# Presentation: 241517

## Opportunities, Challenges, and Risks with The Cancer Biomedical Informatics Grid (caBIGTM)The GOOD, the BAD, and the UGLY

- J. Robert Beck
- Fox Chase Cancer Center
- Philadelphia, Pennsylvania

## Vision:  GOOD

- “When I look into the eyes of a patient losing the battle with cancer, I say to myself, It doesn’t have to be this way.”*The Nation’s Investment in Cancer Research* (2003)
- “Nearly every facet of NCI’s strategic plan to eliminate suffering and death due to cancer is predicated on the revolutionizing potential of caBIGTM.”*Cancer Bulletin, 2005* ** **

**NCI 2015 challenge goal:  eliminate suffering and death due to cancer**

- A.C. von Eschenbach, M.D.Former Director, National Cancer Institute
- Director, Food & Drug Administration

**Notes:**
   caBIGTM is a direct response to both the opportunities and the challenges facing the cancer community.  As Dr. von Eschenbach reminds us, we’re doing this for patients with cancer and those who help them. 

The promise of caBIGTM is to accelerate progress in all aspects of cancer research -- including etiologic research, prevention, early detection and treatment. 

We believe that caBIGTM will help redefine how cancer research is conducted, and eventually, how cancer care is provided.

  [The NCI leadership has clearly and repeatedly confirmed its vision of interoperable informatics infrastructures.  

The Nanotechnology and Clinical Trials initiatives, among others, require interoperability, based on caBIG compatibility—which I’ll talk about later.]

## Scenario, 2009

- 	A researcher involved in a phase II clinical trial of a new molecularly targeted therapeutic for brain tumors observes that cancers derived from one specific tissue progenitor appear to be strongly affected.  The trial has been generating proteomic and microarray data.  The researcher would like to identify potential biochemical and signaling pathways that might be different between this cell type and other potential progenitors in cancer, deduce whether anything similar has been observed in other clinical trials involving agents known to affect these specific pathways, and identify any studies in model organisms involving tissues with similar pathway activity.

- Small Molecules

- Cell Type

- Pathways

- Clinical Trials

- Therapeutics

- Animal Models

- Homologous Proteins

- Michael Ochs, 2005

## Today vs 2009?  UGLY

- 	In 2006 such a study would involve immense manual work getting information locally and from other sites, precluding the possibility of identifying the required data and thus being unable to deduce the likely significance of the trial observation.
-  However, with caBIGTM compliant components now under development, the researcher would be able to perform the analysis routinely, with data flowing through systems and analysis being automatic.
-  This analysis will yield biomarkers and potential drug targets gathered from multiple workspaces and make it possible to develop treatment modalities faster, less expensively, and more effective for patients.

## Clinical Trials Database

- Pathology
- reports

- Discrete and manual annotation on tissues

- Mutation
- identification

- Gene expression profiling

- Analysis

**Potential Drug Targets and Biomarkers**

- Clinical Trials Tumor Samples

- 400 brain tumor tissue samples acquired

- caArray

- FunctionExpress

- Gene
- annotation

- Gene
- Pattern

- Promoter
- DB

- Pathways
- Tool

- caTissue

- caTIES

- Clinical Annotation Modules

- Proteomics LIMS

- Q5

- PIR

- Annotation

- Discovery utilizing caBIGTM
- Integrated Cancer Research Tools

- Identify up-regulated genes in specific pathways

- TrAPSS

- Identify recurring promoter elements

## Thinking about a Solution

***   ***A virtual web of interconnected data, individuals, and organizations redefines how:
- research is conducted
- care is provided
- patients/participants interact with the biomedical research enterprise

## So, caBIG Launched

- Leverage NCICB expertise into community
- Build a cadre of interconnected informatics researchers, developers and adopters
- Engage biomedical and clinical research communities
- Engage patient advocacy community
- Build a world wide web for cancer research and treatment

