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While epistasis detection has been extensively evaluated in case-control studies, its performance with quantitative phenotypes remains comparatively understudied.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We identified and evaluated six epistasis detection methods applicable to quantitative trait analysis: EpiSNP, Matrix Epistasis, MIDESP, PLINK Epistasis, QMDR, and REMMA. Using the EpiGEN simulator, we generated synthetic datasets modeling four classes of pairwise SNP interactions\u2014dominant, multiplicative, recessive, and XOR. We also assessed BOOST and MDR algorithms using discretized (case-control) versions of the same datasets. Performance varied notably by interaction type: REMMA achieved the highest overall detection rate (55%), particularly excelling with dominant interactions (100%). MDR excelled with multiplicative (57%) and XOR (69%) interactions. Meanwhile, EpiSNP attained the best performance for recessive interactions (67%). All methods except BOOST produced F1 scores below 0.05 for most interaction types. We further evaluated the methods using a real-world dataset. When applied to the Adolescent Brain Cognitive Development dataset to analyse the externalizing behavior phenotype, both PLINK Epistasis and PLINK BOOST identified SNPs within the DRD2 and DRD4 genes, consistent with previously reported genetic associations. Given the variability in tool performance across interaction types, no single method provides optimal detection across all scenarios. Leveraging multiple detection algorithms may therefore yield more comprehensive insights into epistatic effects in quantitative trait analyses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Availability and implementation<\/jats:title>\n                    <jats:p>All relevant code and simulated datasets can be found at github.com\/staslist\/Epistasis_Review repository.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/bioinformatics\/btag344","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T11:44:28Z","timestamp":1780487068000},"source":"Crossref","is-referenced-by-count":0,"title":["Evaluation of epistasis detection methods for quantitative phenotypes"],"prefix":"10.1093","volume":"42","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7983-7879","authenticated-orcid":false,"given":"Stanislav","family":"Listopad","sequence":"first","affiliation":[{"name":"Department of 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