Help: KE Relationships

A-C Create a New Key Event Relationship


Identifier

When a KER is created, an ID number is automatically assigned to it. This number is used for tracking the KER in the AOP-KB.

Title

The title of the KER should clearly define the two KEs being considered and the sequential relationship between them (i.e., which is upstream and which is downstream). Consequently all KER titles take the form “upstream KE leads to downstream KE”.

The KER title is automatically created upon adding a relationship to an AOP. On an individual KER page, the title is of the form “[Upstream event] leads to [downstream event].” The individual upstream event and downstream event are listed directly below the title.

To create a new KER, on an AOP page, click the 'Add relationship' button, which will bring you to a new page entitled, "Add Relationship to AOP." You will have an ability to choose an Upstream Event and a Downstream Event, as well as a value for Directness, Evidence, and Quantitative Understanding. Evidence and Quantitative Understanding fields may be left blank and added later. Click 'Create Aop relationship' to save these changes. You will see a new record in the table on the AOP page under the heading, "Relationships Between Two Key Events (Including MIEs and AOs)."

To edit a KER, from the AOP page under the heading "Relationships Between Two Key Events (Including MIEs and AOs)," click 'Edit.' You will be directed to a new page entitled "Editing [Name of Relationship]" where you will have an ability to edit the Directness, Evidence, and Quantitative Understanding fields using the drop down menus. Click 'Update Aop relationship' to save your changes. The changes should be visible in the table on the AOP page under the heading, "Relationships Between Two Key Events (Including MIEs and AOs)."   

To edit a KER, from the AOP page under the heading "Relationships Between Two Key Events (Including MIEs and AOs)," click 'Remove' and when prompted, click 'OK.'  The relationship should no longer be visible in the table on the AOP page under the heading, "Relationships Between Two Key Events (Including MIEs and AOs)."   

Upstream Event

Upstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page.

Downstream Event

Downstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page.

AOPs Referencing Relationship

This table is automatically generated upon addition of a KER to an AOP. All of the AOPs that are linked to this KER will automatically be listed in this subsection. Clicking on the name of the AOP in the table will bring you to the individual page for that AOP.

D Biological Domain of Applicability for KER


Taxonomic Applicability for KER

 Select one or more structured terms that help to define the biological applicability domain of the KER. In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. Authors can indicate the relevant taxa for this KER in this subsection.

To add a taxonomic term to a KER page, under “Taxonomic Applicability” select ‘Add taxon.’ User will be directed to a page entitled “New Relationship Taxon.” The user can search for and select an existing term from the drop down list of existing terms to populate the “Term” field. If a relevant term does not exist, users may use the "Request New Term" menu function to request a term from AOP-Wiki administrators. The "Scientific Name" field is auto-populated upon addition of a common name.  Evidence can be left blank and added later. Click ‘Create Relationship taxon’ to add this term to the AOP page, where it should appear in the table under "Taxonomic Applicability."

To edit a taxonomic term on a KER page, under “Taxonomic Applicability” next to the Term you wish to add evidence for click ‘Edit.’  User will be directed to a page entitled “Editing Relationship Taxon” where they can edit the Evidence field using the drop down menu. Clicking ‘Update Relationship taxon’ will update the Evidence field and redirect the user back to the KER page.

To remove a taxonomic term on a KER page, under “Taxonomic Applicability” next to the Term you wish to add evidence for click ‘Remove’ then click 'OK.'  The KER page should be updated, with the record no longer in the “Taxonomic Applicability” table.

Life Stage Applicability for KER

Select one or more structured terms that help to define the biological applicability domain of the KER. In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. Authors can indicate the relevant life stage for this KER in this subsection.

To add a life stage term to a KER page, under “Life Stage Applicability” select ‘Add life stage term.’ User will be directed to a page entitled “New Relationship Life Stage.” The user can select a term from the drop down list of existing terms to populate the “Term” field. If a relevant term does not exist, users may use the "Request New Term" menu function to request a term from AOP-Wiki administrators.  Evidence can be left blank and added later. Click ‘Create Relationship life stage’ to add this term to the Relationship page, where it should appear in the table under “Life Stage Applicability."

