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We propose that GSEA can be adapted to incorporate SNP and gene-level interactions. To this end, gene scores are derived by Relief-based feature importance algorithms that efficiently detect both univariate and interaction effects (MultiSURF) or exclusively interaction effects (MultiSURF*). We compare these interaction-sensitive GSEA approaches to traditional<jats:italic>\u03c7<\/jats:italic><jats:sup>2<\/jats:sup>rankings in simulated genome-wide array data, and in a target and replication cohort of congenital heart disease patients with conotruncal defects (CTDs).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In the simulation study and for both CTD datasets, both Relief-based approaches to GSEA captured more relevant and significant gene ontology terms compared to the univariate GSEA. Key terms and themes of interest include cell adhesion, migration, and signaling. A leading edge analysis highlighted semaphorins and their receptors, the Slit-Robo pathway, and other genes with roles in the secondary heart field and outflow tract development.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our results indicate that interaction-sensitive approaches to enrichment analysis can improve upon traditional univariate GSEA. This approach replicated univariate findings and identified additional and more robust support for the role of the secondary heart field and cardiac neural crest cell migration in the development of CTDs.<\/jats:p><\/jats:sec>","DOI":"10.1186\/s13040-022-00287-w","type":"journal-article","created":{"date-parts":[[2022,2,12]],"date-time":"2022-02-12T13:02:41Z","timestamp":1644670961000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Gene-Interaction-Sensitive enrichment analysis in congenital heart disease"],"prefix":"10.1186","volume":"15","author":[{"given":"Alexa A.","family":"Woodward","sequence":"first","affiliation":[]},{"given":"Deanne M.","family":"Taylor","sequence":"additional","affiliation":[]},{"given":"Elizabeth","family":"Goldmuntz","sequence":"additional","affiliation":[]},{"given":"Laura E.","family":"Mitchell","sequence":"additional","affiliation":[]},{"given":"A.J.","family":"Agopian","sequence":"additional","affiliation":[]},{"given":"Jason H.","family":"Moore","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0487-5555","authenticated-orcid":false,"given":"Ryan J.","family":"Urbanowicz","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2022,2,12]]},"reference":[{"issue":"43","key":"287_CR1","doi-asserted-by":"publisher","first-page":"15545","DOI":"10.1073\/pnas.0506580102","volume":"102","author":"A Subramanian","year":"2005","unstructured":"Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, et al. 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