IS Domain Controlled Terminology
Please note that the controlled terminology shown in the examples on this page, many of which have not been approved by the appropriate CDISC controlled terminology team. The CDISC Microbiology terminology team is actively reviewing CT for the IS domain. Terminology development is typically out of sync with the publications of SDTMIGs and TAUGs. Please refer to the future published terminology for IS domain related terminology updates.
IS domain definition update
| Domain Short Name | Domain Long Name | Domain Description |
|---|---|---|
| IS | Immunogenicity Specimen Assessments | New definition: A findings domain for assessments of antigen induced humoral or cell-mediated immune response in the subject. |
IS domain assumptions (to replace all current assumptions in SDTMIG 3.3)
- The Immunogenicity Specimen Assessments (IS) domain model holds assessments that describe whether a therapy provoked/caused/induced an immune response in a subject; this therapy may be a biologic, a drug, or vaccine, etc. The response can be either positive or negative. For example, a vaccine is expected to induce a beneficial immune response, while a cellular therapy such as erythropoiesis-stimulating agents may cause an adverse immune response.
- The IS domain model also holds assessments that describe whether an allergen, a microorganism, or an endogenous molecule provoked/caused/induced an immune response in a subject. Examples are a subject's antibody reaction (autoantibodies) against auto/self-antigens for autoimmune studies, or antibody production in response to allergens in allergy trials. Expected outputs can be positive or negative, present or absent for the antibody of interest, as well as quantification of said antibody. Assessments pertaining to antibody produced in response to microbial infection will also be represented by the IS domain.
- Assessments about all other types of humoral (antibody) immune response from a subject will also be represented by the IS domain. Examples are antibodies against HLA proteins.
- An exception will be made to the class of antigen/antibody (ag/ab) combination assays – Microbial Ag/Ab Combination Tests should be represented by the Microbiology Specimen (MB) domain. An example is 4th generation HIV ag/ab combination tests, which are commonly seen as HIV identification/detection assays rather than tests that provide additional details on, and characterization of, a subject’s immunological responses. The outputs of these assays can be expected as “reactive”, “non-reactive, or “indeterminate”. Some of the tests generate separate outputs for antigen and antibody, but others just indicate “reactive” when either or both are detected. The output is generally based on relative light units, where a result of "reactive" typically requires the signal to cutoff ratio to be greater than 1.
- Certain types of cellular immune responses will also be modeled in IS using non-flowcytometry techniques (see examples 7a and 7b).
- Measurements of cytokines, chemokines, and complement proteins should be represented by the Laboratory Test Results (LB) domain.
- IS domain standard variable, Binding Agent/BDAGNT:
- The ISBDAGNT variable is supported by two controlled terminology codelists, which are the Microorganism (SDTM-MICROORG) codelist and the Binding Agent for Immunogenicity Tests/ISBDAGT codelist. Please refer to the "Rules for Immunogenicity Tests" Document for how and when to use each codelist to support this variable on https://www.cdisc.org/standards/terminology.
- For antidrug antibody (ADA) tests, the ISBDAGNT variable is also used to represent the free-text description of the name/identity of the therapeutic to which the antidrug antibody targets. CDISC does not control study therapeutics (e.g. drugs, biologics). For antidrug antibody tests as a part of regulatory agency submissions, the binding study therapeutics should be treated as extensible values in the Binding Agent for Immunogenicity Tests/ISBDAGT codelist, which are defined in the define-XML.
- Any Identifier variables, Timing variables, or Findings general observation class qualifiers may be added to the IS domain.
