Selection bias can, and does, occur, even in randomized clinical trials. Steps need to be taken in order to ensure that this does not compromise the integrity of clinical trials; hence “Selection Bias and Covariate Imbalances in Randomized Clinical Trials” offers a comprehensive treatment of the subject and the methodology involved. This book: Provides an overview of the hierarchy of study designs, and justifies the position of randomised trials at the top of this hierarchy. Discusses the strengths and defects of randomisation, and provides real evidence to justify concern regarding its defects. Outlays the damaging consequences that selection bias causes when it does occur. Considers courses of action that can be taken to manage/ contain the problem. Presents methods that can be used to detect selection bias in randomised trials, and methods to correct for selection bias. Concludes by providing a comprehensive plan for managing baseline imbalances and selection bias in randomised trials, and proposing open problems for future research. Illustrated with case studies, this book introduces groundbreaking ideas and research that will be invaluable to researchers and practitioners who design and analyse clinical trials. It will also be of interest to graduate students within the field of biostatistics.
Is adaptive randomization always better than traditional fixed-schedule randomization? Which procedures should be used and under which circumstances? What special considerations are required for adaptive randomized trials? What kind of statistical inference should be used to achieve valid and unbiased treatment comparisons following adaptive randomization designs? Modern Adaptive Randomized Clinical Trials: Statistical and Practical Aspects answers these questions and more. From novel designs to cutting-edge applications, this book presents several new and key developments in adaptive randomization. It also offers a fresh and critical look at a number of already-classical topics. Featuring contributions from statisticians, clinical trialists, and subject-matter experts in academia and the pharmaceutical industry, the text: Clarifies the taxonomy of the concept of adaptive randomization Discusses restricted, covariate-adaptive, response-adaptive, and covariate-adjusted response-adaptive (CARA) randomization designs, as well as randomized designs with treatment selection Gives an exposition to many novel adaptive randomization techniques such as brick tunnel randomization, targeted least absolute shrinkage and selection operator (LASSO)-based CARA randomization, multi-arm multi-stage (MAMS) designs, to name a few Addresses the issues of statistical inference following covariate-adaptive and response-adaptive randomization designs Describes a successful implementation of a single pivotal phase II/III adaptive trial in infants with proliferating hemangioma Explores some practical aspects of phase II dose-ranging studies and examines statistical monitoring and interim analysis issues in response-adaptive randomized clinical trials Modern Adaptive Randomized Clinical Trials: Statistical and Practical Aspects covers a wide spectrum of topics related to adaptive randomization designs in contemporary clinical trials. The book provides a thorough exploration of the merits of adaptive randomization and aids in identifying when it is appropriate to apply such designs in practice.
Praise for the First Edition "All medical statisticians involved in clinical trials should read this book."--Controlled Clinical Trials Featuring a unique combination of the applied aspects of randomization in clinical trials with a nonparametric approach to inference, Randomization in Clinical Trials: Theory and Practice, Second Edition is the go-to guide for biostatisticians and pharmaceutical industry statisticians. Randomization in Clinical Trials: Theory and Practice, Second Edition features: -Discussions on current philosophies, controversies, and new developments in the increasingly important role of randomization techniques in clinical trials -A new chapter on covariate-adaptive randomization, including minimization techniques and inference -New developments in restricted randomization and an increased focus on computation of randomization tests as opposed to the asymptotic theory of randomization tests -Plenty of problem sets, theoretical exercises, and short computer simulations using SAS to facilitate classroom teaching, simplify the mathematics, and ease readers' understanding Randomization in Clinical Trials: Theory and Practice, Second Edition is an excellent reference for researchers as well as applied statisticians and biostatisticians. The Second Edition is also an ideal textbook for upper-undergraduate and graduate-level courses in biostatistics and applied statistics. William F. Rosenberger, PhD, is University Professor and Chairman of the Department of Statistics at George Mason University. He is a Fellow of the American Statistical Association and the Institute of Mathematical Statistics, and author of over 80 refereed journal articles, as well as The Theory of Response-Adaptive Randomization in Clinical Trials, also published by Wiley. John M. Lachin, ScD, is Research Professor in the Department of Epidemiology and Biostatistics as well as in the Department of Statistics at The George Washington University. A Fellow of the American Statistical Association and the Society for Clinical Trials, Dr. Lachin is actively involved in coordinating center activities for clinical trials of diabetes. He is the author of Biostatistical Methods: The Assessment of Relative Risks, Second Edition, also published by Wiley.
