Help: Key Events

01 To Create a New Key Event


Title

Instructions

On the ‘Key Events’ page, upon selecting the “New key event” button, the user will see a ‘New Key Event’ form with fields for the entry of a ‘Title,’ ‘Short name,’ and a drop down menu for selection of a level of Biological Organization. Upon filling out these fields, click ‘Create key event’ to create a new key event. Upon creation, user will be directed to a new page for this event.

Short name

The KE short name should be a reasonable abbreviation of the long name and will be used in labelling this object throughout the wiki. The short name should be less than 50 characters in length.

Level of Biological Organization

Instructions

To edit the “Level of Biological Organization” section, on a KE page in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing Key Event” listing the Event title and short name, with a drop down for Biological organization. Click on the arrow and select a biological organization from Molecular to Population level. On the upper right hand menu, click ‘Update event’ to add the biological organization and return to the Key Event page.  The biological organization should appear under the “Level of Biological Organization” section on the KE page.

B Describe the Key Event


Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. The following are some general recommendations and “rules of thumb” concerning how specifically to define a KE (see also Villeneuve et al. 2014a, b; https://aopkb.org/saop/workshops/somma.html): a. The biological context of the KE (e.g., the tissue type/ taxa/ life stage / sex/ etc.) should only be restricted to the extent that function changes with context. If the function is equivalent in both sexes, do not restrict the context by sex. If the function is equivalent in all cell types, do not restrict to a specific cell type. This facilitates generalisation which will allow the KE to be linked to multiple AOPs while preserving adequate specificity to define function. b. Define the KE with enough specificity that one would know what to measure to determine the state of the KE. For example “histological changes” is too broad; “oocyte atresia” or “hyperplasia” would be better. c. KEs should generally refer to/focus on a single measurable event within a specific biological level of organisation, rather than compounding events together. For example, it would be better to define a KE as increased enzyme activity (if that can be measured), rather than increased transcription and translation leading to increased enzyme activity. Such compounding essentially embeds KERs into KE descriptions. This can limit the ability to link shared KEs to other AOP descriptions in the AOP-Wiki.

Instructions

To edit the “How this Key Event works” section, on a KE page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing Key Event.” Scroll down to the “How this Key Event works”  section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update event’ to save your changes and return to the AOP page.  The new text should appear under the “How this Key Event works” section on the AOP page.

How it is Measured or Detected

Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (for example – a protein may be measured by ELISA). One of the primary considerations in evaluating AOPs is the confidence and precision with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements As suggested in the guidance document (ENV/JM/MONO(2013)6) key considerations regarding 15 scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which is accepted in the scientific and/or regulatory community.

Instructions

To edit the “How It Is Measured or Detected” section, on a KE page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing Key Event.” Scroll down to the “How this Key Event works” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update event’ to save your changes and return to the AOP page.  The new text should appear under the “How this Key Event works” section on the AOP page.

C Event Components and Biological Context


Event Components

Individual KEs have one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies. Biological process describes dynamics of the underlying biological system (e.g. receptor signaling). The biological object is the subject of the perturbation (e.g. specific biological receptor that is activated or inhibited). Action 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).

Instructions

On a KE page, next to the heading “Key Event Components,” click ‘Add event component’ to go to a new page entitled “New Event Component.” This page lists the associated Event Component and has fields for Process, Object, and Action.  These fields can be searched for existing Biological Process, Object, and Action terms associated with the level of organization of the KE. For example, an existing Biological Process for a KE at the cellular level could be “translation.” Filling in one or more of these fields and then clicking ‘Event Component suggestions’ will bring up a drop down menu listing existing Event Components. Clicking an existing Event Component will autopopulate these fields. If a descriptive Event Component does not exist, individual Process, Object, and Action terms can be added in these fields. Clicking ‘Add event component’ will return the user to the KE page where the new event component will be listed in the Key Event Components table.

Cell Term/Organ Term

The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.

