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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
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HL7 Clinical-Genomics SIG: Tissue-Typing Models and a Reusable Genotype Module HL7 V3 Compliant HL7 Clinical-Genomics SIG Facilitator Amnon Shabo (Shvo)

Mar 27, 2015

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Page 1: HL7 Clinical-Genomics SIG: Tissue-Typing Models and a Reusable Genotype Module HL7 V3 Compliant HL7 Clinical-Genomics SIG Facilitator Amnon Shabo (Shvo)

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

Page 2: HL7 Clinical-Genomics SIG: Tissue-Typing Models and a Reusable Genotype Module HL7 V3 Compliant HL7 Clinical-Genomics SIG Facilitator Amnon Shabo (Shvo)

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.)

Page 3: HL7 Clinical-Genomics SIG: Tissue-Typing Models and a Reusable Genotype Module HL7 V3 Compliant HL7 Clinical-Genomics SIG Facilitator Amnon Shabo (Shvo)

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

Page 4: HL7 Clinical-Genomics SIG: Tissue-Typing Models and a Reusable Genotype Module HL7 V3 Compliant HL7 Clinical-Genomics SIG Facilitator Amnon Shabo (Shvo)

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

Page 5: HL7 Clinical-Genomics SIG: Tissue-Typing Models and a Reusable Genotype Module HL7 V3 Compliant HL7 Clinical-Genomics SIG Facilitator Amnon Shabo (Shvo)

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

Page 6: HL7 Clinical-Genomics SIG: Tissue-Typing Models and a Reusable Genotype Module HL7 V3 Compliant HL7 Clinical-Genomics SIG Facilitator Amnon Shabo (Shvo)

Haifa Research Lab

Tissue Typing

Observation

How the Genotype fits to Tissue-Typing

Page 7: HL7 Clinical-Genomics SIG: Tissue-Typing Models and a Reusable Genotype Module HL7 V3 Compliant HL7 Clinical-Genomics SIG Facilitator Amnon Shabo (Shvo)

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

Page 8: HL7 Clinical-Genomics SIG: Tissue-Typing Models and a Reusable Genotype Module HL7 V3 Compliant HL7 Clinical-Genomics SIG Facilitator Amnon Shabo (Shvo)

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

Page 9: HL7 Clinical-Genomics SIG: Tissue-Typing Models and a Reusable Genotype Module HL7 V3 Compliant HL7 Clinical-Genomics SIG Facilitator Amnon Shabo (Shvo)

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

Page 10: HL7 Clinical-Genomics SIG: Tissue-Typing Models and a Reusable Genotype Module HL7 V3 Compliant HL7 Clinical-Genomics SIG Facilitator Amnon Shabo (Shvo)

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

Page 11: HL7 Clinical-Genomics SIG: Tissue-Typing Models and a Reusable Genotype Module HL7 V3 Compliant HL7 Clinical-Genomics SIG Facilitator Amnon Shabo (Shvo)

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

Page 12: HL7 Clinical-Genomics SIG: Tissue-Typing Models and a Reusable Genotype Module HL7 V3 Compliant HL7 Clinical-Genomics SIG Facilitator Amnon Shabo (Shvo)

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

Page 13: HL7 Clinical-Genomics SIG: Tissue-Typing Models and a Reusable Genotype Module HL7 V3 Compliant HL7 Clinical-Genomics SIG Facilitator Amnon Shabo (Shvo)

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

Page 14: HL7 Clinical-Genomics SIG: Tissue-Typing Models and a Reusable Genotype Module HL7 V3 Compliant HL7 Clinical-Genomics SIG Facilitator Amnon Shabo (Shvo)

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.)

Page 15: HL7 Clinical-Genomics SIG: Tissue-Typing Models and a Reusable Genotype Module HL7 V3 Compliant HL7 Clinical-Genomics SIG Facilitator Amnon Shabo (Shvo)

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

Page 16: HL7 Clinical-Genomics SIG: Tissue-Typing Models and a Reusable Genotype Module HL7 V3 Compliant HL7 Clinical-Genomics SIG Facilitator Amnon Shabo (Shvo)

Haifa Research Lab

New Class Codes Proposal

OBSGEN GenomicObservation

OBSGENPOL Polymorphism

OBSGENPOLMUT Mutation

OBSGENPOLSNP SNP

classCode Class name

Page 17: HL7 Clinical-Genomics SIG: Tissue-Typing Models and a Reusable Genotype Module HL7 V3 Compliant HL7 Clinical-Genomics SIG Facilitator Amnon Shabo (Shvo)

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.

Page 18: HL7 Clinical-Genomics SIG: Tissue-Typing Models and a Reusable Genotype Module HL7 V3 Compliant HL7 Clinical-Genomics SIG Facilitator Amnon Shabo (Shvo)

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

Page 19: HL7 Clinical-Genomics SIG: Tissue-Typing Models and a Reusable Genotype Module HL7 V3 Compliant HL7 Clinical-Genomics SIG Facilitator Amnon Shabo (Shvo)

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

Page 20: HL7 Clinical-Genomics SIG: Tissue-Typing Models and a Reusable Genotype Module HL7 V3 Compliant HL7 Clinical-Genomics SIG Facilitator Amnon Shabo (Shvo)

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

Page 21: HL7 Clinical-Genomics SIG: Tissue-Typing Models and a Reusable Genotype Module HL7 V3 Compliant HL7 Clinical-Genomics SIG Facilitator Amnon Shabo (Shvo)

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 (?)

Page 22: HL7 Clinical-Genomics SIG: Tissue-Typing Models and a Reusable Genotype Module HL7 V3 Compliant HL7 Clinical-Genomics SIG Facilitator Amnon Shabo (Shvo)

Haifa Research Lab

The End…

Thank you…