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HL7 Clinical-Genomics SIG: Tissue-Typing Models and a Reusable Genotype Module
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Transcript of HL7 Clinical-Genomics SIG: Tissue-Typing Models and a Reusable Genotype Module
HL7 Clinical-Genomics SIG:Tissue-Typing Models and a Reusable Genotype Module
HL7 V3 Compliant
HL7 Clinical-Genomics SIG Facilitator
Amnon Shabo (Shvo)
IBM Research Lab in Haifa
May 2004
Haifa Research Lab
The Genotype CMET
Represents genomic data in HL7 RIM Classes Not meant to be a biological model Concise and targeted at healthcare use for
personalized medicine
Consists of: A Genotype (entry point) 1 .. 3 alleles Polymorphisms
Mutations SNPs
Haplotypes DNA Sequencing Gene expression Proteomics Phenotypes (clinical data such as diseases, allergies, etc.)
Haifa Research Lab
The Genotype CMET(cont.)
Design Principles: Reusable component Basic encapsulation of genomic data that might be used in healthcare
regardless of the use case Stemmed from looking for commonalities in specific use cases Presented as the CG SIG DIM (Domain Information Model) in ballot#6 Most of the clones are optional, thus allowing the representation of merely a
genotype with a minimum of one allele (a typical use by early adopters) At the same time, allows the use of finer-grain / raw genomic data, thus
accommodating the more complex use cases such as tissue typing or clinical trials
Its use is currently illustrated in four R-MIMs: Tissue Typing Cystic Fibrosis Viral genotyping Pharmacogenomics
Haifa Research Lab
0..1 pertinentMutation
typeCode*: <= PERT
pertinentInformation
0..1 pertinentGeneExpression
typeCode*: <= PERT
pertinentInformation3
0..* pertinentPolymorphism
typeCode*: <= PERT
pertinentInformation6
IndividualAlleleclassCode*: <= OBSmoodCode*: <= EVNcode*: CE CWE [1..1] (allele identifier & classification, e.g. GeneBank)text: ED [0..1]methodCode: SET<CE> CWE [0..*] (The method by which the code was determined)
SNPclassCode*: <= OBSmoodCode*: <= EVNid: II [0..1]code: CE CWE [0..1] (SNP identifier & classification, e.g. Entrez dbSNP)text: ED [0..1]value: BAG<ED> [0..*] (the SNP itself)methodCode: SET<CE> CWE [0..*]
HaplotypeclassCode*: <= OBSmoodCode*: <= EVNid: II [0..1]code: CE CWE [0..1]
GenotypeclassCode*: <= OBSmoodCode*: <= EVNid: II [0..1]code: CE CWE [0..1] (e.g., HETEROZYGOTE)text: ED [0..1]effectiveTime: IVL<TS> [0..1] (the time of genotyping)
0..* haplotype
typeCode*: <= COMP
componentOf
1..3 individualAllele
typeCode*: <= COMP
component
0..* pertinentSNP
typeCode*: <= PERTpertinentInformation1
AlleleSequenceclassCode*: <= OBSmoodCode*: <= EVNid: II [0..1]code: [1..1] (the sequence standard code, e.g.BSML, GMS)text: (the annotated sequence)effectiveTime: [1..1]value: ED [1..1] (the actual sequence)methodCode: (the sequencingmethod)
0..1 pertinentAlleleSequence
typeCode*: <= PERTpertinentInformation2
GeneExpressionclassCode*: <= OBSmoodCode*: <= EVNid: II [0..1]code: CE CWE <= ActCode (the standard's code (e.g., MAGE-ML identifier)text:effectiveTime:value: ED [1..1] (the actual geneexpression levels)methodCode:
PolypeptideclassCode*: <= OBSmoodCode*: <= EVNid: II [0..1]code*: CE CWE [1..1](idnetifier & classification ofthe protein, e.g., SwissProt,) (PDB, PIR, HUPO)text:
0..* outcomePolypeptide
typeCode*: <= OUTC
outcome
DeterminantPeptideclassCode*: <= OBSmoodCode*: <= EVNid: II [0..1]code: CE CWE (identifier and classification of the determinant, e.g., Entrez)text: ED
0..* pertinentDeterminantPeptide
typeCode*: <= PERT
pertinentInformation2
MutationclassCode*: <= OBSmoodCode*: <= EVNid: II [0..1]code: CE CWE (mutation identifier andclassification, e.g. LOINC MOLECULARGENETICS NAMING)text:
0..* pertinentMutation
typeCode*: <= PERT
pertinentInformation4
ClinicalPhenotypeclassCode*: <= OBSmoodCode*: <= EVNid: II [0..1]code: CE CWE [0..1] (disease, allergy, sensitivity, ADE, etc.)text: ED [0..1]uncertaintyCode: CE CNE [0..1]value: ANY [0..1]
HL7 Clinical Genomics SIGDocument: Individual Genotype DIM (to be registered as a CMET)Subject: Genomics Data Rev: 0.5 Date: April 24, 2004Facilitator: Amnon Shabo (Shvo), IBM Research in Haifa
Note:There must be at least oneIndividualAllele and threeat the most. The 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.
