Virology Therapeutic Area Data Standards User Guide … · © 2012 Clinical Data Interchange ... Provisional Virology Therapeutic Area Data Standards User ... This new Findings domain

© 2012 Clinical Data Interchange Standards Consortium, Inc. All rights reserved Provisional

Virology Therapeutic Area

Data Standards

User Guide (VR-UG)

Prepared by the

CDISC Virology Team

Notes to Readers

This provisional user guide is based upon the forthcoming Version 1.4 of the CDISC Study Data

Tabulation Model and the CDISC Pharmacogenomic/Genetics Study Data Tabulation Model

Implementation Guide (SDTMIG-PGx), currently under development.

See Appendix C for Representations and Warranties, Limitations of Liability, and Disclaimers.

Revision History

Date Version Summary of Changes

September 6, 2012 1.0 Draft Released version for public comment.

December 6, 2012 1.0 Provisional Released version reflecting all changes and correction identified during

the comment period.

CDISC Virology User Guide (Version 1.0)

© 2012 Clinical Data Interchange Standards Consortium, Inc. All rights reserved Page i Provisional December 6, 2012

TABLE OF CONTENTS

1 INTRODUCTION ................................................................................................................................................ 1 1.1 PURPOSE ....................................................................................................................................................... 1 1.2 CDER GUIDANCE ON ANTIVIRAL PRODUCT DEVELOPMENT ......................................................... 1 1.3 RELATIONSHIP TO PRIOR DOCUMENTS ................................................................................................ 2 1.4 ORGANIZATION OF THIS DOCUMENT ................................................................................................... 2 1.5 DESIGN CONSIDERATIONS AND APPROACH ....................................................................................... 2

2 RELATIONSHIPS BETWEEN THE PHARMACOGENOMICS/GENETICS (PGX) AND

BIOSPECIMEN DOMAINS ............................................................................................................................... 4 2.1 RELATIONSHIPS BETWEEN MOLECULAR CONCEPTS ....................................................................... 6

3 VIRAL RESISTANCE FINDINGS (VR) ........................................................................................................... 8 3.1 ASSUMPTIONS FOR VIRAL RESISTANCE TEST FINDINGS (VR) DOMAIN MODEL ..................... 11 3.2 EXAMPLES FOR VIRAL RESISTANCE TEST FINDINGS (VR) DOMAIN MODEL ........................... 11

4 PHARMACOGENOMICS FINDINGS (PF) ................................................................................................... 14 4.1 ASSUMPTIONS FOR PHARMACOGENOMICS TEST FINDINGS (PF) DOMAIN MODEL ................ 17 4.2 GENETIC VARIATION ASSUMPTIONS .................................................................................................. 17 4.3 EXPLANATORY NOTES ON SLC DATABASE GENETIC CODES ...................................................... 18 4.4 EXAMPLES FOR VIRAL GENETICS FINDINGS .................................................................................... 18

5 PHARMACOGENOMICS/GENETICS METHODS AND SUPPORTING INFORMATION (PG) ......... 26 5.1 ASSUMPTIONS FOR PHARMACOGENOMICS (PG) DOMAIN MODEL ............................................. 30 5.2 LIST OF IDENTIFIED COMMON SUPPQUALS ...................................................................................... 30 5.3 EXAMPLES OF TESTCDS FOR REFERENCING PUBLIC DATABASES ............................................. 31 5.4 PG EXAMPLES ............................................................................................................................................ 31

6 PGX BIOLOGICAL STATE (PB) .................................................................................................................... 33 6.1 ASSUMPTIONS FOR THE PGX BIOLOGICAL STATE (PB) DOMAIN MODEL ................................. 34 6.2 EXAMPLES FOR PGX BIOLOGICAL STATE (PB) DOMAIN MODEL ................................................. 34

7 SUBJECT BIOLOGICAL STATE (SB) .......................................................................................................... 35 7.1 ASSUMPTIONS FOR THE SUBJECT BIOLOGICAL STATE MARKER (SB) DOMAIN MODEL ...... 36 7.2 EXAMPLES FOR SUBJECT BIOLOGICAL STATE MARKER (SB) DOMAIN MODEL ...................... 36

APPENDIX A – NEW AND DELETED DOMAINS AND VARIABLES ............................................................ 38

APPENDIX B – VIROLOGY CONCEPT MAPS .................................................................................................. 39 B.1 VIROLOGY RESISTANCE TESTING MAPS ............................................................................................ 39 B. 2 GENETIC TESTING .................................................................................................................................... 40 B. 3 BUILDING KNOWLEDGE OF VIRAL RESISTANCE MUTATION ...................................................... 42 B. 4 INFERRING VIRAL RESISTANCE FROM GENETIC MUTATION RESULTS .................................... 43

APPENDIX C – PARTICIPATING INDIVIDUALS AND ORGANIZATIONS ................................................ 44

APPENDIX D – REPRESENTATIONS AND WARRANTIES, LIMITATIONS OF LIABILITY, AND

DISCLAIMERS .................................................................................................................................................. 45


© 2012 Clinical Data Interchange Standards Consortium, Inc. All rights reserved Page ii Provisional December 6, 2012

LIST OF TABLES

VR.xpt, Pharmacogenomics Findings - one record per viral load observation per specimen collected, per test, per

date of test, per subject, tabulation. ............................................................................................................................... 8 PF.xpt, Pharmacogenomics Findings - one record per method/setup observation per specimen collected, per date of

test, per subject, Tabulation ......................................................................................................................................... 14 PG.xpt, Pharmacogenomics — Findings. One record per method/setup observation per specimen collected, per date

of test, per subject, Tabulation ..................................................................................................................................... 26 PB.xpt, Pharmacogenomics Biological State - Special Purpose Domain. One record per biomarker used in the study,

tabulation. .................................................................................................................................................................... 33 SB.xpt, Subject Biological State – Special-Purpose Domain. One record per subject per observed biological state in

the study, tabulation. .................................................................................................................................................... 35

LIST OF FIGURES

Figure 1: Biologic Specimen Natural Hierarchy .......................................................................................................... 5 Figure 2: Relationships Between Molecular Concepts ................................................................................................. 7


© 2012 Clinical Data Interchange Standards Consortium, Inc. All rights reserved Page 1 Provisional December 6, 2012

1 INTRODUCTION

1.1 PURPOSE

The purpose of this provisional Virology Therapeutic Data Standards Area User Guide (VR-UG) is to

provide guidance on the implementation of the Study Data Tabulation Model (SDTM) data standards for

virology data. This provisional virology user guide is designed to be used in concert with the SDTM model,

the SDTMIG-PGx (currently under development) and the SDTMIG. See paragraph four below and section

1.3 for more information.

This is the first attempt by CDISC to develop submission standards for virology-focused clinical trials, so it

is expected that there will be areas for further development. This user guide is dependent upon the

publication of Version 1.4 of the SDTM. Due to these reasons, the CDISC Virology Team is publishing

this supplement as provisional in order to allow time for completion of the new version of the SDTM and to

collect input from implementers.

The measurement of viral concentration is central to virology studies. The measurement of viral

concentration (i.e., viral load, a measure of disease burden) in specimens from subjects is handled via the

existing SDTM LB domain. This guide provides guidance on handling measurements of viral concentration

from in vitro resistance testing. Virology studies may also record viral genetic variations, and relate these to

changes in antiviral drug resistance and susceptibility. To this end, this VR-UG includes the following draft

domains:

1. Viral Resistance (VR) - This new Findings domain is for data on viral resistance obtained by growing

a virus in culture in the presence of a drug and then quantifying the viral response to the drug.

2. Pharmacogenomics/Genetics Methods and Supporting Information (PG) - This updated Findings

domain describes new SDTM variables and stores information about the test methodology that collects

the set-up and quality control of the test. This contributes to the understanding of the test results

contained in the Pharmacogenomics Findings (PF) domain.

3. Pharmacogenomics Findings (PF) - This updated Findings domain includes new SDTM variables, and

is for the submission of results of genetic variations and gene expression.

4. PGx Biological State (PB) - This new Special-Purpose domain is a reference dataset that relates a set

of genetic variations to an inference about the medical meaning of the set of genetic variations.

5. Subject Biological State (SB) - This new Special-Purpose domain holds the medical statement from the

PB domain for individual subjects. Through the use of the PB and SB domain a mechanism is provided

to stay aligned with current medical knowledge.

A Pharmacogenomic/Genetics Study Data Tabulation Model Implementation Guide (SDTMIG-PGx) is

currently under development. This document will describe how to represent genetic data collected on

samples of DNA and RNA in SDTM-based format. The SDTMIG-PGx is envisioned to describe how to

accommodate genetic information from humans as well as from viruses, bacteria, and other

microorganisms including genetic variation and gene expression. Members of the user community are

encouraged to participate in the vetting of the SDTMIG-PGx standards.

1.2 CDER GUIDANCE ON ANTIVIRAL PRODUCT DEVELOPMENT

Implementers who intend to submit data to FDA are strongly encouraged to review current CDER guidance

documents related to the submission of antiviral drug resistance data, such as the CDER Draft Guidance on

Antiviral Product Development -Conducting and Submitting Virology Studies to the Agency – Guidance

for Submitting HCV Resistance Data (January 2012) and Guidance for Submitting HIV Resistance Data

(June 2012).



1.3 RELATIONSHIP TO PRIOR DOCUMENTS

This document does not replace any of the standards defined in the current Study Data Tabulation Model

Implementation for Human Clinical Trials (SDTMIG) or other implementation guides to the SDTM. When

used for clinical trials data, this SDTM supplement should be implemented together with the current

version of the SDTMIG (available at http://www.cdisc.org/standards). The SDTMIG is based on the

general SDTM conceptual model for representing clinical study data that is submitted to regulatory

authorities and should be read prior to reading the VR-UG v.1.0. An understanding of both of these

documents is needed before attempting to understand this virology addendum.

1.4 ORGANIZATION OF THIS DOCUMENT

This document contains information on how to format tabulation data for the purpose of submission. While

the document is self-contained with respect to virology-specific information, the domains were designed to

work in concert with existing SDTM model constructs. This document has been organized into the

following sections:

Section 1: Introduction - This section provides an orientation to this document.

Section 2: Relationships Between the Pharmacogenomics/Genetics (PGx) and Biospecimen

Domains (BE, BS) - Provides an overview of the new domains and their relationship to each other as

well as to existing domains described in the SDTMIG.

Section 3: Viral Resistance Findings (VR) - Describes the domain, assumptions and examples for

viral resitance findings

Section 4: Pharmacogenomics Findings (PF) - Describes the PF domain and includes domain

models, assumptions, and examples.

Section 5: Pharmacogenomics/Genetics Methods and Supporting Information (PG) - Describes

proposed new virology and updated PGx domains and assumptions for inclusion in a future SDTM

based implementation guide.

Section 6: PGx Biological State (PB) - Describes the domain, assumptions, and examples for a

reference dataset of biomarkers.

Section 7: Subject Biological State (SB) - Describes the domain, assumptions, and examples for

subject-level biomarker data.

Appendices - Contains a table of new and deleted SDTM variables, a list of participating

organizations, and legal notices.

