Last data update: May 06, 2024. (Total: 46732 publications since 2009)
Records 1-5 (of 5 Records) |
Query Trace: Rehm HL[original query] |
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Creation of an Expert Curated Variant List for Clinical Genomic Test Development and Validation: A ClinGen and GeT-RM Collaborative Project (preprint)
Wilcox E , Harrison SM , Lockhart E , Voelkerding K , Lubin IM , Rehm HL , Kalman L , Funke B . medRxiv 2021 2021.06.09.21258594 Modern genomic sequencing tests often interrogate large numbers of genes. Identification of appropriate reference materials for development, validation studies, and quality assurance of these tests poses a significant challenge for laboratories. It is difficult to develop and maintain expert knowledge to identify all variants that must be validated to assure analytic and clinical validity. Additionally, it is usually not possible to procure appropriate and characterized genomic DNA reference materials containing the number and scope of variants required. To address these challenges, the Centers for Disease Control and Prevention’s Genetic Testing Reference Material Program (GeT-RM) has partnered with the Clinical Genome Resource (ClinGen) to develop a publicly available list of expert curated, clinically important variants. ClinGen Variant Curation Expert Panels nominated 546 variants found in 84 disease associated genes, including common pathogenic and difficult to detect variants. Variant types nominated included 346 SNVs, 104 deletions, 37 CNVs, 25 duplications, 18 deletion-insertions, 5 inversions, 4 insertions, 2 complex rearrangements, 3 in difficult to sequence regions, and 2 fusions. This expert-curated variant list is a resource that provides a foundation for designing comprehensive validation studies and for creating in silico reference materials for clinical genomic test development and validation.Competing Interest StatementThe authors have declared no competing interest.Funding StatementClinGen is primarily funded by the National Human Genome Research Institute (NHGRI), through the following three grants: U41HG006834, U41HG009649, U41HG009650. ClinGen also receives support for content curation from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), through the following three grants: U24HD093483, U24HD093486, U24HD093487.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This study did not involve human subjects and therefore no IRB was required.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data is included in the figures, tables and supplement included in the manuscript. |
Creation of an Expert Curated Variant List for Clinical Genomic Test Development and Validation: A ClinGen and GeT-RM Collaborative Project.
Wilcox E , Harrison SM , Lockhart E , Voelkerding K , Lubin IM , Rehm HL , Kalman L , Funke B . J Mol Diagn 2021 23 (11) 1500-1505 Modern genomic sequencing tests often interrogate large numbers of genes. Identification of appropriate reference materials for development, validation studies, and quality assurance of these tests poses a significant challenge for laboratories. It is difficult to develop and maintain expert knowledge to identify all variants that must be validated to assure analytic and clinical validity. Additionally, it is usually not possible to procure appropriate and characterized genomic DNA reference materials containing the number and scope of variants required. To address these challenges, the Centers for Disease Control and Prevention's Genetic Testing Reference Material Program (GeT-RM) has partnered with the Clinical Genome Resource (ClinGen) to develop a publicly available list of expert curated, clinically important variants. ClinGen Variant Curation Expert Panels nominated 546 variants found in 84 disease associated genes, including common pathogenic and difficult to detect variants. Variant types nominated included 346 SNVs, 104 deletions, 37 CNVs, 25 duplications, 18 deletion-insertions, 5 inversions, 4 insertions, 2 complex rearrangements, 3 in difficult to sequence regions, and 2 fusions. This expert-curated variant list is a resource that provides a foundation for designing comprehensive validation studies and for creating in silico reference materials for clinical genomic test development and validation. |
Principles and Recommendations for Standardizing the Use of the Next-Generation Sequencing Variant File in Clinical Settings.
