BRIDG: A Shared Analysis Model of the Domain of Clinical Trials Research

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BRIDG A Shared Analysis Model of the Domain of
Clinical Trials Research

• Douglas B. Fridsma, MD, PhD
• Center for Biomedical Informatics
• University of Pittsburgh School of Medicine

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What is BRIDG?

• An open community of stakeholders interested in
  developing standards for exchanging information
  about clinical trials
• A bridge between
• clinical trial domain experts and technical
  experts
• different models of clinical trials information
• A formal model of the shared semantics of
  regulated clinical trials research
• The semantic foundation for application and
  message development in HL7, caBIG, and CDISC

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A Team Effort

• Modeling Team
• Christo Andonyadis
• Peter Abramovitsch
• Greg Anglin
• Lisa Chatterjee
• Julie Evans
• Douglas B Fridsma
• Smita Hastak
• Ray Heimbuch
• Charlie Mead
• Joyce Niland
• John Speakman
• Cara Willoughby
• Diane Wold
• The Trial Design group in CDISC

• Leadership and collaboration
• Sue Dubman, NCI
• Becky Kush, CDISC
• Linda Quade, Randy Levin, Barbara Tardiff, HL7
• Charlie Mead, HL7

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Team Members (2)

• Current modeling team
• Christo Andonyadis
• Greg Anglin
• Lisa Chatterjee
• Julie Evans
• Douglas B Fridsma
• Smita Hastak
• Joel Hoffman
• Charlie Mead
• Joyce Niland
• John Speakman
• Cara Willoughby
• Diane Wold

• Julie Evans
• Ed Helton
• Pierre-Yves Lastic
• Tony Friebel
• Don Kacher
• Barbara Tardiff
• Chuck Jaffe
• Frank Newby
• Sally Cassels
• Nitin Gupta
• Landen Bain
• Laura Altshuler
• Steve Ruberg,
• Elaine Job
• Becky Kush
• Sylvia Collins
• Udo Siegman
• David Hardison
• David Iberson-Hurst

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BRIDG Development Philosophy

• Scope keep it clear and focused (ie, solve a
  problem that exists) and standardize to the
  extend needed
• Refine through experience, and not endless
  discussions. This keeps the modeling effort clear
  and focused
• Keep it generic, faithful, free of implementation
  specific formalisms, and supporting the
  requirements
• Model in the open
• Collaborate until it hurts
• If the tools and models dont work with reality
  it is probably the tools and the models that need
  to change

With thanks to Dipak Kalra for discussion
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The current stakeholders in BRIDG

• Health Level Seven (HL7)
• BRIDG is the domain analysis model (DAM) for HL7
  RCRIM TC
• Clinical Data Interchange Standards Consortium
  (CDISC)
• Consortium of pharmaceutical companies
• Develops standards for regulatory reporting and
  drug development submissions
• Key participant in HL7
• caBIG CTMS workspace and NCI
• Has real needs for applications and
  interoperability standards
• Funding the participation of cancer centers
• Has created a focus for integrating various
  standards organizations

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BRIDG organization

• BRIDG advisory board
• Strategic direction with representation from all
  the stakeholders (CDISC, HL7, caBIG)
• Technical Harmonization group
• Managing the technical process of harmonizing and
  mentoring subprojects
• Small group of individuals charged with the
  technical aspects of harmonization
• Have to make choices, but approval and vetting
  rests with stakeholders

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Active Subprojects

• Trial design (Diane Wold, GSK and Peter
  Abramowitch, Fasttrack)
• CDISC trial design subcommittee has moved their
  work into enterprise architect and UML modeling
  to speed the development efforts
• Update the model every 2 weeks with results of
  teleconference
• Statistical design (Greg Anglin, Lilly)
• eDCI subproject (Don Kacher, Oracle, Christo
  Andonyadis, NCICB)
• General purpose HL7 message to describe a data
  capture instrument, or case report form. Using
  HL7 early adopter mechanisms.
• Actively using gForge documents, forums,
  webpages, and CVS repository

