Adverse Outcome Pathway Networks and the AOP Knowledgebase Stephen - - PowerPoint PPT Presentation

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Adverse Outcome Pathway Networks and the AOP Knowledgebase Stephen - - PowerPoint PPT Presentation

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Adverse Outcome Pathway Networks and the AOP Knowledgebase Stephen Edwards U.S. Environmental Protection Agency Integrated Systems Toxicology Division Outline Knowledge management Evidence assembly Data organization

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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

  • ffspring,

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

  • ffspring,

Increase DNA, Alkylation

Molecular Cellular Organism

Mutations, Increase

Alkylation of DNA in male pre-meiotic germ cells leading to heritable mutations

Process: DNA alkyla0on Object: DNA Ac0on: increased Context: eukaryo0c cell Process: dna repair Object: DNA Ac0on: func0onal change Context: eukaryotic cell Process: induced mutation Object: DNA Ac0on: increased Context: Process: induced muta0on Object: DNA Ac0on: increased Context: 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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mixed molecular

  • rganelle

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 Event 2 Concentration, [log M] Key Event 1

Transformation of Dose-Response to Response- Response

Key Event 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

Toxicants Macro- Molecular Interactions Cellular Responses Organ Responses Organism Responses Population Responses

Time & Modifying Factors (Genetics, Disease, Prior Exposures, Subsequent Exposures, Sex, Life Stage, …)

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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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Toxicity Pathway, NRC 2007 Aggregate Exposure Pathway, Teeguarden 2016 Adverse Outcome Pathway, Ankley 2010, Villeneuve 2014

Biomarkers of Exposure Bioindicators of Key Events

Measurement Understanding

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