1.5 DESIGN CONSIDERATIONS AND APPROACH

The purpose of this section is to review the design approach and lessons learned by mapping complex PGx

and virology data. This section also serves to document issues encountered during the development process

and their respective resolutions.

1. The initial approach was to represent genetic variation data by using the HUGO Nomenclature

(HGNC). An example HUGO representation of example a codon-level mutation is c.28CTC>ATC,

which means that at position 28 of the DNA sequence where the expected nucleotide sequence is

"CTC" the sequence "ATC" was observed.

During an early review, FDA reviewer participants asked that these data be parsed out into expected

nucleotide (CTC), position (28), and observed nucleotide (ATC).

2. An earlier design handled the position, expected nucleotide, observed nucleotide, and a number of

other test characteristics in separate rows. This design required variables to group rows together and

also resulted in very large files.

3. Given the challenges with the multi-row design, a different structure was proposed, and new variables

were added, so that the multiple results obtained for what was really a single test could be represented

in a single row.

4. The representation of codon changes and amino acid changes were considered to be separate results

and should be submitted as separate rows.

5. SPECIES and STRAIN were added to the domains to allow for the separation of genetic and genomic

data from pathogens, such as viruses (that are the subject of this user guide) from genetic data on their



human hosts (whose species and stain, if not human, would be submitted in the Demographics

domain).

6. It was suggested that SUBSTRAIN and CLADE be added to the domains. However, because of

ambiguous definitions and because the hierarchy used seems to differ, these potential additions were

deferred until a future version.

7. Representing viral resistance data in an SDTM-based domain model is a challenge. An initial attempt

was made to model these data in the Microbiology domains, but this approach was abandoned because

the current MB/MS domain structures are limited to resistance based on only one result. Virology data,

on the other hand, includes multiple results, and a net assessment that summarizes these results. The

use of the LB domain, which already includes examples of viral test data, was next considered but this

approach was felt to create too high a burden for creating test codes which would have included the

virus as part of the test name. After considering these alternatives, the team chose to create a Viral

Resistance (VR) domain that includes the species and strain variables, eliminating the need to maintain

pathogen-specific test names.

8. A draft SDTMIG-PGx document underwent public review in 2010. The need for new examples and

domains was identified to better document the PGx Biological State (PB) and Subject Biological State

(SB). These domains are included in draft form in this VR-UG and will be included SDTMIG-PGx

that is currently under development.



2 RELATIONSHIPS BETWEEN THE

PHARMACOGENOMICS/GENETICS (PGX)

AND BIOSPECIMEN DOMAINS

The section explains the concepts and relationships between the two PGx domains (PG and PF) in this

guide and the three biospecimen domains (BE, BS, ES) that will be included in the forthcoming SDTMIG-

PGx. These domains support specimen re-sectioning (when a portion of a specimen is tested) or specimen

extraction (when a genetic sample such as RNA or DNA is extracted for genetic/genomic testing).

1. In the top left corner of Figure 1 is the Biospecimen Events (BE) domain that is used to capture the

date/time of important steps within the specimen handling process. Examples include the following:

- Date/time specimen was sent to a lab

- Date/time specimen was received by a lab

- Date/time and duration for flash freezing and/or thawing of the specimen

2. Next in line after BE is the Biospecimen Handling domain (BS) that contains the details regarding

biospecimen handling. Examples include specimen volume, flash-frozen temperature, preservative

type, preservative volume, stabilizing reagent, and stabilizing reagent volume.

3. The Extracted Sample (ES) domain stores information regarding materials extracted from sample such

as RNA or DNA from a blood or tissue sample. It may also contain information about resections

obtained from a biospecimen (e.g., RNA/DNA quantity extracted, genetic material extract, and PGx

specimen condition).

4. The results of PGx tests tend to be sensitive to the degree of adherence to the specimen handling and

test-setup processes specified in the test protocol. Therefore, additional quality control (QC)

observations are captured to document compliance to proper procedures. Knowledge of the setup

processes also contributes to improved understanding of the test results. Therefore, a two-domain

structure was developed, in which setup and QC observations are stored separately from test results.

The former are stored in the Pharmacogenomics/Genetics Methods and Supporting Information (PG)

domain (also described as the PG Setup and QC domain for brevity), while results are stored in the

Pharmacogenomics Findings (PF) domain. This separation allows PG set up and QC to appear once,

and be related to multiple pharmacogenomic findings. Examples include the following:

For Gene Expression: Normalization Technique, RNA Integrity Number, A260/A230 ratio,

and A260/A280 ratio.

For Genetic Variation (Genotype / SNP Probe): exons sequenced, sequence start, and

sequence length.

5. The PGx Findings (PF) domain contains the results of genetic variation and gene expression tests. For

genetic variation tests, test results may include portions of the genetic sequence and comparisons with

reference gene sequence.

6. Linking between these five domains is accomplished by means of SDTM identifiers (STUDYID,

LNKID, and REFID).

7. The PGx Biological State (PB) (Reported Medical Condition Associations) domain is a special-

purpose domain that documents known associations between observed variations and medical

conclusions (e.g., disease diagnosis, resistance of a virus to a particular drug).

8. The Subject Biological State (SB) (Subject Medical Condition Associations) domain applies

associations documented in PB to observed subject variation and mutation data in PF to document

medical conclusions for individual subjects.

There are many genetic tests that involve the comparison of subject data to a published database. Under

certain circumstances, a test may be re-evaluated against different versions of the published database. That

being the case, there is a need for additional linking is needed. To accomplish this, records in the PF

domain should use the LINKID to connect to the record in the PG domain that documents the reference

database used. Examples of this linking will be included in the forthcoming SDTMIG-PGx. The diagram

below describes the high-level hierarchy that links these domains starting with the biologic specimen.



Figure 1: Biologic Specimen Natural Hierarchy



2.1 RELATIONSHIPS BETWEEN MOLECULAR CONCEPTS

Figure 2 below shows an example of how the relationships from the collected specimen to the results can

be represented.

1. The Biospecimen Handling domain (BS), which is described in the forthcoming SDTMIG-PGx,

contains information about the collected specimen. For example, this could be a collected tissue from a

normal or cancerous section of an organ. ABC-004 is the specimen identifier held in BSREFID. There

were no Biospecimen Events of interest in the example, so the BE domain is not included.

2. The Extracted Specimen domain (ES) (also described in the SDTMIG-PGx) shows the identifier

assigned to the genetic sample such as DNA once it is extracted. This domain would contain identifiers

for both the collected tissue sample and the extracted genetic sample.

3. Tests reported in the Pharmacogenomics Findings domain (PF) are linked to the specimen on which

they were run by means of the extracted specimen identifier (e.g. ABC-004-01), which is stored in

PFREFID, which is the same value in ESSPID.

4. The gene (in PFGENROI) is then associated with the amino acids that have been detected and

identified in rows containing a PFTESTCD value of AAOBS for the observed amino acid and

GENLOC for the position.

5. The amino acid can then be associated to the actual variation or mutation either represented as a codon

(with three nucleotides) or as individual nucleotides with their respective positions. PFRESCAT

qualifies the result in ORRES and STRESC (e.g., point mutation).



Figure 2: Relationships Between Molecular Concepts

Relationships Among Molecular

Concepts in Virology Examples

Hierarchy is mostly one

to many except between

Amino Acids and

Codons

BS.REFID

ABC-004

[Specimen]

ES.SPID

ABC-004-01

[Genetic Material

Such as DNA]

PF.REFID

ABC-004-01

[DNA}

PF

GENTYP = GENE

GENROI = GENEID

[Gene]

PF

TESTCD = AA

[Amino Acid]

AA=I

GENLOC=71

PF

GENLOC

213

[Codon]

PFTESTCD=CDN

PFORRES= ATT

PFREFRES=GTT

PF

PFSPID

GENLOC=213

GENLOC=214

GENLOC=215

Nucleotide

TESTCD = NUC

ORRES = A

ORRES = A

ORRES = T

RESCAT = “Point

Mutation”

1:1

1:M

1:M

1:M

1:M

1:M



3 VIRAL RESISTANCE FINDINGS (VR)

VR.xpt, Pharmacogenomics Findings - one record per viral load observation per specimen collected, per test, per date of test, per subject, tabulation.

Variable Name Variable Label Type

Controlled

Terms or

Format

Role CDISC Notes Core

STUDYID Study Identifier Char Identifier Definition: Unique identifier for a study within the submission. Req

DOMAIN Domain Abbreviation Char **VR Identifier Definition: Two-character abbreviation for the domain most relevant to the

observation.

Req

USUBJID Unique Subject Identifier Char Identifier Definition: Unique subject identifier within the submission. Req

VRSEQ Sequence Number Num Identifier Definition: Sequence number given to ensure uniqueness within a dataset for a

subject. Can be used to join related records.

Req

VRGRPID Group ID Char Identifier Definition: Used to tie together a block of related records in a single domain to

support relationships within the domain and between domains.

Perm

VRREFID Specimen ID Char Identifier Definition: The identifier of the viral specimen being tested. Perm

VRLNKID Link ID Char Identifier Definition: Supports linking information across different domains Perm

VRASYID Assay ID Char Identifier Definition: A unique identifier for a test as maintained by a lab. Perm

VRTESTCD Genomics Test Code Char * Topic Definition: Short name for the test.

Examples: IC50T, IC50R

Req

VRTEST Pharmacogenomics Test

Description

Char * Synonym

Qualifier

Definition: The verbatim name used to obtain the measurement or finding.

Examples: IC50 result on treatment, IC50 fold change from baseline.

Req

VRTSTRCD Test Reference

Terminology Code

Char * Result Qualifier Definition: The code of the result. For example; R is the code for Arginine and

C49488 is the code for Y.

Perm

VRTSTRNM Test Reference

Terminology Name

Char Result Qualifier Definition: The name of the Reference Terminology for the result. For example;

CDISC, SNOMED, LOINC.

Perm

VRTSTRVR Test Reference

Terminology Version

Char Result Qualifier Definition: The version number of the Reference Terminology, if required. Perm

VRGENTYP Gene Type Char Result Qualifier Definition: Identifies the type of genetic region of interest, for example,

GENENAME, SECTOR, PROTEIN.

Exp

VRGENROI Gene Region of Interest Char Record

Qualifier

Area within the DNA sequences.

Example: Protease (in the case of HIV), NS3/4A, NS5B (in the case of HCV).

Exp

VRSPCIES Biological Classification Char * Grouping

Qualifier

Definition: Biological classifications for an organism capable of breeding and

producing offspring. May also be used to designate organisms.

Example: HOMO SAPIENS, RAT, MOUSE, BACTERIUM, HCV, HIV

Perm

VRSTRAIN Type of Strain Char * Grouping

Qualifier

Definition: A genetic variant or subtype of a micro-organism.

Examples: 1a, 1b.

Perm

VRCAT Category for

Pharmacogenomics Lab

Test

Char * Grouping

Qualifier

Definition: Used to categorize types of viral resistance tests.

Exp




Controlled

Terms or

Format


VRSCAT Subcategory for


Test

Char * Grouping

Qualifier

Definition: A further categorization of the various test types based on particular

characteristics of a test.

Perm

VRDRUG Drug Name Char Record

Qualifier

Definition: the name of the drug for which resistance is based on genetic

biological markers.

