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 Statistics

Adaptive Designs for Sequential Treatment Allocation

Adaptive Designs for Sequential Treatment Allocation presents a rigorous theo-
retical treatment of the results and mathematical foundation of adaptive design
theory. The book focuses on designing sequential randomized experiments to
compare two or more treatments incorporating information accrued along the way.

The authors first introduce the terminology and statistical models most commonly
used in comparative experiments. They then illustrate biased coin and urn designs
that only take into account past treatment allocations as well as designs that use
Adaptive
Designs for
past data, such as sequential maximum likelihood and various types of doubly
adaptive designs. The book also covers multipurpose adaptive experiments in-
volving utilitarian choices and ethical issues. It ends with covariate-adaptive meth-

Sequential
ods. The appendices present basic tools of optimal design theory and address
Bayesian adaptive designs.

Features

Treatment
• Presents adaptive randomized designs for comparing different treatments
• Discusses the statistical properties of adaptive designs and the mathematical
implications of the inference following the experiment

Allocation
• Covers new material, particularly on the trade-off between ethics and
inference
• Shows how to use covariates to improve designs
• Examines all the renowned biased coin and urn designs as well as additional
topics, such as up-and-down designs

This book helps you fully understand the theoretical properties behind various
adaptive designs. You are then equipped to choose the best design for your ex-
periment.

Alessandro Baldi Antognini is a professor of statistics at the University of Bologna.

His main research interests include optimal design theory, sequential methods,
and applied probability.
Alessandro Baldi Antognini
Baldi Antognini
Alessandra Giovagnoli, now retired, was a professor of statistics at the University
Alessandra Giovagnoli
Giovagnoli

of Bologna. She is on the board of Model-Oriented Data Analysis and Optimum

Design (MODA), an international statistical association that promotes research in
the area of experimental designs.

K14585

w w w. c rc p r e s s . c o m

K14585_cover.indd 1 2/25/15 1:21 PM

 Adaptive
Designs for
Sequential
Treatment
Allocation
Editor-in-Chief
Shein-Chung Chow, Ph.D., Professor, Department of Biostatistics and Bioinformatics,
Duke University School of Medicine, Durham, North Carolina

Series Editors
Byron Jones, Biometrical Fellow, Statistical Methodology, Integrated Information Sciences,
Novartis Pharma AG, Basel, Switzerland
Jen-pei Liu, Professor, Division of Biometry, Department of Agronomy,
National Taiwan University, Taipei, Taiwan
Karl E. Peace, Georgia Cancer Coalition, Distinguished Cancer Scholar, Senior Research Scientist
and Professor of Biostatistics, Jiann-Ping Hsu College of Public Health,
Georgia Southern University, Statesboro, Georgia
Bruce W. Turnbull, Professor, School of Operations Research and Industrial Engineering,
Cornell University, Ithaca, New York

Published Titles
Adaptive Design Methods in Bayesian Methods in Epidemiology
Clinical Trials, Second Edition Lyle D. Broemeling
Shein-Chung Chow and Mark Chang Bayesian Methods in Health Economics
Adaptive Designs for Sequential Gianluca Baio
Treatment Allocation Bayesian Missing Data Problems: EM,
Alessandro Baldi Antognini and Data Augmentation and Noniterative
Alessandra Giovagnoli Computation
Adaptive Design Theory and Ming T. Tan, Guo-Liang Tian,
Implementation Using SAS and R, and Kai Wang Ng
Second Edition Bayesian Modeling in Bioinformatics
Mark Chang Dipak K. Dey, Samiran Ghosh,
Advanced Bayesian Methods for Medical and Bani K. Mallick
Test Accuracy Benefit-Risk Assessment in
Lyle D. Broemeling Pharmaceutical Research and
Advances in Clinical Trial Biostatistics Development
Nancy L. Geller Andreas Sashegyi, James Felli, and
Applied Meta-Analysis with R Rebecca Noel
Ding-Geng (Din) Chen and Karl E. Peace Biosimilars: Design and Analysis of
Basic Statistics and Pharmaceutical Follow-on Biologics
Statistical Applications, Second Edition Shein-Chung Chow
James E. De Muth Biostatistics: A Computing Approach
Bayesian Adaptive Methods for Stewart J. Anderson
Clinical Trials Causal Analysis in Biomedicine and
Scott M. Berry, Bradley P. Carlin, Epidemiology: Based on Minimal
J. Jack Lee, and Peter Muller Sufficient Causation
Bayesian Analysis Made Simple: An Excel Mikel Aickin
GUI for WinBUGS Clinical and Statistical Considerations
Phil Woodward in Personalized Medicine
Bayesian Methods for Measures of Claudio Carini, Sandeep Menon,
Agreement and Mark Chang
Lyle D. Broemeling
Clinical Trial Data Analysis using R DNA Microarrays and Related Genomics
Ding-Geng (Din) Chen and Karl E. Peace Techniques: Design, Analysis, and
Clinical Trial Methodology Interpretation of Experiments
Karl E. Peace and Ding-Geng (Din) Chen David B. Allison, Grier P. Page,
T. Mark Beasley, and Jode W. Edwards
Computational Methods in Biomedical
Research Dose Finding by the Continual
Ravindra Khattree and Dayanand N. Naik Reassessment Method
Ying Kuen Cheung
Computational Pharmacokinetics
Anders Källén Elementary Bayesian Biostatistics
Lemuel A. Moyé
Confidence Intervals for Proportions and
Related Measures of Effect Size Frailty Models in Survival Analysis
Robert G. Newcombe Andreas Wienke

