Gene-level pharmacogenetic analysis on survival outcomes using gene-trait similarity regression

TL;DR

This paper introduces a gene-trait similarity regression method for survival analysis, enabling detection of gene or pathway effects on time-to-event outcomes, with applications to stroke recurrence data.

Contribution

It develops a flexible, robust similarity regression framework applicable to various survival models, unifying existing methods and demonstrating effectiveness through simulations and real data.

Findings

TCN2 gene associated with recurrent stroke risk in low-dose arm

Method is robust against model misspecification

Effective in identifying gene associations in survival data

Abstract

Gene/pathway-based methods are drawing significant attention due to their usefulness in detecting rare and common variants that affect disease susceptibility. The biological mechanism of drug responses indicates that a gene-based analysis has even greater potential in pharmacogenetics. Motivated by a study from the Vitamin Intervention for Stroke Prevention (VISP) trial, we develop a gene-trait similarity regression for survival analysis to assess the effect of a gene or pathway on time-to-event outcomes. The similarity regression has a general framework that covers a range of survival models, such as the proportional hazards model and the proportional odds model. The inference procedure developed under the proportional hazards model is robust against model misspecification. We derive the equivalence between the similarity survival regression and a random effects model, which further unifies the current variance component-based methods. We demonstrate the effectiveness of the proposed method through simulation studies. In addition, we apply the method to the VISP trial data to identify the genes that exhibit an association with the risk of a recurrent stroke. The TCN2 gene was found to be associated with the recurrent stroke risk in the low-dose arm. This gene may impact recurrent stroke risk in response to cofactor therapy.