Examples: Saquinavir, Indinavir

Exp

VRORRES Result or Finding in

Original Units

Char Result Qualifier Definition: Result of the measurement or finding as originally received or

collected.

Example: For this domain the results are generally numeric/char value as

provided by the laboratory.

Exp

VRORRESU Original Units Char (UNIT) Variable

Qualifier

Definition: Represents the unit of measure used by VRORRES if applicable.

Example: copies/5uL, LOG10 IU/mL

Exp

VRSTRESC Character Result/Finding

in Std Format

Char Result Qualifier Definition: Provides information such as the gene being tested for genotyping

tests as well as interpretations and other supporting information such as

insertions and deletions or intensity and P-Value for Array tests.

Example for CDNOBS:

AGC

Exp

VRSTRESN Numeric Result/Finding

in Standard Units

Num Result Qualifier Definition: Used for continuous or numeric results or findings in standard

format; copied in numeric format from VRSTRESC. VRSTRESN should store

all numeric test results or findings.

Example for p-Value: 0.5391

Exp

VRSTRESU Standard Units Char * Variable

Qualifier

Definition: Represents the unit of measure used by VRSTRESN. Exp

VRSTAT Pharmacogenomics

Status

Char (ND) Record

Qualifier

Definition: Used to indicate exam not done. Should be null if a result exists in

VRSTRESC.

Perm

VRREASND Reason Test Not Done Char Record

Qualifier

Definition: Describes why a measurement or test was not performed such as

BROKEN EQUIPMENT, SUBJECT REFUSED, or SPECIMEN LOST. Used in

conjunction with VRSTAT when value is NOT DONE.

Perm

VRXFN

Raw Data File or LSID Char Record

Qualifier

Definition: Direct reference identifier for Microarray or Genotypic data

contained in a separate file in its native format.

Life Sciences Identifier (LSID)

Perm

VRNAM Vendor Name Char Record

Qualifier

Definition: Name or identifier of the laboratory or biotech firm that provided the

test results.

Perm

VRSPEC Specimen Type Char * Record

Qualifier

Definition: Defines the type of specimen used for a measurement.

Examples: TISSUE, SERUM, PLASMA, TUMOR, DNA, RNA

Perm

VRSPCCND Specimen Condition Char Record

Qualifier

Definition: Free or standardized text describing the condition of the specimen.

Example: HEMOLYZED, ICTERIC, LIPEMIC, FRESH, FROZEN,

PARAFFIN-EMBEDDED etc.

Perm




Controlled

Terms or

Format


VRMETHOD Method Code for Test Char * Record

Qualifier

Definition: Special instructions for the execution of genomics or genetic testing.

Examples: PhenoSense GT

Req

VRBLFL Baseline Flag Char (NY) Record

Qualifier

Definition: Indicator used to identify a baseline value, Perm

VRDRVFL Derived Flag Char (NY) Record

Qualifier

Definition: Used to indicate a derived record. Perm

VISITNUM Visit Number Num Timing Definition:

1. Clinical encounter number.

2. Numeric version of VISIT, used for sorting.

Exp

VISIT Visit Name Char Timing Definition:

1.Protocol-defined description of clinical Encounter

2.May be used in addition to VISIT and VISITDY.

Perm

VISITDY Planned Study Day of

Visit

Num Timing Definition: Planned study day of the visit based upon RFSTDTC in

Demographics.

Perm

VRDTC Date/Time of Test Char ISO 8601 Timing Definition:

Date/time of specimen collection

Exp

VRDY Study Day of Test Num Timing Definition:

1. Study day of specimen collection, measured as integer days.

2. Algorithm for calculations must be relative to the sponsor-defined RFSTDTC

variable in Demographics. This formula should be consistent across the

submission.

Perm

VRTPT Planned Time Point

Name

Char Timing Definition:

1.Text Description of time when specimen should be taken.

2. This may be represented as an elapsed time relative to a fixed reference point,

such as time of last dose. See VRTPTNUM and VRTPTREF.

Examples: Start, 5 min post.

Perm

VRTPTNUM Planned Time Point

Number

Num Timing Numerical version of VRTPT to aid in sorting. Perm

VRELTM Elapsed Time from

Reference Point

Char ISO 8601 Timing Definition: Elapsed time (in ISO 8601) relative to a planned fixed reference

(VRTPTREF). This variable is useful where there are repetitive measures. Not a

clock time or a date time variable.

Examples: '-P15M' to represent the period of 15 minutes prior to the reference

point indicated by VRTPTREF, or 'P8H' to represent the period of 8 hours after

the reference point indicated by VRTPTREF.

Perm

VRTPTREF Time Point Reference Char Timing Definition: Name of the fixed reference point referred to by VRELTM,

VRTPTNUM, and VRTPT.

Examples: PREVIOUS DOSE, PREVIOUS MEAL.

Perm




Controlled

Terms or

Format


VRRFTDTC Date/Time of Reference

Time Point

Char ISO 8601 Timing Date/time of the reference time point, VRTPTREF. Perm

3.1 ASSUMPTIONS FOR VIRAL RESISTANCE TEST FINDINGS (VR) DOMAIN MODEL

1. This domain is for data on viral resistance obtained by growing virus in culture in the presence of a drug and then quantifying virus (e.g. measuring

“viral load”). This is distinct from “viral load” measured on samples taken directly on a study subject to measure the status of the virus within the

subject that would be submitted in the LB domain. It is also distinct from genetic testing performed to detect viral variations and infer viral

resistance from variations; that data is stored in PF (see Example 4 in Section 4.6 of this supplement).

2. This domain is for clinical and pre-clinical use.

3. Viral resistance is determined by exposing the amplified virus in isolation (in vitro) to an anti-viral drug and then deriving from the raw viral load

values for each concentration the inhibitory concentrations (ICs) for various proportions of virus. For instance the IC50 is a concentration that limits

growth to 50% of what is seen for virus grown without drug. These inhibitory concentrations for a sample taken from a study subject may be

compared with inhibitory concentrations for a control strain of virus, usually a “wild type”, susceptible to the drug in question. The ratio of

inhibitory concentration for study subject virus and control virus is called a “fold increase.” All these measures may be considered in reaching an

overall assessment of the virus’s resistance to the drug.

3.2 EXAMPLES FOR VIRAL RESISTANCE TEST FINDINGS (VR) DOMAIN MODEL

Example 1: This HIV example shows that viral concentrations are measured after exposure to specified concentrations to determine levels of

susceptibility.. This example compares the subject’s specimen’s culture measurements to those of a control sample. A similar comparison could be made

to a baseline measurement for the subject.

In these examples, Rows 1-7 pertain to resistance to Drug A and Rows 8-14 pertain to resistance to Drug B.

Rows 1 and 8 show the response of the virus extracted from the subject based on drug concentrations expected to produce 50% inhibition of the

standard virus growth.

Rows 2 and 9 show a control viral sample response based on drug concentrations expected to produce 50% inhibition of the standard virus

growth.

Rows 3 and 10 show the fold change of the response of the virus extracted from the subject from control viral sample response based on drug

concentrations expected to produce 50% inhibition of the standard virus growth. This is the on-treatment result divided by the reference result.

Rows 4 and 11 show the response of the virus extracted from the subject based on drug concentrations expected to produce 95% inhibition of

the standard virus growth.

Rows 5 and 12 show a control viral sample response based on drug concentrations expected to produce 95% inhibition of the standard virus

growth.



Rows 6 and 13 show the fold change of the response of the virus extracted from the subject from control viral sample response based on drug

concentrations expected to produce 95% inhibition of the standard virus growth. This is the on-treatment result divided by the reference result.

Rows 7 and 14 show the net assessment (Reduced or Increased Susceptibility) based on the measurements.

Row STUDYID DOMAIN USUBJID VRSEQ VRGRPID VRREFID VRGENTYP VRGENROI VRTESTCD VRTEST

1 ABC-123 VR R12345 1 1 16248 SECTOR Nucleoside Reverse

Transcriptase

IC50T IC50 Result on Treatment


Transcriptase

IC50R IC50 Reference Control

Result


Transcriptase

IC50FCR IC50 Fold Change from

Reference


Transcriptase

IC95T IC95 Result on Treatment


Transcriptase

IC95R IC95 Reference Control

Result


Transcriptase

IC95FCR IC95 Fold Change from

Reference


Transcriptase

NETASSMT Net Assessment

8 ABC-123 VR R12345 8 2 16248 SECTOR Protease IC50T IC50 Result on Treatment

9 ABC-123 VR R12345 9 2 16248 SECTOR Protease IC50R IC50 Reference Control

Result

10 ABC-123 VR R12345 10 2 16248 SECTOR Protease IC50FCR IC50 Fold Change from

Reference

11 ABC-123 VR R12345 11 2 16248 SECTOR Protease IC95T IC95 Result on Treatment

12 ABC-123 VR R12345 12 2 16248 SECTOR Protease IC95R IC95 Reference Control

Result

13 ABC-123 VR R12345 13 2 16248 SECTOR Protease IC95FCR IC95 Fold Change from

Reference

14 ABC-123 VR R12345 14 2 16248 SECTOR Protease NETASSMT Net Assessment



Row

(cont)

VRSPCIES VRSTRAIN VRDRUG VRORRES VRORRESU VRSTRESC VRSTRESN VRSTRESU

1 HIV 1 Drug A 13.11 umol 13.11 umol


3 HIV 1 Drug A 4.37471 4.37471



6 HIV 1 Drug A 3.6 3.6

7 HIV 1 Drug A Reduced Susceptibility Reduced Susceptibility

8 HIV 1 Drug B 7.97 umol 7.97 umol


10 HIV 1 Drug B 4.63569 4.63569



13 HIV 1 Drug B 2.4 2.4

14 HIV 1 Drug B Reduced Susceptibility Reduced Susceptibility



4 PHARMACOGENOMICS FINDINGS (PF)

PF.xpt, Pharmacogenomics Findings - one record per method/setup observation per specimen collected, per date of test, per subject, Tabulation


Controlled

Terms

or Format


STUDYID Study Identifier Char Identifier Definition: Unique identifier for a study within the submission. Req

DOMAIN Domain Abbreviation Char **PF Identifier Definition: Two-character abbreviation for the domain most relevant to the

observation.

Req


PFSEQ Sequence Number Num Identifier Definition: Sequence number given to ensure uniqueness within a dataset for a


Req

PFGRPID Group ID Char Identifier Definition: Used to tie together a block of related records in a single domain to

support relationships within the domain and between domains.

Perm

PFREFID Specimen ID Char Identifier Definition: The identifier of the genetic specimen being tested. Perm

PFLNKID Link ID Char Identifier Definition: Supports linking information across different domains. Perm

PFASYID Assay ID Char Identifier Definition: A unique identifier for a test as maintained by a lab. Perm

PFRLOCID Reference Result

Location

Char Identifier Definition: Provides an external database identifier that can be used to locate the

documented reference sequence. Examples: dbSNP RS Number.

Perm

PFTESTCD Genomics Test Code Char * Topic Definition: Short name for the test. Examples: AA, CHGTYP, CDNPOS,

CDNOBS, PATHTYP, POLYTYP, NINT1VAL, NINT2VAL, PVAL,

FOLDCHG, LOTINT, LOGERROR

Req

PFTEST Pharmacogenomics Test

Description

Char * Synonym

Qualifier

Definition: The verbatim name used to obtain the measurement or finding.

