1. Clinical Genomics Work Group (HL7) Mukesh Sharma Washington University in St. Louis

2. Agenda Clinical Genomics Work Group Family History Project Genetic Variation Cytogenetics LOINC codes Gene Expression DAM Genomic Specimen Model Project New Models for Future Ballot Useful Links

3. The HL7 Clinical Genomics (CG) Work Group Established as a SIG in 2003 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 Gene Expression 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.

4. CG Work Group Leadership (Co-Chairs) Joyce Hernandez Merck & Co. Inc. Kevin Hughes MD Partners HealthCare System, Inc. Amnon Shabo, PhD IBM Mollie Ullman-Cullere Dana-Farber Cancer Institute

5. Formal Relationships with Other HL7 Groups CG Work Group coordinates with a large number of other Work Groups in order to accomplish its mission. Strongest relationships are with Orders and Observation Clinical Statement Clinical Decision Support Regulated Clinical Research Information Management Patient Care Electronic Health Records Modeling and Methodology Structured Documents

6. WG meetings/Balloting Cycles 3 times annually January, May, September 2010 meetings January 17–22, 2010 meeting at Pointe Hilton Squaw Peak, Phoenix, AZ May 17-20, 2010 meeting at Windsor Barra Hotel and Congressos, Rio De Janerio, Brazil October 3-8, 2010 meeting at Cambridge, MA

7. Clinical genomics Work Group Meeting OCTOBER, 2010 Update

8. Open Floor Discussed FDA regulations and groups concern about reporting raw data FDA wants raw data to be part of medical record but it is very expensive to store the data. Some members raised concerns that e.g. for next generation sequencing they do not have space to store raw data and quality scores etc.

9. Overview of Activities Three Tracks 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 Normative (V3); DSTU (CDA); Informative (V2)

10. 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

11. Family History Background HL7 and ANSI approved pedigree model Numerous implementations within care setting Deployed by Surgeon General’s My Family Health Portrait and MS Health Vault Status Several groups developing compliant family history tools have confirmed need for compliance testing framework; therefore…. Canonical Pedigree project to develop tools to test compliance to Pedigree standard and interoperability Hosted Web Service, using Pedigree Standard, provides hereditary cancer risk assessments

12. Genetic Variation Background Approved CMET: passed normative ballot under reconciliation Published HL7 v2.5.1 Lab Reporting Implementation Guide (IG) for structured clinical genetic test results Status Genetic Test Report Project using Clinical Document Architecture (CDA) Release 2 of 2.5.1. IG, expanding to new clinical scenarios (e.g. tumor genetic profile) and genetic test definition Genetic test orders will be a collaborative modeling effort (e.g. Clinical Genomics, Orders & Observation, Laboratory) Starting analysis for scope expansion to whole genome sequencing Starting analysis for utility of data set in clinical/research data warehouse

13. Cytogenetics LOINC Codes 1 Background CG has a Genetic Variation Implementation Guide that covers genetic mutations located within a gene. Need to report larger genetic changes found in cytogenetic testing. Develop LOINC codes for representing cytogenetics test results Develop prototype V2 interface based on the LOINC panel structure In Intermountain Healthcare’s DEV environment Potentially real/live interface between ARUP Laboratories and Intermountain Healthcare Status Officially submitted to LOINC for approval Three panels (total 43 codes) Chromosome Analysis G Banded Panel Chromosome Analysis FISH Panel Chromosome Analysis Microarray Copy Number Change Panel Additional 11 codes Drafting HL7 V2 Implementation Guide for Cytogenetics Sample messages, etc. Detailed data models and associated terminology are created in Intermountain Healthcare’s development environment

14. Cytogenetics LOINC Codes 2 Next Step HL7 standard development Target to ballot the v2 IG in January 2011 ballot cycle Develop the cytogenetics section of the CDA Genetic Test Report (GTR) Prototyping implementation, eventually real implementation Real practical challenges

15. Genomic Specimen Model Project Background CG has started a Specimen Process Step Project Discussion with Orders and Observation (O & O) in Jan 2010 meeting concluded that the requirements should be captured in O & O Specimen Model O & O will enhance the Universal Specimen CMET. The scope will be updated and named Specimen CMET enhancement phase 2 CG will drop the specimen process step project and place a change request on the O & O site to make sure that their use cases are captured in the specimen model Update Scope: Project will detail specimen collection, procedure(s) done on specimen and specimen storage that will affect the quality of the specimen. Requirements represented in specimen CMET Requirements not represented in specimen CMET

16. Requirements Represented In Specimen CMET Specimen Handling and Processing Type of preservatives used and amount. Examples: additives used to preserve RNA/DNA Special handling such as flash freezing Storage Type of storage used for collected specimen and any genetic extracted material. Specimen Access Unique identifiers assigned to all materials (both collected and derived) to help manage access to specimens. Specimen Type Whether fluid, tissue, cell or molecular specimen? Specimen Quantity Quantity and/or size of specimen collected. In the Specimen model, Natural class is available to capture this information

17. Requirements Represented In Specimen CMET Specimen Characteristics RNA/DNA characteristics: e.g. Purity values-A260/A230 and A260/A280, RNA integrity number (RIN) number etc. QC needs to be done by the specimen core lab  O&O : Captured in ObservationEvent. Need an implementation guide for details. May separate it out in future from Observation Event

18. Requirements Not Represented In Specimen CMET 1 Genetic Consent Form Linking up with the Genetic Consent Form. Form signed by the patient to allow genetic/genomic testing and in some cases to permit long-term storage of genetic samples for further research. Need to know that there is consent; duration that it allows the specimen to be used for (indefinite or restricted to particular duration or protocols). Consent could be withdrawn and as a result the specimen is pulled out and destroyed.  O&O: Bullet 1 and 2: Present in the current model as part of clinical statement (bullet 1 and 2) Bullet 3: Needs to be handled in Medical Records as Medical record owns consent. Can not tie consent to specific specimen currently. In future, could be captured in the SpecimenProcessStep messaging-and include provision to destroy the specimen. CMET it self does not deal with this activity.

