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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?

Status


colour	Yellow
title	In progress

Here is a mock example modeling his data:

2023-11-02: MB/IS team agreed to extend the use of CONC and CONCU to other specimen-based domains.

2023-11-28: CDISC ISMT (internal leadership team) agreed with extending CONC and CONCU to other domains for agent concentration and unit.

Action Items:

Review, seek approval from the SDS/SDTM team.
Review, seek approval from the GGG
Contact CDISC PM Dianne Dirussle about getting into a version of the SDTMIG post 4.0 release. This would be a scope change for 4.0, at this point, it is too late for inclusion for 4.0.

Here is a mock example modeling his data:

Dataset wrap

Dataset2

hi1style	yellow
hi1	column ISBDAGNT
tableid	IS table 1

Row	STUDYID	DOMAIN	USUBJID	SPDEVID	ISSEQ	ISTESTCD	ISTEST	ISTSTCND	ISCNDAGT

Dataset wrap

Dataset2

hi1style	yellow
hi1	column ISBDAGNT
tableid	IS table 1

Row	STUDYID	DOMAIN	USUBJID	SPDEVID	ISSEQ	ISTESTCD	ISTEST	ISTSTCND	ISCNDAGT	ISORRES	ISORRESU	ISSTRESC	ISSTRESN	ISSTRESU	ISSPEC	ISMETHOD	ISDTC
1	ABC	IS	ABC-01-203	ABC001	1	IFNG	Interferon Gamma	WITHOUT STIMULATING AGENT		2.17	IU/mL	2.17	2.17	IU/mL	SERUM	ELISA/Other Method	2013-08-26
2	ABC	IS	ABC-01-203	ABC001	2	IFNG	Interferon Gamma	WITH STIMULATING AGENT	Study Drug, 20 mg	6.2	IU/mL	6.2	6.2	IU/mL	SERUM	ELISA/Other Method	2013-08-26
3	ABC	IS	ABC-01-203	ABC001	3	IFNG	Interferon Gamma	WITH STIMULATING AGENT	Study Drug, 40 mg	15.8	IU/mL	15.8	15.8	IU/mL	SERUM	ELISA/Other Method	2013-08-26
4	ABC	IS	ABC-01-203	ABC001	4	IFNG	Interferon Gamma	WITH STIMULATING AGENT	Other Test Agent, 5 mg	3.33	IU/mL	3.33	3.33	IU/mL	SERUM	ELISA/Other Method	2013-08-26
5	ABC	IS	ABC-01-203	ABC001	5	IFNG	Interferon Gamma	WITH STIMULATING AGENT	Other Test Agent, 15 mg	7.22	IU/mL	7.22	7.22	IU/mL	SERUM	ELISA/Other Method	2013-08-26

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 (as agreed to with the same TB TAUG INF-y response tests here: https://wiki.cdisc.org/x/azXFBg).
Craig mentioned that 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) in SDTM. These domains have variables for mapping dosing concentrations and units, but we can NOT use EX/EC/AG for in vitro exposure data (Diane W confirmed). In light of this, one option is to pre-coordinate the concentrations and dosing 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.

...

Other Test Agent, 5 mg

3.33

IU/mL

3.33

IU/mL

SERUM

ELISA/Other Method

2013-08-26

5

ABC

IS

ABC-01-203

ABC001

5

IFNG

Interferon Gamma

WITH STIMULATING AGENT

Other Test Agent, 15 mg

7.22

IU/mL

7.22

IU/mL

SERUM

ELISA/Other Method

2013-08-26

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 (as agreed to with the same TB TAUG INF-y response tests here: https://wiki.cdisc.org/x/azXFBg).
Craig mentioned that 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/therapeutic and other types of agents exposure data. One option is to pre-coordinate the concentrations and dosing 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:

Dataset wrap

title	ms.xpt
Name	ms

Rowcaps

Rows 1-4:	Show the minimum inhibitory concentration and the interpretation result reported from Central Lab ABC from a sample that was tested for susceptibility to the sponsor drug and amoxicillin, using an epsilometer test method.
Rows 5-6:	Show that Local Lab XYZ found that the sample was susceptible to the sponsor drug at a concentration of 0.5 ug/dL and resistant to amoxicillin at a concentration of 0.5 ug/dL.
Rows 7-10:	Show the diameter of the zone of inhibition and the interpretation result reported from Local Lab XYZ from a sample that was tested for susceptibility to the sponsor drug and amoxicillin using a disk diffusion test method.

