The External Advisory Committee report for the National Resource for Network Biology 2011

2. Systematic mapping of genes
Cost of human genome
sequencing versus time

3. Systematic mapping
of molecular interactions
andmolecular profiles
Metabolic networks
mRNA & protein
expression
Genetic and protein
interaction networks
Transcriptional networks

4. National Resource for Network Biology:
Mission
To provide freely available, open-source software
technology that broadly enables networkassembly,
analysis, visualization and network-based biomedical
discovery for NIH-funded researchers.
These tools are enabling researchers to assemble large-
scale biological data into models of networks and
pathways and to use these networks to better
understand how biological systems operate under
normal conditions and how they fail in disease.

5. Components of the Network Resource
• Technology Research & Development (TRD)
• Driving Biological Projects (DBP)
• Collaboration and Service (CSP)
• Training
• Dissemination
• Administration
• Core infrastructure (Cytoscape, Supercomputing)

6. Assembling and Using Networks in Biomedicine
Network-based disease
Genes and gene functions
The Working Network Map diagnosis, prognosis, and
stratification
Physical interactions Network-based prediction of
cell fate; regenerative medicine
Genetic interactions Network-based rational
drug design
Gene / proteinexpression
Network wide association
studies (NWAS)
Advanced
Network
Visualization
Assembly of molecular networks Network based applications
via data integration to disease

7. National Resource for Network Biology
Faculty
PI: Trey Ideker Exec. Director: Alex Pico Gary Bader Mike Norman
UCSD Medicine & UCSF / Gladstone U Toronto Donnelly Ctr Director, SDSC
Bioengineering for Mol&BiomolRsrch
Chris Sander James Fowler BennoSchwikowski Chairman of External
Director Bioinformatics UCSD Medicine / Systems Biology Advisory Council:
@ MSKCC Social Sciences Institut Pasteur Stephen Friend,
Sage Bionetworks

8. Our flagship tool: Shannon et al. Genome Research 2003
www.cytoscape.org Cline et al. Nature Protocols 2007
OPEN SOURCE Java platform for
integration of systems biology data
•Layout and query of networks
(physical, genetic, social, functional)
•Visual and programmatic
integration of network state data
(attributes)
•The ultimate goal is to provide
tools to facilitate all aspects of
network assembly, annotation, and
use in biomedicine.
RECENT NEWS
• Version 3.0 due July 2011
•Cytoscape ® Registered Trademark
• The Cytoscape Consortium is a 501(c)3 non-for-profit in the State of California
•Centerpiece of the NCRR-funded National Resource for Network Biology
Downloaded approximately 3000 times per month

9. Agenda
08:30 Introductions, overview and organizational structure of NRNB (Friend, Ideker)
08:45 EAC roles, goals, and responsibilities (Pico, Ideker)
09:00 Discussion of technology projects and matched driving biology (Ideker)
10:00 Break
10:15 Progress in Cytoscape 3.0 (Smoot)
10:40 Collaboration, Training, and Service (Bader, Pico)
11:30 EAC recommendations, formulation and review of NRNB policies (Pico)
12:15 Summary (Friend)
12:30 Lunch

10. EAC roles, goals, and
responsibilities

11. EAC goals and responsibilities
 Feedback on technology we’ve been
working on over first 8 months
 Advice on administrative structure
 Vision and guidance for future years
 Short written report
 Two-way discussion
•Not a presentation of annual report
• We are prepared to listen!
We will report back next year!

12. Technology Projects
Questions:
How are we doing? Strengths and weakness?
Where would you want to see these projects in several
years?
Are there key network tools that we should be
developing yet are not?
Are there network tools we are developing which are
not so exciting?

13. TRD Project A: Network-based biomarkers for
diagnosis and personalized therapy
Bandyopadhyay et al. Science (2010)

14. Visualizing and Analyzing Cancer Genomic Data in the
Context of Biological Pathways and Networks
• Algorithm Development
• Adding Network Visualization and Analysis to the cBio Portal.

