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Modulating factors. Join the discussion
#1
Have you ever considered modulating factors (MFs) when developing your AOP?
In the CIAO project we are developing an AOP network for COVID-19 https://www.ciao-covid.net/ with MFs playing a big role.
But we are facing the challenge on how to properly describe MFs in the Wiki.
Has someone already gained experience with this? Please share your experience.
In general, should we include MFs in AOP descriptions and if yes, how? What is everyone’s opinion on this?
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#2
Good point! I think Modulating Factors play a somewhat second class role in the current AOP Framework, and this should be looked at! Looking forward to the discussion!
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#3
I think modulating factors should be included when we have clear evidence for their role and understand something about how they alter the response-response relationships for one or more KERs. Modulating factors that a purely speculative should not be included.
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#4
I agree that we need clear evidence for their role before including MFs.
But we should not restrict a potenitial impact of variuos factors to KERs. Some factors also modulate KEs.  E.g. gentic polymorphism might lead to an altered initial situation of the same KE.
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#5
(13 May 2021, 15:47)Brigitte Landesmann Wrote: I agree that we need clear evidence for their role before including MFs.
But we should not restrict a potenitial impact of variuos factors to KERs. Some factors also modulate KEs.  E.g. gentic polymorphism might lead to an altered initial situation of the same KE.


Maybe add a definition of Modulating Factors for folks who might not know what it means?

Kevin
AOP Forum Moderator KC
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#6
(13 May 2021, 15:57)Moderator KC Wrote:
(13 May 2021, 15:47)Brigitte Landesmann Wrote: I agree that we need clear evidence for their role before including MFs.
But we should not restrict a potenitial impact of variuos factors to KERs. Some factors also modulate KEs.  E.g. gentic polymorphism might lead to an altered initial situation of the same KE.


Maybe add a definition of Modulating Factors for folks who might not know what it means?

Kevin

I tried to find a good definition of what a "modulating factor" actually is, but it's surprisingly not that easy!

Villeneuve et al. 2014 (Adverse Outcome Pathway Development II: Best Practices) write:

[...] This [the quantitative understanding] is also a section of the KER description in which the developer may want to capture information concerning modulating factors (eg, genetic variations, disease states, and nutritional or environmental factors) known to significantly influence the quantitative relationship between the two KEs linked via the KER. It is recommended that information on modulating factors be supported with citation of appropriate evidence. It should not be speculative in nature. However, well-supported information on known modulating factors can significantly enhance the accurate application of quantitative understanding of a KER and thus should be captured when known and well defined. [...]

Knapen et al. 2018 (Adverse Outcome Pathway Networks I: Development and Applications) differentiate between intrinsic and extrinsic modulating factors and suggest changes to the AOP-KB:

[...] modulating factors that are extrinsic to the AOP network (i.e., are not driven by interactions among existing KEs found in the network) such as dietary factors, genetic susceptibility or resistance, disease states, environmental factors, etc., are currently only captured in the free-text descriptions of quantitative understanding of the KERs. While potential intrinsic modulating factors are captured de facto in the structure of the network since they arise from a shared KE or KER and, therefore, do not need explicit annotation, extrinsic modulating factors require separate descriptions and anchoring to the AOP network. Operationally (i.e., from the perspective of further development of the AOP-KB), the implementation of certain types of layers would involve introducing additional structured annotation fields (Ives and others 2017) in the KE and KER descriptions of the AOP-KB. In the case of known modulating factors, this could for example involve introducing an optional “modulating factor” field to KER descriptions, where users could define a modulating factor and provide additional text description and supporting references. An advanced implementation of feedback loop layers could allow future KEs also affecting the feedback loop to reveal interactions between AOPs that are not necessarily evident from individual KEs. However, even at the most basic level, the ability to apply a layer that identifies those KERs for which feedback or modulating factors are known to influence response-response relationships could be very informative and signal a user to explore the additional details provided in the AOP description in order to determine whether they are relevant to the application in question.[...]

Leist et al. 2017 (Adverse outcome pathways: opportunities, limitations and open questions) also supports a more explicit treatment of Modulating Factors:

[...] downstream KEs do not only get input from the upstream KEs, but from multiple other directions. In initial versions of the AOP guidance, there was more emphasis on such modulatory events, and the graphical display of modifiers as an integral part of the AOP was considered. The removal of modulatory events in graphical representations, as suggested by the current handbook and website procedures, has led to a simplified display, and this provides a faster and easier overview. However, the downside is that major biological information is lost from the display. It is stipulated in the handbook that this information can be added as text. For instance, the information is captured in the “Quantitative understanding of the linkage” section of the KERs. The more completely and quantitatively the KERs and their potential modulating factors are described, the greater is the capacity to predict whether the severity of perturbation (in terms of dose, duration, timing, etc.) at the MIE will be sufficient to elicit the AO. However, it is nevertheless not optimal if pivotal inputs and control mechanisms of high relevance for an AO cannot be displayed graphically. It is often argued that the description of KE and KER leaves all necessary options to add complex information. However, this argument does not consider the fact that the choice between what is displayed graphically (and what most people will use as the main source of information) and what is presented ‘in text form only’ is a prioritization of information. Here, the likely user behavior must be considered; and it is probable that with the availability of hundreds of AOPs, the largest majority of users will not read all text (thousands of pages). The graphical display rules convey the impression that a KE is always more important than a modifier. This assumption can be biologically wrong, and the various modulatory factors may become more important than the KE itself. [...]
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