{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T09:08:54Z","timestamp":1781773734959,"version":"3.54.5"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"18","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,9,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Motivation: Prediction and prioritization of human non-coding regulatory variants is critical for understanding the regulatory mechanisms of disease pathogenesis and promoting personalized medicine. Existing tools utilize functional genomics data and evolutionary information to evaluate the pathogenicity or regulatory functions of non-coding variants. However, different algorithms lead to inconsistent and even conflicting predictions. Combining multiple methods may increase accuracy in regulatory variant prediction.<\/jats:p>\n               <jats:p>Results: Here, we compiled an integrative resource for predictions from eight different tools on functional annotation of non-coding variants. We further developed a composite strategy to integrate multiple predictions and computed the composite likelihood of a given variant being regulatory variant. Benchmarked by multiple independent causal variants datasets, we demonstrated that our composite model significantly improves the prediction performance.<\/jats:p>\n               <jats:p>Availability and Implementation: We implemented our model and scoring procedure as a tool, named PRVCS, which is freely available to academic and non-profit usage at http:\/\/jjwanglab.org\/PRVCS.<\/jats:p>\n               <jats:p>Contact: \u00a0wang.junwen@mayo.edu, jliu@stat.harvard.edu, or limx54@gmail.com<\/jats:p>\n               <jats:p>Supplementary information: \u00a0Supplementary data are available at Bioinformatics online.<\/jats:p>","DOI":"10.1093\/bioinformatics\/btw288","type":"journal-article","created":{"date-parts":[[2016,6,7]],"date-time":"2016-06-07T02:23:25Z","timestamp":1465266205000},"page":"2729-2736","source":"Crossref","is-referenced-by-count":42,"title":["Predicting regulatory variants with composite statistic"],"prefix":"10.1093","volume":"32","author":[{"given":"Mulin Jun","family":"Li","sequence":"first","affiliation":[{"name":"1 Department of Statistics, Harvard University, Cambridge, Boston, 02138-2901\u2009MA, USA,"},{"name":"2 Centre for Genomic Sciences,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhicheng","family":"Pan","sequence":"additional","affiliation":[{"name":"2 Centre for Genomic Sciences,"},{"name":"5 Department of Psychiatry,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zipeng","family":"Liu","sequence":"additional","affiliation":[{"name":"2 Centre for Genomic Sciences,"},{"name":"4 Department of Anaesthesiology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiexing","family":"Wu","sequence":"additional","affiliation":[{"name":"1 Department of Statistics, Harvard University, Cambridge, Boston, 02138-2901\u2009MA, USA,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panwen","family":"Wang","sequence":"additional","affiliation":[{"name":"2 Centre for Genomic Sciences,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Zhu","sequence":"additional","affiliation":[{"name":"2 Centre for Genomic Sciences,"},{"name":"3 School of Biomedical Sciences,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Xu","sequence":"additional","affiliation":[{"name":"2 Centre for Genomic Sciences,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengyuan","family":"Xia","sequence":"additional","affiliation":[{"name":"4 Department of Anaesthesiology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pak Chung","family":"Sham","sequence":"additional","affiliation":[{"name":"2 Centre for Genomic Sciences,"},{"name":"5 Department of Psychiatry,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Pierre A.","family":"Kocher","sequence":"additional","affiliation":[{"name":"8 Department of Health Sciences Research, Center for Individualized Medicine, Mayo Clinic, Scottsdale, AZ 85259, USA and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miaoxin","family":"Li","sequence":"additional","affiliation":[{"name":"2 Centre for Genomic Sciences,"},{"name":"5 Department of Psychiatry,"},{"name":"6 Centre for Reproduction, Development and Growth, LKS Faculty of Medicine, the University of Hong Kong, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun S.","family":"Liu","sequence":"additional","affiliation":[{"name":"1 Department of Statistics, Harvard