Margaret Haber, RN, OCN Co-Director Enterprise Vocabulary Services National Cancer Institute

1. RCRIM Vocabulary and Controlled Terminology for Clinical Research Margaret Haber, RN, OCN Co-Director Enterprise Vocabulary Services National Cancer Institute

2. Clinical Research Challenges • Fundamental new capacities to characterize and intervene in biological systems and the disease process • Hampered by our inability to integrate huge volumes of data due to information fragmentation • Many diverse research and delivery platforms that are disconnected due to a lack of common, interoperable systems and semantics • The problem is International in scope, and with enormous implications for our ability to translate information into knowledge

3. No Controlled Terminology?No Interoperability • Systems cannot exchange or use information if they use incompatible codes or tokens to signify meaning • Terminology services provide token and codes • Proper use of them assures consistent meaning across and among enterprises

4. The Pillars of InteroperabilityNecessary but not sufficient • Common information models across all domains of interest • A foundation of rigorously defined data types (metadata) • A methodology for interfacing with controlled vocabularies

5. Interoperability Keys for Terminology • Use of Industry Standards, where feasible • Must allow for extensions to core standards • Specialty terminology remains common • Mapping is therefore essential • Conformance with Data Models • For process (logical models) • For data flow (messages) • For data at rest (database design)

6. Clinical Data Interchange Standards Consortium (CDISC) • CDISC is an open, multidisciplinary, non-profit organization committed to the development of worldwide industry standards to support the electronic acquisition, exchange, submission and archiving of clinical trials data and metadata for medical and biopharmaceutical product development.

7. HL7 (Health Level Seven) HL7 is a volunteer, ANSI-accredited Standards Developing Organization (SDO) that focuses on clinical and administrative healthcare data. Mission: "To provide standards for the exchange, management and integration of data that support clinical patient care and the management, delivery and evaluation of healthcare services. Specifically, to create flexible, cost effective approaches, standards, guidelines, methodologies, and related services for interoperability between healthcare information systems.“

8. Bringing It AllTogether: RCRIM • The HL7 “Regulated Clinical Research Information Management”Technical Committee formed as a collaboration of CDISC, FDA, and HL7 • Tofacilitate the development of common standards for clinical research information management across a variety of organizations, including government agencies, private research efforts, and sponsored research • To develop standards for interchange of regulated data that are interoperable with general healthcare standards.

9. HL7 Vocabulary (including RCRIM) • Value sets associated with certain domain portions of HL7 models • Most vocabulary domains are published as informative references only • Those domains that have a formal ballot status are shown in bold in the HL7 vocabulary tables on their web site • There are current initiatives to map these values to standard controlled terminologies

10. HL7 Vocabulary - Access • HL7 publishes at http://www.hl7.org/library/data-model/RIM/C30204/vocabulary.htm • There are approximately 8,000 terms or “concepts” in the current HL7 vocabulary • Scroll down to select a specific “table” or set of terms • Also available through an NCI developed “HL7 SDK” (software development kit) application tool • Conversion notes are included, see “HL7_Design.pdf” on NCI’s website

11. What’s Happening Now?CDISC, RCRIM and NCI • CDISC terminology group has established an independent working environment at NCI for the specification and development of broad based clinical trials standard terminology, based on CDISC models (SDTM) • Using the NCI Data Standards Repository (caDSR), which draws controlled terminology from NCI EVS systems, including but not limited to leveraging NCI Thesaurus resources for novel terminology development

12. Collaboration • These open standards, developed in collaboration with FDA, NIH, HL7 and industry experts, can provide the basis for a controlled terminology set submitted to HL7 RCRIM as proposed standards for adoption by the clinical trials community

