MAGNet Center: Andrea Califano

NCIBI: Brian Athey

Simbios: Russ Altman

Creating a DBP Community to Enhance the NCBC Biomedical Impact

NCBC Work Group Report, 18 July 2006

Workgroup Goals Problem: The NCBCs have no workgroup to help build the DBP community

Goal 1: To determine the Mission and Goals for the Applications of Systems Biology, Modeling and Analysis Working Group

Goal 2: To determine how this group would interact with the 2 other NCBC Working Groups to define key sets of: Data Tools Methodologies Ontologies DBPs

Goal 3: Identify NCBC DBPs that are highly motivated to participate in the Working Group

Goal 4: How to link to external communities (e.g., DREAM-like activities)?

Additionally: Discuss as a focused example “Molecular Interaction Maps” in the context of the DBPs

DBP Success Depends on the Availability of an Integrated Resourceome (Not a priority for Core I/Core II Projects)

Integrated Computational Biology Platform Support for gene expression data, physics-

based simulations, image analysis, sequences, pathways, structure, etc. (40+ visualization and analysis modules).

Access to local and remote data sources and analytical services.

Support for workflow scripting. Integration with grid infrastructures.

Development framework Open source development. Modular/extensible architecture, supporting

pluggable components with configurable user interface.

Easy integration of 3rd party components.

…

The integration process must be driven by the DPB requirements rather than by Core I/II activities.

We Must Work With the “Yellow Pages” WG to Assemble an Indexable List of Most Useful Tools and Platforms Many Toolkit and platforms

Internal SimTk Genopia VTK/ITK Brainsuite geWorkbench GenePattern MiMI SAGA miBLAST MarkerInfoFinder

External GenePattern Systems Biology Workbench myGRID Cytoscape and ISB tools

How do we make these tools interoperable? This must be DBP-driven because other cores (I/II) do not necessarily depend on tool interoperability.

GenePattern/geWorkbench Interoperability:An Opportunity and a Starting Point

KNN

WV

SVM

SOM

GSEA

ARACNE

SPLASH

PCA

GenePattern Module Repository

Wrap geWorkbench Wrap geWorkbench modules as modules as GenePattern tasksGenePattern tasks

Execute GenePattern Execute GenePattern modules from within modules from within geWorkbenchgeWorkbench

Interactions with the Scientific Ontology Working Group

@Publish public DSDataSet publish(. . .) { DSDataSet dataSet; // do some work that assigns a value to dataSet. return dataSet;}

@Subscribe public void receive(DSDataSet dataSet, Object source) { // Consume the argument dataSet, as appropriate}

Provide re-usable models of common bioinformatics concepts: Data: sequence, expression, genotype, structure, proteomics Complex data structures: patterns, clusters, HMMs, PSSMs, alignments Algorithms: Clustering, matching, discovery, normalization, filtering

Provide a foundation for the development of interoperable geWorkbench components Endorsed by multiple communities (caBIG, AMDeC, NCBCs)

Component A

Component B

Identifying Specific Tools

There are tools, databases, and methods that have universal value across different DBPs. What are they? Which NCBC or external community is producing them What can we do to standardize their use across the

community.

An Example: Molecular Interaction Maps

A Relevant Example That Was Discussed

Molecular Interaction Maps are becoming the equivalent of an anatomy atlas to map specific measurements in a functional context; e.g. QTLs, expression profiles, etc.

Discussion Goal: To determine how relevant these maps are to the DBPs of the various NCBCs

Limitations: Many Interactomes are limited because they are (1) too generic (e.g. missing cellular and molecular context), (2) poorly annotated (e.g. linked only to the specific data used to produce them), (3) limited to pairwise interactions, (4) lacking quality control/validation, and (5) not associated to the investigation of specific biological/biomedical problems.

Example: From Molecular Interaction Maps to Molecular Interaction Knowledge Bases

What does it take to turn a ridiculome into a relevantome? Quality control metrics (recall/precision) Context specificity

Cellular: Is the interaction specific to a cellular phenotype Molecular: Is the interaction dependent on the availability of

other molecular species Links to data (and literature) Links to analysis of biomedical problems Focus on specific features (e.g. mechanisms)

A Potential Template for NCBC Knowledge Bases:MAGNet Human B Lymphocytes Dataset Integrative Framework

Bayesian Evidence integration of pairwise interactions Protein-Protein, Protein-DNA Prior Knowledge Incorporation

Context Specific ARACNE, GeneWays, REDUCE

B-Cell data or B-cell specific criteria Linked to one of the largest B-Cell expression profiles microarray dataset, ChIP-

Chip assays (MYC/BCL6), miRNA profiles, and Literature

Captures Multi-variate dependencies Three-way interactions via MINDY and MATRIXReduce

Post-translational modulation of transcriptional regulation Combinatorial transcriptional regulation Signal transduction control of Transcriptional Regulation

I.e. the Transferome meets the Transcriptome

Links to literature (via GeneWays, NCIBI, I2B2, GATE, etc.)

Other examples? Oncomine (NCIBI), GenePattern ALL/AML, Others?

Example

Some Key Observations from Attendees:

Systems Biology name is too narrow. Think of Alternatives: “Working group to Biomedical Impacts of Computational Biology

at NCBCs” or NCBC Biomedical Impact Workgroup

Is the intramural program a better place to create atlases and knowledge bases, since it’s not RO1 funding? They could implement contract mechanisms with extramural researchers to leverage outside expertise

Keep in mind that we need to understand what will you deliver at the end of 4 years, positioning each NCBC for renewal. Which communities are using the tools? Are they better off?

Individual centers can work to create a specific resourceome that can be linked and accessible to others

Many working group members had a strong interest in “multi-scale” modeling and biological context

Outcomes:

Create a DBP community within the NCBCs: ACTION: Make an interactome map of the existing DBPs with

potential synergies to be published in Symbios magazine Use this forum to inform target biological communities (not

just NCBCs). E.g. DREAM meeting. Organize a coordinated effort to evaluate the tools and

technologies and make them interoperable ACTION: Coordinate the DBP requirements to drive the

integration of specific tools and data resources Integrate data and annotation in knowledge bases and

models for related DBPs. Identify other common tools, data, and methods

Drop the Systems Biology name: Use something like: “NCBC Biomedical Impact Workgroup”

Commit to a regular T-con and virtual (Wiki) participation Consider a yearly retreat of NCBC DBPs possibliy in

collaboration with other NIH roadmap activities (e.g. ICBPs)

NCBC DBP Interactome I: Useful Starting Point

Peter Woolf, NCIBI

Distribution Model: How Can the 7 NCBCs Effectively Interoperate?

Informatics for IntegratingBiology and the Bedside (i2b2)Isaac Kohane, PI

Center for Computational Biology(CCB)Arthur Toga, PI

Multiscale Analysis of Genomicand Cellular Networks (MAGNet)Andrea Califano, PI

National Alliance for MedicalImaging Computing (NA-MIC)Ron Kikinis, PI

The National Center ForBiomedical Ontology (NCBO)Mark Musen, PI

Physics-Based Simulation ofBiological Structures (SIMBIOS)Russ Altman, PI

National Center for Integrative Biomedical Informatics (NCIBI) Brian D. Athey, PI