University, Cambridge, Boston, 02138-2901\u2009MA, USA,"},{"name":"7 Center for Statistical Science, Tsinghua University, Beijing 100084, China and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junwen","family":"Wang","sequence":"additional","affiliation":[{"name":"2 Centre for Genomic Sciences,"},{"name":"8 Department of Health Sciences Research, Center for Individualized Medicine, Mayo Clinic, Scottsdale, AZ 85259, USA and"},{"name":"9 Department of Biomedical Informatics, Arizona State University, Scottsdale, AZ 85259, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2016,6,6]]},"reference":[{"key":"2023020113391956200_btw288-B1","doi-asserted-by":"crossref","first-page":"e1003649.","DOI":"10.1371\/journal.pgen.1003649","article-title":"Integrative modeling of eQTLs and cis-regulatory elements suggests mechanisms underlying cell type specificity of eQTLs","volume":"9","author":"Brown","year":"2013","journal-title":"PLoS Genet"},{"key":"2023020113391956200_btw288-B2","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1002\/humu.22375","article-title":"Large numbers of genetic variants considered to be pathogenic are common in asymptomatic individuals","volume":"34","author":"Cassa","year":"2013","journal-title":"Human Mut"},{"key":"2023020113391956200_btw288-B3","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1111\/iji.12236","article-title":"The dichotomy between disease phenotype databases and the implications for understanding complex diseases involving the major histocompatibility complex","volume":"42","author":"Clark","year":"2015","journal-title":"Int. J. Immunogenet"},{"key":"2023020113391956200_btw288-B4","doi-asserted-by":"crossref","first-page":"D662","DOI":"10.1093\/nar\/gku1010","article-title":"Ensembl 2015","volume":"43","author":"Cunningham","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"2023020113391956200_btw288-B5","doi-asserted-by":"crossref","first-page":"2156","DOI":"10.1093\/bioinformatics\/btr330","article-title":"The variant call format and VCFtools","volume":"27","author":"Danecek","year":"2011","journal-title":"Bioinformatics"},{"key":"2023020113391956200_btw288-B6","doi-asserted-by":"crossref","first-page":"e1001025","DOI":"10.1371\/journal.pcbi.1001025","article-title":"Identifying a high fraction of the human genome to be under selective constraint using GERP\u2009++","volume":"6","author":"Davydov","year":"2010","journal-title":"PLoS Comput. Biol"},{"key":"2023020113391956200_btw288-B7","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1038\/nature10808","article-title":"DNase I sensitivity QTLs are a major determinant of human expression variation","volume":"482","author":"Degner","year":"2012","journal-title":"Nature"},{"key":"2023020113391956200_btw288-B8","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.1093\/hmg\/ddu733","article-title":"Comparison and integration of deleteriousness prediction methods for nonsynonymous SNVs in whole exome sequencing studies","volume":"24","author":"Dong","year":"2015","journal-title":"Hum. Mol. Genet"},{"key":"2023020113391956200_btw288-B9","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/nature13835","article-title":"Genetic and epigenetic fine mapping of causal autoimmune disease variants","volume":"518","author":"Farh","year":"2015","journal-title":"Nature"},{"key":"2023020113391956200_btw288-B10","doi-asserted-by":"crossref","first-page":"D805","DOI":"10.1093\/nar\/gku1075","article-title":"COSMIC: exploring the world\u2019s knowledge of somatic mutations in human cancer","volume":"43","author":"Forbes","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"2023020113391956200_btw288-B11","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1186\/s13059-014-0480-5","article-title":"FunSeq2: a framework for prioritizing noncoding regulatory variants in cancer","volume":"15","author":"Fu","year":"2014","journal-title":"Genome Biol"},{"key":"2023020113391956200_btw288-B12","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/nature11632","article-title":"An integrated map of genetic variation from 1,092 human genomes","volume":"491","author":"Genomes Project,C","year":"2012","journal-title":"Nature"},{"key":"2023020113391956200_btw288-B13","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1016\/j.ajhg.2011.03.004","article-title":"Improving the assessment of the outcome of nonsynonymous SNVs with a consensus deleteriousness