13. Where? NCI EnterpriseVocabulary Services (EVS) • Services and resources that address NCI and Partner’s needs for controlled vocabularyhttp://evs.nci.nih.gov/ • A collaboration • NCI Office of Communications • Physician Data Query (PDQ), Clinical Trials Portal, Cancer Information Service and the NCI web portal www.cancer.gov • NCI Center for Bioinformatics • Bioinformatics Core Infrastructure (caCORE), including a metadata repository (caDSR) and object models built using EVS terminology for their core semantics

14. NCI EVS Goal – Integration by Meaning • Clinical, translational, and basic research terminology have overlapping but specialized needs, therefore EVS assists to: • Integrate different conceptual frameworks • Create terminological and taxonomic conventions across systems • Vocabulary Products • NCI Thesaurus – an ontology-like terminology • NCI Metathesaurus – maps vocabularies • External vocabularies maintained and served: MedDRA, HL7, NDF-RT, LOINC, etc.

15. NCI Thesaurus (NCIt) • Reference Terminology for NCI, Partners • A Federal Standard Terminology • Broad coverage of the cancer, other research, and clinical domain including prevention and treatment trials • Neoplastic and other Diseases • Findings and Abnormalities • Anatomy, Tissues, Subcellular Structures • Agents, Drugs, Chemicals • Genes, Gene Products, Biological Processes • Animal Models – Mouse, other • Research techniques and management, apparatus, clinical trials, lab, radiology, imagery

16. NCI Thesaurus (2) • Published Monthly • Public domain, open content license • Available on-line and by download (OWL, Ontylog XML, flat files) • 55,000+ “Concepts” hierarchically organized • Description-logic based • “Roles” establish machine readable semantic relationships between Concepts

17. NCI Thesaurus is Deployed: http://nciterms.nci.nih.gov http://www.nci.nih.gov/EVS (full documentation) • API: caCORE public access • Fulfills NCI and collaborators’ needs for controlled vocabulary • Public domain, open content license

18. Example Disease Concept Gastric Mucosa-Associated Lymphoid Tissue Lymphoma A low grade, indolent B-cell lymphoma, usually associated with Helicobacter Pylori infection. Morphologically it is characterized by a dense mucosal atypical lymphocytic (centrocyte-like cell) infiltrate with often prominent lymphoepithelial lesions and plasmacytic differentiation. Approximately 40% of gastric MALT lymphomas carry the t(11;18)(q21;q21). Such cases are resistant to Helicobacter Pylori therapy. -- 2003 Molecular abnormalities: Disease_May_Have_Cytogenetic_Abnormality: Trisomy 3 Disease_May_Have_Cytogenetic_Abnormality: Trisomy 18 Role group 1: Disease_May_Have_Cytogenetic_Abnormality: t(11;18)(q21;q21) Disease_May_Have_Molecular_Abnormality: AP12-MLT fusion protein expression Histogenesis: Disease_Has_Normal_Cell_Origin: Post-germinal center marginal zone B-lymphocyte Pathology: Disease_Has_Abnormal_Cell: Centrocyte-like cell Disease_May_Have_Abnormal_Cell: Neoplastic monocytoid B-lymphocyte Disease_May_Have_Abnormal_Cell: Neoplastic plasma cell Disease_May_Have_Finding: Lymphoepithelial lesion Anatomy: Disease_Has_Primary_Anatomic_Site: Stomach Disease_Has_Normal_Tissue_Origin: Gut associated lymphoid tissue Clinical information: Disease_May_Have_Finding: Indolent clinical course Disease_May_Have_Associated_Disease: Hepatitis C

19. A holistic view of information exchange also requires broader interoperability, but where do we place the fences? • Clinical data, regulatory submissions, discovery research? • Industry agreements, nationally accredited, global standardization? One answer is mapping: Relating Terminologies for Effective Data Exchange

20. Mapping: NCI Metathesaurus • A filtered version of the NLM UMLS Metathesaurus, extended with additional required vocabularies • 1,100,000 concepts, 2,200,000+ terms and phrases with definitions • Mappings among over 55 vocabularies • Extensive synonymy: Over 40,000 terms for neoplasms mapped to 7,000 concepts • Used as online dictionary and thesaurus, for mapping and document indexing

21. NCI Metathesaurus (2) • Minor releases monthly, Major releases two to three times a year • Provides a mapped overlap and partial inter-relation of current versions of NCI and partner required vocabularies, ex. The ICD’s, MedDRA, SNOMED, MeSH (NLM Medical Subject Headings), HCPCS (procedures), LOINC (lab values), drug terminologies (VA NDF-RT, AOD, RxNORM, Multum, NCI Thesaurus drugs, etc.)

