1.
Global Phenotypic Data Sharing
Standards to Maximize Diagnostics and
Mechanism Discovery
Melissa Haendel, PhD @ontowonka

2.
Prevailing clinical genomic pipelines leverage only a
tiny fraction of the available data
PATIENT EXOME
/ GENOME
PATIENT CLINICAL
PHENOTYPES
PUBLIC GENOMIC DATA
PUBLIC CLINICAL PHENOTYPE,
DISEASE DATA
POSSIBLE DISEASES
DIAGNOSIS & TREATMENT
PATIENT ENVIRONMENT
PUBLIC ENVIRONMENT,
DISEASE DATA
PATIENT OMICS PHENOTYPES PUBLIC OMICS PHENOTYPES,
CORRELATIONS
Under-utilized data

3.
Genes Environment Phenotypes+ =
Computable encodings are essential
Base pairs
Variant notation (eg. HGVS)
SNOMED-CTMedical procedure coding
Environment Ontology
@ontowonka

4.
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
 11,813
phenotype
terms
 127,125 rare
disease -
phenotype
annotations
 136,268
common
disease -
phenotype
annotations
http://bit.ly/hpo-paper

5.
Existing clinical vocabularies don’t adequately
cover phenotypic descriptions
Winnenburg and Bodenreider, 2014
0
10
20
30
40
50
60
70
80
90
100
HPO UMLS SNOMED CT CHV MedDRA MeSH NCIT ICD10 OMIM
Percentcoverage
=> HPO is now in the UMLS

6.
monarchinitiative.org
Why model organisms matter to patients
Model data can provide
up to
80% phenotypic coverage
of the human coding
genome

7.
Fuzzy phenotype matching for diagnosis

8.
Deep phenotyping and “fuzzy” matching
algorithms improve diagnostics
Bone et al.
Computational evaluation of exome sequence
data using human and model organism
phenotypes improves diagnostic efficiency
Genetics in Medicine (2015)
doi:10.1038/gim.2015.137
Phenotypic
profile
Genes
Heterozygous,
missense
mutation
STIM-1
Heterozygous,
missense
mutation
STIM-1
Stim1Sax/Sax
4.9% exomes w dual molecular diagnoses,
differentiated w deep phenotyping

9.
Matchmaker Exchange for patients, diseases, and model
organisms to aid diagnosis and mechanistic discovery
www.monarchinitiative.org
http://bit.ly/Monarch-MME
Goal: Get clinical sites & public databases to provide standardized phenotype data

10.
Journals are now requiring HPO terms
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

11.
HPO language translations
We need your help! http://bit.ly/hpo-translations
Translation of labels, synonyms, and text definitions
Italian Spanish Russian French
German English layperson Japanese Chinese
100%11%
12%
100%
19%19%
near 100%
20%

12.
monarchinitiative.org
How much phenotyping is enough?
Enlarged ears (2)Dark hair (6) Female (4)
Male (4)
Blue skin (1)
Pointy ears (1)
Hair absent on head (1)
Horns present (1)
Hair present
on head (7)
Enlarged lip (2)
Increased skin
pigmentation (3)
bit.ly/annotationsufficiency

13.
Genes Environment Phenotypes+ =
Biology central dogma
Standards for exchanging data
must be up to these challenges.
@ontowonka

14.
Genes Environment Phenotypes
VCF PXFGFF
Standard exchange mechanisms exist for
genes … but for phenotypes? Environment?
BED
@ontowonka

15.
Introducing PhenoPackets
A packet of phenotype data to be used
anywhere, written by anyone
http://phenopackets.org

16.
What does a phenopacket look like?
 Alacrima
 Sleep Apnea
 Microcephaly
phenotype_profile:
- entity: ”patient16"
phenotype:
types:
- id: "HP:0000522"
label: ”Alacrima"
onset:
description: “at birth”
types:
- id: "HP:0003577"
label: "Congenital onset"
evidence:
- types:
- id: "ECO:0000033"
label: ”Traceable Author Statement"
source:
- id: ”PMID:"
 Clinical labs
 Public databases
 Journals

17.
Layperson HPO + Phenopackets
 Dry eyes
 Stops breathing during sleep
 Small head
phenotype_profile:
- entity: “Grace”
phenotype:
types:
- id: "HP:0000522"
label: “Alacrima"
onset:
description: “at birth"
types:
- id: "HP:0003577"
label: "Congenital onset"
evidence:
- types:
- id: “ECO:0000033”
label: “Traceable Author Statement"
source:
- id: “
https://twitter.com/examplepatient/status/1
23456789”
• Patient registries
• Social media

18.
Standards are vital to realize a
mechanistic classification of disease

19.
www.monarchinitiative.org
Leadership: Melissa Haendel, Chris Mungall, Peter Robinson,
Tudor Groza, Damian Smedley, Sebastian Köhler, Julie McMurry
Funding: NIH Office of Director: 2R24OD011883; NHGRI UDP: HHSN268201300036C,
HHSN268201400093P;