Cochrane Handbook for Systematic Reviews of Interventions Cochrane Handbook for Systematic Reviews of Interventions Second Edition Edited by Julian P.T. Higgins, James Thomas, Jacqueline Chandler, Miranda Cumpston, Tianjing Li, Matthew J. Page and Vivian A. Welch This edition first published 2019 © 2019 The Cochrane Collaboration This work is a co-publication between The Cochrane Collaboration and John Wiley & Sons Ltd. Edition History 1e The Cochrane Collaboration All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions. The right of Julian P.T. Higgins, James Thomas, Jacqueline Chandler, Miranda Cumpston, Tianjing Li, Matthew J. Page, Vivian A. Welch to be identified as the authors of the editorial material in this work has been asserted in accordance with law. Registered Office(s) John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, USA John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK Editorial Office 9600 Garsington Road, Oxford, OX4 2DQ, UK For details of our global editorial offices, customer services, and more information about Wiley products visit us at www.wiley.com. Wiley also publishes its books in a variety of electronic formats and by print-on-demand. Some content that appears in standard print versions of this book may not be available in other formats. Limit of Liability/Disclaimer of Warranty The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting scientific method, diagnosis, or treatment by physicians for any particular patient. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. While the publisher and authors have used their best efforts in preparing this work, they make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives, written sales materials or promotional statements for this work. The fact that an organization, website, or product is referred to in this work as a citation and/or potential source of further information does not mean that the publisher and authors endorse the information or services the organization, website, or product may provide or recommendations it may make. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for your situation. You should consult with a specialist where appropriate. Further, readers should be aware that websites listed in this work may have changed or disappeared between when this work was written and when it is read. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages. Library of Congress Cataloging-in-Publication Data Names: Higgins, Julian P. T., editor. | Cochrane Collaboration, issuing body. Title: Cochrane handbook for systematic reviews of interventions / edited by Julian P.T. Higgins, James Thomas, Jacqueline Chandler, Miranda Cumpston, Tianjing Li, Matthew J. Page, Vivian A. Welch. Other titles: Cochrane book series. Description: Second edition. | Hoboken, NJ : Wiley-Blackwell, 2019. | Series: Cochrane book series | Includes bibliographical references and index. | “This work is a co-publication between The Cochrane Collaboration and John Wiley & Sons Ltd.”–ECIP title page verso. Identifiers: LCCN 2019024539| ISBN 9781119536628 (hardback) | ISBN 9781119536611 (adobe pdf) | ISBN 9781119536659 (epub) Subjects: | MESH: Outcome and Process Assessment (Health Care) | Evidence-Based Medicine–methods | Meta-Analysis as Topic | Systematic Reviews as Topic Classification: LCC RA427.3 | NLM W 84.41 | DDC 362.1–dc23 LC record available at https://lccn.loc.gov/2019024539 Cover image: © ittipon2002/iStock.com, © Eraxion/iStock.com, © Raycat/iStock.com, © atoss/iStock.com, © anmbph/ iStock.com, © shapecharge/iStock.com, © adventtr/iStock.com, © PeopleImages/iStock.com, © Abel Mitja Varela/ iStock.com, © kiankhoon/iStock.com, © Wavebreakmedia/iStock.com, © 9comeback/iStock.com, © leoniepow/ iStock.com Cover design by Wiley Set in 10/12pt SourceSansPro by SPi Global, Pondicherry, India Printed in the UK by Bell & Bain Ltd, Glasgow HB printing 10 9 87654321 Contents Contributors xiii Preface xxiii Part One Core methods 1 1 Starting a review 3 1.1 Why do a systematic review? 3 1.2 What is the review question? 4 1.3 Who should do a systematic review? 