ClinGen The Clinical Genome Resource Sharing Clinical Genetic ...

ClinGen The Clinical Genome Resource Sharing Clinical Genetic ...

ClinGen The Clinical Genome Resource Sharing Clinical Genetic Knowledge HL7 Clinical Genomics Weekly Call Dec 12, 2017 Larry Babb, ClinGen Data Model WG co-chair [email protected] Disclosure Larry Babb is employed by MitoGen/GeneInsight, a Sunquest Information Systems company. Sunquest is a commercial laboratory software vendor. Todays Objective Stimulate discussion on the need for sharing clinical grade genetic knowledge that is not directly associated to a patient finding. What type of data are we talking about? Is this within the scope of HL7? Might it impact the current HL7 CG models? ng i r

a Sh on ti a r Cu Diss on ti a emin Azzariti D.: ClinGen The Clinical Genome Resource Presentation, European Human Genetics Conference, Copenhagen, Denmark, May, 2017. Clinical Genome Resource Funded by the United States National Institutes of Health Initiated in September, 2013 Represents >570 collaborators from 230 institutions

Image courtesy of Erin Currey and Erin Ramos, NHGRI Azzariti D.: ClinGen The Clinical Genome Resource Presentation, European Human Genetics Conference, Copenhagen, Denmark, May, 2017. ClinGen Acknowledgements Databases, Applications, and Data Models Committee for Software Alignment S. Dwight Core Standards & Expert Curation Genomic Genomic Variation Variation Oversight Committee

Oversight Committee C. Martin, C. Martin, S. S. Plon Plon & & H. H. Rehm Rehm CDWG CDWG Oversight Oversight J. Berg, S. S. Plon Plon & J. Berg, & H. H. Rehm Rehm Education & Outreach

Education E. Riggs & D. Azzariti External Scientific Panel John Carpten Rex Chisholm Deb Leonard Fumi Olopade Holly Peay Rich Sharp Peter Tarczy-Hornach Steering Committee (*PIs) Jonathan Berg, UNC* Hereditary Cardiovascular Consent and Disclosure Sequence Variant Cancer Disease Carlos Bustamante, Stanford*

Data Model Interpretation Recommendations (CADRe) Neuro Inborn Errors of L. Biesecker & S. Harrison Katrina Goddard, Kaiser* L. Babb & C. Bizon developmental Metabolism A. Buchanan & K. Ormond Mitochdondrial David Ledbetter, Geisinger* Dosage Sensitivity Hearing Loss Disorders ClinVar Partnership Christa Lese Martin, Geisinger* E. Anderson & E. Thorland RASopathies Hematology M. Landrum & H. Rehm Sharon Plon, Baylor*

CNV Interpretation S. Aradhya & D. PinedaMODY Program Coordinators Heidi Rehm, Harvard* Electronic Health Records Alvarez Danielle Azzariti Michael Watson, ACMG* (EHR) Integration Inter-lab Discrepancy Somatic Cancer Erin Currey Marc Williams, Geisinger* M. Williams Resolution S. Mudhavan & S. Kulkarni Robert Fullem Adam Buchanan, Geisinger S. Harrison & J. Dolinsky Miranda Hallquist Biocurators

Aleks Milosavljevic, Baylor Jules Savatt J. Goldstein Gene Curation Kelly Ormond, Stanford Kristy Lee J. Berg & C. Martin Lisa Brooks, NHGRI Laura Milko Snehit Pradhu Andy Freedman, NCI Actionability J. Evans & K. Goddard Erin Rooney Riggs Brandi Kattman, NCBI Deborah Ritter Danuta Krotoski, NICHD Meredith Weaver Melissa Landrum, NCBI Working Group Members >570 people from >230 institutions worldwide Erin Ramos, NHGRI Azzariti D.: ClinGen The Clinical Genome Resource Presentation, European Human Genetics Conference, Copenhagen, Denmark, May, 2017.

Data Sharing is Critical to Precision Medicine (not just patient data!) Updates to clinical-grade knowledge repositories and sources inform physician treatment plans. Providing standard, accurate and precise association of knowledge and genetic results is essential to applying that knowledge in clinical care. Both lab and physician systems need the ability to provide access to data in a timely and context appropriate manner Clinicians and researchers alike need to be able to safely and effectively share new findings in order to speed discovery which benefits all. What kinds of data are we talking about? Standardized Variant Representation Sequence Variants allele, haplotype, genotype (precise DNA and AA variants) Structural Variants CNVs, gene fusions, translocations, inversions, others Standardized Gene and Variant Interpretation

ACMG Sequence Variant Interpretation CAP/MVLD Somatic Interpretations PGx metabolism/efficacy interpretations Gene Validity / Gene Dosage Maps Actionability The following is a list of all names submitted to ClinVar for a single variant Source: Maglott, D. The Variant Rosetta Stone [Powerpoint slides] NCBI, 08 May 2015. 9 ClinGen and ClinVar: Growing the Data Sharing Movement Variant Submissions to ClinVar 500000