15. Pathway Commons

16. TRD Project B: How Do Genes
Affect Behavior?
Genes Behaviors
Dopamine Health
Serotonin Happiness
Cooperation
Politics
?
Social
Networks

18. TRD C: Visualization and Representation
of Biological Networks
Cellular
semantics
Interactome
Meaningful modules
Exons to protein domains Complex data views
PIs: Bader, Conklin, Pico

19. Simplified Network View: Thematic Map
Protein-protein Module-module interactions
interaction network

20. Simplified Network View: Enrichment Map

21. Visualizing Complex Data
Multiple timepoints
viewed simultaneously
Nested metanodes
Striped nodes Pie chart nodes
SPIDs: 23 (Wrensch, CSP), 34 (Fletterick), 38 (Ferrin), DBP (Mercola)

22. TRD D: Cytoscape network inference
Mission: Interface Cytoscape with the network inference community

23. Example inferred regulatory network
DBP: Van Dijl laboratory
•Network induced by pathway search in 418 genes
• Transcriptome experiments of selected knockouts underway

24. Dynamic management of TRDs
TRD projects
•These projects should present compelling research and
development opportunities for NRNB.
• TRDs should be coupled to new or existing DBPs.
• They should represent significant improvements to critical
tools and resources for the research community.
• We would provide (or fund) developer time to develop or
enhance a novel tool or resource, defining a 2-5 year TRD
project.
• They should be assessed competitively each cycle with
other new proposals and proposals for continuation of
ongoing TRD projects.

25. Infrastructure report:
Cytoscape 3.0 and SDSC
access
Mike Smoot

26. Functional Overview
• Milestone 2 release just completed.
• All core plugins except "Advanced Network Merge" have
been ported.
• Cytoscape 3 is functional, but there are lots of bugs and the
code hasn't been tuned for performance.

27. Why we needed to redesign the API!

28. 3.0 Package Dependency Graph

29. Architecture Status
• Still using OSGi for modularity.
• Still using Spring-DM to configure modules.
• Still using Maven to build and pull everything together.
• We now have a "simplified" plugin API.
o You only need to know basic Java.
o Just like in 2.X, you extend a single abstract class.
• So far, everything is behaving as planned.
o The application starts correctly, services get registered,
APIs are public, implementation is hidden, plugins start,
etc..

30. Documentation Status
• Lots of documentation written on the Wiki:
o Overview of the Architecture
o Overview of the API
o Plugin Developer's Guide
o Plugin Porting Hints
• A Plugin Developer's tutorial has been added to
OpenTutorials

31. Next Steps
• Fix known bugs.
• Add missing features.
• Analyze and address performance bottlenecks.
• Re-evaluate API.
• Ensure that proper OSGi metadata is being published.
• Refactor build system to that development code - compile -
test cycle is faster.
• Refactor build system so that release generation is easier.
• Help plugin developers port plugins.

32. SDSC’s “Triton” Resource
http://tritonresource.sdsc.edu

33. Collaboration, Training and
Outreach

34. Collaboration and Training
• Collaboration and training
• Win win: collaborators learn network and pathway
analysis, we learn about community needs
• 37 Collaborations and service projects (CSP)
• Project management
– Services e.g. training, dissemination
– Target # of CSPs?
• Balance of R&D and collaborations

35. MHC-I Cell Projection
Microtubule Edge type (gene-set overlap)
& Cell Motility
Cytoskeleton Between gene-sets
Centrosome enriched in deletions
From disease genes
Membrane to enriched gene-sets
Between sets enriched in
Nucleolus deletions and in disease
genes or between disease
SMC flexible hinge domain Cell Motility sets only
(stricter cluster) Cell Proliferation
Urea and amine group metabolism Positive regulation of cell proliferation
Cell cycle Intellectual
Regulation of Disability Regulation of cell proliferation
hormone levels
Aminoacid Behavior
derivative /
amine Organ Morphogenesis
metabolism
Vasculature develepment
CNS Development Palate develepment
Glycosylation Autism Kinase Activity/Regulation
LIS1 in neuronal Heart develepment
Synaptic vescicle maturation migration and
development Regulation of GTPase
Reelin pathway RHO Ras Tyrosin kinase
Zoom of CNS-Development Adhesion
Carboxyl
Cell projection Neuron Zn finger esterase
organization migration domain
domain
Cell morphogenesis Kinase regulation
Cerebral cortex
cell migration Ras signaling GTPase regulator
Negative cKIT
regulation mTor pathway GTPase/Ras
Neurite development Cell Motility of cell cycle pathway Signaling Node type (gene-set)
(stricter cluster)
CNS neuron Enriched Known Enriched only
Brain in deletions disease genes in disease genes
differentiation
development 0% ID ID
Axonogenesis
CNS Projection neuron
development FDR ASD ASD
axonogenesis
12.5% Both
Pinto et al. Functional impact of global rare copy number variation in autism
spectrum disorders. Nature. 2010 Jun 9.