score, Condel","volume":"88","author":"Gonzalez-Perez","year":"2011","journal-title":"Am. J. Hum. Genet"},{"key":"2023020113391956200_btw288-B14","doi-asserted-by":"crossref","first-page":"D107","DOI":"10.1093\/nar\/gkm967","article-title":"ORegAnno: an open-access community-driven resource for regulatory annotation","volume":"36","author":"Griffith","year":"2008","journal-title":"Nucleic Acids Res"},{"key":"2023020113391956200_btw288-B15","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1126\/science.1183863","article-title":"A composite of multiple signals distinguishes causal variants in regions of positive selection","volume":"327","author":"Grossman","year":"2010","journal-title":"Science"},{"key":"2023020113391956200_btw288-B16","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1038\/ng.3477","article-title":"A spectral approach integrating functional genomic annotations for coding and noncoding variants","volume":"48","author":"Ionita-Laza","year":"2016","journal-title":"Nat. Genet"},{"key":"2023020113391956200_btw288-B17","doi-asserted-by":"crossref","first-page":"6131","DOI":"10.1073\/pnas.1318948111","article-title":"Defining functional DNA elements in the human genome","volume":"111","author":"Kellis","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023020113391956200_btw288-B18","doi-asserted-by":"crossref","first-page":"1235587","DOI":"10.1126\/science.1235587","article-title":"Integrative annotation of variants from 1092 humans: application to cancer genomics","volume":"342","author":"Khurana","year":"2013","journal-title":"Science"},{"key":"2023020113391956200_btw288-B19","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1038\/ng.3364","article-title":"Running spell-check to identify regulatory variants","volume":"47","author":"Kircher","year":"2015","journal-title":"Nat. Genet"},{"key":"2023020113391956200_btw288-B20","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":"2023020113391956200_btw288-B21","doi-asserted-by":"crossref","first-page":"D980","DOI":"10.1093\/nar\/gkt1113","article-title":"ClinVar: public archive of relationships among sequence variation and human phenotype","volume":"42","author":"Landrum","year":"2014","journal-title":"Nucleic Acids Res"},{"key":"2023020113391956200_btw288-B22","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1038\/ng.3331","article-title":"A method to predict the impact of regulatory variants from DNA sequence","volume":"47","author":"Lee","year":"2015","journal-title":"Nat. Genet"},{"key":"2023020113391956200_btw288-B23","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1093\/bioinformatics\/btq671","article-title":"Tabix: fast retrieval of sequence features from generic TAB-delimited files","volume":"27","author":"Li","year":"2011","journal-title":"Bioinformatics"},{"key":"2023020113391956200_btw288-B24","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1002\/humu.22766","article-title":"wKGGSeq: A comprehensive strategy-based and disease-targeted online framework to facilitate exome sequencing studies of inherited disorders","volume":"36","author":"Li","year":"2015","journal-title":"Hum. Mut"},{"key":"2023020113391956200_btw288-B25","doi-asserted-by":"crossref","first-page":"D869","DOI":"10.1093\/nar\/gkv1317","article-title":"GWASdb v2: an update database for human genetic variants identified by genome-wide association studies","volume":"44","author":"Li","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"2023020113391956200_btw288-B26","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.ymeth.2014.10.003","article-title":"Current trend of annotating single nucleotide variation in humans - a case study on SNVrap","volume":"79-80","author":"Li","year":"2015","journal-title":"Methods"},{"key":"2023020113391956200_btw288-B27","doi-asserted-by":"crossref","first-page":"W150","DOI":"10.1093\/nar\/gkt456","article-title":"GWAS3D: Detecting human regulatory variants by integrative analysis of genome-wide associations, chromosome interactions and histone modifications","volume":"41","author":"Li","year":"2013","journal-title":"Nucleic Acids Res"},{"key":"2023020113391956200_btw288-B28","doi-asserted-by":"crossref","first-page":"e1003143","DOI":"10.1371\/journal.pgen.1003143","article-title":"Predicting mendelian disease-causing non-synonymous single nucleotide variants in exome sequencing studies","volume":"9","author":"Li","year":"2013","journal-title":"PLoS Genet"},{"key":"2023020113391956200_btw288-B29","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1159\/000334984","article-title":"A