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Unified Cox model based multifactor dimensionality reduction method for gene-gene interaction analysis of the survival phenotype.

ABSTRACT: Background:One strategy for addressing missing heritability in genome-wide association study is gene-gene interaction analysis, which, unlike a single gene approach, involves high-dimensionality. The multifactor dimensionality reduction method (MDR) has been widely applied to reduce multi-levels of genotypes into high or low risk groups. The Cox-MDR method has been proposed to detect gene-gene interactions associated with the survival phenotype by using the martingale residuals from a Cox model. However, this method requires a cross-validation procedure to find the best SNP pair among all possible pairs and the permutation procedure should be followed for the significance of gene-gene interactions. Recently, the unified model based multifactor dimensionality reduction method (UM-MDR) has been proposed to unify the significance testing with the MDR algorithm within the regression model framework, in which neither cross-validation nor permutation testing are needed. In this paper, we proposed a simple approach, called Cox UM-MDR, which combines Cox-MDR with the key procedure of UM-MDR to identify gene-gene interactions associated with the survival phenotype. Results:The simulation study was performed to compare Cox UM-MDR with Cox-MDR with and without the marginal effects of SNPs. We found that Cox UM-MDR has similar power to Cox-MDR without marginal effects, whereas it outperforms Cox-MDR with marginal effects and more robust to heavy censoring. We also applied Cox UM-MDR to a dataset of leukemia patients and detected gene-gene interactions with regard to the survival time. Conclusion:Cox UM-MDR is easily implemented by combining Cox-MDR with UM-MDR to detect the significant gene-gene interactions associated with the survival time without cross-validation and permutation testing. The simulation results are shown to demonstrate the utility of the proposed method, which achieves at least the same power as Cox-MDR in most scenarios, and outperforms Cox-MDR when some SNPs having only marginal effects might mask the detection of the causal epistasis.

SUBMITTER: Lee S

PROVIDER: S-EPMC6295107 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Unified Cox model based multifactor dimensionality reduction method for gene-gene interaction analysis of the survival phenotype.

Lee Seungyeoun S Son Donghee D Kim Yongkang Y Yu Wenbao W Park Taesung T

BioData mining 20181214

<h4>Background</h4>One strategy for addressing missing heritability in genome-wide association study is gene-gene interaction analysis, which, unlike a single gene approach, involves high-dimensionality. The multifactor dimensionality reduction method (MDR) has been widely applied to reduce multi-levels of genotypes into high or low risk groups. The Cox-MDR method has been proposed to detect gene-gene interactions associated with the survival phenotype by using the martingale residuals from a Co ...[more]

PMID: 30564286

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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:The widespread use of high-throughput methods of single nucleotide polymorphism (SNP) genotyping has created a number of computational and statistical challenges. The problem of identifying SNP-SNP interactions in case-control studies has been studied extensively, and a number of new techniques have been developed. Little progress has been made, however, in the analysis of SNP-SNP interactions in relation to time-to-event data, such as patient survival time or time to cancer relapse. We present an extension of the two class multifactor dimensionality reduction (MDR) algorithm that enables detection and characterization of epistatic SNP-SNP interactions in the context of survival analysis. The proposed Survival MDR (Surv-MDR) method handles survival data by modifying MDR's constructive induction algorithm to use the log-rank test. Surv-MDR replaces balanced accuracy with log-rank test statistics as the score to determine the best models. We simulated datasets with a survival outcome related to two loci in the absence of any marginal effects. We compared Surv-MDR with Cox-regression for their ability to identify the true predictive loci in these simulated data. We also used this simulation to construct the empirical distribution of Surv-MDR's testing score. We then applied Surv-MDR to genetic data from a population-based epidemiologic study to find prognostic markers of survival time following a bladder cancer diagnosis. We identified several two-loci SNP combinations that have strong associations with patients' survival outcome. Surv-MDR is capable of detecting interaction models with weak main effects. These epistatic models tend to be dropped by traditional Cox regression approaches to evaluating interactions. With improved efficiency to handle genome wide datasets, Surv-MDR will play an important role in a research strategy that embraces the complexity of the genotype-phenotype mapping relationship since epistatic interactions are an important component of the genetic basis of disease.

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:BackgroundThere is a growing awareness that interaction between multiple genes play an important role in the risk of common, complex multi-factorial diseases. Many common diseases are affected by certain genotype combinations (associated with some genes and their interactions). The identification and characterization of these susceptibility genes and gene-gene interaction have been limited by small sample size and large number of potential interactions between genes. Several methods have been proposed to detect gene-gene interaction in a case control study. The penalized logistic regression (PLR), a variant of logistic regression with L2 regularization, is a parametric approach to detect gene-gene interaction. On the other hand, the Multifactor Dimensionality Reduction (MDR) is a nonparametric and genetic model-free approach to detect genotype combinations associated with disease risk.MethodsWe compared the power of MDR and PLR for detecting two-way and three-way interactions in a case-control study through extensive simulations. We generated several interaction models with different magnitudes of interaction effect. For each model, we simulated 100 datasets, each with 200 cases and 200 controls and 20 SNPs. We considered a wide variety of models such as models with just main effects, models with only interaction effects or models with both main and interaction effects. We also compared the performance of MDR and PLR to detect gene-gene interaction associated with acute rejection(AR) in kidney transplant patients.ResultsIn this paper, we have studied the power of MDR and PLR for detecting gene-gene interaction in a case-control study through extensive simulation. We have compared their performances for different two-way and three-way interaction models. We have studied the effect of different allele frequencies on these methods. We have also implemented their performance on a real dataset. As expected, none of these methods were consistently better for all data scenarios, but, generally MDR outperformed PLR for more complex models. The ROC analysis on the real dataset suggests that MDR outperforms PLR in detecting gene-gene interaction on the real dataset.ConclusionAs one might expect, the relative success of each method is context dependent. This study demonstrates the strengths and weaknesses of the methods to detect gene-gene interaction.

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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Unified Cox model based multifactor dimensionality reduction method for gene-gene interaction analysis of the survival phenotype.

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Unified Cox model based multifactor dimensionality reduction method for gene-gene interaction analysis of the survival phenotype.

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