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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
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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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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
b
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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AOPs in AOP-Wiki contain many types of info
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Adverse Outcome Pathway:- Abstract- Background- Applicability- Key Events- Key Event Relationships- Stressors- Assessment
https://aopwiki.org/aops/38
www.openrisknet.org
AOPs in AOP-Wiki contain many types of info
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Stressor:- Chemical - CAS - DSStox - InchiKey - Names- Evidence- Description
Stressor:- Chemical - CAS - DSStox - InchiKey - Names- Evidence- Description
Stressor:- Chemical - CAS - DSStox - InchiKey - Names- Evidence- Description
Adverse Outcome Pathway:- Abstract- Background- Applicability- Key Events- Key Event Relationships- Stressors- Assessment
https://aopwiki.org/aops/38
www.openrisknet.org
https://aopwiki.org/aops/38
Adverse Outcome Pathway:- Abstract- Background- Applicability- Key Events- Key Event Relationships- Stressors- Assessment
AOPs in AOP-Wiki contain many types of info
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Stressor:- Chemical - CAS - DSStox - InchiKey - Names- Evidence- Description
Stressor:- Chemical - CAS - DSStox - InchiKey - Names- Evidence- Description
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
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
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
Key Event:- Description- Method- Key Event components - Biological process - Biological object - Biological action- Applicability - Taxonomy - Life stage - Sex
www.openrisknet.org
https://aopwiki.org/aops/38
Adverse Outcome Pathway:- Abstract- Background- Applicability- Key Events- Key Event Relationships- Stressors- Assessment
Key Event Relationship:- Description- Biological plausibility- Empirical evidence- Uncertainties- Quantitative understanding- Applicability - Taxonomy - Life stage - Sex
AOPs in AOP-Wiki contain many types of info
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Stressor:- Chemical - CAS - DSStox - InchiKey - Names- Evidence- Description
Stressor:- Chemical - CAS - DSStox - InchiKey - Names- Evidence- Description
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
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
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
Key Event:- Description- Method- Key Event components - Biological process - Biological object - Biological action- Applicability - Taxonomy - Life stage - Sex
Key Event Relationship:- Description- Biological plausibility- Empirical evidence- Uncertainties- Quantitative understanding- Applicability - Taxonomy - Life stage - Sex
Key Event Relationship:- Description- Biological plausibility- Empirical evidence- Uncertainties- Quantitative understanding- Applicability - Taxonomy - Life stage - Sex
Key Event Relationship:- Description- Biological plausibility- Empirical evidence- Uncertainties- Quantitative understanding- Applicability - Taxonomy - Life stage - Sex
Key Event Relationship:- Description- Biological plausibility- Empirical evidence- Uncertainties- Quantitative understanding- Applicability - Taxonomy - Life stage - Sex
Key Event Relationship:- Description- Biological plausibility- Empirical evidence- Uncertainties- Quantitative understanding- Applicability - Taxonomy - Life stage - Sex
Key Event Relationship:- Description- Biological plausibility- Empirical evidence- Uncertainties- Quantitative understanding- Applicability - Taxonomy - Life stage - Sex
www.openrisknet.org
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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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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http://aopwiki-rdf.prod.openrisknet.org/sparql/
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
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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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BridgeDb functionalities through API and UI
Deployed Docker image as API with Swagger User Interfacehttp://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
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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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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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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
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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
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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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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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