Examples: Amino Acid, Genetic Change Type, Codon Position, Observed

Codon, Pathological Type, Normalized Intensity Value 1, Normalized Intensity

Value 2, P Value, Fold Change, Log Intensity Type, Log Error.

Perm

PFTSTRCD Test Reference

Terminology Code

Char * Result Qualifier Definition: The code of the result. For example: LOINC code 48005-3 for amino

acid change.

Perm

PFTSTRNM Test Reference

Terminology Name

Char Result Qualifier Definition: The name of the Reference Terminology for the result. Examples:

CDISC, SNOMED, LOINC.

Perm

PFTSTRVR Test Reference

Terminology Version

Char Result Qualifier Definition: The version number of the Reference Terminology, if required.

Perm

PFGENTYP Genetic Region of

Interest Type

Char Result Qualifier Definition: Identifies the type of genetic region of interest, for example,


Exp

PFGENROI Genetic Region of

Interest

Char Result Qualifier Definition: Area within the DNA sequences.

Example: Protease (in the case of HIV), NS3/4A, NS5B (in the case of HCV).

Exp

PFGENLOC Genetic Location Char Result Qualifier Definition: Specifies a location within a sequence pertaining to the observed

results contained in PFORRES, PFSTRESC and PFSTRESN.

Perm

PFSPCIES Biological classification Char * Grouping

Qualifier



Example: HOMO SAPIENS, RAT, MOUSE, BACTERIUM, HCV, HIV

Perm




Controlled

Terms

or Format


PFSTRAIN Type of Strain Char * Grouping

Qualifier


Examples: 1a, 1b.

Perm

PFCAT Category for


Test

Char * Grouping

Qualifier

Definition: Used to categorize types of genetic/genomic tests.

Examples: MICRO ARRAY, EGFR MUTATION ANALYSIS.

Exp

PFSCAT Subcategory for


Test

Char * Grouping

Qualifier

Definition: A further categorization of the various test types based on particular

characteristics of a test.

Examples: OBSERVED VALUE,

INTERPRETATION, PHENOTYPIC EXPRESSION

Perm

PFMUTYP Mutation Type

Char * Grouping

Qualifier

Definition: Indicates whether a mutation is inheritable or not.

Examples: GERMLINE

Perm

PFORRES Result or Finding in

Original Units


collected.

Example: Observed Nucleotide value: T.

Exp

PFORRESU Original Units Char (UNIT) Variable

Qualifier

Definition: Represents the unit of measure used by PFORRES if applicable.

Example: copies/5uL, LOG10 IU/ml

Perm

PFSTRESC Character Result/Finding

in Std Format

Char Result Qualifier Definition: Provides information such as the gene being tested for genotyping

tests as well as interpretations and other supporting information such as

insertions and deletions or intensity and P-Value for Array tests.

Example: Nucleotide change from reference sequence: A>T.

Exp

PFSTRESN Numeric Result/Finding

in Standard Units


format; copied in numeric format from PFSTRESC. PFSTRESN should store all

numeric test results or findings.

Example for P-Value: 0.5391

Perm

PFSTRESU Standard Units Char * Variable

Qualifier

Definition: Represents the unit of measure used by PFSTRESN. Perm

PFRESRCD Result Reference

Terminology Code

Char * Result Qualifier Definition: The code of the result. For example: R is the code for Arginine and

C49488 is the code for Y.

Perm

PFRESRNM Result Reference

Terminology Name

Char Result Qualifier Definition: The name of the Reference Terminology for the result. For example:

CDISC, SNOMED. LOINC

Perm

PFRESRVR Result Reference

Terminology Version

Char Result Qualifier Definition: This is the code of the result. For example; R is the code for Arginine

and C49488 is the code for Y.

Perm

PFREFRES Reference Result Value Char Result Qualifier Definition: Reference result used to determine variations based on the reference

sequence.

Perm

PFRESCAT Result Category Char Result Qualifier Definition: Identifies the type of result being reported.

Example: RESISTANCE VARIANT

Perm

PFSTAT Test Status Char (ND) Record

Qualifier

Definition: Used to indicate exam not done. Should be null if a result exists in

PFSTRESC.

Perm




Controlled

Terms

or Format


PFREASND Reason Test Not Done Char Record

Qualifier

Definition: Describes why a measurement or test was not performed such as

BROKEN EQUIPMENT, SUBJECT REFUSED, or SPECIMEN LOST. Used in

conjunction with PFSTAT when value is NOT DONE.

Perm

PFXFN

Raw Data File or Life

Science Identifier

Char Record

Qualifier

Definition: Direct reference identifier for Microarray or Genotypic data

contained in a separate file in its native format.

Perm

PFNAM Vendor Name Char Record

Qualifier

Definition: Name or identifier of the laboratory or biotech firm who provides the

test results.

Perm

PFSPEC Specimen Type Char * Record

Qualifier


Examples: DNA, RNA

Perm

PFSPCCND Specimen Condition Char Record

Qualifier

Definition: Free or standardized text describing the condition of the specimen.

Example: CONTAMINATED

Perm

PFMETHOD Method Code for Test Char * Record

Qualifier

Definition: Special instructions for the execution of genomics or genetic testing.

Examples: SNP PROBE, CLIP SEQUENCING, PYROSEQUENCING,

BICHROME GENE EXPRESSION CHIP).

Req

PFBLFL Baseline Flag Char (NY) Record

Qualifier

Definition: Indicator used to identify a baseline value, Perm

PFDRVFL Derived Flag Char (NY) Record

Qualifier

Definition: Used to indicate a derived record. Perm




Exp


1. Protocol-defined description of clinical encounter

2. May be used in addition to VISITNUM and/or VISITDY

Perm


Visit


Demographics.

Perm

PFDTC Date/Time of Specimen

Collection

Char ISO 8601 Timing Definition:


Exp

PFDY Study Day of Specimen

Collection

Num Timing Definition:


2. Algorithm for calculations must be relative to the sponsor-defined RFSTDTC

variable in Demographics. This formula should be consistent across the

submission.

Perm




Controlled

Terms

or Format


PFTPT Planned Time Point

Name

Char Timing Definition: 1.Text Description of time when specimen should be taken.

2. This may be represented as an elapsed time relative to a fixed reference point,

such as time of last dose. See PFTPTNUM and PFTPTREF.


Perm

PFTPTNUM Planned Time Point

Number

Num Timing Definition: Numerical version of PFTPT to aid in sorting. Perm

PFELTM Elapsed Time from

Reference Point


(PFTPTREF). This variable is useful where there are repetitive measures. Not a

clock time or a date time variable.

Examples: '-P15M' to represent the period of 15 minutes prior to the reference

point indicated by PFTPTREF, or 'P8H' to represent the period of 8 hours after

the reference point indicated by PFTPTREF.

Perm

PFTPTREF Time Point Reference Char Timing Definition: Name of the fixed reference point referred to by PFELTM,

PFTPTNUM, and PFTPT.


Perm

PFRFTDTC Date/Time of Reference

Time Point

Char ISO 8601 Timing Definition: Date/time of the reference time point, PFTPTREF. Perm

4.1 ASSUMPTIONS FOR PHARMACOGENOMICS TEST FINDINGS (PF) DOMAIN MODEL

1. PF captures results for genetic variation and gene expression.

2. This domain is for clinical and pre-clinical use, and for tests on a study subject or an infectious microbe.

3. PFASYID is used to distinguish between records for the same genetic test performed using different assays. The combination of PFNAM,

PFASYID, and REFID will be needed to obtain the full set of genomic data produced and sent by the lab for a specific test.

4. PFMETHOD lists techniques for the execution of genomics or genetic testing.

5. Only the p-value calculation performed by the lab and sent to the sponsor should be included in PF.

6. External terminology variables, (e.g., PFRESCD, PFRESRNM, PFRESRVR), will have examples in the forthcoming SDTMIG-PGx.

7. For viral findings, mutation type (PFMUTYP) should always be set to “GERMLINE”.

8. PFCAT is used to designate the technology used, (e.g., GENETIC VARIATION, GENE EXPRESSION).

4.2 GENETIC VARIATION ASSUMPTIONS

1. PFTESTCD generally specifies what the test assessed, such as nucleic acid, amino acid, or codon.

2. PFSCAT is used to categorize the tests, for example, AMINO ACID, MUTATION, or IDENTIFIER.

3. PFASYID provides a mechanism to identify results as belonging to a common set. When a genetic test is performed on an individual subject using

multiple assays, the combination of vendor name and PFASYID will support linking between the PF domains and the full set of genomic data

produced and sent by the lab. This can facilitate delivering additional information to regulatory agencies, if needed.



4. PFORRES and PFSTRESC are used to store genetic and amino acid variants as well as interpretations and other supporting information such as

insertions and deletions or intensity and p-values for array tests. If no standardization is being done, both variables will have identical content.

5. When results indicate a mixture of genetic results, as when two strains of a virus such as HIV are present in a sample, all the results present should

be concatenated using slashes. For example, “C/T” indicates that at that nucleotide position, the virus has both cysteine and tyrosine present,

indicating a multi-strain infection.

4.3 EXPLANATORY NOTES ON SLC DATABASE GENETIC CODES

The following information is provided for those not familiar with genetic nomenclature. Codons are made up of three nucleotides. A nucleotide may

have one of the following values: A (adenosine), G (guanosine), T (thymidine), or C (cytidine). Amino acids are encoded by the nucleotides. It is the

preferred convention to use a single-letter code (SLC) to identify an amino acid. This link, http://www.cbs.dtu.dk/courses/27619/codon.html, provides

the mapping between the single-letter amino acid code and its full text name, which correlates to the codon values.

4.4 EXAMPLES FOR VIRAL GENETICS FINDINGS

Example 1: Only amino acid observations are being reported. In this example, the change type is a substitution.

Row 1: The DNA came from a sample taken from the study subject at Visit 1. The test assesses the observed amino acid in the genetic region shown in

PFGENROI at the location given by PFGENLOC, performed by the vendor (PFNAM) using a particular method (PFMETHOD). The result is an amino

acid, represented by the standard one-letter code. The record also shows a reference result (the amino acid at the same location in the reference

sequence) in PFREFRES, and provides a classification of the result, based on the comparison of the observed result to the reference result, in

PFRESCAT.

Row STUDYID DOMAIN USUBJID PFSEQ PFREFID PFGENTYP PFGENROI PFTESTCD PFTEST PFSPCIES PFSTRAIN PFCAT PFSCAT

1 P7081-

5101

PF P7081-5101-

01201

1 ABC-001 PROTEIN NS5B AA Amino

Acid

HCV 1a GENETIC

VARIATION

AMINO

ACID

Row

(cont) PFORRES PFGENLOC PFREFRES PFRESCAT PFNAM PFSPEC PFMETHOD PFBLFL VISITNUM VISIT VISITDY VFDTC

1 R 65 Q Point

Mutation

Acme

Genetics

DNA CLIP

SEQUENCING

Y 1 Baseline 1 2003-03-27

http://www.cbs.dtu.dk/courses/27619/codon.html



Example 2: This example contains both an amino acid observation and the underlying nucleic acid sequence (codon). The variant identified in these

records is a deletion.