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Active Subprojects

• Clinical Registry message (Lakshmi Grama)
• Development of an HL7 message for registering a
  clinical trial in a clinical trial repository
• Eudract (europe)
• Clinicaltrials.gov, PDQ
• Traditional HL7 project development (not early
  adopter)
• Adverse events (Joyce Niland, COH)
• First significant submodel to be harmonized
• Will lead to both application development and
  message specification
• Harmonization branch and maintenance
• New concepts/classes/definitions added from CTOM
  (Smita Hastak, ScenPro)
• Cleaning up the model and definitions
• Moving away from strict HL7 RIM classes an
  emphasis on clarity in describing the domain

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What have we accomplished?

• BRIDG
• Established excellent collaboration with CDISC,
  HL7 and other caBIG modelers
• Constructed the initial pieces of a comprehensive
  model still much to do
• Have established this model as the HL7 Domain
  analysis model for regulated clinical research TC
  (RCRIM)
• BRIDG will serve as an integrator for CDISC
  message harmonization
• Development of a clinical trials reference
  implementation based on BRIDG (CTOM, caAERS)
• Establishing both organizational and procedures
  to maintain and grow the model
• This model will serve as the semantic foundation
  for data interchange specifications in HL7,
  CDISC, the NCI, and the clinical trials space of
  caBIG

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Rich semantics captured in BRIDG

• CDISC glossary of terms
• Semantics and examples at the class and attribute
  level
• Datatypes help to clarify the semantics around
  the classes and attributes

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Current Priorities

• Static Structures
• Cleaning up the current model to make it more
  accessible to both domain experts and technical
  experts
• Development of a harmonizable analysis model of
  the CDISC SDTM (submission data tabular model)
• Harmonization of adverse events model from CoH,
  harmonization with HL7 Patient Safety SIG UML
  model(s)
• Dynamic Structures
• Defining the Dynamic models at present
• Harmonize with COH dynamic models
• Linking dynamic structures to static structures
• Developing processes to support collaboration,
  input into BRIDG and use of BRIDG
• Work with Training Group to develop BRIDG
  educational bootcamp for domain and technical
  experts

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Existing Standards Harmonization
Existing DMIM

• Process A
• Harmonize existing HL7 DMIM for regulated
  clinical research
• Process B
• extract domain knowledge from existing messages
  and systems into formal UML models
• Process C
• Harmonize and merge UML models into BRIDG

A
BRIDG model
C
C
UML submodel
UML submodel
B\
B
Existing HL7 message
Existing object model
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New Message and Application Development

• Process D
• Generate a release of BRIDG for formal
  requirements traceability with vetting within
  stakeholder organizations
• Process E
• HL7 message generation using HL7 mechanisms
• Process F
• caBIG application development with annotation,
  semantic connector, UML loader

UML loader Semantic Cntr
HL7 message generation
DMIM
Annotated UML model
E
F
BRIDG model release version X
D
BRIDG model
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Tools to Support the People Process

• www.BRIDGproject.org
• Open source
• Used for projects like firefox and mozilla
• Bug and feature tracking
• Discussion forums
• Source control with CVS check-in/check-out
• Project administration
• Email and listservs with notification of code,
  discussion group, or document changes
• Ability to link and synchronize CVS repositories
  across sites

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Working with VCDE

• The need for coded concepts and terminology
  within BRIDG
• Can show some examples of these in the model
• Semantic harmonization at the analysis level
• The difficulty of mapping ODM with RIM at the
  implementation level (CDISC experience)
• Integration at the implementation level requires
  terminology and vocabulary. However, to get
  there, you need to have shared semantics at the
  analysis level.
• If the semantics are different at the analysis
  level, then they will map into different CDEs and
  terminologies at the implementation level.

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Two places that we need VCDE

• Input into the model
• make it easier to be consistent with existing
  standards (ie, HL7 datatypes?)
• Output from the model
• (into semantic connector, UML loader, HL7
  message specifications, etc)
• How do we construct good models that capture the
  domain expertise and can be used to drive
  application and message interchange development?

