adverse outcome pathway networks and the aop knowledgebase · adverse outcome pathway networks and...
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Adverse Outcome Pathway Networks and the AOP Knowledgebase
Stephen Edwards U.S. Environmental Protection Agency Integrated Systems Toxicology Division
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Outline
• Knowledge management – Evidence assembly – Data organization – Computational modeling
• AOP Networks – Automatic assembly by design – Basis for decision support tools – Challenges and opportunities
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AOPs Connect Toxicity Pathways to Regulatory Endpoints
Predictivity of measurement for AO decreases
Time between exposure and effect increases
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Factors Determining Predictivity of Early Key Events
• Evidence supporting the KERs between that KE and the AO • Quantitative understanding of the downstream KERs • Modifying factors that influence downstream KEs & KERs
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AOP-KB e.AOP.portal
Third party Applications,
plugins
AOP-XML
AOP Xplorer Visualize attribute
networks to discover & explore AOPs in a broader
context
Effectopedia Detailed development of
structured & computational AOPs
AOP Wiki Collaborative development of AOP descriptions & evidence
http://aopkb.org/ https://aopwiki.org/ https://www.effectopedia.org/
Intermediate Effects DB
Put chemical-related AOP components in a regulatory
context
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Factors Determining Predictivity of Early Key Events
• Evidence supporting the KERs between that KE and the AO • Quantitative understanding of the downstream KERs • Modifying factors that influence downstream KEs & KERs
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Carole Yauk – https://aopwiki.org/aops/15 Yauk et al., Environ Mol Mutagen (2015) 56:724-50. doi: 10.1002/em.21954.
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Ontologies that describe key events in existing AOPs
Stressor
Event Title
Level of Org
Event(s) Tissue
Key Event Key Event Key Event
AOP
KER KER
(MIE
)
(AO
)
Level of Organization
Molecular Cellular Tissue Organ
Individual Population Event
Component Process Object Action
Process GO, etc Object
GO, etc. Context Cellular (CL)
Organ (Uberon) Species (NCBI)
AOP Components
Lyle Burgoon Cataia Ives
Action PATO
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Event components-Definitions
• Process Biological process, dynamics of the underlying biological system (e.g. receptor signaling). Ideally this represents the normal biology that is perturbed as part of the AOP not the perturbation itself.
• Object Biological object (e.g. specific biological receptor that is activated or inhibited). This term again represents the object only and is associated with the normal biology of the system.
• Action This represents the perturbation of this system described by the other two terms that results in this key event (e.g. ‘decreased’ in the case the a receptor is inhibited to indicate a decrease in the signaling by that receptor).
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https://aopwiki.org/aops/15
Insufficient or incorrect DNA
repair
Heritable mutations in
offspring, Increase
DNA, Alkylation
Molecular Cellular Organism
Mutations, Increase
Alkylation of DNA in male pre-meiotic germ cells leading to heritable mutations
Cataia Ives
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https://aopwiki.org/aops/15
Insufficient or incorrect DNA
repair
Heritable mutations in
offspring, Increase
DNA, Alkylation
Molecular Cellular Organism
Mutations, Increase
Alkylation of DNA in male pre-meiotic germ cells leading to heritable mutations
Process:DNAalkyla0onObject:DNAAc0on:increasedContext:eukaryo0ccell
Process:dnarepairObject:DNA Ac0on:func0onalchangeContext:eukaryotic cell
Process:induced mutation Object:DNA Ac0on:increasedContext:
Process:inducedmuta0onObject:DNA Ac0on:increasedContext:eukaryotic cell
Cataia Ives
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What's new in the AOP Wiki • The AOP Wiki now provides authors the ability to tag AOPs with terms from controlled
vocabularies and ontologies.
• In order to harmonize the tagging of existing AOPs in the Wiki, we worked with authors to annotate all AOPs in the AOP-Wiki as of December 4, 2016.
• Currently working on instructions for authors to annotate their own AOPs in the future.