To edit the “Life Stage Applicability" section, on a KER page under “Life Stage Applicability", click ‘Edit.’ This brings you to a page entitled, “Editing Relationship Life Stage” where an Evidence value may be selected from the drop down menu.  Click ‘Update Relationhsip life stage’ to save your changes.  The edited evidence should appear under the “Life Stage Applicability” section on the KE page.

To remove a life stage term on a KER page, under “Life Stage Applicability" next to the Term you wish to delete click ‘Remove’ then click 'OK.'  The KER page should be updated, with the record no longer in the “Life Stage Applicability” table.

Sex Applicability for KER

 Select one or more structured terms that help to define the biological applicability domain of the KER. In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. Authors can indicate the relevant sex for this KER in this subsection.

To add a sex term to a KER page, under “Sex Applicability” select ‘Add sex term.’ User will be directed to a page entitled “New Relationship Sex Term.” The user can select an existing term from the drop down list of existing terms to populate the “Term” field. If a relevant term does not exist, users may use the "Request New Term" menu function to request a term from AOP-Wiki administrators. Evidence can be left blank and added later. Click ‘Create Relationship sex’ to add this term to the AOP page, where it should appear in the table under "Sex Applicability."

To edit a sex term on a KER page, under “Sex Applicability” next to the Term you wish to add evidence for click ‘Edit.’  User will be directed to a page entitled “Editing Relationship Sex Term" where they can edit the Evidence field using the drop down menu. Clicking ‘Update Relationship sex’ will update the Evidence field and redirect the user back to the KER page.

To remove a sex term on a KER page, under “Sex Applicability” next to the Term you wish to remove click ‘Remove’ then click 'OK.'  The KER page should be updated, with the record no longer in the “Sex Applicability” table.

Evidence Supporting Applicability Domains for KER

As for the KEs, there is also a free-text section of the KER description that the developer can use to explain his/her rationale for the structured terms selected with regard to taxonomic, life stage, or sex applicability, or provide a more generalizable or nuanced description of the applicability domain than may be feasible using standardized terms.

To edit the “Domain of Applicability” section, on a KER page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing KE Relationship.”  Scroll down to the “Domain of Applicability” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update KE relationship’ to save your changes and return to the KER page or "Update and Continue" to continue editing.  The new text should appear under the “Domain of Applicability” section on the KER page.

E Describe the KER


Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE.

Key Event Relationship Description

Provide a brief, descriptive summation of the KER. While the title itself is fairly descriptive, this section can provide details that aren’t inherent in the description of the KEs themselves. The description is also intended to provide a concise overview for readers who may want a brief summation, without needing to read through the detailed support for the relationship.

To edit the “Key Event Relationship Description” section, on a KE page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing KE Relationship.” Scroll down to the “Key Event Relationship Description” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update KE relationship’ to save your changes and return to the KER page or "Update and continue" to continue editing text sections.  The new text should appear under the “Key Event Relationship Description” section on the KER page.

F Evidence Supporting this KER


Evidence Summary

 Assembly and description of the scientific evidence supporting KERs in an AOP is an important step in the AOP development process that sets the stage for overall assessment of the AOP. This section includes any introductory remarks preceding the "Biological Plausibility," “Empirical Support for Linkage,” and “Uncertainties or Inconsistencies” text sections.

To edit the “Evidence Supporting this KER” section, on a KE page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing KE Relationship.” Scroll down to the "Evidence Supporting this KER" section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update KE relationship’ to save your changes and return to the KER page or "Update and continue" to continue editing text sections.  The new text should appear under the "Evidence Supporting this KER" section on the KER page.

