NRNB EAC Meeting 2012

National Resource for Network Biology

External Advisory Council (EAC) Meeting Wednesday December 12, 2012

NRNB Overview• An NIGMS Biomedical Technology Resource Center focused

on Network Biology• Research and develop new bioinformatic technologies to

enable the use of biological networks (molecular, genetic, and social) among NIH-funded investigators

• Collaborate directly with biological and clinical users to push the envelope of network analysis capabilities

• Distribute open-source network technologies to the greater scientific community

• Stimulate a portfolio of educational and outreach opportunities surrounding network biology

Overview Technology Software Collabs Outreach Plans

NRNB InvestigatorsTrey Ideker, PhDPrincipal Investigator, NRNBDepartments of Medicine and BioengineeringUniversity of California, San Diego

Dr. Ideker uses genome-scale measurements to construct network models of DNA damage response and cancer. He was the 2009 recipient of the Overton Prize from the International Society for Computational Biology.

Gary Bader, PhDAssistant Professor, Terrence Donnelly Centrefor Cellular & Biomolecular ResearchUniversity of Toronto

Dr. Bader works on biological network analysis and pathway information resources.

Alex Pico, PhDExecutive Director, NRNBGladstone Institute of Cardiovascular DiseaseStaff Research ScientistUniversity of California, San Francisco

Dr. Pico develops software tools and resources that help analyze, visualize and explore biomedical data in the context of these networks

James Fowler, PhDAssociate Professor, CalIT2 Center for Wireless & Population Health Systems and Political ScienceUniversity of California, San Diego

Dr. Fowler’s research concerns social networks, behavioral economics, evolutionary game theory, and genopolitics (the study of the genetic basis of political behavior). His research on social networks has been featured in Time’s Year in Medicine.

Chris Sander, PhDChair, Computational Biology Center,Tri-Institutional ProfessorMemorial Sloan-Kettering Cancer Center

Dr. Sander’s research focuses on Computational and Systems Biology of molecules, pathways, and processes.

Benno Schwikowski, PhDChef du Laboratoire/Group LeaderPasteur Institute

Dr. Schwikowski’s expertise lies in combinatorial algorithms for Computational and Systems Biology.


The National Resource for Network Biology:Integrating genomes & networks to understand health & disease

Patient genotypeGenome sequencing

1) How to assemble and visualize network models of the cell?

2) How to use networks in healthcare?

PhenotypeDisease diagnosis

Response to therapy/drugSide effects

Developmental outcomeRate of aging, etc.

Gene expression & other large scale molecular state measurements

NIH NCRR / NIGMS P41 GM103504

Draft Network Assembly

Representative Publications:Dutkowski et al. A gene ontology inferred from molecular networks. Nature Biotech. (2013) [cover]

Rügheimer et al. Applications of Intelligent Data Analysis for the Discovery of Gene Regulatory Networks. Computational Intelligence in Intelligent Data Analysis (2013)

R Saito et al. A travel guide to Cytoscape plugins. Nature Methods (2012)

Cerami et al. The cBio Cancer Genomics Portal. Cancer Discovery (2012)

Morris, S. et al. ClusterMaker: multi-algorithm clustering for Cytoscape. BMC Bioinformatics (2011)

Ideker, T. et al. Boosting signal-to-noise in complex biology: prior knowledge is power. Cell (2011)

Dutkowski et al. Protein networks as logic functions in development and cancer. PLoS Comp Bio (2011).

