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FP6
“Molecular Phenotyping to Accelerate Genomic Epidemiology”
Concept of MolPAGE
MolPAGE
MolPAGE
“GENOMIC EPIDEMIOLOGY”
measurement, manipulation and analysis of “omics” scale data in thousands of subjects
MolPAGE ConsortiumEuropean 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 BellProfessor Mark McCarthy
PharmaSMEPublic Body
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”
Programme Overview
1. The evaluation of sample collection and storage methodology;
• to optimally reduce sample variation and maximise analyte stability2. 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
MolPAGE
….with a clinical focus on diabetes and cardiovascular disease
Work Package Overview
StandardizationAssessing variability in omics measuresMedium scale biomarker discoveryApplication to large cohortsData management
Some vignettes
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 multipleEuropean biobanks than currently….
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
Decomposing variance
MZ
40 pairs
MZ female Representative for BMI
DZ
20 pairs
DZ female Representative for BMI
From each twin collect;
Blood For RNA
Urine
Blood For EBV
Serum Plasma
Adipose
MZ
Variance
Technical
Biological
Genetic
Me-DNARNAProteomePeptidomeMetabonome
Power studies
Fig 2b. Total sample size required (MZs +/- DZs) to detect combined 'familiality' (h2+c2) when common environment c2 = 0.3
Measurement scenarios: 2 in MZs and DZs (smooth lines) vs. 2 in MZs and 1 in DZs (small dash) vs. 2 in MZs only (large dash)
0
10
20
30
40
50
60
70
80
0.3 0.35 0.4 0.45 0.5
h2 (heritability)
To
tal n
um
ber
of
twin
pa
irs
(MZ
s +
/- D
Zs
)
r2=0.5, DZ=2
r2=0.6, DZ=2
r2=0.7, DZ=2
r2=0.8, DZ=2
r2=0.9, DZ=2
r2=0.5, DZ=1
r2=0.6, DZ=1
r2=0.7, DZ=1
r2=0.8, DZ=1
r2=0.9, DZ=1
r2=0.5, 2 MZ only
r2=0.6, 2 MZ only
r2=0.7, 2 MZ only
r2=0.8, 2 MZ only
r2=0.9, 2 MZ only
Lon Cardon, Krina Zondervan Oxford (WP9)
MolPAGE
3. Biomarker discoverydiscordantMZ twins
healthy individualsstratified for future
disease disk
legacy samplesfrom prospective
cohorts
new samplesfrom prospective
cohorts
plasma
serum
urine
subcutaneous fat
omental fat
muscle
samplesgathered at
surgery
proteomics
MetabonomicsLC-MS & NMR
peptidomics
epigenomics
Twins discordant for BMI
Plasma
Peptide display
Peptide display heat map
Putative biomarker
4. Evaluation of biomarkers
Need for high throughput methods based on affinity reagents
Tissue micro array, Metabolic array
Serum affibodies Biomarker affibodies
Serum depletion Protocols,
Antibody arrays
pREST antibodies
(HPR)
Serum arrays,Antibody arrays
Candidate gene-list
Microfluidics CD
Large scale Ab generation
http://www.proteinatlas.org/
Serum array performance
Insulin Pancreas
http://www.proteinatlas.org/
Thyroglobulin precusorThyroid
http://www.proteinatlas.org/
Sample Mgnt
Assay Mgnt
DB
Patient Mgnt
Data Warehouse
TRANSCRIPTOMICS
NovoNordiskOGT
Proteomics
BioVisioN
Peptides(Sequence)
Roche
KTH
Proteins(UNIPROT)
Protein Arrays
DNA methylation & SNP
Epigenomics, CNG
Measurement types
Gene
Pepti
des
Assay
Repository
METABONOMICS
NovoNordisk
ICL
NMR
LCMS
TRANSCRIPTOMICS
NovoNordiskOGT
DNA Methylation & SNP
Epigenomics, CNG
Raw/ data files
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)
Dissemination Activities1) 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)
4) Interaction with other projects• EU projects; e.g. MolTOOLS, GenomeEUtwin, GA2LEN• SystemsX consortium interaction
3) Publicity• Project overview presentations, Press release, case studies etc..• Project web pages (www.molpage.org)
2) Contribution to standards• Standard setting workshop (October 2006) • Publication of SOPs
MolPAGE Project CoordinatorMark McCarthy, John BellLon Cardon, Peter Donnelly
Mark LathropIvo Gut
Esper BoelJan Fleckner
Mathius Uhlen
Luisa Bernardinelli
Vladimir Stich
Hanno LangenEverson Nogoceke
Fredrik Ponten
Stephan Hoffmann
Commission Project Officer; Dr. Shahid Baig
Ed SouthernSpiros Servos
Peter Schulz-Knappe
Kurt BerlinFlorian Eckhardt
Thomas Bergman
Jeremy Nicholson
Alvis BrazmaUgis Sarkans
Juris Viksna
Dominique Langin
Tim Spector
• 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
Summary
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