6-序贯试验分析程序tsa manual.pdf

User manual for Trial Sequential Analysis (TSA) Kristian Thorlund, Janus Engstrøm, Jørn Wetterslev, Jesper Brok, Georgina Imberger, and Christian Gluud Copenhagen Trial Unit Centre for Clinical Intervention Research Department 3344, Rigshospitalet DK-2100 Copenhagen Ø Denmark Tel. +45 3545 7171 Fax +45 3545 7101 E-mail: tsa@ctu.dk Contents: Disclaimer 1 Team member roles and contributions 2 Preface 3 1. Concepts and rationale trial sequential analysis 4 1.1. Random error in meta-analysis 4 1.2. ining strength of evidence - information size 6 1.3. Testing for statistical significance before the information size has been reached 7 1.4. Testing for futility before the information size has been reached 8 1.5. Summary 10 2. Methodology TSA 12 2.1. Methods for pooling results from clinical trials 12 2.1.1. Effect measures for dichotomous and continuous data 12 2.1.2. General fixe fect model and random-effects model setup 14 2.1.3. roaches to random-effects model meta-analysis 16 2.1.4. Methods for handling zero-event trials 20 2.2. Adjusted significance testing and futility testing in cumulative meta-analysis 22 2.2.1. The information size required for a conclusive meta-analysis 24 2.2.2. The cumulative test statistic (z-curve) 34 2.2.3. Problems with significance testing in meta-analysis 35 2.2.4. The α-spending function and trial sequential monitoring boundaries 37 2.2.5. Adjusted confidence intervals following trial sequential analysis 44 2.2.6. The law of the iterated logar