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NetBioSIG2012 anyatsalenko-en-viz

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Summary: ENViz performs enrichment analysis for pathways and gene ontology (GO) terms in matched datasets of multiple data types (e.g. gene expression and metabolites or miRNA), then visualizes …

Summary: ENViz performs enrichment analysis for pathways and gene ontology (GO) terms in matched datasets of multiple data types (e.g. gene expression and metabolites or miRNA), then visualizes results as a Cytoscape network that can be navigated to show data overlaid on pathways and GO DAGs.
Background: Modern genomic, metabolomics, and proteomic assays produce multiplexed measurements that characterize molecular composition and biological activity from complimentary angles. Integrative analysis of such measurements remains a challenge to life science and biomedical researchers. We present an enrichment network approach to jointly analyzing two types of sample matched datasets and systematic annotations, implemented as a plugin to the Cytoscape [1] network biology software platform.
Approach: ENViz analyses a primary dataset (e.g. gene expression) with respect to a ‘pivot’ dataset (e.g. miRNA expression, metabolomics or proteomics measurements) and primary data annotation (e.g. pathway or GO). For each pivot entity, we rank elements of the primary data based on the correlation to the pivot across all samples, and compute statistical enrichment of annotation sets in the top of this ranked list based on minimum hypergeometric statistics [2]. Significant results are represented as an enrichment network - a bipartite graph with nodes corresponding to pivot and annotation entities, and edges corresponding to pivot-annotation pairs with statistical enrichmentscores above the user defined threshold. Correlations of primary data and pivot data are visually overlaid on biological pathways for significant pivot-annotation pairs using the WikiPathways resource [3], and on gene ontology terms. Edges of the enrichment network may point to functionally relevant mechanisms. In [4], a significant association between miR-19a and the cell-cycle module was substantiated as an association to proliferation, validated using a high-throughput transfection assay. The figures below show a pathway enrichment network, with pathway nodes green and miRNAs gray (left), network view of the edge between Inflammatory Response Pathway and mir-337-5p (center), and GO enrichment network with red areas indicating high enrichment for immune response and metabolic processes (right).

