Intro; Preface; Contents; Editors and Contributors; 1 Collaborative Targeted Maximum Likelihood Estimation to Assess Causal Effects in Observational Studies; 1.1 Introduction; 1.2 Targeted Minimum Loss-Based Estimation; 1.2.1 Inference; 1.3 C-TMLE; 1.3.1 Collaborative Double Robustness; 1.3.2 Guiding Principles; 1.3.3 Inference; 1.4 C-TMLE Algorithms; 1.4.1 Greedy C-TMLE; 1.4.2 Scalable C-TMLE; 1.5 Applications of C-TMLE in Health Care; 1.5.1 Biomarker Discovery; 1.5.2 Drug Safety; 1.5.3 Future Work; References; 2 Generalized Tests in Clinical Trials; 2.1 Introduction

2.2 Test Variables and Generalized p-Values2.3 Generalized Confidence Intervals; 2.4 Illustrations; 2.5 Statistical Software; Appendix; References; 3 Discrete Time-to-Event and Rank-Based Methods with Application to Composite Endpoint for Assessing Evidence of Disease Activity; 3.1 Introduction; 3.2 Data Structure; 3.3 Analyses Methods; 3.3.1 Collapsed Binary Composite Endpoint; 3.3.2 Summary Estimate Across Studies; 3.4 Example; 3.5 Drawbacks of Collapsed Binary Composite Endpoint; 3.6 Rank-Based Method; 3.6.1 Ranking Binary Endpoints to Reflect Severity

3.6.2 Statistical Analysis of the Ranks3.7 Concluding Remarks; References; 4 Imputing Missing Data Using a Surrogate Biomarker: Analyzing the Incidence of Endometrial Hyperplasia; 4.1 Background; 4.2 Objective of the Study; 4.3 Validation; 4.4 Analysis of Incidence of Endometrial Hyperplasia; 4.5 Results for the Phase 3 Study; Derivation; References; 5 Advancing Interpretation of Patient-Reported Outcomes; 5.1 Introduction; 5.2 Anchor-Based Approaches; 5.2.1 Percentages Based on Thresholds; 5.2.2 Criterion-Group Interpretation; 5.2.3 Content-Based Interpretation

5.2.4 Clinically Important Difference5.2.5 Clinically Important Responder; 5.3 Distribution-Based Approaches; 5.3.1 Effect Size; 5.3.2 Probability of Relative Benefit; 5.3.3 Cumulative Distribution Functions; 5.4 Mediation Models; 5.4.1 Basic Elements; 5.4.2 Basic Model; 5.4.3 Example; 5.5 Summary; References; 6 Network Meta-analysis; 6.1 Introduction; 6.2 Evidence Networks; 6.3 Methodology and Application; 6.3.1 Fixed-Effect Model; 6.3.2 Random-Effects Model; 6.3.3 Reporting and Interpreting; 6.3.4 Application; 6.4 Assumptions; 6.4.1 Homogeneity; 6.4.2 Similarity; 6.4.3 Consistency

6.5 Special Topics6.5.1 PRISMA Guidance; 6.5.2 Individual Patient Data; 6.5.3 Population-Adjusted Indirect Comparisons; 6.6 Summary; References; 7 Detecting Safety Signals Among Adverse Events in Clinical Trials; 7.1 Introduction; 7.2 Sample Data; 7.3 General Considerations for Safety Analyses; 7.3.1 Initial Steps; 7.3.2 Further Analyses; 7.4 Safety Analysis of Sample Data; 7.4.1 Initial Steps; 7.4.2 Accounting for Time and Patient Exposure; 7.4.3 Standardised MedDRA Queries; 7.5 Conclusions; References; 8 Meta-analysis for Rare Events in Clinical Trials; 8.1 Introduction