Clinical Trial Data Analysis Using R and SAS Second Edition 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 Clinical Basic Statistics and Pharmaceutical Trials, Second Edition Statistical Applications, Second Edition Shein-Chung Chow and Mark Chang James E. De Muth Adaptive Designs for Sequential Bayesian Adaptive Methods for Treatment Allocation Clinical Trials Alessandro Baldi Antognini Scott M. Berry, Bradley P. Carlin, and Alessandra Giovagnoli J. Jack Lee, and Peter Muller Adaptive Design Theory and Bayesian Analysis Made Simple: Implementation Using SAS and R, An Excel GUI for WinBUGS Second Edition Phil Woodward Mark Chang Bayesian Designs for Phase I–II Advanced Bayesian Methods for Clinical Trials Medical Test Accuracy Ying Yuan, Hoang Q. Nguyen, Lyle D. Broemeling and Peter F. Thall Analyzing Longitudinal Clinical Trial Data: Bayesian Methods for Measures A Practical Guide of Agreement Craig Mallinckrodt and Ilya Lipkovich Lyle D. Broemeling Applied Biclustering Methods for Big Bayesian Methods for Repeated Measures and High-Dimensional Data Using R Lyle D. Broemeling Adetayo Kasim, Ziv Shkedy, Bayesian Methods in Epidemiology Sebastian Kaiser, Sepp Hochreiter, Lyle D. Broemeling and Willem Talloen Bayesian Methods in Health Economics Applied Meta-Analysis with R Gianluca Baio Ding-Geng (Din) Chen and Karl E. Peace Bayesian Missing Data Problems: EM, Applied Surrogate Endpoint Evaluation Data Augmentation and Noniterative Methods with SAS and R Computation Ariel Alonso, Theophile Bigirumurame, Ming T. Tan, Guo-Liang Tian, Tomasz Burzykowski, Marc Buyse, and Kai Wang Ng Geert Molenberghs, Leacky Muchene, Nolen Joy Perualila, Ziv Shkedy, and Wim Van der Elst Published Titles Bayesian Modeling in Bioinformatics Computational Methods in Biomedical Dipak K. Dey, Samiran Ghosh, Research and Bani K. Mallick Ravindra Khattree and Dayanand N. Naik Benefit-Risk Assessment in Computational Pharmacokinetics Pharmaceutical Research and Anders Källén Development Confidence Intervals for Proportions Andreas Sashegyi, James Felli, and Related Measures of Effect Size and Rebecca Noel Robert G. Newcombe Benefit-Risk Assessment Methods in Controversial Statistical Issues in Medical Product Development: Bridging Clinical Trials Qualitative and Quantitative Assessments Shein-Chung Chow Qi Jiang and Weili He Data Analysis with Competing Risks Bioequivalence and Statistics in Clinical and Intermediate States Pharmacology, Second Edition Ronald B. Geskus Scott Patterson and Byron Jones Data and Safety Monitoring Committees Biosimilar Clinical Development: in Clinical Trials, Second Edition Scientific Considerations and New Jay Herson Methodologies Design and Analysis of Animal Studies Kerry B. Barker, Sandeep M. Menon, in Pharmaceutical Development Ralph B. D’Agostino, Sr., Siyan Xu, and Bo Jin Shein-Chung Chow and Jen-pei Liu Biosimilars: Design and Analysis of Design and Analysis of Bioavailability Follow-on Biologics and Bioequivalence Studies, Third Edition Shein-Chung Chow Shein-Chung Chow and Jen-pei Liu Biostatistics: A Computing Approach Design and Analysis of Bridging Studies Stewart J. Anderson Jen-pei Liu, Shein-Chung Chow, Cancer Clinical Trials: Current and and Chin-Fu Hsiao Controversial Issues in Design and Design & Analysis of Clinical Trials for Analysis Economic Evaluation & Reimbursement: Stephen L. George, Xiaofei Wang, An Applied Approach Using SAS & STATA and Herbert Pang Iftekhar Khan Causal Analysis in Biomedicine and Design and Analysis of Clinical Trials Epidemiology: Based on Minimal for Predictive Medicine Sufficient Causation Shigeyuki Matsui, Marc Buyse, Mikel Aickin and Richard Simon Clinical and Statistical Considerations in Design and Analysis of Clinical Trials with Personalized Medicine Time-to-Event Endpoints Claudio Carini, Sandeep