{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T09:47:05Z","timestamp":1778320025321,"version":"3.51.4"},"reference-count":59,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2020,3,30]],"date-time":"2020-03-30T00:00:00Z","timestamp":1585526400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R15HG009565"],"award-info":[{"award-number":["R15HG009565"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Motivation<\/jats:title><jats:p>Epistasis reflects the distortion on a particular trait or phenotype resulting from the combinatorial effect of two or more genes or genetic variants. Epistasis is an important genetic foundation underlying quantitative traits in many organisms as well as in complex human diseases. However, there are two major barriers in identifying epistasis using large genomic datasets. One is that epistasis analysis will induce over-fitting of an over-saturated model with the high-dimensionality of a genomic dataset. Therefore, the problem of identifying epistasis demands efficient statistical methods. The second barrier comes from the intensive computing time for epistasis analysis, even when the appropriate model and data are specified.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In this study, we combine statistical techniques and computational techniques to scale up epistasis analysis using Empirical Bayesian Elastic Net (EBEN) models. Specifically, we first apply a matrix manipulation strategy for pre-computing the correlation matrix and pre-filter to narrow down the search space for epistasis analysis. We then develop a parallelized approach to further accelerate the modeling process. Our experiments on synthetic and empirical genomic data demonstrate that our parallelized methods offer tens of fold speed up in comparison with the classical EBEN method which runs in a sequential manner. We applied our parallelized approach to a yeast dataset, and we were able to identify both main and epistatic effects of genetic variants associated with traits such as fitness.<\/jats:p><\/jats:sec><jats:sec><jats:title>Availability and implementation<\/jats:title><jats:p>The software is available at github.com\/shilab\/parEBEN.<\/jats:p><\/jats:sec>","DOI":"10.1093\/bioinformatics\/btaa216","type":"journal-article","created":{"date-parts":[[2020,3,26]],"date-time":"2020-03-26T20:14:29Z","timestamp":1585253669000},"page":"3803-3810","source":"Crossref","is-referenced-by-count":5,"title":["A parallelized strategy for epistasis analysis based on Empirical Bayesian Elastic Net models"],"prefix":"10.1093","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3273-7704","authenticated-orcid":false,"given":"Jia","family":"Wen","sequence":"first","affiliation":[{"name":"Department of Genetics , University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Colby T","family":"Ford","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics and Genomics , College of Computing and Informatics"},{"name":"School of Data Science , University of North Carolina at Charlotte, Charlotte, NC 28223, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Janies","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics and Genomics , College of Computing and Informatics"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinghua","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Computer and Information Sciences , Temple University, Philadelphia, PA 19122, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2020,3,30]]},"reference":[{"key":"2023063011295689300_btaa216-B1","doi-asserted-by":"crossref","first-page":"8712","DOI":"10.1038\/ncomms9712","article-title":"Genetic interactions contribute less than additive effects to quantitative trait variation in yeast","volume":"6","author":"Bloom","year":"2015","journal-title":"Nat. Commun"},{"key":"2023063011295689300_btaa216-B2","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1016\/j.cell.2017.05.038","article-title":"An expanded view of complex traits: from polygenic to omnigenic","volume":"169","author":"Boyle","year":"2017","journal-title":"Cell"},{"key":"2023063011295689300_btaa216-B3","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.01381","article-title":"Genetic interactions affecting human gene expression identified by variance association mapping","volume":"3","author":"Brown","year":"2014","journal-title":"Elife"},{"key":"2023063011295689300_btaa216-B4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1471-2105-12-211","article-title":"Fast empirical Bayesian Lasso for multiple quantitative trait locus mapping","volume":"12","author":"Cai","year":"2011","journal-title":"BMC Bioinformatics"},{"key":"2023063011295689300_btaa216-B5","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1038\/nrg1407","article-title":"Epistasis: too often neglected in complex trait studies?","volume":"5","author":"Carlborg","year":"2004","journal-title":"Nat. Rev. Genet"},{"key":"2023063011295689300_btaa216-B6","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1038\/msb4100137","article-title":"Prediction