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Workpackage 7: Data harmonization and statistical analysis

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Objectives
  • To assess the impact of the biomarkers, and develop and validate risk estimation models based on classic cardiovascular risk factors and biomarkers of the assays established in Module 1, using large prospective European population and diseased cohorts.
  • To assess the impact of lifestyle on the level of the biomarkers and the association between the biomarkers and diagnostic imaging phenotypes

Description of Work

The impact of the biomarkers is assessed in a large number of population cohorts from 14 European countries and in five cohorts of persons who already have cardiovascular disease at baseline. All cohorts have prospective follow-up for cardiovascular disease, and many are followed up also for diabetes. Relevant data from the population cohorts are harmonized to the MORGAM database in the BiomarCare Data Centre in Helsinki. Data from the diseased cohorts are harmonized in the BiomarCaRE Data Centre in Lübeck. These Data Centres assess the quality and cohort-specific characteristics of the data, analyze the data and also share the data with other BiomarCaRE Partners for data analysis.

The data analysis involves the assessment of the impact of the biomarkers on the cardiovascular end-points in population cohorts of about 90,000 men and women, 30,000 repeat measurements and 8,850 subjects of the diseased cohorts. Some of the biomarkers are assessed in a case-cohort setting in 20,000 subjects instead of all 90,000. Risk models based on classic cardiovascular risk factors and biomarkers are derived and validated internally. The most promising biomarkers will be validated in separate population cohorts of about 130,000 subjects.

A BiomarCaRE Panel, the set of the most promising biomarkers, will be defined, and applied in clinical trials in WP 8.

The impact of lifestyle on the level of the biomarkers and the association between the biomarkers and diagnostic imaging phenotypes are analyzed locally in the BiomarCaRE Centres whose cohorts have such data available.


Partners involved

THL Helsinki (WP coordinator), UHSH Lübeck, UKE Hamburg, all cohort providers


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Workpackage 6: Measurements of biomarkers in population based and clinical samples

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Objectives
  • To manage sample transfer logistics from European population based and diseased cohorts as well as clinical trials to the centralized BiomarCaRE laboratories
  • To perform measurements of selected emerging and existing biomarkers (WP1) in population based and diseased cohorts by using standard operating procedures.
  • Provide validated and quality controlled biomarker data for analyses to the BiomarCaRE Data Centres at THL and IMBS, to assess the predictive value in European cohorts

Description of Work

A centralized and coordinated management of sample transfer will be arranged by the BiomarCaRE laboratory in Hamburg. The transfer will be coordinated jointly between the BiomarCaRE laboratory and the BiomarCaRE Data Centres to ensure correct identification of samples.
The biomarker measurement will be performed in a two-phase approach. In Phase 1 established and novel biomarkers (selected in WP 1) are determined in a set of population cohorts from 14 different European countries (N=90,000 subjects) as well as in four disease cohorts (N=8,700 subjects). Additionally some selected miRNA, metabolomics and omic-based biomarkers will be measured in the BiomarCaRE case cohort set (N=20,000 subjects)
At Phase 2, the most promising biomarkers from phase 1 are further determined for the European population cohorts (N=130,000 subjects).

Innovative assays and technology developed by the SME's (WP2-5) are applied for emerging biomarkers, as well as state-of-the-art assays for existing biomarkers. Quality controlled and validated biomarker values are transferred to the BiomarCaRE Data Centres to be merged to the other cohort data for analysis.

The result of this work package will generate high-throughput quality controlled biomarker data from all BiomarCaRE cohorts. Additionally it provides a comprehensive evaluation and adaption of innovative SME-driven technology and assays.


Partners involved

UKE Hamburg (WP coordinator), all cohort providers, UHSH Lübeck, THL Helsinki, Cavadis Utrecht, Biocrates Innsbruck, Fleet Bioprocessing, Biocartis Lausanne

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Workpackage 8: Retrospective application of the European BiomarCaRE panel in biobanks of clinical trials

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Objectives

To evaluate the potential effect of various pharmacological cardiovascular interventions on biomarker levels in samples from randomized clinical trials (RCTs) using a nested case-control design.

Description of Work

The work will comprise three statistical approaches:
  1. The predictive value of 3-6 selected biomarkers will be assessed in samples from various RCTs, adjusted for medication and stratified by intervention group.
  2. The change in biomarkers levels from baseline to on the average one year on treatment will be assessed.
  3. The treatment effect will be analysed according to biomarker levels at baseline (high vs. low)
See also Workpackage 6.

Partners involved

UKE Hamburg (WP coordinator), University Ulm, University Sydney, HHS Hamilton, BWH Boston
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Workpackage 4: Assay development: metabolomics

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Objectives

To produce Biocrates AbsoluteIDQ p180 for the quantitative metabolomics profiling of ap-proximately 186 metabolites of around 20,000 samples from specific cohorts of the BiomarCaRE bio-repository with endpoints and image information. To deliver the Kits in-cluding all consumables and software (MetIDQ) for the data analyses of FIA-MS-MS assay available to Partner 5.

Description of Work

In this WP, Biocrates manufactures approximately 250 Absolute IDQ p180 Kits for quanti-tative metabolomics analysis of approximately 180 metabolites from 5 compound classes, (i.e., acyl carnitines, amino acids, biogenic amines, phospho- and sphingolipids, and hex-ose) in 20,000 serum/plasma samples on a case-cohort basis. The assays is delivered in 96 well formats, enabling the analysis of large number of samples; it includes a flow injec-tion tandem mass spectrometry platform, FIA-MS/MS, for the analyses of acyl carnitines, hexoses, and phosphoand sphingolipids, and a liquid chromatography tandem mass spectrometry platform, LC-MS/MS, for amino acids and biogenic amines. Quantifications of metabolites is performed by stable isotope labelling or by the use of chemically homol-ogous internal standards.
The manufacturing of the 250 Kits including consumables is performed in 2 steps because of the large number of samples to be analysed by Partner 5, the shelf-life and the storage capacity of Partner 5. In agreement with Partner 5, 125 Kits are manufactured in the first and, the remaining 125 Kits later in the measurement phase.
Biocrates will train Partner 5 to perform Absolute IDQ p180 Kit based targeted metabo-lomics analyses, in monitoring and documentation of LC-MS/MS system suitability in as well as Kit data management and normalization based on MetIDQ software.

Partners involved

Biocrates Innsbruck (WP coordiantor), UKE Hamburg, ThermoFisher Dreieich