{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2024,6,8]],"date-time":"2024-06-08T20:10:11Z","timestamp":1717877411716},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"17","license":[{"start":{"date-parts":[[2016,10,2]],"date-time":"2016-10-02T00:00:00Z","timestamp":1475366400000},"content-version":"vor","delay-in-days":522,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Motivation: Next-generation sequencing technology is increasingly being used for clinical diagnostic tests. Clinical samples are often genomically heterogeneous due to low sample purity or the presence of genetic subpopulations. Therefore, a variant calling algorithm for calling low-frequency polymorphisms in heterogeneous samples is needed.<\/jats:p><jats:p>Results: We present a novel variant calling algorithm that uses a hierarchical Bayesian model to estimate allele frequency and call variants in heterogeneous samples. We show that our algorithm improves upon current classifiers and has higher sensitivity and specificity over a wide range of median read depth and minor allele fraction. We apply our model and identify 15 mutated loci in the PAXP1 gene in a matched clinical breast ductal carcinoma tumor sample; two of which are likely loss-of-heterozygosity events.<\/jats:p><jats:p>Availability and implementation: \u00a0http:\/\/genomics.wpi.edu\/rvd2\/.<\/jats:p><jats:p>Contact: \u00a0pjflaherty@wpi.edu<\/jats:p><jats:p>Supplementary information: Supplementary data are available at Bioinformatics online.<\/jats:p>","DOI":"10.1093\/bioinformatics\/btv275","type":"journal-article","created":{"date-parts":[[2015,5,1]],"date-time":"2015-05-01T00:01:28Z","timestamp":1430438488000},"page":"2785-2793","source":"Crossref","is-referenced-by-count":6,"title":["RVD2: an ultra-sensitive variant detection model for low-depth heterogeneous next-generation sequencing data"],"prefix":"10.1093","volume":"31","author":[{"given":"Yuting","family":"He","sequence":"first","affiliation":[{"name":"1 Department of Biomedical Engineering, Worcester Polytechnic Institute, Worcester and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fan","family":"Zhang","sequence":"additional","affiliation":[{"name":"1 Department of Biomedical Engineering, Worcester Polytechnic Institute, Worcester and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick","family":"Flaherty","sequence":"additional","affiliation":[{"name":"1 Department of Biomedical Engineering, Worcester Polytechnic Institute, Worcester and"},{"name":"2 Department of Mathematics and Statistics, University of Massachusetts, Amherst, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2015,4,29]]},"reference":[{"key":"2023020202215603500_btv275-B1","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":"1000 Genomes Project Consortium et\u00a0al.","year":"2012","journal-title":"Nature"},{"key":"2023020202215603500_btv275-B2","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1038\/ng.437","article-title":"Personalized copy number and segmental duplication maps using next-generation sequencing","volume":"41","author":"Alkan","year":"2009","journal-title":"Nat. Genet."},{"key":"2023020202215603500_btv275-B3","article-title":"Molecular characterization of tumors using next-generation sequencing","author":"Allen","year":"2013"},{"key":"2023020202215603500_btv275-B4","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: a practical and powerful approach to multiple testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J. R. Stat. Soc. B"},{"key":"2023020202215603500_btv275-B5","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1111\/1469-0691.12056","article-title":"Next-generation sequencing technology in clinical virology","volume":"19","author":"Capobianchi","year":"2012","journal-title":"Clin. Microbiol. Infect."