Controversial Statistical Issues in Generalized Linear Models: A Bayesian

Clinical Trials Perspective
Shein-Chung Chow Dipak K. Dey, Sujit K. Ghosh,
and Bani K. Mallick
Data and Safety Monitoring Committees
in Clinical Trials Handbook of Regression and Modeling:
Jay Herson Applications for the Clinical and
Pharmaceutical Industries
Design and Analysis of Animal Studies in
Daryl S. Paulson
Pharmaceutical Development
Shein-Chung Chow and Jen-pei Liu Inference Principles for Biostatisticians
Ian C. Marschner
Design and Analysis of Bioavailability and
Bioequivalence Studies, Third Edition Interval-Censored Time-to-Event Data:
Shein-Chung Chow and Jen-pei Liu Methods and Applications
Ding-Geng (Din) Chen, Jianguo Sun,
Design and Analysis of Bridging Studies
and Karl E. Peace
Jen-pei Liu, Shein-Chung Chow,
and Chin-Fu Hsiao Joint Models for Longitudinal and Time-
to-Event Data: With Applications in R
Design and Analysis of Clinical Trials for
Dimitris Rizopoulos
Predictive Medicine
Shigeyuki Matsui, Marc Buyse, Measures of Interobserver Agreement
and Richard Simon and Reliability, Second Edition
Mohamed M. Shoukri
Design and Analysis of Clinical Trials with
Time-to-Event Endpoints Medical Biostatistics, Third Edition
Karl E. Peace A. Indrayan

Design and Analysis of Non-Inferiority Meta-Analysis in Medicine and Health

Trials Policy
Mark D. Rothmann, Brian L. Wiens, Dalene Stangl and Donald A. Berry
and Ivan S. F. Chan Mixed Effects Models for the Population
Difference Equations with Public Health Approach: Models, Tasks, Methods and
Applications Tools
Lemuel A. Moyé and Asha Seth Kapadia Marc Lavielle

DNA Methylation Microarrays: Monte Carlo Simulation for the

Experimental Design and Statistical Pharmaceutical Industry: Concepts,
Analysis Algorithms, and Case Studies
Sun-Chong Wang and Arturas Petronis Mark Chang
Multiple Testing Problems in Statistical Analysis of Human Growth
Pharmaceutical Statistics and Development
Alex Dmitrienko, Ajit C. Tamhane, Yin Bun Cheung
and Frank Bretz Statistical Design and Analysis of
Noninferiority Testing in Clinical Trials: Stability Studies
Issues and Challenges Shein-Chung Chow
Tie-Hua Ng Statistical Evaluation of Diagnostic
Optimal Design for Nonlinear Response Performance: Topics in ROC Analysis
Models Kelly H. Zou, Aiyi Liu, Andriy Bandos,
Valerii V. Fedorov and Sergei L. Leonov Lucila Ohno-Machado, and Howard Rockette
Patient-Reported Outcomes: Statistical Methods for Clinical Trials
Measurement, Implementation and Mark X. Norleans
Interpretation Statistical Methods in Drug Combination
Joseph C. Cappelleri, Kelly H. Zou, Studies
Andrew G. Bushmakin, Jose Ma. J. Alvir, Wei Zhao and Harry Yang
Demissie Alemayehu, and Tara Symonds
Statistics in Drug Research:
Quantitative Evaluation of Safety in Drug Methodologies and Recent
Development: Design, Analysis and Developments
Reporting Shein-Chung Chow and Jun Shao
Qi Jiang and H. Amy Xia
Statistics in the Pharmaceutical Industry,
Randomized Clinical Trials of Third Edition
Nonpharmacological Treatments Ralph Buncher and Jia-Yeong Tsay
Isabelle Boutron, Philippe Ravaud, and
Survival Analysis in Medicine and
David Moher
Genetics
Randomized Phase II Cancer Clinical Jialiang Li and Shuangge Ma
Trials
Theory of Drug Development
Sin-Ho Jung
Eric B. Holmgren
Sample Size Calculations for Clustered
Translational Medicine: Strategies and
and Longitudinal Outcomes in Clinical
Statistical Methods
Research
Dennis Cosmatos and Shein-Chung Chow
Chul Ahn, Moonseong Heo, and
Song Zhang
Sample Size Calculations in Clinical
Research, Second Edition
Shein-Chung Chow, Jun Shao
and Hansheng Wang
 Adaptive
Designs for
Sequential
Treatment
Allocation