Row 1 shows the amino acid observed at a particular location in the genetic region NS5B71 and its reference result. This record is marked as derived,

since the amino acid is derived from the observed codon via the standard look-up table.

Row 2 reports the nucleic acid sequence for the associated codon and its reference result and classifies the comparison between the result and the

reference result as a DELETION.

Row STUDYID DOMAIN USUBJID PFSEQ PFREFID PFGENTYP PFGENROI PFTESTCD PFTEST PFSPCIES PFSTRAIN PFCAT PFSCAT

1

P7081-

5101

PF P7081-

5101-

06891

1 ABC-003 PROTEIN NS5B AA Amino

Acid

HCV 1b GENETIC

VARIATION

AMINO ACID

2

P7081-

5101

PF P7081-

5101-

06891

2 ABC-003 PROTEIN NS5B CDN Codon HCV 1b GENETIC

VARIATION

NUCELOTIDE

Row

(cont) PFORRES PFSTRESC PFGENLOC PFREFRES PFRESCAT PFNAM PFSPEC PFMETHOD PFBLFL VISITNUM VISIT VISITDY PFDTC

1 I I 71 V Acme

Genetics

DNA CLIP

SEQUENCING Y 1 Baseline 1 20030327

2 ATT ATT 213 GTT DELETION Acme

Genetics

DNA CLIP

SEQUENCING Y 1 Baseline 1 20030327

Example 3: The example below focuses on how variations would be reported at the nucleotide level. Note that the change type record was not shown,

but would be recorded just as shown in previous examples. There is one record for which the observed nucleotide is different from the reference result.

The nucleic acid at this position is missing, so the change type (PFRESCAT) is "DELETION". Nucleotide-level reporting is suggested only for special

circumstances such as frame shifts since it tends to greatly increase the size of the data files. Codon-level reporting (as in the previous two examples)

will result in a significant 66% saving of space.

Row 1 shows the deletion of a nucleotide at a particular position. This absence of a nucleotide at this position is represented as the result “NONE”.

Rows 2-9 show adjacent nucleotide positions, which are unchanged.



Row STUDYID DOMAIN USUBJID PFSEQ PFREFID PFGENTYP PFGENROI PFTESTCD PFTEST PFASYID PFSPCIES PFSTRAIN PFCAT PFSCAT

1 P7081-

5101

PF P341-

5101-

06345

1 ABC-004 PROTEIN NS5B NUC Nucleotide D391395-

001

HCV 1a GENETIC

VARIATION

NUCLEOTIDE

2 P7081-

5101

PF P341-

5101-

06345


001

HCV 1a GENETIC

VARIATION

NUCLEOTIDE

3 P7081-

5101

PF P341-

5101-

06345


001

HCV 1a GENETIC

VARIATION

NUCLEOTIDE

4 P7081-

5101

PF P341-

5101-

06345


001

HCV 1a GENETIC

VARIATION

NUCLEOTIDE

5 P7081-

5101

PF P341-

5101-

06345S


001

HCV 1a GENETIC

VARIATION

NUCLEOTIDE

6 P7081-

5101

PF P341-

5101-

06345


001

HCV 1a GENETIC

VARIATION

NUCLEOTIDE

7 P7081-

5101

PF P341-

5101-

06345


001

HCV 1a GENETIC

VARIATION

NUCLEOTIDE

8 P7081-

5101

PF P341-

5101-

06345


001

HCV 1a GENETIC

VARIATION

NUCLEOTIDE

9 P7081-

5101

PF P341-

5101-

06345


001

HCV 1a GENETIC

VARIATION

NUCLEOTIDE



Row

(cont) PFORRES PFSTRESC PFSTRESN PFGENLOC PFREFRES PFRESCAT PFNAM PFSPEC PFMETHOD PFBLFL

1 NONE NONE 213 A DELETION Acme

Genetics

DNA DIRECT SEQUENCING Y

2 T T 214 Acme

Genetics


3 C C 215 Acme

Genetics


4 A A 216 Acme

Genetics


5 A A 217 Acme

Genetics

DNA DIRECT

SEQUENCING

Y

6 G G 218 Acme

Genetics


7 A A 219 Acme

Genetics


8 G G 220 Acme

Genetics

DNA DIRECT

SEQUENCING

Y

9 T T 221 Acme

Genetics


Example 4: This is an example of viral genetic testing undertaken to determine drug resistance. Records come in pairs, one record for the observed

codon and one for the amino acid coded by the observed codon. This distinction is made in PFSCAT. All records are for the same sample of RNA from

a strain 1a of HIV.

Rows 1 and 2: These results show a variation in the Protease region of the virus. The change in the codon shown in Row 2 is classified as a point

mutation. The change in amino acid is classified as a resistance mutation (PFRESCAT).

Rows 3-26: Illustrate the representation of other variants in a similar manner.

Row STUDYID DOMAIN USUBJID PFSEQ PFGRPID PFREFID PFGENTYP PFGENROI PFTESTCD PFTEST PFSPCIES PFSTRAIN PFCAT PFSCAT

1 STDY-

505357

PF 521298 1 1 D391395 SECTOR Protease AA Amino

Acid

HIV 1a GENETIC

VARIATION

AMINO ACID

2 STDY-

505357

PF 521298 2 1 D391395 SECTOR Protease CDN Codon HIV 1a GENETIC

VARIATION

NUCLEOTIDE

3 STDY-

505357


Acid

HIV 1a GENETIC

VARIATION

AMINO ACID




4 STDY-

505357


VARIATION

NUCLEOTIDE

5 STDY-

505357


Acid

HIV 1a GENETIC

VARIATION

AMINO ACID

6 STDY-

505357


VARIATION

NUCLEOTIDE

7 STDY-

505357


Acid

HIV 1a GENETIC

VARIATION

AMINO ACID

8 STDY-

505357


VARIATION

NUCLEOTIDE

9 STDY-

505357

PF 521298 9 5 D391395 SECTOR Reverse

Transcriptase

AA Amino

Acid

HIV 1a GENETIC

VARIATION

AMINO ACID

10 STDY-505357

PF 521298 10 5 D391395 SECTOR Reverse Transcriptase

CDN Codon HIV 1a GENETIC VARIATION

NUCLEOTIDE

11 STDY-505357


AA Amino Acid

HIV 1a GENETIC VARIATION

AMINO ACID

12 STDY-

505357


Transcriptase

CDN Codon HIV 1a GENETIC

VARIATION

NUCLEOTIDE

13 STDY-505357


AA Amino Acid


AMINO ACID

14 STDY-

505357


Transcriptase

CDN Codon HIV 1a GENETIC

VARIATION

NUCLEOTIDE

15 STDY-505357


AA Amino Acid


AMINO ACID

16 STDY-505357


CDN Codon HIV 1a GENETIC VARIATION

NUCLEOTIDE

17 STDY-505357

PF 521298 17 9 D391395 SECTOR Protease AA Amino Acid


AMINO ACID

18 STDY-

505357


VARIATION

NUCLEOTIDE

19 STDY-505357

PF 521298 19 10 D391395 SECTOR Protease AA Amino Acid


AMINO ACID




20 STDY-

505357


VARIATION

NUCLEOTIDE

21 STDY-

505357


Acid

HIV 1a GENETIC

VARIATION

AMINO ACID

22 STDY-

505357


VARIATION

NUCLEOTIDE

23 STDY-

505357


Acid

HIV 1a GENETIC

VARIATION

AMINO ACID

24 STDY-

505357


VARIATION

NUCLEOTIDE

25 STDY-

505357


Acid

HIV 1a GENETIC

VARIATION

AMINO ACID

26 STDY-505357

PF 521298 26 13 D391395 SECTOR Protease CDN Codon HIV 1a GENETIC VARIATION

NUCLEOTIDE

Row

(cont)

PFORRES PFSTRESC PFGENLOC PFREFRES PFRESCAT PFNAM PFSPEC PFMETHOD PFBLFL PFDRVFL

1 I I 10 L Resistance Mutation Acme

Genetics

DNA CLIP

SEQUENCING Y

2 ATC ATC 28 CTC Point Mutation Acme

Genetics

DNA CLIP

SEQUENCING Y

3 G G 17 G Silent Mutation Acme

Genetics

DNA CLIP

SEQUENCING Y

4 GGG GGG 49 GGR Duplication Acme

Genetics

DNA CLIP

SEQUENCING Y

5 I I 13 V Polymorphism Acme

Genetics

DNA CLIP

SEQUENCING Y

6 ATA ATA 37 GTA Point Variation Acme

Genetics

DNA CLIP

SEQUENCING Y

7 L L 33 I Unexpected Mutation Acme

Genetics

DNA CLIP

SEQUENCING Y

8 TTA TTA 97 ATA Point Mutation Acme

Genetics

DNA CLIP

SEQUENCING Y



Row

(cont)


9 M M 41 L Resistance Mutation Acme

Genetics

DNA CLIP

SEQUENCING Y

10 ATG ATG 121 TTA Point Mutation Acme

Genetics

DNA CLIP

SEQUENCING Y

11 V V 90 V Silent Mutation Acme

Genetics

DNA CLIP

SEQUENCING Y

12 GTT GTT 268 GTY Deletion Acme

Genetics

DNA CLIP

SEQUENCING Y

13 I I 135 V Polymorphism Acme

Genetics

DNA CLIP

SEQUENCING Y

14 ATA ATA 103 GTA Point Variation Acme

Genetics

DNA CLIP

SEQUENCING Y

15 K K 70 E Unexpected Mutation Acme

Genetics

DNA CLIP

SEQUENCING Y

16 AAA AAA 208 AGA Point Mutation Acme

Genetics

DNA CLIP

SEQUENCING Y

17 G G 48 V Unexpected Mutation Acme

Genetics

DNA CLIP

SEQUENCING Y

18 GGG GGG 142 GTG Point Mutation Acme

Genetics

DNA CLIP

SEQUENCING Y

19 K K 20 K/R Unexpected Mutation Acme

Genetics

DNA CLIP

SEQUENCING Y

20 AAG AAG 58 ARG Point Mutation Acme

Genetics

DNA CLIP

SEQUENCING Y

21 M M 36 I Unexpected Mutation Acme

Genetics

DNA CLIP

SEQUENCING Y

22 106 106 106 ATA Point Mutation Acme

Genetics

DNA CLIP

SEQUENCING Y

23 A A 71 V Unexpected Mutation Acme

Genetics

DNA CLIP

SEQUENCING Y

24 GCT GCT 211 GTT Point Mutation Acme DNA CLIP Y



Row

(cont)


Genetics SEQUENCING

25 V V 82 T/S Unexpected Mutation Acme

Genetics

DNA CLIP

SEQUENCING Y

26 GCT GCT 244 GTT Point Mutation Acme

Genetics

DNA CLIP

SEQUENCING Y

The PB domain that would accompany this findings example can be found in Example 1 of the PB domain.

