Genevestigator Training

Transcription

1 Genevestigator Training Gent, 6 November 2012 Philip Zimmermann, Nebion AG

2 Goals Get to know Genevestigator What Genevestigator is for For who Genevestigator was created How to use Genevestigator for your research

3 Background: our company NEBION AG Spin-off company from the Swiss Federal Institute of Technology Zurich (ETH) Founded in 2008 Product: Genevestigator Services: curation of proprietary data data analysis services

4 Number of datasets Value of public -omics data Thousands of -omics experiments have been published; soon millions! Highly specialized experiments Genome-wide coverage Wealth of information! Total number of datasets available in GEO e.g. Publicly available microarray studies

5 Problem with public -omics data Not systematically curated No annotation using controlled vocabularies No normalization No quality control Rudimentary sample descriptions Many annotation errors!!! Therefore: Not easily exploitable! Extensive curation needed Methods and tools for global exploration are lacking

6 OUR SOLUTION Quality control Normalization Annotation Search Engine 1. Professional biocuration of public data 2. Powerful search engine 3. User-friendly Web based tools

7 Interpreting your results Pathways, biological processes Networks Diseases GSEA, GO enrichment Literature Your results e.g. List of genes INTERPRETATION Compare with data from public and proprietary omics experiments. View/cluster expression by: - Tissue types, cell lines - Genotypes - Diseases, perturbations, cancers - etc.

8 Annotation ontologies mouse example Perturbations ontology Anatomy ontology SPACE Neoplasm ontology SPACE TIME CLINICAL PARAMETERS RESPONSE

9 Concept of meta-profiles

10 Deep data integration Proof of principle

11 Tissue type versus perturbations

12 Database content - overview Status: october 2013

13 Database content diseases 172 diseases from 28 disease areas cancer types and subtypes Human and animal models

14 Genevestigator website

15 Genevestigator is an online tool Website Java Client Application INTERNET Search Engine

16 Comparison with other products experiment Sample annotation via keywords Sample annotation with controlled vocabularies using ontologies proprietary public analysis of one or a few experiments Individual experiment normalization Combine results Global compendium normalization Search engine Analysis on deeply integrated data Genedata expressionist Qlucore Omics Explorer Partek, Omicsoft, etc. MeV, GenePattern, etc. Nextbio Oncomine Medisapiens Genelogic GENEVESTIGATOR

17 Application areas Functional genomics Bring gene expression into the context of thousands of conditions Find gene-gene and gene-condition associations Interpret lists of genes Target validation / drug repositioning Find out when, where, and in response to what a target is expressed Biomarker identification / validation Find genes highly specific for selected diseases or conditions

18 Demo

19 Analytical approach 1: Condition Search genes which conditions? Anatomy [space] Development [time] Stimulus / Mutation [response]

20 Case study 1 Drug repositioning Example of Glivec (Novartis) Glivec inhibits ABL (used for CML treatment) Glivec also inhibits KIT: in which conditions is this gene strongly up regulated? cell culture (107) non-cancer tissues (177) neoplasms (1040 / 850 subtypes)

21 Analytical approach 2: Gene Search conditions which genes? Anatomy [space] Development [time] Stimulus / Mutation [response]

22 Gene Search Identify genes that exhibit specific expression characteristics Anatomy Development Stimulus / Mutation

23 condition 1 condition 2 condition 3 condition 4 condition 5 condition 6 condition 7 condition 8 condition 9 condition 10 condition 11 condition 12 condition 13 condition 14 condition 15 condition 16 condition 17 Concept of gene search in Genevestigator gene 1 gene 2 gene 3 gene 4 gene 5 most biomarker search approaches look for the genes, which respond the most to a given condition gene 6 gene 7 gene 8 gene 9 gene 10 gene 11 gene 12 gene 13 gene 14 gene 15?? This condition may include multiple similar studies How these genes respond to other conditions is unknown, because they were not included into the analysis gene 16 gene 17