37. Collaboration Triage Workflow
NRNB site
Check information Discard if low quality
and process
If unrelated to
appropriately network biology
Collaboration General bioinfo / data processing
request
Web form input
•Request type
Development of tools
• General bioinfo / data processing
• Cytoscape training Scientific research collaboration Beginners
• Development of tools (ex. Plug-ins) Data provider Simple consultation by
• Scientific research collaboration
Cytoscape training E-Mail, giving some
• Data provider
•Contact info options of what they can
•Research proposal do (I & some graduate
•Publications students?)
Discussion in regular meeting - Recommendation of using
Discard if proposal is Web tutorial, Quick start
not appropriate for Work member guide.
collaboration or no assignment - Providing Cytoscape retreat
available human information
resource. Research Collaboration
Researchers, Cytoscape team,
Post-docs, graduate students
37

38. Services NRNB should provide to select CSPs
Organizational
•Impact: Measure impact of project - e.g. track relevant publications and
collaborations
•Interface: identify related resources, project and programs; facilitate new
collaborations; hold joint conferences
•Host: link to project download, documentation and tutorial pages from nrnb.org
•Advisory: provide recommendations and proposals to project leads regarding
technical development aims and organizational opportunities
Training
•Tutorials: prioritize, produce and promote tutorial materials; organize events
•Feedback: collect and organize feedback from training events to share with
developers
Community
•Events: organize, promote and staff lectures, tutorials and workshops
•News: highlight news items related to the project and project leads
•Communication: coordinate discussion lists, help desk, Facebook, Twitter, etc
•GSoC: support project ideas, mentors and students in annual Summer of Code
program sponsored by Google
•Retreat: organizing the annual retreat for project in conjunction with Cytoscape and
NRNB

39. Dynamic management of TRDs and CSPs
CSP projects
• The NRNB should continually engage in new Collaborative
and Service projects which should be highly relevant to
network biology and represent the “best in class.”
• They should have demonstrated stability and a designated
point-person for NRNB collaboration.
• There should be obvious and direct synergy with existing
NRNB projects.
• We should take on such projects as a long-term
commitment.
• We will commit to providing a set of services to the user
and development communities, ranging from organizational
to training to communications.

40. Training and Outreach
1. Launched new NRNB website
2. Redesigned Cytoscape website
3. Launched new tutorial system, Open Tutorials
4. Out training events, presentations and GSoC

41. 4. Handling requests for external
training events
What to do with requests for external training support?
 We send staff, our “Roving Engineer”
 We provide tutorial materials through OpenTutorials,
(including customizable online content, slideshows, and handouts)
 Proposal: Sponsor travel and accommodations for a
number of external personnel to attend the annual
Cytoscape Retreat. We would use the opportunity to
“train the trainers” and thereby multiply our outreach
capability with efficient investment of resources.

42. EAC Discussion

43. Acknowledgments: NCRR P41 RR031228
PI: Trey Ideker Exec. Director: Alex Pico co- PI: Gary Bader, U Toronto
UCSD Medicine / Bioengineering UCSF / Gladstone Donnelly CtrMol&BiomolRsrch
Chris Sander James Fowler BennoSchwikowski Chairman of External
Director Bioinformatics UCSD Medicine / Systems Biology Advisory Council:
@ MSKCC Social Sciences Institut Pasteur Stephen Friend,
Sage Bionetworks

44. Protein networks as
biomarkers of disease
Network guided
random forests
Dutkowski et al. submitted
Previous work:
Chuang et al. MSB 2007
Lee et al. PLoS Comp Bio 2008
Ravasi et al. Cell 2010