Fowler et al. Correlated genotypes in friendship networks. PNAS (2011)

Bandyopadhyay and Ideker. Integrated Systems Biology [Poster], Nature Genetics (2010)


Year 3 of 5 funded years, $700,000 per year direct + $175,000 supplement4 technology projects with matched driving biology20 NRNB-supported publications since start of fundingCytoscape used in ~250 pubs / year and has supported ~1400 NIH grants 96 collaborations with NIH-funded investigators (60 new this year)27 training events over 7 countries, 32 academic courses by NRNB staff16 Google Summer of Code Students = $80,000 invested by Google

NRNB statistics ‘at-a-glance’

NIGMS, 354

NCI, 205

NCRR, 110

NIAID, 103

NHLBI, 88

NIDDK, 88

NIEHS, 62

NHGRI, 58

NLM, 54

NIMH, 47

NINDS, 39

Wellcome Trust, 29

NIDA, 25

Canadian Institutesof Health

Research, 23 NICHD, 22

Ot

Use of Cytoscape by grantees. We have identified >1,400 grants acknowledged in publications citing a Cytoscape paper (Shannon P et al. 2003; Cline MS et al. 2007; Smoot ME et al. 2011). One pie slice represents the number of grants from a particular agency. NIH institutes are represented by standard abbreviations.


Year 1 Year 20

100

200

300

400

500

600

700

800

900

1000Supp-CrowdsourcingCollaboration OutreachAdmin-PicoAdmin-IdekerAdmin-Asst.Core Comp/SoftwareTRD-A-IdekerTRD-A-SanderTRD-B-FowlerTRD-C-PicoTRD-C-BaderTRD-D-SchwikowskiCo-I Salaries

$100

0s


NRNB Funding Allocation

Response to previous EAC critiques• Clearly articulate the link between funding and progress

See previous chart; all described work is directly funded by NRNB• Focus not only on network visualization but on network-based

analysis and decision makingExciting progress has been made for using networks as diagnostic biomarkers under TRD A

• Encourage increased citation of CytoscapeRefactored Cytoscape.org to encourage citation; perform systematic literature tracking

• Better track Cytoscape plugins and leverage developersDeveloped new Appstore (apps.cytoscape.org)

• Track use of Cytoscape in the classroomIdentified 32 courses using Cytoscape in 2011 - 2012


Agenda

• Progress on Technology Research & Dev.• Release of Cytoscape 3.0• Review of Collaboration and Service Projects• Progress on Training and Outreach• Plans for NRNB moving forward• Generate discussion and seek advice on all

aspects


Pico (UCSF)


Janusz Dutkowski et al PLoS Comp Bio 2011

TRD A:Protein networks as

biomarkers of disease Ideker group

Patie

nt E

xpre

ssio

n(o

r som

atic

mut

ation

) Networks (in various states of curation) Circuits Coupled w/ Decision Tree Logic


TRD A: Network Biomarkers (Ideker); DBP 2 (Kipps)Publication: Chuang et al. Blood (2012) [cover article]


TRD A: cBio Cancer Genomics Portal (Chris Sander / MSKCC)http://www.cbioportal.org

Cerami et al. 2012, Cancer Discovery

• Make Cancer Genomics data available to a broad audience: – “Wet lab” biologists involved in functional

studies.– Computational biologists

• Allow quick access to small data slices (few genes, subset of samples)

• Facilitate explorative data analysis / hypothesis generation and testing


http://www.cbioportal.org/

Cerami et al 2010, Nucl Acids Res


Features for the network viewTargeted-drugs

Direct targets (Released)Suggesting new targeted-drugs

indirect targets (work in progress)

Sources: DrugBank, KEGG Drugs, Cancer.gov

Pathway dataTargeted-drug data

Tumor data

Infer and suggest novel, drug-based therapy options

e.g. AKT inhibitor for PTEN deletion


TRD B: Using Cytoscape for Social Network Research

Social network of the Hadza hunter-gatherers of Tanzania. This analysis in Cytoscape reproduces the results published earlier this year in Nature by Fowler et al., which show a strong social network-dependence on the donation of public goods across and within groups. The histogram plot is based on the correlation values calculated by CyNetworkSignificance on the original and randomized networks.


TRD C: Network Visualization and Representation (Pico / Bader)Visualizing Complex Networks as Ontology-Partitioned Mosaics

Mosaic control panel, context menu and tiled result windows. The control panel shows both the color mapping legend and subnetwork display. Context menus for listed subnetworks allow the user to partition deeper within a given ontology branch.