D Domain of Applicability


Taxonomic Applicability

The KE description should also include an indication of the general taxonomic relevance of the biology and the rationale or scientific basis for that assessment. For example, for a KE that is described as a measurable enzyme activity, the taxonomic relevance of that KE may be defined by the phylogenetic conservation of an orthologous protein. In the case of a KE related to the function of a specific organ, that KE would only be relevant to taxa that possess that organ. For example, a measure of lung capacity would have little relevance to a fish. Likewise, a measure of gill damage would have little relevance to terrestrial vertebrates. Defining the taxonomic relevance of each KE helps to bound the taxonomic relevance of the AOP as a whole and provides an understanding of how broadly data represented by a KE measurement may be extrapolated. In practice, specific taxa in which the KE has been measured can be identified using drop-down taxonomic relevance tables found on the KE description pages within the AOP-Wiki. More general, biological plausibilitybased rationale for the probable taxonomic applicability of the KE should be defined in the corresponding free text section on the KE description page.

Instructions

To add a taxonomic term to a KE page, under “Taxonomic Applicability” select ‘add taxon.’ User will be directed to a page entitled “Adding Taxonomic Term to Event.” 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, click ‘Request New Taxon Term’ to request a term from AOP-Wiki administrators. Click ‘Add taxonomic term’ to add this term to the AOP page. Evidence can be left blank and added later.

To edit a taxonomic term on a KE page, under “Taxonomic Applicability” click ‘Edit.’  User will be directed to a page entitled “Editing AOP Taxonomic Term” where they can edit the Evidence field using the drop down menu. Clicking ‘Update taxonomic term’ will update the Evidence field and redirect the user back to the KE page.

Life Stage Applicability

Instructions

To edit the “Life Stages” section, on a KE page next to “Life Stages”, click ‘Add life stage term.’ This brings you to a page entitled, “New Event Life Stage” listing the Event name, with drop down options for Life stage term and Evidence fields. Evidence can be added later. Click ‘Create Event life stage’ to create a new life stage.  The new life stage should appear under the “Life Stage Applicability” section on the KE page.

Sex Applicability

Instructions

To edit the “Sex Applicability” section, on a KE page next to “Sex Applicability”, click ‘Add sex term.’ This brings you to a page entitled, “New Event Sex Term” listing the Event name, with drop down options for Term and Evidence fields. Evidence can be added later. Click ‘Create Event sex’ to create a new Event sex.  The Event sex should appear under the “Sex Applicability” section on the KE page.

Evidence Supporting Taxonomic Applicability

The KE description should also include an indication of the general taxonomic relevance of the biology and the rationale or scientific basis for that assessment. For example, for a KE that is described as a measurable enzyme activity, the taxonomic relevance of that KE may be defined by the phylogenetic conservation of an orthologous protein. In the case of a KE related to the function of a specific organ, that KE would only be relevant to taxa that possess that organ. For example, a measure of lung capacity would have little relevance to a fish. Likewise, a measure of gill damage would have little relevance to terrestrial vertebrates. Defining the taxonomic relevance of each KE helps to bound the taxonomic relevance of the AOP as a whole and provides an understanding of how broadly data represented by a KE measurement may be extrapolated. In practice, specific taxa in which the KE has been measured can be identified using drop-down taxonomic relevance tables found on the KE description pages within the AOP-Wiki. More general, biological plausibility based rationale for the probable taxonomic applicability of the KE should be defined in the corresponding free text section on the KE description page.

Instructions

To edit the “Evidence Supporting Taxonomic Applicability” section, on a KE page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing Key Event.” Scroll down to the “Evidence Supporting Taxonomic Applicability”  section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update event’ to save your changes and return to the AOP page.  The new text should appear under the “Evidence Supporting Taxonomic Applicability” section on the AOP page.

