1. HL7 v3 Clinical Genomics – Overview The HL7 Clinical Genomics Work Group Prepared by Amnon Shabo (Shvo), PhD HL7 Clinical Genomics WG Co-chair and Modeling Facilitator HL7 Structured Documents WG CDA Co-editor CCD Implementation Guide Co-editor

2. Haifa Research Lab 2 The HL7 Clinical Genomics Work Group  Mission To enable the standard use of patient-related genetic data such as DNA sequence variations and gene expression levels, for healthcare purposes (‘personalized medicine’) as well as for clinical trials & research  Work Products and Contributions to HL7 Processes The Work Group will collect, review, develop and document clinical genomics use cases in order to determine what data needs to be exchanged. The WG will review existing genomics standards formats such as BSML (Bioinformatics Sequence Markup Language), MAGE-ML (Microarray and GeneExpression Markup Language), LSID (Life Science Identifier) and other. This group will recommend enhancements to and/or extensions of HL7's normative standards for exchange of information about clinical genomic orders and observations. In addition, Clinical Genomics will seek to assure that related or supportive standards produced by other HL7 groups are robust enough to accommodate their use in both research and clinical care use. The group will also monitor information interchange standards developed outside HL7, and attempt harmonization of information content and representation of such standards with the HL7 content and representation.

3. Haifa Research Lab 3 Overview of Activities v3:  Family History (Pedigree) Topic  Genetic Variations Topic  Gene Expression Topic  CMETs defined by the Domain v2: v2 Implementation Guides * The IG “Genetic Test Result Reporting to EHR” is modeled after the HL7 Version 2.5.1 Implementation Guide: Orders And Observations; Interoperable Laboratory Result Reporting To EHR (US Realm), Release 1 CDA:  A CDA Implementation Guide for Genetic Testing Reports Common:  Domain Analysis Models for the various topics  A Domain Information Model (v3) describing the common semantics  Semantic alignment among the various specs Three Tracks: Normative DSTU Informative

4. Haifa Research Lab 4 HL7 Clinical Genomics: The v3 Track Family History Domain Information Model: Genome Gene Expression Phenotype (utilizing the HL7 Clinical Statement) Utilize Constrain Genetic Variation Constrain utilize

5. Haifa Research Lab 5 To achieve semantic interoperability… Clinical Trials Imaging EHR Orders & Observations Pharmacy Clinical Guidelines Health RIM Clinical Documents Clinical Genomics Central Health RIM (e.g., an extended HL7 V3 Reference Information Model): Bio & medical-informatics standard specs are derived from the same RIM …we need standard specs derived from a Central Health RIM: Bioinformatics Data Models ?

6. Haifa Research Lab 6 Utilizations / Implementation  Utilization by other HL7 Domains  HL7 RCRIM Work Group (clinical trials specs) utilized the CG models in their Pharmacogenomics message, which was an extension of the CTLab message (an approved but expired DSTU)  The Lab Work Group might utilize a constrained version of the Genetic Variation model in their Result message  Selected Implementations  The Family History spec is used in Mass General Hospital  Expanding to other family history applications including the US Surgeon General Family History tool  The Genetic Variation model is used in Hypergenes (a European project on essential hypertension, http://www.hypergenes.eu/)http://www.hypergenes.eu/  The Pedigree and Genetic Variation models are used in Italy, the Rizzoli institute in Bologna

7. Haifa Research Lab 7 The Locus and its Alleles Sequence Variations Expression Data Sequence and Proteomics Clinical Phenotypes The DSTU GeneticLocus Model Focal Areas (DIM forerunner):

8. Haifa Research Lab 8 The Underlying Paradigm: Encapsulate & Bubble-up Clinical Practices Genomic Data Sources EHR System HL7 CG Messages with mainly Encapsulating HL7 Objects HL7 CG Messages with encapsulated data associated with HL7 clinical objects (phenotypes) Bubble up the most clinically-significant raw genomic data into specialized HL7 objects and link them with clinical data from the patient EHR Decision Support Applications Knowledge (KBs, Ontologies, registries, reference DBs, Papers, etc.) Bridging is the challenge… Encapsulation by predefined & constrained bioinformatics schemas Bubbling-up is done continuously by specialized DS applications

