{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,22]],"date-time":"2025-02-22T00:44:53Z","timestamp":1740185093209,"version":"3.37.3"},"reference-count":32,"publisher":"Oxford University Press (OUP)","issue":"15","license":[{"start":{"date-parts":[[2017,3,11]],"date-time":"2017-03-11T00:00:00Z","timestamp":1489190400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/about_us\/legal\/notices"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Science Foundation of China","doi-asserted-by":"publisher","award":["81473035","31401124"],"award-info":[{"award-number":["81473035","31401124"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005847","name":"Health and Medical Research Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005847","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 GM031575"],"award-info":[{"award-number":["R01 GM031575"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 GM031575"],"award-info":[{"award-number":["R01 GM031575"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Motivation<\/jats:title>\n                  <jats:p>Increasing amounts of whole exome or genome sequencing data present the challenge of analysing rare variants with extremely small minor allele frequencies. Various statistical tests have been proposed, which are specifically configured to increase power for rare variants by conducting the test within a certain bin, such as a gene or a pathway. However, a gene may contain from several to thousands of markers, and not all of them are related to the phenotype. Combining functional and non-functional variants in an arbitrary genomic region could impair the testing power.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We propose a Zoom-Focus algorithm (ZFA) to locate the optimal testing region within a given genomic region. It can be applied as a wrapper function in existing rare variant association tests to increase testing power. The algorithm consists of two steps. In the first step, Zooming, a given genomic region is partitioned by an order of two, and the best partition is located. In the second step, Focusing, the boundaries of the zoomed region are refined. Simulation studies showed that ZFA substantially increased the statistical power of rare variants\u2019 tests, including the SKAT, SKAT-O, burden test and the W-test. The algorithm was applied on real exome sequencing data of hypertensive disorder, and identified biologically relevant genetic markers to metabolic disorders that were undetectable by a gene-based method. The proposed algorithm is an efficient and powerful tool to enhance the power of association study for whole exome or genome sequencing data.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Availability and Implementation<\/jats:title>\n                  <jats:p>The ZFA software is available at: http:\/\/www2.ccrb.cuhk.edu.hk\/statgene\/software.html<\/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\/btx130","type":"journal-article","created":{"date-parts":[[2017,3,9]],"date-time":"2017-03-09T13:14:14Z","timestamp":1489065254000},"page":"2330-2336","source":"Crossref","is-referenced-by-count":4,"title":["A Zoom-Focus algorithm (ZFA) to locate the optimal testing region for rare variant association tests"],"prefix":"10.1093","volume":"33","author":[{"given":"Maggie Haitian","family":"Wang","sequence":"first","affiliation":[{"name":"Division of Biostatistics and Centre for Clinical Research and Biostatistics, JC School of Public Health and Primary Care, The Chinese University of Hong Kong, Shatin, N.T, Hong Kong SAR"},{"name":"CUHK Shenzhen Research Institute, Shenzhen, China"}]},{"given":"Haoyi","family":"Weng","sequence":"additional","affiliation":[{"name":"Division of Biostatistics and Centre for Clinical Research and Biostatistics, JC School of Public Health and Primary Care, The Chinese University of Hong Kong, Shatin, N.T, Hong Kong SAR"},{"name":"CUHK Shenzhen Research Institute, Shenzhen, China"}]},{"given":"Rui","family":"Sun","sequence":"additional","affiliation":[{"name":"Division of Biostatistics and Centre for Clinical Research and Biostatistics, JC School of Public Health and Primary Care, The Chinese University of Hong Kong, Shatin, N.T, Hong Kong SAR"},{"name":"CUHK Shenzhen Research Institute, Shenzhen, China"}]},{"given":"Jack","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Biostatistics and Centre for Clinical Research and Biostatistics, JC School of Public Health and Primary Care, The Chinese University of Hong Kong, Shatin, N.T, Hong Kong SAR"},{"name":"CUHK Shenzhen Research Institute, Shenzhen, China"}]},{"given":"William Ka Kei","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong SAR"}]},{"given":"Ka Chun","family":"Chong","sequence":"additional","affiliation":[{"name":"Division of Biostatistics and Centre for Clinical Research and Biostatistics, JC School of Public Health and Primary Care, The Chinese University of Hong Kong, Shatin, N.T, Hong Kong SAR"},{"name":"CUHK Shenzhen Research Institute, Shenzhen, China"}]},{"given":"Benny Chung-Ying","family":"Zee","sequence":"additional","affiliation":[{"name":"Division of Biostatistics and Centre for Clinical Research and Biostatistics, JC School of Public Health and Primary Care, The