Mutation
0..* haplotype
typeCode*: <= COMP
componentOf
Constrained to a restricted MAGE-MLcontent model, specified elesewhere.
Constraint: GeneExpression.value
Constrained to a restrictedBSML or GMS content model,specified elsewhere.
Constraint: AlleleSequence.value
0..* pertinentMethod
typeCode*: <= PERTpertinentInformation1
MethodclassCode*: <= PROCmoodCode*: <= EVNid: II [0..1]code: CD CWE [0..1] <=ActCode (type of method)text: ED [0..1] (free text description of themethod used)methodCode: SET<CE>CWE [0..*]
0..* pertinentIndividualAllele
typeCode*: <= PERT
pertinentInformation5
Note:A related allele that is on adifferent haplotype, and stillhas significant interrelationwith the source allele.
IndividualAllele
0..* priorClinicalPhenotype
typeCode*: <= SEQL
sequelTo
ExternalClinicalPhenotypeclassCode*: <= OBSmoodCode*: <= EVNid*: II [1..1] (The id of an external observation (e.g., in a problemlist)
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 a clinical conditionrepresented internally in this model.
Note: Shadowed observationsare copies of other observationsand thus have all of the originalact attributes.
Note:Use methodCode ifyou don’t use theassociated methodprocedure.
Note:Could refine ActRelationship typeCodeto elaborate on different types of genomicto phenotype effects.
Method0..* pertinentMethod
typeCode*: <= PERTpertinentInformation
Note:Usually this is a computed outcome, i.e.,the lab does not produce the actual protein.
0..* referredToExternalClinicalPhenotype
typeCode*: <= x_ActRelationshipExternalReference
reference
ClinicalPhenotype
ClinicalPhenotype
ClinicalPhenotype0..* priorClinicalPhenotype
typeCode*: <= SEQLsequelTo
0..* priorClinicalPhenotype
typeCode*: <= SEQL
sequelTo
0..* priorClinicalPhenotype
typeCode*: <= SEQL
sequelTo
Haplotype
Note:The classCode should beOBSGENPOLMUTwhich stands for mutation-polymorphismgenomic observation,a subtype ofOBSGENPOL (polymorphismgenomic observation) whichis a subtype ofOBSGEN (genomicobservation).
Note:The classCode should beOBSGENPOLSNP whichstands forSNP-polymorphismgenomic observation,a subtype ofOBSGENPOL(polymorphism genomicobservation) which is asubtype of OBSGEN(genomic observation).
PolymorphismclassCode*: <= OBSmoodCode*: <=EVNid: II [0..1]code: CD CWE [0..1] <= ActCodetext: ED [0..1]value: ANY [0..1]
Note:The classCode should beOBSGENPOL which standsfor polymorphism genomicobservation, a subtype ofOBSGENPOL (polymorphismgenomic observation) whichis a subtype of OBSGEN(genomic observation).
Genotype(POCG_RM000004)
Entry point to theClinical-GenomicsGenotype Model
The Genotype Model
Individual Allele (1..3)
SNP
Allele Sequence
MutationProteomic
s
Gene Expression
Clinical Phenotype
Haplotype
Entry Point: Genotype
Sequencing
Method
Polymorphism
Haifa Research Lab
The Genotype Model in Tissue Typing
BMT Tissue Typing
Tissue Typing Observation
Genotype
AlleleSNP
Haplotype
Individual1 HLA
Matching
Individual2 HLA
Donor Banks
BMT
Ward
Tissue-Typing Lab
Haifa Research Lab
Tissue Typing
Observation
How the Genotype fits to Tissue-Typing
Haifa Research Lab
How the Genotype fits to Tissue-Typing
Tissue Typing
Observation
Class I Antigens
Class II Antigens
The Genotype model is used for each HLA
Antigen
Haifa Research Lab
Tissue Typing Scenario Simulation
Real Case with… A Hutch Patient and sibling and unrelated donor candidates are in Hadassah
Information exchange… is simulated through a series of XML files following the TT storyboard activity diagram and using the HL R-MIMs + Genotype CMET
Documented in the following doc: HL7-Clinical-Genomics-TissueTypingInfoExchangeSimulation.doc
Haifa Research Lab
The Genotype Model in Cystic Fibrosis
Entry Point: Blood Sample
Patient
Provider EMR System
MGS Report
DNA
Genotype CMET
MLG Counselor
ML Consultant
Molecular Genetic
lab
Haifa Research Lab
The Genotype Model in Viral Genotyping
Entry Point: Blood Sample
Pathogen
Patient
Viral DNA Sequencing
Viral DNA Regions
Genotype CMET
DNA Lab
Test Panel
Sponsor
Report
Resistance
Profile
Haifa Research Lab
The Genotype Model in Pharmacogenomics-Based Clinical Trial & Submission
Pharmacogenomics testing
Patient
Gene Selection
Genotype CMET
Genomic data Submission
Sponsor
CRO
Report
