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FP6

FP6. “ Mol ecular P henotyping to A ccelerate G enomic E pidemiology”. MolPAGE. MolPAGE. Concept of MolPAGE. “GENOMIC EPIDEMIOLOGY”. measurement, manipulation and analysis of “omics” scale data in thousands of subjects. Pharma SME Public Body. MolPAGE Consortium.

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FP6

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  1. FP6 “Molecular Phenotyping to Accelerate Genomic Epidemiology”

  2. MolPAGE MolPAGE Concept of MolPAGE “GENOMIC EPIDEMIOLOGY” measurement, manipulation and analysis of “omics” scale data in thousands of subjects

  3. Pharma SME Public Body MolPAGE Consortium European Consortium • 11 Universities/Research Institutes • 2 Pharma • 5 Biotech/SME • 4 Year programme (Oct 04-08) • 12 million Euro Coordinated by the University of Oxford Professor John Bell Professor Mark McCarthy

  4. Programme Goals “The application of genomic, metabonomic and proteomic tools to develop novel technical, data analysis and integration protocols that will enable disease biomarker typing and discovery projects on an epidemiological scale” “The identification and validation of biomarkers for use as pre-clinical predictors of metabolic disease”

  5. MolPAGE Programme Overview 1. The evaluation of sample collection and storage methodology; • to optimally reduce sample variation and maximise analyte stability 2. The development of genomic, metabonomic and proteomic tools; • to prepare for molecular phenotyping on an epidemiologic scale • relevant to both biomarker discovery and subsequent biomarker measurement in large sample sets • Includes proof of principle biomarker discovery (medium-scale) 3. The development of project specific tools to support data warehousing, data interrogation and statistical analysis • integrated approaches to data analysis across multiple platforms • integrated approach to data storage and dissemination ….with a clinical focus on diabetes and cardiovascular disease

  6. Work Package Overview

  7. Some vignettes • Standardization • Assessing variability in omics measures • Medium scale biomarker discovery • Application to large cohorts • Data management

  8. 1. Standardisation • Contribute to efforts to standardise sample collection strategies for genomic epidemiology: “future-proofing” biobank collections for future analysis. Build on UK Biobank efforts in this respect…. • Contribute to efforts to generate standards and norms for genomic epidemiology • * study design and analysis • * sample collection, processing and storage • * measurement of exposure and clinical phenotypes • * data formats, management, manipulation and storage • * analyte measurement (-omics scale) • * ethics, data privacy, material transfer • * meta-data • To ensure that in 5 years from now, it will be much easier to work across multiple • European biobanks than currently….

  9. 2. Sources of variation in omics data • UK TWIN STUDY • Twin volunteers recruited through media campaigns • Healthy adult population 18+ • Representative of UK pop • 500 MZ and 1,500 DZ pairs seen clinically in detail • Body comp DEXA fat total and central, fasting glucose,insulin,leptins, lipids • >10000 twins on database with questionnaire data • All will have fresh DNA & fasting blood by 2007

  10. From each twin collect; Blood For EBV Blood For RNA Plasma Serum Urine Adipose Decomposing variance MZ female Representative for BMI DZ female Representative for BMI Technical Variance Biological 40 pairs 20 pairs Genetic MZ DZ Me-DNA RNA Proteome Peptidome Metabonome MZ

  11. MolPAGE Power studies Lon Cardon, Krina Zondervan Oxford (WP9)

  12. 3. Biomarker discovery discordant MZ twins plasma serum urine subcutaneous fat omental fat muscle healthy individuals stratified for future disease disk proteomics Metabonomics LC-MS & NMR legacy samplesfrom prospective cohorts peptidomics samples gathered at surgery epigenomics new samplesfrom prospective cohorts

  13. Twins discordant for BMI Plasma

  14. Peptide display

  15. Peptide display heat map

  16. Putative biomarker

  17. Candidate gene-list Tissue micro array, Metabolic array pREST antibodies (HPR) Serum arrays, Antibody arrays Serum depletion Protocols, Antibody arrays Microfluidics CD Serum affibodies Biomarker affibodies 4. Evaluation of biomarkers Need for high throughput methods based on affinity reagents

  18. Large scale Ab generation http://www.proteinatlas.org/

  19. Serum array performance

  20. Insulin Pancreas http://www.proteinatlas.org/

  21. Thyroglobulin precusor Thyroid http://www.proteinatlas.org/

  22. Patient Mgnt Sample Mgnt DB Assay Mgnt Data Warehouse Repository Gene Peptides Raw/ data files METABONOMICS NovoNordisk ICL NMR LCMS Measurement types Assay Proteomics TRANSCRIPTOMICS BioVisioN Peptides (Sequence) NovoNordisk OGT Proteins (UNIPROT) Roche Protein Arrays KTH DNA Methylation & SNP TRANSCRIPTOMICS Epigenomics, CNG NovoNordisk OGT DNA methylation & SNP Epigenomics, CNG

  23. WP11 - Training • 1) Annual training courses • Statistical genetics training (Pavia, 4-8th July 2005) • Transcriptomics workshop (Pavia, 20-24th March 2006) • Data reduction techniques in metabonomics & proteomics (2007) • 2) Mobility awards • Competitive awards to support inter-partner training visits • 3) Science Workshops(technology/analysis) • Data Warehousing workshop (September 2006) • Proteomics workshop (March 2007)

  24. Dissemination Activities • 1) Project events open to wider scientific community • Training courses in Pavia • Public Technology Workshop (Paris May 8-10th 2005) • Follow up Technology Workshop (autumn 2008) • 2) Contribution to standards • Standard setting workshop (October 2006) • Publication of SOPs • 3) Publicity • Project overview presentations, Press release, case studies etc.. • Project web pages (www.molpage.org) • 4) Interaction with other projects • EU projects; e.g. MolTOOLS, GenomeEUtwin, GA2LEN • SystemsX consortium interaction

  25. MolPAGE Project Coordinator Mark McCarthy, John Bell Lon Cardon, Peter Donnelly Thomas Bergman Peter Schulz -Knappe Ed Southern Spiros Servos Mark Lathrop Ivo Gut Stephan Hoffmann Kurt Berlin Florian Eckhardt Mathius Uhlen Dominique Langin Fredrik Ponten Tim Spector Vladimir Stich Juris Viksna Luisa Bernardinelli Alvis Brazma Ugis Sarkans Jeremy Nicholson Hanno Langen Everson Nogoceke Esper Boel Jan Fleckner Commission Project Officer; Dr. Shahid Baig

  26. Summary • MolPAGE: developing approaches to enable large scale genomic epidemiology • Contributing to standardisation methods development informatics, and analysis • Medium-scale biomarker discovery • Long term: application to existing/future European biobanking initiatives

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