Alessandro Baldi Antognini

University of Bologna, Italy

Alessandra Giovagnoli
University of Bologna, Italy
CRC Press
Taylor & Francis Group
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Boca Raton, FL 33487-2742
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This book is dedicated to all those teachers and colleagues
who have made us love and respect mathematics.
Contents

List of Figures xiii

List of Tables xv

Preface xvii

Acknowledgments xix

Introduction xxi

1 Fundamentals and preliminary results 1

1.1 Contents of this chapter . . . . . . . . . . . . . . . . . . . . . . . 1
1.2 Some notation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
1.3 Statistical models . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
1.4 The likelihood and Fisher’s information . . . . . . . . . . . . . . . 5
1.5 Inference: Conditional on the design or unconditional? . . . . . . . 8
1.6 Inferential optimality of an adaptive design . . . . . . . . . . . . . 8
1.7 Most informative targets . . . . . . . . . . . . . . . . . . . . . . . 9
1.8 Asymptotic inference . . . . . . . . . . . . . . . . . . . . . . . . . 12
1.8.1 Convergence to a target . . . . . . . . . . . . . . . . . . . . 12
1.8.2 Asymptotic properties of maximum likelihood estimators . . 13
1.8.3 Asymptotic optimality of a sequential design . . . . . . . . 15
1.9 Some examples of convergence of designs . . . . . . . . . . . . . . 15
1.9.1 A likelihood-based design targeting Neyman’s allocation . . 16
1.9.2 An asymptotically E-optimal design for the binary model . 16
1.10 The class of Markovian designs . . . . . . . . . . . . . . . . . . . 17
1.11 Some examples of Markovian designs . . . . . . . . . . . . . . . . 18
1.11.1 Efron’s coin . . . . . . . . . . . . . . . . . . . . . . . . . . 19
1.11.2 Zelen’s play-the-winner . . . . . . . . . . . . . . . . . . . 19
1.11.3 An “up-and-down” design . . . . . . . . . . . . . . . . . . 20
1.12 Sequential designs and stopping rules . . . . . . . . . . . . . . . . 22
1.13 Some practical issues in the implementation of adaptive designs . . 24
1.14 Simulating adaptive designs . . . . . . . . . . . . . . . . . . . . . 25

ix
x Contents

2 Randomization procedures that are functions of the past allocations 29

2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
2.2 Randomization and balance as conflicting demands . . . . . . . . . 30
2.3 Indicators of balance and randomness . . . . . . . . . . . . . . . . 32
2.3.1 Measures of imbalance . . . . . . . . . . . . . . . . . . . . 32
2.3.2 Measures of lack of randomness . . . . . . . . . . . . . . . 35
2.3.3 Some critical remarks . . . . . . . . . . . . . . . . . . . . 36
2.4 Classic biased coin designs . . . . . . . . . . . . . . . . . . . . . . 37
2.4.1 The Biased Coin Design . . . . . . . . . . . . . . . . . . . 38
2.4.2 The Adjustable Biased Coin Design . . . . . . . . . . . . . 38
2.4.3 Wei’s Adaptive Biased Coin Design, Atkinson’s
DA -optimum BCD and Smith’s Generalized BCD . . . . . 42
2.4.4 Comparisons of the Adjustable Biased Coin and Adaptive
Biased Coin Designs . . . . . . . . . . . . . . . . . . . . . 46
2.5 Urn designs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
2.5.1 A special class of urn designs . . . . . . . . . . . . . . . . 51
2.5.2 Generalizations of Friedman’s urn . . . . . . . . . . . . . . 53
2.6 Some extensions of the biased coin and urn designs of this chapter . 54