• Annotation• Gene set analysis• Edge analysis• Module analysis


TRD C: Network visualization and representation (Ideker)

Introducing NeXO

A Network eXtracted Ontology

Janusz Dutkowski et al.Nature Biotechnology (2013)


Assembly and alignment of a network-extracted gene ontology



TRD D: Inference of Transcriptional Networks (Schwikowski group)

• Create ‘fill-in-the-algorithm’ infrastructure for inference of gene regulatory networks• Make methods accessible to biologists within the Cytoscape frameworkApproach: Create a software infrastructure (CYNI) for network inference algorithms

Since the last EAC meeting – Summary

-C design prototype-Hired engineer Oriol Guitart-Pla (02/15/12)-Working CYNI App-Documented API-User and CYNI App writer documentation-Additional CYNI functionality: Discretization and Imputation-Implemented and documented downloadable “Hello World examples”-CYNI App presented at two French network biology meetings-CYNI App and Comprehensive documentation publicly available


TRD Outreach IdeasOverview Technology Software Collabs Outreach Plans


Cytoscape 3.0 Progress(Core NRNB Software)Major update of technology behind CytoscapeCreates a fully modular architecture and APICytoscape 2.x would not support the features needed for the current vision of network analysis, e.g. scripting, multiple and 3D renderers, crowd-sourcing, interoperability with web and other tools

- Cytoscape 2.x: Maintenance Releases

- 2.8.2: Bug fixes and Improved memory allocation

- 2.8.3: Bug fixes and better trackpad support for Mac platforms

- Cytoscape 3

- 3.0.0 M5: June 2012: For developers

- 3.0.0-Beta1: 10/9/2012: First Release for Users

- 3.0.0 Final: This Week


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New Features for 3

•Edge Bundling•Welcome Screen•New Data Import Clients•Network Annotations•Network Collections•Enhanced Search•Cleaner API•Experimental Headless Mode


31

Disadvantages:

• Unproven stability (i.e., likely numerous bugs)• Slow startup (4 times longer than v2.8)• Fewer plugins (though the missing plugins are the less popular ones)• Larger memory footprint leaves less room (especially on WinXP) for networks

Feature Beneficiary

Welcome screen New users (for solicitousness), existing users (for convenience)

Import network Experienced users (for ease of use)

Edge bend visual property Paper and presentation writers

Edge bundling Users of high degree networks

Network annotations Users of hierarchical networks

Enhanced search Users of highly populated networks

Show All in Table Browser Users with highly annotated networks

Multiple network management All users

Cytoscape 3.0 Advantages:


32

TRD Outreach IdeasOverview Technology Software Collabs Outreach Plans

NOW, on to Collaborations

Count and scope Highlights Impact


COLLABORATIONS• Total: 97• 60 new collaborations in Year-2

UCSD, 8External,

7

Research collaboration

, 7

Cytoscape support, 5

Consulting only, 3

Ongoing, 7

Ended, 7

Rejected, 1

External/Internal

Type of Collaboration

*Percentages estimated from UCSD numbers

Collaboration Requests

47% 53%

20%

33%

47%

Completed47%

Ongoing47%

Rejected 6%


SCOPE of COLLABORATIONS• Applications of Network Tools to Biomedical Research

• Frontal Temporal Dementia, Alzheimer’s disease, Diabetes, Anorexia nervosa, Glaucoma, Heart disease, Leukemia, Brain tumors, Autism, Prostate cancer, Breast cancer, Endometrial cancer, Colorectal cancer, Lung cancer, and Malaria.

• Inflammation, stem cell differentiation, B-cell differentiation, ciliogenesis, cell-cell communication, oxidative stress response, DNA repair, cancer stem cells, and wound healing.

• Interactome, proteomics and metabolomics research. • Development of Cytoscape Plugins/Apps

• Connect to public databases• New types of data visualizations• Ontology analysis, graph analysis, partitioning, quantitative modeling.• New data types such as next-gen sequencing data and variant data. • Interoperability with 3D molecular visualization tools, and integrated workbenches.