of phenotype and gene expression for combinations of mutations","volume":"3","author":"Carter","year":"2007","journal-title":"Mol. Syst. Biol"},{"key":"2023063011295689300_btaa216-B7","first-page":"208","author":"Chen","year":"2012"},{"key":"2023063011295689300_btaa216-B8","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1109\/TCBB.2014.2363459","article-title":"Searching high-order SNP combinations for complex diseases based on energy distribution difference","volume":"12","author":"Ding","year":"2015","journal-title":"IEEE\/ACM Trans. Comput. Biol. Bioinform"},{"key":"2023063011295689300_btaa216-B9","doi-asserted-by":"crossref","first-page":"e157","DOI":"10.1371\/journal.pgen.0020157","article-title":"Two-stage two-locus models in genome-wide association","volume":"2","author":"Evans","year":"2006","journal-title":"PLoS Genet"},{"key":"2023063011295689300_btaa216-B10","author":"Ford","year":"2018"},{"key":"2023063011295689300_btaa216-B12","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1038\/ng.3800","article-title":"Accounting for genetic interactions improves modeling of individual quantitative trait phenotypes in yeast","volume":"49","author":"Forsberg","year":"2017","journal-title":"Nat. Genet"},{"key":"2023063011295689300_btaa216-B13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.tpb.2009.10.002","article-title":"Epistasis in a quantitative trait captured by a molecular model of transcription factor interactions","volume":"77","author":"Gertz","year":"2010","journal-title":"Theor. Popul. Biol"},{"key":"2023063011295689300_btaa216-B14","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1006\/tpbi.1996.0003","article-title":"Epistasis and pleiotropy as natural properties of transcriptional regulation","volume":"49","author":"Gibson","year":"1996","journal-title":"Theor. Popul. Biol"},{"key":"2023063011295689300_btaa216-B15","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1038\/ng0710-558","article-title":"Hints of hidden heritability in GWAS","volume":"42","author":"Gibson","year":"2010","journal-title":"Nat. Genet"},{"key":"2023063011295689300_btaa216-B16","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/1756-0381-2-5","article-title":"Spatially Uniform ReliefF (SURF) for computationally-efficient filtering of gene\u2013gene interactions","volume":"2","author":"Greene","year":"2009","journal-title":"BioData Min"},{"key":"2023063011295689300_btaa216-B17","doi-asserted-by":"crossref","first-page":"e66545","DOI":"10.1371\/journal.pone.0066545","article-title":"A simple and computationally efficient approach to multifactor dimensionality reduction analysis of gene\u2013gene interactions for quantitative traits","volume":"8","author":"Gui","year":"2013","journal-title":"PLoS One"},{"key":"2023063011295689300_btaa216-B18","doi-asserted-by":"crossref","first-page":"W628","DOI":"10.1093\/nar\/gks550","article-title":"BiForce Toolbox: powerful high-throughput computational analysis of gene\u2013gene interactions in genome-wide association studies","volume":"40","author":"Gyenesei","year":"2012","journal-title":"Nucleic Acids Res"},{"key":"2023063011295689300_btaa216-B19","doi-asserted-by":"crossref","first-page":"1957","DOI":"10.1093\/bioinformatics\/bts304","article-title":"High-throughput analysis of epistasis in genome-wide association studies with BiForce","volume":"28","author":"Gyenesei","year":"2012","journal-title":"Bioinformatics"},{"key":"2023063011295689300_btaa216-B20","author":"Huang","year":"2015"},{"key":"2023063011295689300_btaa216-B21","author":"Huang","year":"2016"},{"key":"2023063011295689300_btaa216-B22","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1038\/hdy.2014.79","article-title":"Empirical Bayesian Elastic Net for multiple quantitative trait locus mapping","volume":"114","author":"Huang","year":"2015","journal-title":"Heredity"},{"key":"2023063011295689300_btaa216-B23","doi-asserted-by":"crossref","first-page":"51","DOI":"10.3389\/fgene.2013.00051","article-title":"eQTL epistasis\u2014challenges and computational approaches","volume":"4","author":"Huang","year":"2013","journal-title":"Front. Genet"},{"key":"2023063011295689300_btaa216-B24","doi-asserted-by":"crossref","first-page":"5755","DOI":"10.1073\/pnas.0901620106","article-title":"The cost of gene expression underlies a fitness trade-off in yeast","volume":"106","author":"Lang","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023063011295689300_btaa216-B25","first-page":"1306","article-title":"Adaptive multi-task Lasso: with application to eQTL detection","author":"Lee","year":"2010"},{"key":"2023063011295689300_btaa216-B27","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1002\/gepi.21720","article-title":"Efficient two-step testing of gene\u2013gene interactions in genome-wide association