- If an antibody measurement is a detection or quantification of the antibody whose presence is not the result of antigen-stimulation (i.e. not induced by an antigen), which means there is no binding agent for the said antibody, it should stay in LB. Examples are: Immunoglobulin A (C81969), Immunoglobulin G Subclass 1 (C122127). (need more discussion)
New IS domain-specific variables
Illustration of variables:
| Variable Short Name | Variable Long Name | Variable Description and Usage Notes | Order of the Variable | Controlled Terminology | Additional Notes |
|---|---|---|---|---|---|
| --SCMBCL | Secreted Molecule by Cells | Usage: This is a domain specific variable, and qualifies the ISTEST variable. Description: The textual description of the entity secreted by the cells represented in the ISTEST. The combination of ISTEST and ISSCMBCL should describe "the thing, the entity or the analyte" one is measuring, without the need of additional variables. | It is placed right after BDAGNT | No. Free-text description. | |
--BDAGNT | Binding Agent | Usage: This is a domain specific variable, and qualifies the ISTEST variable. Description: The textual description of the agent that's binding to the entity in the ISTEST variable. The ISBDAGNT variable is used to indicate that there is a binding relationship between the entities in the ISTEST and ISBDAGNT variables, regardless of direction. ISBDAGNT is not a method qualifier. It should only be used when the actual interest of the measurement is the binding interaction between the two entities in ISTEST and ISBDAGNT. In other words, the combination of ISTEST and ISBDAGNT should describe "the thing, the entity or the analyte" one is measuring, without the need of additional variables. The binding agent may be, but not limited to, a test article, a portion of the test article, a related compound, an endogenous molecule, an allergen or an infectious agent. | It is placed right after ISTEST. (this is used more than SCMBCL) | Yes. Two codelists. -Microorgansim (MICROORG) -Binding Agent for Immunogenicity Assessments (ISBDAGT). | |
--TSTOPO | Test Operational Objective | Usage: This is a domain-specific variable for LB and IS that qualifies the --TEST variable. This is a permissible variable. Description: The textual description of the high-level purpose of the test at the operational level. | It is placed right after ISTSTDTL. *When getting this ready for internal review, make sure to add TSTDTL into the IS specification table. | Yes. One codelist. Codelist Rules: this is a non-extensible codelist and the MB SDS/CT team reserves the right to review future term request to this codelist and decide whether addition of new terms are appropriate. Controlled Terminology: -SCREEN: A test whose operational purpose is to determine the presence or absence of a substance or organism. -CONFIRM: A test whose operational purpose is to verify the presence or absence of a substance or organism. -QUANTIFY: A test whose operational purpose is to determine the amount or concentration of a substance or organism.
| Notes for Variable Name/Description:
Controlled Terminology Notes: Is "Detection" a valid value for this codelist? We had said before that one should use "detection" when one does not know whether the test is for screening or confirmatory, however is this a synonym to screen? look at the definition for screening, how is it different from detection? Confirm is to verify the previously detected substance is present.
How about "quantify to confirm", what does that mean, is this also a valid value?
|
ISTEST, ISBDAGNT, ISSCMBCL, ISTSTDTL, ISTSTOPO - this is order to be added.
Example 1: Tiered Testing of ADA
This example shows the tiered testing of antidrug antibody (ADA). Typical tiered testing scheme for ADA evaluation includes the following steps: screening, confirmatory, and "characterization". In the first tier, all evaluable samples are run in the screen assay. Samples that score positive in the screen assay are then analyzed in a confirmatory assay (tier 2). Samples that are positive for ADA in the screen and confirmatory tiers are reported as positive, while samples that are negative in either tier are reported as negative. Further tiered testing of positive samples frequently includes analysis of antibody titer and neutralizing activity. The variable "TSTOPO" has the following controlled values: SCREEN, CONFIRM and QUANTIFY to describe the operational objective or the reason behind each testing step, and also to provide uniqueness to each row of record. ISGRPID is used in this example to show that the records are related to each other, and in this case, tests are done in a tiered, sequential manner.
Dataset Wrapper Debug Message
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Example 2: Consolidated Reporting of ADA
The example below shows how to represent the various types of antidrug antibody tests (ADA). Of note, while most ADAs do not inhibit the pharmacodynamic activity of the drug, neutralizing antidrug antibodies (NAbs) can inhibit drug activity soon after the drug is administered. However, most ADAs, or rather, the non-NAbs can lower the drug's systemic exposure just as well by increasing the rate of drug clearance, resulting in a clinically similar outcome to that of Nabs – reduced clinical efficacy.
