1. 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

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 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

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 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.

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
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 Enterprise Vocabulary Services (EVS)
Services and resources that address NCI and Partner’s needs for controlled vocabulary
A collaboration
NCI Office of Communications
Physician Data Query (PDQ), Clinical Trials Portal, Cancer Information Service and the NCI web portal
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.

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

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
Kind==(disjoint classes)
Terms Concepts Category
1,691, ,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)

17. NCI Thesaurus is Deployed:
(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
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. 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

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
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, ,158 NCI Metathesaurus

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 Content ftp://ftp1.nci.nih.gov/pub/cacore/EVS/ThesaurusTermsofUse.htm
NCI Metathesaurus is Mostly Open Source
See Each Source’s License
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:
and

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 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 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)

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
Web Servlet at

32. Concept Details
URI:
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 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.

36. 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

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, OCN Co-Director NCI Enterprise Vocabulary Services NCI Office of the Director