HL7 Clinical-Genomics SIG: A Shared Genotype Model

1. HL7 Clinical-Genomics SIG:A Shared Genotype Model HL7 V3 Compliant Amnon Shabo (Shvo) IBM Research Lab in Haifa HL7 Clinical-Genomics SIG Facilitator Atlanta, September 2004

2. Current Work Clinical-Genomics Storyboard Clinical-Genomics Storyboard Family History Genotype Shared Model BRCA Tissue Typing Cystic Fibrosis Pharmacogenomics Clinical-Genomics Storyboard Clinical-Genomics Storyboard Clinical Statement Shared Model

3. 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.)

4. The Genotype CMET (cont.) • Design Principles: • Shared model (a reusable component in different use cases) • 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&8 • 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

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

6. Coexistence of HL7 Objects and Bioinformatics Markup Genomic Data Sources Clinical Practice Knowledge (KBs, Ontologies, registries, Evidence-Based, Papers, etc.) HL7 CG Messages with both encapsulating and Specialized HL7 Objects HL7 CG Messages with mainly Encapsulating HL7 Objects EHR System Bubbling up the clinically-significant raw genomic data into specialized HL7 objects and linked them with clinical data from the patient EHR Decision Support Applications

7. Coexistence of HL7 Objects and Bioinformatics Markup (cont.) Genetic Counseling DNA Lab Sequencing Example… HL7 CG Messages with both encapsulating and Specialized HL7 Objects HL7 CG Messages with an AlleleSequence HL7 Object encapsulating the raw sequencing results EHR System Bubbling up the clinically-significant SNP data into HL7 SNP and Mutation objects and linked them with clinical data from the patient EHR Decision Support Applications

8. Coexistence of HL7 Objects and Bioinformatics Markup (cont.) The patient's allele HL7 genomic-specialized Objects Bubbling-up… Bubbling-up… Sequencing data encapsulated as bioinformatics markup Bubbling-up… Bubbling-up…

9. The Family History Model Genotype CMET

10. Family History – Harmonization Proposals • Age: • Age of subject when subject’s diagnosis was made • Age at time of death • Proposed solution: a new data type to refer to from effectiveTime:<effectiveTime xsi:type="TSR"> <!--TSR=Time Stamp Relative--> <epoch code="B"/> <offset value="20" unit="mo"/></effectiveTime> • Vocabulary proposals • Observation Interpretation (Deleterious, Unknown significance, Polymorphism, No mutation) • Personal relation codes and qualifiers • Personal Relationship association names • A naming algorithm problem (HL7 tooling issue)

11. 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

12. How the Genotype fits to Tissue-Typing Tissue Typing in the context of Bone-Marrow Transplantation: BMT Center BMT unique Order/Entry Donor Bank Tissue Typing Observation

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

14. 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 • Contact Amnon Shabo to get the document (shabo@il.ibm.com)

15. 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

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

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

18. 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

19. Constrained-MAGE-ML Schema • Cope with data outside of the XML (referenced) • Shared issues: • Eliminate research & display elements and 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 • Require that data will refer to only one allele with which the encapsulating HL7 object is associated

20. 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.)

21. Genomic Specializations of Observation GenomicObservation LSID Polymorphism Gene Expression Bio Sequence type position length reference region MAGE BSML SNP Mutation tagSNP knownAssciatedDiseases (not the actual phenotype)

22. New Class Codes Proposal classCode Class name

23. 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.

24. Proposed HL7 Vocabularies • Genomics Vocabularies: • Polymorphism: • General types (SNP, Mutation, Sequence Variation) • Nucleotide-based types (substitution, insertion, deletion, etc.) • Alleles Relation (recessive / dominant, homozygote / heterozygote) • Genotype-to-phenotype types of effects • Genomic observation interpretation (Deleterious, Unknown significance, polymorphism, No mutation) • SequencingMethodCode(example in next slide)

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

26. Proposed HL7 Vocabularies (cont.) • Tissue Typing related Vocabularies: • TissueTypingLocusMatchingClass • TissueTypingMatchingClass • TissueTypingTestingClass • TissueTypingTestingMethod • TissueTypingDocumentType • TissueTypingOrderClass • DonorType (allogeneic, autologous, etc.) • Class I & II antigens classification

27. 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

28. Next Steps • HL7 • Formally submission of our harmonization proposals • Continue with 2 alternatives until harmonization is resolved • Register the Genotype Family History models as CMETs • Hand craft sample instances (for review and experimental use) • Derive a Genetic Testing model from the HL7 Lab SIG Models • 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) • caBIO (?)

29. Linking to the NCI Rembrandt Model Use-case driven modeling, designed with the HL7-Genotype model as a starting point and will eventually extend the caBio model.

30. Alternative Genotype Models Entry Point: Genotype A model without genomic specializations of the HL7 RIM Observation class: Polymorphism Polymorphism Attributes Container Polymorphism Attributes Shadow asso. W / Mutation Polymorphism Attributes

31. Comments received on the Genotype Model • Revalidate/collapse the polymorphism hierarchy • Add a RIM class “SequenceVariance” • Representing all types of polymorphisms • Type could be placed in the code attribute • ‘position’ and ‘length’ could be parts of a boundary in a RegionOfInterest type of Observation • Could represent any bio-sequence (DNA, RNA, Protein, etc.) • Patient data vs. generic knowledge • tagSNP, knownAssociatedDiseases and haplotype are a type of knowledge • Should they only be referenced (pointing to KBs)? • Types of relationships between the various Genotype observations: Pertinent, Component, Subject,…? • It’s tricky as it should apply to the observations and not to the observed entities

32. Comments on the Genotype Model (cont.) • Distinguishing the encapsulating objects from the bubbled-up ones • associate encapsulated objects to a bubbled-up objects, with options: XFRM (transformation), XCRPT (excerpt), SUMM (summary), DRIV (derived from)… what’s best? • Method object should be in DEF mood? • Could it be that there is a need to describe a method per patient? • Is the SNP  Mutation association useful? • Changed the association type to XFRM to demonstrate a possible “bubbled-up” association, i.e., a SNP was encountered as a mutation

33. SLIST Data Type • Use HL7 data types to represent bio-sequences • SLIST<CV> (applied to CV=Coded Value) could hold either of the following: • ACGTCGGTTCA… • Leu-Ala-Met-Gly-Ala-… Table 37: Components of Sampled Sequence

34. Issues with just SequenceVariation… • SNP: • Link to Haplotype is valid only for SNP type of Polymorphism • tagSNP is valid only for SNP • Mutation: • code&value are constrained to LOINC or other medical-oriented taxonomy rather than to an LS taxonomy as in polymorphism • The attribute knownAssociatedDiseases moves to the phenotype choice so it’s resolved • SNP  Mutation association needs now a recursive association within Sequence Variation • Technical issue: cannot shadow a choice box

35. The End… Thank you…