Rows 1-4 in this example show binding antidrug antibody reaction against the administered analogue drug, whereas rows 5-8 show cross-reactive antidrug antibody reaction against the endogenous protein that's structurally similar to the analogue study drug. Both the study drug and the endogenous protein are represented by the IS domain-specific variable "ISBDAGNT", which only qualifies the ISTEST variable. The variable, "ISTSTOPO", is also used in this dataset to describe the purpose of each testing step, and provides uniqueness to each record. ISGRPID is used to show which records are related.
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Example 3 - ADA Reaction Against Drug Components - Breakdown Product
This example shows the production of antidrug antibody in response to both the prodrug and its active metabolite. A prodrug is a compound that, after administration, is metabolized into a pharmacologically active drug. Please note in this example, even though only confirmatory records are reported and shown, it is assumed that the screening step has also been performed.
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Example 4 - ADA Reaction Against Drug Components: Multiple Epitopes per Molecule
The example below shows the production of antidrug antibody in response to both the study biologic drug and also to different immunogenic epitopes of the biologic drug. This also captures an example for when the tier stops at screening (interferon beta1a assay) and goes straight into NAB from there. While unusual, it reflects the flexibility of these fields to incorporate multiple options.
A biologic drug may be biotechnology-derived therapeutic proteins (including mAbs) and peptides, some plasma-derived products (e.g., coagulation factor replacement products), and naturally derived proteins (e.g. therapeutic enzymes and toxins).
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Example 5 - Autoimmune Disease Diagnosis
The example below shows how to represent autoantibody data.
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Example 6 - Vaccine Studies
The example below shows how to represent data about vaccine-induced immunological responses, as well immunological data collected during the trial but are not germane to the study vaccine.
Recommended ISCAT values for Vaccine Studies
For vaccine studies, below are the recommended ISCAT and ISSCAT values to provide extra clarity. ISCAT and ISSCAT are not controlled therefore the below values are not mandated.
- For immunological data pertaining to the study vaccine : ISCAT = VACCINE-RELATED IMMUNOGENICITY.
- For immunological data that are collected during the trial but are not assessments about the study vaccine: ISCAT= HISTORICAL INFECTION OR PREVIOUS VACCINATION.
- For assessments measuring the "induced-antibody response", ISSCAT = HUMORAL IMMUNITY.
- For assessments measuring the "induced-cellular response", ISSCAT = CELLULAR IMMUNITY.
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Example 7: Testing of Antibody-secreting Cells
Traditional methods such as ELISA that monitor humoral immune responses after immunization or infection typically only quantify specific antibody titers in serum. These methods do not provide any information about the actual number and location of the immune cells that secrete antibodies or cytokines.
The Enzyme-Linked ImmunoSpot (ELISpot) assay is a method to detect and quantify analyte-secreting T or B cells. Generally during Elispot testing, a colored precipitate forms and appears as spots at the sites of analyte localization (analytes typically are cytokines or antibodies), with each individual spot representing an individual analyte-secreting cell. The spots can be counted with an automated ELISpot reader system or manually, using a stereomicroscope. The example below shows how to represent the quantification of antibody-secreting cells (ASCs) as the number of spots per million peripheral blood mononuclear cells (PBMC) as determined by B-cell ELISpot from a vaccine trial.
The IS domain-specific variable, Secreted Molecule by Cells/SCMBCL, is introduced in the example below to allow flexibility in data representation and post-coordination of the various secreted antibody types and their respective ASCs. This approach liberates the ISTEST variable from having to house pre-coordinated and thus hyper-specific values crafted based on secretion and cell types.
