Dataset Information

Performance of model-based multifactor dimensionality reduction methods for epistasis detection by controlling population structure.

ABSTRACT:

Background

In genome-wide association studies the extent and impact of confounding due to population structure have been well recognized. Inadequate handling of such confounding is likely to lead to spurious associations, hampering replication, and the identification of causal variants. Several strategies have been developed for protecting associations against confounding, the most popular one is based on Principal Component Analysis. In contrast, the extent and impact of confounding due to population structure in gene-gene interaction association epistasis studies are much less investigated and understood. In particular, the role of nonlinear genetic population substructure in epistasis detection is largely under-investigated, especially outside a regression framework.

Methods

To identify causal variants in synergy, to improve interpretability and replicability of epistasis results, we introduce three strategies based on a model-based multifactor dimensionality reduction approach for structured populations, namely MBMDR-PC, MBMDR-PG, and MBMDR-GC.

Results

Simulation results comparing the performance of various approaches show that in the presence of population structure MBMDR-PC and MBMDR-PG consistently better control type I error rate at the nominal level than MBMDR-GC. Moreover, our proposed three methods of population structure correction outperform MDR-SP in terms of statistical power.

Conclusion

We demonstrate through extensive simulation studies the effect of various degrees of genetic population structure and relatedness on epistasis detection and propose appropriate remedial measures based on linear and nonlinear sample genetic similarity.

SUBMITTER: Abegaz F

PROVIDER: S-EPMC7893746 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Publications

Performance of model-based multifactor dimensionality reduction methods for epistasis detection by controlling population structure.

Abegaz Fentaw F Van Lishout François F Mahachie John Jestinah M JM Chiachoompu Kridsadakorn K Bhardwaj Archana A Duroux Diane D Gusareva Elena S ES Wei Zhi Z Hakonarson Hakon H Van Steen Kristel K

BioData mining 20210219 1

<h4>Background</h4>In genome-wide association studies the extent and impact of confounding due to population structure have been well recognized. Inadequate handling of such confounding is likely to lead to spurious associations, hampering replication, and the identification of causal variants. Several strategies have been developed for protecting associations against confounding, the most popular one is based on Principal Component Analysis. In contrast, the extent and impact of confounding due ...[more]

PMID: 33608043

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Project description:BackgroundApplying a statistical method implies identifying underlying (model) assumptions and checking their validity in the particular context. One of these contexts is association modeling for epistasis detection. Here, depending on the technique used, violation of model assumptions may result in increased type I error, power loss, or biased parameter estimates. Remedial measures for violated underlying conditions or assumptions include data transformation or selecting a more relaxed modeling or testing strategy. Model-Based Multifactor Dimensionality Reduction (MB-MDR) for epistasis detection relies on association testing between a trait and a factor consisting of multilocus genotype information. For quantitative traits, the framework is essentially Analysis of Variance (ANOVA) that decomposes the variability in the trait amongst the different factors. In this study, we assess through simulations, the cumulative effect of deviations from normality and homoscedasticity on the overall performance of quantitative Model-Based Multifactor Dimensionality Reduction (MB-MDR) to detect 2-locus epistasis signals in the absence of main effects.MethodologyOur simulation study focuses on pure epistasis models with varying degrees of genetic influence on a quantitative trait. Conditional on a multilocus genotype, we consider quantitative trait distributions that are normal, chi-square or Student's t with constant or non-constant phenotypic variances. All data are analyzed with MB-MDR using the built-in Student's t-test for association, as well as a novel MB-MDR implementation based on Welch's t-test. Traits are either left untransformed or are transformed into new traits via logarithmic, standardization or rank-based transformations, prior to MB-MDR modeling.ResultsOur simulation results show that MB-MDR controls type I error and false positive rates irrespective of the association test considered. Empirically-based MB-MDR power estimates for MB-MDR with Welch's t-tests are generally lower than those for MB-MDR with Student's t-tests. Trait transformations involving ranks tend to lead to increased power compared to the other considered data transformations.ConclusionsWhen performing MB-MDR screening for gene-gene interactions with quantitative traits, we recommend to first rank-transform traits to normality and then to apply MB-MDR modeling with Student's t-tests as internal tests for association.

Dataset Information

Performance of model-based multifactor dimensionality reduction methods for epistasis detection by controlling population structure.

Background

Methods

Results

Conclusion

Publications

Performance of model-based multifactor dimensionality reduction methods for epistasis detection by controlling population structure.

Similar Datasets

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