},{"key":"2023020202215603500_btv275-B6","first-page":"213","article-title":"Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples","volume":"31","author":"Cibulskis","year":"2013","journal-title":"Nature"},{"key":"2023020202215603500_btv275-B7","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1111\/j.2517-6161.1984.tb01318.x","article-title":"Multinomial goodness-of-fit tests","volume":"46","author":"Cressie","year":"1984","journal-title":"J. R. Stat. Soc. B"},{"key":"2023020202215603500_btv275-B8","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1186\/1756-0500-6-206","article-title":"Rvd: a command-line program for ultrasensitive rare single nucleotide variant detection using targeted next-generation DNA resequencing","volume":"6","author":"Cushing","year":"2013","journal-title":"BMC Res. Notes"},{"key":"2023020202215603500_btv275-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":"2023020202215603500_btv275-B10","doi-asserted-by":"crossref","DOI":"10.1017\/CBO9780511761362","volume-title":"Large-Scale Inference: Empirical Bayes Methods for Estimation, Testing, and Prediction","author":"Efron","year":"2010"},{"key":"2023020202215603500_btv275-B11","doi-asserted-by":"crossref","first-page":"16266","DOI":"10.1073\/pnas.0808319105","article-title":"Noninvasive diagnosis of fetal aneuploidy by shotgun sequencing DNA from maternal blood","volume":"105","author":"Fan","year":"2008","journal-title":"PNAS"},{"key":"2023020202215603500_btv275-B12","volume-title":"Statistical Methods for Research Workers","author":"Fisher","year":"1970"},{"key":"2023020202215603500_btv275-B13","doi-asserted-by":"crossref","first-page":"e2","DOI":"10.1093\/nar\/gkr861","article-title":"Ultrasensitive detection of rare mutations using next-generation targeted resequencing","volume":"40","author":"Flaherty","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"2023020202215603500_btv275-B14","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1093\/infdis\/jiq040","article-title":"Deep sequencing reveals mixed infection with 2009 pandemic influenza A (H1N1) virus strains and the emergence of oseltamivir resistance","volume":"203","author":"Ghedin","year":"2010","journal-title":"J. Infect. Dis."},{"key":"2023020202215603500_btv275-B15","doi-asserted-by":"crossref","first-page":"3345","DOI":"10.1038\/sj.onc.1210993","article-title":"Array painting reveals a high frequency of balanced translocations in breast cancer cell lines that break in cancer-relevant genes","volume":"27","author":"Howarth","year":"2007","journal-title":"Oncogene"},{"key":"2023020202215603500_btv275-B16","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1101\/gr.114116.110","article-title":"Large duplications at reciprocal translocation breakpoints that might be the counterpart of large deletions and could arise from stalled replication bubbles","volume":"21","author":"Howarth","year":"2011","journal-title":"Genome Res."},{"key":"2023020202215603500_btv275-B17","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1214\/088342304000000026","article-title":"Graphical models","volume":"19","author":"Jordan","year":"2004","journal-title":"Stat. Sci."},{"key":"2023020202215603500_btv275-B18","doi-asserted-by":"crossref","first-page":"137ra76","DOI":"10.1126\/scitranslmed.3004323","article-title":"Noninvasive whole-genome sequencing of a human fetus","volume":"4","author":"Kitzman","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"2023020202215603500_btv275-B19","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1101\/gr.129684.111","article-title":"VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing","volume":"22","author":"Koboldt","year":"2012","journal-title":"Genome Res."},{"key":"2023020202215603500_btv275-B20","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.cell.2013.09.006","article-title":"The next-generation sequencing revolution and its impact on genomics","volume":"155","author":"Koboldt","year":"2013","journal-title":"Cell"},{"key":"2023020202215603500_btv275-B21","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1038\/nrg2732","article-title":"Principles and challenges of genomewide DNA methylation analysis","volume":"11","author":"Laird","year":"2010","journal-title":"Nat. Rev. Genet."},{"key":"2023020202215603500_btv275-B22","doi-asserted-by":"crossref","first-page":"2987","DOI":"10.1093\/bioinformatics\/btr509","article-title":"A statistical framework for SNP calling, mutation discovery, association mapping and population genetical parameter estimation from sequencing data","volume":"27","author":"Li","year":"2011","journal-title":"Bioinformatics"},{"key":"2023020202215603500_btv275-B23","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":"2023020202215603500_btv275-B24","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1101\/gr.099622.109","article-title":"Inferring tumor progression from genomic heterogeneity","volume":"20","author":"Navin","year":"2010","journal-title":"Genome Res."