Randomization, Masking, and Allocation Concealment is indispensable for any trial researcher who wants to use state of the art randomization methods, and also wants to be able to describe these methods correctly. Far too often the subtle nuances that distinguish proper randomization from flawed randomization are completely ignored in trial reports that state only that randomization was used, with no additional information. Experience has shown that in many cases, the type of randomization that was used was flawed. It is only a matter of time before medical journals and regulatory agencies come to realize that we can no longer rely on (or publish) flawed trials, and that flawed randomization in and of itself disqualifies a trial from being robust or high quality, even if that trial is of high quality otherwise. This book will help to clarify the role randomization plays in ensuring internal validity, and in drawing valid inferences from the data. The various chapters cover a variety of randomization methods, and are not limited to the most common (and most flawed) ones. Readers will come away with a profound understanding of what constitutes a valid randomization procedure, so that they can distinguish the valid from the flawed among not only existing methods but also methods yet to be developed.
A practical guide to analysing partially observeddata. Collecting, analysing and drawing inferences from data iscentral to research in the medical and social sciences.Unfortunately, it is rarely possible to collect all the intendeddata. The literature on inference from the resultingincomplete data is now huge, and continues to grow both asmethods are developed for large and complex data structures, and asincreasing computer power and suitable software enable researchersto apply these methods. This book focuses on a particular statistical method foranalysing and drawing inferences from incomplete data, calledMultiple Imputation (MI). MI is attractive because it is bothpractical and widely applicable. The authors aim is to clarify theissues raised by missing data, describing the rationale for MI, therelationship between the various imputation models and associatedalgorithms and its application to increasingly complex datastructures. Multiple Imputation and its Application: Discusses the issues raised by the analysis of partiallyobserved data, and the assumptions on which analyses rest. Presents a practical guide to the issues to consider whenanalysing incomplete data from both observational studies andrandomized trials. Provides a detailed discussion of the practical use of MI withreal-world examples drawn from medical and social statistics. Explores handling non-linear relationships and interactionswith multiple imputation, survival analysis, multilevel multipleimputation, sensitivity analysis via multiple imputation, usingnon-response weights with multiple imputation and doubly robustmultiple imputation. Multiple Imputation and its Application is aimed atquantitative researchers and students in the medical and socialsciences with the aim of clarifying the issues raised by theanalysis of incomplete data data, outlining the rationale for MIand describing how to consider and address the issues that arise inits application.
Statistical Methods for Experiments, Quasi-Experiments, and Single-Case Studies
Author: Bradley Huitema
Publisher: John Wiley & Sons
A complete guide to cutting-edge techniques and best practices for applying covariance analysis methods The Second Edition of Analysis of Covariance and Alternatives sheds new light on its topic, offering in-depth discussions of underlying assumptions, comprehensive interpretations of results, and comparisons of distinct approaches. The book has been extensively revised and updated to feature an in-depth review of prerequisites and the latest developments in the field. The author begins with a discussion of essential topics relating to experimental design and analysis, including analysis of variance, multiple regression, effect size measures and newly developed methods of communicating statistical results. Subsequent chapters feature newly added methods for the analysis of experiments with ordered treatments, including two parametric and nonparametric monotone analyses as well as approaches based on the robust general linear model and reversed ordinal logistic regression. Four groundbreaking chapters on single-case designs introduce powerful new analyses for simple and complex single-case experiments. This Second Edition also features coverage of advanced methods including: Simple and multiple analysis of covariance using both the Fisher approach and the general linear model approach Methods to manage assumption departures, including heterogeneous slopes, nonlinear functions, dichotomous dependent variables, and covariates affected by treatments Power analysis and the application of covariance analysis to randomized-block designs, two-factor designs, pre- and post-test designs, and multiple dependent variable designs Measurement error correction and propensity score methods developed for quasi-experiments, observational studies, and uncontrolled clinical trials Thoroughly updated to reflect the growing nature of the field, Analysis of Covariance and Alternatives is a suitable book for behavioral and medical scineces courses on design of experiments and regression and the upper-undergraduate and graduate levels. It also serves as an authoritative reference work for researchers and academics in the fields of medicine, clinical trials, epidemiology, public health, sociology, and engineering.
