Adverse Outcome Pathways Linking experimental data to · 2019. 3. 27. · OpenRiskNet: Open...

www.openrisknet.org

OpenRiskNet: Open e-Infrastructure to Support Data Sharing, Knowledge Integration and in silico Analysis and Modelling in Risk Assessment

Project Number 731075

AOPLinkLinking experimental data to Adverse Outcome Pathways

Marvin Martens, Egon Willighagen, Chris Evelo

www.openrisknet.org

Vision: Connect scientist and regulators

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Goals of this AOPLink webinar

1. Describe which research questions can be answered with AOPLink

2. Describe the OpenRiskNet tools that are used

3. Plans for 2019

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1. Research questions to answer with AOPLink

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AOPLink: two major research questions

Q1: For an AOP, which experimental data is available to support the AOP?

Q2: Can this experimental data support an existing AOP?

Experimental data Adverse Outcome Pathways

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Adverse Outcome Pathways (AOPs)

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Adverse Outcome Pathway (AOP) concept

Framework that captures mechanistic knowledge of toxicological processes to support decision making in risk assessments

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Ankley et al. 2010: https://doi.org/10.1002/etc.34Leist et al. 2017: https://doi.org/10.1007/s00204-017-2045-3

https://doi.org/10.1002/etc.34

https://doi.org/10.1007/s00204-017-2045-3

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AOPs can play major role in risk assessment

Aid Integrated Approaches to Testing and Assessment

Predictive value

Less need for animal testing

Identify knowledge gaps

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AOPLink: Linking data to Adverse Outcome Pathways

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www.openrisknet.orgBerggren et al. https://doi.org/10.1016/j.comtox.2017.10.001

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https://doi.org/10.1016/j.comtox.2017.10.001

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AOPLink in context of OpenRiskNet

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2. Which OpenRiskNet tools are involved in AOPLink?

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AOPLink overview

AOP-Wiki

TG-GATES

ToxCastAOP

Adverse Outcome

Chemical (CAS-RN)

WikiPathways

Chemical databases

BridgeD

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ToxRefDB

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AOPLink overview + project data + other case studies

AOP-Wiki

TG-GATES

ToxCastAOP

Adverse Outcome

Chemical (CAS-RN)

WikiPathways

Chemical databases

TGX SysGroup

EU-ToxRisk data

BridgeD

b

ToxRefDB

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AOPLink overview + project data + other case studies + pathway analysis

AOP-Wiki

TG-GATES

ToxCastAOP

Adverse Outcome

Chemical (CAS-RN)

WikiPathways

Chemical databases

TGX SysGroup

EU-ToxRisk data

BridgeD

b

PathVisioRPCToxRefDB

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Central tool in AOPLink: AOP-Wiki

AOP-Wiki is the main qualitative AOP repository of the AOP-KB

Joint effort between EC-JRC and US EPA

Element Number

Adverse Outcome Pathways 246

Key Events 1190

Key Event Relationships 1493

Stressors 438

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AOPs in AOP-Wiki contain many types of info

https://aopwiki.org/aops/38

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Adverse Outcome Pathway:- Abstract- Background- Applicability- Key Events- Key Event Relationships- Stressors- Assessment



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Stressor:- Chemical - CAS - DSStox - InchiKey - Names- Evidence- Description






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Stressor:- Chemical - CAS - DSStox - InchiKey - Names- Evidence- Description Key Event:

- Description- Method- Key Event components - Biological process - Biological object - Biological action- Applicability - Taxonomy - Life stage - Sex

Key Event:- Description- Method- Key Event components - Biological process - Biological object - Biological action- Applicability - Taxonomy - Life stage - Sex







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Key Event Relationship:- Description- Biological plausibility- Empirical evidence- Uncertainties- Quantitative understanding- Applicability - Taxonomy - Life stage - Sex


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Stressor:- Chemical - CAS - DSStox - InchiKey - Names- Evidence- Description Key Event:

- Description- Method- Key Event components - Biological process - Biological object - Biological action- Applicability - Taxonomy - Life stage - Sex














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RDF scheme covers most of the AOP-WikiMain elements converted in RDF:

- Adverse Outcome Pathways- Key Events- Key Event Relationships- Stressors- Chemicals- Taxonomy- Cell-terms- Organ-terms

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AOP-Wiki RDF Virtuoso SPARQL endpoint

Deployed in OpenRiskNet e-infrastructure

As a SPARQL endpoint with AOP-Wiki RDF using a Virtuoso base docker image: (openlink/virtuoso-opensource-7)

Available from: http://aopwiki-rdf.prod.openrisknet.org/sparql/

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http://aopwiki-rdf.prod.openrisknet.org/sparql/

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AOP-Wiki RDF - Example SPARQL queries

Example query #1: From an AOP, give me all measurement methods.

Example query #2: Provide me with all Key Events that could result from a certain chemical.

Example query #3: Give me all Molecular Initiating Events that lead to a particular Adverse Outcome.

Example (federated) query #4: From all chemicals in AOP-Wiki, give me all molecular pathways of WikiPathways that contain the chemical.