},{"key":"2023020202215603500_btv275-B25","doi-asserted-by":"crossref","first-page":"e64991","DOI":"10.1371\/journal.pone.0064991","article-title":"The relative timing of mutations in a breast cancer genome","volume":"8","author":"Newman","year":"2013","journal-title":"PLoS One"},{"key":"2023020202215603500_btv275-B26","doi-asserted-by":"crossref","first-page":"21521","DOI":"10.1073\/pnas.0904863106","article-title":"ChIP-Seq of transcription factors predicts absolute and differential gene expression in embryonic stem cells","volume":"106","author":"Ouyang","year":"2009","journal-title":"PNAS"},{"key":"2023020202215603500_btv275-B27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1471-2164-13-341","article-title":"A tale of three next generation sequencingplatforms: comparison of Ion Torrent, PacificBiosciences and Illumina MiSeq sequencers","volume":"13","author":"Quail","year":"2012","journal-title":"BMC Genomics"},{"key":"2023020202215603500_btv275-B28","doi-asserted-by":"crossref","first-page":"2041","DOI":"10.1093\/bioinformatics\/btt314","article-title":"Isaac: ultra-fast whole genome secondary analysis on illumina sequencing platforms","volume":"29","author":"Raczy","year":"2013","journal-title":"Bioinformatics"},{"key":"2023020202215603500_btv275-B29","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.cell.2013.09.011","article-title":"Mapping human epigenomes","volume":"155","author":"Rivera","year":"2013","journal-title":"Cell"},{"key":"2023020202215603500_btv275-B30","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/nrg3655","article-title":"The role of replicates for error mitigation in next-generation sequencing","volume":"15","author":"Robasky","year":"2013","journal-title":"Nat. Rev. Genet."},{"key":"2023020202215603500_btv275-B31","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.1093\/bioinformatics\/bts271","article-title":"Strelka: accurate somatic small-variant calling from sequenced tumor-normal sample pairs","volume":"28","author":"Saunders","year":"2012","journal-title":"Bioinformatics"},{"key":"2023020202215603500_btv275-B32","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.jmoldx.2013.09.003","article-title":"Performance of common analysis methods for detecting low-frequency single nucleotide variants in targeted next-generation sequence data","volume":"16","author":"Spencer","year":"2013","journal-title":"J. Mol. Diagn."},{"key":"2023020202215603500_btv275-B33","doi-asserted-by":"crossref","first-page":"1432","DOI":"10.1002\/humu.22365","article-title":"Accurately identifying low-allelic fraction variants in single samples with next-generation sequencing: applications in tumor subclone resolution","volume":"34","author":"Stead","year":"2013","journal-title":"Hum. Mutat."},{"key":"2023020202215603500_btv275-B34","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1038\/nature11209","article-title":"A framework for human microbiome research","volume":"486","author":"The Human Microbiome Project Consortium","year":"2013","journal-title":"Nature"},{"key":"2023020202215603500_btv275-B35","doi-asserted-by":"crossref","first-page":"R92","DOI":"10.1186\/gb-2010-11-9-r92","article-title":"A statistical approach for detecting genomic aberrations in heterogeneous tumor samples from single nucleotide polymorphism genotyping data","volume":"11","author":"Yau","year":"2010","journal-title":"Genome Biol."},{"key":"2023020202215603500_btv275-B36","doi-asserted-by":"crossref","first-page":"7400","DOI":"10.1093\/nar\/gkq655","article-title":"Error correction of next-generation sequencing data and reliable estimation of HIV quasispecies","volume":"38","author":"Zagordi","year":"2010","journal-title":"Nucleic Acids Res."}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/31\/17\/2785\/49035448\/bioinformatics_31_17_2785.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/31\/17\/2785\/49035448\/bioinformatics_31_17_2785.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,8]],"date-time":"2024-06-08T19:02:20Z","timestamp":1717873340000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/31\/17\/2785\/183308"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,4,29]]},"references-count":36,"journal-issue":{"issue":"17","published-print":{"date-parts":[[2015,9,1]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btv275","relation":{},"ISSN":["1367-4811","1367-4803"],"issn-type":[{"value":"1367-4811","type":"electronic"},{"value":"1367-4803","type":"print"}],"subject":[],"published-other":{"date-parts":[[2015,9,1]]},"published":{"date-parts":[[2015,4,29]]}}}