respond Effectively to the AIDS-TB Epidemic (CREATE), funded by the Bill
and Melinda Gates Foundation, have been important factors in this book’s
conception and completion. We are grateful to Rebecca Hardy who reviewed
the first draft of the manuscript and provided many useful comments and
suggestions. Her input has considerably improved the book. We would also
like to thank Natasha Larke and Liz Turner who checked and commented
on various drafts of the material. Natasha Larke also worked with the first
author on the adaptation of some of the material for use in a study mod-
ule offered as part of the MSc distance learning course in Clinical Trials at
the London School of Hygiene and Tropical Medicine. Finally, we are grate-
ful for the constant love and support of our families, to whom this book is
dedicated.

C8164_C000a.indd xviii 11/17/08 10:00:18 AM

 Authors

Richard Hayes is professor of epidemiology and international health at

the London School of Hygiene & Tropical Medicine and Head of the MRC
Tropical Epidemiology Group. He is a statistical epidemiologist whose main
research interest is in the epidemiology of infectious diseases of public health
importance in developing countries. He has a particular interest in the epide-
miology and control of HIV and other sexually transmitted diseases, tuber-
culosis and malaria. He is one of the principal investigators of a collaborative
programme of research in Mwanza, Tanzania, whose aim is to develop and
evaluate effective preventive interventions against the HIV epidemic. He is
also involved in collaborative research on HIV and related infections in other
parts of Africa, including Uganda, Zimbabwe, Zambia and South Africa.
Richard also conducts research on statistical and epidemiological methods,
and is involved in work on the design and analysis of cluster-randomised
trials, and on transmission models of HIV and other STDs.

Lawrence Moulton is professor of the departments of international

health and biostatistics, at the Johns Hopkins Bloomberg School of Public
Health. He has been the principal statistician on several large cluster ran-
domised field trials of infectious disease interventions. His expertise is in
correlated data analysis, study design, and statistical epidemiology. His sub-
stantive areas of interest include safety and effectiveness of childhood vac-
cines, and the prevention of HIV and tuberculosis transmission. At Johns
Hopkins University, he directs the PhD program in global disease epidemi-
ology and control and the Peace Corps/Masters International Program, and
is co-director of the Institute for Vaccine Safety.

xix

C8164_C000b.indd xix 11/17/08 10:01:47 AM

 Glossary of Notation

Statistics and Parameters

d = observed number of events or number of subjects with the event
x = quantitative outcome
n = total number of individuals
m = number of individuals per cluster
y = person-years of observation
c = number of clusters
z = covariate
e = expected number of events or number of subjects with the event
e– = expected mean of quantitative outcome
μ = population mean
π = population proportion
λ = population rate
σ = population standard deviation
σW = within-cluster standard deviation
x– = sample mean
p = sample proportion
r = sample rate
l = log sample rate
h = difference in log sample rate between treatment arms
s = sample standard deviation
RR = risk ratio or rate ratio
OR = odds ratio
Rr = ratio-residual
Rd = difference-residual
Note: Greek characters are generally used for true (population) values and
Latin characters for observed (sample) values.

Subscripts
i = treatment arm (i = 1: intervention; i = 0: control)
j = cluster (j = 1,…, c)
k = individual (k = 1, …, m)
l = covariate (l = 1, …, L)
s = stratum (s = 1, …, S)
e.g., dijk = number of observed events in kth individual in jth cluster in ith
treatment arm.

xxi

C8164_C000c.indd xxi 12/4/08 10:51:34 AM

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