Menon, and Mark Chang Karl E. Peace Clinical Trial Data Analysis Using R Design and Analysis of Non-Inferiority Trials Ding-Geng (Din) Chen and Karl E. Peace Mark D. Rothmann, Brian L. Wiens, Clinical Trial Data Analysis Using R and SAS, and Ivan S. F. Chan Second Edition Difference Equations with Public Health Ding-Geng (Din) Chen, Karl E. Peace, Applications and Pinggao Zhang Lemuel A. Moyé and Asha Seth Kapadia Clinical Trial Methodology Karl E. Peace and Ding-Geng (Din) Chen Published Titles DNA Methylation Microarrays: Interval-Censored Time-to-Event Data: Experimental Design and Statistical Methods and Applications Analysis Ding-Geng (Din) Chen, Jianguo Sun, Sun-Chong Wang and Arturas Petronis and Karl E. Peace DNA Microarrays and Related Genomics Introductory Adaptive Trial Designs: Techniques: Design, Analysis, and A Practical Guide with R Interpretation of Experiments Mark Chang David B. Allison, Grier P. Page, Joint Models for Longitudinal and Time- T. Mark Beasley, and Jode W. Edwards to-Event Data: With Applications in R Dose Finding by the Continual Dimitris Rizopoulos Reassessment Method Measures of Interobserver Agreement Ying Kuen Cheung and Reliability, Second Edition Dynamical Biostatistical Models Mohamed M. Shoukri Daniel Commenges and Medical Biostatistics, Third Edition Hélène Jacqmin-Gadda A. Indrayan Elementary Bayesian Biostatistics Meta-Analysis in Medicine and Lemuel A. Moyé Health Policy Emerging Non-Clinical Biostatistics in Dalene Stangl and Donald A. Berry Biopharmaceutical Development and Methods in Comparative Effectiveness Manufacturing Research Harry Yang Constantine Gatsonis and Sally C. Morton Empirical Likelihood Method in Mixed Effects Models for the Population Survival Analysis Approach: Models, Tasks, Methods Mai Zhou and Tools Essentials of a Successful Biostatistical Marc Lavielle Collaboration Modeling to Inform Infectious Disease Arul Earnest Control Exposure–Response Modeling: Methods Niels G. Becker and Practical Implementation Modern Adaptive Randomized Clinical Jixian Wang Trials: Statistical and Practical Aspects Frailty Models in Survival Analysis Oleksandr Sverdlov Andreas Wienke Monte Carlo Simulation for the Fundamental Concepts for New Clinical Pharmaceutical Industry: Concepts, Trialists Algorithms, and Case Studies Scott Evans and Naitee Ting Mark Chang Generalized Linear Models: A Bayesian Multiregional Clinical Trials for Perspective Simultaneous Global New Drug Dipak K. Dey, Sujit K. Ghosh, and Development Bani K. Mallick Joshua Chen and Hui Quan Handbook of Regression and Modeling: Multiple Testing Problems in Applications for the Clinical and Pharmaceutical Statistics Pharmaceutical Industries Alex Dmitrienko, Ajit C. Tamhane, Daryl S. Paulson and Frank Bretz Inference Principles for Biostatisticians Ian C. Marschner Published Titles Noninferiority Testing in Clinical Trials: Statistical Design and Analysis of Clinical Issues and Challenges Trials: Principles and Methods Tie-Hua Ng Weichung Joe Shih and Joseph Aisner Optimal Design for Nonlinear Response Statistical Design and Analysis of Models Stability Studies Valerii V. Fedorov and Sergei L. Leonov Shein-Chung Chow Patient-Reported Outcomes: Statistical Evaluation of Diagnostic Measurement, Implementation and Performance: Topics in ROC Analysis Interpretation Kelly H. Zou, Aiyi Liu, Andriy Bandos, Joseph C. Cappelleri, Kelly H. Zou, Lucila Ohno-Machado, and Howard Rockette Andrew G. Bushmakin, Jose Ma. J. Alvir, Statistical Methods for Clinical Trials Demissie Alemayehu, and Tara Symonds Mark X. Norleans Quantitative Evaluation of Safety in Drug Statistical Methods for Drug Safety Development: Design, Analysis and Robert D. Gibbons and Anup K. Amatya Reporting Statistical Methods for Healthcare Qi Jiang and H. Amy Xia Performance Monitoring