Minutes from 08/10/07 Conference Call

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Present on the call: Bron Kisler, Jim Zheng, Jennifer Fostel, Richard Scheuermann, Herb Hagler and Richard's Lab

OCI Conference Call with Doug Fridsma M.D., Ph.D.

Presenting: BRIDG: A Model to support interoperability in Clinical Research

Doug Fridsma's presentation can be Downloaded here: http://pathcuric1.swmed.edu/Research/haglerdocs/Fridsma2007-08-OCI-Presentation-v2.ppt

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The following notes were compiled by several people present during the presentation

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“ You can’t build a skyscraper by nailing together 10,000 dog houses.” Grady Booch

There is a need for a blueprint to support clinical research.

Agenda

• Why do we need BRIDG?
• Why is BRIDG?
• What are the lessons learned
• Does it work?
• Current Status

Clinical and Translational research is complex systems of organizations. You must know the definition of data and the process of care. All Clinical Trials must work in a single enterprise. But Clinical and translational data must be able to interoperate with the larger research enterprise. Standardization and the ability to hand off the data are critical to innovation. Ultimately to be successful information must pass not only with in organizations but also between organizations

What are we trying to do?

• To define implementation-independent domain semantics (define the what and the how of clinical research)
• To uncover the myriad of semantic ambiguities present in the complex domain of clinical research
• To build a foundation for achieving computable semantic interoperability

BRIDG supports the syntactic with links to the semantics.

• The ability of multiple systems to exchange information and to be able to use the information that has been exchanged.

What is BRIDG? Biomedical Research Integrated Domain Group

• A model of the shared semantics of regulated clinical research
• A communication bridge between
• Clinical research domain experts and technical experts
• Different models of clinical research information (EPOCH-BRIDG)
• An open community of stakeholders interested in developing standards for exchanging information about clinical research
• HL7, NCI, CDISC, FDA, ITN
• The semantic foundation for application and message development in HL7, caBIG, and CDISC
• A foundation for research in knowledge representation and semantic interoperability

How is BRDIG funded? Thru caBIG and NCI and some pharma companies.

Two important streams of development that have been brought together into a collaborative framework

• CDISC – 2003, started constructing an analysis model to map ODM standards to HL7
• NCI – 2004, started caBIG initiative to construct a structured protocol representation and interoperability among clinical research in cancer

Desiderata

• Did not want to construct “Yet another standard…”
• The good thing about standards is there are so many to choose from…
• Open-source
• Modeled processes and organization after other successful open-source projects Mozilla, Firefox, Linux, etc
• Model is small groups (Technical Harmonization Committee), vet in large groups (Advisory Board)
• Provide a mechanism to scale the development work
• Parallelize the development
• Prevent collaborators from “colliding” with each other

Allow us do the modeling in the open

In the BRIDG project, we have tried to operationalize the collaborative models required for roadmap initiatives

Current classes of core elements- Conceptual Domains

• Noun things Organization, People
• Role things PIs
• Do things Participate
• Happening things Milestones
• Measurement things Things you measure

I*nterpretation things Low Blood Count

• Documentation things Consent…

This is conceptual to HL7 RIM as well.

The Communications conundrum

• Experts know about the how to do clinical research but don’t understand how to build software

• Technologists understand how to build software but don’t understand the intricacies of the clinical environments and clinical research
• Any implementation (i.e. solution) is a compromise of the original problem statement
• Compromises must be chosen wisely
• Should be based on a deep understanding of the problem and a dialogue between Problem Space and Solution Space Experts

The Communication Pyramid This is formal Specification of requirements. It must be bi-directional Semantic traceability before they can be balloted.

