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A likelihood ratio-based Mann-Whitney approach finds novel replicable joint gene action for type 2 diabetes.

ABSTRACT: The potential importance of the joint action of genes, whether modeled with or without a statistical interaction term, has long been recognized. However, identifying such action has been a great challenge, especially when millions of genetic markers are involved. We propose a likelihood ratio-based Mann-Whitney test to search for joint gene action either among candidate genes or genome-wide. It extends the traditional univariate Mann-Whitney test to assess the joint association of genotypes at multiple loci with disease, allowing for high-order statistical interactions. Because only one overall significance test is conducted for the entire analysis, it avoids the issue of multiple testing. Moreover, the approach adopts a computationally efficient algorithm, making a genome-wide search feasible in a reasonable amount of time on a high performance personal computer. We evaluated the approach using both theoretical and real data. By applying the approach to 40 type 2 diabetes (T2D) susceptibility single-nucleotide polymorphisms (SNPs), we identified a four-locus model strongly associated with T2D in the Wellcome Trust (WT) study (permutation P-value < 0.001), and replicated the same finding in the Nurses' Health Study/Health Professionals Follow-Up Study (NHS/HPFS) (P-value = 3.03×10-11). We also conducted a genome-wide search on 385,598 SNPs in the WT study. The analysis took approximately 55 hr on a personal computer, identifying the same first two loci, but overall a different set of four SNPs, jointly associated with T2D (P-value = 1.29×10-5). The nominal significance of this same association reached 4.01×10-6 in the NHS/HPFS.

SUBMITTER: Lu Q

PROVIDER: S-EPMC3634342 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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A likelihood ratio-based Mann-Whitney approach finds novel replicable joint gene action for type 2 diabetes.

Lu Qing Q Wei Changshuai C Ye Chengyin C Li Ming M Elston Robert C RC

Genetic epidemiology 20120703 6

The potential importance of the joint action of genes, whether modeled with or without a statistical interaction term, has long been recognized. However, identifying such action has been a great challenge, especially when millions of genetic markers are involved. We propose a likelihood ratio-based Mann-Whitney test to search for joint gene action either among candidate genes or genome-wide. It extends the traditional univariate Mann-Whitney test to assess the joint association of genotypes at m ...[more]

PMID: 22760990

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Project description:When the distributional assumptions for a t-test are not met, the default position of many analysts is to resort to a rank-based test, such as the Wilcoxon-Mann-Whitney Test to compare the difference in means between two samples. The Wilcoxon-Mann-Whitney Test presents no danger of tied observations when the observations in the data are continuous. However, in practice, observations are discretized due various logical reasons, or the data are ordinal in nature. When ranks are tied, most textbooks recommend using mid-ranks to replace the tied ranks, a practice that affects the distribution of the Wilcoxon-Mann-Whitney Test under the null hypothesis. Other methods for breaking ties have also been proposed. In this study, we examine four tie-breaking methods-average-scores, mid-ranks, jittering, and omission-for their effects on Type I and Type II error of the Wilcoxon-Mann-Whitney Test and the two-sample t-test for various combinations of sample sizes, underlying population distributions, and percentages of tied observations. We use the results to determine the maximum percentage of ties for which the power and size are seriously affected, and for which method of tie-breaking results in the best Type I and Type II error properties. Not surprisingly, the underlying population distribution of the data has less of an effect on the Wilcoxon-Mann-Whitney Test than on the t-test. Surprisingly, we find that the jittering and omission methods tend to hold Type I error at the nominal level, even for small sample sizes, with no substantial sacrifice in terms of Type II error. Furthermore, the t-test and the Wilcoxon-Mann-Whitney Test are equally effected by ties in terms of Type I and Type II error; therefore, we recommend omitting tied observations when they occur for both the two-sample t-test and the Wilcoxon-Mann-Whitney due to the bias in Type I error that is created when tied observations are left in the data, in the case of the t-test, or adjusted using mid-ranks or average-scores, in the case of the Wilcoxon-Mann-Whitney.

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A likelihood ratio-based Mann-Whitney approach finds novel replicable joint gene action for type 2 diabetes.

Publications

A likelihood ratio-based Mann-Whitney approach finds novel replicable joint gene action for type 2 diabetes.

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