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

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

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

The Pillars of Interoperability Necessary 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

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)

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.

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.“

Bringing It All Together: 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.

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

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

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

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

Where? NCI Enterprise Vocabulary Services (EVS) Services and resources that address NCI and Partner’s needs for controlled vocabulary http://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 OC using EVS and working to integrate EVS terminology into PDQ and cancer.gov.

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.

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 Neoplastic disease – clinical goes to the Molecular – findings and abnormalities

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 Kind==(disjoint classes) Terms Concepts Category 1,691,850 783,158 NCI Metathesaurus 100,000 34,000 NCI Thesaurus 10,521 Disease, Abnormality, Finding (5,901) ...Neoplasm (within Disease) 3,531 Drug 2,773 Chemotherapy Regimens 4,320 Anatomy 1,767 Gene 2,200 Protein (Gene Product)

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

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

Clinical data, regulatory submissions, discovery research? 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

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 The current numbers are a little lower than this, 1.6 M, but they will be somewhat higher after our next build (will include CT) 1,691,850 783,158 NCI Metathesaurus

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.)

NCI Metathesaurus: Browser Example

EVS Products & Services Are Open NCI Thesaurus is Open Content ftp://ftp1.nci.nih.gov/pub/cacore/EVS/ThesaurusTermsofUse.htm NCI Metathesaurus is Mostly Open Source See Each Source’s License http://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.gov and http://ncimeta.nci.nih.gov http://ncicb.nci.nih.gov/core/caBIO http://ncicb.nci.nih.gov/core

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

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

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

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

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

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)

FDA-NCI MOU Significance of MOU Leverages multiple efforts 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)

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

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)

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

NCIt Browser: CDISC Tagged Concept

NCI Thesaurus Concept: Race Terminology concept for Race showing harmonization of different users, including CDISC, NCI, CDC, etc. This first slide is a screen shot from an NCI-Thesaurus search on the terminology concept RACE. This middle area shows the results of the search. The yellow area depicts what the CDISC tag for this concept will look like and how the CDISC term for RACE appears in the terminology. So, RACE is a CDISC preferred term (PT) You can also see the harmonization of this term with other major stakeholders and that RACE is a shared terminology concept with other context users…such as NCI, CDC, etc. Could also be FDA,, etc… If we referred back to our example of SEX, the GENDER context would likely appear here as well as another preferred term Also, for this term there is a direct link to the UMLS concept identifier. At the bottom of the form, will be listed the parent / child relationships.

Leverages the power of shared knowledge Benefits of Terminology Development in a Common Environment A 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 Controlled vocabulary A restricted set of preferred terms used within an organization for a given purpose. (van Bemmel & Musen) A controlled vocabulary should be a restricted set of terminological phrases used within an organization for a given purpose in a specific subject field…. should provide unambiguous transformation tables towards relevant coding systems. (CEN) Provide significant advantages non-ambiguous representation of concepts lossless data transformation facilitation of mapping among terminologies data re-use in different contexts

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

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.

Contact: Margaret W. Haber, RN, OCN Co-Director NCI Enterprise Vocabulary Services NCI Office of the Director mhaber@mail.nih.gov http://evs.nci.nih.gov/