Dataset2

Row	STUDYID	DOMAIN	USUBJID	NHOID	MSGRPID	MSSEQ	MSREFID	MSLNKGRP	MSTESTCD	MSTEST	MSAGENT	MSCONC	MSCONCU	MSORRES	MSORRESU	MSSTRESC	MSSTRESN	MSSTRESU	MSNAM	MSMETHOD	MSDTC
1	ABC	MS	ABC-001-002	ENTEROCOCCUS FAECALIS	1	1	SPEC01	1	MIC	Minimum Inhibitory Concentration	Sponsor Drug			0.25	ug/dL	0.25	0.25	ug/dL	CENTRAL LAB ABC	EPSILOMETER	2005-06-19T08:00
2	ABC	MS	ABC-001-002	ENTEROCOCCUS FAECALIS	1	2	SPEC01	1	MICROSUS	Microbial Susceptibility	Sponsor Drug			SUSCEPTIBLE		SUSCEPTIBLE			CENTRAL LAB ABC	EPSILOMETER	2005-06-19T08:00
3	ABC	MS	ABC-001-002	ENTEROCOCCUS FAECALIS	2	3	SPEC01	1	MIC	Minimum Inhibitory Concentration	Amoxicillin			1	ug/dL	1	1	ug/dL	CENTRAL LAB ABC	EPSILOMETER	2005-06-19T08:00
4	ABC	MS	ABC-001-002	ENTEROCOCCUS FAECALIS	2	4	SPEC01	1	MICROSUS	Microbial Susceptibility	Amoxicillin			RESISTANT		RESISTANT			CENTRAL LAB ABC	EPSILOMETER	2005-06-19T08:00
5	ABC	MS	ABC-001-002	ENTEROCOCCUS FAECALIS		5	SPEC01	2	MICROSUS	Microbial Susceptibility	Sponsor Drug	0.5	ug/dL	SUSCEPTIBLE		SUSCEPTIBLE			LOCAL LAB XYZ	MACRO BROTH DILUTION	2005-06-19T08:00
6	ABC	MS	ABC-001-002	ENTEROCOCCUS FAECALIS		6	SPEC01	2	MICROSUS	Microbial Susceptibility	Amoxicillin	0.5	ug/dL	RESISTANT		RESISTANT			LOCAL LAB XYZ	MACRO BROTH DILUTION	2005-06-19T08:00
7	ABC	MS	ABC-001-002	ENTEROCOCCUS FAECALIS	3	7	SPEC01	2	DIAZOINH	Diameter of the Zone of Inhibition	Sponsor Drug			23	mm	23	23	mm	LOCAL LAB XYZ	DISK DIFFUSION	2005-06-26T08:00
8	ABC	MS	ABC-001-002	ENTEROCOCCUS FAECALIS	3	8	SPEC01	2	MICROSUS	Microbial Susceptibility	Sponsor Drug			SUSCEPTIBLE		SUSCEPTIBLE			LOCAL LAB XYZ	DISK DIFFUSION	2005-06-26T08:00
9	ABC	MS	ABC-001-002	ENTEROCOCCUS FAECALIS	4	9	SPEC01	2	DIAZOINH	Diameter of the Zone of Inhibition	Amoxicillin			25	mm		25	mm	LOCAL LAB XYZ	DISK DIFFUSION	2005-06-26T08:00
10	ABC	MS	ABC-001-002	ENTEROCOCCUS FAECALIS	4	10	SPEC01	2	MICROSUS	Microbial Susceptibility	Amoxicillin			RESISTANT		RESISTANT			LOCAL LAB XYZ	DISK DIFFUSION	2005-06-26T08:00

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