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Discussion questions

• How do we work with VCDE ?
• Identification of best of breed coded concepts
  (SNOMED, etc)
• Development of new enumerated lists and code sets
• Setting Priorities for development?
• Best practice for model and terminology
  development
• How do we work with groups outside of caBIG?
• HL7 defined value sets? caBIG defined value sets?
  Others?
• Input into the model
• How do we develop harmonizable models?
• Output from the model
• How do analysis models flow into caBIG tools?
• Constrained models

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Douglas B. Fridsma fridsma_at_cbmi.pitt.edu www.BRIDG
project.org
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The goal Constructing Harmonizable Models

• Semantically robust static and dynamic
  representations of the problem to be solved
  described in an implementation-independent way.

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Static Portions of the Model

• UML class diagram
• Documentation of each class and all attributes
• Bound to data types
• Candidate terminologies identified
• Other attribute value sets
• OCL business rules (could be structured text with
  OCL equivalence) For example, person class and
  credit card class the person class might have a
  gender (MF) and the credit card class would have
  Mr/Mrs, there needs to be a rule that helps to
  disambiguate how the credit card class would
  manage this.

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Dynamic Portions of the Model

• Process flow
• story boards
• Scenarios
• Use cases
• Text UML activity diagrams
• Links to static structures
• Interaction diagrams (?)
• Sequence diagrams
• Collaboration diagrams (UML 2.0)

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Examples

• Model A with entities and roles combined
• Model B with separation across moods
• Study as higher-level concept
• Protocol as higher-level concept

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Interchange Standards Long-term Desired
Outcomes

• A holistic approach to standards, facilitating
  data interchange from sites through regulatory
  submission, utilizing XML
• Standards for data acquisition supporting the
  population of a cross-trial warehouse within FDA
• HL7-CDISC models harmonized to yield value for
  both clinical research and healthcare sharing
  of information between EMR and clinical trials
• Global adoption of CDISC data standards

CDISC Meeting with FDA Commissioner, April 2003
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Biomedical Research Integrated Domain Group
(BRIDG) Model

• A domain analysis model that reflects the domain
  space of clinical/biomedical research using
  language domain experts comprehend
• Follows the HL7 Development Framework (HDF) led
  by HL7 RIM expert
• Initiated in January 2004 by CDISC Board
• Developed through numerous modeling and vetting
  sessions with domain experts from CDISC, FDA, and
  NCI/NIH
• Is being adopted by the HL7 Regulated Clinical
  Research Information Management (RCRIM) Technical
  Committee and implemented at NCI
• Now posted on an open website
  www.bridgproject.org
• A means of bridging together the clinical
  research standards within CDISC and between CDISC
  and HL7 (towards interoperability)
• Has also bridged organizations

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CDISC and HL7Why BRIDG?
Domain Anaysis Model or Problem Space Model (a la
HDF)
Level of Abstraction
RIM
ODM
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The BRIDG Model

• What is it? A collaborative effort between CDISC,
  HL7, caBIGTM, NCI, FDA, and Industry to produce
  one common, shared data exchange standard
• Vision Create a domain analysis model for the
  clinical research domain to harmonize clinical
  research standards among each other and to
  harmonize standards between clinical research and
  healthcare
• Key Goal Define a structured computable protocol
  representation that supports the entire
  life-cycle of clinical trials protocol to achieve
  syntactic and semantic interoperability

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Why BRIDG?

