Clinical Data ARS Use Case - Y3 Prioritization #2 - Drug Target Landscape

[ehinderer]

As I outlined in the Slack channel I believe having a clear goal and shared process in mind with respect to drug repurposing will help align the efforts we're going to be putting forth in upcoming hack-a-thons. This should also help insure that we are producing answers that are in line with current rational drug development/repurposing practices.

I found the this 2010 review from Pfizer helpful

Specifically, it describes two lines of evidence that can be used to characterize the "druggability" of targets, which is displayed in the following figure:

Where (a) describes the target's relevance to the disease and (b) describes the nature of available compounds which interact with the target (therapeutic, or potentially therapeutic)

When plotted as the x and y axis of a matrix, we can see clusters of drug targets that can be grouped into "zones":

Important for our case, zone "C" is described as having high likelihood of repurposing, since there is moderate to high disease relevancy and compound relevancy for the targets that are not indicated for that disease (but are for some other disease).

My proposal was to use figure 1 as a starting point for formulating our use case queries.

• The questions listed on the "component info" section could be relevant use cases for Translator to attempt to answer. Some need to be creatively reformatted into a query graph, however.

• The "Example Scoring Basis" serves as a guideline for the EPC requirements that would be needed for making decisions about classifying and explaining answers. This would help determine which ARAs to invoke for the query.

• The "Data Source" section serves as a guideline for which KPs or ARAs would be relevant for aggregating relevant knowledge graphs.

We could start by brainstorming how to formulate these questions into query graphs and select KPs and ARAs that might be able to respond with the desired EPC. For instance the first question under "Expression" might look like a multi-hop query graph:

(target) -transcribed from-> Transcript -expressed_in-> AnatomicalEntity -related_to*> Disease
*not sure if related_to is appropriate

Required EPC might include the expression levels of a transcript within the disease-relevant tissue on the expressed_in edge. Optional EPC might include confidence values that associate the anatomical entity to the disease, or the number of alternative splice forms that the target has in addition to the Transcript identified (as this might indicate possible off-target effects).

[karafecho]

Does this use case still seem relevant to folks?

[ehinderer]

I recall seeing an option for voting for the February relay that seemed similar to what I was proposing here. It was called "Using DrugMechDB to train a ranker specifically focused on drug repositioning." It's significantly different from this IMO, but still the same general theme. I doubt I will personally have the time to commit to fleshing this out further without more interest.

[ehinderer]

Reopening this issue for others who expressed interest @webyrd (and others who I do not know their usernames!) Please feel free to contact me on slack or in this thread.

[karafecho]

FYI: Eugene will be walking folks through this use case during the next Clinical Data Committee meeting on Wednesday, 1/24/2022 at 2 pm ET.

[ehinderer]

Sounds good, I will be there!

[ozborn]

I'm interested in this use case as well, but can't make the meeting on Wednesday. Will figure out how to follow up on slack/email.

[karafecho]

Great! Thanks, John. Please feel free to reach out to me and/or Eugene H. after tomorrow's meeting. Also, @jzigterman : perhaps you can take notes? I will try to do so, too, but it's always best to have more than one person capture a discussion.

[jzigterman]

@karafecho - yes I can take notes as well!

[karafecho]

Thanks!

[ehinderer]

Thanks for the discussion today everyone! Here is a link to the Google Drive with my slides and a copy of the paper:
https://drive.google.com/drive/folders/1phKDxdDpIr8LtEYNo8Z6K4FU-Ejoo8NM?usp=sharing

We can continue brainstorming on the slides themselves.

[karafecho]

Thanks, Eugene!

[ehinderer]

Just to update everyone, I am still in the process of slowly updating the spreadsheet, I've just had very little time to commit to rounding it off.

[karafecho]

Thanks for the update, @ehinderer.

I, too, have had very little time to work on this since our last meeting, although as you know, I did submit a relay session suggestion that proposes to leverage the drug discovery/repurposing workflow (formerly known as 'drug target landscape' workflow) in the context of rare pulmonary diseases. As such, I thought that it might be a good idea for the committee to review tab 4 of the spreadsheet, DiseaseX Options, and see if the general plan makes sense. This way, we will be prepared to move forward with the relay session suggestion, should NCATS approve it.

[ehinderer]

Thanks for refactoring the questions into the Repurposing use case @karafecho by the way, that was really helpful.