Chinese University of Hong Kong, Shatin, N.T, Hong Kong SAR"},{"name":"CUHK Shenzhen Research Institute, Shenzhen, China"}]}],"member":"286","published-online":{"date-parts":[[2017,3,11]]},"reference":[{"key":"2023063012415504700_btx130-B1","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/nature11247","article-title":"An integrated encyclopedia of DNA elements in the human genome","volume":"489","year":"2012","journal-title":"Nature"},{"key":"2023063012415504700_btx130-B2","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1038\/nature09410","article-title":"Hundreds of variants clustered in genomic loci and biological pathways affect human height","volume":"467","author":"Allen","year":"2010","journal-title":"Nature"},{"key":"2023063012415504700_btx130-B3","doi-asserted-by":"crossref","first-page":"2119","DOI":"10.1001\/jama.2015.3595","article-title":"The precision medicine initiative: a new national effort","volume":"313","author":"Ashley","year":"2015","journal-title":"JAMA"},{"key":"2023063012415504700_btx130-B4","doi-asserted-by":"crossref","first-page":"16.","DOI":"10.1186\/s13073-015-0138-2","article-title":"Rare variant association studies: considerations, challenges and opportunities","volume":"7","author":"Auer","year":"2015","journal-title":"Genome Med"},{"key":"2023063012415504700_btx130-B5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13073-016-0265-4","article-title":"From genomic medicine to precision medicine: highlights of 2015","volume":"8","author":"Auffray","year":"2016","journal-title":"Genome Med"},{"key":"2023063012415504700_btx130-B6","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1038\/nature15393","article-title":"A global reference for human genetic variation","volume":"526","author":"Consortium","year":"2015","journal-title":"Nature"},{"key":"2023063012415504700_btx130-B7","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/529009a","article-title":"China embraces precision medicine on a massive scale","volume":"529","author":"Cyranoski","year":"2016","journal-title":"Nature"},{"key":"2023063012415504700_btx130-B8","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1161\/CIRCGENETICS.108.825224","article-title":"Association of novel genetic loci with circulating fibrinogen levels a genome-wide association study in 6 population-based cohorts","volume":"2","author":"Dehghan","year":"2009","journal-title":"Circ. Cardiovasc. Gene"},{"key":"2023063012415504700_btx130-B9","doi-asserted-by":"crossref","first-page":"9615","DOI":"10.1073\/pnas.170179197","article-title":"Scan statistics to scan markers for susceptibility genes","volume":"97","author":"Hoh","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023063012415504700_btx130-B10","doi-asserted-by":"crossref","first-page":"e1004729","DOI":"10.1371\/journal.pgen.1004729","article-title":"Identification of rare causal variants in sequence-based studies: methods and applications to VPS13B, a gene involved in cohen syndrome and autism","volume":"10","author":"Ionita-Laza","year":"2014","journal-title":"PLoS Genet"},{"key":"2023063012415504700_btx130-B11","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1073\/pnas.1309475110","article-title":"Scan statistic-based analysis of exome sequencing data identifies FAN1 at 15q13.3 as a susceptibility gene for schizophrenia and autism","volume":"111","author":"Ionita-Laza","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023063012415504700_btx130-B12","doi-asserted-by":"crossref","first-page":"2229","DOI":"10.1056\/NEJMsb1503104","article-title":"Precision medicine\u2014personalized, problematic, and promising","volume":"372","author":"Jameson","year":"2015","journal-title":"N. Engl. J. Med"},{"key":"2023063012415504700_btx130-B13","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1038\/ng.2892","article-title":"A general framework for estimating the relative pathogenicity of human genetic variants","volume":"46","author":"Kircher","year":"2014","journal-title":"Nat. Genet"},{"key":"2023063012415504700_btx130-B31","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1002\/gepi.20516","article-title":"Quality control and quality assurance in genotypic data for genome - wide association studies","volume":"34","author":"Laurie","year":"2010","journal-title":"Genetic epidemiology"},{"key":"2023063012415504700_btx130-B14","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.ajhg.2014.06.009","article-title":"Rare-variant association analysis: study designs and statistical tests","volume":"95","author":"Lee","year":"2014","journal-title":"Am. J. Hum. Genet"},{"key":"2023063012415504700_btx130-B15","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1093\/biostatistics\/kxs014","article-title":"Optimal tests for rare variant effects in sequencing association studies","volume":"13","author":"Lee","year":"2012","journal-title":"Biostatistics"},{"key":"2023063012415504700_btx130-B16","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.ajhg.2008.06.024","article-title":"Methods for detecting associations with rare variants for common diseases: application to analysis of sequence data","volume":"83","author":"Li","year":"2008","journal-title":"Am. J. Hum. Genet"},{"key":"2023063012415504700_btx130-B17","doi-asserted-by":"crossref","first-page":"e1001156.","DOI":"10.1371\/journal.pgen.1001156","article-title":"A