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However, neglecting correlations between multiple pathways can result in misleading solutions, and pathway-based analyses of large-scale genetic datasets require massive computational burden. We propose a Pathway-based approach using HierArchical components of collapsed RAre variants Of High-throughput sequencing data (PHARAOH) for the analysis of rare variants by constructing a single hierarchical model that consists of collapsed gene-level summaries and pathways and analyzes entire pathways simultaneously by imposing ridge-type penalties on both gene and pathway coefficient estimates; hence our method considers the correlation of pathways without constraint by a multiple testing problem.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Through simulation studies, the proposed method was shown to have higher statistical power than the existing pathway-based methods. In addition, our method was applied to the large-scale whole-exome sequencing data with levels of a liver enzyme using two well-known pathway databases Biocarta and KEGG. This application demonstrated that our method not only identified associated pathways but also successfully detected biologically plausible pathways for a phenotype of interest. These findings were successfully replicated by an independent large-scale exome chip study.<\/jats:p><\/jats:sec><jats:sec><jats:title>Availability and Implementation<\/jats:title><jats:p>An implementation of PHARAOH is available at http:\/\/statgen.snu.ac.kr\/software\/pharaoh\/.<\/jats:p><\/jats:sec><jats:sec><jats:title>Contact<\/jats:title><jats:p>tspark@stats.snu.ac.kr<\/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\/btw425","type":"journal-article","created":{"date-parts":[[2016,9,1]],"date-time":"2016-09-01T07:53:39Z","timestamp":1472716419000},"page":"i586-i594","source":"Crossref","is-referenced-by-count":40,"title":["Pathway-based approach using hierarchical components of collapsed rare variants"],"prefix":"10.1093","volume":"32","author":[{"given":"Sungyoung","family":"Lee","sequence":"first","affiliation":[{"name":"Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul 151-747, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sungkyoung","family":"Choi","sequence":"additional","affiliation":[{"name":"Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul 151-747, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young Jin","family":"Kim","sequence":"additional","affiliation":[{"name":"Center for Genome Science, National Institute of Health, Osong Health Technology Administration Complex, Chungcheongbuk-Do 363-951, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bong-Jo","family":"Kim","sequence":"additional","affiliation":[{"name":"Center for Genome Science, National Institute of Health, Osong Health Technology Administration Complex, Chungcheongbuk-Do 363-951, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"T2d-Genes Consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heungsun","family":"Hwang","sequence":"additional","affiliation":[{"name":"Department of Psychology, McGill University, Montreal, QC H3A 1B1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taesung","family":"Park","sequence":"additional","affiliation":[{"name":"Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul 151-747, Korea"},{"name":"Department of Statistics, Seoul National University, Seoul 151-747, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2016,8,29]]},"reference":[{"key":"2023020113331982300_btw425-B1","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1086\/513471","volume":"80","author":"Ahituv","year":"2007","journal-title":"Am. 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