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ACMG Annual Clinical Genetics MeetingMarch 8 – 12, 2016 • Tampa, Florida
@monarchinit
ACMG Annual Clinical Genetics MeetingMarch 8 – 12, 2016 • Tampa, Florida
Melissa Haendel, PhD
A semantic phenomics approach to disease discovery
@monarchinit @ontowonka
ACMG Annual Clinical Genetics MeetingMarch 8 – 12, 2016 • Tampa, Florida
@monarchinit
Disclosures
NIH funding:• Monarch Initiative• BD2K Center for Genomics• FaceBase• NHGRI• NCI
ACMG Annual Clinical Genetics MeetingMarch 8 – 12, 2016 • Tampa, Florida
@monarchinit
The central dogma
ACMG Annual Clinical Genetics MeetingMarch 8 – 12, 2016 • Tampa, Florida
@monarchinit
What do all those variations do?
ACMG Annual Clinical Genetics MeetingMarch 8 – 12, 2016 • Tampa, Florida
@monarchinit
Genomic Data
Algorithmic Analysis
Traditional medical genomics pipeline
Patient:
Exomes/Genome
Patient:
Exomes/Genome
ACMG Annual Clinical Genetics MeetingMarch 8 – 12, 2016 • Tampa, Florida
@monarchinit
We have a common language for sequence data…. ATCTTAGCACGTTAC… ….not so much for phenotypes
ACMG Annual Clinical Genetics MeetingMarch 8 – 12, 2016 • Tampa, Florida
@monarchinit
Ulcerated paws
Palmoplantar hyperkeratos
is
Thick hand skin
ACMG Annual Clinical Genetics MeetingMarch 8 – 12, 2016 • Tampa, Florida
@monarchinit
Can we help machines understand phenotypic features?
“Palmoplantar hyperkeratosi
s”
Human phenotypic featureI have absolutely
no idea what that means
???
ACMG Annual Clinical Genetics MeetingMarch 8 – 12, 2016 • Tampa, Florida
@monarchinit
Obstacles to phenome-based interpretation
Building a comprehensive phenomic database requires multiple disparate sources:
Human Genes, Variants, etc. databases Orthologous genes in model organisms
Phenotype Search and Matching How do utilize phenotypes in a variant filtering pipeline? How do we match phenotypes in different species? How much difference does phenotyping make?
ACMG Annual Clinical Genetics MeetingMarch 8 – 12, 2016 • Tampa, Florida
@monarchinit
The Human Phenotype Ontology
ACMG Annual Clinical Genetics MeetingMarch 8 – 12, 2016 • Tampa, Florida
@monarchinit
Existing clinical vocabularies don’t adequately cover phenotypic descriptions
Winnenburg and Bodenreider, ISMB PhenoDay, 2014
UMLS
SNOMED CT
CHV
MedDRA
MeSH
NCIT
ICD10-C
ICD9-CM
ICD-10
OMIM
MedlinePlus
ACMG Annual Clinical Genetics MeetingMarch 8 – 12, 2016 • Tampa, Florida
@monarchinit
A disease is a collection of phenotypic features
Patient
Disease XDifferential diagnosis with similar but non-matching phenotypes is difficult
Flat back of head Hypotonia
Abnormal skull morphology Decreased muscle mass
ACMG Annual Clinical Genetics MeetingMarch 8 – 12, 2016 • Tampa, Florida
@monarchinit
Ontology-based phenotypic profile matching
https://github.com/monarch-initiative/owlsim-v3
ACMG Annual Clinical Genetics MeetingMarch 8 – 12, 2016 • Tampa, Florida
@monarchinit
Making OMIM and other disease resources computable
Free text -> ontology curation enables interoperability
ACMG Annual Clinical Genetics MeetingMarch 8 – 12, 2016 • Tampa, Florida
@monarchinit
Which phenotypic profile is most similar?Model X
Patient
Disease Y
ACMG Annual Clinical Genetics MeetingMarch 8 – 12, 2016 • Tampa, Florida
@monarchinit
Model X
Patient
Disease Y
Fuzzy phenotype feature matching
ACMG Annual Clinical Genetics MeetingMarch 8 – 12, 2016 • Tampa, Florida
@monarchinit
Inferring phenotypic knowledge of the human coding genome from model organisms
Other= rat, fly, worm, mouse, zebrafish
ACMG Annual Clinical Genetics MeetingMarch 8 – 12, 2016 • Tampa, Florida
@monarchinit
Genes & Phenotypic features. Integrated & Computable.
