{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,22]],"date-time":"2025-02-22T00:45:50Z","timestamp":1740185150837,"version":"3.37.3"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"20","license":[{"start":{"date-parts":[[2019,3,23]],"date-time":"2019-03-23T00:00:00Z","timestamp":1553299200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"National Institute of Dental and Craniofacial Research Interdisciplinary Training in Systems and Developmental Biology and Birth Defects","award":["T32HD075735"],"award-info":[{"award-number":["T32HD075735"]}]},{"name":"Mount Sinai Medical Scientist Training Program"},{"name":"Pediatric Cardiac Genomics Consortium"},{"name":"PCGC"},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["UM1HL128711","UM1HL098162","UM1HL098147","UM1HL098123","UM1HL128761","U01HL131003"],"award-info":[{"award-number":["UM1HL128711","UM1HL098162","UM1HL098147","UM1HL098123","UM1HL128761","U01HL131003"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013114","name":"Broad Institute","doi-asserted-by":"publisher","award":["U24 HD090743-01"],"award-info":[{"award-number":["U24 HD090743-01"]}],"id":[{"id":"10.13039\/100013114","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,10,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Motivation<\/jats:title>\n                  <jats:p>Non-coding rare variants (RVs) may contribute to Mendelian disorders but have been challenging to study due to small sample sizes, genetic heterogeneity and uncertainty about relevant non-coding features. Previous studies identified RVs associated with expression outliers, but varying outlier definitions were employed and no comprehensive open-source software was developed.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We developed Outlier-RV Enrichment (ORE) to identify biologically-meaningful non-coding RVs. We implemented ORE combining whole-genome sequencing and cardiac RNAseq from congenital heart defect patients from the Pediatric Cardiac Genomics Consortium and deceased adults from Genotype-Tissue Expression. Use of rank-based outliers maximized sensitivity while a most extreme outlier approach maximized specificity. Rarer variants had stronger associations, suggesting they are under negative selective pressure and providing a basis for investigating their contribution to Mendelian disorders.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Availability and implementation<\/jats:title>\n                  <jats:p>ORE, source code, and documentation are available at https:\/\/pypi.python.org\/pypi\/ore under the MIT license.<\/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\/btz202","type":"journal-article","created":{"date-parts":[[2019,3,20]],"date-time":"2019-03-20T20:23:04Z","timestamp":1553113384000},"page":"3906-3912","source":"Crossref","is-referenced-by-count":7,"title":["ORE identifies extreme expression effects enriched for rare variants"],"prefix":"10.1093","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3429-9621","authenticated-orcid":false,"given":"F","family":"Richter","sequence":"first","affiliation":[{"name":"Graduate School of Biomedical Sciences"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G E","family":"Hoffman","sequence":"additional","affiliation":[{"name":"Icahn Institute for Genomics and Multiscale Biology"},{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai , New York, NY, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"K B","family":"Manheimer","sequence":"additional","affiliation":[{"name":"Sema4, A Mount Sinai Venture , Stamford, CT, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"N","family":"Patel","sequence":"additional","affiliation":[{"name":"Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai , New York, NY, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A J","family":"Sharp","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai , New York, NY, USA"},{"name":"Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai , New York, NY, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D","family":"McKean","sequence":"additional","affiliation":[{"name":"Department of Genetics, Harvard Medical School , Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S U","family":"Morton","sequence":"additional","affiliation":[{"name":"Department of Genetics, Harvard Medical School , Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S","family":"DePalma","sequence":"additional","affiliation":[{"name":"Department of Genetics, Harvard Medical School , Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J","family":"Gorham","sequence":"additional","affiliation":[{"name":"Department of Genetics, Harvard Medical School , Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A","family":"Kitaygorodksy","sequence":"additional","affiliation":[{"name":"Department of Systems Biology, Columbia University , New