24 condition 1 condition 2 condition 3 condition 4 condition 5 condition 6 condition 7 condition 8 condition 9 condition 10 condition 11 condition 12 condition 13 condition 14 condition 15 condition 16 condition 17 Concept of gene search in Genevestigator gene 1 gene 2 gene 3 gene 4 gene 5 gene 6 gene 7 gene 8 gene 9 gene 10 gene 11 gene 12 gene 13 gene 14 gene 15 gene 16 gene 17 Genevestigator allows to find out how specific these genes are (Meta-Profile Analysis -> Stimulus/Mutation tools) Only few are responsive only to condition 9 (black arrows). All others are sensitive to one (grey arrows) or more other conditions.

25 condition 1 condition 2 condition 3 condition 4 condition 5 condition 6 condition 7 condition 8 condition 9 condition 10 condition 11 condition 12 condition 13 condition 14 condition 15 condition 16 condition 17 Concept of gene search in Genevestigator gene 3 gene 5 gene 7 gene 13 gene 17 gene 10 gene 2 gene 15 gene 9 gene 12 gene 4 gene 11 gene 16 gene 1 gene 6 gene 8 gene 14 The Genevestigator Biomarker Search tools identify genes that are specifically responsive to the chosen condition (they respond minimally to other conditions). These genes are not necessarily the ones with the strongest response to the chosen condition The Genevestigator Biomarker Search tools usually find other target candidates than classical tools, which analyze only a subset of experiments

26 condition 1 condition 2 condition 3 condition 4 condition 5 condition 6 condition 7 condition 8 condition 9 condition 10 condition 11 condition 12 condition 13 condition 14 condition 15 condition 16 condition 17 condition 18 condition 19 condition 20 condition 21 condition 22 condition 23 condition 24 condition 25 condition 26 condition 27 condition 28 condition 29 condition 30 condition 31 condition 32 condition 33 condition 34 condition 35 condition 36 condition 37 condition 38 condition 39 condition 40 condition 41 condition 42 condition 43 condition 44 condition 45 condition 46 condition 47 condition 48 condition 49 condition 50 condition 51 condition 52 condition 53 condition 54 condition 55 condition 56 condition 57 condition 58 condition 59 condition 60 condition 61 condition 62 condition 63 condition 64 condition 65 condition 66 condition 67 condition 68 condition 69 condition 70 condition 71 condition 72 condition 73 condition 74 condition 75 Concept of gene search in Genevestigator Imagine extending this to a much wider set of conditions you may find other conditions to which the set of genes respond target condition gene 3 gene 5 gene 7 gene 13 gene 17 gene 10 gene 2 gene 15 gene 9 gene 12 gene 4 gene 11 gene 16 gene 1 gene 6 gene 8 gene 14 other conditions to which the genes are responding

27 Example of co-regulation Similar mechanisms of action cause similar transcriptional effects target condition(s) Actinomycin-D vmyb Oncolytic herpes simplex virus Propiconazole Sapphyrin Echinomycin Cell cycle inhibition co-inducing conditions Chemical: ARC

28 Clustering tools Goal: to identify groups of genes that have similar expression characteristics Tools: Hierarchical clustering (with leaf ordering) Biclustering (BiMax algorithm)

29 RefGenes

30 RefGenes - validation Reference genes searched from a set of 197 mouse liver samples 4 candidates compared to 4 commonly used genes Validation experiment on mouse liver Experimental validation on 16 mouse liver samples (RT-qPCR) Selection using GeNorm genorm selection of the most stable reference genes within this experiment

31 RefGenes study experimental validation

32 RefGenes concept

33 RefGenes website

34 Summary Genevestigator is... A gene expression search engine High quality compendium of manually curated expression data The world s largest and growing collection of expression data A flexible software application (plug-in architecture) Web-based (Internet or Intranet) User-friendly and extremely fast

35 Summary: it s all about CONTEXT!