Community Research and Development Information Service - CORDIS

Periodic Report Summary 3 - BESTAGEING (Biomarker Research Alliance for Diagnosing Heart Disease in the Ageing European Population)

Project Context and Objectives:
The ageing of the European population represents a growing health care problem, threatening future economic growth and quality of life of our society. In particular, cardiovascular diseases show a marked increase with age and have remained the leading cause of morbidity and mortality in the elderly. Unfortunately, cardiovascular disorders and their associated risks are often difficult to diagnose in the elderly due to many age-related confounders and co-morbidities, leading to substantial uncertainties in diagnostic classification and therapeutic decision making with huge impact on patients’ outcomes. Hence, there is an unmet need for novel biomarkers to enable a more accurate diagnosis, sub-classification, risk assessment and treatment guidance for both acute and chronic cardiovascular diseases in the elderly.
The BestAgeing consortium aims to improve this unsatisfactory situation by developing and validating novel omics-based biomarkers that may complement or substitute traditional biomarkers for more accurate or earlier diagnosis, better risk assessment and appropriate guidance of therapies, overcoming limitations inherent with traditional biomarkers – supporting healthy ageing in Europe. By combining leading experts in the field of “classical” biomarker development, high-throughput technologies, omics-biomarker research, research intensive SME and industry, and clinical institutions, we are confident that our efforts will generate novel European medical technologies that can improve the efficacy and efficiency of our care for elderly patients, which will also impact on the competiveness of research-intensive European industries and socioeconomic wealth in Europe.
The main objectives of BestAgeing are:
1.) The Validation of novel omics-based biomarkers in elderly patients in Europe.
In the context of the project we already validated previously identified omics-biomarkers in available retrospective and prospective cohorts. Additionally, we defined comparative reference markers, statistical validation concepts and we developed a dedicated IT infrastructure which enables a sophisticated analysis of the complex omics and phenotype data. As in the omics-field standardization and quality control (QC) are essential prerequisites for successful validation of biomarkers by the different technologies, we established various SOPs to assure standardization processes for sampling, storage and exchange of biomaterials.

2.) Development of novel assays for selected omics-biomarkers.
Although technologies for screening of hundreds or thousands of omics features in parallel were developed over the last years, until now well-established, clinically applicable and robust assays to assess subsets of these omics-features harbouring diagnostic information are lacking. Therefore, specific assay technologies will be developed to circumvent existing and unsolved limitations of current methodologies, such as missing analytical robustness, standardization, and turnaround times. Two main goals of the BestAgeing project are the development of new miRNA test assays and the development and optimization of a targeted, quantitative mass spectrometry-based method for the simultaneous quantification of 20-50 metabolite biomarkers.

3.) Development of multi-marker strategies based on diverse omics and established biomarkers as well as advanced imaging modalities for diagnosis, risk prediction and treatment guidance in elderly patients.
Since several pathways are activated in cardiovascular diseases, we will integrate our data from genomics, epigenomics, proteomics and metabolomics together with clinical variables in individual patients. Multi-marker strategies accounting for disease specific changes on different levels may enhance the predictive power over single biomarkers, a hypothesis that will be tested in our elderly HF cohorts. Additionally, the gathered information and potential of the evaluated markers will be used to model the potential socioeconomic impact of the novel biomarkers.
Our study design addresses the most frequent and severe cardiovascular diseases of elderly patients by incorporating the appropriate phenotype and reference cohorts and biomaterials from European populations. Our strengths are our extensive previous work on biomarker identification and validation, our long-standing expertise in technology development and omics-based research, as well as our experience in translational research and test development as exemplified by the invention, the successful translation, and continuous refinement of cardiac Troponin T to a world-wide standard of good clinical practice in diagnosing myocardial infarction and prognosis of cardiac risk.

