Integrating clinical and model organism genotype-phenotype

data for improved disease discovery

Melissa HaendelClinGen/DECIPHER meeting

2015.05.28@monarchinit

www.monarchinitiative.org

@ontowonka

There are 47,964 variants of unknown significance in

ClinVar

What are we gonna do about that?

The Human Phenotype Ontology

Each disease is associated with different phenotype nodes in the graph

Disease or Patient

HPO concepts are not well represented in other

vocabularies

Winnenburg and Bodenreider, ISMB PhenoDay, 2014

UMLS

SNOMED CT

CHV

MedDRA

MeSH

NCIT

ICD10-C

ICD9-CM

ICD-10

OMIM

MedlinePlus

Phenotype “Blast”: Which phenotypic profile is graphically

most similar?Disease X

Patient

Disease Y

Finding the phenotype graph in common

Disease X

Patient

Disease Y

The Human Phenotype Ontology

Why we need all the organisms

Clinicians and researchers speak different languages

Diversity of disease and phenotype vocabularies

Using semantics to bridge vocabularies

Using semantics to bridge vocabularies

Standardizing Cross-species G2P Data + Ontologies

SciGraph: A Neo4j-backed ontology store All species ontologies and G2P data can be

stored in a graph together Advantages: Semantics + Speed + Flexibility Propagate provenance and evidence Using to develop and evaluate GA4GH G2P

schemas

https://github.com/SciGraph/SciGraph

Combining genotype and phenotype data for variant

prioritizationWhole exome

Remove off-target and common variants

Variant score from allele freq and pathogenicity

Phenotype score from phenotypic similarity

PHIVE score to give final candidateshttps://www.sanger.ac.uk/resources/databases/exomiser/query/exomiser2

Mendelian filters

Cross-species phenotypic profile comparison for disease

discovery

Visualizing phenotypic similarity

http://monarchinitiative.org/page/phenogrid

AcknowledgmentsOHSUNicole VasileskyMatt BrushBryan LarawayShahim EssaidKent Shefchek

NIH-UDPWilliam BoneMurat SincanDavid AdamsJoie DavisNeal BoerkoelCyndi TifftBill Gahl

UDNAlexa McCrayRachel Ramoni

GarvanTudor Groza

Lawrence BerkeleyNicole WashingtonSuzanna LewisJeremy XuanChris Mungall

UCSDJeff GretheChris ConditMaryann Martone

U of PittChuck BorromeoVincent AgrestiHarry Hochheiser

SangerAnika OehlrichJules JacobsonDamian Smedley

CharitéSebastian KohlerSandra DoelkenSebastian BauerPeter Robinson

TorontoMarta GirdeaSergiu DumitriuHeather TrangBailey GallingerOrion BuskeMike Brudno

JAXCynthia SmithCurrent Funding:

NIH Office of Director: 1R24OD011883HHSN268201300036C, HHSN268201400093P

If you use Monarch ontologies or tools, please attribute us!

Please send feedback too, don’t let it be a one way street.

Extra

Propagating phenotypes across genotypic levels

We learn different things from different organisms

Monarch in the GA4GH MatchMaker Exchange