Example 5:

The example shows typical results for genetic variation tests. The Findings data structure was extended to accommodate genetic concepts. It now

supports genetic region of interest (PFGENROI), its type (PFGENTYP), the reference result (PFREFRES), and genetic location (PFGENLOC). Rows 1

and 2 both show the use of the HUGO nomenclature in the PFSTRESC variable. The reference sequence can be represented in the PG domain as a row

with a test code of GENBNKID. The result variable in PG reported the NIH Genetic Sequence Database (GenBank) accession number associated with

the reference sequence being used. The XFN variable may contain a pointer to a file containing the entire reference sequence. This example also shows

the use of the new terminology variables (PFTSTRCD, PFTSTRNM, PFTSTRVR) to link the tests to an external dictionary such as LOINC.

Row 1-2 shows that at nucleotide at position 2155 a genetic change occurred where a G was changed to an A.

It also shows that a change occurred from the amino acid Glycine (Gly) at location 719 to Serine. Since the amino acid change is not directly observed

but derived from the variation, the derived flag is set to "Y" if the sponsor is performing the interpretation.

Row STUDYID DOMAIN USUBJID PFSEQ PFREFID PFASYID PFTESTCD PFTEST PFTSTRCD PFTSTRNM PFTSTRVR

1 ABC-01234 PF 17C0154 1 8250863 X421395-

001

AA Amino

Acid

48005-3 LOINC 2.40

2 ABC-01234 Pf 1 8250863 X421395-

001

CDN Codon 48004-6 LOINC 2.40

Row

(cont) PFGENTYP PFGENROI PFGENLOC PFSPCIES PFCAT PFORRES PFSTRESC PFREFRES PFRESCAT PFNAM PFSPEC

1 SECTOR Protease 13 HCV GENETIC

VARIATION

S C.13G>S G Disease

Mutation

Biotech

ABC

DNA

2 SECTOR Protease 2155 HCV GENETIC

VARIATION

AGC C.2155GGC>AGC GGC Point

Mutation

Biotech

ABC

DNA



5 PHARMACOGENOMICS/GENETICS METHODS AND

SUPPORTING INFORMATION (PG)

PG.xpt, Pharmacogenomics — Findings. One record per method/setup observation per specimen collected, per date of test, per subject, Tabulation


Controlled

Terms or

Format


STUDYID Study Identifier Char Identifier Definition: Unique identifier for a study within a submission. Req

DOMAIN Domain Abbreviation Char **PG Identifier Definition: Two-character abbreviation for the domain most relevant to the

observation.

Req

USUBJID Unique Subject Identifier Char Identifier Definition: Unique subject identifier within a submission. Req

PGSEQ Sequence Number Num Identifier Definition: Sequence number given to ensure uniqueness of records for a

subject within a dataset. Can be used to join related records.

Req

PGGRPID Group ID Char Identifier Definition: Used to tie together a block of related records in a single domain

to support relationships within the domain and between domains.

Example: For PGx we have decided that a simple numbering convention

works quite well (e.g. 1, 2, 3, etc.)

Perm

PGREFID Specimen ID Char Identifier Definition: The identifier of the genetic specimen being tested.

Example: Specimen ID.

Perm

PGSPID Sponsor ID Char Identifier Definition: Optional sponsor-defined reference number. Perm

PGLNKID Link ID Char Identifier Definition: Supports linking information across different domains. Perm

PGASYID Assay ID Char Identifier Definition: A unique identifier for a test as maintained by a lab. Exp

PGTESTCD Pharmacogenomics Test

Code

Char * Topic Definition: Short name for the test or measurement described in PGTEST.

Examples:

QTYEXT represents the DNA or RNA Quantity Extracted.

ACTSEQ for Active Sequence

NORMMETH for Normalization Technique

DIAG for Diagnosis

DNAPUR for DNA Purity

LBLCMPND for Label Compound

EXON for Exon with Change

EXONSEQ for Exons Sequenced

Req




Controlled

Terms or

Format


PGTEST Pharmacogenomics Test

Description

Char * Synonym

Qualifier

Definition: Verbatim name of the test or examination used to obtain the

measurement or finding.

Example: Quantity Extracted

Req

PGTSTRCD Test Reference

Terminology Code

Char * Result Qualifier Definition: The code of the test.

Example: 48019-4 is the code for Genetic Change Type using LOINC.

Perm

PGTSTRNM Test Reference

Terminology Name

Char * Result Qualifier Definition: The name of the Reference Terminology for the test.

Example: CDISC, SNOMED, LOINC.

Exp

PGTSTRVR Test Reference

Terminology Version

Char Result Qualifier Definition: The version number of the Reference Terminology, if required. Exp

PGGENTYP Genetic Region of Interest

Type

Char Result Qualifier

Definition: Identifies the type of genetic region of interest, for example,


Exp

PGGENROI Genetic Region of Interest Char

Result Qualifier

Definition: Area within the DNA sequences.

Example: Protease (in the case of HIV), NS3/4A, NS5B (in the case of

HCV).

Exp

PGSPCIES Biological classification Char * Grouping

Qualifier

Definition: Biological classifications for an organism capable of breeding

and producing offspring.

Examples: HOMO SAPIENS, RAT, MOUSE, STAPHYLOCCCUS

AUREUS, HCV

Perm

PGSTRAIN Strain Char * Grouping

Qualifier


Example: 1a for HCV

Perm

PGCAT Category for

Pharmacogenomics Test

Char * Grouping

Qualifier

Definition: Used to categorize types of genetic/genomic tests.

Examples: GENETIC VARIATION, GENE EXPRESSION.

Exp

PGSCAT Reference Subcategory for

Pharmacogenomics Test

Char * Grouping

Qualifier

Definition: A further categorization of the various test types based on

particular characteristics of a test.

Examples: INTERPRETATION, SETUP, and QC.

Perm

PGORRES Result or Finding in

Original Units


collected.

Example for Exons Sequenced: 13-21

Exp

PGORRESU Original Units Char (UNIT) Variable

Qualifier

Definition: Represents the unit of measure used by PGORRESU if

applicable.

Example: copies/5ul, LOG10 IU/ml

Perm

PGSTRESC Character Result/Finding

in Std Format

Char Result Qualifier Definition: An expression of the genetic change recorded in PGORRES in a

standard nomenclature such HUGO.

Exp

PGSTRESN Numeric Result/Finding in

Standard Units


format; copied in numeric format from PGSTRESC. PGSTRESN should

store all numeric test results or findings.

Example: Exon that is exhibiting the variant: 18

Perm

PGSTRESU Standard Units Char * Variable

Qualifier

Definition: Represents the unit of measure used by STRESN if applicable.

Example: copies/5ul

Perm




Controlled

Terms or

Format


PGRESRCD Result Reference

Terminology Code

Char * Result Qualifier Definition: The code of the result. For example: R is the code for Arginine

and C49488 is the code for Y.

Exp

PGRESRNM Result Reference

Terminology Name

Char Result Qualifier Definition: The name of the Reference Terminology for the result. For

example; CDISC, SNOMED, LOINC

Exp

PGRESRVR Result Reference

Terminology Version

Char Result Qualifier Definition: The version number of the Reference Terminology, if applicable.

Example: LOINC 2.38.

Exp

PGSTAT Completion Status Char **ND Result Qualifier Definition: Used to indicate exam not done. Should be null if a result exists

in PGORRES.

Perm

PGREASND Reason Test Not Done Char Record

Qualifier

Definition: Describes why a measurement or test was not performed.

Examples: BROKEN EQUIPMENT, SUBJECT REFUSED, SPECIMEN

LOST AND AMPLIFYING PROBLEM.

Perm

PGXFN

Raw Data File or LSID Char Record

Qualifier

Definition: Direct reference identifier for a raw Microarray or Genotypic data

file.

Perm

PGNAM Vendor Name Char Record

Qualifier

Definition: Name or identifier of the laboratory or biotech firm who provides

the test results.

Perm

PGSPEC Specimen Type Char * Record

Qualifier


Examples: TISSUE, SERUM, PLASMA, TUMOR, DNA, RNA

Perm

PGSPCCND Specimen Condition Char Record

Qualifier

Definition: Free or standardized text describing the condition of the

specimen.

Example: HEMOLYZED, ICTERIC, LIPEMIC, FRESH, FROZEN,

PARAFFIN-EMBEDDED.

Perm

PGMETHOD Method of Test or

Examination

Char * Record

Qualifier

Definition: Special instructions for the execution of genomics or genetic

testing.

Examples: SNP PROBE, LASER MICRODISSECTION, POPULATION,

CLIP SEQUENCING, DIRECT SEQUENCING, PYROSEQUENCING,

REAGENT, GENE chip such as AGILENT or AFFYMETRIX.

Req




Exp


1. Protocol-defined description of clinical encounter

2. May be used in addition to VISITNUM and/or VISITDY

Perm


Visit


Demographics.

Perm




Controlled

Terms or

Format


PGDTC Date/Time of Specimen

Collection

Char ISO 8601 Timing Definition: Date and time of specimen collection. Exp

PGDY Study Day of Specimen

Collection

Num Timing Definition:


2. Algorithm for calculations must be relative to the sponsor-defined

RFSTDTC variable in Demographics. This formula should be consistent

across the submission.

Perm

PGTPT Planned Time Point Name Char Timing Definition:

1. Text Description of time when specimen should be taken.

2. This may be represented as an elapsed time relative to a fixed reference

point, such as time of last dose. See PGTPTNUM and PGTPTREF.


Perm

PGTPTNUM Planned Time Point

Number

Num Timing Definition: Numerical version of PGTPT to aid in sorting. Perm

PGELTM Elapsed Time from

Reference Point


(PGTPTREF). This variable is useful where there are repetitive measures.

Not a clock time or a date time variable.

Examples: '-P15M' to represent the period of 15 minutes prior to the

reference point indicated by PGTPTREF, or 'P8H' to represent the period of

8 hours after the reference point indicated by PGTPTREF.

Perm

PGTPTREF Time Point Reference Char Timing Definition: Name of the fixed reference point referred to by PGELTM,

PGTPTNUM, and PGTPT.


Perm

PGRFTDTC Date/Time of Reference

Time Point

Char ISO 8601 Timing Date/time of the reference time point, PGTPTREF. Perm

* Indicates variable may be subject to controlled terminology



5.1 ASSUMPTIONS FOR PHARMACOGENOMICS (PG) DOMAIN MODEL

1. PG will capture information about the test methodology that contributes to the understanding of the test results contained in the PF domain. These

are methods that are used for test setup or quality control.

2. This domain is for both clinical and pre-clinical use and for tests on both study subjects and infectious microbes.

3. This domain contains the following new variables: PGTSTRCD, PGPSTRNM, PGPSTRDE, PGRESRCD, PGRESRNM, and PGRESRVR. These

are needed to link to external terminology such as LOINC. Examples for use of these variables will be included in the forthcoming SDTMIG-PGx

document.

4. Additional data elements that are specific to Pharmacogenomics Findings will be supported via the use of Supplemental Qualifiers. Examples of

typical data that might be submitted via a SUPPPG dataset include those listed in the table below.

5. PGREFID should contain an identifier for the DNA or RNA extraction sample.

6. PGREASND is used in conjunction with PGSTAT when value is NOT DONE.

7. PGTESTCD and PGTEST should not include gene codes. Whether collecting the complete detail for a variation or mutation or a subset, the test

code GENEID will be used to collect the gene of interest in the results variable. DISC plans to use test codes that correspond to LOINC codes.

