The concepts of estimands, analyses (estimators), and sensitivity are interrelated. Therefore, great need exists for an integrated approach to these topics. This book acts as a practical guide to developing and implementing statistical analysis plans by explaining fundamental concepts using accessible language, providing technical details, real-world examples, and SAS and R code to implement analyses. The updated ICH guideline raises new analytic and cross-functional challenges for statisticians. Gaps between different communities have come to surface, such as between causal inference and clinical trialists, as well as among clinicians, statisticians, and regulators when it comes to communicating decision-making objectives, assumptions, and interpretations of evidence. This book lays out a path toward bridging some of these gaps. It offers A common language and unifying framework along with the technical details and practical guidance to help statisticians meet the challenges A thorough treatment of intercurrent events (ICEs), i.e., postrandomization events that confound interpretation of outcomes and five strategies for ICEs in ICH E9 (R1) Details on how estimands, integrated into a principled study development process, lay a foundation for coherent specification of trial design, conduct, and analysis needed to overcome the issues caused by ICEs: A perspective on the role of the intention-to-treat principle Examples and case studies from various areas Example code in SAS and R A connection with causal inference Implications and methods for analysis of longitudinal trials with missing data Together, the authors have offered the readers their ample expertise in clinical trial design and analysis, from an industrial and academic perspective.

The concepts of estimands, analyses (estimators), and sensitivity are interrelated. Therefore, great need exists for an integrated approach to these topics. This book acts as a practical guide to developing and implementing statistical analysis plans by explaining fundamental concepts using accessible language, providing technical details, real-world examples, and SAS and R code to implement analyses. The updated ICH guideline raises new analytic and cross-functional challenges for statisticians. Gaps between different communities have come to surface, such as between causal inference and clinical trialists, as well as among clinicians, statisticians, and regulators when it comes to communicating decision-making objectives, assumptions, and interpretations of evidence. This book lays out a path toward bridging some of these gaps. It offers ? A common language and unifying framework along with the technical details and practical guidance to help statisticians meet the challenges ? A thorough treatment of intercurrent events (ICEs), i.e., postrandomization events that confound interpretation of outcomes and five strategies for ICEs in ICH E9 (R1) ? Details on how estimands, integrated into a principled study development process, lay a foundation for coherent specification of trial design, conduct, and analysis needed to overcome the issues caused by ICEs: ? A perspective on the role of the intention-to-treat principle ? Examples and case studies from various areas ? Example code in SAS and R ? A connection with causal inference ? Implications and methods for analysis of longitudinal trials with missing data Together, the authors have offered the readers their ample expertise in clinical trial design and analysis, from an industrial and academic perspective.

Past, Present, and Future of Statistical Science was commissioned in 2013 by the Committee of Presidents of Statistical Societies (COPSS) to celebrate its 50th anniversary and the International Year of Statistics. COPSS consists of five charter member statistical societies in North America and is best known for sponsoring prestigious awards in statistics, such as the COPSS Presidents' award. Through the contributions of a distinguished group of 50 statisticians who are past winners of at least one of the five awards sponsored by COPSS, this volume showcases the breadth and vibrancy of statistics, describes current challenges and new opportunities, highlights the exciting future of statistical science, and provides guidance to future generations of statisticians. The book is not only about statistics and science but also about people and their passion for discovery. Distinguished authors present expository articles on a broad spectrum of topics in statistical education, research, and applications. Topics covered include reminiscences and personal reflections on statistical careers, perspectives on the field and profession, thoughts on the discipline and the future of statistical science, and advice for young statisticians. Many of the articles are accessible not only to professional statisticians and graduate students but also to undergraduate students interested in pursuing statistics as a career and to all those who use statistics in solving real-world problems. A consistent theme of all the articles is the passion for statistics enthusiastically shared by the authors. Their success stories inspire, give a sense of statistics as a discipline, and provide a taste of the exhilaration of discovery, success, and professional accomplishment.

An important factor that affects the duration, complexity and cost of a clinical trial is the endpoint used to study the treatment's efficacy. When a true endpoint is difficult to use because of such factors as long follow-up times or prohibitive cost, it is sometimes possible to use a surrogate endpoint that can be measured in a more convenient or cost-effective way. This book focuses on the use of surrogate endpoint evaluation methods in practice, using SAS and R.