York, NY, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"suffix":"Jr","given":"G A","family":"Porter","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Rochester Medical Center , Rochester, NY, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A","family":"Giardini","sequence":"additional","affiliation":[{"name":"Cardiorespiratory Unit, Great Ormond Street Hospital and University College London , London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Y","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Systems Biology, Columbia University , New York, NY, USA"},{"name":"Department of Biomedical Informatics, Columbia University , New York, NY, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"W K","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Medicine, Columbia University , New York, NY, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J G","family":"Seidman","sequence":"additional","affiliation":[{"name":"Department of Genetics, Harvard Medical School , Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C E","family":"Seidman","sequence":"additional","affiliation":[{"name":"Department of Genetics, Harvard Medical School , Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"E E","family":"Schadt","sequence":"additional","affiliation":[{"name":"Icahn Institute for Genomics and Multiscale Biology"},{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai , New York, NY, USA"},{"name":"Sema4, A Mount Sinai Venture , Stamford, CT, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B D","family":"Gelb","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai , New York, NY, USA"},{"name":"Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai , New York, NY, USA"},{"name":"Department of Pediatrics, Icahn School of Medicine at Mount Sinai , New York, NY, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2019,3,23]]},"reference":[{"key":"2023013108190024300_btz202-B1","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1101\/gr.187101","article-title":"Segmental duplications: organization and impact within the current human genome project assembly","volume":"11","author":"Bailey","year":"2001","journal-title":"Genome Res"},{"key":"2023013108190024300_btz202-B2","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1016\/j.ajhg.2018.10.025","article-title":"OUTRIDER: a statistical method for detecting aberrantly expressed genes in RNA sequencing data","volume":"103","author":"Brechtmann","year":"2018","journal-title":"Am. J. Hum. Genet"},{"key":"2023013108190024300_btz202-B3","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1089\/bio.2015.0032","article-title":"A novel approach to high-quality postmortem tissue procurement: the GTEx project","volume":"13","author":"Carithers","year":"2015","journal-title":"Biopreserv. Biobank"},{"key":"2023013108190024300_btz202-B4","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1038\/ng.3834","article-title":"The impact of structural variation on human gene expression","volume":"49","author":"Chiang","year":"2017","journal-title":"Nat. Genet"},{"key":"2023013108190024300_btz202-B5","doi-asserted-by":"crossref","first-page":"e0121263.","DOI":"10.1371\/journal.pone.0121263","article-title":"Elucidating the foundations of statistical inference with 2 \u00d7 2 tables","volume":"10","author":"Choi","year":"2015","journal-title":"PLoS One"},{"key":"2023013108190024300_btz202-B6","doi-asserted-by":"crossref","first-page":"eaal5209.","DOI":"10.1126\/scitranslmed.aal5209","article-title":"Improving genetic diagnosis in Mendelian disease with transcriptome sequencing","volume":"9","author":"Cummings","year":"2017","journal-title":"Sci. Transl. Med"},{"key":"2023013108190024300_btz202-B7","doi-asserted-by":"crossref","first-page":"3423","DOI":"10.1093\/bioinformatics\/btr539","article-title":"Pybedtools: a flexible Python library for manipulating genomic datasets and annotations","volume":"27","author":"Dale","year":"2011","journal-title":"Bioinformatics"},{"key":"2023013108190024300_btz202-B8","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":"2023013108190024300_btz202-B9","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1038\/ng.806","article-title":"A framework for variation discovery and genotyping using next-generation DNA sequencing data","volume":"43","author":"DePristo","year":"2011","journal-title":"Nat. Genet"},{"key":"2023013108190024300_btz202-B10","doi-asserted-by":"crossref","first-page":"12923.","DOI":"10.1038\/ncomms12923","article-title":"Genome-wide compendium and functional assessment of in vivo heart enhancers","volume":"7","author":"Dickel","year":"2016","journal-title":"Nat. Commun"},{"key":"2023013108190024300_btz202-B11","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1161\/CIRCRESAHA.111.300297","article-title":"The Congenital Heart Disease Genetic Network Study: rationale, design, and