5 1.4 The importance of reliability 7 1.5 Protocol development 8 1.6 Data management and quality assurance 11 1.7 Chapter information 12 1.8 References 12 2 Determining the scope of the review and the questions it will address 13 2.1 Rationale for well-formulated questions 13 2.2 Aims of reviews of interventions 15 2.3 Defining the scope of a review question 16 2.4 Ensuring the review addresses the right questions 21 2.5 Methods and tools for structuring the review 24 2.6 Chapter information 29 2.7 References 29 3 Defining the criteria for including studies and how they will be grouped for the synthesis 33 3.1 Introduction 33 3.2 Articulating the review and comparison PICO 35 3.3 Determining which study designs to include 51 3.4 Eligibility based on publication status and language 60 3.5 Chapter information 61 3.6 References 61 v Contents 4 Searching for and selecting studies 67 4.1 Introduction 68 4.2 General issues 68 4.3 Sources to search 70 4.4 Designing search strategies 79 4.5 Documenting and reporting the search process 90 4.6 Selecting studies 92 4.7 Chapter information 99 4.8 References 99 5 Collecting data 109 5.1 Introduction 109 5.2 Sources of data 110 5.3 What data to collect 114 5.4 Data collection tools 125 5.5 Extracting data from reports 130 5.6 Extracting study results and converting to the desired format 136 5.7 Managing and sharing data 136 5.8 Chapter information 137 5.9 References 137 6 Choosing effect measures and computing estimates of effect 143 6.1 Types of data and effect measures 143 6.2 Study designs and identifying the unit of analysis 145 6.3 Extracting estimates of effect directly 148 6.4 Dichotomous outcome data 150 6.5 Continuous outcome data 156 6.6 Ordinal outcome data and measurement scales 168 6.7 Count and rate data 170 6.8 Time-to-event data 172 6.9 Conditional outcomes only available for subsets of participants 173 6.10 Chapter information 174 6.11 References 174 7 Considering bias and conflicts of interest among the included studies 177 7.1 Introduction 177 7.2 Empirical evidence of bias 180 7.3 General procedures for risk-of-bias assessment 185 7.4 Presentation of assessment of risk of bias 188 7.5 Summary assessments of risk of bias 188 7.6 Incorporating assessment of risk of bias into analyses 190 7.7 Considering risk of bias due to missing results 192 7.8 Considering source of funding and conflict of interest of authors of included studies 193 7.9 Chapter information 199 7.10 References 199 vi Contents 8 Assessing risk of bias in a randomized trial 205 8.1 Introduction 205 8.2 Overview of RoB 2 206 8.3 Bias arising from the randomization process 212 8.4 Bias due to deviations from intended interventions 214 8.5 Bias due to missing outcome data 217 8.6 Bias in measurement of the outcome 220 8.7 Bias in selection of the reported result 221 8.8 Differences from the previous version of the tool 225 8.9 Chapter information 226 8.10 References 227 9 Summarizing study characteristics and preparing for synthesis 229 9.1 Introduction 229 9.2 A general framework for synthesis 230 9.3 Preliminary steps of a synthesis 231 9.4 Checking data before synthesis 238 9.5 Types of synthesis 238 9.6 Chapter information 240 9.7 References 240 10 Analysing data and undertaking meta-analyses 241 10.1 Do not start here! 242 10.2 Introduction to meta-analysis 242 10.3 A generic inverse-variance approach to meta-analysis 245 10.4 Meta-analysis of dichotomous outcomes 246 10.5 Meta-analysis of continuous outcomes 251 10.6 Combining dichotomous and continuous outcomes 254 10.7 Meta-analysis of ordinal outcomes and measurement scales 255 10.8 Meta-analysis of counts and rates 255 10.9 Meta-analysis of time-to-event outcomes 256 10.10 Heterogeneity 257 10.11 Investigating heterogeneity 265 10.12 Missing data 272 10.13 Bayesian approaches to meta-analysis 276 10.14 Sensitivity analyses 277 10.15 Chapter information 279 10.16 References 280 11 Undertaking network meta-analyses 285 11.1 What is network meta-analysis? 285 11.2 Important concepts 287 11.3 Planning a Cochrane Review to compare multiple interventions 293 11.4 Synthesis