Current Collaborators

• HL7

Official domain analysis model for the HL7 RCRIM technical committee

• All HL7 messages must be able to demonstrate “bi-directional semantic traceability” before they can be balloted

• CDISC

The integrative model for all current CDISC standards

• FDA

Developing an HL7 message based on CDISC SDTM in with the RFA requires capturing the semantics in BRIDG Regulated Product Submission (RPS) is the next HL7/FDA message to use BRIDG

• Immune Tolerance Network (ITN)
• Using BRIDG to integrate open-source caBIG tools with existing MDA applications

caBIG

• Utilized as framework for NCI’s caBIG™ (standard within CTMS WS)
• Additional non-CTMS semantics (e.g. FireBird, CDUS, etc.) being incorporated

BRIDG uses a complex process to harmonize. Using the STDM Implementation Guide and Model. They look at definitions level and fold into BRIDG. This may create two classes. The outcome is a mapping spreadsheet. Then they add things not present. Then they ask, “Here is A and B, describe how they are different”.

We look at CDISC Terminology and look at the NCI definitions in terms of BRIDG and you may of may not have to create definitions and you may or may not have to harmonize for CDISC or NCI

OBI has a similar process. OBI looked at having two definitions for the same term and quickly decided that was a recipe for disaster.

Pilot Study mapping BRIDG to EPOCH This looked at the semantic alignment. They had to overcome both language and choice mismatch. BRIDG HL7, caBIG, CDISC stakeholders Developed collaboratively with stakeholders Shared domain model for protocol-driven clinical research Comprehensive Consensus-based Abstract and context neutral EPOCH Immune Tolerance Network (ITN) International collaborative research effort that sponsors clinical trials and mechanistic assays on immune tolerance EPOCH clinical trial model Developed at Stanford Medical Informatics Designed to provide semantic foundation for management of clinical trials Approach taken Semantic alignment Use Excel spreadsheet to systematically review and document possible mappings Define necessary preconditions for mapping Overcoming representation language mismatch Overcoming representation choice mismatches

We had to understand the definitions to harmonize Subclass of Larger class must be careful to not get into trouble. Can do this in one direction, but can’t always do in the other which is problematic.

Semantic Alignment: Restrictions on EPOCH

• Mapping from EPOCH to BRIDG => Place restrictions on EPOCH
• Only one schedule of activities
• Period has no subperiods
• Limited temporal annotations

The EPOCH representation is in OWL, the BRIDG representation in UML. There is a representation of BRIDG in OWL for EPOCH. There may be some circumstances to use this version.

This pilot demonstrated that we could overcome these mismatches. The BRIDG –EPOCH model has a notion of period that map as screening in EPOCH.

SWRL rules were used to write formal rules. The Herold Protocol in EPOCH successfully used EPOCH in a Clinical Trial

Successfully used an EPOCH clinical trial to configure BRIDG Patient Study Calendar application Automated mappings except for one relationship Because of OWL/SWRL’s open-world assumption, First epoch cannot be derived as an epoch that has no predecessor

Pilot Conclusion Semantic interoperability requires Harmonization of subsets of ontologies/models Overcoming mismatches in representation languages and representation choices OWL restrictions and SWRL rules help to overcome semantic and syntactic mismatches Possible future work Continued harmonization of BRIDG/EPOCH Scalability and (semi-)automation of method

What lessons have we learned? 1. Scope – keep it clear and focused (i.e., solve a problem that exists) and standardize to the extend needed

• Keep the model generic, faithful, free of implementation-specific formalisms, and supporting the requirements
• Refine through experience, and not endless discussions

The domain of the regulated clinical research information management technical committee in HL7: Protocol-Driven Research with human, animal or device subjects, plus appropriate associated regulatory documentation.

