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A Unified Clinical Genomics Database

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Presentation on theme: "A Unified Clinical Genomics Database"— Presentation transcript:

1 A Unified Clinical Genomics Database
NHGRI - U41 Genomic Resource Grant

2 Variant Analysis for General Genome Report
3-5 million variants Genes ~20,000 Coding/Splice Variants Published as Disease-Causing <1% Pharmacogenetics Rare CDS/Splice Variants 5-10 Variants 20-40 “Pathogenic” Variants LOF in Disease Associated Genes PharmGKB Levels of Evidence: PharmGKB curators use specific criteria to assess the PharmGKB “variant annotations” and determine the level of evidence. Level 1 annotations require at least one study with at least 1000 cases and 1000 controls of the same ethnicity with statistically significant p-values <0.05. Level 2 associations are those found in at least one population of >100 with a statistically significant p-value of <0.05, and may or may not be replicated. Level 3 associations with lower levels of evidence are those that do not meet the above criteria for population size or p-value, or may be in vitro studies. 30-50 Variants Review evidence for variant pathogenicity Review evidence for gene-disease association and LOF role

3 Classification of Reported Pathogenic Variants found in Human Genomes
Likely Path – 1% Pathogenic – 2% Benign 18% Uncertain significance – 52% Likely Benign 26%

4 U41 Genomic Resource Grant:
A Unified Clinical Genomics Database To raise the quality of patient care by: Standardizing the annotation and interpretation of genomic variants Sharing variant and case level data through a centralized database for clinical and research use Implementing an evidence-based expert consensus process for curating genes and variant interpretations

5 Supporting data collection, submission and curation
Work with NCBI to design ClinVar to meet the needs of the community Develop data dictionary, ontologies, and work with standards bodies Define data submission and access policies for variant and case-level data including genotypes and phenotypes Work with labs to solicit and support data submission Evidence-based curation of structural variants - (Riggs et al ) Evidence-based curation of sequence variants (ACMG Committee work in progress) Develop a gene-centric resource to define the medical exome and provide tools to support use in genomic medicine Work with vendors to improve reagents for genomic analysis (CMA, WES, WGS)

6 NIH NCBI ClinVar

7 ClinVar Submitters Variants Genes OMIM 23524 3077 Harvard Medical School and Partners Healthcare 6996 155 InVitae Inc. 5526 4 International Standards For Cytogenomic Arrays 4194 46 GeneReviews 2913 287 ARUP Laboratories 1415 6 LabCorp 1391 140 Sharing Clinical Reports Project 902 2 Finland Institute for Molecular Medicine 840 39 Tuberous Sclerosis Database 431 1 ClinSeq Project 425 35 Leiden Muscular Dystrophy Database 220 10 GeneDx 205 3 Emory Genetics Laboratory 48 13 American College of Medical Genetics and Genomics 23 Osteogenesis Imperfecta Database; University of Leicester 15 Ambry Genetics Other laboratories (19) 52 25 Total 49130 3848

8 Sequencing Laboratories Which Have Agreed to Share Data
Alfred I Dupont Hospital for Children Illumina Clinical Services Lab All Children's Hospital St. Petersburg Indiana University/Perdue University Ambry Laboratories InSiGHT ARUP LabCorp / Integrated Genetics / Correlagen Athena Diagnostics Masonic Medical Research Laboratory Baylor Medical Genetic Laboratories Mayo Clinic Boston Children's Hospital Mt. Sinai School of Medicine Boston University Nationwide Children's Hospital Children's Hospital of Philadelphia Nemours Biomolecular Core, Jefferson Medical Children's Mercy Hospital, Kansas City Oregon Health Sciences University Cincinnati Children's Hospital Providence Sacred Heart Medical Center City of Hope Molecular Diagnostic Lab Quest Diagnostics CureCMD SickKids Molecular Genetic Laboratory Denver Genetic Laboratories Transgenomics Detroit Medical Center University of Chicago Emory University University of Michigan Fullerton Genetics Laboratory University of Nebraska Medical Center GeneDx University of Oklahoma Cleveland Clinic University of Penn Greenwood Genetics University of Sydney Harvard-Partners Lab for Molec. Medicine University of Washington Henry Ford Hospital Women and Children's Hospital Huntington Medical Research Institutes Wayne State University School of Medicine Yale University