Project Results:
In the first reporting period of the BestAgeing project the consortium established the foundation for the collaborative work planned in the project years 2-4. The main tasks of the first year were the intense preparatory work for the retrospective and prospective validation studies. First, the definition of the clinical phenotypes addressed in BestAgeing has been carefully redefined. This phenotype characterization is of major importance because the clinical phenotype must be very precise on the one hand and fully applicable for the different European clinical centers, and on the other hand compatible with existing retrospective cohorts and newly established prospective European cohorts. A further major achievement in the first period was the development of the BestAgeing database. This important project resource will host all clinical and selected omics data and comparison markers from the validation studies. The data base is deployed in a highly secure data center and all consortium partners have access to the data via web based client server applications and state of the art encrypted protocols. In the first version, the initial definitions of the markers, description of the studies, diagnostic tests etc. were discussed and implemented. After re-evaluation of the clinical phenotypes and the database as a whole at the end of the first period by the consortium, the database was finally established as an important resource of the consortium in the second period.
In parallel to the definition of the clinical phenotypes and the implementation of the database, we started with the development of advanced and specialized Standard Operating Procedures (SOPs) for various preanalytic processes from sampling, through sample preparation, aliquoting, storage, shipping of biomaterials to the analysis of specific omics based biomarkers. In the BestAgeing project we established a dedicated “Samples Group” which was able to finalize the comprehensive protocols early in the second period so that the groundwork for the prospective validation studies is clearly given. In addition to the mentioned SOPs, study specific quality assessment SOPs were developed covering all challenges arising from complex omics analyses. The consortium also decided to store the biomaterial at the Heidelberg CardioBiobank which operates as a trustee for the BestAgeing samples. Therefore the long.-term experience in handling, storage and processing of various biomaterials is given. We were also able to agree on a first parameter set to combine analyses of metabolite profiling, miRNA-omics and protein markers in the same cohort which will enable the first approaches to the multimarker concept of BestAgeing.
The SMEs and industry partners are constantly working to develop new assay technologies for improved analyses of the omics biomarkers. The first achievements even resulted in new patent applications covering the highly relevant intellectual property of translational research for future commercial exploitation. Based on our ongoing validation studies we could provide the first revision of our comprehensive table of biomarker candidates.
The major goal of the second and third period was the implementation of new prospective validation studies by the consortium. In this period the whole consortium met twice to discuss and decide about the study synopses, study protocols, implementation of ethics votes and the recruitment of patients. Six prospective studies were planned and the ethic applications were prepared. Unfortunately the start of the recruitments at all clinical partner sites were delayed because the ethics committees from several partner sites came up with specific requests which were unforeseen as the studies are planned as observational studies. In order to fast and efficiently solve the various issues with the different local ethics application the Coordinator took the role as trial leader and supported the partners in their local implementation of ethics votes. The coordinator and her group then invested much effort to provide “master ethics application” documents for ethics application, patient informed consent, patient information etc. and to preparing partner specific drafts of the before mentioned documents and to support the partners in the negotiation process of all ethics related issues. This huge effort led to the completion of the last clinical partner receiving green light from its ethics committee and all clinical partners are to date recruiting for prospective recruitment according to the six prospective biomarker validation studies defined by the consortium.
As a result of the successful collaborative work of BestAgeing, numerous publications were released within the last three years (see EC participant portal).

Potential Impact:
BestAgeing focuses on the most prevalent cardiovascular diseases: Acute Coronary syndrome, Coronary Artery Disease and Heart Failure in the ageing European population. These diseases, predominantly Heart Failure, are also the main cost drivers in clinical care and facing the ageing of European population these diseases increasingly challenge the health care and socioeconomic systems of Europe. Currently available clinical therapies may help to delay the time of onset of the progress of the disease, if optimal and individualized treatment is applied at early stages of disease. This optimal treatment requires early and precise diagnosis and risk assessment of the patient. To further improve the clinical diagnosis, outcome prediction and to guide therapeutic treatment of elderly patients, the BestAgeing consortium was established. In a unique interdisciplinary approach of clinical scientists, molecular biologists, statisticians and bioinformaticians from 19 excellent European partners BestAgeing brings together leading academic, SME´s and industry partners. BestAgeing ultimately aims to validate a panel of novel omics based biomarkers for ACS, CAD and HF, which have been identified by the consortium members in previous studies. These novel markers will now be validated in several multicenter studies based on retrospective and prospective studies. We expect that analyzing different omics markers in one patient and application of our multimarker approach the diagnostic precision and outcome prediction together with established biomarkers will be significantly improved. The strong expertise in assay development and assay technology provided by the SME´s and industry partners enable us to translate our novel biomarkers towards clinical application.
Healthy ageing is a critical determinant for economic growth and prosperity in Europe. The economical productivity for instance will increasingly depend on the contribution of elderly workers. Already today CVD accounts for 20.4% of disability adjusted life years (DALY) in developed countries and for 32.8% of all deaths (Murray et al. Lancet 1997). Not surprisingly due to the trend towards demographic ageing in Europe and the increasing prevalence of CVD with age, it is predicted that CVD will remain the leading cause of death in industrialized countries and continue to contribute markedly to morbidity and health care costs. It is therefore paramount to detect affected subjects early, to identify those at high risk for cardiac events properly, and to provide sensitive diagnostic tools for immediate therapeutic interventions.
Considering the rising expenses for health-care, results from health economic research will likely influence medical decision-making in the future. Hence, payers and health care providers in Europe need to be provided with robust information on optimal resource allocation to support healthy-ageing. As part of our work packages, we will test the impact of novel biomarkers on European health-care and socioeconomic systems. This ambitious aim can be achieved within the BestAgeing project, since we have longstanding experience and insights into relevant national and international data sources and economic measures of diagnostic and therapeutic procedures. With our concomitant activities for public outreach, we will disseminate our scientific work, the results of biomarker development, and the potential medical and economic consequences to the European community and society.

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