3 Randomization procedures that depend on the responses 57

3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
3.2 A more general model for the response . . . . . . . . . . . . . . . 58
3.3 The Sequential Maximum Likelihood design . . . . . . . . . . . . 60
3.3.1 Asymptotic properties and drawbacks of the SML design . . 61
3.3.2 An example . . . . . . . . . . . . . . . . . . . . . . . . . . 62
3.4 The Doubly-adaptive Biased Coin Design . . . . . . . . . . . . . . 63
3.5 The Efficient Randomized Adaptive Design . . . . . . . . . . . . . 69
3.6 The Up-and-Down design . . . . . . . . . . . . . . . . . . . . . . 70
3.6.1 Definition and properties of U&D designs . . . . . . . . . . 71
3.6.2 A special case: Binary responses . . . . . . . . . . . . . . . 73
3.6.3 A special case: Binomial responses . . . . . . . . . . . . . 74
3.6.4 A special case: Normal responses . . . . . . . . . . . . . . 75
3.6.5 Asymptotic inference for Up-and-Down experiments . . . . 76
3.6.6 On the asymptotic optimality of U&D experiments . . . . . 78
3.6.7 Extensions of U&Ds . . . . . . . . . . . . . . . . . . . . . 79

4 Multipurpose adaptive designs: Step-by-step procedures 81

4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
4.2 Designs of play-the-winner and drop-the-loser type . . . . . . . . . 83
4.2.1 The Play-the-Winner design . . . . . . . . . . . . . . . . . 83
4.2.2 The Biased Coin Play-the-Winner . . . . . . . . . . . . . . 84
4.2.3 Wei and Durham’s Randomized Play-the-Winner . . . . . . 85
4.2.4 Drop-the-Loser and Generalized Drop-the-Loser . . . . . . 87
4.2.5 Further extensions of the PW design . . . . . . . . . . . . . 90
4.3 Bandyopadhyay and Biswas’ link-based design . . . . . . . . . . . 91
Contents xi

4.4 The compound probability approach . . . . . . . . . . . . . . . . . 92

4.4.1 The Doubly Adaptive Weighted Difference design . . . . . 93
4.4.2 Atkinson and Biswas’ skewed DA -optimum Biased Coin
Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
4.5 Randomly Reinforced Urn designs . . . . . . . . . . . . . . . . . . 95
4.6 Asymptotic inference for multipurpose designs . . . . . . . . . . . 97
4.7 Extensions of the step-by-step strategies to the case of several
treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98

5 Multipurpose adaptive designs: Constrained and combined optimality 101

5.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
5.2 Optimality of target allocations for two treatments . . . . . . . . . 102
5.2.1 Inferentially optimal targets . . . . . . . . . . . . . . . . . 102
5.2.2 Ethically optimal targets . . . . . . . . . . . . . . . . . . . 103
5.3 Non-admissible targets . . . . . . . . . . . . . . . . . . . . . . . . 103
5.4 Multi-objective optimal targets: The constrained optimization
approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
5.5 Multi-objective optimal targets: The combined optimization
approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
5.5.1 The choice of the weights . . . . . . . . . . . . . . . . . . 112
5.5.2 Combined optimization approach involving efficiencies . . . 115
5.5.3 Similarities and differences between constrained and
combined optimization approaches . . . . . . . . . . . . . . 117
5.6 The case of several treatments . . . . . . . . . . . . . . . . . . . . 118
5.6.1 Inferential and ethical targets for v treatments . . . . . . . . 118
5.6.2 Combined and constrained optimal targets for v treatments . 120

6 Randomization procedures that depend on the covariates 123

6.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
6.2 Inferentially optimal target allocations in the presence of
covariates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
6.2.1 Balanced designs for the linear model without
treatment/covariate interactions . . . . . . . . . . . . . . . 125
6.2.2 Marginal balance versus joint balance . . . . . . . . . . . . 127
6.2.3 Balanced designs for the linear model with treatment/covariate
interactions . . . . . . . . . . . . . . . . . . . . . . . . . . 129
6.3 Covariate-adaptive randomization . . . . . . . . . . . . . . . . . . 131
6.3.1 Pocock and Simon’s minimization methods . . . . . . . . . 131
6.3.2 Covariate-adaptive procedures based on Optimal Design
theory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
6.3.3 The Covariate-Adaptive Biased Coin Design introduced by
Baldi Antognini and Zagoraiou . . . . . . . . . . . . . . . 136
6.3.4 Hu and Hu’s covariate-adaptive procedure . . . . . . . . . . 139
6.4 Covariate-Adjusted Response-Adaptive designs . . . . . . . . . . . 140
6.4.1 Covariate-adjusted Sequential Maximum Likelihood design 140
xii Contents

