The overall hypothesis of HT-ADVANCE is that omics-derived strategies directed at patients with HT can provide a means for improved identification of EHT for curative treatment and prevention of cardiovascular and metabolic complications as well as stratification of patients with PHT for efficient and cost-effective therapy according to the underlying pathogenic makeup revealed by MOMICS biomarkers.

Partners of this consortium have developed MOMICS biomarkers for EHT, but the effectiveness of these biomarkers in clinical practice needs to be established.


The HT-Advance project builds on results from the previously funded H2020 ENSAT-HT program, which has generated MOMICS signatures for the identification of EHT, enabling us to discriminate between PA, PPGL, CS and PHT based on composite biomarkers, including urinary and plasma steroids, plasma catecholamine metabolites, plasma miRNAs and plasma small metabolites.

Stratification approach

In this respect, we have developed a ML pipeline that has integrated >400 MOMICS features measured in 487 subjects from a retrospective cohort; subsequently it has been retrained and validated on ~1100 hypertensive patients prospectively recruited within the ENSAT-HT multicentre study.

This innovative approach to stratification has allowed us to distinguish the four conditions in multi-class, all versus all comparisons with 96% specificity and 0.95 AUC using a set of 57 features (Patent application PCT/EP2022/053142; Reel et al, Lancet EBioMed under review). As such, ENSAT-HT has generated several technological and methodological innovations, such as algorithms and security-oriented data integration methods, novel ML predictors, software, web-based tools for disease classification, establishment of standardized operating procedures (SOPs) for omics measurements and economic models for the evaluation of omics technologies (Nind et al, GigaScience, 2018:7:giy060; Reel et al, Biotechnology Advances, 2021: 49: 107739; Arlt et al, JCI insight, 2017;2: e93136; MacKenzie et al, Cancers, 2021, 13:5312; Barna et al, International Journal of Technology Assessment in Health Care, 2018:34, 368-377).

Challenges and technologies

Key advances include the identification of MOMICS signatures for EHT (Patent application PCT/EP2022/053142; Reel et al, Lancet EBioMed under review), as well as different mono-omics signatures providing not only useful biomarker options, but also functional and mechanistic insights into disease mechanisms (Erlic et al, J Clin Endocrinol Metab. 2021 Mar 25;106(4):1111–1128; Williams et al, Hypertension, 2016;67:139–145). In addition, ENSAT-HT has allowed us to identify and address major challenges and methodological barriers related to the implementation of omics technologies and AI as companion diagnostics in clinical practice.


All this expertise is now assembled in HT-ADVANCE, allowing us to successfully address the complexity of our project and to deliver its objectives. HT-ADVANCE will take advantage of the collaboration of six European Society of Hypertension (ESH) Centres of Excellence for Hypertension (APHP, RADBOUD, UNITO, UNIPD, CUS, UZH), who are also members of ENS@T (European Network for Study of Adrenal Tumors).


This will provide unique capability for the recruitment and workup of a large cohort of hypertensive patients, including patients with EHT. These centers have previously shown their capacity to run successful clinical trials in patients with EHT as well as PHT (Dekkers et al, Lancet. Diabetes & endocrinology. 2016;4:739-746; Azizi et al, Lancet. 2021;397:2476-2486).

Project structuration

The project will be structured into six work packages (WP) interacting in a seamless and coordinated fashion to address the aims of HT-ADVANCE. The rationale for this structure relates to the main objectives that will be achieved in the context of this proposal, which will be integrated as the proposal advances. Each WP is subdivided into specific tasks that are methodologically related but explore different aspects of the addressed objectives.

Specific objectives


Validation of MOMICS biomarkers for the identification of EHT

Validation of the previously developed MOMICS biomarkers for EHT (MOMICS-ENDO biomarkers) in an outcome-based RCT (HT-ENDO) for the stratification of patients with HT and the identification of patients with PA, PPGL and CS.
(WP1, WP2, WP3).


Identification and validation of MOMICS biomarkers for treatment efficacy in patients with PHT (MOMICS-TREAT biomarkers)

Extension of the previous successful MOMICS biomarker strategy to identify biomarkers of treatment response in PHT by performing an incomplete crossover trial (HT-PREDICT) of major drug classes. This aims to improve blood pressure control and guide personalized treatment strategies in daily clinical practice. The identified multi-omics signature will then be validated in an outcome-based pragmatic RCT (HT-TREAT) to establish the performance of MOMICS signatures as a treatment response prediction tool in clinical HT.
(WP1, WP2, WP3)


Development of an end-to-end pipeline for use of MOMICS biomarkers in clinical practice

The state of the art high performance computing and cloud-based infrastructure will help to generate a virtual research environment (VRE), providing an integrative, secure and effective research data management service, supporting the clinical trials (with eCRFs), sample tracking and quality control, omics data collection and analysis, for a seamless end-to-end solution allowing data flow from/to clinical studies. This innovative platform will employ proven machine learning (ML) pipelines to provide MOMICS predictions from the clinical trials to the clinicians through a dedicated results interface.


Development of strategies to implement the MOMICS biomarkers into clinical practice

HT-Advance will devise strategies for the deployment of MOMICS biomarkers as companion diagnostics by providing a roadmap and recommendations to prepare their translation into health policies and healthcare systems and industrial exploitation.
(WP4, WP5)


Assessment of the MOMICS approach as companion diagnostics for improved health outcomes in HT

An economic evaluation of the use of MOMICS biomarkers as companion diagnostics for improved treatment in HT regarding care pathways, outcomes and costs will be conducted. We will also address ethical, legal and regulatory issues related to the uptake of our MOMICS strategy, in particular the ethical issues of implementing artificial intelligence (AI)-based companion diagnostics into clinical practice.