early results","volume":"112","author":"Gelb","year":"2013","journal-title":"Circ. Res"},{"key":"2023013108190024300_btz202-B12","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1038\/nrg3118","article-title":"Rare and common variants: twenty arguments","volume":"13","author":"Gibson","year":"2012","journal-title":"Nat. Rev. Genet"},{"key":"2023013108190024300_btz202-B13","doi-asserted-by":"crossref","first-page":"E4901","DOI":"10.1073\/pnas.1508425112","article-title":"Plasma metabolomic profiles enhance precision medicine for volunteers of normal health","volume":"112","author":"Guo","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023013108190024300_btz202-B14","doi-asserted-by":"crossref","first-page":"15824.","DOI":"10.1038\/ncomms15824","article-title":"Genetic diagnosis of Mendelian disorders via RNA sequencing","volume":"8","author":"Kremer","year":"2017","journal-title":"Nat. Commun"},{"key":"2023013108190024300_btz202-B15","doi-asserted-by":"crossref","first-page":"R29.","DOI":"10.1186\/gb-2014-15-2-r29","article-title":"voom: precision weights unlock linear model analysis tools for RNA-seq read counts","volume":"15","author":"Law","year":"2014","journal-title":"Genome Biol"},{"key":"2023013108190024300_btz202-B16","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/nature19057","article-title":"Analysis of protein-coding genetic variation in 60, 706 humans","volume":"536","author":"Lek","year":"2016","journal-title":"Nature"},{"key":"2023013108190024300_btz202-B17","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":"2023013108190024300_btz202-B18","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","article-title":"The Sequence Alignment\/Map format and SAMtools","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"2023013108190024300_btz202-B19","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","article-title":"Fast and accurate short read alignment with Burrows-Wheeler transform","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"2023013108190024300_btz202-B20","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1038\/nature24267","article-title":"The impact of rare variation on gene expression across tissues","volume":"550","author":"Li","year":"2017","journal-title":"Nature"},{"key":"2023013108190024300_btz202-B21","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.ajhg.2014.08.004","article-title":"Transcriptome sequencing of a large human family identifies the impact of rare noncoding variants","volume":"95","author":"Li","year":"2014","journal-title":"Am. J. Hum. Genet"},{"key":"2023013108190024300_btz202-B22","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1093\/bioinformatics\/btt656","article-title":"featureCounts: an efficient general purpose program for assigning sequence reads to genomic features","volume":"30","author":"Liao","year":"2014","journal-title":"Bioinformatics"},{"key":"2023013108190024300_btz202-B23","doi-asserted-by":"crossref","first-page":"e108.","DOI":"10.1093\/nar\/gkt214","article-title":"The Subread aligner: fast, accurate and scalable read mapping by seed-and-vote","volume":"41","author":"Liao","year":"2013","journal-title":"Nucleic Acids Res"},{"key":"2023013108190024300_btz202-B24","doi-asserted-by":"crossref","first-page":"12824","DOI":"10.1038\/ncomms12824","article-title":"Loss of RNA expression and allele-specific expression associated with congenital heart disease","volume":"7","author":"McKean","year":"2016","journal-title":"Nat. Commun"},{"key":"2023013108190024300_btz202-B25","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1101\/gr.107524.110","article-title":"The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data","volume":"20","author":"McKenna","year":"2010","journal-title":"Genome Res"},{"key":"2023013108190024300_btz202-B26","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1007\/s00439-015-1631-9","article-title":"Clinical sequencing: is WGS the better WES?","volume":"135","author":"Meienberg","year":"2016","journal-title":"Hum. Genet"},{"key":"2023013108190024300_btz202-B27","doi-asserted-by":"crossref","first-page":"e1002144.","DOI":"10.1371\/journal.pgen.1002144","article-title":"Rare and common regulatory variation in population-scale sequenced human genomes","volume":"7","author":"Montgomery","year":"2011","journal-title":"PLoS Genet"},{"key":"2023013108190024300_btz202-B28","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.1093\/bioinformatics\/btv722","article-title":"Fast and efficient QTL mapper for thousands of molecular phenotypes","volume":"32","author":"Ongen","year":"2016","journal-title":"Bioinformatics"},{"key":"2023013108190024300_btz202-B29","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1038\/nature25461","article-title":"Enhancer redundancy provides phenotypic robustness in mammalian