8. When using the pharmacogenomics domains for viral test reporting, the identification of the virus requires the virus name be placed in the

PGSPCIES field and if available, the strain, type or subtype is placed in PGSTRAIN field.

5.2 LIST OF IDENTIFIED COMMON SUPPQUALS

QNAM QLABEL COMMENTS

GNANLDTC Gene Analysis Date and Time Can be used to indicate when genetic/genomic data was re-evaluated against the public database(s).

RPANLDTC Reported Gene Analysis Date and Time Used to reference date/time results were reported back to the sponsor.

ACCESNO ACCESSION NUMBER The accession number is obtained from the lab for a lab test. Accession numbers can be useful in cases where

the FDA requests more information for a particular test. The accession number helps locate information in the

public databases.

Note: DO NOT confuse this with Assay ID which is an identifier assigned to the work order at the lab.



5.3 EXAMPLES OF TESTCDS FOR REFERENCING PUBLIC DATABASES

The following examples show how reference databases can be identified using the PGTEST and PGTESTCD fields.

PGTESTCD PGTEST COMMENTS

XREFDB Reference Database Identifies the public database used to identify variants and mutations.

HGNCID HUGO ID

HUGO Gene Nomenclature Committee Database Reference. For example, the HGNCID for the EGFR gene

is HGNC: 3326

PROTDB HUMAN PROTEIN DATABASE Database Reference

GENBNKID Gen Bank ID of Reference Gene Bank Identification of Reference

5.4 PG EXAMPLES

Example 1:

This example shows genotypic data collected about the exons that were sequenced, the associated gene name, the sequence position, and length.

Row 1 specifies the gene name related to the results in the PF domain.

Row 2 identifies the GenBank identifier for the Reference Sequence.

Row 3 identifies the exons that were sequenced during the test.

Row 4 points to additional documentation related to the conduct of the genetic tests whose results will be reported in the PF domain.

Rows 5-6 show the quality control information for the starting position and length of the gene sequence used in the test SEQSTART and SEQLTH.

Row STUDYID DOMAIN USUBJID PGSEQ PGGRPID PGREFID PGTESTCD PGTEST PGASYID PGGENTYP PGGENROI PGCAT PGNAM

1 ABC-

01234

PG 17C0154 1 1 5493283 GENEID Gene

Identifier

1 GENE EGFR IDENTIFIER Biotech

ABC

2 ABC-

01234

PG 17C0154 2 1 5493283 GENBNKID Gen Bank

ID of

Reference

1 GENE EGFR IDENTIFIER Biotech

ABC

3 ABC-

01234

PG 17C0154 3 1 5493283 EXONSEQ Exons

Sequenced

1 GENE EGFR VARIANT Biotech

ABC

4 ABC-

01234

PG 17C0154 4 1 5493283 REFERENC Submission

Reference

Document


ABC

5 ABC-

01234

PG 17C0154 5 1 5493283 SEQSTART Sequence

Start


ABC

6 ABC-

01234

PG 17C0154 6 1 5493283 SEQLTH Sequence

Length


ABC



Row PGORESS PGSTRESC PGSTRESN PGSPEC PGMETHOD PGDTC

1 EGFR EGFR Tumor MASSIVELY PARALLEL

SEQUENCING

2012-10-

23T10:06

2 NM_005228.3 NM_005228.3 Tumor MASSIVELY PARALLEL

SEQUENCING

2012-10-

23T10:06

3 13-21 13-21 DNA MASSIVELY PARALLEL

SEQUENCING

2012-10-

23T10:06

4 5.23.445.1.4.165008.1.8:86175 5.23.445.1.4.165008.1.8:86175 MASSIVELY PARALLEL

SEQUENCING

2012-10-

23T10:06

5 1 1 1 DNA MASSIVELY PARALLEL

SEQUENCING

2012-10-

23T10:06

6 5616 5616 5616 DNA MASSIVELY PARALLEL

SEQUENCING

2012-10-

23T10:06



6 PGX BIOLOGICAL STATE (PB)

PB.xpt, Pharmacogenomics Biological State - Special Purpose Domain. One record per biomarker used in the study, tabulation.

Variable Name Variable Label

BRIDG

Mapping Type

ISO 21090

Datatype Controlled Terms or

Format Role CDISC Notes Core

STUDYID Study Identifier Char Identifier Definition: Unique identifier for a study. Req

DOMAIN Domain Abbreviation Char **PS Identifier Definition: Two-character abbreviation for the domain. Req

PBSEQ Sequence Number Num Identifier Definition: Sequence number given to ensure uniqueness

within a dataset for a subject. Can be used to join related

records.

Req

PBMRKRID Biological State

Identifier

Char * Identifier Definition: Uniquely identifies an individual or group of

biological markers that have medical significance in the

study.

Req

PBGENTYP Genetic Region of

Interest Type

Char Record

Qualifier

Definition: Identifies the type of genetic region of interest,

for example, GENENAME, SECTOR, PROTEIN.

Exp

PBGENROI Genetic Region of

Interest

Char Record

Qualifier


Example: Protease (in the case of HIV), NS3/4A, NS5B

(in the case of HCV).

Perm

PBSPCIES Biological

classification

Char * Grouping

Qualifier

Definition: Biological classifications for an organism

capable of breeding and producing offspring. May also be

used to designate organisms.

Examples: HOMO SAPIENS, RAT, MOUSE,

BACTERIUM, HCV, HIV

Perm

PBSTRAIN Type of Strain Char * Grouping

Qualifier

Definition: A genetic variant or subtype of a micro-

organism.

Examples: 1a, 1b.

Perm

PBDRUG Drug Name Char Record

Qualifier

Definition: the name of the drug for which resistance is

based on genetic biological markers.

Examples: Saquinavir, Indinavir

Exp

PBDIAG Diagnosis Char Record

Qualifier

Definition: Disease diagnosis based on detected genetic

biological markers.

Example: Adenocarcinoma.

Exp

PBMRKR Biological Marker Char * Record

Qualifier

Definition: Identifies a biological marker that is part of the

group identified by PBMRKID.

Examples: G48V, L10I

Exp



Variable Name Variable Label

BRIDG

Mapping Type

ISO 21090

Datatype Controlled Terms or

Format Role CDISC Notes Core

PBSTMT Medical Statement Char * Record

Qualifier

Definition: Represents a medical conclusion such as

confirmation of a diagnosis or resistance to a particular

medication based on genetic biological markers.

Example: RESISTANCE (when PBDRUG is populated),

POSITIVE (when PBDIAG is populated)

Exp

6.1 ASSUMPTIONS FOR THE PGX BIOLOGICAL STATE (PB) DOMAIN MODEL

1. The Pharmacogenomic Biological State domain is a special-purpose reference dataset (i.e., independent of data about study subjects) that relates a

set of genetic variations to an inference about the medical meaning of that set of genetic variations (i.e., a Medical Statement).

2. The medical statement in PBSTMT may document the implications of these variations for use of a drug, (in PBDRUG) or for the diagnosis of a

medical condition (in PBDIAG).

3. In some cases, a medical statement may be inferred from the presence of a single genetic variant, but more often all genetic variations in a set must

be present for an inference to be drawn. The PB domain is structured with one record for each variant contained in the set. PBMRKR identifies the

genetic variation. It is recommended that standard nomenclature be used to identify the genetic variations.

4. PBMRKRID is used to group genetic variation records which belong to a set and which form the basis for medical statement inference. It is

recommended that the value in PBMRKID be formed from the short names of the genetic variations that make up the set, separated with a plus (+)

symbol. This uniquely identifies each set of genetic variations and is also intelligible to reviewers.

6.2 EXAMPLES FOR PGX BIOLOGICAL STATE (PB) DOMAIN MODEL

Example 1:

This example shows two sets of genetic variations with associated inferences about a drug.

Row 1 shows a single genetic variant (set of one) whose presence infers resistance to Saquinavir.

Rows 2-6 shows the individual genetic variations in a group of genetic variations, which, if all are presence, infers resistance to Indinavir.

ROW STUDYID DOMAIN PBSEQ PBMRKRID PBGENROI PBGENTYP PBSPCIES PBSTRAIN PBDRUG PBMRKR PBSTMT

1 STDY-505357 PB 1 G48V Protease SECTOR HIV 1a Saquinavir G48V RESISTANCE

2 STDY-505357

PB 2

L101+K20R+M361+

A71+V82T

Protease SECTOR HIV 1a

lndinavir L10I RESISTANCE

3 STDY-505357

PB 3

L101+K20R+M361+

A71+V82T


lndinavir K20R RESISTANCE

4 STDY-505357

PB 4

L101+K20R+M361+

A71+V82T


lndinavir M361 RESISTANCE

5 STDY-505357

PB 5

L101+K20R+M361+

A71+V82T


lndinavir A71V RESISTANCE

6 STDY-505357

PB 6

L101+K20R+M361+

A71+V82T


lndinavir V82T RESISTANCE



7 SUBJECT BIOLOGICAL STATE (SB)

SB.xpt, Subject Biological State – Special-Purpose Domain. One record per subject per observed biological state in the study, tabulation.

Variable Name Variable Label Type Controlled

Terms or

Format


STUDYID Study Identifier Char Identifier Definition: Unique identifier for a study. Req

DOMAIN Domain Abbreviation Char SB Identifier Definition: Two-character abbreviation for the domain. Req


SBSEQ Sequence Number Num Identifier Definition: Sequence number given to ensure uniqueness within a dataset for a


Req

SBGRPID Group ID Char Identifier Used to tie together a block of related records in a single domain for a subject Perm

SBREFID Specimen ID Char Identifier Definition: The identifier of the genetic or viral specimen being tested. Perm

SBMRKRID Biological Marker

Identifier

Char * Identifier Definition: Uniquely identifies an individual or a group of biological markers that

has medical significance in the study.

Req

SBGENTYP Genetic Region of

Interest Type

Char Record

Qualifier

Definition: Identifies the type of genetic region of interest.

Examples: GENENAME, SECTOR, PROTEIN.

Exp

SBGENROI Genetic Region of

Interest

Char Record

Qualifier


Example: A genotype or subtype of a microorganism.

Perm

SBSPCIES Biological Classification Char * Grouping

Qualifier



Examples: HOMO SAPIENS, RAT, MOUSE, BACTERIUM, HCV, HIV

Perm

SBSTRAIN Type of Strain Char * Grouping

Qualifier

Definition: A genetic variant or subtype of a microorganism.

Examples: 1a, 1b.

Perm

SBNAM Vendor Name Char Record

Qualifier

Definition: Name or identifier of the laboratory or biotech firm who provides the

test results.

Perm




Exp


1.Protocol-defined description of clinical Encounter

2.May be used in addition to VISIT and VISITDY.

Perm


Visit


Demographics.

Perm



Variable Name Variable Label Type Controlled

Terms or

Format


SBDTC Date/Time of Test Char ISO 8601 Timing Definition:


Exp

7.1 ASSUMPTIONS FOR THE SUBJECT BIOLOGICAL STATE MARKER (SB) DOMAIN MODEL

1. The SB domain provides the linkage between a subject's observed genomic or virological findings and medical statements defined within the PB

domain. Thus, based on one or more subject findings, a statement about a subject's clinical state, or about the response of a subject's virus to a treatment

is made.