9. Haifa Research Lab 9 Decision Support Applications Encapsulate & Bubble-up Example Genetic Counseling DNA Lab HL7 CG Messages with a Sequence HL7 Object encapsulating the raw sequencing results HL7 CG Messages with encapsulated sequencing data associated with clinical phenotypes Bubble up the most clinically-significant SNP data into HL7 SNP and Mutation objects and link them with clinical data from the patient EHR Sequencing Example… Encapsulation by a constrained BSML schema Bubbling-up is done dynamically by specialized applications, e.g., sequence analyzing programs EHR System Knowledge Sources on genetic variants (e.g., OMIM)

10. Haifa Research Lab 10 Example: Family History XML Encoding Point back… Bubble up… To phenotype and beyond…. Taken from a patient pedigree, the portion related to patient’s daughter (in collaboration with Partners HealthCare & other HL7 CG SIG members) Point back to the raw data of this relative providing “personal evidence”

11. Haifa Research Lab 11 XML Fusion: Encapsulation of Raw Genomic Data Raw genomic data represented in Bioinformatics markup HL7 v3 XML

12. Haifa Research Lab 12 The Phenotype Model Observed Phenotype Interpretiv e Phenotype

13. Haifa Research Lab 13 The Genetic Variation CMET (passed normative in Jan. 2010) Geneti c Loci Geneti c Locus Individual Allele Sequenc e Variation Sequence (observed or reference) Participants (including specimen) Associated data (vocab. Controlled) Observed or Interpretive phenotypes Genetic Report (CDA) Genetic Testing Order

14. Haifa Research Lab 14 The HL7 RCRIM CT Laboratory Model- The Pharmacogenomics Extension Utilizes the Clinical Genomics CMET Genetic Lab Clinical Trial Enrolled Subject Specimen Consent to Genotype Pharmacogenomics Test

15. Haifa Research Lab 15 Gene Expression Topic  Domain Analysis Model (DAM)  Passed informative ballot  Based on several models for gene expression data along with extensions

16. Haifa Research Lab 16 New v3 Models for Future Ballot  Gene Expression CMET Model  An Implementation Guide constraining the Genotype models for gene expression data  Domain Information Model (Genome )  Allows non-locus specific data (e.g., large deletions, cytogenetics, etc.) to be represented  Link to the locus-specific models, i.e., GeneticLoci & GeneticLocus  Query Model  Based on the HL7 V3 Query by Parameter Infrastructure  Adds selected attributes from the Clinical Genomics models as parameters of the query message

17. Haifa Research Lab 17 The Gene Expression CMET Draft Genetic Loci Genetic Locus Gene Expression Associated observations GTR Report Participants

18. Haifa Research Lab 18 The Domain Information Model - Genome Individual Allele Bio Sequenc e Sequence Variation (SNP, Mutation, Polymorphism, etc.) Polypeptide Expression Data Phenotype Entry Point: Geneome Expression Attributes Variation Attributes Encapsulating Obj. Bubbled-up Obj. genotype  phenotype Genetic Loci Genetic Locus Non-locus specific data

19. Haifa Research Lab 19 The CG V3 Query Model: Query by Parameter GeneticLocus parameters Starting point with query identifiers and attributes Miscellaneous parameters GeneticLoci parameters participants parameters Phenotype parameters

20. Haifa Research Lab 20 V2 Implementation Guides  The IG “Genetic Test Result Reporting to EHR” passed informative ballot  It is modeled after the HL7 Version 2.5.1 Implementation Guide: Orders And Observations; Interoperable Laboratory Result Reporting To EHR (US Realm), Release 1  Is used in a pilot of information exchange between Partners Healthcare and Intermountain Health Care