22. NCI Metathesaurus: Browser Example

23. EVS Products & Services Are Open • NCI Thesaurus is Open Contentftp://ftp1.nci.nih.gov/pub/cacore/EVS/ThesaurusTermsofUse.htm • NCI Metathesaurus is Mostly Open Source See Each Source’s Licensehttp://ncimeta.nci.nih.gov/MetaServlet/GenerateSourcesServlet • NCI EVS Servers Are Freely Accessible • On the Web: • Via API: • All Software Developed by NCI EVS is Public Open Source and Free for the Asking: http://nciterms.nci.nih.govandhttp://ncimeta.nci.nih.gov http://ncicb.nci.nih.gov/core/caBIO http://ncicb.nci.nih.gov/core

24. NCI builds on EVS via caCORE Infrastructure • Enhanced Information integration • Cross-discipline reasoning capabilities biomedical objects common data elements controlled vocabulary

25. Enterprise Vocabulary • NCI Meta-Thesaurus (Cross-mapped standard vocabularies, e.g. ICD’s, MedDRA, SNOMED) • Semantic integration, inter-vocabulary mapping among 55+ vocabularies • UMLS Metathesaurus extended with numerous additional vocabularies • 1,100,000+ Concepts, 2,200,000 terms and phrases • NCI Thesaurus • Description logic-based • 55,000+ “Concepts” • Concept is the semantic unit • One or more terms describe a Concept – synonymy • Semantic relationships between Concepts • Freestanding terminologies • MedDRA, MGED, NDF-RT, GO, SNOMED, etc. biomedical objects common data elements controlled vocabulary

26. Common Data Elements (caDSR) • Structured data reporting elements • Precisely defined, harmonized questions and answers • Standardized questions for forms • Standard lists of coded valid values for answers biomedical objects common data elements controlled vocabulary

27. Biomedical Information Objects (caBIO) • UML object models representing clinical and research entities such as genes, sequences, chromosomes, pathways, etc. • Public access APIs provide an information interface independent of back-end data platforms biomedical objects common data elements controlled vocabulary

28. Controlled Terminology is integrated into NCI’s standards supporting infrastructure • Enterprise Vocabulary Services (EVS) • Core Semantics for caCORE and many other applications • Public access browsers • APIs • cancer Data Standards Repository (caDSR) • ISO 11179 metadata repository • Common Data Elements (CDE’s) for multiple templates, such as Case Report Forms, drawn from EVS terminology • cancer Bioinformatics Infrastructure Objects (caBIO) • UML Models annotated with EVS concepts/terms, loadable into caDSR • Public access APIs

29. EVS: Extending Interoperability Beyond the Enterprise • Leverage Collaborations • Federal: FDA, VA, CDC, other NIH Institutes • Major Standards Organizations: HL7, CDISC, W3C • Cancer Centers and Cooperative Groups (caBIG, caGRID) • Many research collaborators such as the Microarray Gene Expression Data Society (MGED)

30. FDA-NCI MOU • Significance of MOU • NCI is leveraging its terminology-related resources to address FDA needs • Avoids expenditure at FDA to replicate existing, available resources at NCI, increases return on investment for NIH/NCI • Leverages multiple efforts • FDA collaboration with NIH/NCI will result in improved trial drug and related regulatory terminology for the broader clinical trials community • FDA and NCI are to coordinate regarding terminology standards efforts such as HL7 RCRIM (including CDISC)