450000 400000 350000 300000 250000 200000 150000 100000 50000 0 13 13 13 13 13 14 14 14 14 14 14 15 15 15 15 15 15 16 16 16 16 16 16 17 17 20 /20 /20 /20 /20 /20 /20 /20 /20 /20 /20 /20 /20 /20 /20 /20 /20 /20 /20 /20 /20 /20 /20 /20 /20 / 5 1 1 1 1 1 1 1 1 1

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 4/ 6/ 8/ 10/ 12/ 2/ 4/ 6/ 8/ 10/ 12/ 2/

4/ 6/ 8/ 10/ 12/ 2/ 4/ 6/ 8/ 10/ 12/ 2/ 4/ ClinVar welcomes submissions from clinical testing labs, healthcare providers, patient registries, researchers, locus-specific databases, expert panels and professional societies Azzariti D.: ClinGen The Clinical Genome Resource Presentation, European Human Genetics Conference, Copenhagen, Denmark, May, 2017. Pawlicek P., BCM/ClinGen: ClinGen Allele Registry presentation to GA4GH VMC group, November, 2017.

Data Model WG Roadmap Variant Modeling ClinGen Baylor Allele Registry www. Interpretation Modeling Pawlicek P., BCM/ClinGen: ClinGen Allele Registry presentation to GA4GH VMC group, November, 2017. Pawlicek P., BCM/ClinGen: ClinGen Allele Registry presentation to GA4GH VMC group, November, 2017. Adopting VMC Specifications VMC Working Group (Chair: Hart R.), Variation Modelling Collaboration Data Model and Specifications master version, pg 16, December 11, 2017. Gene-Disease Validity Progress: ClinGen gene-disease validity framework completed in 2017 49 gene-disease associations finalized to date 7 ongoing gene curation efforts:

Breast and Ovarian Cancer Brugada Syndrome Colon Cancer and Polyposis Familial Thoracic Aortic Aneurysm and Dissection Hereditary Hearing Loss Hypertrophic Cardiomyopathy Pediatric Neurology Azzariti D.: ClinGen The Clinical Genome Resource Presentation, European Human Genetics Conference, Copenhagen, Denmark, May, 2017. Dosage Sensitivity

www.ncbi.nlm.nih.gov/projects/dbvar/clingen/ Progress: Continuing efforts of the International Standards of Cytogenomic Arrays Consortium (ISCA) 1,324 genes reviewed for dosage sensitivity to date Goal: to create a genome-wide dosage sensitivity map Azzariti D.: ClinGen The Clinical Genome Resource Presentation, European Human Genetics Conference, Copenhagen, Denmark, May, 2017. Variant Pathogenicity Progress: Recommendations from SVI WG

10 ongoing variant curation efforts are specifying ACMG-AMP criteria in the following gene-disease areas: CDH1 KCNQ1 MYH7 Interpretations in ClinVar PAH PTEN TP53 Familial Hypercholesterolemia Hereditary Hearing Loss Pediatric Neurology

RASopathies Azzariti D.: ClinGen The Clinical Genome Resource Presentation, European Human Genetics Conference, Copenhagen, Denmark, May, 2017. Clinical Actionability Progress: Scored Domains of Clinical Actionability Assessed clinical actionability for 122 gene/condition topics Scored 284 outcomespecific interventions Includes all 59 genes on the ACMG Recommendations for Reporting Secondary Findings

Azzariti D.: ClinGen The Clinical Genome Resource Presentation, European Human Genetics Conference, Copenhagen, Denmark, May, 2017. Problem: NGS has been largely automated but clinical interpretation of genomic alterations remains a major bottleneck for realizing precision medicine Data Exchange between Lab and Provider Separation of Variant Interpretation Standards and Reporting Standards Needed! Physicians Good BM, Ainscough BJ, McMichael JF, Su AI, Griffith OL. 2014. Genome Biology. 15(8):438.

