A penalized linear mixed model with generalized method of moments estimators for complex phenotype prediction.

Abstract

Linear mixed models (LMMs) have long been the method of choice for risk prediction analysis on high-dimensional data. However, it remains computationally challenging to simultaneously model a large amount of variants that can be noise or have predictive effects of complex forms. In this work, we have developed a penalized LMM with generalized method of moments (pLMMGMM) estimators for prediction analysis. pLMMGMM is built within the LMM framework, where random effects are used to model the joint predictive effects from all variants within a region. Different from existing methods that focus on linear relationships and use empirical criteria for variable screening, pLMMGMM can efficiently detect regions that harbor genetic variants with both linear and non-linear predictive effects. In addition, unlike existing LMMs that can only handle a very limited number of random effects, pLMMGMM is much less computationally demanding. It can jointly consider a large number of regions and accurately detect those that are predictive. Through theoretical investigations, we have shown that our method has the selection consistency and asymptotic normality. Through extensive simulations and the analysis of PET-imaging outcomes, we have demonstrated that pLMMGMM outperformed existing models and it can accurately detect regions that harbor risk factors with various forms of predictive effects. The R-package is available at https://github.com/XiaQiong/GMMLasso. Supplementary data are available at Bioinformatics online.