19. Requirements Not Represented In Specimen CMET 2 Specimen Management Specimen Collection Two use cases: i) Patient comes in and we take 2 or more specimens ii) Patient comes in and we take 1 specimen We need to capture the relationship between multiple specimens collected at one time (use case i) The universal CMET only has one entry point (SpecimenChoice) i.e. all CMETs are starting from Specimen Suggested Action In the SpecimenChoice Box add the SpecimenCollectionGroup class (especially for use case i)

20. Requirements Not Represented In Specimen CMET 3 Current ModelProposed Change

21. Gene Expression DAM Update Currently reviewing results of the last ballot ( informative ballot in May, 2010) Next steps: Finish NCI Generic Assay (IRWG/ICR) Changes to GE DAM Add “generic” classes from Generic Assay Bring over additional BRIDGE Classes Apply suggested changes from the ballot (use case, BRIDG compatibility)

22. Clinical Genomics DAM (50,000 foot level view) Genetic Variation Bio-Specimen Gene Expression

23. Color Coding Scheme

24. CG DAM Views Process Models Specimen Handling and Collection (based on NCI public protocol) Genomics Testing Process (high level) Future – interaction diagrams for message flows per Use Case Gene Expression – Whole Model Bio-specimen Experiment Definition (Gene express specific protocol, not entire study) Array Design Common Classes Data Relationships Generic Assay Overview

25. Generic Assay Overview 1 Study Experiment Data Protocol Equipment Software ExperimentalItem * * * * * * Study: A detailed examination or analysis designed to discover facts about a system under investigation. Systems may include intact organisms, biologic specimens, and natural or synthetic materials. Experiment: A coordinated set of actions and observations designed to generate data, with the ultimate goal of discovery or hypothesis testing. Protocol: A rule which guides how an activity should be performed. ExperimentalItem: Items used in the execution of an experiment: specimens - samples either taken from nature or created for the purpose of study and which are to be the subject of an experiment, and reagents and supplies which will be used in the execution of an experiment. It is not instruments, analysis tools, and general- purpose resources (common reagents, lab equipment, personnel).

26. Generic Assay Overview 2 Notes: 1.ProcessedData has association to Finding; not included on the diagram to keep things focused 1.Isn’t the result of an analytical experiment what we’ve called ProcessedData? 2.Do we need to have distinction between Data and ProcessedData? Can we have self association on Data to handle both in the DAM 2.Software needs to be defined 3.What about association from ExperimentalItem to ExperimentalStudy?

27. New v3 Models for Future Ballot 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

28. Useful links HL7.org http://www.hl7.org/ HL 7 Wiki http://wiki.hl7.org/index.php?title=Main_Page Clinical Genomics Wiki http://wiki.hl7.org/index.php?title=CG HL7 Standards http://www.hl7.org/implement/standards/index.cfm HL7v3 Ballot Site http://www.hl7.org/v3ballot/html/welcome/environment/index.htm ICR (IRWG) Wiki https://wiki.nci.nih.gov/x/kQiG ICR (IRWG) comments on CG Gene Expression DAM https://wiki.nci.nih.gov/x/FZZ9AQ Clinical genomics Oct 2010 Meeting Slides http://www.hl7.org/Special/committees/clingenomics/docs.cfm?wg_id=7&wg_docs_subfolder_name=present ations

29. Questions?

30. CG Gene Expression DAM May 2010 Ballot; Model Details Subpackages Array Design Classes e.g Array, ArrayDesign, ArrayGroup, Reporter etc. Common Classes Identifiable, OntologySource, OntologyTerm etc. Data DataFile, DataMatrix, Image, ImageAcquistion etc. Design Element DesignElement, DimensionElement etc. Experiement Definition GenomicProtocol, LabExperiment, NormalizationTypes, ProtocolParameter etc. Relationship Relationships between: Samples, Arrays and Data Bio-Specimen Diagrams Classes e.g BioSpecimen, Bio-Specimen-Characteristics, Specimen Handling etc.

31. Clinical Genomics DAM May 2010 Ballot; Terminology Terminology: definitions from NCI EVS team for a number of terms needed for genetic sample type entries nDNA (Nuclear DNA) pDNA (plasmid DNA) RNA (Ribonucleic acid) RNAP (RNA polymerase) mRNA (Messenger Ribonucleic Acid) snRNA (Small nuclear RNA) miRNA (microRNA) ssRNA (single-stranded RNA) dsRNA (double-stranded RNA) snoRNA (small nucleolar RNA) tRNA (Transfer RNA) hnRNA (heterogeneous nuclear RNA) RNP (Ribonucleoprotein) snRNP (small nuclear ribonucleoproteins)

32. CG Gene Expression DAM May 2010 Ballot Model available at http://www.hl7.org/v3ballot/html/domains/uvcg/uvcg_GeneExpressionDA M.htm#POCG_DO000000UV-GeneExpressionDam-ic.&nbsp http://www.hl7.org/v3ballot/html/domains/uvcg/uvcg_GeneExpressionDA M.htm#POCG_DO000000UV-GeneExpressionDam-ic.&nbsp Comments submitted by IRWG (ICR WS) on May 7, 2010 https://wiki.nci.nih.gov/display/ICR/IRWG+Review+of+HL7+CG+DAM+2.0 Review of the ballot results on the Gene Expression DAM Received 16 Negatives and 30 Affirmative votes Negatives from : CDISC, NCI, FDA and Siemens