• Analysis-level semantics
• Business processes
• Static structures

Use-case driven

• n-scope and out-of-scope determined by the use-case

Does not include vocabulary or terminology choices BRIDGCodedConcept Datatype links to other “places” where domain semantics can be represented Area of active research in understanding how ontologies and information models “link” to vocabularies and terminologies 2. Understand the difference between consensus, abstraction, and harmonization Consensus:

• Consensus statements often achieve agreement through being ambiguous

United Nations, guideline consensus statements

Abstraction:

• generalized models that are useful for a broad range of different domains (HL7 RIM)
• definitions are abstract, domain independent (although specific to an implementation) and more helpful for implementation than they are for domain experts

Harmonization:

• Creating definitions that all experts agree on, creating distinctions between concepts to clarify the semantics when they don’t agree, and imbedding those semantics in the business processes
• Harmonize concepts not words

3.Models are only a piece of the puzzle

• Datatypes, vocabularies and terminologies provide additional clarification of the semantics

4.Use a larger development framework to organize, iterate, and trace the semantics Provides a mechanism to integrate multiple projects, manage change

5. Translational research is a cycle.

In BRIDG: Process Matters Modeled on open-source software development initiatives Scalable processes to support coordination and collaboration across multiple modeling groups Organizational structure with stakeholder representation Focus on semantics, not representation or implementation allows for variation around a common model

6.The importance of capturing dynamic semantics (activities) of clinical trials research Clarifies the data and concept definitions Provides the context for use of the data structures Sets the stage for a service-oriented architecture

Recent Experience With BRIDG: The CTMS WS Interoperability Project (1) Goal: In 9 weeks (including Holidays), build interoperable support for three Use Cases across five applications in the Clinical Trial Management System (CTMS) Work Space Use Cases to be defined by group of SMEs as ‘pain points’ Applications include:

• Patient Study Calendar
• Static model has been harmonized with BRIDG
• Lab Hub
• Static model has been harmonized with BRIDG
• Adverse Event Reporting System
• Application development began concurrent with Interoperability Project
• Early analysis work already done and compliant with BRIDG
• Patient/Clinical Trial Registry
• Repository of links between patients and trials
• COT CTDMS (Oracle Clinical)
• Trial repository – export capability only

The CTMS WS Interoperability Project (2) Process: Iterative/Incremental SEP utilizing BRIDG as DAM

• Two one-month iterations
• Limited ability to change existing code base
• Process began with Business Modeling
• Activity Diagrams for each Use Case mapped to BRIDG
• “BRIDG Extract” generated based on AD → BRIDG mapping
• BRIDG Extract → XMI → analysis-level XSD → implementation-level XSM (“common wire format”)

– short time-line → no ‘formal’ messaging structures (V3 messages will be developed at a future date)

The Conclusion: The project could not have succeed without the use of a DAM The previous harmonization/common application of BRIDG by 3/5 of the applications (and the ability of the other 2 applications to map appropriate static structures to BRIDG) enabled the project to succeed

Current Status

• BRIDG is no longer a modeling exercise, but a robust model used by

the National Cancer Institute for all application development

• Commercial clinical trials software developers
• CDISC to unify their existing models
• HL7 for all HL7 messages related to clinical trials research
• FDA for electronic data submission standards
• Other collaborators (immune tolerance network) to integrate applications and clinical trials work processes

BRIDG release V1 – June, 2007 Download: http://gforge.nci.nih.gov/frs/?group_id=342

In the process we have

• Developed generalizable scaleable processes to support collaboration across organizations, models, and domains
• Begun to understand how to overcoming semantic and representational differences between different ontologies and terminologies

Value of analysis modeling for semantic interoperability If you understand

• The processes (activities) that you do within your organization to support clinical and translational research
• The information (data) that you use for these activities

You can

• Reduce redundancy in your organization
• Redesign organizational processes
• Know what to share (and what not to)
• Integrate custom and commercial applications (you know where they fit in your organizational activities and data)
• Create a shared understanding of the work of clinical trials research (facilitates “culture change”)

This becomes critical for any program in which you want to

• Exchange data between different disciplines (translational research)
• Clinical trials and translational programs (CTSA)

Action Items/Future Work identified during and after the teleconference:

1. Application of BRIDG and evaluate the model and get a paper out
2. Subject Eligibility as a trial piece for the modeling exercise at UT Southwestern
3. CDISC vocabulary and Ontology
4. Concept Paper (Barry as a probable co-author) CDISC-BRIDG-Ontolgy integration