development","volume":"554","author":"Osterwalder","year":"2018","journal-title":"Nature"},{"key":"2023013108190024300_btz202-B30","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1038\/ng.3840","article-title":"Population- and individual-specific regulatory variation in Sardinia","volume":"49","author":"Pala","year":"2017","journal-title":"Nat. Genet"},{"key":"2023013108190024300_btz202-B31","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1093\/bioinformatics\/btq033","article-title":"BEDTools: a flexible suite of utilities for comparing genomic features","volume":"26","author":"Quinlan","year":"2010","journal-title":"Bioinformatics"},{"key":"2023013108190024300_btz202-B32","doi-asserted-by":"crossref","first-page":"R25.","DOI":"10.1186\/gb-2010-11-3-r25","article-title":"A scaling normalization method for differential expression analysis of RNA-seq data","volume":"11","author":"Robinson","year":"2010","journal-title":"Genome Biol"},{"key":"2023013108190024300_btz202-B33","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1038\/nature01434","article-title":"Genetics of gene expression surveyed in maize, mouse and man","volume":"422","author":"Schadt","year":"2003","journal-title":"Nature"},{"key":"2023013108190024300_btz202-B34","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.ajhg.2017.06.001","article-title":"Integrative genetic and epigenetic analysis uncovers regulatory mechanisms of autoimmune disease","volume":"101","author":"Shooshtari","year":"2017","journal-title":"Am. J. Hum. Genet."},{"key":"2023013108190024300_btz202-B35","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1038\/nature25983","article-title":"De novo mutations in regulatory elements in neurodevelopmental disorders","volume":"555","author":"Short","year":"2018","journal-title":"Nature."},{"key":"2023013108190024300_btz202-B36","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1038\/nprot.2011.457","article-title":"Using probabilistic estimation of expression residuals (PEER) to obtain increased power and interpretability of gene expression analyses","volume":"7","author":"Stegle","year":"2012","journal-title":"Nat. Protoc"},{"key":"2023013108190024300_btz202-B37","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/nature11232","article-title":"The accessible chromatin landscape of the human genome","volume":"489","author":"Thurman","year":"2012","journal-title":"Nature"},{"volume-title":"Current Protocols in Bioinformatics","year":"2002","author":"Van der Auwera","key":"2023013108190024300_btz202-B38"},{"key":"2023013108190024300_btz202-B39","doi-asserted-by":"crossref","first-page":"1798","DOI":"10.1101\/gr.139105.112","article-title":"Sequence features and chromatin structure around the genomic regions bound by 119 human transcription factors","volume":"22","author":"Wang","year":"2012","journal-title":"Genome Res"},{"key":"2023013108190024300_btz202-B40","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"},{"key":"2023013108190024300_btz202-B41","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1038\/ng.3539","article-title":"Enhancer-promoter interactions are encoded by complex genomic signatures on looping chromatin","volume":"48","author":"Whalen","year":"2015","journal-title":"Nat. Genet"},{"key":"2023013108190024300_btz202-B42","doi-asserted-by":"crossref","first-page":"e1004942.","DOI":"10.1371\/journal.pgen.1004942","article-title":"Aberrant gene expression in humans","volume":"11","author":"Zeng","year":"2015","journal-title":"PLoS Genet"},{"key":"2023013108190024300_btz202-B43","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/j.ajhg.2015.12.023","article-title":"A burden of rare variants associated with extremes of gene expression in human peripheral blood","volume":"98","author":"Zhao","year":"2016","journal-title":"Am. J. Hum. Genet"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/bioinformatics\/advance-article-pdf\/doi\/10.1093\/bioinformatics\/btz202\/28533888\/btz202.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/35\/20\/3906\/48976074\/bioinformatics_35_20_3906.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/35\/20\/3906\/48976074\/bioinformatics_35_20_3906.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,31]],"date-time":"2023-01-31T15:07:44Z","timestamp":1675177664000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/35\/20\/3906\/5418790"}},"subtitle":[],"editor":[{"given":"Oliver","family":"Stegle","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2019,3,23]]},"references-count":43,"journal-issue":{"issue":"20","published-print":{"date-parts":[[2019,10,15]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btz202","relation":{},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"type":"print","value":"1367-4803"},{"type":"electronic","value":"1367-4811"}],"subject":[],"published-other":{"date-parts":[[2019,10,15]]},"published":{"date-parts":[[2019,3,23]]}}}