Covariate adjustment and estimation of difference in proportions in randomized clinical trials

• Published in: Pharmaceutical statistics : the journal of the pharmaceutical industry
• Main Authors: Liu, Jialuo, Xi, Dong
• Format: Journal Article
• Language: English
• Published: England 19.05.2024
• Subjects: covariate adjustment; risk difference; binary outcome; difference in proportions; variance estimation; sandwich formula
• ISSN: 1539-1604; 1539-1612
• DOI: 10.1002/pst.2397

Difference in proportions is frequently used to measure treatment effect for binary outcomes in randomized clinical trials. The estimation of difference in proportions can be assisted by adjusting for prognostic baseline covariates to enhance precision and bolster statistical power. Standardization or g-computation is a widely used method for covariate adjustment in estimating unconditional difference in proportions, because of its robustness to model misspecification. Various inference methods have been proposed to quantify the uncertainty and confidence intervals based on large-sample theories. However, their performances under small sample sizes and model misspecification have not been comprehensively evaluated. We propose an alternative approach to estimate the unconditional variance of the standardization estimator based on the robust sandwich estimator to further enhance the finite sample performance. Extensive simulations are provided to demonstrate the performances of the proposed method, spanning a wide range of sample sizes, randomization ratios, and model specification. We apply the proposed method in a real data example to illustrate the practical utility.