1. HL7 Clinical Genomics – RIM Constraining Issues May 2008 The HL7 Clinical Genomics SIG Amnon Shabo (Shvo), PhD HL7 Clinical Genomics SIG Co-chair and Modeling Facilitator HL7 Structured Documents TC CDA R2 Co-editor CCD Implementation Guide Co-editor

2. Haifa Research Lab 2 To achieve semantic interoperability… Clinical Trials Imaging EHR Orders & Observations Pharmacy Clinical Guidelines Health RIM Clinical Documents Clinical Genomics But how do we cope with the challenge of personalized healthcare? Need to bring mass genomic data into healthcare oriented standards! …we need standard specs derived from a Central Health RIM: Bioinformatics Data Models Encapsulate & bubble-up Our solution:

3. Haifa Research Lab 3 The Locus and its Alleles Sequence Variations Expression Data Sequence and Proteomics Phenotypes The HL7 v3 DSTU GeneticLocus Model - Focal Areas:

4. Haifa Research Lab 4 The Underlying Paradigm: Encapsulate & Bubble-up End user Applications for clinical practice & research 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 Decision Support applications

5. Haifa Research Lab 5 Coexistence of HL7 Classes and Bioinformatics Markup (cont.) A patient's allele Observation HL7 genomic- specialized Classes Bubbling-up… Sequencing data encapsulated in bioinformatics markup SNP mutation SNP Haplotype

6. Haifa Research Lab 6 The Refinement Process Starts in the RIM Observation Act Specialization DiagnosticImage Observation Specialization PublicHealthCase Observation Specialization So why not a genomic specialization? Where do we draw the line and stop specializing? The core classes: An Entity plays a Role which Participates in an Act Generic ontology

7. Haifa Research Lab 7 Refining a RIM Class in a Static Model This process of refinement is needed in Clinical Genomics Clinical Genomics brings new & unique concepts into HL7 Therefore we proposed new RIM classes but got rejected e.g., SequenceVariance with attributes like position, length, etc. We then developed the GEN code hierarchy instead… classCode attr. Clone B. Name code attr. OBS BaseBattery LOINC code for Test Battery/Panel OBS BaseUnitaryResult LOINC code for Test Examples from the RCRIM CT Lab Model: OBS ToxicityGrade LOINC

8. Haifa Research Lab 8 The GEN Hierarchy (in ActClass vocabulary)

9. Haifa Research Lab 9 The GEN Hierarchy (in ActClass vocabulary) The GEN code hierarchy was accepted by RIM Harmonization already in July 2006! It indentifies core classes of the genomic models Enables further specialization of classes like sequence variation by using the code attribute It allows Decision Support & Data Mining to bubble-up, i.e., creating and looking for genotype phenotype associations We need minor refinements of this hierarchy, e.g.: Add ALLELE code to the GEN hierarchy This is also addressing Bob Dolins ballot comment about SEQVAR for IndividualAllele wild type which is not an appropriate code PHN (Phenotype) is a genomic-related observation (edit GEN definition)

10. Haifa Research Lab 10 Complex Genotype Phenotype Associations Some patients, particularly young children, may be born with a genetic mutation which means they are at risk of hearing loss after taken antibiotics called aminoglycosides. There is now a drive to consider screening patients for the genetic mutation known as m.1555A-G which is held in around 1 in 1,611 newborns in the USA, 1 in 206 newborns in New Zealand and 1 in 40,000 newborns in the UK. Aminoglycosides are valuable antibiotics used for serious infections such as complicated urinary tract infections, TB and septicemia. They are known to potentially cause damage to the ear - otoxicity. Individuals holding the mutation have an inherited predisposition which makes them extremely sensitive to the effects - they can end up with severe and permanent hearing loss."

11. Haifa Research Lab 11 The PHN (Phenotype) Class Code Signifies that an observation is a phenotype Typically is associated with a source genomic observation But not necessarily in cases where the exact genetic sources is yet unknown A genomic observation could be associated with other genomic observations or with other observations not necessarily classified as phenotypes Prepare the ground for a disease model expressed in RIM so that patient data could be better checked against it The IBM Clinical Genomics solution as used the Hypergenes project - http://www.hypergenes.eu/) relies on the GEN hierarchy and performs semantic computations based on these codeshttp://www.hypergenes.eu/

12. Haifa Research Lab 12 General Vocabulary Issues What are the clear-cut criteria that distinguish between ActClass and ActCode, preferably in a way that a designer of a clinical decision support application could use them programmatically? ActCode should specialize ActClass but current guidance and the actual values in the two vocabularies sometime blur the differences between the two, e.g.: _MedicationObservationType act code doesnt specialize any act class SpecimenTransport act code could be specializing TRANS or SPCTRT _ActCognitiveProfessionalServiceCode act code doesnt specialize a.class If indeed one specializes the other, why not merge them into one coherent vocabulary where sub-typing will become explicit? The fields classCode, [clone name] and code will bind to the appropriate layer in this proposed consolidated vocabulary

13. Haifa Research Lab 13 What if GEN is Moved to ActCode… In lack of class code & clone name - need to rely on the code attribute, however… This poses the following problems: Code attribute is often drawn from external terminology Giving up class code & clone name leads to loss of granularity in the data represented by the class Inferring the generic GEN code from a value in the code attribute might not be easy, especially if drawn from external terminology

14. Haifa Research Lab 14 Clone Business Names DO Carry Semantics Current guidance: Clone business names should not carry semantics Rebuttal: These names are meaningful to committee members and are balloted and approved by the HL7 membership An example – CDA AuthoringDevice vs. Device The CDA R2 AuthoringDevice and Device clones have the same class code (DEV) and the same binding of the code attribute (EntityCode). In fact, they have the very same set of attributes refined exactly the same (cardinality, coding strength, vocab, etc). The only way to distinguish between the two is through the clone name (unless you rely on the traversal path). The two clones are semantically distinct: AuthoringDevice has to do with the authoring of the document and Device has to do with some specimen mentioned in the body of the document. In addition, the clone AuthoringDevice does carry semantics which cannot be found in either EntityClass or EntityCode vocabularies. ???

15. Haifa Research Lab 15 Clone Business Names (cont.) The CDA R2 Encounter and EncompassingEncounter have the same class code (ENC) and the same binding of the code attribute (ActEncounterCode). Semantically they're distinct: the EncompassingEncounter is the encounter documented in the CDA instance and the other clone represents an encounter you may refer to in the body of the document. A different example of the clone business name semantics is from Patient Administration (Emergency Encounter) model: the clone ValuablesLocation has class code<=OBS, no code attribute and value attribute that is not bound to any vocabulary (it also has mood & negation attributes). Obviously, the semantics carried by ValuablesLocation cannot be found under OBS but also cannot be found in both ActClass and ActCode vocabularies. ???

16. Haifa Research Lab 16 Formalize Clone Business Names Or… Either… Formalize the clone business name into a vocabulary domain, intertwined in the consolidated ActClass/AcCode vocabulary Adding a definition for each clone name is already done in the walk- through of each model, and possibly in the glossary In this way, we can relate to clone names as codes in the cascading 'identification' of a class This could ease the burden of class identification by the class code attribute, if indeed the wish is to keep the ActClass as minimal as possible Or… Disallow the use of clone business names as if they are class names Enforce the automatic naming mechanism of clone names In either of the options: Continue to propagate clone names to the generated XML schemas!

17. Haifa Research Lab 17 Thank You for Your Attention… Questions? Comments: shabo@il.ibm.comshabo@il.ibm.com