Biological Plausibility

Define, in free text, the biological rationale for a connection between KEupstream and KEdownstream. What are the structural or functional relationships between the KEs? For example, there is a functional relationship between an enzyme’s activity and the product of a reaction it catalyses.

To edit the “Biological Plausibility” section, on a KER page in the upper right hand menu click ‘Edit.’ This brings you to a page entitled, “Editing KE Relationship.” Scroll down to the “Biological Plausibility”section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update KE relationship’ to save your changes and return to the KER page or "Update and continue" to continue editing text sections.  The new text should appear under the“Biological Plausibility” section on the KER page.

Empirical Support for Linkage

In this section authors are encouraged to cite specific evidence that supports the idea that a change in the upstream KE (KEupstream) will lead to, or is associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. Given the likelihood that new empirical support will be developed over time, particularly as various AOPs are tested and applied, it is most practical to provide empirical support in the form of bulleted lists or tables that include a short description of the nature of the empirical support along with the corresponding reference(s).

To edit the “Empirical Evidence” section, on a KER page in the upper right hand menu click ‘Edit.’ This brings you to a page entitled, “Editing KE Relationship.” Scroll down to the “Empirical Evidence” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update KE relationship’ to save your changes and return to the KER page or "Update and continue" to continue editing text sections.  The new text should appear under the“Empirical Evidence” section on the KER page.

Uncertainties or Inconsistencies

In addition to outlining the evidence supporting a particular linkage, it is also important to identify inconsistencies or uncertainties in the relationship. This could include, for example, empirical evidence showing changes in KEupstream that did not elicit alterations in KEdownstream. It could also include descriptions of gaps in biological understanding that lend to uncertainties in understanding of the exact nature of the structural or functional relationship between the two KEs.

To edit the "Uncertainties or Inconsistencies" section, on a KER page in the upper right hand menu click ‘Edit.’ This brings you to a page entitled, “Editing KE Relationship.” Scroll down to the "Uncertainties or Inconsistencies" section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update KE relationship’ to save your changes and return to the KER page or "Update and continue" to continue editing text sections.  The new text should appear under the "Uncertainties or Inconsistencies" section on the KER page.

G Quantitative Understanding of the KER


Response-response relationship

This subsection should be used to define sources of data that define the response-response relationships between the KEs. In particular, information regarding the general form of the relationship (e.g., linear, exponential, sigmoidal, threshold, etc.) should be captured if possible.

To edit the "Response-response Relationship" section, on a KER page in the upper right hand menu click ‘Edit.’ This brings you to a page entitled, “Editing KE Relationship.” Scroll down to the "Response-response Relationship" section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update KE relationship’ to save your changes and return to the KER page or "Update and continue" to continue editing text sections.  The new text should appear under the "Response-response Relationship" section on the KER page.

Time-scale

This sub-section should be used to provide information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). This can be useful information both in terms of modelling the KER, as well as for analysing the critical or dominant paths through an AOP network (e.g., identification of an AO that could kill an organism in a matter of hours may render consideration of other potential AOs that take weeks or months to develop lower priority).

To edit the "Time-scale" section, on a KER page in the upper right hand menu click ‘Edit.’ This brings you to a page entitled, “Editing KE Relationship.” Scroll down to the "Time-scale" section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update KE relationship’ to save your changes and return to the KER page or "Update and continue" to continue editing text sections.  The new text should appear under the "Time-scale" section on the KER page.

Known modulating factors

This sub-section presents information regarding modulating factors/variables known to alter the shape of the response-response function that describes the quantitative relationship between the two KEs (for example, an iodine deficient diet causes a significant increase in the slope of the relationship; a particular genotype doubles the sensitivity of KEdownstream to changes in KEupstream). Information on these known modulating factors should be listed in this subsection, along with relevant information regarding the manner in which the modulating factor can be expected to alter the relationship (if known).