Lubin IM , Aziz N , Babb LJ , Ballinger D , Bisht H , Church DM , Cordes S , Eilbeck K , Hyland F , Kalman L , Landrum M , Lockhart ER , Maglott D , Marth G , Pfeifer JD , Rehm HL , Roy S , Tezak Z , Truty R , Ullman-Cullere M , Voelkerding KV , Worthey E , Zaranek AW , Zook JM . J Mol Diagn 2017 19 (3) 417-426 A national workgroup convened by the Centers for Disease Control and Prevention identified principles and made recommendations for standardizing the description of sequence data contained within the variant file generated during the course of clinical next-generation sequence analysis for diagnosing human heritable conditions. The specifications for variant files were initially developed to be flexible with regard to content representation to support a variety of research applications. This flexibility permits variation with regard to how sequence findings are described and this depends, in part, on the conventions used. For clinical laboratory testing, this poses a problem because these differences can compromise the capability to compare sequence findings among laboratories to confirm results and to query databases to identify clinically relevant variants. To provide for a more consistent representation of sequence findings described within variant files, the workgroup made several recommendations that considered alignment to a common reference sequence, variant caller settings, use of genomic coordinates, and gene and variant naming conventions. These recommendations were considered with regard to the existing variant file specifications presently used in the clinical setting. Adoption of these recommendations is anticipated to reduce the potential for ambiguity in describing sequence findings and facilitate the sharing of genomic data among clinical laboratories and other entities. |
Good laboratory practice for clinical next-generation sequencing informatics pipelines.
Gargis AS , Kalman L , Bick DP , da Silva C , Dimmock DP , Funke BH , Gowrisankar S , Hegde MR , Kulkarni S , Mason CE , Nagarajan R , Voelkerding KV , Worthey EA , Aziz N , Barnes J , Bennett SF , Bisht H , Church DM , Dimitrova Z , Gargis SR , Hafez N , Hambuch T , Hyland FC , Luna RA , MacCannell D , Mann T , McCluskey MR , McDaniel TK , Ganova-Raeva LM , Rehm HL , Reid J , Campo DS , Resnick RB , Ridge PG , Salit ML , Skums P , Wong LJ , Zehnbauer BA , Zook JM , Lubin IM . Nat Biotechnol 2015 33 (7) 689-93 We report principles and guidelines (Supplementary Note) that were developed by the Next-Generation Sequencing: Standardization of Clinical Testing II (Nex-StoCT II) informatics workgroup, which was first convened on October 11–12, 2012, in Atlanta, Georgia, by the US Centers for Disease Control and Prevention (CDC; Atlanta, GA). We present here recommendations for the design, optimization and implementation of an informatics pipeline for clinical next-generation sequencing (NGS) to detect germline sequence variants in compliance with existing regulatory and professional quality standards1. The workgroup, which included informatics experts, clinical and research laboratory professionals, physicians with experience in interpreting NGS results, NGS test platform and software developers and participants from US government agencies and professional organizations, also discussed the use of NGS in testing for cancer and infectious disease. A typical NGS analytical process and selected workgroup recommendations are summarized in Table 1, and detailed in the guidelines presented in the Supplementary Note. |
Assuring the quality of next-generation sequencing in clinical laboratory practice.
Gargis AS , Kalman L , Berry MW , Bick DP , Dimmock DP , Hambuch T , Lu F , Lyon E , Voelkerding KV , Zehnbauer BA , Agarwala R , Bennett SF , Chen B , Chin EL , Compton JG , Das S , Farkas DH , Ferber MJ , Funke BH , Furtado MR , Ganova-Raeva LM , Geigenmuller U , Gunselman SJ , Hegde MR , Johnson PL , Kasarskis A , Kulkarni S , Lenk T , Liu CS , Manion M , Manolio TA , Mardis ER , Merker JD , Rajeevan MS , Reese MG , Rehm HL , Simen BB , Yeakley JM , Zook JM , Lubin IM . Nat Biotechnol 2012 30 (11) 1033-6 We direct your readers’ attention to the principles and guidelines (Supplementary Guidelines) developed by the Next-generation Sequencing: Standardization of Clinical Testing (Nex-StoCT) workgroup. These guidelines represent initial steps to ensure that results from tests based on next-generation sequencing (NGS) are reliable and useful for clinical decision making. The US Centers for Disease Control and Prevention (CDC) convened this national workgroup, which collaborated to define platform-independent approaches for establishing technical process elements of a quality management system (QMS) to assure the analytical validity and compliance of NGS tests with existing regulatory and professional quality standards. The workgroup identified and addressed gaps in quality practices that could compromise the quality of both clinical laboratory services and translational efforts needed to advance the implementation and utility of NGS in clinical settings. | The workgroup was composed of experts with knowledge of and experience with NGS and included clinical laboratory directors, clinicians, platform and software developers and informaticians, as well as individuals actively engaged in NGS guideline development from accreditation bodies and professional organizations. Representatives from US government agencies also participated. |
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