1. 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

2. 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.)

3. 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

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

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

6. Haifa Research Lab Tissue Typing Observation How the Genotype fits to Tissue-Typing

7. 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

8. 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

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

10. Haifa Research Lab The Genotype Model in Viral Genotyping Entry Point: Blood Sample Pathoge n Patient Viral DNA Sequencing Viral DNA Regions Genotype CMET DNA Lab Test Panel Sponso r Repor t Resistance Profile

11. Haifa Research Lab The Genotype Model in Pharmacogenomics- Based Clinical Trial & Submission Pharmacogenomics testing Patient Gene Selection Genotype CMET Genomic data Submission Sponso r CRO Repor t CR O Regulator Data Validation Analysi s device Data Analysis Trial design

12. 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

13. 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

14. 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.)

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

16. Haifa Research Lab New Class Codes Proposal OBSGENGenomicObservation OBSGENPOLPolymorphism OBSGENPOLMUTMutation OBSGENPOLSNPSNP classCode Class name

17. 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 SNP A 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.

18. 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

19. 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

20. Haifa Research Lab XML Examples Genotype Examples: o GenotypeSample1.xml A genotype of two HLA alleles in the B locus o GenotypeSample2.xml A 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.xml Consists 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

21. 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)Genotype 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. Haifa Research Lab The End… Thank you…