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<p>Contributors xiii</p> <p>Preface xxiii</p> <p><b>Part One Core methods 1</b></p> <p><b>1 Starting a review 3</b></p> <p>1.1 Why do a systematic review? 3</p> <p>1.2 What is the review question? 4</p> <p>1.3 Who should do a systematic review? 5</p> <p>1.4 The importance of reliability 7</p> <p>1.5 Protocol development 8</p> <p>1.6 Data management and quality assurance 11</p> <p>1.7 Chapter information 12</p> <p>1.8 References 12</p> <p><b>2 Determining the scope of the review and the questions it will address 13</b></p> <p>2.1 Rationale for well-formulated questions 13</p> <p>2.2 Aims of reviews of interventions 15</p> <p>2.3 Defining the scope of a review question 16</p> <p>2.4 Ensuring the review addresses the right questions 21</p> <p>2.5 Methods and tools for structuring the review 24</p> <p>2.6 Chapter information 29</p> <p>2.7 References 29</p> <p><b>3 Defining the criteria for including studies and how they will be grouped for the synthesis 33</b></p> <p>3.1 Introduction 33</p> <p>3.2 Articulating the review and comparison PICO 35</p> <p>3.3 Determining which study designs to include 51</p> <p>3.4 Eligibility based on publication status and language 60</p> <p>3.5 Chapter information 61</p> <p>3.6 References 61</p> <p><b>4 Searching for and selecting studies 67</b></p> <p>4.1 Introduction 68</p> <p>4.2 General issues 68</p> <p>4.3 Sources to search 70</p> <p>4.4 Designing search strategies 79</p> <p>4.5 Documenting and reporting the search process 90</p> <p>4.6 Selecting studies 92</p> <p>4.7 Chapter information 99</p> <p>4.8 References 99</p> <p><b>5 Collecting data 109</b></p> <p>5.1 Introduction 109</p> <p>5.2 Sources of data 110</p> <p>5.3 What data to collect 114</p> <p>5.4 Data collection tools 125</p> <p>5.5 Extracting data from reports 130</p> <p>5.6 Extracting study results and converting to the desired format 136</p> <p>5.7 Managing and sharing data 136</p> <p>5.8 Chapter information 137</p> <p>5.9 References 137</p> <p><b>6 Choosing effect measures and computing estimates of effect 143</b></p> <p>6.1 Types of data and effect measures 143</p> <p>6.2 Study designs and identifying the unit of analysis 145</p> <p>6.3 Extracting estimates of effect directly 148</p> <p>6.4 Dichotomous outcome data 150</p> <p>6.5 Continuous outcome data 156</p> <p>6.6 Ordinal outcome data and measurement scales 168</p> <p>6.7 Count and rate data 170</p> <p>6.8 Time-to-event data 172</p> <p>6.9 Conditional outcomes only available for subsets of participants 173</p> <p>6.10 Chapter information 174</p> <p>6.11 References 174</p> <p><b>7 Considering bias and conflicts of interest among the included studies 177</b></p> <p>7.1 Introduction 177</p> <p>7.2 Empirical evidence of bias 180</p> <p>7.3 General procedures for risk-of-bias assessment 185</p> <p>7.4 Presentation of assessment of risk of bias 188</p> <p>7.5 Summary assessments of risk of bias 188</p> <p>7.6 Incorporating assessment of risk of bias into analyses 190</p> <p>7.7 Considering risk of bias due to missing results 192</p> <p>7.8 Considering source of funding and conflict of interest of authors of included studies 193</p> <p>7.9 Chapter information 199</p> <p>7.10 References 199</p> <p><b>8 Assessing risk of bias in a randomized trial 205</b></p> <p>8.1 Introduction 205</p> <p>8.2 Overview of RoB 2 206</p> <p>8.3 Bias arising from the randomization process 212</p> <p>8.4 Bias due to deviations from intended interventions 214</p> <p>8.5 Bias due to missing outcome data 217</p> <p>8.6 Bias in measurement of the outcome 220</p> <p>8.7 Bias in selection of the reported result 221</p> <p>8.8 Differences from the previous version of the tool 225</p> <p>8.9 Chapter information 226</p> <p>8.10 References 227</p> <p><b>9 Summarizing study characteristics and preparing for synthesis 229</b></p> <p>9.1 Introduction 229</p> <p>9.2 A general framework for synthesis 230</p> <p>9.3 Preliminary steps of a synthesis 231</p> <p>9.4 Checking data before synthesis 238</p> <p>9.5 Types of synthesis 238</p> <p>9.6 Chapter information 240</p> <p>9.7 References 240</p> <p><b>10 Analysing data and undertaking meta-analyses 241</b></p> <p>10.1 Do not start here! 242</p> <p>10.2 Introduction to meta-analysis 242</p> <p>10.3 A generic inverse-variance approach to meta-analysis 245</p> <p>10.4 Meta-analysis of dichotomous outcomes 246</p> <p>10.5 Meta-analysis of continuous outcomes 251</p> <p>10.6 Combining dichotomous and continuous outcomes 254</p> <p>10.7 Meta-analysis of ordinal outcomes and measurement scales 255</p> <p>10.8 Meta-analysis of counts and rates 255</p> <p>10.9 Meta-analysis of time-to-event outcomes 256</p> <p>10.10 Heterogeneity 257</p> <p>10.11 Investigating heterogeneity 265</p> <p>10.12 Missing data 272</p> <p>10.13 Bayesian approaches to meta-analysis 276</p> <p>10.14 Sensitivity analyses 277</p> <p>10.15 Chapter information 279</p> <p>10.16 References 280</p> <p><b>11 Undertaking network meta-analyses 285</b></p> <p>11.1 What is network meta-analysis? 