© CDISC 2014

CDISC Pharmacogenomics Standards

Joyce Hernandez (Joyce Hernandez Consulting, LLC)

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© CDISC 2014

Agenda

• Project background• Domains, Relationships & Molecular Concepts• Variables• Specimen Genealogy• Specimen Hierarchy• Pharmacogenomics (PGx) Examples:

Biospecimen events and findings Genetic Variation Gene Expression

• Next steps and team

© CDISC 2014

Background

• Initial Data Focus for Version 1.0 Specimen Collection and Handling Specimen Hierarchy Genetic Variation utilizing well-known standards (HGVS) Genotyping data (common formats currently used) Viral Genetics (includes some viral classification

variables)

• Special sections to enhance understanding Glossary of genetic and genomic terms Nomenclatures (HGVS, HLA) CMAPS to document common processes

© CDISC 2014

New Domains to support PGx

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© CDISC 2014

DomainRelationshipswithin a STUDYID

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BS - Specimen

BSREFID

BE - Specimen Event

BEREFIDUSUBJID

USUBJID

PG - Setup and QC

PGREFIDUSUBJID

PF -Findings

PGREFIDUSUBJID

SB - Subject Biological State

USUBJIDSBREFID

PB - PGx Biologoical State

PBMRKRIDPBREFID

SBMRKRID

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Molecular concepts represented in the domains

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1

3

2

4a

4b

4c

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© CDISC 2014

PGx Specific Variables - Specimen

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Name Label Notes

--REFID Reference ID Specimen identifier.

--PARENT Specimen Parent When the specimen in question has been obtained from another specimen (e.g., via resectioning, aliquoting), --PARENT holds the ‑‑REFID of the “parent specimen;” that is, the specimen from which the current specimen has been obtained.

--SPCLVL Specimen Level Any specimen obtained directly from the subject has a specimen level of 1. Specimens obtained from a level 1 specimen have a specimen level of 2; from a level 2 specimen have a specimen level of 3; etc. A level 4 specimen, therefore, would be a specimen (4) obtained from a specimen (3) obtained from a specimen (2) obtained from a specimen (1) obtained from the subject.

--DTC Date/Time Collected Date/time of specimen collection. For specimens with a specimen level greater than 1, ‑‑DTC refers specifically the date/time of collection for the originating specimen, i.e., the specimen obtained directly from the subject. A specimen is a sample of the subject which undergoes a test in place of the subject when the test cannot be performed on the subject directly, with the understanding that any results obtained thereby may be treated as pertaining to the subject. However, once the specimen has been separated from the subject, any changes in the subject’s state will not be reflected by the specimen. Therefore, when a test is performed on a specimen, the results cannot be guaranteed to pertain to the subject as they are at the time of the test, only to the subject as they were at the time of specimen collection.

RELSPEC

© CDISC 2014

List of IG Use Cases• BE/BS – Biospecimen Domains

Specimen handling such as freeze/thaw cycles and transportation. Steps in obtaining cell-free RNA from blood plasma. Types of quality evaluation.

• RELSPEC – Related Specimens Specimen genealogy and hierarchy.

• PF – Pharmacogenomics Findings Protein variation in viral genetics. Protein and nucleic variation in viral genetics. Frame shifts, both viral and subject. Nucleotide reads. Zygosity. Single-nucleotide polymorphisms (SNP) reads. HLA allelic records Observed somatic vs. gremlins variations. Observed levels of somatic variations in a biopsy sample. Gene expression measured via qRT-PCR. Gene expression measured via microarray.

• PG – PGx Methods and Supporting Information Run parameters for PCR. Details of SNP probe assays.

• PB/SB – PGx Marker Domains Simple and complex genetic markers for drug resistance.

• Relating PGx Domains A somatic variation and its related medical diagnosis. Germline variations and related inherited risk of cancer. Genetic variations relating to drug metabolism.