To edit the "Known modulating factors" section, on a KER page in the upper right hand menu click ‘Edit.’ This brings you to a page entitled, “Editing KE Relationship.” Scroll down to the "Known modulating factors" section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update KE relationship’ to save your changes and return to the KER page or "Update and continue" to continue editing text sections.  The new text should appear under the "Known modulating factors" section on the KER page.

Feedforward/Feedback loops

This subsection should define whether there are known adaptive or feedback mechanisms or feedforward mechanisms involved and what is understood about their time-course and homeostatic limits? In some cases where feedback or feedforward processes are measurable and causally linked to the outcome, they should be represented as KEs (see development tip 4). However, in most cases these features are expected to predominantly influence the shape of the response-response, time-course, behaviours between selected KEs.

To edit the "Known Feedforward/Feedback loops influencing this KER" section, on a KER page in the upper right hand menu click ‘Edit.’ This brings you to a page entitled, “Editing KE Relationship.” Scroll down to the "Known Feedforward/Feedback loops influencing this KER" section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update KE relationship’ to save your changes and return to the KER page or "Update and continue" to continue editing text sections.  The new text should appear under the "Known Feedforward/Feedback loops influencing this KER" section on the KER page.

Quantitative Understanding

The quantitative understanding section of the KER description is intended to capture information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. While empirical support addresses the expected patterns of quantitative relationships between and among KEs, the quantitative understanding helps to define the precision with which the state of the downstream KE can be predicted from knowledge of the state of the upstream KE. Regardless of form, the idea is to briefly describe what is known regarding the quantitative relationship between the KEs and cite appropriate literature that defines those relationships and/or provides support for them.

To edit the "Quantitative Understanding of the Linkage" section, on a KER page in the upper right hand menu click ‘Edit.’ This brings you to a page entitled, “Editing KE Relationship.” Scroll down to the "Quantitative Understanding of the Linkage" section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update KE relationship’ to save your changes and return to the KER page or "Update and continue" to continue editing text sections.  The new text should appear under the "Quantitative Understanding of the Linkage" section on the KER page.

Classification of quantitative understanding

To aid in overall assessment of the AOP and whether it is fit-for-purpose for various applications, developers are also asked to classify the extent of quantitative understanding of the KER as low, moderate, or high.

The Classification of Quantitative Understanding is edited from the AOP page under the heading "Relationships Between Two Key Events (Including MIEs and AOs)", see here for further instructions: https://aopwiki.org/info_pages/2/info_linked_pages/1#Relationships Between Two Key Events .

H Other KER Information


References for KER

List of the literature that was cited for this KER description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide (https://www.oecd.org/about/publishing/OECD-Style-Guide-Third-Edition.pdf) (OECD, 2015).

To edit the “References” section, on a KER page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing KE Relationship.” Scroll down to the “References” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update KE relationship’ to save your changes and return to the KER page or 'Update and continue' to continue editing text sections.  The new text should appear under the “References” section on the KER page.

Comments and Discussion

See here for further instructions on how to comment and contribute to discussion.

View KER History

To view detailed changes to an AOP, KE, KER, or Stressor page, click 'View History' on the upper right hand panel menu on the page. You will be brought to a page entitled "Versions of [AOP/KE/KER/Stressor:#]" listing text changes to the AOP/KE/KER/Stressor by date. To compare two versions, select the versions you would like to compare using the "from" and "to" buttons.  Click 'Compare.' You will be brought to a page showing the comparison of the two versions. If you are a contributor to this AOP, you can also click 'revert to this version' at the bottom of the page to revert to a previous version of an AOP/KE/KER/Stressor.

The Change log lists all changes to an AOP/KE/KER/Stressor including text changes, the date and the user who made the change.

KER Watch list

The Watch List provides a list of individual AOP, KE, KER, or Stressor that a user is currently watching, similar to Bookmarks on an internet browser.

To add a page to the Watch List, navigate to the indivdual AOP, KE, KER, or Stressor page and in the upper right hand navigation menu, click 'Watch.' To remove a page from the Watch List, click 'Watch' to unselect the check box.