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Example 8: Testing of Cytokine-secreting Cells
The example below shows data from the vaccine study for Respiratory Syncytial Virus (RSV) where the subject is being vaccinated with a viral vector containing RSV Epitope B. Peripheral blood mononuclear cells are isolated from the the subject and are tested before (as baseline) and after vaccination in order to investigate whether the circulating PBMCs produce increasing amounts of Interferon gamma after re-stimulating with control or RSV-Epitope B in vitro.
The example below shows how to represent the quantification of cytokine-secreting cells as the number of spots per million peripheral blood mononuclear cells (PBMC) as determined by T-Cell ELISpot from a vaccine trial.
Dataset Wrapper Debug Message
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Example 9 - Microneutralization Assay
In vaccine studies, microneutralization assays are commonly used in vitro assays to quantify viral-specific neutralizing antibodies in the subject’s specimen that can block viral infection in vitro, and so provide output of vaccine efficacy.
Typically, a subject's serum and the virus of interest are added to in vitro cell cultures. If neutralizing antibodies are present in the serum, those antibodies will bind to the virus and thereby "blocking" and preventing the virus from infecting the cells in the culture plates. By vaccination with a vaccine that induces antibody response, one thus assumes that the quantity of viral-specific antibodies that are able to block viral infection are increased. The neutralization titer is the antiviral antibody titer that blocks viral infection of the cells. The NEUTRALIZING TITER 50% (also known as NT50) in the context of microneutralization assays is defined as the antiviral antibody titer that blocks 50% of viral infection of the cells. Please note that some users may also represent "Neutralizing Titer 50%" as "IC50 titer" or other test descriptors. CDISC recommends housing values such as NT50, IC50 neutralizing titer, etc. in the ISTSTDTL variable.
The example below shows data from the same Respiratory Syncytial Virus (RSV) vaccine study where the subject is being vaccinated with a viral vector containing RSV Epitope B. The subject is tested before (baseline) and after vaccination (visits 1 and 2) whether the anti-RSV binding antibodies present in the subject’s serum also have the functionality to neutralize RSV infection in vitro.
*A Neutralizing antibody is defined as antibodies that bind to, block and prevent non-self agents from infecting cells.
Example 10 - Opsonophagocytic Killing Assay
In vaccine trials, the opsonophagocytic killing (OPK) assay is used as a correlate for protection to measure the "functional capacities" of vaccine-induced antibodies. This in vitro assay aids selecting promising vaccines by demonstrating whether the vaccine-induced antibodies drive efficient complement deposition and subsequent opsonophagocytic killing.
Typically this test is performed by incubating post-immunization sera of a subject with the bacterial strain of interest, phagocytes and complement proteins. If anti-bacterial antibodies are present in the subject's serum, those antibodies will bind to the bacteria together with complement proteins, this subsequently targets the bacteria for opsonization, which is the ingestion and destruction of invading non-self agents by phagocytes. By vaccination, one thus assumes that the quantity of bacterial-specific antibodies are increased, leading to a decreased number of viable bacterial cells in the presence of phagocytes, functional antibodies and complement. The assay read-out is expressed in Opsonization Index (OI) which is calculated using linear interpolation of the serum dilution containing functional antibody killing the desired percentage (usually 50%) of the bacteria, using a pre-specified algorithm.
The example below shows data from a vaccine study for Escherichia Coli (E.Coli) where the subject is being vaccinated with a vector containing E.Coli epitope X. The subject is tested before (baseline, row1) and after vaccination (rows 2-3) whether the vaccine-induced antibodies drive efficient complement deposition and subsequent opsonophagocytic killing of the E.Coli in vitro. The assay read-out is expressed in Opsonization Index (ISTSTDTL), which is a unit-less test.
A functional antibody is defined as antibodies that bind to non-self agents and initiate opsonization (destruction by complement and phagocytes) or active killing of the said non-self agent by other types of cells. Being able to recruit and activate the complement system is the key and definitive nature of a functional antibody.
Example 11 - Hemagglutination Inhibition Assay
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