pharmacogenomics update rcrim tc philip m. pochon covance enterprise architecture

1HL7 Jan 2007 Working Group Meetings Pharmacogenomics Update

Pharmacogenomics Update

RCRIM TC

Philip M. PochonCovance Enterprise Architecture


History

• HL7 Models

Single Gene (Genetic Locus) common message element• Draft Standard for Trial Use – May 2005 (Revised May 2006)

Multiple Gene (Genetic Loci) model common message element• Draft Standard for Trial Use – Jan 2007

Pharmacogenomics Clinical Research Message• Extension of the CDISC/HL7 LAB message• Draft Standard for Trial Use – May 2006

Clinical Genomics Clinical Practice Message• Piloted in pre-ballot form, June 2006

• CDISC SDTM

Pharmacogenomics domains• Under development


Genetic Locus CMET Structure

0..* derivedPolypeptide

typeCode*: <= DRIV

derivation1

0..* derivedExpressionProperty

typeCode*: <= DRIV

derivation

SEQUENCES & PROTEOMICS

0..* expression

typeCode*: <= COMPcomponent5

0..* sequenceVariation

typeCode*: <= COMP

component3

IndividualAlleleclassCode*: <= OBSmoodCode*: <= EVNid: II [0..1]text: ED [0..1]effectiveTime: GTS [0..1]value: CD [0..1] (allele code, drawn from HUGO, GenBank, Locus link, Refseq, etc.)methodCode: SET<CE> CWE [0..*]

HaplotypeclassCode*: <= OBSmoodCode*: <= EVNid: II [0..1]text: ED [0..1]effectiveTime: GTS [0..1]value: CD [0..1]

GenotypeclassCode*: <= OBSmoodCode*: <= EVNid: II [0..1]code: CE CWE [0..1] (e.g., ALLELIC, NON_ALLELIC)text: ED [0..1]effectiveTime: IVL<TS> [0..1]value: CD [0..1] (Can hold a gene code, when no alleles are associated, i.e., code=NON_ALLELIC)methodCode: SET<CE> CWE [0..*]

0..* haplotype

typeCode*: <= COMP

componentOf

0..* individualAllele

typeCode*: <= COMP

component2

SequenceclassCode*: <= OBSmoodCode*: <= EVNid: II [0..1]code: CD CWE [1..1] (the sequence standard code, e.g. BSML)text: ED [0..1] (sequence's annotations)effectiveTime: GTS [0..1]value: ED [1..1] (the actual sequence)methodCode: SET<CE> CWE [0..*] (the sequencing method)

ExpressionclassCode*: <= OBSmoodCode*: <= EVNid: II [0..1]code: CE CWE [1..1] <= ActCode (the standard's code (e.g., MAGE-ML identifier)text: ED [0..1]effectiveTime: GTS [0..1]value: ED [1..1] (the actual gene or protein expression levels)methodCode: SET<CE> CWE [0..*]

PolypeptideclassCode*: <= OBSmoodCode*: <= EVNid: II [0..1]text: ED [0..1]effectiveTime: GTS [0..1]value: CD [0..1] (protein code, drawn from SwissProt, PDB, PIR, HUPO, etc.)methodCode: SET<CE> CWE [0..*]

DeterminantPeptideclassCode*: <= OBSmoodCode*: <= EVNid: II [0..1]text: ED [0..1]effectiveTime: GTS [0..1]value: CD [0..1] (peptide code, drawn from referencedatabases like those used in the Polypeptide class)methodCode: SET<CE> CWE [0..*]

0..* derivedDeterminantPeptide

typeCode*: <= DRIV

derivation2

ClinicalPhenotypeclassCode*: <= OBSmoodCode*: <= EVNid: II [0..1]code: CD CWE [0..1] <= ObservationType (e.g., disease, allergy, sensitivity, ADE, etc.)text: ED [0..1]effectiveTime: GTS [0..1]value: ANY [0..1]

HL7 Clinical Genomics SIGDocument: Genotype Shared ModelSubject: Genomic Data Rev: POCG_DM000020-c Date: January 20, 2005Facilitator: Amnon Shabo (Shvo), IBM Research in Haifa, [email protected]

Note:There could be one to threeIndividualAllele objects in aspecific instance. A typical casewould be an allele pair, oneon the paternal chromosome andone on the maternal chromosome.The third allele could bepresent if the patient hasthree copies of a chromosome asin the Down’s Syndrome.