• Reduce costs eliminate duplication of effort
• Facilitate data sharing
• Help to speed delivery of innovative solutions to
  the patient based on research
• Improve the efficiency and timeliness of data
  reporting
• Enhance patient safety during clinical trials
• Improve the shared care of patients

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Protocol and the Semiotic Triangle
Symbol Protocol
Source John Speakman/Charlie Mead
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The Communication PyramidCommunicating
complexity is HARD

• How do you link the people who know about
  clinical domain (domain experts) with the
  technology implementers who will develop tools to
  support clinical work so that we have semantic
  interoperability?
• The Problem Space (Domain Space)
• A structured way to describe and document the
  information requirements of a particular area of
  interest
• What
• Discovered through Analysis
• The Solution Space (Implementation/Technical
  Space)
• How
• Discovered through Design
• One Problem ? Many Solutions
• The domain analysis model BRIDG is a bridge
  between domain experts and technical experts

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The Communication Pyramid

Domain Experts
Technical Experts
Communication
Source Charlie Mead, MD, HL7
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The BRIDG model update How do I get involved?
Douglas B. Fridsma, MD, PhD Center for Biomedical
Informatics Center for Pathology and Oncology
Informatics University of Pittsburgh
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Update on activities since last meeting

• New URL for the BRIDG project
• www.BRIDGproject.org
• Active participation from CDISC, pharmaceutical
  companies (GSK, Lilly, others), and industry
  (Fasttrack, Digital Infuzion, Oracle), caBIG
  (COH, UPMC, MSKCC, and others)
• Committing real resources and time to the effort
• A true collaboration with the various
  stakeholders in the effort

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Technology

• Still working on access control, roles, and
  supplemental tools to assist in the development
  effort
• CVS repository open up the process to other SIG
  and project leads, while protecting the trunk
  of the CVS tree
• CVS_ACL vs subversion vs. other
• Parallel HTML pages to augment those in gForge
  for individual subprojects
• Sig and project maintained
• PHP and wiki features to integrate into gForge
  for collaborative authoring of the model
• Novel methods of disseminating the model
• Trackers, Web pages, and downloads
• Supporting subproject development with mailing
  lists, document management, and CVS access (TDM,
  eDCI)

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Processes

• caBIG testing subproject coordination and
  harmonization processes with eDCI, and TDM. Will
  harmonize caERS when it is ready.
• HL7 multiple proposals about how to use BRIDG
  for message specification.
• Harmonization of existing message specifications
• Model management project at HL7
• Development of new messages
• CDISC harmonization of glossary with vocabulary
  and definitions in the model

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Ways to participate

• HTML view of the model
• www.bridgproject.org/model
• Updated ever 110-14 days represents the current
  active model
• Trackers
• Modeled after HL7 Harmonization forms
• Useful for smaller comments, definitions,
  suggestions
• Download the model from the CVS repository or
  file release
• file release
• CVS repository
• DBMS implementation (pending and testing)
• Active model development in subprojects

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How do I create an application based on BRIDG?

• We have checked in the original version of the
  BRIDG model to the CVS trunk, and created a
  released that version of the model.
• The trunk represents the released version of
  the model, and may be tied to requirements
  traceability.

Version 1
BRIDG trunk
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How do I create an application based on BRIDG?

• The Harmonization branch is similar to a bug
  fix it allows developers to break the model,
  fix things that need to be changed, and maintain
  versioning control while they do it.

Version 1
BRIDG trunk
Version 1
V 1.1
Harmonization branch
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How do I create an application based on BRIDG?

• When a team begins a new project to develop a
  message or application, they would check out the
  most recent version of the model that is
  currently developed. Typically this is the
  Harmonization branch.

Version 1
BRIDG trunk
Version 1
V 1.1
Harmonization branch
eDCI development branch
eDCI 1.1
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How do I create an application based on BRIDG?

• New projects will begin in the same way
  checking out the current version of the model
  from the harmonization branch
• We now have three versions of the model, all
  working in parallel.
• Although EA helps with synchronizing models,
  there is no substitute for good coordination and
  collaboration.

