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Survival dimensionality reduction (SDR): development and clinical application of an innovative approach to detect epistasis in presence of right-censored data.

ABSTRACT: BACKGROUND: Epistasis is recognized as a fundamental part of the genetic architecture of individuals. Several computational approaches have been developed to model gene-gene interactions in case-control studies, however, none of them is suitable for time-dependent analysis. Herein we introduce the Survival Dimensionality Reduction (SDR) algorithm, a non-parametric method specifically designed to detect epistasis in lifetime datasets. RESULTS: The algorithm requires neither specification about the underlying survival distribution nor about the underlying interaction model and proved satisfactorily powerful to detect a set of causative genes in synthetic epistatic lifetime datasets with a limited number of samples and high degree of right-censorship (up to 70%). The SDR method was then applied to a series of 386 Dutch patients with active rheumatoid arthritis that were treated with anti-TNF biological agents. Among a set of 39 candidate genes, none of which showed a detectable marginal effect on anti-TNF responses, the SDR algorithm did find that the rs1801274 SNP in the Fc gamma RIIa gene and the rs10954213 SNP in the IRF5 gene non-linearly interact to predict clinical remission after anti-TNF biologicals. CONCLUSIONS: Simulation studies and application in a real-world setting support the capability of the SDR algorithm to model epistatic interactions in candidate-genes studies in presence of right-censored data. AVAILABILITY: http://sourceforge.net/projects/sdrproject/.

SUBMITTER: Beretta L

PROVIDER: S-EPMC2928804 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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Survival dimensionality reduction (SDR): development and clinical application of an innovative approach to detect epistasis in presence of right-censored data.

Beretta Lorenzo L Santaniello Alessandro A van Riel Piet L C M PL Coenen Marieke J H MJ Scorza Raffaella R

BMC bioinformatics 20100806

<h4>Background</h4>Epistasis is recognized as a fundamental part of the genetic architecture of individuals. Several computational approaches have been developed to model gene-gene interactions in case-control studies, however, none of them is suitable for time-dependent analysis. Herein we introduce the Survival Dimensionality Reduction (SDR) algorithm, a non-parametric method specifically designed to detect epistasis in lifetime datasets.<h4>Results</h4>The algorithm requires neither specifica ...[more]

PMID: 20691091

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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: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.

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

Survival dimensionality reduction (SDR): development and clinical application of an innovative approach to detect epistasis in presence of right-censored data.

Publications

Survival dimensionality reduction (SDR): development and clinical application of an innovative approach to detect epistasis in presence of right-censored data.

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