285</p> <p>11.2 Important concepts 287</p> <p>11.3 Planning a Cochrane Review to compare multiple interventions 293</p> <p>11.4 Synthesis of results 297</p> <p>11.5 Evaluating confidence in the results of a network meta-analysis 304</p> <p>11.6 Presenting network meta-analyses 309</p> <p>11.7 Concluding remarks 315</p> <p>11.8 Chapter information 316</p> <p>11.9 References 316</p> <p><b>12 Synthesizing and presenting findings using other methods 321</b></p> <p>12.1 Why a meta-analysis of effect estimates may not be possible 321</p> <p>12.2 Statistical synthesis when meta-analysis of effect estimates is not possible 324</p> <p>12.3 Visual display and presentation of the data 330</p> <p>12.4 Worked example 333</p> <p>12.5 Chapter information 345</p> <p>12.6 References 346</p> <p><b>13 Assessing risk of bias due to missing results in a synthesis 349</b></p> <p>13.1 Introduction 350</p> <p>13.2 Minimizing risk of bias due to missing results 351</p> <p>13.3 A framework for assessing risk of bias due to missing results in a synthesis 354</p> <p>13.4 Summary 369</p> <p>13.5 Chapter information 370</p> <p>13.6 References 370</p> <p><b>14 Completing ‘Summary of findings’ tables and grading the certainty of the evidence 375</b></p> <p>14.1 ‘Summary of findings’ tables 375</p> <p>14.2 Assessing the certainty or quality of a body of evidence 389</p> <p>14.3 Describing the assessment of the certainty of a body of evidence using the GRADE framework 398</p> <p>14.4 Chapter information 399</p> <p>14.5 References 399</p> <p><b>15 Interpreting results and drawing conclusions 403</b></p> <p>15.1 Introduction 403</p> <p>15.2 Issues of indirectness and applicability 405</p> <p>15.3 Interpreting results of statistical analyses 408</p> <p>15.4 Interpreting results from dichotomous outcomes (including numbers needed to treat) 411</p> <p>15.5 Interpreting results from continuous outcomes (including standardized mean differences) 416</p> <p>15.6 Drawing conclusions 422</p> <p>15.7 Chapter information 427</p> <p>15.8 References 428</p> <p><b>Part Two Specific perspectives in reviews 433</b></p> <p><b>16 Equity and specific populations 435</b></p> <p>16.1 Introduction to equity in systematic reviews 435</p> <p>16.2 Formulation of the review 437</p> <p>16.3 Identification of evidence 441</p> <p>16.4 Appraisal of evidence 443</p> <p>16.5 Synthesis of evidence 443</p> <p>16.6 Interpretation of evidence 444</p> <p>16.7 Concluding remarks 445</p> <p>16.8 Chapter information 445</p> <p>16.9 References 445</p> <p><b>17 Intervention complexity 451</b></p> <p>17.1 Introduction 451</p> <p>17.2 Formulation of the review 461</p> <p>17.3 Identification of evidence 468</p> <p>17.4 Appraisal of evidence 469</p> <p>17.5 Synthesis of evidence 469</p> <p>17.6 Interpretation of evidence 472</p> <p>17.7 Chapter information 473</p> <p>17.8 References 474</p> <p><b>18 Patient-reported outcomes 479</b></p> <p>18.1 Introduction to patient-reported outcomes 479</p> <p>18.2 Formulation of the review 480</p> <p>18.3 Appraisal of evidence 482</p> <p>18.4 Synthesis and interpretation of evidence 485</p> <p>18.5 Chapter information 488</p> <p>18.6 References 489</p> <p><b>19 Adverse effects 493</b></p> <p>19.1 Introduction to issues in addressing adverse effects 493</p> <p>19.2 Formulation of the review 496</p> <p>19.3 Identification of evidence 500</p> <p>19.4 Appraisal of evidence 502</p> <p>19.5 Synthesis and interpretation of evidence 503</p> <p>19.6 Chapter information 504</p> <p>19.7 References 505</p> <p><b>20 Economic evidence 507</b></p> <p>20.1 Introduction 507</p> <p>20.2 Formulation of the review 512</p> <p>20.3 Identification of evidence 517</p> <p>20.4 Appraisal of evidence 519</p> <p>20.5 Synthesis and interpretation of evidence 519</p> <p>20.6 Chapter information 521</p> <p>20.7 References 522</p> <p><b>21 Qualitative evidence 525</b></p> <p>21.1 Introduction 525</p> <p>21.2 Designs for synthesizing and integrating qualitative evidence with intervention reviews 526</p> <p>21.3 Defining qualitative evidence and studies 527</p> <p>21.4 Planning a qualitative evidence synthesis linked to an intervention review 528</p> <p>21.5 Question development 529</p> <p>21.6 Questions exploring intervention implementation 