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Risk score modeling of multiple gene to gene interactions using aggregated-multifactor dimensionality reduction.

ABSTRACT: UNLABELLED: BACKGROUND:Multifactor Dimensionality Reduction (MDR) has been widely applied to detect gene-gene (GxG) interactions associated with complex diseases. Existing MDR methods summarize disease risk by a dichotomous predisposing model (high-risk/low-risk) from one optimal GxG interaction, which does not take the accumulated effects from multiple GxG interactions into account. RESULTS:We propose an Aggregated-Multifactor Dimensionality Reduction (A-MDR) method that exhaustively searches for and detects significant GxG interactions to generate an epistasis enriched gene network. An aggregated epistasis enriched risk score, which takes into account multiple GxG interactions simultaneously, replaces the dichotomous predisposing risk variable and provides higher resolution in the quantification of disease susceptibility. We evaluate this new A-MDR approach in a broad range of simulations. Also, we present the results of an application of the A-MDR method to a data set derived from Juvenile Idiopathic Arthritis patients treated with methotrexate (MTX) that revealed several GxG interactions in the folate pathway that were associated with treatment response. The epistasis enriched risk score that pooled information from 82 significant GxG interactions distinguished MTX responders from non-responders with 82% accuracy. CONCLUSIONS:The proposed A-MDR is innovative in the MDR framework to investigate aggregated effects among GxG interactions. New measures (pOR, pRR and pChi) are proposed to detect multiple GxG interactions.

SUBMITTER: Dai H

PROVIDER: S-EPMC3560267 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Risk score modeling of multiple gene to gene interactions using aggregated-multifactor dimensionality reduction.

Dai Hongying H Charnigo Richard J RJ Becker Mara L ML Leeder J Steven JS Motsinger-Reif Alison A AA

BioData mining 20130108 1

<h4>Unlabelled</h4><h4>Background</h4>Multifactor Dimensionality Reduction (MDR) has been widely applied to detect gene-gene (GxG) interactions associated with complex diseases. Existing MDR methods summarize disease risk by a dichotomous predisposing model (high-risk/low-risk) from one optimal GxG interaction, which does not take the accumulated effects from multiple GxG interactions into account.<h4>Results</h4>We propose an Aggregated-Multifactor Dimensionality Reduction (A-MDR) method that e ...[more]

PMID: 23294634

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Project description:BackgroundRecently, 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.MethodsIn 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.ResultsResults 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.ConclusionsIn 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:BackgroundDetection of gene-gene interaction (GGI) is a key challenge towards solving the problem of missing heritability in genetics. The multifactor dimensionality reduction (MDR) method has been widely studied for detecting GGIs. MDR reduces the dimensionality of multi-factor by means of binary classification into high-risk (H) or low-risk (L) groups. Unfortunately, this simple binary classification does not reflect the uncertainty of H/L classification. Thus, we proposed Fuzzy MDR to overcome limitations of binary classification by introducing the degree of membership of two fuzzy sets H/L. While Fuzzy MDR demonstrated higher power than that of MDR, its performance is highly dependent on the several tuning parameters. In real applications, it is not easy to choose appropriate tuning parameter values.ResultIn this work, we propose an empirical fuzzy MDR (EF-MDR) which does not require specifying tuning parameters values. Here, we propose an empirical approach to estimating the membership degree that can be directly estimated from the data. In EF-MDR, the membership degree is estimated by the maximum likelihood estimator of the proportion of cases(controls) in each genotype combination. We also show that the balanced accuracy measure derived from this new membership function is a linear function of the standard chi-square statistics. This relationship allows us to perform the standard significance test using p-values in the MDR framework without permutation. Through two simulation studies, the power of the proposed EF-MDR is shown to be higher than those of MDR and Fuzzy MDR. We illustrate the proposed EF-MDR by analyzing Crohn's disease (CD) and bipolar disorder (BD) in the Wellcome Trust Case Control Consortium (WTCCC) dataset.ConclusionWe propose an empirical Fuzzy MDR for detecting GGI using the maximum likelihood of the proportion of cases(controls) as the membership degree of the genotype combination. The program written in R for EF-MDR is available at http://statgen.snu.ac.kr/software/EF-MDR .

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.

Dataset Information

Risk score modeling of multiple gene to gene interactions using aggregated-multifactor dimensionality reduction.

Publications

Risk score modeling of multiple gene to gene interactions using aggregated-multifactor dimensionality reduction.

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