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Identification of interactions using model-based multifactor dimensionality reduction.

ABSTRACT: BACKGROUND:Common complex traits may involve multiple genetic and environmental factors and their interactions. Many methods have been proposed to identify these interaction effects, among them several machine learning and data mining methods. These are attractive for identifying interactions because they do not rely on specific genetic model assumptions. To handle the computational burden arising from an exhaustive search, including all possible combinations of factors, filter methods try to select promising factors in advance. METHODS:Model-based multifactor dimensionality reduction (MB-MDR), a semiparametric machine learning method allowing adjustment for confounding variables and lower level effects, is applied to Genetic Analysis Workshop 19 (GAW19) data to identify interaction effects on different traits. Several filtering methods based on the nearest neighbor algorithm are assessed in terms of compatibility with MB-MDR. RESULTS:Single nucleotide polymorphism (SNP) rs859400 shows a significant interaction effect (corrected p value <0.05) with age on systolic blood pressure (SBP). We identified 23 SNP-SNP interaction effects on hypertension status (HS), 42 interaction effects on SBP, and 26 interaction effects on diastolic blood pressure (DBP). Several of these SNPs are in strong linkage disequilibrium (LD). Three of the interaction effects on HS are identified in filtered subsets. CONCLUSIONS:The considered filtering methods seem not to be appropriate to use with MB-MDR. LD pruning is further quality control to be incorporated, which can reduce the combinatorial burden by removing redundant SNPs.

SUBMITTER: Gola D

PROVIDER: S-EPMC5133504 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Identification of interactions using model-based multifactor dimensionality reduction.

Gola Damian D König Inke R IR

BMC proceedings 20161018 Suppl 7

<h4>Background</h4>Common complex traits may involve multiple genetic and environmental factors and their interactions. Many methods have been proposed to identify these interaction effects, among them several machine learning and data mining methods. These are attractive for identifying interactions because they do not rely on specific genetic model assumptions. To handle the computational burden arising from an exhaustive search, including all possible combinations of factors, filter methods t ...[more]

PMID: 27980625

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Project description:Identifying gene-gene interactions or gene-environment interactions in studies of human complex diseases remains a big challenge in genetic epidemiology. An additional challenge, often forgotten, is to account for important lower-order genetic effects. These may hamper the identification of genuine epistasis. If lower-order genetic effects contribute to the genetic variance of a trait, identified statistical interactions may simply be due to a signal boost of these effects. In this study, we restrict attention to quantitative traits and bi-allelic SNPs as genetic markers. Moreover, our interaction study focuses on 2-way SNP-SNP interactions. Via simulations, we assess the performance of different corrective measures for lower-order genetic effects in Model-Based Multifactor Dimensionality Reduction epistasis detection, using additive and co-dominant coding schemes. Performance is evaluated in terms of power and familywise error rate. Our simulations indicate that empirical power estimates are reduced with correction of lower-order effects, likewise familywise error rates. Easy-to-use automatic SNP selection procedures, SNP selection based on "top" findings, or SNP selection based on p-value criterion for interesting main effects result in reduced power but also almost zero false positive rates. Always accounting for main effects in the SNP-SNP pair under investigation during Model-Based Multifactor Dimensionality Reduction analysis adequately controls false positive epistasis findings. This is particularly true when adopting a co-dominant corrective coding scheme. In conclusion, automatic search procedures to identify lower-order effects to correct for during epistasis screening should be avoided. The same is true for procedures that adjust for lower-order effects prior to Model-Based Multifactor Dimensionality Reduction and involve using residuals as the new trait. We advocate using "on-the-fly" lower-order effects adjusting when screening for SNP-SNP interactions using Model-Based Multifactor Dimensionality Reduction analysis.