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© CDISC 2014

Specimen Genealogy

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Row STUDYID USUBJID REFID SPEC PARENT SPCLVL

1 ABC-123 001-01 SPC-001 TISSUE   1

2 ABC-123 001-01 SPC-001-A TISSUE SPC-001 2

3 ABC-123 001-01 SPC-001-B TISSUE SPC-001 2

4 ABC-123 001-01 SPC-001-B-1 DNA SPC-001-B 3

5 ABC-123 001-01 SPC-003 BRAIN   1

6 ABC-123 001-01 SPC-003-A RNA SPC-003 2

RELSPEC

© CDISC 2014

Biospecimen Events and Findings

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Row STUDYID DOMAIN USUBJID SPDEVID BESEQ BEREFID BETERM BEDECOD BEPARTY BEPRTYID BECAT BESCAT

1 ABC134 BE 43871TS409871

1 1148.267 Excision EXCISION COLLECTIONSOFT

TISSUE

2 ABC134 BE 43871 

2 1148.267 Flash FrozenFLASH

FROZENPREP

3 ABC134 BE 43871309827

3 1148.267Stored in Freezer

STORED     STORING  

4 ABC134 BE 43871   4 1148.267 Thaw THAW PREP

5 ABC134 BE 43871 LN43871 5 1148.267 Shipped SHIPPED ABC LAB 01 TRANSPORT

Row BEBODSYS BELOC VISITNUM VISIT BEDTC BESTDTC BEENDTC

1 (cont)Nervous System

[A08]BRAIN 1 BASELINE

2005-03-202005-03-20T15:07  

2 (cont)Nervous System

[A08]BRAIN 1 BASELINE

2005-03-202005-03-20T15:07 2005-03-20T13:22

3 (cont)Nervous System

[A08]BRAIN 1 BASELINE

2005-03-202005-03-20T13:22 2005-03-21T10:29

4 (cont)Nervous System

[A08]BRAIN 1 BASELINE

2005-03-202005-03-21T10:29 2005-03-21T10:36

5 (cont)Nervous System

[A08]BRAIN 1 BASELINE

2005-03-202005-03-21T11:00 2005-03-21T15:00

Row BSSTRESU BSPEC BSANTREG BSBLFL VISITNUM BSDTC

1 (cont) cm3 BRAINCEREBRAL AQUEDECT

     

2 (cont) C BRAINCEREBRAL AQUEDECT

Y 1 2005-03-20

Row STUDYID DOMAIN USUBJID BSSEQ BSREFID BSTESTCD BSTEST BSCAT BSORRES BSORRESU BSSTRESC BSSTRESN

1 ABC134 BS 43871 11148.267

VOLUME VolumeSPECIMEN MEASURE

MENT2 cm3 2 2

2 ABC134 BS 43871 21148.267

FFRZTMPFlash

Frozen Temp

SPECIMEN HANDLING

-80 C -80  

© CDISC 2014

Variables – (Pathogens)

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Name Label Notes

--MSPCES*** MicroorganismSpecies

In findings domains, --SPCIES holds the species of the pathogen to which the subject is a host when the pathogen is the focus of the. In instances when both the subject and the pathogen are tested, records for the pathogen are distinguished and differentiated from records for the subject by the use of the --SPCIES variable. Not to be confused with DMSPCIES, which holds the species of the subject.

--MSTRN MicroorganismStrain

As --SPCIES. --STRAIN holds the strain of the pathogen to which the subject is a host when the pathogen is the focus of the test.

*** SDTMIG omits --SPCIES because all subjects in most human clinical trials must be homo sapiens; the nature of the study obviates the need for

this information to be included in SDTM datasets. The exception is Virology when a viral species must be identified.

© CDISC 2014

Variables – (Genetics/Genomics Test related)

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Name Label Notes

--TEST Test NameFor genetic variation, usually the level of granularity and/or molecular component of interest: Examples: Nucleotide, Amino Acid, Allele

--REFSEQ Reference Sequence Depending on the type of test method, the reference sequencing is most likely to be either the rsID from dbSNP (for targeted tests) or a GenBank accession number (for non-targeted tests).

--GENTYP Type of Genetic Region of Interest

The type the portion of the genome serving as a locus for the experiment/test. Examples: GENE, SECTOR, PROTEIN

--GENRI Genetic Region of Interest The portion of the genome serving as a locus for the experiment/test. Often the name of a gene. Examples: EGFR, KRAS, CYP2D6

--GENLI Genetic Location of Interest

The numeric position within the sequence for the targeted read. Compare vs. --GENLOC. --GENLI and --GENTGT are variables that should be used only when the the test specifies a single genetic read to the exclusion of all other possibilities, and the result is a matter of occurrence, either as a percentage or as a boolean observation.