## From the caBIG Strategic Plan, 2005

***Vision: ****“caBIG will become a self-sustaining network, which will foster improvements in collaborative projects and increase the speed and efficacy of treatment to benefit patients.” *
***Mission: ****“caBIG participants will develop readily disseminated standards tools and information systems for the management of clinical and research activities in oncology. These will include systems for the management of cancer clinical trials, standards for integrative research systems, a coherent approach to biospecimen informatics management, and the underlying architectures, vocabularies and data elements that will facilitate sharing and access to these systems.”*

## caBIG Commencement, 2004

- Original idea:  10-12 pilot sites at $500K/yr/site
- That dog would not hunt...BAD
- 41 lucky winners!
- Each with developer, adopter, or member role in workspace
- All modestly funded:  UGLY

## “Two hundred thousand dollars is a lot of money. We're gonna have to earn it.”

- Blondie:  *The Good, the Bad, and the Ugly*

## So, the caBIG community began to take shape...

## GOOD caBIG principles

- Open source
- Open access
- Open development
- Federated

## and we quickly learned....

## This isn’t Rocket Science

- A lot of caBIGTM isn’t even computer science
- Most industries did much of this years ago
- But it is hard to achieve – it takes time
- caBIGTM’s goal (oversimplified): facilitate the exchange of data useful for cancer research and care
- Between research domains, systems, investigators, and organizations
- For instance, the caBIGTM compatibility of a system is determined by how easily the system can exchange data  (i.e., interoperability)

**Notes:**
It’s important to remember that the kind of transformation involved here is not unique to biomedicine. 

 Lessons from other industries suggest we need to be patient.  Technology is only part of the equation.  

Creating the capacity to exchange data is hard enough; getting people and organizations to actually share the data requires more than IT. 

## Architecture

- Conceptually, caBIG has adopted two primary guiding principles:
- To bring systems on-line quickly, caBIG is committed to a “**bias for action**.” This implies a commitment to making decisions and moving forward, even if perfection cannot be achieved.
- To allow long-term evolution and improvement of architectural design, caBIG is committed to “**designing for change**.”
- To turn these thoughts into action, caBIG has also adopted a two-pronged practical approach:
- If requirements are well-understood and good solutions are available, caBIG initiates developmental activities within the architectural workspace.
- If requirements are less clear or if solutions are not yet available, caBIG commissions analysis and assessment activities.  This can get UGLY

## caBIGTM Compatibility Guidelines

- The caBIGTM compatibility guidelines are designed to insure that systems designed in a Federated environment are still interoperable on the caBIGTM Grid, both syntactically and semantically
- Since achieving interoperability is a process, caBIGTM recognizes four levels of compatibility, starting from Legacy (not interoperable) through Bronze, Silver and Gold (fully interoperable)
- caBIGTM compatibility is all about _interfaces_ rather than the scientific content of the system

**Notes:**
The analogy is to a city
In cities architects are free to design buildings that perform myriad functions and that take many distinct forms
Nevertheless, all buildings in the city are required to conform to certain specifications in order to receive electricity, water, steam, mail, etc.

## caBIG Compatibility Guidelines

**SYNTACTIC**

**caBIG Compatibility Guidelines**

## Overall Goals for caBIGTMThree-year (mid-2008)

- Develop sufficient research tools and standards to have a positive impact on the cancer research community, as measured by adoption of relevant caBIG principles in project proposals.
- Ensure widespread adoption of developer standards so that funded developer projects are operating under the Gold standard of compatibility.
- Adopt and use caBIG interoperable tools and data sets within the caBIG community.
- Develop mechanisms for engaging and promoting caBIG compliant technologies and established datasets within the oncology research community.

## Overall Goals for caBIGTMFive-year (mid-2010)

- Ensure widespread adoption, dissemination, and use of caBIG interoperable tools, standards, and data sets within the larger cancer community, to include the biopharmaceutical industry, non-NCI cancer centers, and the national cancer research enterprise.
- Begin to see results of caBIG-compliant interdisciplinary and inter-institutional research affecting clinical oncology care.