Ivana Campia
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Factors Determining Predictivity of Early Key Events
• Evidence supporting the KERs between that KE and the AO • Quantitative understanding of the downstream KERs • Modifying factors that influence downstream KEs & KERs
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AOP Provides Understanding & Scaffold for Data
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mix
ed
molecular organelle cellular Level of Biological Organisation
Fadrozole
Aromatase Inhibition
amphioxus vertebrates
Reduced E2 synthesis
amphioxus vertebrates
Pathway Elements and quantitative information
Sex
In-Vitro H295R
human cells Fadrozole
f(x)
In-Vivo Aromatase inhibition in
primary tissue Fathead minnow
Fadrozole
f(x)
Ex-Vivo
Aromatase inhibition
Fathead minnow
Fadrozole
f(x)
In-Vitro Tox21
Aromatase Inhibition
Fadrozole
f(x)
In-Silico Petko Petkov’s
model • Applicability domain • Executable source code
f(x)
In-vivo
Radio Immuno Assay
Fathead minnow
Fadrozole
f(x)
In-Silico Model
• Applicability
domain • Executable
source code
f(x)
Effectopedia Hristo Aladjov
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Key
Eve
nt 2
Concentration, [log M]
Key
Eve
nt 1
Transformation of Dose-Response to Response-
Response
Key
Eve
nt 2
Key Event 1
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Factors Determining Predictivity of Early Key Events
• Evidence supporting the KERs between that KE and the AO • Quantitative understanding of the downstream KERs • Modifying factors that influence downstream KEs & KERs
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AOP networks emerge as AOPs are entered into the AOP-Wiki
Courtesy of Dan Villeneuve
AOP:30
AOP:25
AOP:23
Key Events Shared by Multiple AOPs
Linkages Shared by Multiple AOPs
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AOP Network as Stored in the AOP-Wiki
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Dan Villeneuve – https://aopwiki.org/aops/25
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Chemical Interactions Emerge from AOP Networks
Nelms, M.D., et al. (2017) in Chemical Mixtures and Combined Chemical and Nonchemical Stressors: Exposure, Toxicity, Analysis and Risk
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AOP Networks Incorporate “Effect Modifiers”
Gallagher, et al., (2010) in “Biomarkers in Medicine, Drug Discovery and Environmental Health”
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Factors Determining Predictivity of Early Key Events
• Evidence supporting the KERs between that KE and the AO • Quantitative understanding of the downstream KERs • Modifying factors that influence downstream KEs & KERs
ToxicantsMacro-
MolecularInteractions
CellularResponses
OrganResponses
OrganismResponses
PopulationResponses
Time & Modifying Factors (Genetics, Disease,PriorExposures, SubsequentExposures, Sex,LifeStage,…)
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Too many AOPs, too little time…
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Noffisat Oki, Shannon Bell
Bell et al. (2016) Toxicol. Sci., 150:510-520 doi:10.1093/toxsci/kfw017 Oki & Edwards (2016) Toxicology, 350–352:49–61 doi:10.1016/j.tox.2016.04.004 Oki et al. (2016) Current Environmental Health Reports, 3(1):53-63 doi:10.1007/s40572-016-0079-y
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Accelerating AOP Development
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AOP-KB e.AOP.portal
Third party Applications,
plugins
AOP-XML
AOP Xplorer Visualize attribute
networks to discover & explore AOPs in a broader
context
Effectopedia Detailed development of
structured & computational AOPs
AOP Wiki Collaborative development of AOP descriptions & evidence
https://github.com/DataSciBurgoon/aop_networks
Intermediate Effects DB
Put chemical-related AOP components in a regulatory
context
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OECD AOP-KB (http://aopkb.org/) Supports All Stages of Development
AOP-Xplorer –http://apps.cytoscape.org/apps/aopxplorer AOP-Wiki –https://aopwiki.org/ Effectopedia –http://effectopedia.org/
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ToxicityPathway,NRC2007
AggregateExposurePathway,Teeguarden2016 AdverseOutcomePathway,Ankley2010,Villeneuve2014
Biomarkers of Exposure
Bioindicators of Key Events
Measurem
ent U
nderstanding
Environmental/Personal Exposure Monitoring
Apical Endpoints/ Adverse Outcomes
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Acknowledgements OECD AOP-KB Working Group
• Clemens Wittwehr• Brigitte Landesmann• Ivana Campia• Sharon Munn• Ahmed Sayed• Maurice Whelan
• Ed Perkins• Lyle Burgoon• Natalia Garcia
Reyero
• Hristo Aladjov• Magda Sachana• Joop DeKnecht
• Stephen Edwards• Dan Villeneuve• Kevin Crofton• Gary Ankley• Robert Kavlock
• Evgeniia Kazymova• Cataia Ives• Rose Combs• Landon Grindheim• Max Felsher• Brendan Ferreri-Hanberry• David Lyons
• Collaborative Partners– OECD External Advisory Group on
Molecular Screening & Toxicogenomics
– IPCS/WHO Mode of Action Steering Committee
OECD AOP Ontology Efforts
• AOP-KB Ontology Effort
• Stephen Edwards• Cataia Ives
• Clemens Wittwehr• Ivana Campia• Brigitte Landesmann
• Hristo Aladjov• Magda Sachana
• Lyle Burgoon
• OECD Ontology WG
• Richard Currie (chair)• Ahmed Abdelaziz• Annamaria Colacci• George Fotakis• Ignacio Tripodi• Nikolai Georgiev Nikolov• Nina Jeliazkova• Olga Tcheremenskaia
• AOP-KB Representatives
•Cataia Ives•Ivana Campia•Clemens Wittwehr
•Rong-Lin Wang
•Lyle Burgoon•Kyle Painter
CSS AOP Discovery & Development Project
Team
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Additional Information Available Online • Reference
– https://www.epa.gov/chemical-research/adverse-outcome-pathway-aop-research-brief
– http://www.oecd.org/chemicalsafety/testing/adverse-outcome-pathways-molecular-screening-and-toxicogenomics.htm
– http://www.saaop.org/workshops/somma.html – http://www.saaop.org/workshops/pellston2017.html
• Training – https://aopwiki.org/training/ – https://humantoxicologyproject.org/about-pathways-2/ – http://setac.sclivelearningcenter.com/index.aspx?PID=9484&SID=215605