• Development and Application of Other NRNB Tools and Resources • Cytoscape Web in cBio. • Curation of biofuel pathways at WikiPathways• Network analysis functionality to Broad’s IGV (Integrative Genomics Viewer)• Promoting the use of BaSysBio (Bacillus Systems Biology).


Actual Request #3(1) Dr. Joseph Gleeson’s lab at UCSD

Elucidating miRNA network underlying Ciliome

miRNAsmiRNA transfection

In vitro ciliogenesis model:htRPE cell (Serum starvetion induces ciliogenesis in hRPE cells)

Ciliogenesis faciliating miRNAs(26)

Ciliogenesis inhibitory miRNAs(55)

Control (25)Prediction of target mRNAs, assessment of enriched GOs


Yates Laboratory TSRIJeffrey Savas, PhD

Alzheimer's disease

Pre 3 month

Post 12 month

•Hippocampus•Cortex•Cerebellum (Ctrl)


Wild type



• For protein measurement, N14 is used for subject mouse and N15 is used for reference mouse. Log N14 / log N15 denotes relative abundance of corresponding protein.• Uses PDAPP as mouse model, N5 as second mouse• Dealing with ~18,000 proteins• ANOVA P-values and log2 fold changes are major values used for the analyses (more than two-fold changes and p-value 0.05 or less)

Pre 3 month

Post 12 month

First step is to find proteins whose abundances are altered in hippocampus or cortex, but no alteration in cerebellum.

Find candidate proteins which show alteration in protein abundance at statistically significant level

Map altered proteins onto protein-protein interaction network (Cytoscape)


GSOC’12 Project• Mondrian

– Cytoscape 3 application that facilitates acquiring data from cBio Genomics Portal.

Collaboration• IGV (Network view)

– Broad Institute (work in progress)

• Network visualization (cBio Genomics Portal)• Bilkent University, Turkey (iViz

Research Group)

http://bit.ly/cbioportal




IMPACT


COLLABORATIONS

• 16 GSoC and 5 NRNB Academy students

GSoC


Outreach• Significant traffic through nrnb.org: a real resource• New content and new development since last EAC

Just to make it clear… R01s would not cover this work


http://nrnb.org/cyretreat/

Cytoscape Workshops 2012




Cytoscape Europe 2013Date June 5-7, 2013, Institut Pasteur, Paris

Audience• New and existing users•New and existing plug-in developers•Researchers interested in network biology

Other plans•Present CYNI at other meetings (ICML, ICSB, ...)•Expand CYNI functionality/documentation as needed by new CYNI Apps


Ideas and Discussion Topics • Vision for the Technology Research and Development• Additional ways to link social network research (TRD B) with

other TRDs• How do we most effectively disseminate resources we have

worked so hard to put together:• Better integration with NIH sites/media• Publish many papers:

NRNB position paper; Nature protocols; 3.0 paper; App store paper• How do we make sure that NRNB scientists are getting career

acknowledgement for non-research activities• Publication tracking issues:

• APRSIS is broken (only pulls up 3 NRNB citations).• We need to do much better (10/20 supported papers ref. NRNB).

• When is next EAC?


Let’s Discuss


Additional ideas and topics:

• Infovis work on• Multi-dimensional attribute visualization• Interactive alternative views e.g. lenses

• E.g. tag cloud lenses at http://www.birdvis.org/ (Juliana Freire)• Intuitive user interfaces for defining interactive filters

• Training: Development of interactive workflows• Continue GSoC and NetBio SIG

• What else could help to position Cytoscape as a network inference platform of choice in the future?

• How can we deal technically with the fact that much academic work ends with a paper and MATLAB code?

• What are the best ways for making computationally costly approaches accessible in CYNI?

• How can we expand from showing an inferred network to a distribution over networks?


NRNB EAC Meeting 2012

Health & Medicine

Transcript of NRNB EAC Meeting 2012