Missing data affect nearly every discipline by complicating the statistical analysis of collected data. But since the 1990s, there have been important developments in the statistical methodology for handling missing data. Written by renowned statisticians in this area, Handbook of Missing Data Methodology presents many methodological advances and the latest applications of missing data methods in empirical research. Divided into six parts, the handbook begins by establishing notation and terminology. It reviews the general taxonomy of missing data mechanisms and their implications for analysis and offers a historical perspective on early methods for handling missing data. The following three parts cover various inference paradigms when data are missing, including likelihood and Bayesian methods; semi-parametric methods, with particular emphasis on inverse probability weighting; and multiple imputation methods. The next part of the book focuses on a range of approaches that assess the sensitivity of inferences to alternative, routinely non-verifiable assumptions about the missing data process. The final part discusses special topics, such as missing data in clinical trials and sample surveys as well as approaches to model diagnostics in the missing data setting. In each part, an introduction provides useful background material and an overview to set the stage for subsequent chapters. Covering both established and emerging methodologies for missing data, this book sets the scene for future research. It provides the framework for readers to delve into research and practical applications of missing data methods.

Although many books currently available describe statistical models and methods for analyzing longitudinal data, they do not highlight connections between various research threads in the statistical literature. Responding to this void, Longitudinal Data Analysis provides a clear, comprehensive, and unified overview of state-of-the-art theory and applications. It also focuses on the assorted challenges that arise in analyzing longitudinal data.

After discussing historical aspects, leading researchers explore four broad themes: parametric modeling, nonparametric and semiparametric methods, joint models, and incomplete data. Each of these sections begins with an introductory chapter that provides useful background material and a broad outline to set the stage for subsequent chapters. Rather than focus on a narrowly defined topic, chapters integrate important research discussions from the statistical literature. They seamlessly blend theory with applications and include examples and case studies from various disciplines.

Destined to become a landmark publication in the field, this carefully edited collection emphasizes statistical models and methods likely to endure in the future. Whether involved in the development of statistical methodology or the analysis of longitudinal data, readers will gain new perspectives on the field.

Many methods for analyzing clustered data exist, all with advantages and limitations in particular applications. Compiled from the contributions of leading specialists in the field, Topics in Modelling of Clustered Data describes the tools and techniques for modelling the clustered data often encountered in medical, biological, environmental, and social science studies. It focuses on providing a comprehensive treatment of marginal, conditional, and random effects models using, among others, likelihood, pseudo-likelihood, and generalized estimating equations methods.

The authors motivate and illustrate all aspects of these models in a variety of real applications. They discuss several variations and extensions, including individual-level covariates and combined continuous and discrete outcomes. Flexible modelling with fractional and local polynomials, omnibus lack-of-fit tests, robustification against misspecification, exact, and bootstrap inferential procedures all receive extensive treatment. The applications discussed center primarily, but not exclusively, on developmental toxicity, which leads naturally to discussion of other methodologies, including risk assessment and dose-response modelling.

Clearly written, Topics in Modelling of Clustered Data offers a practical, easily accessible survey of important modelling issues. Overview models give structure to a multitude of approaches, figures help readers visualize model characteristics, and a generous use of examples illustrates all aspects of the modelling process.

Past, Present, and Future of Statistical Science was commissioned in 2013 by the Committee of Presidents of Statistical Societies (COPSS) to celebrate its 50th anniversary and the International Year of Statistics. COPSS consists of five charter member statistical societies in North America and is best known for sponsoring prestigious awards in statistics, such as the COPSS Presidents' award. Through the contributions of a distinguished group of 50 statisticians who are past winners of at least one of the five awards sponsored by COPSS, this volume showcases the breadth and vibrancy of statistics, describes current challenges and new opportunities, highlights the exciting future of statistical science, and provides guidance to future generations of statisticians. The book is not only about statistics and science but also about people and their passion for discovery. Distinguished authors present expository articles on a broad spectrum of topics in statistical education, research, and applications. Topics covered include reminiscences and personal reflections on statistical careers, perspectives on the field and profession, thoughts on the discipline and the future of statistical science, and advice for young statisticians. Many of the articles are accessible not only to professional statisticians and graduate students but also to undergraduate students interested in pursuing statistics as a career and to all those who use statistics in solving real-world problems. A consistent theme of all the articles is the passion for statistics enthusiastically shared by the authors. Their success stories inspire, give a sense of statistics as a discipline, and provide a taste of the exhilaration of discovery, success, and professional accomplishment.