9 Documenting arguments will improve the
evidence-based assessment of variants

10 U41/ClinVar pilot project
Comparison of three laboratories classifications for variants in 12 RASopathy genes: BRAF, CBL, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, PTPN11, RAF1, SHOC2, SOS1, SPRED1 Scope Number of alleles Total submitted to ClinVar 997 Multiple assertions 269 20% discrepant 53 discrepancies: 60% differ based upon likelihood (Benign vs LB, P vs LP) 34% differed VUS vs Likely Pathogenic/Likely Benign 6% differed VUS vs Pathogenic

11 Lab Classification Differences
84% differences were Lab A reporting a more aggressive assertion (Pathogenic/Benign) than Lab B/C (LP, LB, VUS) 16% of differences were Labs B/C reporting a more aggressive assertion than Lab A

12 ACMG Lab QA Committee on the Interpretation of Sequence Variants
Sue Richards (chair), Heidi Rehm (co-chair) Sherri Bale, David Bick, Soma Das, Wayne Grody, Madhuri Hegde, Elaine Spector AMP Julie Gastier-Foster, Elaine Lyon CAP Nazneen Aziz, Karl Voelkerding

13 Uncertain significance Likely benign Benign
5 Categories: Pathogenic Likely Pathogenic Uncertain significance Likely benign Benign Pathogenic = 1 stand-alone OR 2 strong OR 1 strong + ≥3 supporting Likely Pathogenic = 1 strong + 2 supporting OR ≥4 supporting Benign = 1 stand-alone Likely benign = 1 strong + 2 supporting OR ≥4 supporting

14  *Variants should be classified as Uncertain Significance if other criteria are unmet

15 QC and Expert Concensus
Guideline Practice guidelines Expert Curation Evidence-based review ClinVar Multi-Source Curation Inter-laboratory Single-Source Curation Intra-laboratory Uncurated Large variant datasets dbSNP/dbVar

16 Curation - ClinVar

17 Analysis of LOF Variants - single genome
below 5% MAF from one case Common 33 8 Reported Rare LOFs Novel/Rare - 41 Pathogenic - 2 (Both AR 1 novel 1 known) VUS – 1 (novel) Update database Example from a single genome (PM ) – Kalotina’s data Not Mendelian 14 Excluded 46 False Positives 13 LOF not a disease Mechanism - 2

18 Gene-centric resource
Define genes with medical relevance Technical challenges High GC Pseudogenes/homologies Repeat expansions Common sites of structural variation Variant types (denote common vs rare types) Sequence variants (substitutions, small indels) Loss-of-function vs. Gain-of-function CNV – haploinsufficient vs. triplosensitive Other structural changes (translocations, inversions, etc) Imprinted loci Medically relevant transcripts Gene regions of pathogenic relevance Patterns of inheritance (dominant, recessive, X-linked, mitochondrial, de novo, etc) Phenotypes and evidence base for phenotype associations Available approaches to define variant pathogenicity (assays, tools, etc) Clinical utility measures Clinical decision support opportunities Initiated through collaboration amongst CHOP, Emory, and Harvard/Partners and Structural Variant workgroup

19 U41 - Working with Existing Efforts
NCBI (ClinVar, dbSNP, dbVar, dbGaP, GTR) and EBI NHGRI (CRVR, eMERGE, CSER, ROR), IRDiRC Regulatory and Standards: ACMG, CAP, CDC, FDA, ASHG, AMP, CMGS, Global Alliance Locus Specific Databases (LSDBs – LOVD and non-LOVD) InSiGHT, PharmGKB, MSeqDB, CFTR2, ENIGMA, etc Human Variome Project and HGVS PhenoDB (Ada Hamosh) and Human Phenotype Ontology (Peter Robinson) OMIM (Ada Hamosh) and GeneReviews (Bonnie Pagon) Patient Advocacy Groups (Genetic Alliance, Patient CrossRoads, UNIQUE, Disease Specific Groups) Industry partners (reagents, instruments, software, etc) Christa/Heidi

