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Deep Phenotyping for Improved Diagnostics and Analysis
- 1. Monarch Initiative: Deep Phenotyping for Improved Diagnostics and Analysis Melissa Haendel, PhD @ontowonka haendel@ohsu.edu @monarchinit
- 2. Prevailing clinical diagnostic pipelines leverage only a tiny fraction of the available data Under-utilized data Loss of discriminatory power ?
- 3. Can we help machines understand phenotypes? “Palmoplantar hyperkeratosis” Human phenotype I have absolutely no idea what that means
- 4. Ulcerated paws Palmoplantar hyperkeratosis Thick hand skin "HandsEBS" by James Heilman, MD - Own work. Licensed under CC BY-SA 3.0 via Commons – https://commons.wikimedia.org/wiki/File:HandsEBS.JPG#/media/File:HandsEBS.JPG http://www.guinealynx.info/pododermatitis.html Different communities use different languages
- 5. The Human Phenotype Ontology 13,156 phenotype terms 143,759 annotations for 7321 monogenic diseases 132,006 annotations for 3145 common diseases bit.ly/hpo-paper Peter Robinson, Sebastian Koehler, Chris Mungall
- 6. Defining disease and clinical pathogenicity: A lumping and splitting problem source IDs split/merge manage resolution & provenance MONDO Unified Disease Ontology SEPIOScientific Evidence and Provenance Information One disease or two? What does the evidence favor? One disease or two? How do we manage identifiers, hierarchy? http://bit.ly/Monarch-Disease
- 7. More species = more knowledge 19,008 78% 14,779 Number of human protein-coding genes in ExAC DB as per Lek et al. Nature 2016 19,008 Even inclusion of just four species boosts phenotypic coverage of genes by 38% (5189%) Combined = 89% 19,008 2,195 7,544 7,235 = 16,974 (union of coverage in any species) 9,739 51% Mungall et al Nucleic Acids Research bit.ly/monarch-nar-2016
- 8. “Fuzzy” phenotypic profile matching
- 10. Example case solved by Exomiser Phenotypic profile Genes Heterozygous, missense mutation STIM-1 N/A Heterozygous, missense mutation STIM-1 N/A Stim1Sax/Sax Ranked STIM-1 variant maximally pathogenic based on cross-species G2P data, in the absence of traditional data sources https://exomiser.github.io/Exomiser/ bit.ly/stim1paper In Genomics England 100K Genomes, of first 1936 diagnosed patients, 82% are in the top 5 Exomiser hits across a range of rare diseases and family structures
- 11. IMPC: Disease discovery from 3,328 gene knockouts Meehan et al, 2017, Nature Genetics, doi:10.1038/ng.3901 135 new candidate genes for Mendelian disorders New model for Diamond–Blackfan anemia • Phenotype profile similarity: increased mean corpuscular hemoglobin and decreased erythrocyte cell numbers • Differential expression May account for 46% of people with Diamond–Blackfan anemia with unknown genetic causes
- 12. Lay-person HPO for patient use
- 13. Layperson-HPO driven phenotyping tool https://www.pcori.org/research-results/2017/realization-standard-care-rare- diseases-using-patient-engaged-phenotyping Catherine Brownstein, Ingrid Holm
- 14. Matchmaker Exchange for patients, diseases, and model organisms to aid diagnosis and mechanistic discovery Computational matching of rare disease patients and model organisms across clinical & public sources bit.ly/mme-matchbox patientarchive.org bit.ly/exomiser-2017
- 15. www.monarchinitiative.org PIs: Melissa Haendel (OHSU), Chris Mungall (LBNL), Peter Robinson (JAX), Damian Smedley (GEL), Tudor Groza (Garvan), David Osumi-Sutherland (EBI) Funding: NIH Office of Director: 1R24OD011883; NIH-UDP: HHSN268201300036C, HHSN268201400093P; NCINCI/Leidos #15X1
Notes de l'éditeur
- Geospatial social determinants of health
- Our approach is to try and get the machine to understand the terms so that it can assist us intelligently.
- If clinvar + omim 20 80%
- This was the novel case we solved. The UDP patient had a number of signs and symptoms including various platelet abnormalities. The same heterozygous, missense mutation was seen in 2 patients and ranked top by Exomiser. It had never been seen in any of the SNP databases and was predicted maximally pathogenic. Finally a mouse curated by MGI involving a heterozygous, missense point mutation introduced by chemical mutagenesis exhibited strikingly similar platelet abnormalities. In thefirst 1936 patients, 82% are in the top 5 Exomiser hits. This is across a whole range of different rare diseases and family structures ie. 34% cases are just simple singletons.
- Human disease models were identified by measuring the degree of phenotypic similarity between IMPC null mutant mouse strains and their orthologous genetic loci associated with human diseases. Models of mendelian disease: of 889 potential disease models, 360 mutant strains had both phenotypic overlap and an orthologous null allele, as compared with diseases with known mutations described in OMIM and Orphanet. Novel mendelian disease candidates: 135 strains had phenotypic overlap and null alleles syntenic to linkage or cytogenetic regions associated with human diseases with unknown molecular mechanisms. New functional knowledge: of 2,564 genes with a nonlethal IMPC phenotype, IMPC data provided new functional experimental evidence for 1,092 of these genes, on the basis of GO annotation. Fam53b: Fam53btm1b(EUCOMM)Hmgu homozygous mutant mice had significantly decreased red blood cell counts (b) and enlarged erythrocytes (c). In b, female control, n = 597 mice; female homozygous, n = 8; male control, n = 635; male homozygous, n = 8; linear mixed-effects model without weight, P = 2.81 × 10−11). In c, female control, n = 598; female homozygous, n = 8; male control, n = 634; male homozygous, n = 9; linear mixed-effects model without weight, P = 0), consistent with Diamond–Blackfan anemia (MIM105650). First and third quartiles; line, median; whiskers, minimum and maximum values; asterisks, significant difference between mutant and same-sex controls, mixed-effects-model P < 0.0000.
- Fully translational – from bench to bedside – group of stakeholders, contributors and partners