Version 1
BRIDG trunk
Version 1
V 1.1
V 1.2
Harmonization branch
CAERs development branch
caERs 1.1
eDCI development branch
eDCI 1.1
eDCI 1.2
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Support for subprojects

• Developing php-based webpages that can be
  maintained and customized by subproject leads
• Limitation in gForge with project and subproject
  descriptions
• Developing less error-prone CVS access controls
• check-in to CVS grants root access to the entire
  CVS tree
• Subproject leads need flexibility in organizing
  the CVS tree to fit their needs
• CVS root needs to be protected from inadvertent
  check-in
• Parallel constructs with documents, webpages, cvs
  repository, etc
• TROVE map is too high-level, but need an
  ontology to help organize and find information
  on the gForge site.
• Improved search capabilities?

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How do I create an application based on BRIDG?

• Development can continue on both of these
  branches, using the master-replica features of
  Enterprise Architect

Version 1
BRIDG trunk
Version 1
V 1.1
V 1.2
Harmonization branch
CAERs development branch
eDCI development branch
eDCI 1.1
eDCI 1.2
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How do I create an application based on BRIDG?

• New projects will repeat the process of checkout,
  modeling, etc.
• As the development continues, there will be
  periodic new releases of the model.
• The arrow from version 1 to version two
  represents some vetting of the model from
  stakeholders in the project and incorporation of
  harmonization branch changes.

Version 1
Version 2
BRIDG trunk
Version 1
V 1.1
V 1.2
V 1.3
Harmonization branch
CAERs development branch
caERs 1.1
caERs 1.2
eDCI development branch
eDCI 1.1
eDCI 1.2
eDCI 1.3
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How do I create an application based on BRIDG?

• As a development branch matures, it can be merged
  with the harmonization branch (using
  master-replicas)
• The model then can be vetted with the
  stakeholders, and a release generated

Version 2
Version 3
BRIDG trunk
V 1.3
V 1.3
V 1.3
Harmonization branch
CAERs development branch
caERs 1.2
caERs 1.3
caERs 1.4
eDCI development branch
eDCI 1.3
eDCI 1.2
eDCI 1.3
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HL7 Model management processes for vetting
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How do I create an application based on BRIDG?
Version 3
BRIDG trunk
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How do I create an application based on BRIDG?

• A portion of the BRIDG model will need to be
  annotated and modified for the constraints of the
  semantic connector and UML loader
• Future releases may accept a broader range of
  relationships

Version 3
BRIDG trunk
Annotated model
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How do I create an application based on BRIDG?

• The output of the processes related to the
  semantic connector and UML loader will be used
  for application development

Version 3
BRIDG trunk
Annotated model
Semantic Connector
UML Loader
caCORE tools
Application
Application Module
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Other issues

• GREATLY simplified, but a lot of people are
  working on the processes
• NCICB with the processes around the UML loader
  and semantic connector
• HL7 with regard to using the model for message
  development
• BRIDG group working on processes that touch on
  BRIDG
• Input/outputs
• Versioning
• Harmonization
• Collaboration and coordination
• Adopters/developers trying to figure out what it
  means for them

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Technology and Processes

• Technology and process go hand-in-hand
• Features in EA for synchronization
• Features of CVS repository and gForge
• Vertical vs Horizontal project integration
• CVS vs subversion and branch-level access
  controls
• The best way to move forward is to start seeing
  what works, (and what doesnt) and have the
  flexibility to adapt to new requirements to the
  process and technology

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Current ongoing project

• eDCI message
• Participants Oracle, caBIG, CDISC and others
• developing an HL7 message that describes
  electronic data collection instruments (case
  report forms)
• Clinical Trial Registration message project
• Participants caBIG, CDISC, HL7, Eudract,
  clinicaltrials.gov, PDQ
• Developing a clinical trial registration message
• Adverse events application development
• Participants caBIG, COH
• Developing an adverse events reporting system
• Trial Design modeling
• Participants caBIG, CDISC, FastTrack, others
• Extending the trial design portions of the model
  in BRIDG
• Statistical modeling extensions
• Participants CDISC, Eli Lilly, other pharma,
  FastTrack
• Extending the statistical modeling portions of
  the model

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Clinical Research Back Office The motivation for
integration
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