Project description:BACKGROUND: Recently, one of the greatest challenges in genome-wide association studies is to detect gene-gene and/or gene-environment interactions for common complex human diseases. Ritchie et al. (2001) proposed multifactor dimensionality reduction (MDR) method for interaction analysis. MDR is a combinatorial approach to reduce multi-locus genotypes into high-risk and low-risk groups. Although MDR has been widely used for case-control studies with binary phenotypes, several extensions have been proposed. One of these methods, a generalized MDR (GMDR) proposed by Lou et al. (2007), allows adjusting for covariates and applying to both dichotomous and continuous phenotypes. GMDR uses the residual score of a generalized linear model of phenotypes to assign either high-risk or low-risk group, while MDR uses the ratio of cases to controls. METHODS: In this study, we propose multivariate GMDR, an extension of GMDR for multivariate phenotypes. Jointly analysing correlated multivariate phenotypes may have more power to detect susceptible genes and gene-gene interactions. We construct generalized estimating equations (GEE) with multivariate phenotypes to extend generalized linear models. Using the score vectors from GEE we discriminate high-risk from low-risk groups. We applied the multivariate GMDR method to the blood pressure data of the 7,546 subjects from the Korean Association Resource study: systolic blood pressure (SBP) and diastolic blood pressure (DBP). We compare the results of multivariate GMDR for SBP and DBP to the results from separate univariate GMDR for SBP and DBP, respectively. We also applied the multivariate GMDR method to the repeatedly measured hypertension status from 5,466 subjects and compared its result with those of univariate GMDR at each time point. RESULTS: Results from the univariate GMDR and multivariate GMDR in two-locus model with both blood pressures and hypertension phenotypes indicate best combinations of SNPs whose interaction has significant association with risk for high blood pressures or hypertension. Although the test balanced accuracy (BA) of multivariate analysis was not always greater than that of univariate analysis, the multivariate BAs were more stable with smaller standard deviations. CONCLUSIONS: In this study, we have developed multivariate GMDR method using GEE approach. It is useful to use multivariate GMDR with correlated multiple phenotypes of interests.

Project description:BackgroundIdentifying interaction effects between genes is one of the main tasks of genome-wide association studies aiming to shed light on the biological mechanisms underlying complex diseases. Multifactor dimensionality reduction (MDR) is a popular approach for detecting gene-gene interactions that has been extended in various forms to handle binary and continuous phenotypes. However, only few multivariate MDR methods are available for multiple related phenotypes. Current approaches use Hotelling's T2 statistic to evaluate interaction models, but it is well known that Hotelling's T2 statistic is highly sensitive to heavily skewed distributions and outliers.ResultsWe propose a robust approach based on nonparametric statistics such as spatial signs and ranks. The new multivariate rank-based MDR (MR-MDR) is mainly suitable for analyzing multiple continuous phenotypes and is less sensitive to skewed distributions and outliers. MR-MDR utilizes fuzzy k-means clustering and classifies multi-locus genotypes into two groups. Then, MR-MDR calculates a spatial rank-sum statistic as an evaluation measure and selects the best interaction model with the largest statistic. Our novel idea lies in adopting nonparametric statistics as an evaluation measure for robust inference. We adopt tenfold cross-validation to avoid overfitting. Intensive simulation studies were conducted to compare the performance of MR-MDR with current methods. Application of MR-MDR to a real dataset from a Korean genome-wide association study demonstrated that it successfully identified genetic interactions associated with four phenotypes related to kidney function. The R code for conducting MR-MDR is available at https://github.com/statpark/MR-MDR .ConclusionsIntensive simulation studies comparing MR-MDR with several current methods showed that the performance of MR-MDR was outstanding for skewed distributions. Additionally, for symmetric distributions, MR-MDR showed comparable power. Therefore, we conclude that MR-MDR is a useful multivariate non-parametric approach that can be used regardless of the phenotype distribution, the correlations between phenotypes, and sample size.

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Identification of interactions using model-based multifactor dimensionality reduction.

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Identification of interactions using model-based multifactor dimensionality reduction.

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