--GENTGT Genetic Target The genetic read targeted by the probe at the position specified by --GENLI.

--ALLELC Allele Humans are diploid: they have two homologous copies of each chromosome. However, the two copies are not necessarily identical, since one chromosome is inherited from each parent. Therefore, in tests that compare chromosomes, or parts of chromosomes (alleles), the --ALLELE variable is used to denote results for one or the other of the two alleles (chromosomes).

© CDISC 2014

Variables – (Genetics/Genomics Result related)

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Name Label Notes

--GENSR Genetic Sub-Region The sub-region within the genetic region of interest in which the observed varition at the position given in --GENLOC is located, if relevant. Because exon numbers can be variable and are not regulated, caution should be exercised when populating this variable.

--GENLOC Genetic Location One of the three variables used to define a genetic read. --GENLOC holds the numeric position within the sequence for the observed result.

--ORRES Result or Finding in Original Units One of the three variables used to define a genetic read. --ORRES holds the observed result at the position

specified by --GENLOC.When --GENLI is populated, --ORRES follows the standard rules.

--ORREF Reference Result One of the three variables used to define a genetic read. --ORREF holds the expected result at the position specified by --GENLOC according to the reference sequence specified by --REFSEQ.

--STRESC Result or Finding in Standard Format

When --GENLOC is populated, --STRESC holds the observed variation, given in HGVS nomenclature. When --GENLI is populated and --ORRES=Y, --STRESC holds the observed variation as targeted, given in HGVS nomenclature. Otherwise, --STRESC is copied or derived from --ORRES.

--RSNUM Reference SNP Reference identifier for previously identified instances of the variation, such as the rs# in dbSNP.

--MUTYP Mutation Type The type of mutation, usually either GERMLINE (inherited) or SOMATIC (arising only in parts of the individual, as in cancer).

--ANMETH Analysis Method Analysis method applied to obtain a summarized result. Analysis method describes the method of secondary processing applied to a complex observation result (e.g. an image or a genetic sequence).

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Genetic Variation ExampleRow STUDYID DOMAIN USUBJID PGSEQ PGTESTCD PGTEST PGGENTYP PGGENRI PGCAT PGORRES PGSTRESC

