An Introduction to the AOP Knowledgebase

Transcription

1 An Introduction to the AOP Knowledgebase Dr. Kellie Fay, Research Toxicologist, University of Minnesota-Duluth in cooperative agreement with the US EPA ORD Mid-Continent Ecology Division* *The contents of this presentation neither represent nor necessarily reflect official US EPA policy.

2 Introduction to the AOP-KB Objectives: Why do we need an AOP-KB? What are the components of the AOP-KB? How do I access the AOP-wiki? What information is there and how is it organized? How do I navigate the wiki to find the information that is of interest?

3 Need for an AOP-KB Needs from a regulatory standpoint: Systematically organized Transparent, well documented Scientifically-defensible, credible How certain are we? Pathway-based bioactivity profile Potential/ probable AO OECD Guidance on Developing and Assessing AOPs Review and evaluation process Conceptually, AOP description documents could meet those needs.

4 Need for an AOP-KB

5 Need for an AOP-KB Documents are not ideal for: Facilitating collaboration and crowd-sourcing Avoiding duplicative effort Integration and analysis Accessible and searchable

6 AOP-KB supports principles of AOP development AOPs are modular KEs and KERs are shared by multiple AOPs No need to re-write the same descriptions over and over Reusability (best practices) AOPs are living documents KE and KER descriptions can be expected to evolve over time As descriptions are updated and expanded all AOP descriptions they link to update automatically AOP networks for prediction Entry of structured information in KB allows for de-facto assembly of AOP networks.

7 Components of the AOP-KB

8 Roles of individual modules AOP-KB e.aop.portal "Main entry point for the AOP-KB" Search engine for all AOPs (currently from AOP-Wiki & Effectopedia) Will house the status of all AOPs in the OECD work plan & the official copy of OECD endorsed AOPs Will allow browsing of review reports e.aop.portal

9 Roles of individual modules AOP-KB Effectopedia: "Explicitly captures quantitative information" Supports OECD review & endorsement of quantitative AOPs Quantitative information is intrinsic, ultimately also code execution 2017

10 Roles of individual modules AOP-KB Xplorer: "Creates and visualizes AOPs in a network context" Web version: Will create and visualize AOP networks Will use Wiki and Effectopedia AOPs Next: Download version with additional capabilities for data analysis to support chemical assessments 2017

11 Roles of individual modules AOP-KB Intermediate Effects DB (IEDB): "Provides AOP-related data from well documented chemical studies" Supports AOPs with OHT201 based results Based on IUCLID6 Possible to re-use data in other OHT contexts Potential bridge to OECD echemportal 2017

12 Roles of individual modules AOP-KB Wiki: "Entry level module for evaluating an AOP s scientific evidence" Supports OECD review and endorsement of formal AOPs Default go-to module for all qualitative AOPs Quantitative information is given verbally in appropriate sections No modelling tool Publically accessible since September 2014

13 Modular organization. Allows independent KE, KER pages to be linked to multiple AOPs. Section 5b MIE, KE, and AO descriptions OECD Handbook Step by step guide to AOP development common/ AOP_Handbook.pdf Section 1 Title Section 2 Authors Section 3 - Status Section 4 Abstract Background (Optional) AOP Page Section 5a Summary of the AOP MIE KEs MIE Page Chemical initiator(s) Description Measurement/ detection Taxonomic applicability Evidence for chemical initiation KE Pages Description Measurement/ detection Taxonomic applicability AO Page Description Measurement/ detection Taxonomic applicability Regulatory relevance AOP-Wiki Provides consistent structure based on the OECD handbook and facilitates collaborative AOP development Linkage table AO Key Event Relationships Applicability domain(s) of the AOP Life-stage Taxonomic Sex Section 7 Overall Assessment of the AOP Modified Bradford Hill Considerations Section 8 Considerations for Potential Applications of the AOP Section 6 Scientific evidence supporting the linkages in the AOP KER Pages Title Description Biological plausibility Empirical support Inconsistencies and uncertainties Quantitative understanding

14 Accessing the AOP-Wiki Read access Open to anyone, no account required Commenting Create account, no approvals required Author/write access Gardener (experienced AOP developers/ wiki users) Create account Submit brief developer application for approval Help ensure consistency with published principles and OECD guidelines

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16 Requesting Author Status Two Options Submit a proposal for the OECD programme Request wiki access first, develop the AOPs, then submit OECD proposal To request wiki access For OECD projects (option 1), just provide the project title and leader . Once information has been confirmed access is automatic. Otherwise, submit a brief description of the proposed AOP. You may be paired with an experience wiki developer or need to refine the proposed AOP before access is granted. One request can be made for all authors related to a single project.