6.4.2 The Covariate-adjusted Doubly-adaptive Biased Coin

Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
6.4.3 The Reinforced Doubly-adaptive Biased Coin Design . . . . 142
6.5 Combined optimal designs with covariates . . . . . . . . . . . . . 145
6.5.1 Ethical and inferential criteria . . . . . . . . . . . . . . . . 145
6.5.2 Compound optimal allocations . . . . . . . . . . . . . . . . 146
6.6 Other adaptive designs with covariates . . . . . . . . . . . . . . . . 147
6.6.1 Atkinson’s Biased Coin Design for heteroscedastic normal
models with covariates . . . . . . . . . . . . . . . . . . . . 148
6.6.2 Atkinson’s Biased Coin Design for binary data with
covariates . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
6.6.3 Randomized Play-the-Winner and Drop-the-Loser with
covariates . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
6.7 Some conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . 149

Appendix A Optimal designs 151

Appendix B Bayesian approaches in adaptive designs 161

Bibliography 167

Index 185
List of Figures

2.1 Comparisons between BCD and ABCD . . . . . . . . . . . . . . 40

2.2 GBCD(t) with t = 1, 2, 3 . . . . . . . . . . . . . . . . . . . . . 44
2.3 Atkinson’s DA -BCD modified by p f2 with p = 1, 0.9, 2/3 . . . . 45
2.4 Comparisons of average imbalance for DA -BCD, BCD and
ABCD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
2.5 Comparisons of selection bias for DA -BCD, BCD and ABCD . . 48
∗
5.1 Optimal constrained target πC as C varies . . . . . . . . . . . . . 109
∗
5.2 Optimal combined target πω as ω varies . . . . . . . . . . . . . . 116

xiii
List of Tables

1.1 Some optimal targets for the exponential family . . . . . . . . . . 11

2.1 Comparisons between BCD and GBCD(t) with t = 1, 2, 3 . . . . 45

2.2 Comparisons between ABCD and DA -BCD . . . . . . . . . . . 47
2.3 Comparisons of expected loss for DA -BCD, BCD and ABCD . . 47
2.4 Comparisons of predictability for DA -BCD, BCD and ABCD . . 49

3.1 Allocation probabilities for D-BCD with g̃, ġ and gα with α = 1, 2 68

3.2 Transition probabilities and stationary distribution of the DF rule . 74
3.3 Transition probabilities and stationary distribution of U&D with
normal responses. . . . . . . . . . . . . . . . . . . . . . . . . . 77

5.1 Ethical gain and loss of efficiency for πω∗ as ω varies . . . . . . . 114
5.2 Optimum combined target πω∗ with ω as in (5.30) . . . . . . . . . 114
∗
5.3 Targets πN , πP∗ W and πω∗ with ω = 0.5, ω = (| pA − pB | +1)/2 117

6.1 Minimization methods: two different scenarios. . . . . . . . . . . 132

6.2 Allocation probabilities to A of subject 101 under the range
method. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
6.3 Allocation probabilities to A of subject 101 under the variance
method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133