studies","volume":"37","author":"Lewinger","year":"2013","journal-title":"Genet. Epidemiol"},{"key":"2023063011295689300_btaa216-B28","doi-asserted-by":"crossref","first-page":"6441","DOI":"10.1073\/pnas.0810208106","article-title":"Modularity and interactions in the genetics of gene expression","volume":"106","author":"Litvin","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023063011295689300_btaa216-B29","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1016\/j.cell.2019.04.014","article-title":"Trans effects on gene expression can drive omnigenic inheritance","volume":"177","author":"Liu","year":"2019","journal-title":"Cell"},{"key":"2023063011295689300_btaa216-B30","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1038\/ng1537","article-title":"Genome-wide strategies for detecting multiple loci that influence complex diseases","volume":"37","author":"Marchini","year":"2005","journal-title":"Nat. Genet"},{"key":"2023063011295689300_btaa216-B31","year":"2017"},{"key":"2023063011295689300_btaa216-B32","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1586\/14737159.4.6.795","article-title":"Computational analysis of gene\u2013gene interactions using multifactor dimensionality reduction","volume":"4","author":"Moore","year":"2004","journal-title":"Expert Rev. Mol. Diagn"},{"key":"2023063011295689300_btaa216-B33","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s13040-017-0139-3","article-title":"Grid-based stochastic search for hierarchical gene\u2013gene interactions in population-based genetic studies of common human diseases","volume":"10","author":"Moore","year":"2017","journal-title":"BioData Min"},{"key":"2023063011295689300_btaa216-B34","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1101\/gr.172901","article-title":"A combinatorial partitioning method to identify multilocus genotypic partitions that predict quantitative trait variation","volume":"11","author":"Nelson","year":"2001","journal-title":"Genome Res"},{"key":"2023063011295689300_btaa216-B26"},{"key":"2023063011295689300_btaa216-B35","author":"Pendergrass","year":"2015"},{"key":"2023063011295689300_btaa216-B36","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1086\/519795","article-title":"PLINK: a tool set for whole-genome association and population-based linkage analyses","volume":"81","author":"Purcell","year":"2007","journal-title":"Am. J. Hum. Genet"},{"key":"2023063011295689300_btaa216-B37","doi-asserted-by":"crossref","first-page":"S5","DOI":"10.1186\/1471-2105-16-S5-S5","article-title":"An integrated network of microRNA and gene expression in ovarian cancer","volume":"16","author":"Quitadamo","year":"2015","journal-title":"BMC Bioinformatics"},{"key":"2023063011295689300_btaa216-B38","year":"2015"},{"key":"2023063011295689300_btaa216-B39","author":"Weston","year":"2015"},{"key":"2023063011295689300_btaa216-B40","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1186\/1471-2156-13-63","article-title":"Recent developments in statistical methods for detecting genetic loci affecting phenotypic variability","volume":"13","author":"R\u00f6nneg\u00e5rd","year":"2012","journal-title":"BMC Genet"},{"key":"2023063011295689300_btaa216-B41","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.1093\/bioinformatics\/btq147","article-title":"FastEpistasis: a high performance computing solution for quantitative trait epistasis","volume":"26","author":"Sch\u00fcpbach","year":"2010","journal-title":"Bioinformatics"},{"key":"2023063011295689300_btaa216-B42","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1093\/bioinformatics\/bts163","article-title":"Matrix eQTL: ultra fast eQTL analysis via large matrix operations","volume":"28","author":"Shabalin","year":"2012","journal-title":"Bioinformatics"},{"key":"2023063011295689300_btaa216-B43","doi-asserted-by":"crossref","first-page":"e1002839","DOI":"10.1371\/journal.pgen.1002839","article-title":"Inheritance beyond plain heritability: variance-controlling genes in Arabidopsis thaliana","volume":"8","author":"Shen","year":"2012","journal-title":"PLoS Genet"},{"key":"2023063011295689300_btaa216-B44","doi-asserted-by":"crossref","first-page":"106","DOI":"10.3389\/fgene.2014.00106","article-title":"Analysis pipeline for the epistasis search\u2014statistical versus biological filtering","volume":"5","author":"Sun","year":"2014","journal-title":"Front. Genet"},{"key":"2023063011295689300_btaa216-B45","doi-asserted-by":"crossref","first-page":"e1000464","DOI":"10.1371\/journal.pgen.1000464","article-title":"Epistatic module detection for case\u2013control studies: a Bayesian model with a Gibbs sampling strategy","volume":"5","author":"Tang","year":"2009","journal-title":"PLoS Genet"},{"key":"2023063011295689300_btaa216-B46","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1109\/TST.2014.6961031","article-title":"Methods for population-based eQTL analysis in human genetics","volume":"19","author":"Tian","year":"2014","journal-title":"Tsinghua