Statistical Assessment of Biomarker Replicability using MAJAR Method

Abstract

In the era of precision medicine, many biomarkers have been discovered to be associated with drug efficacy and safety responses, which can be used for patient stratification and drug response prediction. Due to small sample size and limited power of randomized clinical studies, meta-analysis is usually conducted to aggregate all available studies to maximize the power for identifying prognostic and predictive biomarkers. Since all available data are already aggregated, it is often challenging to find an independent study to replicate the discoveries from the meta-analysis (e.g., in meta-analysis of pharmacogenomics genome-wide association studies (PGx GWAS)), which seriously limits the potential impacts of the discovered biomarkers. To overcome this challenge, we develop a novel statistical framework, MAJAR (Meta-Analysis of Joint effect Associations for biomarker Replicability assessment), to jointly test prognostic and predictive effects and assess the replicability of identified biomarkers by implementing an enhanced Expectation-Maximization algorithm and calculating their posterior-probability-of-replicabilities (PPR) and Bayesian false discovery rates (Fdr). Extensive simulation studies were conducted to compare the performance of MAJAR and existing methods in terms of Fdr, power, and computational efficiency. The simulation results showed improved statistical power with well-controlled Fdr of MAJAR over existing methods and robustness to outliers under different data generation processes while considering both prognostic and predictive effects in the model. We further demonstrated the advantages of MAJAR over existing methods by applying MAJAR to the PGx GWAS summary statistics data from a large cardiovascular randomized clinical trial (IMPROVE-IT). Compared to testing main effects only, MAJAR identified 12 novel variants associated with the treatment-related LDL cholesterol (LDL-C) reduction from baseline.