{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:22:25Z","timestamp":1785543745790,"version":"3.56.0"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"13","license":[{"start":{"date-parts":[[2017,2,17]],"date-time":"2017-02-17T00:00:00Z","timestamp":1487289600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/about_us\/legal\/notices"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Motivation<\/jats:title>\n                  <jats:p>Second generation sequencing technologies are being increasingly used for genetic association studies, where the main research interest is to identify sets of genetic variants that contribute to various phenotypes. The phenotype can be univariate disease status, multivariate responses and even high-dimensional outcomes. Considering the genotype and phenotype as two complex objects, this also poses a general statistical problem of testing association between complex objects.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We here proposed a similarity-based test, generalized similarity U (GSU), that can test the association between complex objects. We first studied the theoretical properties of the test in a general setting and then focused on the application of the test to sequencing association studies. Based on theoretical analysis, we proposed to use Laplacian Kernel-based similarity for GSU to boost power and enhance robustness. Through simulation, we found that GSU did have advantages over existing methods in terms of power and robustness. We further performed a whole genome sequencing (WGS) scan for Alzherimer\u2019s disease neuroimaging initiative data, identifying three genes, APOE, APOC1 and TOMM40, associated with imaging phenotype.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Availability and Implementation<\/jats:title>\n                  <jats:p>We developed a C\u2009++ package for analysis of WGS data using GSU. The source codes can be downloaded at https:\/\/github.com\/changshuaiwei\/gsu.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Supplementary information<\/jats:title>\n                  <jats:p>Supplementary data are available at Bioinformatics online.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/bioinformatics\/btx103","type":"journal-article","created":{"date-parts":[[2017,2,16]],"date-time":"2017-02-16T21:28:08Z","timestamp":1487280488000},"page":"1963-1971","source":"Crossref","is-referenced-by-count":12,"title":["A generalized association test based on <i>U<\/i> statistics"],"prefix":"10.1093","volume":"33","author":[{"given":"Changshuai","family":"Wei","sequence":"first","affiliation":[{"name":"Department of Biostatistics and Epidemiology, University of North Texas Health Science Center, Fort Worth, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2017,2,17]]},"reference":[{"key":"2023020206012332900_btx103-B1","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1038\/nature09534","article-title":"A map of human genome variation from population-scale sequencing","volume":"467","author":"Abecasis","year":"2010","journal-title":"Nature"},{"key":"2023020206012332900_btx103-B2","doi-asserted-by":"crossref","DOI":"10.1007\/978-1-4419-9096-9","volume-title":"Reproducing Kernel Hilbert Spaces in Probability and Statistics","author":"Berlinet","year":"2004"},{"key":"2023020206012332900_btx103-B3","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1038\/nrg2779","article-title":"Uncovering the roles of rare variants in common disease through whole-genome sequencing","volume":"11","author":"Cirulli","year":"2010","journal-title":"Nat. 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