20 ClinGen: The Clinical Genome Resource Program
Collaboration between: NHGRI U41 Grant PIs: Ledbetter (Geisinger), Martin (Geisinger), Nussbaum (UCSF), Mitchell (Utah), Rehm (Partners/Harvard) NHGRI U01 “Clinically Relevant Variant Resource” Grants Grant 1 PIs: Bustamante (Stanford), Plon (Baylor) Grant 2 PIs: Berg (UNC), Ledbetter (Geisinger), Watson (ACMG) NCBI ClinVar

21 ClinGen Delegation of Responsibilities
Data Collection Structural Variation Sequence Variation Other Genomic Data Phenotype Curation Variant Curation – Clinical Significance Gene-Variant Pairs – Actionability Clinical Domain Curation Machine Learning Curation IT/Biofx Data Extraction Data Analysis Data Dissemination Laboratory Bioinformatics/IT EHR Integration Community Education ELSI/ Actionability Patient Registry U41 UNC Geisinger ACMG U01 Stanford Baylor U01

22 ClinGen System Interactions
Private Labs Labs Patient Registries Controlled Access Public Access LSDBs Labs (Genotypes & Phenotypes) dbGaP OMIM Case-level Data Medical Lit External Informatics Activities Enabled Crowd- sourced Curation ClinVar Pharm GKB Variant-level Data Population Datasets Expert Curated Variants Data Application Interface Gene Resource (Medical Exome, Actionability) CoreDB EHR Interface CNV Curation Tool (JIRA) Machine Learning Algorithms Portal for the Public Disease Area Curation Tool Disease WGs Clinical Domain WGs Expert Curation of Genes and Variants by Clinical Domain and Disease Area Workgroups

23 International Collaboration for Clinical Genomics
Over 190 institutional members Over 2800 individual members Annual Conference June 10-12, 2014, Bethesda, MD Attendees include laboratory directors, physicians, genetic counselors, researchers, parents, government employees, regulatory agency representatives, and vendor partners

24 U41 Principal Investigators and Workgroups
NIH U41 PIs: David Ledbetter (Geisinger), Christa Martin (Geisinger), Joyce Mitchell (Utah), Robert Nussbaum (UCSF), Heidi Rehm (Harvard) Sequence Variant Workgroup Madhuri Hegde (co-chair, Emory) Sherri Bale (co-chair, GeneDx) Carlos Bustamante (Stanford) Soma Das (U Chicago) Matt Ferber (Mayo) Birgit Funke (Harvard/MGH) Marc Greenblat (UVM) Elaine Lyon (ARUP) Dona Maglott (NCBI) Sharon Plon (Baylor) Heidi Rehm (Harvard/Partners) Avni Santani (CHOP) Patrick Willems (Gendia) Structural Variant Workgroup Erik Thorland (co-chair, Mayo) Swaroop Aradhya (co-chair, InVitae) Deanna Church (NCBI) Hutton Kearney (Fullerton) Charles Lee (Jackson Labs) Christa Martin (Emory) Sarah South (ARUP) Chad Shaw (Baylor) Karin Wain (Utah) Phenotyping Workgroup David Miller (chair, Harvard) Ada Hamosh (Hopkins) Karen Eilbeck (Utah) Monica Giovanni (Geisinger) Robert Green (Harvard/BWH) Mike Murray (Geisinger) Robert Nussbaum (USCF) Erin Riggs (Emory) Peter Robinson (Berlin) Steven Van Vooren (Cartagenia) Patrick Willems (Gendia) Engagement, Education and Access Workgroup Andy Faucett (chair, Geisinger) Erin Riggs (Emory) Danielle Metterville (Partners) Genetic Counselors from participating laboratories Bioinformatics and IT Workgroup Karen Eilbeck (co-chair) and Sandy Aronson (co-chair) ARUP: Brendon O’Fallon; Cartagenia: Steven Van Vooren; Emory: Stuart Tinker; GeneDx: Rhonda Brandon, Lisa Vincent; Mayo: Eric Klee; NCBI: Deanna Church, Jennifer Lee, Donna Maglott; George Riley; Partners Healthcare: Eugene Clark, Larry Babb, Matt Varugheese; University of Chicago Teja Nelakuditi; Utah: Karen Eilbeck, Shawn Rynearson Consultants Les Biesecker, Johan den Dunnen, Robert Green, Ada Hamosh, Laird Jackson, Stephen Kingsmore, Jim Ostell, Sue Richards, Peter Robinson, Lisa Salberg, Joan Scott, Sharon Terry


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