Many methods for analyzing clustered data exist, all with advantages and limitations in particular applications. Compiled from the contributions of leading specialists in the field, Topics in Modelling of Clustered Data describes the tools and techniques for modelling the clustered data often encountered in medical, biological, environmental, and social science studies. It focuses on providing a comprehensive treatment of marginal, conditional, and random effects models using, among others, likelihood, pseudo-likelihood, and generalized estimating equations methods. The authors motivate and illustrate all aspects of these models in a variety of real applications. They discuss several variations and extensions, including individual-level covariates and combined continuous and discrete outcomes. Flexible modelling with fractional and local polynomials, omnibus lack-of-fit tests, robustification against misspecification, exact, and bootstrap inferential procedures all receive extensive treatment. The applications discussed center primarily, but not exclusively, on developmental toxicity, which leads naturally to discussion of other methodologies, including risk assessment and dose-response modelling. Clearly written, Topics in Modelling of Clustered Data offers a practical, easily accessible survey of important modelling issues. Overview models give structure to a multitude of approaches, figures help readers visualize model characteristics, and a generous use of examples illustrates all aspects of the modelling process.

Missing data affect nearly every discipline by complicating the statistical analysis of collected data. But since the 1990s, there have been important developments in the statistical methodology for handling missing data. Written by renowned statisticians in this area, Handbook of Missing Data Methodology presents many methodological advances and the latest applications of missing data methods in empirical research. Divided into six parts, the handbook begins by establishing notation and terminology. It reviews the general taxonomy of missing data mechanisms and their implications for analysis and offers a historical perspective on early methods for handling missing data. The following three parts cover various inference paradigms when data are missing, including likelihood and Bayesian methods; semi-parametric methods, with particular emphasis on inverse probability weighting; and multiple imputation methods. The next part of the book focuses on a range of approaches that assess the sensitivity of inferences to alternative, routinely non-verifiable assumptions about the missing data process. The final part discusses special topics, such as missing data in clinical trials and sample surveys as well as approaches to model diagnostics in the missing data setting. In each part, an introduction provides useful background material and an overview to set the stage for subsequent chapters. Covering both established and emerging methodologies for missing data, this book sets the scene for future research. It provides the framework for readers to delve into research and practical applications of missing data methods.

An important factor that affects the duration, complexity and cost of a clinical trial is the endpoint used to study the treatment's efficacy. When a true endpoint is difficult to use because of such factors as long follow-up times or prohibitive cost, it is sometimes possible to use a surrogate endpoint that can be measured in a more convenient or cost-effective way. This book focuses on the use of surrogate endpoint evaluation methods in practice, using SAS and R.

This book provides a comprehensive treatment of linear mixed models for continuous longitudinal data. Next to model formulation, this edition puts major emphasis on exploratory data analysis for all aspects of the model, such as the marginal model, subject-specific profiles, and residual covariance structure. Further, model diagnostics and missing data receive extensive treatment. Sensitivity analysis for incomplete data is given a prominent place. Most analyses were done with the MIXED procedure of the SAS software package, but the data analyses are presented in a software-independent fashion.

The linear mixed model has become the main parametric tool for the analysis of continuous longitudinal data, as the authors discussed in their 2000 book.

Without putting too much emphasis on software, the book shows how the different approaches can be implemented within the SAS software package.

The authors received the American Statistical Association's Excellence in Continuing Education Award based on short courses on longitudinal and incomplete data at the Joint Statistical Meetings of 2002 and 2004.

Statistical methods have become an increasingly important and integral part of research in the health sciences. Many sophisticated methodologies have been developed for specific applications and problems. This self-contained volume, an outgrowth of an International Conference on Statistics in Health Sciences, covers a wide range of topics pertaining to new statistical methods in the health sciences. The chapters, written by leading experts in their respective fields, are thematically divided into the following areas: prognostic studies and general epidemiology, pharmacovigilance, quality of life, survival analysis, clustering, safety and efficacy assessment, clinical design, models for the environment, genomic analysis, and animal health. This comprehensive volume will serve the health science community as well as practitioners, researchers, and graduate students in applied probability, statistics, and biostatistics.

The linear mixed model has become the main parametric tool for the analysis of continuous longitudinal data, as the authors discussed in their 2000 book.

Without putting too much emphasis on software, the book shows how the different approaches can be implemented within the SAS software package.