Modified for: Babb, L. : GeneInsights role in eMERGE III: enabling EMR integration presentation, iGNITE monthly meeting, Dec, 2016 Two Separate Clinical Lab Workflows (data merging considerations) Same Assay Definition Report w/ Structured Results Variant Interp. Updates

Add into Site EHR Not the same process, structures, & content Combined Deidentified Results Variant Interp. Updates Research Use LMM/Broad Report w/ Structured Results

Variant Interp. Updates Add into Site EHR Good BM, Ainscough BJ, McMichael JF, Su AI, Griffith OL. 2014. Genome Biology. 15(8):438. Data Exchange Baylor = Modified for: Babb, L. : GeneInsights role in eMERGE III: enabling EMR integration presentation, iGNITE monthly meeting, Dec, 2016 Structured Reports & Variant Interpretations

XML Schema Interpretation Revision Approval Information Interpretation Clinical Significance Explanation Disease / Phenotype Current Interpretation Revision Reference Variant Genomic alignment data Transcript / Protein data, Other useful information

Report Report identifier Indication Overall interpretation Sign out info (status/user) Report document Patient Report messages additionally include all referenced info needed to reproduce report including Reference Variants Current Interpretation Reference Genes Reference Diseases Reference Assays Order

Physician Specimen Assay Report Section Patient/Interp Disease Report Variant Allelic state Genomic source Clinical Significance Babb, L. : S84: Design and Implementation of a Structured Sequencing Report Format: A Multi-Stakeholder Perspective from eMERGE presentation, AMIA 2017, Washington DC, Nov 7, 2017 Review of Core Concepts Identifiers / Codes Standard HL7-like namespace model (system + code/id + text/display name)

Variant Representation (reported and reference) Sequence Variants - genomic coordinates as a baseline (grch37) CNVs no common computational approach PGx star alleles not computationally ideal (i.e. CYP2C9*2) Disease Coding 39 pre-determined indication / patient disease values, required. OMIM, Orphanet, Disease Ontology (align with Monarch Initiative ontology) Interpretation / Clinical Significance ACMG LOINC codes (Pathogenic, Likely Path, Uncertain Sig, Likely Ben, Benign) Common structure (variant, disease, inheritance, clinical significance, explanation) Assay coverage Single assay for both SCs, some differences however. No computational representation of assay coverage or methodology or other aspects Patients Identifiers, Demographics (DOB, race-coded, sex-coded,) Babb, L. : S84: Design and Implementation of a

Structured Sequencing Report Format: A Multi-Stakeholder Perspective from eMERGE presentation, AMIA 2017, Washington DC, Nov 7, 2017 Genetic Test Results v Variant Interpretation Genetic Test Results Patient Specimen Centric Variant Findings (Genotype) Patient Indication Overall Interpretation Indication Context Incidental Findings Assay Methodology Narrative Report Variant Interpretation Patient Agnostic Reference Variant (Allele)

Variant Assessment Evidence collection Method, rules (e.g. ACMG PS1) Variant Interpretation Context GermlineDisease / Pathogenicity PGx / Metabolism, Efficacy Somatic / Prognostic, Predictive, Modified for: Babb, L. : GeneInsights role in Diagnostic eMERGE III: enabling EMR Approval Process integration presentation, iGNITE monthly meeting, Dec, 2016 ClinGen-SEPIO Interpretation Model Monarch ClinGen Collaboration

Brush M., SEPIO ontology github wiki, Monarch Initiative, Nov 2017 Brush M., SEPIO ontology github wiki, Monarch Initiative, Nov 2017 ClinGen Minimal Set of Evidence Item Types for the ACMG 2015 Guidelines Powell, B, MD, et al. ClinGen Interpretation Data Model Poster Showing your work, ASHG 2017. Brush M., SEPIO ontology github wiki, Monarch Initiative, Nov 2017 ClinGen Interpretation Model Status

Fully harmonized with SEPIO using ClinGen defined terms Defined 23 minimal evidence concepts for v1 (ACMG guidelines) Defined 33 value sets controlled vocabulary for key attributes Used a comprehensive set of real world examples to validate & document Initiate a "scripted" approach for generating a ClinVar submission using the model Next steps Extend to Gene validity, Actionability, and other assertion-based models Implement models in Data Exchange for internal and public use Babb, L. : Data Model WG Status Report, ClinGen Steering Committee meeting, Wash. DC, Nov, 2017 ClinGen Data Model WG, Interpretation Model website, Nov 2017 Related web sites and resources ClinGen http://clinicalgenome.org ClinGen Data Model http://datamodel.clinicalgenome.org ClinGen Allele Registry http://reg.clinicalgenome.org/ Test instance http://reg.test.genome.network

API docs - http://reg.clinicalgenome.org/doc/AlleleRegistry_0.12.xx_api_v2.pdf SEPIO wiki - https://github.com/monarch-initiative/SEPIO-ontology/wiki ClinVar http://www.ncbi.nlm.nih.gov/clinvar/ GA4GH VMC Specification https://docs.google.com/document/d/12E8WbQlvfZWk5NrxwLytmympPby6vsv60RxCeD5w c1E VMC github project - https://github.com/ga4gh/vmc Acknowledgements ClinGen Grant Working group chairs Program coordinators Steering committee members Variation Modeling Collaboration Working Group (GA4GH) Monarch Initiative / SEPIO (Matt Brush) eMERGE Grant Phase III ClinVar - Clinical Variant Archive (NCBI)

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