{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T02:39:25Z","timestamp":1782787165785,"version":"3.54.5"},"reference-count":25,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2017,10,27]],"date-time":"2017-10-27T00:00:00Z","timestamp":1509062400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["N02\u2010HL\u201064278"],"award-info":[{"award-number":["N02\u2010HL\u201064278"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007878","name":"Diabetes Research Center","doi-asserted-by":"publisher","award":["DK063491"],"award-info":[{"award-number":["DK063491"]}],"id":[{"id":"10.13039\/100007878","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["MH095797"],"award-info":[{"award-number":["MH095797"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genetic Epidemiology"],"published-print":{"date-parts":[[2017,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Over the past few years, an increasing number of studies have identified rare variants that contribute to trait heritability. Due to the extreme rarity of some individual variants, gene\u2010based association tests have been proposed to aggregate the genetic variants within a gene, pathway, or specific genomic region as opposed to a one\u2010at\u2010a\u2010time single variant analysis. In addition, in longitudinal studies, statistical power to detect disease susceptibility rare variants can be improved through jointly testing repeatedly measured outcomes, which better describes the temporal development of the trait of interest. However, usual sandwich\/model\u2010based inference for sequencing studies with longitudinal outcomes and rare variants can produce deflated\/inflated type I error rate without further corrections. In this paper, we develop a group of tests for rare\u2010variant association based on outcomes with repeated measures. We propose new perturbation methods such that the type I error rate of the new tests is not only robust to misspecification of within\u2010subject correlation, but also significantly improved for variants with extreme rarity in a study with small or moderate sample size. Through extensive simulation studies, we illustrate that substantially higher power can be achieved by utilizing longitudinal outcomes and our proposed finite sample adjustment. We illustrate our methods using data from the Multi\u2010Ethnic Study of Atherosclerosis for exploring association of repeated measures of blood pressure with rare and common variants based on exome sequencing data on 6,361 individuals.<\/jats:p>","DOI":"10.1002\/gepi.22081","type":"journal-article","created":{"date-parts":[[2017,10,27]],"date-time":"2017-10-27T05:44:43Z","timestamp":1509083083000},"page":"801-810","source":"Crossref","is-referenced-by-count":4,"title":["Rare\u2010variant association tests in longitudinal studies, with an application to the Multi\u2010Ethnic Study of Atherosclerosis (MESA)"],"prefix":"10.1002","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8220-4183","authenticated-orcid":false,"given":"Zihuai","family":"He","sequence":"first","affiliation":[{"name":"Department of Biostatistics Columbia University  New York New York United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8097-3878","authenticated-orcid":false,"given":"Seunggeun","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biostatistics University of Michigan  Ann Arbor Michigan United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biostatistics University of Michigan  Ann Arbor Michigan United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer A.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Epidemiology University of Michigan  Ann Arbor Michigan United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuqing","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Harbor\u2010UCLA Medical Center  Torrance California United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter","family":"Palmas","sequence":"additional","affiliation":[{"name":"Department of Medicine Columbia University  New York New York United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon L.R.","family":"Kardia","sequence":"additional","affiliation":[{"name":"Department of Epidemiology University of Michigan  Ann Arbor Michigan United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iuliana","family":"Ionita\u2010Laza","sequence":"additional","affiliation":[{"name":"Department of Biostatistics Columbia University  New York New York United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhramar","family":"Mukherjee","sequence":"additional","affiliation":[{"name":"Department of Biostatistics University of Michigan  Ann Arbor Michigan United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,10,27]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwf113"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.0000044938.94050.E3"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.21689"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.21673"},{"key":"e_1_2_7_6_1","first-page":"66","volume-title":"Statistical methods for research workers","author":"Fisher R. 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