Sci. Technol"},{"key":"2023063011295689300_btaa216-B47","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1111\/j.2517-6161.1996.tb02080.x","article-title":"Regression shrinkage and selection via the Lasso","volume":"58","author":"Tibshirani","year":"1996","journal-title":"J. R. Stat. Soc"},{"key":"2023063011295689300_btaa216-B48","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1111\/j.1467-9868.2005.00490.x","article-title":"Sparsity and smoothness via the fused Lasso","volume":"67","author":"Tibshirani","year":"2005","journal-title":"J. R. Stat. Soc"},{"key":"2023063011295689300_btaa216-B49","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1007\/s00439-019-01987-w","article-title":"How to increase our belief in discovered statistical interactions via large-scale association studies?","volume":"138","author":"Van Steen","year":"2019","journal-title":"Hum. Genet"},{"key":"2023063011295689300_btaa216-B50","doi-asserted-by":"crossref","first-page":"e12264","DOI":"10.1371\/journal.pone.0012264","article-title":"Epistasis: obstacle or advantage for mapping complex traits","volume":"5","author":"Verhoeven","year":"2010","journal-title":"PLoS One"},{"key":"2023063011295689300_btaa216-B51","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1089\/cmb.2014.0026","article-title":"Finding alternative expression quantitative trait loci by exploring sparse model space","volume":"21","author":"Wang","year":"2014","journal-title":"J. Comput. Biol"},{"key":"2023063011295689300_btaa216-B52","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/s12864-017-4130-7","article-title":"Epistasis analysis of microRNAs on pathological stages in colon cancer based on an Empirical Bayesian Elastic Net method","volume":"18","author":"Wen","year":"2017","journal-title":"BMC Genomics"},{"key":"2023063011295689300_btaa216-B53","author":"Weston","year":"2017"},{"key":"2023063011295689300_btaa216-B54","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1093\/bioinformatics\/btr603","article-title":"Detecting genome-wide epistases based on the clustering of relatively frequent items","volume":"28","author":"Xie","year":"2012","journal-title":"Bioinformatics"},{"key":"2023063011295689300_btaa216-B55","doi-asserted-by":"crossref","first-page":"e1002382","DOI":"10.1371\/journal.pgen.1002382","article-title":"Hierarchical generalized linear models for multiple groups of rare and common variants: jointly estimating group and individual-variant effects","volume":"7","author":"Yi","year":"2011","journal-title":"PLoS Genet"},{"key":"2023063011295689300_btaa216-B56","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1145\/2934664","article-title":"Apache Spark: a unified engine for big data processing","volume":"59","author":"Zaharia","year":"2016","journal-title":"Commun. ACM"},{"key":"2023063011295689300_btaa216-B57","doi-asserted-by":"crossref","first-page":"e1000642","DOI":"10.1371\/journal.pcbi.1000642","article-title":"A Bayesian partition method for detecting pleiotropic and epistatic eQTL modules","volume":"6","author":"Zhang","year":"2010","journal-title":"PLoS Comput. Biol"},{"key":"2023063011295689300_btaa216-B58","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1038\/ng2110","article-title":"Bayesian inference of epistatic interactions in case\u2013control studies","volume":"39","author":"Zhang","year":"2007","journal-title":"Nat. Genet"},{"key":"2023063011295689300_btaa216-B59","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1111\/j.1469-1809.2010.00621.x","article-title":"Bayesian models for detecting epistatic interactions from genetic data","volume":"75","author":"Zhang","year":"2011","journal-title":"Ann. Hum. Genet"},{"key":"2023063011295689300_btaa216-B60","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1073\/pnas.1119675109","article-title":"The mystery of missing heritability: genetic interactions create phantom heritability","volume":"109","author":"Zuk","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/bioinformatics\/advance-article-pdf\/doi\/10.1093\/bioinformatics\/btaa216\/33199715\/btaa216.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/36\/12\/3803\/50747814\/bioinformatics_36_12_3803.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/36\/12\/3803\/50747814\/bioinformatics_36_12_3803.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,2]],"date-time":"2024-08-02T23:06:07Z","timestamp":1722639967000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/36\/12\/3803\/5813727"}},"subtitle":[],"editor":[{"given":"Russell","family":"Schwartz","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2020,3,30]]},"references-count":59,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2020,6,1]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btaa216","relation":{},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"value":"1367-4803","type":"print"},{"value":"1367-4811","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,6,15]]},"published":{"date-parts":[[2020,3,30]]}}}