0..1 haplotype

typeCode*: <= COMP

componentOf

Constrained to a restrictedMAGE-ML or MIAME contentmodel, specified in aseparate schema.

Constraint: GeneExpression.value

Constrained to a restrictedBSML content model,specified in a separateschema.

Constraint: AlleleSequence.value

0..* referredToIndividualAllele

typeCode*: <= REFR

reference

Note:A related allele that is on adifferent locus, and stillhas significant interrelationwith the source allele. Forexample: in cases ofmulti-allelic phenotype ortranslocated duplicatesof the gene. We develop avocabulary for the type ofrelationship as a domain inActRelationshipType vocabassigned to typeCode.

IndividualAllele

0..* pertinentClinicalPhenotypeChoice

typeCode*: <= PERTpertinentInformation

ExternalClinicalPhenotypeclassCode*: <= OBSmoodCode*: <= EVNid*: II [1..1] (The unique id of an external observation, e.g.,residing in a problem list or in the patient's EHR)effectiveTime: GTS [0..1]

Note:An external observation is a valid Observationinstance existing in any other HL7-compliantartifact, e.g., a document or a message.

Note:An observation of an observationrepresented internally in this model.

Note: Shadowed observationsare copies of other observationsand thus have all of the originalact attributes as well as all‘outbound’ associations. Theyare used for convenience ofdrawing only.

Note:This is a computed outcome, i.e.,the lab does not measure the actualprotein, but secondary processespopulate this class with thetranslational protein.

ClinicalPhenotype

ClinicalPhenotype

ClinicalPhenotype

0..* pertinentClinicalPhenotype

typeCode*: <= PERT

pertinentInformation


typeCode*: <= PERT


SequenceVariationclassCode*: <= OBSmoodCode*: <= EVNid: II [0..1]code: CD CWE [0..1] <= ActCodetext: ED [0..1]effectiveTime: GTS [0..1]value: ANY [0..1] (The variation itself expressed with markup like BSML or drawn from an external reference like LOINC or dbSNP.)interpretationCode: SET<CE> CWE [0..*] <= ObservationInterpretationmethodCode: SET<CE> CWE [0..*]

DeterminantPeptide

0..* derivedDeterminantPeptidetypeCode*: <= DRIVderivation

KnownAssociatedDiseaseclassCode*: <= OBSmoodCode*: <= DEFcode: CD CWE [0..1] <= ActCodetext: ED [0..1]value: CD [0..1] <= Diagnosis

Note:These diseases are not the actualphenotype for the patient, rather theyare the known risks of this mutation.

TagSNPclassCode*: <= OBSmoodCode*: <= DEF

Note:The presence of thisclass indicates that thesource SNP object is atag SNP (note that ithas a DEF mood).

ClinicalPhenotypeChoice

Note:Code: COPY_NUMBER, ZYGOSITY, DOMINANCY, GENE_FAMILY,etc. For example, if code = COPY_NUMBER, then the value is oftype INT and is holding the no. of copies of this gene or allele.

ClinicalPhenotype


typeCode*: <= PERT


EXPRESSION DATA

SEQUENCE VARIATIONS

ClinicalPhenotype

Note: All derivation associations represent the process of “bubbling-up” the clinically-significant portions of the the raw genomic data embedded in the encapsulatingclasses (i.e., Sequence and ExpressionProfile) into the HL7 specialized classes(e.g., SequenceVariation or DeterminantPeptide).