CRO
Regulator
Data Validation
Analysis
device
Data Analysis
Trial design
Haifa Research Lab
Constrained-BSML Schema
BSML – Bioinformatics Sequence Markup Language
Aimed at any biological sequence, for example: DNA RNA Protein
Constraining the BSML DTD to fit the healthcare needs Leave out research and display markup Ensure the patient identification
Creating an XML Schema, set up as the content model of an HL7 attribute of type ED
Haifa Research Lab
Constrained-MAGE-ML Schema
Convert MAGE-ML DTD to XML Schema and eliminate research elements
Shared issues: not only eliminate research & display related data but requires the
presence of certain elements, for example - patient identifiers Require that one and only one patient will be the subject of the data,
to avoid bringing data of another patient into the HL7 message
Haifa Research Lab
OBS Specialization Examples
PublicHealthCase detectionMethodCode :: CE transmissionModeCode :: CE diseaseImportedCode :: CE
Diagnostic Image subjectOrientationCode:: CE
The above examples are relatively ‘simple’ considering the uniqueness of the genomic observation attributes
Propose to add a genomic specialization to the RIM Observation Class
Rationale: has additional attributes that are unique to genomics (LSID, Bioinformatics Markup, etc.)
Haifa Research Lab
Genomic Specializations of Observation
GenomicObservation
LSID
Polymorphism
typepositionlengthreferenceregion
SNP
tagSNP
Mutationvalue (constrained to LOINC genetic naming)
Gene Expression
MAGE
DNA Sequences
BSML
Haifa Research Lab
New Class Codes Proposal
OBSGEN GenomicObservation
OBSGENPOL Polymorphism
OBSGENPOLMUT Mutation
OBSGENPOLSNP SNP
classCode Class name
Haifa Research Lab
New Attributes Proposal GenomicObservation: LSIDIdentifier
AlleleSequence: moleculeSequence A constrained XML Markup based on the BSML markup.
Polymorphism:o type (SNP, Mutation, Other)o position (the position of the polymorphism)o length (the length of the polymorphism)o reference (the base reference for the above attributes)o region (when the polymorphism scope is a specific gene region)
SNP: Tag SNPA Boolean field indicating whether this SNP is part of small SNP-Set that determines a SNP-haplotype.
GeneExpression: expressionLevels A constrained XML Markup based on the MAGE markup.
Proteomic clones: TBD.
Haifa Research Lab
Proposed HL7 Vocabularies
Tissue Typing related Vocabularies: TissueTypingLocusMatchingClass
TissueTypingMatchingClass
TissueTypingTestingClass
TissueTypingTestingMethod
TissueTypingDocumentType
TissueTypingOrderClass
DonorType (allogeneic, autologous, etc.)
Class I & II antigens classification
Genomics related Vocabularies: AllelesRelation (recessive, heterozygote, etc.)
SequencingMethodCode
Genotype-to-phenotype types of effects
Haifa Research Lab
HL7 Vocabulary Example
SequencingMethodCode:
SSOPH -Sequence specific oligonucleotide probe hybridization
SSP -Sequence specific primers
SBT -Sequence-based typing
RSCA -Reference strand conformation analysis
Haifa Research Lab
XML Examples
Genotype Examples:o GenotypeSample1.xml
A genotype of two HLA alleles in the B locus
o GenotypeSample2.xmlA genotype of two HLA alleles in the B locus, along with a SNP designation in the first allele
Tissue Typing Observation Examples:o TissueTypingObservationSample1.xml
Consists of a single tissue typing observation of a patient or a donor
o TissueTypingObservationSample2.xmlConsists of two tissue typing observations of a patient & donor, leading to a tissue typing matching observation
Donor Search Examples:o TissueTypingDonorBankSample1.xml
This example is aimed at illustrating an unsolicited message from a BMT Center to a donor bank, sending a patient's tissue typing observation for the purpose of searching an appropriate donor
Haifa Research Lab
Next Steps
HL7 Derive message models (R-MIMs) from each use case ‘DIM’ Schemas ( a draft is already available for the Genotype model) Instances (for review and experimental use)
Vocabularies HL7- develop External- get HL7 to recognize them
Constraining Bioinformatics Markup (continue the effort and include markup in the next ballot) MAGE-ML or MIAME BSML (done) Hapmap (?)
Haifa Research Lab
The End…
Thank you…