The Monarch Initiative: Unifying, Integrating, and Sharing Genotype ...

Integrating clinical and model organism genotype-phenotype data

for improved disease discovery

Melissa Haendel ClinGen/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 prioritization

Whole exome

Remove off-target and common variants

Variant score from allele freq and pathogenicity

Phenotype score from phenotypic similarity

PHIVE score to give final candidates https://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

Acknowledgments OHSU Nicole Vasilesky Matt Brush Bryan Laraway Shahim Essaid Kent Shefchek

NIH-UDP

William Bone Murat Sincan David Adams Joie Davis Neal Boerkoel Cyndi Tifft Bill Gahl

UDN Alexa McCray Rachel Ramoni

Garvan Tudor Groza

Lawrence Berkeley Nicole Washington Suzanna Lewis Jeremy Xuan Chris Mungall

UCSD

Jeff Grethe Chris Condit Maryann Martone

U of Pitt

Chuck Borromeo Vincent Agresti Harry Hochheiser

Sanger Anika Oehlrich Jules Jacobson Damian Smedley

Charité

Sebastian Kohler Sandra Doelken Sebastian Bauer Peter Robinson

Toronto

Marta Girdea Sergiu Dumitriu Heather Trang Bailey Gallinger Orion Buske Mike Brudno

JAX

Cynthia Smith

Current Funding: NIH Office of Director: 1R24OD011883 HHSN268201300036C, 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