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dc.contributor.authorWhiffin, Nen_US
dc.contributor.authorWalsh, Ren_US
dc.contributor.authorGovind, Ren_US
dc.contributor.authorEdwards, Men_US
dc.contributor.authorAhmad, Men_US
dc.contributor.authorZhang, Xen_US
dc.contributor.authorTayal, Uen_US
dc.contributor.authorBuchan, Ren_US
dc.contributor.authorMidwinter, Wen_US
dc.contributor.authorWilk, AEen_US
dc.contributor.authorNajgebauer, Hen_US
dc.contributor.authorFrancis, Cen_US
dc.contributor.authorWilkinson, Sen_US
dc.contributor.authorMonk, Ten_US
dc.contributor.authorBrett, Len_US
dc.contributor.authorO'Regan, DPen_US
dc.contributor.authorPrasad, SKen_US
dc.contributor.authorMorris-Rosendahl, DJen_US
dc.contributor.authorBarton, PJRen_US
dc.contributor.authorEdwards, Een_US
dc.contributor.authorWare, JSen_US
dc.contributor.authorCook, SAen_US
dc.coverage.spatialUnited Statesen_US
dc.date.accessioned2019-02-20T07:51:06Z
dc.date.issued2018-10en_US
dc.identifierhttps://www.ncbi.nlm.nih.gov/pubmed/29369293en_US
dc.identifier10.1038/gim.2017.258en_US
dc.identifier.citationGenet Med, 2018, 20 (10), pp. 1246 - 1254en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3066
dc.identifier.eissn1530-0366en_US
dc.identifier.doi10.1038/gim.2017.258en_US
dc.description.abstractPURPOSE: Internationally adopted variant interpretation guidelines from the American College of Medical Genetics and Genomics (ACMG) are generic and require disease-specific refinement. Here we developed CardioClassifier ( http://www.cardioclassifier.org ), a semiautomated decision-support tool for inherited cardiac conditions (ICCs). METHODS: CardioClassifier integrates data retrieved from multiple sources with user-input case-specific information, through an interactive interface, to support variant interpretation. Combining disease- and gene-specific knowledge with variant observations in large cohorts of cases and controls, we refined 14 computational ACMG criteria and created three ICC-specific rules. RESULTS: We benchmarked CardioClassifier on 57 expertly curated variants and show full retrieval of all computational data, concordantly activating 87.3% of rules. A generic annotation tool identified fewer than half as many clinically actionable variants (64/219 vs. 156/219, Fisher's P = 1.1  ×  10-18), with important false positives, illustrating the critical importance of disease and gene-specific annotations. CardioClassifier identified putatively disease-causing variants in 33.7% of 327 cardiomyopathy cases, comparable with leading ICC laboratories. Through addition of manually curated data, variants found in over 40% of cardiomyopathy cases are fully annotated, without requiring additional user-input data. CONCLUSION: CardioClassifier is an ICC-specific decision-support tool that integrates expertly curated computational annotations with case-specific data to generate fast, reproducible, and interactive variant pathogenicity reports, according to best practice guidelines.en_US
dc.format.extent1246 - 1254en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.subjectbioinformaticsen_US
dc.subjectclinical genomicsen_US
dc.subjectinherited cardiac conditionsen_US
dc.subjectnext-generation sequencingen_US
dc.subjectvariant interpretationen_US
dc.subjectCardiovascular Abnormalitiesen_US
dc.subjectComputational Biologyen_US
dc.subjectDecision Support Techniquesen_US
dc.subjectGenetic Testingen_US
dc.subjectGenome, Humanen_US
dc.subjectGenomicsen_US
dc.subjectHigh-Throughput Nucleotide Sequencingen_US
dc.subjectHumansen_US
dc.subjectMutationen_US
dc.subjectSoftwareen_US
dc.titleCardioClassifier: disease- and gene-specific computational decision support for clinical genome interpretation.en_US
dc.typeJournal Article
dcterms.dateAccepted2017-12-05en_US
rioxxterms.versionofrecord10.1038/gim.2017.258en_US
rioxxterms.licenseref.startdate2018-10en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfGenet Meden_US
pubs.issue10en_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Genetics and Epidemiology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Genetics and Epidemiology/Molecular & Population Genetics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Molecular & Population Genetics
pubs.publication-statusPublisheden_US
pubs.volume20en_US
pubs.embargo.termsNot knownen_US
icr.researchteamMolecular & Population Geneticsen_US
dc.contributor.icrauthorWhiffin, Nicolaen_US


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