The authors received the American Statistical Association's Excellence in Continuing Education Award based on short courses on longitudinal and incomplete data at the Joint Statistical Meetings of 2002 and 2004.

Covers the latest research on a sensitive and controversial topic in a professional and well researched manner.

Provides practical outlook as well as model guidelines and software tools that should be of interest to people who use the software tools described and those who do not.

Related title by Co-author Geert Molenbergh has sold more than 3500 copies world wide.

Provides dual viewpoints: from scientists in the industry as well as regulatory authorities.

This book provides a comprehensive treatment of linear mixed models for continuous longitudinal data. Next to model formulation, this edition puts major emphasis on exploratory data analysis for all aspects of the model, such as the marginal model, subject-specific profiles, and residual covariance structure. Further, model diagnostics and missing data receive extensive treatment. Sensitivity analysis for incomplete data is given a prominent place. Several variations to the conventional linear mixed model are discussed (a heterogeity model, condional linear mid models). This book will be of interest to applied statisticians and biomedical researchers in industry, public health organizations, contract research organizations, and academia. The book is explanatory rather than mathematically rigorous. Most analyses were done with the MIXED procedure of the SAS software package, and many of its features are clearly elucidated. How3ever, some other commercially available packages are discussed as well. Great care has been taken in presenting the data analyses in a software-independent fashion. Geert Verbeke is Assistant Professor at the Biostistical Centre of the Katholieke Universiteit Leuven in Belgium. He received the B.S. degree in mathematics (1989) from the Katholieke Universiteit Leuven, the M.S. in biostatistics (1992) from the Limburgs Universitair Centrum, and earned a Ph.D. in biostatistics (1995) from the Katholieke Universiteit Leuven. Dr. Verbeke wrote his dissertation, as well as a number of methodological articles, on various aspects of linear mixed models for longitudinal data analysis. He has held visiting positions at the Gerontology Research Center and the Johns Hopkins University. Geert Molenberghs is Assistant Professor of Biostatistics at the Limburgs Universitair Centrum in Belgium. He received the B.S. degree in mathematics (1988) and a Ph.D. in biostatistics (1993) from the Universiteit Antwerpen. Dr. Molenberghs published methodological work on the analysis of non-response in clinical and epidemiological studies. He serves as an associate editor for Biometrics, Applied Statistics, and Biostatistics, and is an officer of the Belgian Statistical Society. He has held visiting positions at the Harvard School of Public Health.

This is author-approved bcc: This book provides a comprehensive treatment of linear mixed models, a technique devised to analyze continuous correlated data. It focuses on examples from designed experiments and longitudinal studies. The target audience includes applied statisticians and biomedical researchers in industry, public health organizations, contract research organizations, and academia. The book is explanatory rather than mathematical rigorous. Although most analyses were done with the MIXED procedure of the SAS software package, and many of its features are clearly elucidated, considerable effort was spent in presenting the data analyses in a software-independent fashion. Geert Verbeke is Assistant Professor at the Biostatistical Centre for Clinical Trials of the Katholieke Universiteit Leuven in Belgium. He received the B.S. degree in mathematics (1989) from the Katholieke Universiteit Leuven, the M.S. in biostatistics (1992) from the Limburgs Universitair Centrum, and earned a PhD in biostatistics (1995) from the Katholieke Universiteit Leuven. Dr. Verkeke wrote his dissertation, as well as a number of methodological articles, on various aspects on linear mixed models for longitudinal data analysis. He has held visiting positions at the Gerontology Researh Center and the Johns Hopkins University (Baltimore, MD). Geert Molenberghs is Assistant Professor of Biostatistics at the Limburgs Universitair Centrum in Belgium. He received the B.S. degree in mathematics (1988) and a PhD in biostatistics (1993) from the Universiteit Antwerpen. Dr. Molenberghs published methodological work on the analysis of non-response, and non-compliance in clinical trials. He serves as an associateeditor for Biometrics and Applied

This book provides a comprehensive treatment of linear mixed models for continuous longitudinal data. Next to model formulation, this edition puts major emphasis on exploratory data analysis for all aspects of the model, such as the marginal model, subject-specific profiles, and residual covariance structure. Further, model diagnostics and missing data receive extensive treatment. Sensitivity analysis for incomplete data is given a prominent place.
Most analyses were done with the MIXED procedure of the SAS software package, but the data analyses are presented in a software-independent fashion.