HL7 Clinical-Genomics SIG: Tissue-Typing Models and a Reusable Genotype Module

1. HL7 Clinical-Genomics SIG:Tissue-Typing Models and a Reusable Genotype Module HL7 V3 Compliant Amnon Shabo (Shvo) IBM Research Lab in Haifa HL7 Clinical-Genomics SIG Facilitator May 2004

2. 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.)

3. 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

4. Entry Point: Genotype The Genotype Model Haplotype Individual Allele (1..3) Allele Sequence Sequencing Method SNP Proteomics Mutation Gene Expression Clinical Phenotype Polymorphism

5. BMT Tissue Typing Donor Banks BMT Ward Tissue Typing Observation Individual1 HLA Genotype Tissue-Typing Lab Matching SNP Allele Haplotype Individual2 HLA The Genotype Model in Tissue Typing

6. How the Genotype fits to Tissue-Typing Tissue Typing Observation

7. How the Genotype fits to Tissue-Typing Class II Antigens Class I Antigens The Genotype model is used for each HLA Antigen Tissue Typing Observation

8. 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

9. The Genotype Model in Cystic Fibrosis EMR System Provider Entry Point: Blood Sample MGS Report MLG Counselor Patient ML Consultant DNA Molecular Genetic lab Genotype CMET

10. The Genotype Model in Viral Genotyping Report Patient Sponsor Pathogen Viral DNA Sequencing Entry Point: Blood Sample Test Panel Resistance Profile Genotype CMET Viral DNA Regions DNA Lab

11. The Genotype Model in Pharmacogenomics-Based Clinical Trial & Submission Data Analysis Patient Report Pharmacogenomics testing CRO Gene Selection Analysis device CRO Genotype CMET Sponsor Data Validation Trial design Genomic data Submission Regulator

12. 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

13. 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

14. 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.)

15. Genomic Specializations of Observation GenomicObservation LSID Polymorphism Gene Expression DNA Sequences type position length reference region MAGE BSML SNP Mutation tagSNP value (constrained to LOINC genetic naming)

16. New Class Codes Proposal classCode Class name

17. New Attributes Proposal • GenomicObservation: LSIDIdentifier • AlleleSequence: moleculeSequenceA constrained XML Markup based on the BSML markup. • Polymorphism: • type (SNP, Mutation, Other) • position (the position of the polymorphism) • length (the length of the polymorphism) • reference (the base reference for the above attributes) • 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: expressionLevelsA constrained XML Markup based on the MAGE markup. • Proteomic clones: TBD.

18. 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

19. HL7 Vocabulary Example SequencingMethodCode: • SSOPH -Sequence specific oligonucleotide probe hybridization • SSP -Sequence specific primers • SBT -Sequence-based typing • RSCA -Reference strand conformation analysis

20. XML Examples • Genotype Examples: • GenotypeSample1.xmlA genotype of two HLA alleles in the B locus • GenotypeSample2.xmlA genotype of two HLA alleles in the B locus, along with a SNP designation in the first allele • Tissue Typing Observation Examples: • TissueTypingObservationSample1.xmlConsists of a single tissue typing observation of a patient or a donor • TissueTypingObservationSample2.xmlConsists of two tissue typing observations of a patient & donor, leading to a tissue typing matching observation • Donor Search Examples: • TissueTypingDonorBankSample1.xmlThis 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

21. 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 (?)

22. The End… Thank you…