| Request | Notes | Status |
|---|---|---|
From Stefan Konermann. | Email from Stefen: In a new trial, the secretion of cytokines by immune cells is measured in a mixture of likely serum and culture medium. The procedure is like this: Blood is drawn and is then incubated for 24 hours in that medium. Substances that are supposed to provoke an immune reaction are added, such as specific antibodies or the study drug. After 24 hours, the cells are removed and the supernatant is collected and analyzed for cytokines such as Interferon gamma and Interleukins. The secretion is provoked by a Stimulating Agent (Test Condition) and we know what substance was used (Test Condition Agent). However, now comes the tricky part: the study drug should be added to that test tube in different concentrations in order to assess if there are differences in the reaction of the immune cells (T cells and NK cells) secreting Interferon and Interleukins. So the question is: How would you capture these different concentrations of the Test Condition Agent? Would you recommend to have separate codes in the Test Condition Agent for, let’s say, “Study drug, concentration A”, “Study drug, concentration B”, … and then set up different analytes, one per concentration? Would you use a supplemental qualifier? Or would there be a further option you would recommend we have not yet considered? | IN PROGRESS |
Here is a mock example modeling his data:
Background Information:
- This was sent to the lab team for discussion and we decided that the INF-y response tests should be modeled in IS.
- Craig said there are NO other variables to capture the units and dosing concentrations for the test agents that are added to the samples. In fact, this is a gap in the CDISC model that we lack variables (or a domain) to help mapping in vitro drug/non-drug exposure data. The EX/EC and AG domains are used for mapping in vivo drug and non-drug agents exposure data (respectively). These domains have variables for mapping dosing concentrations and units, but we can't use them for in vitro exposure data. Craig said he would pre-coordinate the concentrations and units of the added agents into the ISCNAGT (test condition agent) variable, see the texts in red in the above example.
- This is a problem because a single CDISC variable should be designed for a single meaning and a single purpose. The Test Condition Agent variable is used for the name/identity of the added study/control drugs or other materials. I think we would be breaking rules to also include the concentration and unit in this variable as well.
- While brain storming Stefan's use-case, I remembered that in the MS domain, there are MSAGENT (Agent Name), MSCONC (Agent Concentration), MSCONCU (Agent Concentration Units) variables that were added back in SDTMIG v3.2 to represent the study and control drugs used for microbial resistance testing. The 3 variables, MSAGENT, MSCONC, and MSCONCU are used to map the name of the study/control drugs, their concentrations and units respectively. Basically, for these MS tests, you dump study drugs, likely an antibiotic (at varying concentrations) on a plate to see if the bacteria would be resistant or susceptible for the drug by measuring a few specific outputs. Below is a MS example from IG3.4 to show how the 3 variables are used together with the MSTESTs:
"After E. faecalis was identified in the subject sample, drug susceptibility testing was performed at each of the labs using both the sponsor's investigational drug and amoxicillin. Because an identified organism is the subject of the test, the NHOID variable is populated with "ENTEROCOCCUS FAECALIS". Between the 2 labs (MSNAM), a total of 3 susceptibility testing methods were used: epsilometer, disk diffusion, and macro broth dilution (MSMETHOD). Epsilometer and disk diffusion both use agar diffusion methods, in which an agar plate is inoculated with the microorganism of interest and either a strip (epsilometer) or discs (disk diffusion) containing various concentrations of the drug are placed on the agar plate. The epsilometer test method provides both a minimum inhibitory concentration (MSTESTCD = "MIC"), the lowest concentration of a drug that inhibits the growth of a microorganism, and a qualitative interpretation (MSTESTCD = "MICROSUS") such as susceptible, intermediate, or resistant. The disk diffusion test method provides the diameter of the zone of inhibition (MSTESTCD = "DIAZOINH") and a qualitative interpretation such as susceptible, intermediate, or resistant (MSTESTCD = " MICROSUS" ). The quantitative and qualitative results are grouped together using MSGRPID.
The third method, macro broth dilution, was used to test the specimen at a predefined drug concentration of each of the drugs. When the drug and amount are a predefined part of the test, the variable MSAGENT is populated with the name of the drug being used in the susceptibility test. The variables MSCONC and MSCONCU represent the concentration and units of the drug being used."
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Questions/Discussion Needed:
I want to run this by the team to see if we can take advantage of the existing standard variables? Do we also have "duplicate variables" in different domains that serve the same purpose?
- Are we using the Test Condition Agent (ISCNDAGT) variable the same as the Agent Name (MSAGENT)? Do we use them for the same purpose?
- They both are used to map the name of the thing/entity (e.g. study/control drug, stimulating test materials like TB antigens, etc) that are added to a sample to "induce" a response.
- The "induced" response can be stimulatory (in immune response) or inhibitory (in bacterial resistance response).
- If yes, do we need to merge these two variables? Seeing as we are making changes for IG4.0, this might be worth considering, and will need multiple team's review and approval.
- This also means there would be one less standard variable out there (as people complain that there are too many new variables in IG3.4).
- As a separate conversation, can we extend the use of the standard variables --CONC (Agent Concentration), --CONCU (Agent Concentration Units) to the other specimen-based domains? For mapping concentration and unit of the in vitro exposure agents? There are now use-cases needing these variables in IS, MS and CP. Right now --CONC and --CONCU are limited to MS only. They also only qualify --AGENT.
- This way we can take advantage of existing standard variables, instead of creating new ones.
- This also means we don't need to tell users to pre-coordinate unit and dosing concentration of the exposure agent into the same variable - which would be breaking rules.
Recommendations:
- We can tell Stefan to use --CONC and --CONCU for exposure agent concentration and unit, and add them to the IS domain as NSVs, because IG3.2 and SDTM 2.0 still limit these variables to the MS domain only. Meanwhile, we work on getting these variables officially added to the other domains for IG4.0 or a later version of the IG (IS, CP, maybe GF too).
- Or we tell Stefan to pre-coordinate all that information into the Test Condition Agent (ISCNDAGT) variable.
- Other thoughts? Other ways forward?
Here is a mock example of Stefan's data using --CONC and --CONCU:
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