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18 Tour of the AOP-Wiki

19 AOP-Wiki

20 AOP-Wiki Can browse AOP list for content relevant to your question of interest. Organized according to development/review status

21 Searching the AOP-Wiki Follow links from the search page to examine page content.

22 Searching the AOP-Wiki Can also view a listing of KEs organized alphabetically. Search KEs

23 Searching the AOP-Wiki

24 Searching the AOP-Wiki AOPs are not chemical-specific Chemicals known to trigger MIEs are captured as chemical initiator pages.

25 Searching the AOP-Wiki Can find all AOPs that have been linked to this chemical initiator Eventually the goal will be to link-in from chemical information sources like EPA s chemistry dashboard, Chem-Spider, Pub- Chem, etc.

26 AOP-Wiki: Content and Organization AOP Title takes the form [MIE] leading to [AO] If no MIE, earliest KE If multiple AOPs with same MIE and AO, may refer to one or more distinctive KEs.

27 AOP-Wiki: Content and Organization Convention: Name and contact information for individual(s)/organization(s) that developed the AOP. Indicate author to whom correspondence should be addressed.

28 AOP-Wiki: Content and Organization Why?: Keeps users informed about how actively the AOP is being developed. Helps AOP users evaluate whether the AOP has evolved markedly since it was approved for use, cited, or otherwise applied (aids with version control). Communicates status in terms of readiness for comment and/or review. Functionality to create and view a snapshot

29 OECD AOP Review Process Work Process for Development and Review of AOPs through OECD 1. Proposal by a stakeholder to develop an AOP 2. Development of an AOP on the AOP-KB 3. Content and structure review by EAGMST 4. Technical review by OECD expert groups 5. Approval by sub-bodies and publication of accepted AOP

30 OECD AOP Review Process

31 AOP-Wiki: Content and Organization Convention: Concise and informative summation Background and purpose for development Brief description of MIE, AO, major KEs Short summation of overall WOE and major knowledge gaps Optional suggestions for potential applications

32 AOP-Wiki: Content and Organization

33 Key Event Pages: Example Each event page has a unique identifier Table links to all AOP (pages) that include this key event

34 Key Event Pages: Example Example of content found only on MIE pages. Links to chemical-initiator page. Structured taxonomy information generally used for selected species upon which much of the supporting data are based.

35 Chemical Initiator Pages: Example

36 Key Event Pages: Example What type of change in biological state does the KE refer to? How is that change in biological state measured? More general qualitative description of the taxonomic, life/stage, sex domain the KE applies to. Example of content found only on MIE pages.

37 AOP-Wiki: Content and Organization

38 Section 6. KER Pages: Information Content KER Pages Title Description Biological plausibility Empirical support Inconsistencies and uncertainties Quantitative understanding KER titles take the form: KEup [directly leads to] [indirectly leads to] KEdown.

39 Direct vs. Indirect KERs KER Pages: Information Content KERs always link a pair of KEs (one upstream, one downstream). Those KEs may be adjacent (direct) or non-adjacent (indirect). Indirect KERs allow for assembly of weight of evidence that skips over/bridges some of the KEs in the pathway. Indirect KER Indirect KER KER 1 KER 2 KER n-1 KER n MIE KE 1 KE n-1 KE n AO Indirect KER

40 KER Pages: Information Content KER Pages Title Description Biological plausibility Empirical support Inconsistencies and uncertainties Quantitative understanding Description Additional specificity/context that dictates which downstream KE a more generalized upstream KE will lead to. Inflammation In liver In lung In brain KE1 KE2 KE3

41 KER Pages: Example Each relationship page has a unique identifier Table links to each of the KEs connected via this relationship Table links to all AOP (pages) that include this KER

42 KER Pages: Example Note: KEs and AOPs are written to be generalizable across chemical, species, etc. as much as possible KER pages include specific details about species, chemicals, conditions under which supporting evidence for the relationship were generated.

43 Overall Assessment of the AOP Critical information that informs: Level of confidence/certainty Appropriate domain of application Key data gaps/data needs Suitable regulatory applications

44 Overall Assessment of the AOP Effective summation of expert opinion regarding confidence in extrapolation along the AOP Based on developer(s) knowledge Critical to application of the AOPs in the regulatory community Transparency and rationale to support an inherently subjective determination.

45 Consideration of Potential Applications of the AOP

46 OECD AOP-KB Working Group Stephen Edwards Dan Villeneuve Kevin Crofton Gary Ankley Robert Kavlock Collaborative Partners OECD External Advisory Group on Molecular Screening & Toxicogenomics IPCS/WHO Mode of Action Steering Committee David Lyons Max Felsher Rose Combs Landon Grindheim Cataia Ives Clemens Wittwehr Brigitte Landesmann Ivana Campia Sharon Munn Maurice Whelan Ed Perkins Lyle Burgoon Natalia Garcia Reyero Hristo Aladjov Magda Sachana Joop DeKnecht