## caBIG as a Shibboleth:  BAD

- Data sharing required in moderate or larger grants
- caBIG invoked in program projects, cancer center support grants, SPORE and related activities
- Software development projects claim “of course we will be caBIG compliant”

- Judges 12:4-6

## A Lot of Stuff Has Emerged...

- And much of it is based on standard tools and architectures

## caBIG Deliverables: Clinical Trials Management Systems

- Componentized, interoperable and standards-based Clinical Trials Management Systems, both purpose-built and commercial off-the-shelf to handle, in an automated fashion, many aspects of developing, managing, conducting, and reporting Clinical Trials

- Biomedical Research Integrated Domain Group Model (BRIDG)
- Adverse Events Reporting Tool
- C3D
- C3PR
- caBIGTM Compatibility evaluation for existing commercial tools
- Harmonization of UML Representations
- Ontological Representations and Data Elements for Clinical Trials
- Metadata Harmonization

## caBIG Deliverables: Tissue Banks and Pathology Tools

- Systematic description and characterization of tissue resources – tools to inventory, track, mine, and visualize tissue samples from geographically dispersed repositories, with an ability to link tissue resources to clinical and molecular correlative descriptions

- caTISSUE Core
- caTIES
- caTISSUE Clinical Annotation Engine
- caTISSUE Experimental Annotation Engine
- Requirements Specifications Survey and Results
- Federated Tissue Data Set White Paper

## caBIG Deliverables: Integrative Cancer Research

- caArray
- caWorkbench 2.0
- GenePattern
- Gene Ontology Miner (GOMiner)
- Protein Information Resource (PIR)*
- RProteomics*
- Pathways Tool Development
- Tools Distance-Weighted Discrimination
- Magellan
- Visual and Statistical Data Analyzer (VISDA)
- Cancer Molecular Pages

- The ICR Workspace seeks to provide for the development of a “Plug and Play” analytic tool set, suitable for a variety of experiemental methodologies, including microarrays, proteomics, biological pathways, data analysis and statistical methods, gene annotation, et al.  It will also develop a diverse library of raw, structured data and facilitate the integration of different types of data.  All of these tools would help in integration of clinical and basic research

## caBIG Deliverables: Integrative Cancer Research (cont’d)

- Proteomics Laboratory Information Management System Prototype (LIMS) Prototype
- Q5
- TrAPSS
- Gene Connect
- Integrating Bioconductor and R into caBIGTM
- Reverse Phase Protein Lysate Array based data for caArray

- FunctionExpress
- HapMap, PromoterDB
- SEED
- NCI-60 Data Sharing
- Quantitative Pathway Analysis in Cancer (QPACA)
- Reactome (GKB) Data

## caBIG Deliverables: Architecture

- caBIGTM Compatibility Guidelines
- caGrid 0.5 Security White Paper
- caGrid Software Version 0.5
- caGrid – 1.0
-  Technology Evaluation White Paper
-  caBIGTM  - The Security White Paper (Technology Evaluation)
- Workflow Language Recommendations White Paper
- ID Management White Paper
- Common Query Language White Paper

- The Architecture Cross-Cutting Workspace provides for the development of the underlying standards used by the program, and ensures that common mechanisms are used throughout the caBIGTM community via mentoring, white papers and a structured review process.

## caBIG Deliverables: Vocabularies and Common Data Elements

- LexGrid
- CDE Governance Model
- VCDE Guidance Mentoring Teams
- Vocabularies Deployment Document
- Data Standards Approval Guidelines
- Procedures for the Review and Approval of New VCDE Content
- Mouse/Human Anatomy Ontology Mapping
- Nutrition Ontology

- The Vocabularies and Common Data Elements Cross-Cutting Workspace provides for the development of the underlying data elements and vocabularies used by the program, and ensures that common mechanisms are used throughout the caBIGTM community via mentoring, white papers and a structured review process.

## caGrid:  The Testbed

- The proof of the pudding

- Academic institutions (Ohio State, Georgetown)
- Industry (SAIC, Oracle, Panther, Terrapin)
- NCICB
- Booz Allen Hamilton

## “There are two kinds of people in the world, my friend. Those who have a rope around their neck and those who have the job of cutting.” 

