Permutation-based variance component test in generalized linear mixed model with application to multilocus genetic association study

Abstract

Background: In many medical studies the likelihood ratio test (LRT) has been widely applied to examine whether the random effects variance component is zero within the mixed effects models framework; whereas little work about likelihood-ratio based variance component test has been done in the generalized linear mixed models (GLMM), where the response is discrete and the log-likelihood cannot be computed exactly. Before applying the LRT for variance component in GLMM, several difficulties need to be overcome, including the computation of the log-likelihood, the parameter estimation and the derivation of the null distribution for the LRT statistic.

Methods: To overcome these problems, in this paper we make use of the penalized quasi-likelihood algorithm and calculate the LRT statistic based on the resulting working response and the quasi-likelihood. The permutation procedure is used to obtain the null distribution of the LRT statistic. We evaluate the permutation-based LRT via simulations and compare it with the score-based variance component test and the tests based on the mixture of chi-square distributions. Finally we apply the permutation-based LRT to multilocus association analysis in the case-control study, where the problem can be investigated under the framework of logistic mixed effects model.

Results: The simulations show that the permutation-based LRT can effectively control the type I error rate, while the score test is sometimes slightly conservative and the tests based on mixtures cannot maintain the type I error rate. Our studies also show that the permutation-based LRT has higher power than these existing tests and still maintains a reasonably high power even when the random effects do not follow a normal distribution. The application to GAW17 data also demonstrates that the proposed LRT has a higher probability to identify the association signals than the score test and the tests based on mixtures.

Conclusions: In the present paper the permutation-based LRT was developed for variance component in GLMM. The LRT outperforms existing tests and has a reasonably higher power under various scenarios; additionally, it is conceptually simple and easy to implement.