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Example query #1:

prefix dc: <http://purl.org/dc/elements/1.1/>prefix dcterms: <http://purl.org/dc/terms/>prefix rdfs: <http://www.w3.org/2000/01/rdf-schema#>prefix aop: <http://identifiers.org/aop/>prefix aopo: <http://aopkb.org/aop_ontology#>prefix mmo: <http://purl.obolibrary.org/obo/MMO_>

select ?AopLabel?KeLookUp ?AssayTextwhere { ?KeLook a aopo:KeyEvent ; rdfs:label ?KeLookUp ; dcterms:isPartOf ?aop ; mmo:0000000 ?AssayText . ?aop dc:identifier ?AopAssoc ; rdfs:label ?AopLabel . filter (?aop = aop:12)

}

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Example query #2: Look up all KEs related to AOPs that are affected by a certain chemical (allyl alcohol in this case, related to previously shown AOP)

prefix dc: <http://purl.org/dc/elements/1.1/>prefix dcterms: <http://purl.org/dc/terms/>prefix rdfs: <http://www.w3.org/2000/01/rdf-schema#>prefix aop: <http://identifiers.org/aop/>prefix aopo: <http://aopkb.org/aop_ontology#>prefix ke: <http://identifiers.org/aop.events/>prefix stressor: <http://identifiers.org/aop.stressor/>prefix casrn: <http://identifiers.org/cas/>prefix ncit: <http://ncicb.nci.nih.gov/xml/owl/EVS/Thesaurus.owl#>

select ?chemicalName ?StressorLookUp ?AOPname ?AOPLookUp ?KEname ?KEofAOPwhere { ?chemical a cheminf:CHEMINF_000000 ; dc:title ?chemicalName ; dcterms:isPartOf ?StressorLookUp . ?StressorLookUp a ncit:C54571 ; dcterms:isPartOf ?AOPLookUp . ?AOPLookUp a aopo:AdverseOutcomePathway ; aopo:has_key_event ?KEofAOP ; dc:title ?AOPname . ?KEofAOP a aopo:KeyEvent ; dc:title ?KEname . filter (?chemical = casrn:107-18-6)}

https://github.com/marvinm2/AOPwikiVirtuoso


https://github.com/marvinm2/AOPwikiVirtuoso

www.openrisknet.org

Example query #3:

prefix dc: <http://purl.org/dc/elements/1.1/>prefix aop: <http://identifiers.org/aop/>prefix aopo: <http://aopkb.org/aop_ontology#>

select ?KE ?KEname ?AOP ?AOPname ?MIE ?MIEnamewhere { ?KE a aopo:KeyEvent ; dc:identifier ?AOLookup ; dc:title ?KEname . ?AOP a aopo:AdverseOutcomePathway ; dc:title ?AOPname ; aopo:has_adverse_outcome ?AOLookup; aopo:has_molecular_initiating_event ?MIE. ?MIE dc:title ?MIEname .

filter (?KE = ke:345)}

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Example query #4:

prefix dc: <http://purl.org/dc/elements/1.1/>prefix dcterms: <http://purl.org/dc/terms/>prefix cheminf: <http://semanticscience.org/resource/> prefix wdt: <http://www.wikidata.org/prop/direct/>prefix wp: <http://vocabularies.wikipathways.org/wp#>prefix aopo: <http://aopkb.org/aop_ontology#>

select distinct ?ChemicalName ?LinkedAOP ?LinkedAOPURI ?CASRN ?ChemicalURI ?PathwayID ?PathwayURI where{select *where { ?cheLook a cheminf:CHEMINF_000000 ; dc:identifier ?ChemicalURI ; dc:title ?ChemicalName ; cheminf:CHEMINF_000446 ?CASRN ; dcterms:isPartOf ?LinkedStressor. ?LinkedStressor dcterms:isPartOf ?LinkedAOPURI . ?LinkedAOPURI a aopo:AdverseOutcomePathway ; rdfs:label ?LinkedAOP. service <https://query.wikidata.org/bigdata/namespace/wdq/sparql>{ ?wikidata wdt:P231 ?CASRN. service <http://sparql.wikipathways.org/>{ ?metabolite wp:bdbWikidata ?wikidata; dcterms:isPartOf ?PathwayURI. ?PathwayURI a wp:Pathway ; dcterms:identifier ?PathwayID.

}}}} order by ?ChemicalName

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BridgeDb - bridging biological databases

Identifier mapping for a variety of things:

- Metabolites- Genes - Proteins- Genetic variants- Metabolite interactions

Van Iersel et al. https://doi.org/10.1186/1471-2105-11-5

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https://doi.org/10.1186/1471-2105-11-5

www.openrisknet.org

BridgeDb functionalities through API and UI

Deployed Docker image as API with Swagger User Interfacehttp://bridgedbfull.prod.openrisknet.org/swagger/

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http://bridgedbfull.prod.openrisknet.org/swagger/

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WikiPathways - general description

Biological pathway database

Molecular knowledge

Interoperable

- RDF, SPARQL endpoint, ontologies

Used for omics analysis with PathVisio and Cytoscape for network analysis

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Waagmeester et al. https://doi.org/10.1371/journal.pcbi.1004989 Slenter et al. https://doi.org/10.1093/nar/gkx1064

https://doi.org/10.1371/journal.pcbi.1004989

https://doi.org/10.1093/nar/gkx1064

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WikiPathways SPARQL endpoint: demo