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  • 1. Enrichment Network Analysisand Visualization (ENViz) global program that offers student developers stipends toAnya Tsalenko write code for various openAllan Kuchinsky source projects.Agilent LaboratoriesJuly 13, 2012 Agilent Confidential
  • 2. Agenda• Introduction to integrative analysis• Cytoscape at a glance• ENViz walkthrough• Next steps
  • 3. Integrative Biology Primary Analysis NMR Proteins Genomic Workbench GeneSpring MassHunter Workstation Public Data LC/MS Integrated Biology Metabolites GC/MS Informatics Microarrays DNA / RNA Target Enrichment Network Biology Integrated Analysis Genome Browser miRNA Microfluidics Hypothesis, experiment, model
  • 4. Example: breast cancer study“miRNA-mRNA integratedanalysis reveals roles for miRNAsin primary breast tumors”, 2011• Cancer dataset from Anne-Lise Børresen-Dale Lab in Norwegian Radium Hospital, Oslo• 100 breast tumor samples with various characteristics• Matched miRNA and mRNA data, Agilent microarrays
  • 5. Correlation of miRNA and mRNA expression,miR-150 Sorted expression of miRNA -150 Genes most correlated to miR-150 across 100 breast cancer samples
  • 6. Enrichment analysis of genes correlated to miR-150 mHG p-value<E-147GO terms enrichment analysis in the top of the list of genes ordered bycorrelation to miR-150 based on minimum Hypergeometric Statistics(Eden et al, PLoS CB 2007)
  • 7. Biological validation GO enrichmentAssociation between miR-19a for genesand the cell-cycle module was correlated tosubstantiated as an association miR-19ato proliferation.Further validated using high-throughput transfection assayswhere transfection of miR-19ato MCF7 cell lines resulted inincreased proliferation.
  • 8. Generic 3 matrices enrichment software Two different types of measurements in the same set of samples:  mRNA and miRNA expression (or Annotation other non-coding RNAs)Roy Navon  mRNA expression and quantitative clinical phenotype  mRNA expression and metabolites levels  mRNA expression and copy number Analysis is based on statistical enrichment in lists ranked by correlation Enrichment can be calculated based on any other annotation such as GO, pathway or disease ontology
  • 9. Agenda• Introduction to integrative analysis• Cytoscape at a glance• ENViz walkthrough• Next steps
  • 10. Cytoscape at a glance Shannon et al. Genome Research 2003 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) • Ultimate goal: provide tools to facilitate all aspects of network assembly, annotation, and use in biomedicine. Downloaded approximately 3000 times per month, ~137 plugins (1st June 2011) Signaling, metabolic pathways Genetic regulatory networks http://www.cytoscape.org Host pathogen Functional enrichment Linked structural,Genetic and protein Subnetworks active in maps networked data interactionsinteraction networks disease
  • 11. Agenda• Introduction to integrative analysis• Cytoscape at a glance• ENViz walkthrough• Next steps
  • 12. ENViz: what it isEnrichment Network Visualization (ENViz): a Cytoscape pluginfor integrative statistical analysis and visualization of multiple sample matcheddata sets
  • 13. Control PanelUse the main control panel to:• Specify input primary data, pivot, and annotation files• Run analysis• Set thresholds that control the size of the enrichment network to visualize• Run the visualizationSeparate sub-panels can be collapsed orexpanded by clicking on their handles(collapsible subpanels, Bader Lab, UToronto)Interactive Legend:• graphical overview of the workflow.• click on labeled boxes for file prompt.• drag and drop a file reference onto alabeled box.
  • 14. Enrichment Network• Example of enrichment network built from mRNA and miRNA data from Enerly et al, using WikiPathway annotation.• Results are represented as bi-partite graph: nodes = pathways (green) and miRNAs (grey).• Edge (i,j) represents enrichment of pathway j in the set of genes whose expression correlate the expression pattern of miRNA i. red = positive correlation, blue = negative correlation • Double-click on edge to load its pathway into Cytoscape.
  • 15. Enrichment Network Zoom:• Zoom in to see details around selected nodes and edges• See zoomed-in network in the context of the whole network on the bottom left
  • 16. Pathway visualization in WikiPathways• Click on selected edge shows corresponding WikiPathway• All gene nodes in the mRNA processing pathway that map to primary data elements are color coded (blue -> red) for correlation score between the primary data element (mRNA) and the pivot data element for the clicked edge (hsa-miR- 92a) • thick borders and high opacity those genes above correlation threshold that were included in the gene set used for enrichment analysis.
  • 17. Tiling Pathway views• Double-click on a pathway Node to loads multiple WikiPathways, each one colored by correlationwith the specific pivot datum for an Edge, connected to the Node, up to a user-configurable limit• Network views are tiled in a ‘small multiples’ view that accentuates contrasts between correlationsfor different pivot data.
  • 18. Gene Ontology visualization• enrichment networks built from Enerly et al. mRNA and miRNA data and Gene Ontologyannotation.• left = bi-partite graph for GO terms (yellow -> red scale) and miRNA (grey)• edge (i,j) is enrichment of GO term j in in the set of genes that correlate with miRNA i.• right = GO summary network for GO terms in the left enrichment network. Each GO nodescolor-coded (yellow to red) by maximum enrichment score for its set of pivot nodes.• parent terms are added, to complete the GO hierarchy view.
  • 19. miR-150 - oriented GO Terms• Double-click on an pivot node in the enrichment network to show GO terms in the GO Summarynetwork that have significant enrichment values for the pivot datum.• Enrichments for GO terms and genes correlated to miR-150 are color-coded yellow -> red.
  • 20. Agenda• Introduction to integrative analysis• Cytoscape at a glance• ENViz walkthrough• Next steps
  • 21. Next steps• Working on performance, completeness, robustness• Extend support for other organisms beyond Homo sapiens, Mus Musculus, mycobacterium tuberculosis• Extend the range of database id mappings• beta-release tentatively planned for end of Summer 2012• Possible future features: heatmap view, sample grouping, more annotation types (TFs, disease ontologies), crosstalk visualization
  • 22. Acknowledgements• Agilent Technologies – Roy Navon, Zohar Yakhini, Michael Creech• Technion – Israel Steinfeld• Collaborators – Norwegian Radium Hospital, Oslo: Espen Enerly, Kristine Kleivi, Vessela N. Kristensen, Anne-Lise Børresen-Dale – UCSF/Gladstone: Alex Pico, Nathan Salomonis, Kristina Hanspers, Bruce Conklin, Scooter Morris – Maastricht University: Thomas Kelder, Martijn van Iersel, Chris Evelo – Cytoscape core developers and PIs: Trey Ideker, Chris Sander, Gary Bader, Benno Schwikowski, Mike Smoot, Peng Liang, Kei Ono, Leroy Hood, Ben Gross, Ethan Cerami

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