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Application of omics-based strategies for improved diagnosis and treatment of endocrine hypertension

Periodic Reporting for period 4 - ENSAT-HT (Application of omics-based strategies for improved diagnosis and treatment of endocrine hypertension)

Reporting period: 2019-05-01 to 2020-04-30

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 Cushing’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.
Creation, development and maintenance of ENSAT-HT clinical data capture model. Creation and maintenance of online registry supporting data capture, biomaterial transfer inventory and connection to ENSAT registry. Main work in this period is the further development of and output of monitoring report of eCRFs, as well as continuous linkage between ENSAT-HT and ENSAT.
The Automated Multi-omics Integrative Pipeline was developed and successfully deployed on the hardware. It is used for the extensive machine learning based analysis of multiomics data under different scenarios. The first identified multiomics signature and related classification accuracies were shared with collaborators.
A patent application is currently being drafted for the final multiomics signature. Also multiomics and monomics manuscripts are drafted and circulated amongst collaborators for their feedback.
Within period 4, WP2 has made significant progress. Omics analysis of the retrospective samples has been completed. Complex data normalisation processes and missing data imputation procedures have been implemented. Using this expansive data set, a single-omics and multi-omics signature for each disease has been generated by WP1 which will be tested in the prospective study in WP4. Samples from WP4 have been processed and circulated and OMICs measurements have commenced.
There have been a number of highly productive scientific exchanges within WP2, including visits to partner laboratories. Work has been presented at several national and international conferences and several high-impact factor publications acknowledging ENSAT-HT have been produced. Discussion with intellectual property officers regarding the single omics and multi-omics signature is ongoing.
Samples from the prospective study in WP4 have been received by all centers. Measurement and analysis of plasma metanephrine, normetanephrine and 19 adrenal steroids have started and are predicted to be completed by September 2020. Measurement of urinary steroids on samples from the retrospective cohort have been run at UOB by a newly developed high throughput LC-MS/MS method to quantify 27 adrenal steroids. The method has been re-validated on a new mass spectrometer in anticipation of the measurements to perform for the prospective cohort. Plasma and urine samples were collected and analyzed by NMR spectroscopy and the spectral processing pipeline was further developed and validated for the prospective study.
In WP4, the clinical work package, recruitment of patients for a prospective accuracy study took off with the establishment of a clinical protocol, which was submitted and approved in all participating centers. Patient recruitment initially lagged behind, but with the inclusion of additional centers, currently more than 2200 patients have been included. A new statistical plan has been developed to determine the accuracy of the omics signature in diagnosing endocrine forms of hypertension.
A Review of the literature on health technology assessment of omics has been published. A cross country comparison of current workup strategies for endocrine hypertension and costs of the current workups for patients with endocrine hypertension have been initiated in period 4.
In period 4 of ENSAT-HT the main activity for WP6 was the preparation of the patent filing of the biomarker signature and the different discussions for future uptake/exploitation of this signature and the efforts for finding and industrial partners for its uptake. The twitter account of ENSAT-HT has been updated regularly throughout the period.
In period 4 the main activity was the preparation of the amendment for the no-cost extension request of the project of 12 months. The monitoring of the project has been done very regularly, especially in view of the establishment and keeping of the new timeline including the prolongation period. A patent application is currently being drafted for the final multiom
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.
Work package scheme of the project
Gepgraphic map of Partners participating in the project
Photo bought from istock