530</p> <p>21.7 Searching for qualitative evidence 531</p> <p>21.8 Assessing methodological strengths and limitations of qualitative studies 532</p> <p>21.9 Selecting studies to synthesize 533</p> <p>21.10 Selecting a qualitative evidence synthesis and data extraction method 534</p> <p>21.11 Data extraction 534</p> <p>21.12 Assessing the confidence in qualitative synthesized findings 537</p> <p>21.13 Methods for integrating the qualitative evidence synthesis with an intervention review 537</p> <p>21.14 Reporting the protocol and qualitative evidence synthesis 538</p> <p>21.15 Chapter information 539</p> <p>21.16 References 539</p> <p><b>Part Three Further topics 547</b></p> <p><b>22 Prospective approaches to accumulating evidence 549</b></p> <p>22.1 Introduction 549</p> <p>22.2 Evidence surveillance: active monitoring of the accumulating evidence 550</p> <p>22.3 Prospectively planned meta-analysis 554</p> <p>22.4 Statistical analysis of accumulating evidence 561</p> <p>22.5 Chapter information 564</p> <p>22.6 References 565</p> <p><b>23 Including variants on randomized trials 569</b></p> <p>23.1 Cluster-randomized trials 569</p> <p>23.2 Crossover trials 576</p> <p>23.3 Studies with more than two intervention groups 585</p> <p>23.4 Chapter information 590</p> <p>23.5 References 591</p> <p><b>24 Including non-randomized studies on intervention effects 595</b></p> <p>24.1 Introduction 595</p> <p>24.2 Developing criteria for including non-randomized studies of interventions 601</p> <p>24.3 Searching for non-randomized studies of interventions 606</p> <p>24.4 Selecting studies and collecting data 608</p> <p>24.5 Assessing risk of bias in non-randomized studies 610</p> <p>24.6 Synthesis of results from non-randomized studies 611</p> <p>24.7 Interpretation and discussion 614</p> <p>24.8 Chapter information 617</p> <p>24.9 References 617</p> <p><b>25 Assessing risk of bias in a non-randomized study 621</b></p> <p>25.1 Introduction 622</p> <p>25.2 Biases in non-randomized studies 623</p> <p>25.3 The ROBINS-I tool 626</p> <p>25.4 Risk of bias in follow-up (cohort) studies 632</p> <p>25.5 Risk of bias in uncontrolled before-after studies (including interrupted time series) 635</p> <p>25.6 Risk of bias in controlled before-after studies 638</p> <p>25.7 Chapter information 640</p> <p>25.8 References 640</p> <p><b>26 Individual participant data 643</b></p> <p>26.1 Introduction 643</p> <p>26.2 Collecting IPD 647</p> <p>26.3 Managing and checking IPD 650</p> <p>26.4 Analysis of IPD 652</p> <p>26.5 Reporting IPD reviews 655</p> <p>26.6 Appraising the quality of IPD reviews 655</p> <p>26.7 Chapter information 655</p> <p>26.8 References 655</p> <p>Index 659</p>

<p><b>Julian P. T. Higgins</b> is Professor of Evidence Synthesis at Bristol Medical School, University of Bristol, UK. He has worked in methods for systematic review and meta-analysis for over 25 years and acts as Senior Methods Advisor to Cochrane. <p><b>James Thomas</b> is Professor of Social Research and Policy at the EPPI-Centre, UCL Institute of Education. He has broad interests in systematic review methodology and tools and is Director of the Systematic Reviews Facility for the Department of Health, England.

<p><b>The revised edition of the</b> <b><i>Handbook</i></b><b> offers the only guide on how to conduct, report and maintain a Cochrane Review</b> <p>The second edition of the<i> Cochrane Handbook for Systematic Reviews of Interventions</i> contains essential guidance for preparing and maintaining Cochrane Reviews of the effects of health interventions. Designed to be an accessible resource, the <i>Handbook</i> will also be of interest to anyone undertaking systematic reviews of interventions outside Cochrane, and many of the principles and methods presented are appropriate for systematic reviews addressing research questions other than effects of interventions. <p>This fully updated edition contains extensive new material on systematic review methods addressing a wide range of topics including network meta-analysis, equity, complex interventions, narrative synthesis, and automation. Also new to this edition, integrated throughout the <i>Handbook,</i> is the set of standards Cochrane expects its reviews to meet. <p>Written for review authors, editors, trainers and others with an interest in Cochrane Reviews, the second edition of the<i> Cochrane Handbook for Systematic Reviews of Interventions</i> continues to offer an invaluable resource for understanding the role of systematic reviews, critically appraising health research studies and conducting reviews.

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