novel adaptive method for the analysis of next-generation sequencing data to detect complex trait associations with rare variants due to gene main effects and interactions","volume":"6","author":"Liu","year":"2010","journal-title":"PLoS Genet"},{"key":"2023063012415504700_btx130-B18","doi-asserted-by":"crossref","first-page":"e1000384.","DOI":"10.1371\/journal.pgen.1000384","article-title":"A groupwise association test for rare mutations using a weighted sum statistic","volume":"5","author":"Madsen","year":"2009","journal-title":"PLoS Genet"},{"key":"2023063012415504700_btx130-B19","doi-asserted-by":"crossref","first-page":"1190","DOI":"10.1126\/science.1222794","article-title":"Systematic localization of common disease-associated variation in regulatory DNA","volume":"337","author":"Maurano","year":"2012","journal-title":"Science"},{"key":"2023063012415504700_btx130-B20","doi-asserted-by":"crossref","first-page":"e1001322","DOI":"10.1371\/journal.pgen.1001322","article-title":"Testing for an unusual distribution of rare variants","volume":"7","author":"Neale","year":"2011","journal-title":"PLoS Genet"},{"key":"2023063012415504700_btx130-B21","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1001\/jama.299.11.1335","article-title":"How to interpret a genome-wide association study","volume":"299","author":"Pearson","year":"2008","journal-title":"JAMA"},{"key":"2023063012415504700_btx130-B22","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1038\/nrg2765","article-title":"Insulators and promoters: closer than we think","volume":"11","author":"Raab","year":"2010","journal-title":"Nat. Rev. Genet"},{"key":"2023063012415504700_btx130-B23","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1038\/ng1119","article-title":"Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans","volume":"33","author":"Robertson","year":"2003","journal-title":"Nat. Genet"},{"key":"2023063012415504700_btx130-B24","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/s12863-015-0316-7","article-title":"Progress in methods for rare variant association","volume":"17","author":"Santorico","year":"2016","journal-title":"BMC Genet"},{"key":"2023063012415504700_btx130-B25","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1002\/gepi.21649","article-title":"Detecting association of rare and common variants by testing an optimally weighted combination of variants","volume":"36","author":"Sha","year":"2012","journal-title":"Genet. Epidemiol"},{"key":"2023063012415504700_btx130-B32","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1038\/nrg3706","article-title":"Statistical power and significance testing in large-scale genetic studies","volume":"15","author":"Sham","year":"2014","journal-title":"Nat. Rev. Genet"},{"key":"2023063012415504700_btx130-B26","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1002\/gepi.22000","article-title":"AW-test collapsing method for rare-variant association testing in exome sequencing data","volume":"40","author":"Sun","year":"2016","journal-title":"Genet. Epidemiol"},{"key":"2023063012415504700_btx130-B27","doi-asserted-by":"crossref","first-page":"e115","DOI":"10.1093\/nar\/gkw347","article-title":"A fast and powerful W-test for pairwise epistasis testing","volume":"44","author":"Wang","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"2023063012415504700_btx130-B28","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.1038\/ng.2797","article-title":"Discovery and refinement of loci associated with lipid levels","volume":"45","author":"Willer","year":"2013","journal-title":"Nat. Genet"},{"key":"2023063012415504700_btx130-B29","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.ajhg.2011.05.029","article-title":"Rare-variant association testing for sequencing data with the sequence Kernel association test","volume":"89","author":"Wu","year":"2011","journal-title":"Am. J. Hum. Genet"},{"key":"2023063012415504700_btx130-B30","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1002\/humu.21194","article-title":"Inferring the functional effects of mutation through clusters of mutations in homologous proteins","volume":"31","author":"Yue","year":"2010","journal-title":"Hum. Mut"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/33\/15\/2330\/50756380\/bioinformatics_33_15_2330.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/33\/15\/2330\/50756380\/bioinformatics_33_15_2330.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,30]],"date-time":"2023-06-30T12:42:28Z","timestamp":1688128948000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/33\/15\/2330\/3065931"}},"subtitle":[],"editor":[{"given":"Oliver","family":"Stegle","sequence":"additional","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2017,3,11]]},"references-count":32,"journal-issue":{"issue":"15","published-print":{"date-parts":[[2017,8,1]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btx130","relation":{},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"type":"print","value":"1367-4803"},{"type":"electronic","value":"1367-4811"}],"subject":[],"published-other":{"date-parts":[[2017,8,1]]},"published":{"date-parts":[[2017,3,11]]}}}