In response to the US FDA’s Critical Path Initiative, innovative adaptive designs are being used more and more in clinical trials due to their flexibility and efficiency, especially during early phase development. Handbook of Adaptive Designs in Pharmaceutical and Clinical Development provides a comprehensive and unified presentation of the principles and latest statistical methodologies used when modifying trial procedures based on accrued data of ongoing clinical trials. The book also gives a well-balanced summary of current regulatory perspectives. The first several chapters focus on the fundamental theory behind adaptive trial design, the application of the Bayesian approach to adaptive designs, and the impact of potential population shift due to protocol amendments. The book then presents a variety of statistical methods for group sequential design, classical design, dose-finding trials, Phase I/II and Phase II/III seamless adaptive designs, multiple stage seamless adaptive trial design, adaptive randomization trials, hypotheses-adaptive design, and treatment-adaptive design. It also covers predictive biomarker diagnostics for new drug development, clinical strategies for endpoint selection in translational research, the role of independent data monitoring committees in adaptive clinical trials, the enrichment process in targeted clinical trials for personalized medicine, applications of adaptive designs that use genomic or genetic information, adaptive trial simulation, and the efficiency of adaptive design. The final chapters discuss case studies as well as standard operating procedures for good adaptive practices. With contributions from leading clinical researchers in the pharmaceutical industry, academia, and regulatory agencies, this handbook offers an up-to-date, complete treatment of the principles and methods of adaptive design and analysis. Along with reviewing recent developments, it examines issues commonly encountered when applying adaptive design methods in clinical trials.
The second volume in the Wiley reference series in Biostatistics. Featuring articles from the prestigious Encyclopedia of Biostatistics, many of which have been fully revised and updated to include recent developments, Biostatistics in Clinical Trials also includes up to 25% newly commissioned material reflecting the latest thinking in: Bayesian methods Benefit/risk assessment Cost-effectiveness Ethics Fraud With exceptional contributions from leading experts in academia, government and industry, Biostatistics in Clinical Trials has been designed to complement existing texts by providing extensive, up-to-date coverage and introducing the reader to the research literature. Offering comprehensive coverage of all aspects of clinical trials Biostatistics in Clinical Trials: Includes concise definitions and introductions to numerous concepts found in current literature Discusses the software and textbooks available Uses extensive cross-references helping to facilitate further research and enabling the reader to locate definitions and related concepts Biostatistics in Clinical Trials offers both academics and practitioners from various disciplines and settings, such as universities, the pharmaceutical industry and clinical research organisations, up-to-date information as well as references to assist professionals involved in the design and conduct of clinical trials.
Evidence-based practice has become a central part of physiotherapy today, but it is still an area which is constantly expanding and being updated. Written by an international team of experts, this second edition continues to outline the basic definitions of evidence-based practice and clinical reasoning, while detailing how to find and critically appraise evidence and clinical practice guidelines and the steps to follow in the implementation and evaluation of evidence. For those struggling to understand both the concepts and how to implement them, this book will prove to be an invaluable and practical guide. Considers how both quantitative and qualitative research can be used to answer clinical questions Written for readers with different levels of expertise Highlighted critical points and text box summaries (basic) Detailed explanations in text (intermediate) Footnotes (advanced) Presents detailed strategies for searching physiotherapy-relevant databases Extensive consideration of clinical practice guidelines Chapter asking the question: When and how should new therapies be introduced into clinical practice? Search strategies Evaluating quality of interventions Placebo effects Meta-regression
Although adaptive design methods are flexible and useful in clinical research, little or no regulatory guidelines are available. One of the first books on the topic, Adaptive Design Methods in Clinical Trials presents the principles and methodologies in adaptive design and analysis that pertain to adaptations made to trial or statistical procedures that are based on accrued data of ongoing clinical trials. The book also offers a well-balanced summary of current regulatory perspectives and recently developed statistical methods in this area. After an introduction to basic concepts and statistical considerations of adaptive design methods, the book questions the impact on target patient populations as the result of protocol amendments and discusses the generalization of statistical inference. The authors also present various adaptive design methods, including where hypotheses are modified during the conduct of clinical trials, for dose selection, and commonly used adaptive group sequential design methods in clinical trials. Following a discussion of blind procedures for sample size re-estimation, the book describes statistical tests for seamless phase II/III adaptive designs and statistical inference for switching adaptively from one treatment to another. The book concludes with computer simulations and various case studies of clinical trials. By providing theoretical and computer simulation results, method comparisons, and practical guidelines for choosing an optimal design, Adaptive Design Methods in Clinical Trials fills the need for a unified, comprehensive, and updated resource in the clinical research and development of adaptive design and analysis.