Presented as part of the "Tools and Approaches to Assess the Genetic Basis of Disease" ACMG short course.

1. ACMG Annual Clinical Genetics Meeting
March 8 – 12, 2016 • Tampa, Florida
@monarchinit
ACMG Annual Clinical Genetics Meeting
March 8 – 12, 2016 • Tampa, Florida
Melissa Haendel, PhD
A semantic phenomics approach
to disease discovery
@monarchinit @ontowonka

2. ACMG Annual Clinical Genetics Meeting
March 8 – 12, 2016 • Tampa, Florida
@monarchinit
Disclosures
NIH funding:
• Monarch Initiative
• BD2K Center for Genomics
• FaceBase
• NHGRI
• NCI

3. ACMG Annual Clinical Genetics Meeting
March 8 – 12, 2016 • Tampa, Florida
@monarchinit
The central dogma

4. ACMG Annual Clinical Genetics Meeting
March 8 – 12, 2016 • Tampa, Florida
@monarchinit
What do all those variations do?

5. ACMG Annual Clinical Genetics Meeting
March 8 – 12, 2016 • Tampa, Florida
@monarchinit
Genomic Data
Algorithmic
Analysis
Traditional medical genomics pipeline
Patient:
Exomes/
Genome
Patient:
Exomes/
Genome

6. ACMG Annual Clinical Genetics Meeting
March 8 – 12, 2016 • Tampa, Florida
@monarchinit
We have a common language
for sequence data….
ATCTTAGCACGTTAC…
….not so much for phenotypes

7. ACMG Annual Clinical Genetics Meeting
March 8 – 12, 2016 • Tampa, Florida
@monarchinit
Ulcerated
paws
Palmoplantar
hyperkeratosis
Thick hand skin

8. ACMG Annual Clinical Genetics Meeting
March 8 – 12, 2016 • Tampa, Florida
@monarchinit
Can we help machines understand
phenotypic features?
“Palmoplantar
hyperkeratosis”
Human phenotypic feature
I have absolutely
no idea what
that means

9. ACMG Annual Clinical Genetics Meeting
March 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?

10. ACMG Annual Clinical Genetics Meeting
March 8 – 12, 2016 • Tampa, Florida
@monarchinit
The Human Phenotype Ontology
Hyposmia
Abnormality of
globe location
eyeball of
camera-type eye
sensory
perception of smell
Abnormal eye
morphology
Motor neuron
atrophyDeeply set eyes
motor neuronCL
34571 annotations in
22 species
157534 phenotype
annotations
2150 phenotype
annotations

11. ACMG Annual Clinical Genetics Meeting
March 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

12. ACMG Annual Clinical Genetics Meeting
March 8 – 12, 2016 • Tampa, Florida
@monarchinit
A disease is a collection of
phenotypic features
Patient
Disease X
Differential diagnosis with similar but non-matching phenotypes is difficult
Flat back of head Hypotonia
Abnormal skull morphology Decreased muscle mass

13. ACMG Annual Clinical Genetics Meeting
March 8 – 12, 2016 • Tampa, Florida
@monarchinit
Ontology-based phenotypic profile matching
https://github.com/monarch-initiative/owlsim-v3

14. ACMG Annual Clinical Genetics Meeting
March 8 – 12, 2016 • Tampa, Florida
@monarchinit
Making OMIM and other disease resources computable
Free text -> ontology curation
enables interoperability

15. ACMG Annual Clinical Genetics Meeting
March 8 – 12, 2016 • Tampa, Florida
@monarchinit
Which phenotypic profile is most similar?
Model X
Patient
Disease Y

16. ACMG Annual Clinical Genetics Meeting
March 8 – 12, 2016 • Tampa, Florida
@monarchinit
Model X
Patient
Disease Y
Fuzzy phenotype feature matching

17. ACMG Annual Clinical Genetics Meeting
March 8 – 12, 2016 • Tampa, Florida
@monarchinit
Inferring phenotypic knowledge of the human
coding genome from model organisms
Other= rat, fly, worm, mouse, zebrafish

18. ACMG Annual Clinical Genetics Meeting
March 8 – 12, 2016 • Tampa, Florida
@monarchinit
Genes & Phenotypic features. Integrated & Computable.

19. 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

20. 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

21. ACMG Annual Clinical Genetics Meeting
March 8 – 12, 2016 • Tampa, Florida
@monarchinit
Disease diagnosis: using the interactome

22. ACMG Annual Clinical Genetics Meeting
March 8 – 12, 2016 • Tampa, Florida
@monarchinit
Image 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?

23. Phenotypic sufficiency score
http://monarchinitiative.org/
page/services

24. ACMG Annual Clinical Genetics Meeting
March 8 – 12, 2016 • Tampa, Florida
@monarchinit
Each Case Report
associated 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

25. ACMG Annual Clinical Genetics Meeting
March 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

26. ACMG Annual Clinical Genetics Meeting
March 8 – 12, 2016 • Tampa, Florida
@monarchinit
HPO synonyms for the patient / layperson
Small
Lower Jaw
Hypoplasia
of the
mandible
Bat earsOtopastasis
HP:0000394
Pref Label: Otopastasis
Synonyms: lop ear, prominent ears
Suggested synonyms:
Bat ears; ears sticking out
HP:0009118
Pref Label: Aplasia/Hypoplasia of the mandible
Suggested Synonyms: Small Mandible; Small lower
Jaw; Little Lower Jaw; Mandibular micrognathia;
MicroMandible; Mandibular Deficiency; Mandibular
Retrognathia …
Small Head
Micro-
cephaly
HP:0000252
Pref Label: Microcephaly
Synonyms: Decreased Head Circumference; Reduced
Head Circumference; Small head circumference
Suggested Synonyms : Small Head; Little Head; Small
Skull; Little Skull; Small Cranium…

27. ACMG Annual Clinical Genetics Meeting
March 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

28. ACMG Annual Clinical Genetics Meeting
March 8 – 12, 2016 • Tampa, Florida
@monarchinit
www.monarchinitiative.org
PDs: 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)