Polypeptide

Note:Expression profile refersto both gene and proteinexpression levels.

reference

0..1 referredToExternalClinicalPhenotype

typeCode*: <= x_ActRelationshipExternalReference

0..* polypeptide


0..1 sequence


0..* pertinentClinicalPhenotypetypeCode*: <= PERT



typeCode*: <= PERT


Note:The ClinicalPhenotype objects should be replaced withthe HL7 Clinical Statement model when it’s ready for use.Also, since the HL7 tooling doesn’t enable the shadowingof a choice box, all other objects in the Genotype modelare associated with merely ClinicalPhenotype instead ofthe entire “ClinicalPhenotype” choice box.Consequently, the KnownAssociatedDisease object isaccessible only from the Sequence Variation object andits common main use case is annotating a mutation.

Note:The code attribute indicates inwhat molecule the variation occurs,i.e., DNA, RNA or Protein.

0..1 haplotypetypeCode*: <= COMPcomponentOf

TranslocationclassCode*: <= OBSmoodCode*: <= EVNid: SET<II> [0..*]effectiveTime: GTS [0..1]value: ED [0..1]

Designating maternal orpaternal haplotype.

Constraint: Haplotype.code

Haplotype

Haplotype

0..1 tagSNPtypeCode*: <= INST

definition

0..* translocation

typeCode*: <= COMPcomponent

Expression

0..* expression

typeCode*: <= COMP

component1

Note:Use this association when theexpression data set is not at theallelic level and is thetranslational result of both alleles.In this case, populate theGenotype value attribute with thegene code, while the Genotypecode attribute should be set toNON_ALLELIC.

0..* geneAssociatedObservationtypeCode*: <= COMP

component3

0..1 geneAssociatedObservation

typeCode*: <= COMP

component4derivation3 0..1 derivedSequence

typeCode*: <= DRIV

Note:This recursive associationenables the association of anRNA sequence derived froma DNA sequence and apolypeptide sequence derivedfrom the RNA sequence.

0..* derivedDeterminantPeptidetypeCode*: <= DRIVderivation


typeCode*: <= PERT


ClinicalPhenotype


typeCode*: <= PERT


0..* derivedSequenceVariationProperty

typeCode*: <= DRIV

derivation

SequenceVariation

0..* derivedSequenceVariation

typeCode*: <= DRIV

derivation10

Note:The term ‘Genotype’ refers to ALL genomicaspects of a specific chromosomal locus.

Note:The term 'Individual Allele' doesn't refer necessarilyto a known variant of the gene, rather it refers to thepersonalized data regarding the gene that might wellcontain personal variations w/unknown significance.

GeneAssociatedObservationclassCode*: <= OBSmoodCode*: <= EVNid: SET<II> [0..*]code: CD CWE [0..1] <= ActCodetext: ED [0..1]effectiveTime: GTS [0..1]value: ANY [0..1]methodCode: SET<CE> CWE [0..*]

ExpressionPropertyclassCode*: <= OBSmoodCode*: <= EVNcode: CD CWE [0..1] <= ActCodetext: ED [0..1]value: ANY [0..1]

Note:Code: NORMALIZED_INTENSITY, QUALITATIVE_EXPRESSION,P_VALUE

Value: is populated based on the selected code from theabove vocabulary and its type is then selected accordigly.

For example, if code = NORMALIZED_INTENSITY, then value isof type PQ and holds the actual numeric value representing thenormalized intensity.If howver the code = QUALITATIVE_EXPRESSION, then value istype ST and holds either PRESENT or ABSENCE.

The full description of the allowed vocabularies for codes and itsrespective values could be found in the specifcation.

