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No study has examined the ability of tree-based methods to detect epistasis in the presence of a polygenic signal. We sought to apply decision tree-based methods, C5.0 and logic regression, to detect epistasis under several simulated conditions, varying strength of interaction and linkage disequilibrium (LD) structure. We then applied the same methods to the phenotype of educational attainment in a large population cohort.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>LD pruning improved the power and reduced the type I error. C5.0 had a conservative type I error rate whereas logic regression had a type I error rate that exceeded 5%. Despite the more conservative type I error, C5.0 was observed to have higher power than logic regression across several conditions. In the presence of a polygenic signal, power was generally reduced. Applying both methods on educational attainment in a large population cohort yielded numerous interacting SNPs; notably a SNP in RCAN3 which is associated with reading and spelling and a SNP in NPAS3, a neurodevelopmental gene.<\/jats:p><\/jats:sec><jats:sec><jats:title>Availability and implementation<\/jats:title><jats:p>All methods used are implemented and freely available in R.<\/jats:p><\/jats:sec><jats:sec><jats:title>Supplementary information<\/jats:title><jats:p>Supplementary data are available at Bioinformatics online.<\/jats:p><\/jats:sec>","DOI":"10.1093\/bioinformatics\/bty462","type":"journal-article","created":{"date-parts":[[2018,6,14]],"date-time":"2018-06-14T19:26:06Z","timestamp":1529004366000},"page":"181-188","source":"Crossref","is-referenced-by-count":9,"title":["Using tree-based methods for detection of gene\u2013gene interactions in the presence of a polygenic signal: simulation study with application to educational attainment in the Generation Scotland Cohort Study"],"prefix":"10.1093","volume":"35","author":[{"given":"Joeri J","family":"Meijsen","sequence":"first","affiliation":[{"name":"Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK"},{"name":"Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandros","family":"Rammos","sequence":"additional","affiliation":[{"name":"Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK"},{"name":"Department of Genetics, Smurfit Institute of Genetics and Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Archie","family":"Campbell","sequence":"additional","affiliation":[{"name":"Centre for Genomic and Experimental Medicine, Institute of Genetics and 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UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Riccardo E","family":"Marioni","sequence":"additional","affiliation":[{"name":"Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK"},{"name":"Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristin K","family":"Nicodemus","sequence":"additional","affiliation":[{"name":"Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK"},{"name":"Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, 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