Global Phenotypic Data Sharing Standards to Maximize Diagnostics and

Mechanism Discovery

Melissa Haendel, PhD @ontowonka

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

Genes Environment Phenotypes + =

Computable encodings are essential

Base pairs

Variant notation (eg. HGVS) SNOMED-CT

Medical procedure coding

Environment Ontology

@ontowonka

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

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

Pe

rce

nt

co

vera

ge

=> HPO is now in the UMLS

monarchinitiative.org

Why model organisms matter to patients

Model data can provide

up to

80% phenotypic coverage

of the human coding

genome

Fuzzy phenotype matching for diagnosis

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

Ph

en

oty

pic

pro

file

G

en

es

Heterozygous,

missense

mutation

STIM-1

Heterozygous,

missense

mutation

STIM-1

Stim1Sax/Sax

4.9% exomes w dual molecular diagnoses,

differentiated w deep phenotyping

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

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

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%

97%

19% 19%

near 100%

20%

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

Genes Environment Phenotypes + =

Biology central dogma

Standards for exchanging data

must be up to these challenges.

@ontowonka

Genes Environment Phenotypes + =

Biology central dogma

Standards for exchanging data

must be up to these challenges.

@ontowonka

Genes Environment Phenotypes

VCF PXF GFF

Standard exchange mechanisms exist for

genes … but for phenotypes? Environment?

BED

@ontowonka

Introducing PhenoPackets

A packet of phenotype data to be used

anywhere, written by anyone

http://phenopackets.org

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

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

Standards are vital to realize a

mechanistic classification of disease

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;

NCATS: UDN U01TR001395, Biomedical Data Translator: 1OT3TR002019; E-RARE 2015: Hipbi-RD 01GM1608