- Tuco:  *The Good, the Bad, and the Ugly*

## Cancer centers (esp. directors) want tools, particularly for clinical research support 
Developers want to work on the large problem of the Grid and all it entails

- Developers want to work on the large problem of the Grid and all it entails

- Operational Challenges...tension between infrastructure and deliverables

- CONFLICT

## The Main Challenge Now

- Deliver enough tools to satisfy a growing and appropriately restive community, in the face of decreasing overall NIH budgets
- Reserve the bulk of time, money, and effort for the infrastructure projects that will truly execute the mission

## We Need to Stay Focused on the Vision for caBIGTM

- “...if you don't have a framework for a vision, nobody moves in a really new direction. Today there are genuinely new opportunities, but the new science will require interdisciplinary collaborations. That will be key.” **National Institutes of Health (NIH) director Elias Zerhouni, M.D., interviewed by Barbara Culliton for *****Health Affairs***

## Infrastructure – Today

- Standards for vocabularies and common data elements established and housed at NCICB

- Sample Applications

**Building on a foundation of established infrastructure points**

**+**

- NCICB housed infrastructure for CDEs, and vocabularies
- Grid reference implementations lead the way

- Compatibility guidelines and initial compatibility evaluation process for caBIGTM program projects established

- A rich set of harmonized standards and vocabularies is available

- A group of mentors has been identified to ensure consistency across key projects

## Infrastructure – Tomorrow

- Instantiated formal process for evaluation and harmonization

- Many applications Grid enabled (e.g., gene pattern, reactome)

- A compatibility evaluation process for caBIGTM program projects and a certification process for externally developed tools are established

- NCICB housed infrastructure for CDEs, and vocabularies

**Increased growth and interoperability of infrastructure, Easier to add**
**new tools, workflow support established**

**+**

- End user portal available, security infrastructure)

- A rich set of harmonized standards and vocabularies continues to grow in size

- Tooling available to provide site-specific vocabularies and ontology management and support

- Mentors actively working in caBIGTM Community and beyond to ensure consistency across key projects and adherence to caBIGTM goals

- API’s with common interfaces facilitate scientific workflows

## Infrastructure – The Future

- Multiple sites host portions of the federated,
- scaleable, standards-based infrastructure

- Functional applications part of standard practice/fully deployed on GRID

- NCICB housed infrastructure for CDEs and vocabularies

**Broad adoption and independent support, across and beyond the**
**cancer research community; increased growth and interoperability**
**of infrastructure; easier to add new tools (data and services);**
**workflow support expanded; greater interconnectedness, and automation**

**+**

- Developed standards increase in number; mechanisms exists for community to develop and harmonize standards and compatibility guidelines

- Certification process for externally developed tools

- A rich set of community developed harmonized standards and vocabularies continues to grow

- Tooling available to provide site specific vocabularies and ontology management and support

- Mentors actively working in caBIGTM Community and beyond to ensure consistency across key projects/adherence to caBIGTM goals

- Vocabulary services are federated

## caBIGTM Tools – Today

**caBIGTM Tools – Today**

- TBPT

- CTMS

- ICR

## caBIGTM Tools – Tomorrow

**caBIGTM Tools – Tomorrow**

- TBPT

- CTMS

- ICR

## caBIGTM Tools  – The Future

**caBIGTM Tools  – The Future**

- TBPT

- CTMS

- ICR

## “If caBIGTM accomplishes its mission and creates a robust grid for translational and clinical research, within the cancer community, it will be deemed a failure.”

- Bob Robbins (Fred Hutchinson Cancer Research Center), at the initial Strategic Planning Workspace meeting

## “Prevention is Better than Cure”

- --Desiderius Erasmus (1466-1536)

- Embedding caBIGTM in the larger biomedical research community

## Embrace the Larger Community

- Biomedical Informatics Research Network (BIRN):  launched in 2001 by NIH, same concept, neurological disorders, smaller scale
- National Center for Biomedical Ontologies: Roadmap project drawing medical informatics expertise
- HealthgridTM: International (Europe-based) project developing standards for information sharing, very present here at AMIA 2006

## “When I'm paid, I always follow my job through.”

- Angel Eyes:  *The Good, the Bad, and the Ugly*