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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 3 - ENSAT-HT (Application of omics-based strategies for improved diagnosis and treatment of endocrine hypertension)

Teaser

Summary

Arterial hypertension affects up to 45% of the general population and is responsible for 7.1 million deaths per year worldwide. However, optimal blood pressure control is not being achieved in up to two thirds of patients. Endocrine forms (E) of high (H) blood pressure (BP, EHBP), such as primary aldosteronism (PA), pheochromocytoma/functional paraganglioma (PPGL) and Cushingâ€™s syndrome (CS) represent the most frequent forms of secondary and curable hypertension and thus major targets for stratified approaches of hypertension.

This project will develop and evaluate an omics-based stratified health promotion program for patients with EHBP.
The program is structured into 7 work packages (WP) interacting in a seamless and coordinated fashion. We will define specific omics profiles for patients with PA, PPGL and CS by integrating high throughput genetics, genomics and metabolomics data (WP2, WP3) with phenome annotations through bioinformatics modelling (WP1). Established profiles will be validated as stratification biomarkers and applied to the screening of referred hypertensive patients for both stratifying primary forms of hypertension for effective and cost efficient therapy as well as improving identification of endocrine causes for curative treatment and prevention of cardiovascular and metabolic complications (WP4). The program will be assessed for its medical, social, economic and ethical impact (WP5). Dissemination and communication will ensure international visibility as well as the optimal exploitation of the results of ENSAT-HT (WP6). Strategic and administrative management will be performed in WP7.

Work performed

WP1
Creation, development and maintenance of ENSAT-HT clinical data capture model and maintenance of online registry supporting data capture, biomaterial transfer inventory and connection to ENSAT registry have been done. Advanced functionality includes the development of pairing algorithm for secondary study and the bulk upload of extended retrospective clinical data.
A Research Data Management Platform (RDMP) has been deployed and populated with 7 omics datasets recently provided by collaborators along with its provenance. Procurement, installation and configuration of infrastructure and hardware, for hosting omics data within Safe Heaven environment have been completed.
The Automated Multi-omics Integrative Pipeline is developed and successfully deployed on the hardware. This pipeline accesses the ENSAT-HT omics datasets through RDMP Software. It is used for the extensive analysis of multiomics data under different scenarios. The best feature selection methods and machine learning algorithms for each scenario are finalised. Multiomics signatures were identified which provide high classification accuracies.
WP2
All partners have completed pilot studies, have characterised and validated their techniques and produced standard operating procedures. Omics analysis of retrospective samples from all categories of patients has been completed. Sample bias, data normalisation processes and missing data imputation procedures have been discussed extensively and implemented. A single-omics and multi-omics signature has now been generated by WP1.
Work has been presented at national and international conferences and several high-impact factor publications have been produced.
WP3
Nearly 6000 blood and urine samples have been collected, circulated and analysed amongst the partners of WP3. Potential biomarkers for the distinction of primary and various types of endocrine hypertension have been identified using advanced measurement methods like mass-spectrometry and nuclear magnetic resonance (NMR). High classification accuracy has been achieved in single diagnostic methods. Combining catecholamine metabolites with plasma steroids obtained even better results than the single omics alone. This provides a promising outlook for the distinct combination of biomarkers that finally create the signature of biomarkers.
WP4
The clinical protocol has been written and all the criteria for the e-CRF have been established in collaboration with WP1, WP2 and WP5. Standard operating procedures for the management of blood samples for the omics assessment and hormonal assessment have been written. Four centers have started recruitment of patients for the clinical accuracy study during the first periods. Additional center have been identified to increase inclusion rates. During period 3, three new clinical centers have received ethical approval. Seven active centers are now including patients in the protocol. Recruitment rates have significantly increased over the last period.
WP5
A review of omics assessment methods used by the main HTA bodies - national public agencies, other public and private organizations â€“ was undertaken, in order to identify the evidence required, in terms of criteria used and methods applied. Only multi-analyte assays with algorithmic analyses (MAAA), cancer and non-cancer, non-companion (stand-alone) tests that are actionable and have been evaluated by at least one HTA body until May 2016 were included. As assessment criteria, clinical validity and clinical utility were largely used, as well as economic, ethical, legal and social aspects. The two main models used were the EUnetHTA Core model or the ACCE framework, which could be adapted to the assessment of MAAAs. The work was validated with EUnetHTA.
The endpoint selection for the economic evaluation has been finalized. The economic evaluation will start once the clinical study will have been further advanced.
WP6
A project website was created and regularly updated with

Final results

ENSAT-HT will provide innovative solutions for the development of better diagnostic biomarkers to improve identification of EHBP, with further exploration for stratifying patients with PHT. Results obtained through ENSAT-HT will lead to the development of new bioinformatic tools, data management solutions, the implementation of new statistical methods to deal with multi-signal assays in clinical practice and new HTA methods for their evaluation.

This project will have a strong impact on knowledge, by improving the understanding of the molecular and pathophysiological mechanisms involved in the most common forms of endocrine hypertension, allowing the redefinition of a novel, prognostically and therapeutically relevant disease taxonomy. Patient benefit will be derived from earlier, more precise and cost-efficient diagnosis, and from widespread availability of diagnostic tests outside from specialized referral centres, which has the potential to reduce health care disparity over the territory. Better informed medical decisions will improve therapeutic outcome thanks to better targeted therapies and earlier disease intervention, improving cure rate and QoL and reducing comorbidities.
A decrease in health care costs is expected from the early detection and improved effective and cost efficient treatment of EHBP at a subclinical stage and from prevention of cardiovascular and metabolic complications.