Deployed as a SPARQL endpoint with WikiPathways RDF using a Virtuoso base docker image: (openlink/virtuoso-opensource-7):http://wikipathways.prod.openrisknet.org/sparql/

Deployment configurations available: https://github.com/wikipathways/WikiPathwaysVirtuosoDocker

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http://wikipathways.prod.openrisknet.org/sparql/

https://github.com/wikipathways/WikiPathwaysVirtuosoDocker

www.openrisknet.org

Databases by EdelweissData Explorer

EdelweissData Explorer allows queries for data from:

- ToxCast- ToxRefDB- TG-GATES

Link to the service: https://data.douglasconnect.com/

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https://data.douglasconnect.com/

www.openrisknet.org

Status: ready to answer research questions

Required services are working and deployed in the OpenRiskNet e-Infrastructure:

- AOP-Wiki SPARQL endpoint- BridgeDb- WikiPathways SPARQL endpoint- DC Data Explorer

To answer the research questions, workflows need to be developed

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3. 2019: Refining and Coverage

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Completing the AOP-Wiki RDF scheme

Missing elements:

- Key Event Components- Confidence levels- Biological levels- Key Event Relationship evidence

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Extending the AOP-Wiki RDF scheme

Possible additions:

- Additional chemical identifiers- Human gene ID mapping- Chemical-target interactions- Links to ToxCast (sAOP)

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Integration of PathVisioRPC

PathVisio functionalities withoutneeding to install the software

From a variety of preferred programming languages

Visualise and analyse expression data on molecular pathways from WikiPathways

https://doi.org/10.1186/s12859-015-0708-836

www.openrisknet.org

Plans for inclusion of the AOP-DB

Winners of the OpenRiskNet implementation challengehttps://openrisknet.org/associated-partner-programme/implementation-challenge/

Database of AOPs with connections to:- Genes- Chemicals- Pathways- ToxCast- Diseases

AOP-DB webinar on April 8th, 2019, 4PM CESThttps://openrisknet.org/events/60/

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Pittman et al. https://doi.org/10.1016/j.taap.2018.02.006Mortensen et al. https://doi.org/10.1007/s00335-018-9738-7

https://openrisknet.org/associated-partner-programme/implementation-challenge/

https://openrisknet.org/events/60/

https://dx.doi.org/10.1016%2Fj.taap.2018.02.006

https://doi.org/10.1007/s00335-018-9738-7

www.openrisknet.org

AOP-Wiki

TG-GATES

ToxCastAOP

Adverse Outcome

Chemical (CAS-RN)

WikiPathways

Chemical databases

TGX SysGroup

EU-ToxRisk dataB

ridgeDb

PathVisioRPC

ToxRefDB

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AOP-Wiki

TG-GATES

ToxCastAOP

Adverse Outcome

Chemical (CAS-RN)

WikiPathways

Chemical databases

TGX SysGroup

EU-ToxRisk dataB

ridgeDb

PathVisioRPC

ToxRefDBAOP-DB-Genes-Chemicals-Pathways-ToxCast -Diseases

KEs sAOP

ArrayExpressGEODiXa

Key Event Components

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AOP-Wiki

TG-GATES

ToxCastAOP

Adverse Outcome

Chemical (CAS-RN)

WikiPathways

Chemical databases

TGX SysGroup

EU-ToxRisk dataB

ridgeDb

PathVisioRPC

ToxRefDBAOP-DB-Genes-Chemicals-Pathways-ToxCast -Diseases

LAZAR:Chemical similarity

KEs sAOP ChemIdConverter

ArrayExpressGEODiXa

Key Event Components

SCAIView

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Workflows will be written in Jupyter

Jupyter notebooks allow systematic workflows

JupyterHub deployed in the OpenRiskNet e-Infrastructurehttps://jupyterhub-jupyter.prod.openrisknet.org/hub/login

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https://jupyterhub-jupyter.prod.openrisknet.org/hub/login

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Acknowledgements

OpenRiskNet (Grant Agreement 731075) is a project funded by the European Commission within Horizon 2020 Programme

Project partners:P1 Douglas Connect GmbH, Switzerland (DC)P2 Johannes Gutenberg-Universität Mainz, Germany (JGU)P3 Fundacio Centre De Regulacio Genomica, Spain (CRG)P4 Universiteit Maastricht, Netherlands (UM)P5 The University Of Birmingham, United Kingdom (UoB)P6 National Technical University Of Athens, Greece (NTUA)P7 Fraunhofer Gesellschaft Zur Foerderung Der Angewandten Forschung E.V.,

Germany (Fraunhofer)P8 Uppsala Universitet, Sweden (UU)P9 Medizinische Universität Innsbruck, Austria (MUI)P10 Informatics Matters Limited, United Kingdom (IM)P11 Institut National De L’environnement Et Des Risques INERIS, France (INERIS)P12 Vrije Universiteit Amsterdam, Netherlands (VU)

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