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

2. Haifa Research Lab Current Work Clinical-Genomics Storyboard Clinical-Genomics Storyboard Clinical-Genomics Storyboard Clinical-Genomics Storyboard Genotype Shared Model Tissue Typing Cystic FibrosisPharmacogenomics BRCA Family History Clinical Statement Shared Model

3. 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.)

4. Haifa Research Lab 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. 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

6. Haifa Research Lab Coexistence of HL7 Objects and Bioinformatics Markup Clinical Practice Genomic Data Sources EHR System HL7 CG Messages with mainly Encapsulating HL7 Objects HL7 CG Messages with both encapsulating and Specialized HL7 Objects 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 Knowledge (KBs, Ontologies, registries, Evidence-Based, Papers, etc.)

7. Haifa Research Lab Coexistence of HL7 Objects and Bioinformatics Markup (cont.) Genetic Counseling DNA Lab EHR System HL7 CG Messages with an AlleleSequence HL7 Object encapsulating the raw sequencing results HL7 CG Messages with both encapsulating and Specialized HL7 Objects 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 Sequencing Example…

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

9. Haifa Research Lab The Family History Model Genotype CMET

10. Haifa Research Lab 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:  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. 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

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

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

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

15. 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

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

17. 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 SNP/Hap Discovery

18. 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

19. Haifa Research Lab 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. 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.)

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

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

23. 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.

24. Haifa Research Lab 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. 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

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

27. 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

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

31. Haifa Research Lab 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. Haifa Research Lab 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. Haifa Research Lab SLIST Data Type Table 37: Components of Sampled Sequence NameTypeDescription originT The origin of the list item value scale, i.e., the physical quantity that a zero-digit in the sequence would represent. scaleT.diff A ratio-scale quantity that is factored out of the digit sequence. digitslist A sequence of raw digits for the sample values. This is typically the raw output of an A/D converter.  Use HL7 data types to represent bio-sequences  SLIST (applied to CV=Coded Value) could hold either of the following:  ACGTCGGTTCA…  Leu-Ala-Met-Gly-Ala-…

34. Haifa Research Lab 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. Haifa Research Lab The End… Thank you…