xv
Preface

This book addresses the issue of designing experiments for comparing two or more
treatments, when the experiment is sequential and the experimenter wishes to make
use of the information accrued along the way. This type of experimental design is
called adaptive. The aim of the book is reviewing and reorganizing the existing re-
sults of adaptive design theory, with particular attention to its mathematical foun-
dation. It is intended primarily as a research book. Our approach is essentially the-
oretical, highlighting the mathematical difficulties and the statistical properties of
adaptive designs as regards statistical inference following the experiment. We feel
that this approach is needed, since the choice of an experimental design cannot be
made without a full understanding of its properties, and we hope that this book will
complement part of the present day literature in which a large number of authors
base their conclusions on simulations. Simulations are generally very useful, but not
always sufficiently convincing, and in some cases they may be plainly misleading.
Ours is a book mainly devoted to general results, so it does not address problems
related only to particular applications. Specifically, it is not a book on clinical trials,
although a large number of the designs we present are clearly inspired by clinical
and pharmaceutical research, and the vast bibliography dedicated to this field. These
designs are discussed, in particular, in Atkinson and Biswas’ survey Randomized
Response-Adaptive Designs in Clinical Trials, 2014; our motivations are different
and we have chosen to dwell on general aspects more than on individual trials, so
there is little overlap, and we think of our book as a complement to theirs. This book
follows the lead of two fundamental works by W. F. Rosenberger and his coauthors
(Hu and Rosenberger, The Theory of Response-Adaptive Randomization in Clinical
Trials, 2006, and Rosenberger and Lachin, Randomization in Clinical Trials: The-
ory and Practice, 2002), to whom we are deeply indebted. We have updated several
results and included new topics.
The first chapter introduces the terminology and the statistical models most com-
monly used in comparative experiments. We present target allocations of the treat-
ments motivated by inferential considerations, and give new conditions for the con-
vergence of a sequential experiment to a given target. A discussion of asymptotic
inference plays a central role in the chapter. We also introduce a unifying definition
(Markovian Designs) to describe a large class of adaptive designs that share interest-
ing properties. We emphasize the role of randomization throughout, as an important
tool to avoid several types of bias. The randomized adaptive designs that we present
in the remaining chapters are grouped mainly according to methods of construction.
In Chapter 2 we illustrate designs whose assignment rule takes into account past
treatment allocations only, namely the renown biased coins and some urn ones. Then

xvii
xviii Preface

in Chapter 3 there come designs that make use of past data, too: sequential maximum
likelihood designs and doubly-adaptive designs, with a further section on the topic
of up-and-down experiments. In Chapters 4 and 5 we present multipurpose adaptive
experiments, involving also utilitarian choices and/or ethical issues: these are classi-
fied according to whether the decision on how to proceed is based on a step-by-step
compromise among the different objectives (Chapter 4), or an overall strategy that
seeks a compound optimal allocation target (Chapter 5); the latter is a fairly novel
approach, so the relative designs too are almost all new. The acquisition of covariate
information (like prognostic factors, biomarkers) about the statistical units involved
in the experiment is also of fundamental importance and should not be ignored in the
design. In Chapter 6 adaptive experiments are revisited to include covariates and new
adaptive methods for this context are presented. Throughout this book we make ex-
tensive reference to design optimality in the context of adaptive experiments, and the
basic tools of optimal design theory used in this book are included as a separate ap-
pendix. There is also another appendix on Bayesian adaptive designs: this is a widely
used methodology, and although our approach is frequentist, we regard this type of
design conceptually very important, so much so as to deserve a full book devoted to
them.
We are aware that several issues of great relevance for applied adaptive designs
are not included or not fully discussed in this monograph, such as dose-ranging es-
timation, sample size re-estimation, adaptive hypotheses designs and seamless trial
designs, to mention just a few. We do not feel that the theoretic study of some of
these methodologies has reached sufficient maturity to be included in this mono-
graph. Some other central topics are just hinted at, the most prominent of which is
stopping rules (at the end of Chapter 1). This is due to the fact that there already exist
outstanding books on this subject. Lastly, note that ours is a model-based approach,
thus we do not include designing experiments for randomization-based inference.
We hope that researchers working in the area of adaptive designs will find this
book a useful reference. Teachers of graduate-level courses on designs may find this
useful since it includes a fair number of examples. The degree of mathematical so-
phistication required from the readers is a knowledge of elementary algebra, calculus
and probability, and rudimentary notions of stochastic processes—in particular the
theory of Markov chains. We have tried to avoid making explicit use of more ad-
vanced mathematical tools, such as Martingale theory, although some of the results
we present (without proofs) are indeed based on such theories.
Acknowledgments

We are grateful to all our colleagues who showed their encouragement and gave
us useful advice, in particular Anthony C. Atkinson, Rosemary Bailey, Barbara Bo-
gacka, Steve Coad, Nancy Flournoy, Stefania Gubbiotti, Ludovico Piccinato, Gio-
vanni Pistone, Luc Pronzato, Yosef Rinott, Bill Rosenberger, Piercesare Secchi,
Henry Wynn, Maroussa Zagoraiou.
We are also deeply indebted to the referees who read early versions of the
manuscript and helped us with their constructive remarks.
Dr. Giovagnoli wishes to express her thanks to The Newton Institute for the Math-
ematical Sciences, Cambridge, UK, for hospitality during the 2011 Design and Anal-
ysis of Experiments (DAE) Workshop, which marked the start of this work.

xix
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