21. Haifa Research Lab 21 The v2 Message Structure

22. Haifa Research Lab 22 V2 Sample Message  OBR|1||PM-08-J00094^HPCGG- LMM^2.16.840.1.113883.3.167.1^ISO|lm_DCM-pnlB_L^Dilated Cardiomyopathy Panel B (5 genes)^99LMM-ORDER-TEST- ID||20080702000000|20080702100909|||||||||234567891^Pump^Patrick^^^^^^ NPI^L||||||20080703000000|||F||||||00000009^Cardiovascular^99HPCGG- GVIE-INDICATION^^^^^^Clinical Diagnosis and Family History of DCM|&Geneticist&Gene&&&&&NPI^^^^^^^HPCGG- LMM&2.16.840.1.113883.3.167.1&ISO|||||||||||||||55233-1^Genetic analysis master panel ^LN  SPM|1|||119273009&Peripheral blood&SNM3&&&&0707Intl&&Blood, Peripheral|||||||||||||20080702000000  OBR|2||PM-08-J00094-1^HPCGG- LMM^2.16.840.1.113883.3.167.1^ISO|55232-3^Genetic analysis summary panel^LN|||20080702000000|||||||||||||||20080703000000|||F||||^PM-08- J00094&HPCGG-LMM&2.16.840.1.113883.3.167.1&ISO  OBX|1|CWE|51967-8^Genetic disease assessed^LN||399020009^DCM- Dilated Cardiomyopathy^SNM3^^^0707Intl||||||F|20080702100909|||||||||||Laboratory for Molecular Medicine^L^22D1005307^^^CLIA&2.16.840.1.113883.4.7&ISO|1000 Laboratory Lane^Ste. 123^Cambridge^MA^99999^USA^B

23. Haifa Research Lab 23 CDA IG for Genetic Testing Reports  Scope  The Clinical Genomics Work Group develops a CDA Implementation Guide (IG) for genetic testing report co-sponsored by the Structured Documents Work Group  Design principles  Follow existing report formats commonly used in healthcare & research  Emphasize interpretations & recommendations  Provide general background information on tests performed  Represent interpretation by utilizing patterns of ‘genotype- phenotype’ associations in the HL7 v3 Clinical Genomics and implement them as harmonized clinical statement entry-level templates in this IG  Reference HL7 Clinical Genomics instances as the place holders of raw data (personal evidences), similarly to referencing images (technically-wise)  Developed using the MDHT open source tool (OHT)

24. Haifa Research Lab 24 CDA GTR Ballot Status  Balloted as DSTU and passed in October 2010  Major negative comments:  Vocabulary binding (need to align to the new principles)  Layout issues (needs to get the help of the MDHT developers)  Sample XML snippets cannot have sample data  OIDs for LOINC panels  Sub-template ids registration  Document type refinement  Alignment with sub-templates in other CDA IGs (e.g., Findings, Care Plan, etc.)  Add drug safety  Clarify definitions of LOINC codes

25. Haifa Research Lab 25 CDA GTR Issues  Ballot a Universal IG along with specific types of GTR: Healthcare - US Realm; Research; etc.  Get family history data by linking to an HL7 Pedigree instance  Similarly, link to HL7 Clinical Genomics instances to get the richest expression of genotype-phenotype associations along with encapsulated raw data (e.g., sequences)  Get volenteers to contribute to the editorial group

26. Haifa Research Lab 26 CDA GTR Section Outline

27. Haifa Research Lab 27 GTR Genetic Variation Section

28. Haifa Research Lab 28 Clinical Genomic Statement

29. Haifa Research Lab 29 Interpretive Phenotype Observation

30. Haifa Research Lab 30 Summary Section

31. Haifa Research Lab 31 Alignment Among the Various Specs  v3 specs and CDA are all based the RIM  CDA GTR-IG will be based on CDA R3  Depending on the “right side” of R3, if it allows RIM-based domain models, then alignment is trivial  v3-v2 alignment:  Proposal: represent semantics with v3 and implement it in various ways, one of which is v2; develop an “v2 ITS” for the v3 models  See proposal made by Amnon in a separate presentation (click here to see that presentation)here

32. Haifa Research Lab 32 Summary  Small group coping with  v3, v2 and CDA  Clinical & Research environments  Genetic Variation - Normative CMET  Vocabulary harmonization's (facilitator is back to activity)  Timing confusing: collecting specimen, extracting genetic material, identifying genomic observations, interpretation  Entry point into a choice box  CDA GTR through OHT CDA Editor

33. Haifa Research Lab 33 The End Thank you for your attention… Questions? Contact Amnon at shabo@il.ibm.comshabo@il.ibm.com Comments of general interest should be posted to the CG mailing list at clingenomics@lists.hl7.orgclingenomics@lists.hl7.org