SequenceVariationPropertyclassCode*: <= OBSmoodCode*: <= EVNcode: CD CWE [0..1] <= ActCodetext: ED [0..1]activityTime: TS [0..1]value: ANY [0..1]

Note:Code: TYPE, POSITION.GENOME, POSITION.GENE, POSITION,LENGTH, REFERENCE, REGION.

Value: is populated based on the selected code from theabove vocabulary and its type is then selected accordingly.Here are a few examples:If code = TYPE, then the value is of type CV and holds one of thefollowing: SNP, INSERTION, DELETION

if code = POSITION, then value is of type INT and holdsthe actual numeric value representing the variation positionalong the gene.

if code = LENGTH, then value is of type INT and holdsthe actual numeric value representing the variation length.

If code = POSITION.GENE, then value is of type CV and is oneof the following codes:INTRON, EXON, UTR, PROMOTER

If code = POSITION.GENOME, then value is of type CV and is oneof the following codes:NORMAL_LOCUS, ECTOPIC, TRANSLOCATION

If the code = REFERENCE, then value istype CD and holds the reference gene identifier drawn from areference database like GenBank.

The full description of the allowed vocabularies for codes and itsrespective values could be found in the specification.

GeneAssociatedObservation

SequencePropertyclassCode*: <= OBSmoodCode*: <= EVNcode: CD CWE [0..1] <= ActCodetext: ED [0..1]value: ANY [0..1]

0..* derivedSequencePropertytypeCode*: <= DRIVderivation7

Note:Code: CLASSIFICATION, etc.For example, if code =CLASSIFICATION, then the valueis of type CV and is holding eitherKNOWN or NOVEL.

reference

0..* referredToGenotype

typeCode*: <= REFR

Note:A related gene that is on adifferent locus, and stillhas significant interrelationwith the source gene (similarto the recursive associationof an IndividualAllele).

Genotype(POCG_DM000020)

Entry point to theClinical GenomicsGenotype Model

CMET: (ASSIGNED) R_AssignedEntity

[universal](COCT_MT090000)

0..1 scopedRoleName

0..* assignedEntity

typeCode*: <= PRFperformer

0..*

performer

0..*

performer

The Genotype and its Alleles

SignificantVariations

ExpressionData

SequenceData

ClinicalPhenotypes


SDTM Domain Assumptions

• CDISC PG Domain Content Specimen Data Specimen Preparation Results Testing Methods Mainly Derived from RCRIM/CTLAB

• CDISC PR Domain Genetic Results Interpretation of Results Links to Scientific databases Mainly Derived from CG CMETs


CTLABR2 Changes Needed

• Inclusion of new genetic LOCI CMET to handle multiple gene tests


FDA Use Issues

• Need to Handle Animal and Human Genetic Data SDTM domains can easily be converted to

CDISC SEND domains No format/message available for the animal

observation data

• FDA Pilot to include National Center for Toxicology Research (NCTR), which has used Array Track with animal data


Current State

• SDTM and HL7 message work well with SNP Probe, Sequence, Electrophoresis and PCR methods (Classic Genetic Method)

• Some model fitting work with Gene Expression Array data Need to continue/expand this work


Next Steps

• Vocabulary development At least for Genetic Methodologies

• Implementation Guide for pilot participants CMET guide updated in draft model CTLAB Release 1 guide available to be updated

• End-to-end pilot projects Use of

• HL7 Pharmacogenomics Message• CDISC SDTM Pharmacogenomics Domains• Pre-Clinical data with CDISC SEND?


Time Lines for 2007

• Q1 Complete Gene Expression Array Work Informal Vocabularies Completed HL7 XML to SDTM mapping completed

• Q2-Q3 Complete Implementation Guide Execute pilot projects (4+)

• Submission and Lab to Sponsor

• Q4 Lessons Learned and Recommendations


Contact Information

Philip M. PochonCovance CLS8211 SciCor DriveIndianapolis, IN [email protected]

pharmacogenomics update rcrim tc philip m. pochon covance enterprise architecture

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