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Pearson-TCGC-2013
The document discusses advancements in genomically personalized healthcare, emphasizing methods for accurate genomic sequencing and analysis. It highlights the need for community standards in validation, reporting, and interpretation of genetic data, focusing on genotypes over variants to better understand individual genomes. Key recommendations include using ancestrally informative references and refining genotype classifications to improve patient care and disease understanding.
Pearson-TCGC-2013
- 1. Proprietary and Confidential Wendingtoward genomically personalized healthcare Nathan Pearson Principal Genome Scientist Ingenuity Systems/QIAGEN npearson@ingenuity.com Platform Ingenuity’s Views mine Talk #tweetable @genomenathan
- 2. • Conveying howbench and drylab methods work, fail, and change • Setting standards for pipeline validation, reporting, other sharing, and payment • Starting to teach med students • Convening stakeholders • Blunting hype Proprietary and Confidential What we, as a community, are doing right
- 3. • Plain English(see genomena.com/variants) • Treatment response findings • Reference genome(s) • Genotypes vs. variants • Sharing individuated genomes Proprietary and Confidential What we, as a community, are neglecting
- 4. • Read: accuratelysequence person’s chromosomes Recommend: Align & call against a genome most like this person’s Where hard to guess (e.g., HLA), try many • Write: compress person’s genome; compare to others’ via common coordinates Recommend: Report against human ancestral reference Report no-calls • Interpret: understand person who carries this genome Recommend: Focus on genotypes, not variants For QC, start with heterozygosity Proprietary and Confidential Reference genome: 3 distinct uses
- 5. • Arbitrary, unrealistic,and ethnocentric • Misaligns most real people’s genomes • Hides informative summary patterns (QC, functionally relevant evolution) • Includes rare and risky variants • Mismatches gene-specific references used by clinical geneticists Proprietary and Confidential Reference genome: Why today’s fails Switch to common-variant-only reference? Switch to healthy-variant-only reference? Instead… Switch to common-variant-only reference? What’s common varies. Switch to healthy-variant-only reference? What’s healthy depends.
- 6. • Read: accuratelysequence person’s chromosomes Recommend: Align & call against a genome most like this person’s. Where hard to guess (e.g., HLA), try many. • Write: compress person’s genome; compare to others’ via common coordinates Recommend: Report against human ancestral reference. Report no-calls. • Interpret: understand person who carries this genome Recommend: Focus on genotypes, not variants. For QC, start with heterozygosity. Proprietary and Confidential Reference genome: 3 distinct uses
- 7. • At eachsite, base carried by last forebear of all people • Like current reference, comprises mostly common and healthy variants • Includes source DNA for nearly all alignment-relevant chunks of real genomes • Roughly equidistant from everyone • Clearly reveals summary patterns of variation and evolution • Lesson long learned for mtDNA1 But gene-specific reference discrepancies will remain, so… 1See Behar et al. 2012 (PMID 22482806), as well as Balasubramanian et al. 2011 (PMID 21205862) Proprietary and Confidential Report against human ancestral reference
- 8. • Reference-independent • Moreclearly convey what’s risky & what’s not, in given person • Slightly bigger data • Needed, to capture complexity that big studies are already revealing Neatly convey: dominant/recessive/complex site-specific effects sex-specific risk (sex chromosome epistasis) Readily extrapolate to: classic compound het etiology haplotypes (and diplotypes) other compound etiology Proprietary and Confidential Classify genotypes, not variants
- 9. • What variantsappear together, at what zygosities, in sick vs. healthy genomes? • Needed, to capture complex etiology Classic compound heterozygous etiology Sex-specific risk (sex chromosome epistasis) Other compound association (e.g., classic burden) • Lets us refine sequence (phase, impute) Proprietary and Confidential Query individuated genomes, not allele frequencies
- 10. • Defined bymultiple variants (rs429358C, rs7412C) • One variant rare, one common (neither is a mutation) • Harmful for Alzheimer disease & longevity…but helpful for cancer? • Genotype matters…as does interaction (e.g., intronic BACE1 variant) • Chronically hard to call…highlights need to report no-calls • Other familiar examples: globinopathies, BRCA1 modifiers, &c. Proprietary and Confidential Why this stuff is tricky: APOE4 example
- 11. • Secure (HIPAA-,Safe Harbor-compliant) web platform for interpreting called human genomes • Smart interface to flexibly annotate & compare genomes, to shortlist candidate variants, genes, & gene sets • Leverages field’s deepest functional knowledge base, with rigorous clinical-depth curation of published findings, well structured ontology, and smart interaction modeling • Statistically robust methods for interpreting single/multi-proband, matched tumor, (multi- )kindred, and big case/control cohort studies • Suits central labs’ needs to manage clients’ human genome data, help interpret it, and broker sensible sharing • Clinicians, stay tuned. Proprietary and Confidential Ingenuity® Variant Analysis™ in a nutshell
- 12.
Editor's Notes
- #3 Sharing:TocliniciansConsents in research & carePublication of research findingsAmong clinicians: means & formats of exchange, EHR integrationReturn of results
- #7 Reporting no-calls has low burden of interpretation: is site already annotated, or not?
- #13 Last, a warning: Let’s not dither, lest nationalized systems pass us.Biggest seq efforts already in such states, where individual and population-scale interests more directy align, especially where burdened with recessive disease &c.