2. SBMRKRID should match a value of PBMRKRID in the PB domain.

3. In order to access medical statement pertaining to a subject, link via --MRKRID the SB and PB domains (PBSTMT).

4. The PBMRKR variable is used to identify the members (biological markers) that belong to the group identified by PBMRKRID in the PB domain.

These are then linked via SBMRKRID-PBMRKRID to the SB domain.

5. The medical statement is about either a drug (PBDRUG) or a medical condition (PBDIAG) as designated in the PB domain.

7.2 EXAMPLES FOR SUBJECT BIOLOGICAL STATE MARKER (SB) DOMAIN MODEL

Example 1:

This example below shows how to associate markers to a subject in order to communicate the presence of a particular biological state.

Row 1 shows an example of one biological marker (G48V) being in the group and related back to a subject.

Row 2 shows an example of multiple biological markers (L101, K20R, M361, A71, and V82T) that must be present before a virus can be said to have

resistance to Indinavir.

STUDYID DOMAIN USUBJID SBSEQ SBGRPID SBREFID SBMRKRID SBGENTYP SBGENROI SPSPCIES SBSTRAIN SBNAME

STDY-

505357

SB 521298 1 1 D391395 G48V Sector Protease HIV 1a BIOTECHA

STDY-

505357

SB 521298 2 1 D391395 L101+K20R+M361+A71+V82T Sector Protease HIV 1a BIOTECHA

VISITNUM VISIT VISITDY SBDTC

1 BASELINE -1 3/1/2010

1 BASELINE -1 3/1/2010



APPENDICES



Appendix A – New and Deleted Domains and Variables

In order to develop this virology supplement to the SDTM, new SDTM domains and variables were created to

complement the SDTM and SDTMIG.

Classification Type Domain(s) Description

Major Deletion PG/PF The LOINC variable will be deleted in the next version of the

SDTM. New terminology variable will provide more

functionality will take its place.

Major Addition BS, BE, ES New domains for specimen collection and handling.

Major Addition PG, PF, PB, SB New domains for OMICS data (e.g., gene expression, genetic

variation). Future releases will include cytogenetics.

Major Addition VR New domain to store viral resistance data collecting during

viral load testing.

Major Addition to

Findings

PG, PF --TSTRCD, --TSTRNM, --TSTRVR

Terminology variables that support the content in TEST and

TESTCD.

Major Addition to

Identifiers

PG, PF --ASYID for Assay ID – a unique identifier for a test

maintained by the lab.

Major Addition to

Findings

PG, PF --SPCIES and --STRAIN – use to describe the organism whose

DNA/RNA is undergoing testing.

Major Addition to

Findings

PG, PF --RESRCD, --RESRNM, --RESRVR

Terminology variables that support the encoding of the test

results.

Major Addition to

Identifiers

PG, PF --LNKID used to support the linking of results between

domains.

Major Addition to

Findings

PB --DRUG, --INDIC, --MRKR, --STMT, --DIAG to support

documenting the PGx biological markers being used.

Major Addition to

Findings

PG, PF, SB, PB --GENROI, --GENTYP, --GENLOC

Major Addition to

Findings

PB, SB --MRKRID is a biomarker identifier.

Major Addition to

Findings

PF --RLOCID is a public database entry identifier.

Major Addition to

Findings

PF --MUTYP can be used to designate somatic or germline.



Appendix B – Virology Concept Maps

This section includes initial concept maps for viral drug resistance testing, viral genetic variation testing, and

inference of drug resistance from genetic variations results. The VR concept map shows viral resistance testing to

produce inhibitory concentration results (IC50, IC95), and results derived from inhibitory concentration results. The

genetic testing diagram shows the mapping of date into the PG and PF domains. The combination of viral resistance

and genetic testing to develop knowledge of genetic variations that cause viral resistance is mapped to the PB

domain. Inferred viral resistance from genetic testing results is shown mapped to the SB domain. Note that specimen

collection includes extraction of part of a specimen to create a different kind of specimen. Figure 1 below shows the

color codes used in the maps that follow.

Figure 1 - Color Codes

B. 1 Virology Resistance Testing Maps

Details of specimen handling may be stored in biospecimen domains being developed as part of the SDTMIG-PGx

document. Figure 2 shows inhibitory concentration results (IC50, IC95) stored in the VR domain.

Figure 2 – Inhibitory Concentration Results



Figure 3 shows derivation of ‘fold increase” results (comparisons between two inhibitory concentration results).

Shows the net assessment based on all the “fold increase” results. Note: Comparisons to baseline are not always part

of the net assessment,

Figure 3 – From Inhibitory Concentrations to New Assessment of Resistance

B. 2 Genetic Testing

Figure 4 for genetic testing shows original specimen collection and processing of a specimen to produce a viral

DNA specimen not shown. The map also includes set-up parameters and QC testing results (at the far left in the

diagram) stored in PG. Genetic results are mapped to the PF domain.



Figure 4: Genetic Testing of Virus



B. 3 Building Knowledge of Viral Resistance Mutation

Viral samples undergo both viral resistance and genetic mutation testing. Results of these tests are compiled, and

from them knowledge of what genetic variations confer resistance to what drugs can be determined. These sets of

variations that confer resistance to a particular drug are stored in the PB domain.

Figure 5: Combining Viral Resistance and Viral Mutation Knowledge



B. 4 Inferring Viral Resistance from Genetic Mutation Results

Once it is known which sets of genetic variations confer resistance to a drug, a sample need not be tested for viral

resistance directly. Genetic testing shows what genetic variations a virus has. A virus’s genetic variations can be

compared to reference data in the PB domain to infer its resistance to drugs. Inferred resistance is stored in the SB

domain.

Figure 6: Viral Drug Resistance Inferred from Variations



Appendix C – Participating Individuals and Organizations

Leadership Team Organization Affiliation Carol Vaughn Sanofi-Aventis

Chuck Cooper FDA, CDER Data Standards Program

Diane Wold GSK

Doris Li IMCLONE

Fatima Elnigoumi FDA, CDER Data Standards Program

Fred Wood Octagon Research Solutions

Helena Sviglin FDA, Center for Drug Evaluation and Research

(CDER)

James Sullivan Vertex

Jenise Gillespie-Pederson FDA, CDER Data Standards Program

Joy Li FDA, Center for Drug Evaluation and Research

(CDER)

Joyce Hernandez Merck (Project Leader)

Patricia Wesolowski Vertex

Patrick Harrington FDA, Center for Drug Evaluation and Research

(CDER)

Phil Pochon Covance (Project Co-Leader)

Rhonda Facile CDISC (Project Co-Leader)

Rich Nagel Liaison Technologies

Sharon Wang Genentech

Ward Lemaire J&J

Wayne Kubick CDISC



Appendix D – Representations and Warranties, Limitations of Liability, and Disclaimers

CDISC Patent Disclaimers

It is possible that implementation of and compliance with this standard may require use of subject matter covered by

patent rights. By publication of this standard, no position is taken with respect to the existence or validity of any

claim or of any patent rights in connection therewith. CDISC, including the CDISC Board of Directors, shall not be

responsible for identifying patent claims for which a license may be required in order to implement this standard or

for conducting inquiries into the legal validity or scope of those patents or patent claims that are brought to its

attention.

Representations and Warranties

Each Participant in the development of this standard shall be deemed to represent, warrant, and covenant, at the time

of a Contribution by such Participant (or by its Representative), that to the best of its knowledge and ability: (a) it

holds or has the right to grant all relevant licenses to any of its Contributions in all jurisdictions or territories in

which it holds relevant intellectual property rights; (b) there are no limits to the Participant¹s ability to make the

grants, acknowledgments, and agreements herein; and (c) the Contribution does not subject any Contribution, Draft

Standard, Final Standard, or implementations thereof, in whole or in part, to licensing obligations with additional

restrictions or requirements inconsistent with those set forth in this Policy, or that would require any such

Contribution, Final Standard, or implementation, in whole or in part, to be either: (i) disclosed or distributed in

source code form; (ii) licensed for the purpose of making derivative works (other than as set forth in Section 4.2 of

the CDISC Intellectual Property Policy (³the Policy²)); or (iii) distributed at no charge, except as set forth in Sections

3, 5.1, and 4.2 of the Policy. If a Participant has knowledge that a Contribution made by any Participant or any other

party may subject any Contribution, Draft Standard, Final Standard, or implementation, in whole or in part, to one or

more of the licensing obligations listed in Section 9.3, such Participant shall give prompt notice of the same to the

CDISC President who shall promptly notify all Participants.

No Other Warranties/Disclaimers. ALL PARTICIPANTS ACKNOWLEDGE THAT, EXCEPT AS PROVIDED

UNDER SECTION 9.3 OF THE CDISC INTELLECTUAL PROPERTY POLICY, ALL DRAFT STANDARDS

AND FINAL STANDARDS, AND ALL CONTRIBUTIONS TO FINAL STANDARDS AND DRAFT

STANDARDS, ARE PROVIDED ³AS IS² WITH NO WARRANTIES WHATSOEVER, WHETHER EXPRESS,

IMPLIED, STATUTORY, OR OTHERWISE, AND THE PARTICIPANTS, REPRESENTATIVES, THE CDISC

PRESIDENT, THE CDISC BOARD OF DIRECTORS, AND CDISC EXPRESSLY DISCLAIM ANY

WARRANTY OF MERCHANTABILITY, NONINFRINGEMENT, FITNESS FOR ANY PARTICULAR OR

INTENDED PURPOSE, OR ANY OTHER WARRANTY OTHERWISE ARISING OUT OF ANY PROPOSAL,

FINAL STANDARDS OR DRAFT STANDARDS, OR CONTRIBUTION.

Limitation of Liability

IN NO EVENT WILL CDISC OR ANY OF ITS CONSTITUENT PARTS (INCLUDING, BUT NOT LIMITED

TO, THE CDISC BOARD OF DIRECTORS, THE CDISC PRESIDENT, CDISC STAFF, AND CDISC

MEMBERS) BE LIABLE TO ANY OTHER PERSON OR ENTITY FOR ANY LOSS OF PROFITS, LOSS OF

USE, DIRECT, INDIRECT, INCIDENTAL, CONSEQUENTIAL, OR SPECIAL DAMAGES, WHETHER

UNDER CONTRACT, TORT, WARRANTY, OR OTHERWISE, ARISING IN ANY WAY OUT OF THIS

POLICY OR ANY RELATED AGREEMENT, WHETHER OR NOT SUCH PARTY HAD ADVANCE NOTICE

OF THE POSSIBILITY OF SUCH DAMAGES.

Note: The CDISC Intellectual Property Policy can be found at:

http://www.cdisc.org/about/bylaws_pdfs/CDISCIPPolicy-FINAL.pdf

http://www.cdisc.org/about/bylaws_pdfs/CDISCIPPolicy-FINAL.pdf

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Virology Therapeutic Area Data Standards User Guide … · © 2012 Clinical Data Interchange ... Provisional Virology Therapeutic Area Data Standards User ... This new Findings domain