Making Phenotypic data FAIR++ for

Disease Diagnosis and Discovery

Findable Accessible outside paywalls and private data sources Attributable Interoperable and Computable, Reusable, exchangeable across contexts and disciplines

Melissa Haendel, PhD @ontowonka

Biology central dogma

Genes Environment Phenotypes + =

Standards for encoding and exchanging data must be up to these challenges

@ontowonka

Computable encodings are essential

Genes Environment Phenotypes + =

Base pairs Medical procedure coding Human Phenotype Variant notation (eg. HGVS) Environment Ontology Ontology

Mammalian Phenotype Ontology

@ontowonka

Standard exchange formats exist for genes … but for phenotypes? Environment?

Genes Environment Phenotypes

VCF PXFGFF BED

@ontowonka

- - -

Ontologies provide pre-packaged phenotype descriptions

Köhler, S., Doelken, S. C., Mungall, C. J., … Robinson, P. N. (2013). The Human Phenotype Ontology project: linking molecular biology and disease through phenotype data. Nucleic Acids Res. doi:10.1093/nar/gkt1026

Smith, C. L., & Eppig, J. T. (2015). Expanding the mammalian phenotype ontology to support automated exchange of high throughput mouse phenotyping data generated by large-scale mouse knockout screens, J Biomed Semantics. 2015; 6: 11 doi:10.1186/s13326 015 0009 1

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4378007/

A simple data model Entities

– Organism • Patient • Non-human animal • Population

– Genetic/genomic element – Condition

• Disease • Phenotype

Associations – E.g. between disease and phenotype – Each association has

• Evidence • Provenance

Entity

Evidence

Condition

association

Disease Phenotype

Phenopackets for clinical labs Patient medical history

Patient and family history

Diagnostic tests,

clinical phenotypes

Genomic information

Physical exam

Clinical testing lab

Clinical labs often get no phenotypes or one-line descriptions. What if we could make the phenotype data PHI-free and

simultaneously more descriptive?

Phenopackets for journals

Each phenopacket can be shared via

DOI in any repository outside paywall (eg. Figshare, Zenodo,

Each article can be associated with a

phenopacket

etc) and cited as a 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 data citation

Phenopackets for biomedical

databases

OMIA

Databases could share G2P data in a standardized format, retaining domain or species specificity

Phenopackets for laypersons

• Dry eyes • Developmental delay • Elevated liver function

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: ”

• Disease registries • Patient communities • Social media Image credits: ngly1.org https://twitter.com/examplepatient/status/1

23456789"

http:ngly1.orghttps://twitter.com/examplepatient/status/1

PhenoPacket formats

CSV JSON RDF OWL

Export phenopacket to

Simple Example (patient profile) phenotype_profile: - entity: “#1”

phenotype: types: - id: HP:0100024

label: conspicuously happy disposition - entity: “#1”

phenotype: types: - id: MP:0001284

label: absent vibrissae - entity: “#2”

phenotype: types:

- id: HP:0100024 label: conspicuously happy disposition

header

entities

assocs

persons: - id: „#1“

label: Mickey Mouse date_of_birth: 1928-01-01 sex: M

- id: „#2“ label: Goofy sex: M

patients.pxf

Nesting allows refinement phenotype_profile: - entity: “#1”

phenotype: types: - id: HP:0100024

label: conspicuously happy disposition onset: types:

- id: HP:0011463 label: Childhood onset

description: “welcomes strangers with open arms” - entity: “#1”

phenotype: types: - id: MP:0001284

label: absent vibrissae - entity: “#2”

phenotype: types:

- id: HP:0100024 label: conspicuously happy disposition

header

entities

assocs

persons: - id: „#1“

label: Mickey Mouse date_of_birth: 1928-01-01 sex: M

- id: „#2“ label: Goofy sex: M

patients.pxf

Simple Example (variants) variants.pxf

phenotype_profile: - entity: “var#1”

phenotype: types: - id: HP:0001595

label: Abnormality of the hair onset: types:

- id: HP:0011463 label: Childhood onset

description: “missing whiskers” …

header

entities

assocs

variants: - id: „var#1“

label: "c.2441+7A>G” descrHGVS: “c.2441+7A>G" startPosition: 0 endPosition: 0 …

Insert GA4GH module here

https://monarchinitiative.org/variant/ClinVarVariant:195890https://monarchinitiative.org/variant/ClinVarVariant:195890

Semantics with JSON-LD

{ "@context" : { "id": "@id", "label": "rdfs:label", "types": { "@id": "rdf:type", "@type": "@id"

}, "negated_types": { "@id": "owl:complementOf", "@type": "@id"

}, "title": "dc:title",

"dc": "http://purl.org/dc/terms/", "MP" : "http://purl.obolibrary.org/obo/MP_",

Provides a direct mapping to RDF

Allows reasoning to be performed on phenopackets

Provides a prefix map to unambiguously interpret CURIE-style identifiers (e.g. as recorded in PrefixCommons)

http://purl.obolibrary.org/obo/MPhttp://purl.org/dc/terms

Summary: Phenotype Exchange Format • One model, derive alternate concrete forms

– YAML, JSON, RDF, TSV (subset) • Species-agnostic

– From microbes through plants through humans – clinical and basic research

• Applicable to a variety of entities – Patients/individual organisms, cohorts, populations – Diseases – Papers – Genes, genotypes, alleles, variants

• Simple for simple cases… – Bag of terms model

• …Incremental expressivity – Temporality and causality – Quantitative as well as qualitative – Negation, severity, frequency, penetrance,

expressivity • Ontology-smart

– Rational Composition (post-coordination) – Explicit semantics

http://phenopackets.org

http://phenopackets.org/

Acknowledgments • Chris Mungall

(schema/architecture) • Jules Jacobsen (java API) • James Balhoff (pxftools) • Jeremy Nguyen-Xuan (pxftools) • Seth Carbon (web phenote) • Kent Shefcheck (python API) • Matt Brush (modeling) • Dan Keith (web phenote) • Satwik Bhattamishra (GSOC

student, PhenoPacketScraper)

• Julie McMurry • Peter Robinson • Pier Buttigieg • Ramona Walls • Damian Smedley • Sebastian Kohler • Tudor Groza • Harry Hochheiser • Mark Diekhans • Melanie Courtot • Michael Baudis • Helen Parkinson • Suzanna Lewis

Monarch Initiative NIH R24 OD011883

Phenopacket Tool ecosystem

• Non JVM language bindings – Python (beta)

• https://github.com/phenopackets/phenopacket-python/ – Javascript (alpha)

• https://github.com/phenopackets/phenopacket-js/ • Pxftools

– command line library, Scala utilities – https://github.com/phenopackets/pxftools

• PhenoPacketScraper – GSOC project to make phenopackets from case study articles – https://github.com/monarch-initiative/phenopacket-scraper-core

• OwlSim – Like blast, for phenotypes – https://github.com/monarch-initiative/owlsim-v3

• WebPhenote – Noctua extension for phenopacket creation – http://create.monarchinitiative.org

https://github.com/phenopackets/phenopacket-python/https://github.com/phenopackets/phenopacket-js/https://github.com/phenopackets/pxftoolshttps://github.com/monarch-initiative/phenopacket-scraper-corehttps://github.com/monarch-initiative/owlsim-v3http://create.monarchinitiative.org/

Making Phenotypic data FAIR++ for Disease Diagnosis and DiscoveryBiology central dogmaComputable encodings are essentialStandard exchange formats exist for genes … �but for phenotypes? Environment?�Slide Number 5A simple data modelPhenopackets for clinical labsPhenopackets for journalsPhenopackets for biomedical databasesPhenopackets for laypersonsPhenoPacket formatsSimple Example (patient profile)Nesting allows refinementSimple Example (variants)Semantics with JSON-LDSummary: Phenotype Exchange FormatAcknowledgmentsPhenopacket Tool ecosystem