Date of Award
Doctor of Philosophy (PhD)
Clinical Epidemiology/Clinical Epidemiology & Biostatistics
Eleanor Pullenayegum, PJ Devereaux
Background and objectives
We investigate three issues related to the adjustment for baseline covariates in late phase clinical trials: (1) the analysis of correlated outcomes in multicentre RCTs, (2) the assessment of the probability and implication of prognostic imbalance in RCTs, and (3) the adjustment for baseline confounding in cohort studies.
Project 1: We investigated the properties of six statistical methods for analyzing continuous outcomes in multicentre randomized controlled trials (RCTs) where within-centre clustering was possible. We simulated studies over various intraclass correlation (ICC) values with several centre combinations.
Project 2: We simulated data from RCTs evaluating a binary outcome by varying risk of the outcome, effect of the treatment, power and prevalence of a binary prognostic factor (PF), and sample size. We compared logistic regression models with and without adjustment for the PF, in terms of bias, standard error, coverage of confidence interval, and statistical power. A tool to assess sample size requirement to control for chance imbalance was proposed.
Project 3: We conducted a prospective cohort study to evaluate the effect of tuberculosis (TB) at the initiation of antiretroviral therapy (ART) on all cause mortality using Cox proportional hazard model on propensity score (PS) matched patients to control for potential confounding. We assessed the robustness of results using sensitivity analyses.
Results and conclusions
Project 1: All six methods produce unbiased estimates of treatment effect in multicentre trials. Adjusting for centre as a random intercept leads to the most efficient treatment effect estimation, and hence should be used in the presence of clustering.
Project 2: The probability of prognostic imbalance in small trials can be substantial. Covariate adjustment improves estimation accuracy and statistical power, and hence should be performed when strong PFs are observed.
Project 3: After controlling for the important confounding variables, HIV patients who had TB at the initiation of ART have a moderate increase in the risk of overall mortality.
Chu, Rong, "STATISTICAL AND METHODOLOGICAL ISSUES ON COVARIATE ADJUSTMENT IN CLINICAL TRIALS" (2013). Open Access Dissertations and Theses. Paper 7593.
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