Clinical Validation of Copy Number Variants Using the AMP Guidelines
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This document discusses Golden Helix's software for clinical variant analysis and summarizing copy number variants using American College of Medical Genetics (ACMG) and Association for Molecular Pathology (AMP) guidelines. It acknowledges funding support from several National Institutes of Health grants. It also lists upcoming discussion sessions on applying ACMG/AMP guidelines in clinical practice and analyzing copy number variants from next-generation sequencing data.
Clinical Validation of Copy Number Variants Using the AMP Guidelines
- 1. Clinical Validation of Copy Number Variants Using the AMP Guidelines Dr. Eli Sward – Field Application Scientist sward@goldenhelix.com 20 Most Promising Biotech Technology Providers Top 10 Analytics Solution Providers
- 3. NIH Grant Funding Acknowledgments • Research reported in this publication was supported by the National Institute Of General Medical Sciences of the National Institutes of Health under: • Award Number R43GM128485-01 • Award Number R43GM128485-02 • Award Number 2R44 GM125432-01 • Award Number 2R44 GM125432-02 • Montana SMIR/STTR Matching Funds Program Grant Agreement Number 19-51-RCSBIR-005 • PI is Dr. Andreas Scherer, CEO Golden Helix. • The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
- 4. Filtering and Annotation ACMG & AMP Guidelines Clinical Reports CNV Analysis Pipeline: Run Workflows Variant Warehouse Centralized Annotations Hosted Reports Sharing and Integration CNV Analysis GWAS | Genomic Prediction Large-N Population Studies RNA-Seq Large-N CNV-Analysis Who Are We? Golden Helix is a global bioinformatics company founded in 1998
- 5. Cited in 1,000s of Peer-Reviewed Publications
- 6. Over 400 Customers Globally
- 7. SIMPLE, SUBSCRIPTION- BASED BUSINESS MODEL o Yearly fee o Unlimited training & support SOFTWARE IS VETTED o 20,000+ users at 400+ organizations o Quality & feedback DEEPLY ENGRAINED IN SCIENTIFIC COMMUNITY o Give back to the community o Contribute content and support INNOVATIVE SOFTWARE SOLUTIONS o Cited in 1,000s of publications When you choose Golden Helix, you receive more than just the software
- 9. Power of NGS CNV Detection Small:1 50b+ Medium: 1 – 10Kb Large: 10Kb+ Gene panel Whole exome Whole genome MLPA ✓ ✓ CMA ✓ ✓ VS-CNV ✓ ✓ ✓ ✓ ✓ ✓ Detectable events Supported Data types ▪ One single testing paradigm ▪ True simplification of clinical workflow ▪ Saves time and money – all on site
- 10. Addressing Issues - CNV Detection via NGS ▪ CNVs detected from coverage data in BAM ▪ Challenges • Coverage varies between samples • Coverage fluctuates between targets • *Systematic biases impact coverage ▪ Solutions • Data Normalization • Reference Sample Comparison • Algorithm works without case/control data ▪ Requirements • ≥ 30 ref samples • From same library prep method • Ideally ≥100X coverage
- 11. CNV Detection ▪ Metrics • Ratio: normalized sample coverage divided by the average normalized reference sample coverage • Z-score: standard deviations from reference sample mean • Confidence • P-value is produced for all called events and can be customized to determine the probability that the CNV event is true • Annotations • Population catalogs • SuperDups • Classification
- 12. 225+ Users and 15+ Publications • Journals • Atherosclerosis • Journal of lipid research • Journal of Clinical Lipidology • American Journal of Medical Genetics • BMC Medical Genomics • Medicine • Analysis topics • Hypercholesterolemia • Retinal dystrophy • Pituitary hormone deficiency • Rare Mendelian disorders • Lacocca et al. • Whole exome CNV detection comparison • 100% concordance MLP&CMA with VSCNV • Improves resources, cost, analysis time
- 13. • Automates both ACMG and AMP Guidelines all in one suite • Single nucleotide variants, insertions and deletions, copy number variants, gene fusions • Creates consistency in evaluations / reduces workflow fatigue • Educational purposes • Word-based reporting capabilities Germline Somatic
- 14. Tier I: Variants of Strong Clinical Significance Therapeutic, prognostic & diagnostic Level A Evidence FDA-approved therapy Included in professional guidelines Level B Evidence Well-powered studies with consensus from experts in the field Tier II: Variants of Potential Clinical Significance Therapeutic, prognostic & diagnostic Level C Evidence FDA-approved therapy for different tumor types or investigational therapies Multiple small published studies with some consensus Level D Evidence Preclinical trials or a few case reports without consensus Tier III: Variants of Unknown Clinical Significance Not observed at a significant allele frequency in the general or specific subpopulation database, or pan-cancer or tumor-specific variant database No convincing published evidence of cancer association Tier IV: Benign or Likely Benign Variants Observed at a significant allele frequency in the general or specific subpopulation databases No existing published evidence of cancer association (2017) Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: VSClinical - AMP Guidelines: Biomarkers ▪ Biomarkers: - Biological states with indications for treatments, prognostic, or diagnostic outcomes ▪ AMP Guidelines: 4 Tiers - Tier 1: FDA-approved therapy - Tier 2: FDA-approved for different tumor type / Preclinical - Tier 3: No evidence of cancer association - Tier 4: High allele frequency variants
- 15. AMP Guidelines – Annotations Population Database to exclude common variants Cancer Specific Databases Sequence Repositories Clinical, Drug, and Prediction annotations Splice Site and Functional Prediction Algorithms
- 16. VSClinical AMP: Golden Helix CancerKB Haroche J. et al. Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation. Blood 2013 121 ▪ Interpretations for Cancer Biomarkers - Biomarker and Gene interpretations - Assess drug sensitivity, resistance, prognostic, and diagnostic information - Build biomarker classification and interpretation ▪ Updated by users and reviewed by expert panel ▪ Jumpstarts interpretation enhances knowledge base and productivity to final report
- 17. VSClinical – Clinical Report • VSClinical conducts the clinical variant analysis based on ACMG and AMP guidelines - Automated population of the clinical report-based workflow outcome - Standardizing of variant level interpretation based on customizable assessment catalogs - For somatic variants, GHI provides predefined clinical assessments via our CancerKB catalog • Rendering of clinical reports within seconds • Supported output formats - Word - PDF
- 18. VSClinical – AMP Guidelines: Project Demonstration • CNV background - ~ 50 Reference samples - Predefined workflow - Quality/Confidence filtering - Remove common CNVs - Targeted phenotype • Evaluate CNV in VSClinical – AMP hub - Patient info - Mutation selection - Biomarker interpretation + treatment options - Clinical report
- 20. NIH Grant Funding Acknowledgments • Research reported in this publication was supported by the National Institute Of General Medical Sciences of the National Institutes of Health under: • Award Number R43GM128485-01 • Award Number R43GM128485-02 • Award Number 2R44 GM125432-01 • Award Number 2R44 GM125432-02 • Montana SMIR/STTR Matching Funds Program Grant Agreement Number 19-51-RCSBIR-005 • PI is Dr. Andreas Scherer, CEO Golden Helix. • The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
- 22. CoLab Discussions: Wednesday, Oct 16th - 12:45-1:30pm | Clinical Variant Analysis: Applying the AMP & ACMG Guidelines in the Clinical Practice Thursday, Oct 17th - 12:45-1:30pm | State of the Art Clinical Copy Number Variant Analysis in Next- Gen Sequencing Data: Gene Panels, Whole Exome, Whole Genome
- 24. Additional Questions? info@goldenhelix.com | goldenhelix.com