E AO Information


Regulatory Examples Using This Adverse Outcome

This section only appears on AO pages. A key criterion of defining the terminal end of an AOP is that it represents an outcome that is considered relevant to regulatory decision-making (i.e., it corresponds to an accepted protection goal or common apical endpoint in an established regulatory guideline study). For example in humans, this may constitute increased risk of disease in a particular organ or organ system in an individual or in either the entire or a specified subset of the population. In wildlife, this will most often be an outcome of demographic significance that has meaning in terms of estimates of population sustainability. Given this consideration, in addition to describing the biological state associated with the AO, how it can be measured, and its taxonomic applicability, it is useful to describe the established regulatory relevance of the AO.

Instructions

To edit the “Regulatory Examples Using This Adverse Outcome” section, on a KE page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing Key Event.”  Scroll down to the “Regulatory Examples Using This Adverse Outcome” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update event’ to save your changes and return to the AOP page.  The new text should appear under the “Regulatory Examples Using This Adverse Outcome”  section on the AOP page.

E MIE Information


Stressors

Describes stressors known to trigger the MIE and provides evidence supporting that initiation. This will often be a list of prototypical compounds demonstrated to interact with the target molecule in the manner detailed in the MIE description to initiate a given pathway (e.g., 2,3,7,8-TCDD as a prototypical AhR agonist; 17α-ethynyl estradiol as a prototypical ER agonist). However, depending on the information available, this could also refer to chemical categories (i.e., groups of chemicals with defined structural features known to trigger the MIE). It can also include non-chemical stressors such as genetic or environmental factors. The evidence supporting the stressor will typically consist of a brief description and citation of literature showing that particular stressors can trigger the MIE.

Instructions

To add a stressor associated with an MIE, under “Key Event Overview” click ‘Add Stressor’ will bring user to the “New Event Stressor” page. In the Name field, user can search for stressor by name. Choosing a stressor from the resulting drop down populates the field. Users can add any supporting evidence in the text box. Click ‘Add stressor’ to add the stressor to the KE page. The stressor will be listed in the Stressors table.

Evidence for Perturbation of this MIE by Stressor

This section only appears on MIE pages. The MIE is the direct site of interaction with a chemical. The MIE involves a chemical interaction (e.g., a reaction, covalent binding, hydrogen bonding, electrostatic interaction, etc.) between a chemical stressor and chemically defined biomolecules within an organism. In some cases, this may be a highly specific interaction, for example between an exogenous ligand and a specific receptor. In other cases, it may be non-specific, as in the case of a reactive chemical that can covalently modify a wide array of proteins. Either can be described as an MIE, provided that the general nature of the stressor-biomolecule interaction is understood. Therefore, when a specific MIE can be defined (i.e., the molecular target and nature of interaction is known), in addition to describing the biological state associated with the MIE, how it can be measured, and its taxonomic applicability it is useful to list known chemical initiators (or other stressors known to trigger the MIE) and provide evidence supporting that initiation. This will often be a list of prototypical compounds demonstrated to interact with the target molecule in the manner detailed in the MIE description to initiate a given pathway (e.g., 2,3,7,8-TCDD as a prototypical AhR agonist; 17α-ethynyl estradiol as a prototypical ER agonist). However, depending on the information available, this could also refer to chemical categories (i.e., groups of chemicals with defined structural features known to trigger the MIE). The evidence supporting the chemical initiation will typically consist of a brief description and citation of literature showing that particular chemicals, or classes of chemicals, can trigger the MIE.

Instructions

To edit the “Evidence for Perturbation of This Molecular Initiating Event by Stressor” section, on a KE page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing Key Event.”  Scroll down to the “Evidence for Perturbation of This Molecular Initiating Event by Stressor” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update event’ to save your changes and return to the AOP page.  The new text should appear under the “Evidence for Perturbation of This Molecular Initiating Event by Stressor” section on the AOP page.

F Other Information


AOPs Including this Key Event

This table lists AOP’s associated with this KE, and the role of the event in the AOP (MIE, KE, or AO). Clicking on any one of the listed AOPs will link to that AOP page.

References

List the bibliographic references to original papers, books or other documents used to support the Key Event.

Instructions

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