combined functional annotation score for non-synonymous variants","volume":"73","author":"Lopes","year":"2012","journal-title":"Hum. Hered"},{"key":"2023020113391956200_btw288-B30","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1038\/ng.3432","article-title":"Large-scale identification of sequence variants influencing human transcription factor occupancy in vivo","volume":"47","author":"Maurano","year":"2015","journal-title":"Nat. Genet"},{"key":"2023020113391956200_btw288-B31","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1038\/ng.3332","article-title":"Recurrent somatic mutations in regulatory regions of human cancer genomes","volume":"47","author":"Melton","year":"2015","journal-title":"Nat. Genet"},{"key":"2023020113391956200_btw288-B32","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/nbt.2136","article-title":"Massively parallel functional dissection of mammalian enhancers in vivo","volume":"30","author":"Patwardhan","year":"2012","journal-title":"Nat. Biotechnol"},{"key":"2023020113391956200_btw288-B33","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1093\/bioinformatics\/btu703","article-title":"DANN: a deep learning approach for annotating the pathogenicity of genetic variants","volume":"31","author":"Quang","year":"2015","journal-title":"Bioinformatics"},{"key":"2023020113391956200_btw288-B34","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1038\/nmeth.2832","article-title":"Functional annotation of noncoding sequence variants","volume":"11","author":"Ritchie","year":"2014","journal-title":"Nat. Methods"},{"key":"2023020113391956200_btw288-B35","first-page":"79","article-title":"SuRFing the genomics wave: an R package for prioritising SNPs by functionality","volume":"6","author":"Ryan","year":"2014","journal-title":"Genome Med"},{"key":"2023020113391956200_btw288-B36","doi-asserted-by":"crossref","first-page":"1536","DOI":"10.1093\/bioinformatics\/btv009","article-title":"An integrative approach to predicting the functional effects of non-coding and coding sequence variation","volume":"31","author":"Shihab","year":"2015","journal-title":"Bioinformatics"},{"key":"2023020113391956200_btw288-B37","doi-asserted-by":"crossref","first-page":"1034","DOI":"10.1101\/gr.3715005","article-title":"Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes","volume":"15","author":"Siepel","year":"2005","journal-title":"Genome Res"},{"key":"2023020113391956200_btw288-B38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00439-013-1358-4","article-title":"The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine","volume":"133","author":"Stenson","year":"2014","journal-title":"Hum. Genet"},{"key":"2023020113391956200_btw288-B39","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1126\/science.1243490","article-title":"Exonic transcription factor binding directs codon choice and affects protein evolution","volume":"342","author":"Stergachis","year":"2013","journal-title":"Science"},{"key":"2023020113391956200_btw288-B40","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.1101\/gr.190090.115","article-title":"Massively parallel quantification of the regulatory effects of noncoding genetic variation in a human cohort","volume":"25","author":"Vockley","year":"2015","journal-title":"Genome Res"},{"key":"2023020113391956200_btw288-B41","doi-asserted-by":"crossref","first-page":"e164.","DOI":"10.1093\/nar\/gkq603","article-title":"ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data","volume":"38","author":"Wang","year":"2010","journal-title":"Nucleic Acids Res"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/32\/18\/2729\/49021034\/bioinformatics_32_18_2729.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/32\/18\/2729\/49021034\/bioinformatics_32_18_2729.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,1]],"date-time":"2023-02-01T23:44:22Z","timestamp":1675295062000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/32\/18\/2729\/1743328"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,6,6]]},"references-count":41,"journal-issue":{"issue":"18","published-print":{"date-parts":[[2016,9,15]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btw288","relation":{},"ISSN":["1367-4811","1367-4803"],"issn-type":[{"value":"1367-4811","type":"electronic"},{"value":"1367-4803","type":"print"}],"subject":[],"published-other":{"date-parts":[[2016,9,15]]},"published":{"date-parts":[[2016,6,6]]}}}