1 ABC-01234 PG 17C0154 1 EXONExons

SequencedGENE EGFR

GENETIC VARIATION

13-21 13-21

2 ABC-01234 PG 17C0154 2 SEQSTARTSequence

StartGENE EGFR

GENETIC VARITATION

1499 1499

3 ABC-01234 PG 17C0154 3 SEQLONGSequence

LengthGENE EGFR

GENETIC VARITATION

1127 1127

Row STUDYID DOMAIN USUBJID PFSEQ PFREFID PFTESTCD PFTEST PFGENRI PFREFSEQ PFCAT PFORRES PFORREF PFGENLOC

1 ABX-01256 PF XX7-154 1 5493283 NUC Nucleotide EGFR NM_005228.3 GENETIC VARIATION

C G 2156

2 ABX-01256 PF XX7-212 1 8970343 NUC Nucleotide EGFR NM_005228.3GENETIC

VARIATION T C 2369

3 ABX-01256 PF XX7-220 1 7629230 NUC Nucleotide EGFR NM_005228.3GENETIC

VARIATION T A 2073

Row PFGENSR PFSTRESC PFXNAM PFNAM PFMETHOD PFRUNID VISITNUM PFDTC

1 (cont) Exon 18 c.2156G>C5.23.445.1.4.1650

08.1.8:86175 Biotech ABCMassively Parallel

Sequencing 8970723 12012-10-23T10:06

2 (cont) Exon 20 c.2369C>T 5.23.445.1.4.165008.1.8:87952

Biotech ABC Massively ParallelSequencing

8925000 1 2012-10-23T12:50

3 (cont) Exon 16 c.2073A>T 5.23.445.1.4.165008.1.8:87970

Biotech ABC Massively ParallelSequencing

8925018 1 2012-10-23T13:03

Row STUDYID DOMAIN PBSEQ PBMRKRID PBGENTYP PBGENRI PBDRUG PGDIAG PBMRKR PBSTMT

1 ABC-01234 PB 1 2073A>T GENE EGFR   Astrocytoma 2073A>TDecreased risk of diffusely infiltrating

astrocytoma

2 ABC-01234 PB 2 G719A GENE EGFR EGFR TKIs   G719A Increased sensitivity

3 ABC-01234 PB 3 T790M GENE EGFR EGFR TKIs   T790M Decreased sensitivity

Row STUDYID DOMAIN USUBJID SBSEQ SBREFID SBMRKRID SBGENTYP SBGENRI SBNAM VISITNUM SBDTC

1 ABC-01234 SB 17C0154 1 5493283 G719A GENE EGFR Biotech ABC 1 2012-10-23T10:06

2 ABC-01234 SB 17C0212 1 8970343 T790M GENE EGFR Biotech ABC 1 2012-10-23T10:06

3 ABC-01234 SB 17C0220 1 7629230 2073A>T GENE EGFR Biotech ABC 1 2012-10-23T10:06

© CDISC 2014 15

Gene Expression Example – ArraysRow STUDYID DOMAIN USUBJID SPDEVID PFSEQ PFGRPID PFREFID PFTESTCD PFTEST PFCAT PFORRES

1 A12345 PF 43871AGS-

G4900DA2 1 2287.09443 NINT1VAL Normalized Intensity 1 Value Analytic 1.16279

2 A12345 PF 43871AGS-

G4900DA3 1 2287.09443 NINT2VAL Normalized Intensity 2 Value Analytic 0.96469

3 A12345 PF 43871 MANAN03 4 1 2287.09443 PVAL P Value Post-Analytic 0.05391

4 A12345 PF 43871 MANAN03 5 1 2287.09443 FOLDCHG Fold Change Post-Analytic 1.8

Row PFSTRESC PFSTRESN PFXFN PFNAM PFSPEC PFMETHOD PFRUNID PFANMETH PFBLFL VISITNUM PFDTC

1 (cont) 1.16279 1.16279 2.16.090.1.135764.3.4:7280912

Deluxe Central Labs

RNA Microarray 1000450001 LOWESS  2 2005-03-

21T11:28:17

2 (cont) 0.96469 0.964692.16.090.1.135764.3.4:7280912

Deluxe Central Labs RNA

Microarray1000450001

LOWESS  2 2005-03-

21T11:28:17

3 (cont) 0.05391 0.053912.16.090.1.135764.3.4:7280912

Deluxe Central Labs RNA

Microarray1000450001

    2 2005-03-21T11:28:17

4 (cont) 1.8 1.82.16.090.1.135764.3.4:7280912

Deluxe Central Labs RNA Microarray 1000450001

    2 2005-03-21T11:28:17

Row STUDYID DOMAIN SPDEVID DISEQ DIPARMCD DIPARM DIVAL

1 A12345 DI AGM-G4851B 1 TYPE Device Type Microarray Kit2 A12345 DI AGM-G4851B 2 MANUF Manufacturer Agilent3 A12345 DI AGM-G4851B 3 MODEL Model G4851B

4 A12345 DIAGS- G4900DA

1 TYPE Device Type Microarray Scanner

5 A12345 DI AGS- G4900DA 2 MANUF Manufacturer Agilent6 A12345 DI AGS- G4900DA 3 MODEL Model G4900DA7 A12345 DI MANAN03 1 TYPE Device Type Workstation

© CDISC 2014

Next Steps

• Currently under CDISC internal review• Public Review Posting – 2nd Quarter• Final Posting – 3rd Quarter• Next Project – 4th Quarter - Cytogenetics

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© CDISC 2014

Contact Information and Team

Name CompanyJoyce Hernandez, Team Leader Joyce Hernandez Consulting

Mohtaram Bahmanian ImCloneSally Cassals Independent ConsultantRhonda Facile CDISCDoris Li ImCloneCliona Molony MerckMona Oakes ImClonePhil Pochon CovanceJanet Reich AmgenEllen Schatz Eli LillyJames Sullivan VertexRichard Tyhach Eli LillyPatricia Wesolowski Vertex Diane Wold GSKDarcy Wold Independent ConsultantFred Wood Accenture   Helena Sviglin FDA LiaisonPatrick Harrington FDAJoy Li FDA

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Anyone that wishes to join the team please contact Joyce:Joyce.hernandez_0029@yahoo.com