Jonathan J. Deeks is Professor at the Institute of Applied Health Research at the University of Birmingham in the United Kingdom. He is a member of Cochrane's Diagnostic Test Accuracy Editorial team.

Patrick M. Bossuyt is Professor at the Amsterdam UMC, University of Amsterdam, Department of Epidemiology and Data Science in the Netherlands.

Mariska M. Leeflang is Associate Professor at the Amsterdam UMC, University of Amsterdam, Department of Epidemiology and Data Science in the Netherlands. She is a Convenor of Cochrane's Screening and Diagnostic Tests Methods Group.

Yemisi Takwoingi is Professor at the Institute of Applied Health Research at the University of Birmingham, UK and a Convenor of Cochrane's Screening and Diagnostic Tests Methods Group.

Contributors xv

Preface xix

Part One About Cochrane Reviews of diagnostic test accuracy 1

1 Planning a Cochrane Review of diagnostic test accuracy 3

1.1 Introduction 4

1.2 Why do a systematic review of test accuracy? 4

1.3 Undertaking a Cochrane Review of diagnostic test accuracy 5

1.3.1 The role of the Diagnostic Test Accuracy Editorial Team 5

1.3.2 Expectations for the conduct and reporting of Cochrane Reviews of diagnostic test accuracy 5

1.3.3 Data management and quality assurance 6

1.3.4 Keeping the Review up to date 6

1.4 Proposing a new Cochrane Review of diagnostic test accuracy 6

1.5 Cochrane Protocols 7

1.6 The author team 11

1.6.1 The importance of the team 11

1.6.2 Criteria for authorship 12

1.6.3 Incorporating relevant perspectives and stakeholder involvement 12

1.7 Resources and support 13

1.7.1 Identifying resources and support 13

1.7.2 Funding and conflicts of interest 14

1.7.3 Training 14

1.7.4 Software 15

1.8 Chapter information 15

1.9 References 16

Part Two Introducing test accuracy 19

2 Evaluating medical tests 21

2.1 Introduction 21

2.2 Types of medical tests 22

2.3 Test accuracy 23

2.4 How do diagnostic tests affect patient outcomes? 24

2.4.1 Direct test effects 25

2.4.2 Altering clinical decisions and actions 25

2.4.3 Changes to time frames and populations 25

2.4.4 Influencing patient and clinician perceptions 26

2.5 Evaluations of test accuracy during test development 26

2.5.1 Evaluations of accuracy during biomarker discovery 26

2.5.2 Early evaluations of test accuracy 27

2.5.3 Clinical evaluations of test accuracy 28

2.6 Other purposes of medical testing 28

2.6.1 Predisposition 29

2.6.2 Risk stratification 29

2.6.3 Screening 29

2.6.4 Staging 29

2.6.5 Prognosis 30

2.6.6 Treatment selection 30

2.6.7 Treatment efficacy 31

2.6.8 Therapeutic monitoring 31

2.6.9 Surveillance for progression or recurrence 31

2.7 Chapter information 32

2.8 References 32

3 Understanding the design of test accuracy studies 35

3.1 Introduction 35

3.2 The basic design for a test accuracy study 36

3.3 Multiple groups of participants 39

3.4 Multiple reference standards 42

3.5 More on reference standards 44

3.5.1 Delayed verification 44

3.5.2 Composite reference standard 44

3.5.3 Panel- based reference 44

3.5.4 Latent class analysis 45

3.5.5 Gold standard 45

3.5.6 Clinical reference standard 45

3.6 Comparative test accuracy studies 45

3.6.1 Paired comparative accuracy study 46

3.6.2 Randomized comparative accuracy study 46

3.6.3 Non- randomized comparative accuracy study 47

3.7 Additional aspects of study designs 47

3.7.1 Prospective versus retrospective 48

3.7.2 Pragmatic versus explanatory 48

3.8 Concluding remarks 49

3.9 Chapter information 49

3.10 References 50

4 Understanding test accuracy measures 53

4.1 Introduction 53

4.2 Types of test data 54

4.3 Inconclusive index test results 55

4.4 Target condition 56

4.5 Analysis of a primary test accuracy study 56

4.5.1 Sensitivity and specificity 57

4.5.2 Predictive values 58

4.5.3 Proportion with the target condition 58

4.5.4 Pre- test and post- test probabilities 59

4.5.5 Interpretation of sensitivity, specificity and predictive values 59

4.5.6 Confidence intervals 60

4.5.7 Other test accuracy measures 61

4.6 Positivity thresholds 64

4.7 Receiver operating characteristic curves 66

4.8 Analysis of a comparative accuracy study 68

4.9 Chapter information 71

4.10 References 72

Part Three Methods and presentation of systematic reviews of test accuracy 73

5 Defining the review question 75

5.1 Introduction 75

5.2 Aims of systematic reviews of test accuracy 76

5.2.1 Investigations of heterogeneity 77

5.3 Identifying the clinical problem 77

5.3.1 Role of a new test 77

5.3.2 Defining the clinical pathway 80

5.3.3 Unclear and multiple clinical pathways 83

5.4 Defining the review question 84

5.4.1 Population 84

5.4.2 Index test(s) 85

5.4.3 Target condition 85

