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

BMC Medical Research Methodology

Feng Chen³  Ting Wang²  Hongliang Li¹  Yang Zhao³  Ping Zeng² 

[1] Center for Disease Control and Prevention of Pudong New Area, Pudong New Area, Shanghai 200136, People’s Republic of China;Department of Epidemiology and Biostatistics, Center of Medical Statistics and Data Analysis, School of Public Health, Xuzhou Medical College, Xuzhou 221004, Jiangsu, People’s Republic of China;Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, , Jiangsu, People’s Republic of China

关键词: Logistic mixed effects model;    Generalized linear mixed model;    Penalized quasi-likelihood algorithm;    Working response;    Multilocus association analysis;    Variance component;    Permutation procedure;    Likelihood ratio test;   

Others  :  1178884
DOI  :  10.1186/s12874-015-0030-1

 received in 2014-12-04, accepted in 2015-04-07,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Zeng et al.; licensee BioMed Central.

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