ACMG Annual Clinical Genetics MeetingMarch 8 – 12, 2016 • Tampa, Florida
Combining genotype and phenotypic data for variant prioritization
Remove off-target and common variants
Variant score from allele freq and pathogenicity
Phenotype score from phenotypic similarity
PHIVE score to give final candidates
Mendelian filters
tinyurl.com/exomiser
ACMG Annual Clinical Genetics MeetingMarch 8 – 12, 2016 • Tampa, Florida
York platelet syndrome and STIM1
Markello T et al. Molecular Genetics and Metabolism 2015, 114: 474 Grosse J, J Clin Invest 2007 117: 3540-50
Impaired platelet aggregation(HP:0003540)
Thromocytopenia (HP:0001873)
Abnormal platelet activation(MP:0006298)
Thrombocytopenia (MP:0003179)
UDP_2542 Stim1Sax/Sax
http://www.nature.com/gim/journal/vaop/ncurrent/full/gim2015137a.html
ACMG Annual Clinical Genetics MeetingMarch 8 – 12, 2016 • Tampa, Florida
@monarchinit
Disease diagnosis: using the interactome
ACMG Annual Clinical Genetics MeetingMarch 8 – 12, 2016 • Tampa, Florida
@monarchinitImage credit: Viljoen and Beighton, J Med Genet. 1992
Schwartz-Jampel Syndrome, Type I
Hspg2 mutation, a proteoglycan
~100 phenotype annotations
How much phenotyping is a enough?
ACMG Annual Clinical Genetics MeetingMarch 8 – 12, 2016 • Tampa, Florida
Phenotypic sufficiency score
http://monarchinitiative.org/page/services
ACMG Annual Clinical Genetics MeetingMarch 8 – 12, 2016 • Tampa, Florida
@monarchinit
Each Case Reportassociated with an HPO profile
Robinson, P. N., Mungall, C. J., & Haendel, M. (2015). Capturing phenotypes for precision medicine. Molecular Case Studies, 1(1), a000372. doi:10.1101/mcs.a000372
Capturing phenotypes for precision medicine
ACMG Annual Clinical Genetics MeetingMarch 8 – 12, 2016 • Tampa, Florida
@monarchinit
patientarchive.org: Patient data and knowledge exchange
Automatic extraction of HPO from clinical summaries
Intuitive visualization Encrypted patient sensitive
data Search over encrypted data Collaborative diagnosis Fine-grained patient data
sharing
ACMG Annual Clinical Genetics MeetingMarch 8 – 12, 2016 • Tampa, Florida
@monarchinit
HPO synonyms for the patient / layperson
Small Lower
Jaw
Hypoplasia of the mandible
Bat earsOtopastasis
HP:0000394Pref Label: OtopastasisSynonyms: lop ear, prominent earsSuggested synonyms:Bat ears; ears sticking out
HP:0009118Pref Label: Aplasia/Hypoplasia of the mandibleSuggested Synonyms: Small Mandible; Small lower Jaw; Little Lower Jaw; Mandibular micrognathia; MicroMandible; Mandibular Deficiency; Mandibular Retrognathia …
Small Head
Micro-cephaly
HP:0000252Pref Label: MicrocephalySynonyms: Decreased Head Circumference; Reduced Head Circumference; Small head circumferenceSuggested Synonyms : Small Head; Little Head; Small Skull; Little Skull; Small Cranium…
ACMG Annual Clinical Genetics MeetingMarch 8 – 12, 2016 • Tampa, Florida
@monarchinit
Conclusions Making phenotypic features computable is crucial for precision
medicine• Variant interpretation needs more than genomic data• Methods of incorporating phenotypic features are evolving• We need all the organisms’ G2P data
The Monarch Portal integrates and organizes gene-phenotype data• Ontologies make phenotypes computable• Depth and breadth of structured phenotype data is growing
Future work• Environmental/exposure• Quantitative/imaging data• Complex/common diseases and cancer
ACMG Annual Clinical Genetics MeetingMarch 8 – 12, 2016 • Tampa, Florida
@monarchinit
www.monarchinitiative.orgPDs: Melissa Haendel, Chris Mungall, Peter Robinson
Funding:NIH Office of Director: 1R24OD011883; NIH-UDP: HHSN268201300036C, HHSN268201400093P; NCINCI/Leidos #15X143, BD2K U54HG007990-S2 (Haussler) & BD2K PA-15-144-U01 (Kesselman)