5.4.4 The review question: PIT 86

5.4.5 From review question to objectives 86

5.4.6 Broad versus narrow questions 87

5.5 Defining eligibility criteria 88

5.5.1 Types of studies 88

5.5.2 Participants 89

5.5.3 Index test(s) 90

5.5.4 Target condition 91

5.5.5 Reference standard 92

5.6 Chapter information 93

5.7 References 93

6 Searching for and selecting studies 97

6.1 Introduction 98

6.2 Searching for studies 98

6.2.1 Working in partnership 100

6.2.2 Advice for review teams that do not include an information specialist 101

6.3 Sources to search 101

6.3.1 Bibliographic databases 101

6.3.1.1 MEDLINE, PubMed and Embase 102

6.3.1.2 National and regional databases 103

6.3.1.3 Subject- specific databases 103

6.3.1.4 Dissertations and theses databases 104

6.3.2 Additional sources to search 104

6.3.2.1 Related reviews, guidelines and reference lists as sources of studies 105

6.3.2.2 Handsearching 105

6.3.2.3 Forward citation searching and co- citation searching 105

6.3.2.4 Web searching 106

6.3.2.5 Grey literature databases 107

6.3.2.6 Trial registries 107

6.3.2.7 Contacting colleagues, study authors and manufacturers 108

6.4 Designing search strategies 108

6.4.1 Structuring the search strategy 109

6.4.2 Controlled vocabulary and text words 110

6.4.3 Text word or keyword searching 112

6.4.4 Search filters 113

6.4.5 Language, date and type of document restrictions 113

6.4.6 Identifying fraudulent studies, other retracted publications, errata and comments 114

6.4.7 Minimizing the risk of bias through search methods 114

6.5 Documenting and reporting the search process 115

6.5.1 Documenting the search process 116

6.5.2 Reporting the search process 116

6.5.2.1 Reporting the search process in the protocol 116

6.5.2.2 Reporting the search process in the review 117

6.6 Selecting relevant studies 119

6.6.1 Examine full- text reports for compliance of studies with eligibility criteria 120

6.7 Future developments in literature searching and selection 121

6.8 Chapter information 121

6.9 References 122

7 Collecting data 131

7.1 Introduction 132

7.2 Sources of data 132

7.2.1 Studies (not reports) as the unit of interest 133

7.2.2 Correspondence with investigators 134

7.3 What data to collect 135

7.3.1 What are data? 135

7.3.2 Study methods (participant recruitment and sampling) 137

7.3.3 Participant characteristics and setting 138

7.3.4 Index test(s) 139

7.3.5 Target condition and reference standard 140

7.3.6 Flow and timing 140

7.3.7 Extracting study results and converting to the desired format 141

7.3.7.1 Obtaining 2×2 data from accuracy measures 141

7.3.7.2 Using global measures 144

7.3.7.3 Challenges defining reference standard positive and negative: strategies when there are more than two categories 145

7.3.7.4 Challenges defining index test positive and negative: inconclusive results 145

7.3.7.5 Challenges defining index test positive and negative: test failures 147

7.3.7.6 Challenges defining index test positive and negative: dealing with multiple thresholds and extracting data from ROC curves or other graphics 147

7.3.7.7 Extracting data from figures with software 148

7.3.7.8 Corrections for missing data: adjusting for partial verification bias 148

7.3.7.9 Multiple index tests from the same study 148

7.3.7.10 Subgroups of patients 150

7.3.7.11 Individual patient data 150

7.3.7.12 Extracting covariates 151

7.3.8 Other information to collect 151

7.4 Data collection tools 152

7.4.1 Rationale for data collection forms 152

7.4.2 Considerations in selecting data collection tools 152

7.4.3 Design of a data collection form 154

7.5 Extracting data from reports 157

7.5.1 Introduction 157

7.5.2 Who should extract data? 157

7.5.3 Training data extractors 158

7.5.4 Extracting data from multiple reports of the same study 158

7.5.5 Reliability and reaching consensus 159

7.5.6 Suspicions of scientific misconduct 159

7.5.7 Key points in planning and reporting data extraction 160

7.6 Managing and sharing data and tools 160

7.7 Chapter information 163

7.8 References 164

8 Assessing risk of bias and applicability 169

8.1 Introduction 170

8.2 Understanding bias and applicability 171

8.2.1 Bias and imprecision 171

8.2.2 Bias versus applicability 171

8.2.3 Biases in test accuracy studies: empirical evidence 172

8.3 Quadas- 2 173

8.3.1 Background 173

8.3.2 Risk- of- bias assessment 173

8.3.3 Applicability assessment 174

8.3.4 Using and tailoring QUADAS- 2 174

8.3.5 Flow diagram 174

8.3.6 Performing the QUADAS- 2 assessment 175

8.4 Domain 1: Participant selection 176

8.4.1 Participant selection: risk- of- bias signalling questions (QUADAS- 2) 176

8.4.2...