Quantitative Methods for Traditional Alex Bottle and Paul Aylin Chinese Medicine Development Statistical Methods for Immunogenicity Shein-Chung Chow Assessment Randomized Clinical Trials of Harry Yang, Jianchun Zhang, Binbing Yu, Nonpharmacological Treatments and Wei Zhao Isabelle Boutron, Philippe Ravaud, Statistical Methods in Drug Combination and David Moher Studies Randomized Phase II Cancer Wei Zhao and Harry Yang Clinical Trials Statistical Testing Strategies in the Sin-Ho Jung Health Sciences Repeated Measures Design with Albert Vexler, Alan D. Hutson, Generalized Linear Mixed Models for and Xiwei Chen Randomized Controlled Trials Statistics in Drug Research: Toshiro Tango Methodologies and Recent Sample Size Calculations for Clustered Developments and Longitudinal Outcomes in Clinical Shein-Chung Chow and Jun Shao Research Statistics in the Pharmaceutical Industry, Chul Ahn, Moonseong Heo, Third Edition and Song Zhang Ralph Buncher and Jia-Yeong Tsay Sample Size Calculations in Clinical Survival Analysis in Medicine and Research, Second Edition Genetics Shein-Chung Chow, Jun Shao, Jialiang Li and Shuangge Ma and Hansheng Wang Theory of Drug Development Statistical Analysis of Human Growth Eric B. Holmgren and Development Yin Bun Cheung Translational Medicine: Strategies and Statistical Methods Dennis Cosmatos and Shein-Chung Chow Clinical Trial Data Analysis Using R and SAS Second Edition Ding-Geng (Din) Chen Karl E. Peace Pinggao Zhang Harry Yang CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 2017 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U.S. Government works Printed on acid-free paper Version Date: 20170407 International Standard Book Number-13: 978-1-4987-7952-4 (Hardback) This book contains information obtained from authentic and highly regarded sources. Reasonable efforts have been made to publish reliable data and information, but the author and publisher cannot assume responsibility for the validity of all materials or the consequences of their use. The authors and publishers have attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. 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Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data Names: Chen, Ding-Geng. | Peace, Karl E., 1941- | Zhang, Pinggao. | Chen, Ding-Geng. Clinical trial data analysis using R. Title: Clinical trial data analysis using R and SAS. Other titles: Clinical trial data analysis using R Description: Second edition / Ding-Geng Chen, Karl E. Peace, Pinggao Zhang. | Boca Raton : CRC Press, 2017. | “Major updates to include SAS programs”--Preface. | Previous edition: Clinical trial data analysis using R / Ding-Geng Chen, Karl E. Peace (Boca Raton, Florida : CRC Press, 2011). Identifiers: LCCN 2016057399 | ISBN 9781498779524 (hardback) Subjects: LCSH: Clinical trials--Statistical methods. | R (Computer program language) | SAS (Computer program language) Classification: LCC R853.C55 C43 2017 | DDC 610.72/7--dc23 LC record available at https://lccn.loc.gov/2016057399 Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http://www.crcpress.com Dedication To my parents and parents-in-law who value high education and hard work, andtomywife,Ke,myson,JohnD.Chen,andmydaughter,JennyK.Chen, for their love and support. Ding-Geng(Din) Chen Tothememoryofmylatemother,ElsieMaeCloudPeace,mylatewife,Jiann- PingHsu(JP),andtomyson,ChristopherK.Peace,daughter-in-law,Ashley Hopkins Peace, granddaughter, Camden, and grandson, Henry. Memories of my mom and wife JP continue to sustain me. My son, Chris, and his family provide much joy and esteem. Karl E. Peace To my wife, Jenny Z. Yang, and my sons, Andrew Y. Zhang and Anthony Y. Zhang, for their love and support. I am particularly thankful to my wife for her patience and understanding while I worked on the book. Pinggao Zhang ix