{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T08:41:09Z","timestamp":1791189669532,"version":"4.1.0"},"reference-count":31,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2013,7,8]],"date-time":"2013-07-08T00:00:00Z","timestamp":1373241600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genetic Epidemiology"],"published-print":{"date-parts":[[2013,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The need for improved algorithmic support for variant prioritization and disease\u2010gene identification in personal genomes data is widely acknowledged. We previously presented the Variant Annotation, Analysis, and Search Tool (VAAST), which employs an aggregative variant association test that combines both amino acid substitution (AAS) and allele frequencies. Here we describe and benchmark VAAST 2.0, which uses a novel conservation\u2010controlled AAS matrix (CASM), to incorporate information about phylogenetic conservation. We show that the CASM approach improves VAAST's variant prioritization accuracy compared to its previous implementation, and compared to SIFT, PolyPhen\u20102, and MutationTaster. We also show that VAAST 2.0 outperforms KBAC, WSS, SKAT, and variable threshold (VT) using published case\u2010control datasets for Crohn disease (\n                    <jats:italic>NOD2<\/jats:italic>\n                    ), hypertriglyceridemia (\n                    <jats:italic>LPL<\/jats:italic>\n                    ), and breast cancer (\n                    <jats:italic>CHEK2<\/jats:italic>\n                    ). VAAST 2.0 also improves search accuracy on simulated datasets across a wide range of allele frequencies, population\u2010attributable disease risks, and allelic heterogeneity, factors that compromise the accuracies of other aggregative variant association tests. We also demonstrate that, although most aggregative variant association tests are designed for common genetic diseases, these tests can be easily adopted as rare Mendelian disease\u2010gene finders with a simple ranking\u2010by\u2010statistical\u2010significance protocol, and the performance compares very favorably to state\u2010of\u2010art filtering approaches. The latter, despite their popularity, have suboptimal performance especially with the increasing case sample size.\n                  <\/jats:p>","DOI":"10.1002\/gepi.21743","type":"journal-article","created":{"date-parts":[[2013,7,8]],"date-time":"2013-07-08T13:57:02Z","timestamp":1373291822000},"page":"622-634","source":"Crossref","is-referenced-by-count":140,"title":["VAAST 2.0: Improved Variant Classification and Disease\u2010Gene Identification Using a Conservation\u2010Controlled Amino Acid Substitution Matrix"],"prefix":"10.1002","volume":"37","author":[{"given":"Hao","family":"Hu","sequence":"first","affiliation":[{"name":"Department of Epidemiology The University of Texas M.D. Anderson Cancer Center  Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chad D.","family":"Huff","sequence":"additional","affiliation":[{"name":"Department of Epidemiology The University of Texas M.D. Anderson Cancer Center  Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barry","family":"Moore","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Eccles Institute of Human Genetics University of Utah School of Medicine  Salt Lake City Utah"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Flygare","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Eccles Institute of Human Genetics University of Utah School of Medicine  Salt Lake City Utah"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin G.","family":"Reese","sequence":"additional","affiliation":[{"name":"Omicia, Inc  Emeryville California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Yandell","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Eccles Institute of Human Genetics University of Utah School of Medicine  Salt Lake City Utah"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2013,7,8]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth0410-248"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature09534"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/26.1.285"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1181498"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1086\/521032"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.185.4154.862"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.628"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkh103"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1086\/513473"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1002496"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1186\/bcr2810"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1086\/339432"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2008.06.024"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1001156"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1000384"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mrfmmm.2006.09.003"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1217876"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.genom.7.080505.115630"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2010.04.005"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2010-11-8-r88"},{"issue":"1","key":"e_1_2_8_22_1","first-page":"70","article-title":"Rare loss\u2010of\u2010function mutations in ANGPTL family members contribute to plasma triglyceride levels in humans","volume":"119","author":"Romeo S","year":"2009","journal-title":"J Clin 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