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

Abstract

BackgroundEpistasis 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.ResultsThe 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 FcγRIIa gene and the rs10954213 SNP in the IRF5 gene non-linearly interact to predict clinical remission after anti-TNF biologicals.ConclusionsSimulation 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/

Physiological and Pathological Inflammation Induced by Antibodies and Pentraxins

“…While single nucleotide polymorphisms (SNPs) in FcRs that change their affinities for antibodies are associated with diseases such as CD and UC, there are conflicting findings on whether these SNPs have a direct effect on antibody-induced inflammation [ 30 , 97 , 138 ]. This discrepancy may be related to the involvement of other FcR-dependent functions that are affected by these SNPs (e.g., phagocytosis and complement activation), but could also be related to a phenomenon known as epistasis, meaning that the effect of the FcR SNPs may be dependent on other genes [ 139 ]. Based on findings by us and others, IRF5 poses as an interesting therapeutic target [ 29 , 140 , 141 , 142 , 143 , 144 , 145 ].…”

Genetic interaction ofP2X7receptor andVEGFR-2polymorphisms identifies a favorable prognostic profile in prostate cancer patients

“…The Survival Dimensionality Reduction (SDR) methodology was applied (using version 2.0a of SDR software available on http://sourceforge.net/projects/sdrproject/ ) to detect non-linear gene-gene interactions in presence of right-censored data in identifying biomarkers of prognosis in OS [ 18 ]. The best combination of SDR model was chosen based on the lowest testing Integrated Brier Score (IBS) value.…”

“…The aim of this new approach should be to unveil a genetic profile with a reliable prognostic value. Beretta and colleagues have created and validated a methodology called survival dimensionality reduction (SDR), an innovative approach to detect epistasis in presence of right-censored data, to identify a genetic profile with the ability to predict a better survival of patients [ 18 ].…”

A knowledge-based decision support system in bioinformatics: an application to protein complex extraction

“…Examples of DSS in Bioinformatics are ProCKSI [19], a system that is able to put together various protein similarity measures in order to obtain the comparison of multiple proteins simultaneously; and INTERPRET [20], a software that offers support in the analysis of Magnetic Resonance Spectroscopy (MRS) data.…”