A fast and powerful tree-based association test for detecting complex joint effects in case-control studies

Abstract

Motivation:Multivariate tests derived from the logistic regression model are widely used to assess the joint effect of multiple predictors on a disease outcome in case-control studies. These tests become less optimal if the joint effect cannot be approximated adequately by the additive model. The tree-structure model is an attractive alternative, as it is more apt to capture non-additive effects. However, the tree model is used most commonly for prediction and seldom for hypothesis testing, mainly because of the computational burden associated with the resampling-based procedure required for estimating the significance level. Results:We designed a fast algorithm for building the tree-structure model and proposed a robust TREe-based Association Test (TREAT) that incorporates an adaptive model selection procedure to identify the optimal tree model representing the joint effect. We applied TREAT as a multilocus association test on >20 000 genes/regions in a study of esophageal squamous cell carcinoma (ESCC) and detected a highly significant novel association between the gene CDKN2B and ESCC (). We also demonstrated, through simulation studies, the power advantage of TREAT over other commonly used tests. Availability and implementation:The package TREAT is freely available for download at http://www.hanzhang.name/softwares/treat, implemented in C++ and R and supported on 64-bit Linux and 64-bit MS Windows. Supplementary information:Supplementary data are available at Bioinformatics online. © Published by Oxford University Press 2014.