31. Example:NCI EVS and FDA SPL • NCI EVS maintains and provides access to FDA SPL Terminology • NCI Thesaurus will be a primary namespace used • Also FDA standard terminology for the ICSR, IND/NDA, device nomenclature, others • Access Via • Download at ftp://ftp1.nci.nih.gov/pub/cacore/EVS/ • Public, open API http://ncicb.nci.nih.gov/core/caBIO • Web Servlet at http://nciterms.nci.nih.gov

32. Concept Details URI: http://nciterms.nci.nih.gov:80/NCIBrowser/ConceptReport.jsp? dictionary=NCI_Thesaurus&code=C42887 Version: December 30, 2004 (04.12g) Aerosol Dosage Form Identifiers: name Aerosol_Dosage_Form code C42887 Information about this concept: Preferred_Name Aerosol Dosage Form Semantic_Type Manufactured Object DEFINITION FDA|A product that is packaged under pressure and contains therapeutically active ingredients that are released upon activation of an appropriate valve system; it is intended for topical application to the skin as well as local application into the nose (nasal aerosols), mouth (lingual aerosols), or lungs (inhalation aerosols). Synonym with source data AER|AB|FDA_CDER|246 Synonym with source data Aerosol Dosage Form|PT|NCI Synonym with source data Aerosol|PT|FDA|246 Synonym AER Synonym Aerosol Synonym Aerosol Dosage Form Synonym Aerosol Dose Form Superconcepts: Pharmaceutical Dosage Form Subconcepts: Aerosol Foam Dosage Form Aerosol Spray Dosage Form Metered Aerosol Dosage Form Powder Aerosol Dosage Form This indicates the concept is used in the FDA Structured Product Label (SPL)

33. A Vital Collaboration:CDISC and NCI –Shared models, metadata standards, and core semantics drawn from standard terminology • CDISC terminology group is working with NCI tools through EVS for the specification and development of broad based clinical trials standard terminology, based on CDISC models • CDISC is using the NCI Data Standards Repository and controlled terminology from NCI EVS, including but not limited to NCI Thesaurus, for novel terminology development • These open CDISC standards, developed in collaboration with FDA, NIH, HL7 and others, can provide the basis for a controlled terminology set able to be adopted across the clinical trials community

34. NCIt Browser: CDISC Tagged Concept

35. NCI ThesaurusConcept: Race Terminology concept for Race showing harmonization of different users, including CDISC, NCI, CDC, etc.

36. Benefits of Terminology Development in a Common EnvironmentA Step Towards Semantic Interoperability • Support and maintenance of terminologies in NCI EVS provides access to and common usage of standard terminologies • Enables use of controlled terminology by clinicians and researchers for data encoding, retrieval, reporting, and aggregation • Facilitates collaboration and information exchange by increasing the ability to predictably use information that is gathered • Leverages the power of shared knowledge

37. You can collaborate • Joint Participation: In standards groups such as HL7 RCRIM in order to inform relevant standards decisions • Joint Development: Contributing to clinical trials standard terminology development efforts, i.e. through CDISC terminology group • Providing validation and testing: Content and modeling developed with industry input is more robust, better able to meet your needs, and you can better plan/anticipate implementation/impacts on your organization

38. Participate in HL7 RCRIM • The HL7 “Regulated Clinical Research Information Management” Technical Committee, formed as a collaboration of CDISC, FDA, and HL7 • To facilitate the development of common standards for clinical research information management across a variety of organizations -- including government agencies, private research efforts, and sponsored research • To develop standards for interchange of regulated data that are interoperable with general healthcare standards.

39. Contact:Margaret W. Haber, RN, OCNCo-DirectorNCI Enterprise Vocabulary ServicesNCI Office of the Directormhaber@mail.nih.govhttp://evs.nci.nih.gov/