Periodic Reporting for period 2 - TO_AITION (A high-dimensional approach for unwinding immune-metabolic causes of cardiovascular disease-depression multimorbidities)
Période du rapport: 2021-07-01 au 2022-12-31
Depression is a common and serious comorbidity of cardiovascular disease (CVD) affecting one in three patients, among which women earlier and more frequently. Depression increases the risk for cardiovascular disease development, acute events and mortality by >2 fold, independently of traditional risk factors, and constitutes an enormous socioeconomic burden in terms of morbidity, mortality and healthcare costs. Still, the patients that are at risk of developing cardiovascular disease and depression, the trajectories of disease development (i.e. what develops first and when), and the causative mechanisms involved remain unknown.
TO_AITION addresses the hypothesis that the common theme for the development of these diseases is low grade systemic inflammation which is of low intensity and goes unnoticed but which eventually causes cardiovascular disease, depression or both. The project thus focuses at the genetic, lifestyle and environmental risk factors that can drive drives low grade systemic inflammation and disease, aiming at characterizing critical biological pathways, molecules and biomarkers involved. Central to the project's objectives is the use of large population studies with long-term follow up and comprehensive disease (cardiovascular disease or depression) and molecular data, and the use of some of the most advanced methodologies for obtaining, combining and analyzing molecular data, and characterizing individuals at risk, disease phenotypes and novel targets for therapy. Preclinical studies with cell assays based on patients' cells, and experimental animal models further complement this approach.
The purpose of TO_AITION is translational, aiming at developing novel tools for the diagnosis, prognosis and monitoring of patients.
In order to disseminate the problem TO_AITION is dealing with, to both patients and physicians of different disciplines, effective patient-oriented awareness actions, dissemination, exploitation and management activities are also implemented through the project's website, social media, scientific meetings and other channels of communication.
TO_AITION is therefore trying to rationally change our current understanding of the causative mechanisms driving cardiovascular disease, comorbidity, unravelling patients’ complexity and improving their diagnosis, monitoring and management.
TO_AITION addresses the hypothesis that the common theme for the development of these diseases is low grade systemic inflammation which is of low intensity and goes unnoticed but which eventually causes cardiovascular disease, depression or both. The project thus focuses at the genetic, lifestyle and environmental risk factors that can drive drives low grade systemic inflammation and disease, aiming at characterizing critical biological pathways, molecules and biomarkers involved. Central to the project's objectives is the use of large population studies with long-term follow up and comprehensive disease (cardiovascular disease or depression) and molecular data, and the use of some of the most advanced methodologies for obtaining, combining and analyzing molecular data, and characterizing individuals at risk, disease phenotypes and novel targets for therapy. Preclinical studies with cell assays based on patients' cells, and experimental animal models further complement this approach.
The purpose of TO_AITION is translational, aiming at developing novel tools for the diagnosis, prognosis and monitoring of patients.
In order to disseminate the problem TO_AITION is dealing with, to both patients and physicians of different disciplines, effective patient-oriented awareness actions, dissemination, exploitation and management activities are also implemented through the project's website, social media, scientific meetings and other channels of communication.
TO_AITION is therefore trying to rationally change our current understanding of the causative mechanisms driving cardiovascular disease, comorbidity, unravelling patients’ complexity and improving their diagnosis, monitoring and management.
During this period, significant progress has been realized in several areas as highlighted below.
First, the TO_AITION cloud platform has been implemented, enabling data storage and processing of the many datasets of the project. Harmonization activities of the various cohorts’ datasets, rendering data in a similar format so that they can be analyzed together, have also taken place. There has also been enrichment of the Athero-Express Biobank Study with the OLINK® proteomics technology, providing new data for circulating biomarkers for about 700 patients.
For the analysis of the various cohorts, numerous methodologies are employed, and new analytical and computational models, and pipelines, are under development. The construction of multiplex disease networks, the identification of shared risk markers common to both CVD outcomes and depression, and the uncovering of synergistic associations within disease networks and markers linked to multimorbidity is ongoing. Initial analyses have been performed using datasets from the NESDA, HELIUS, LIFELINES, LURIC and YFS studies.
Work to implement and evaluate a range of causal inference methods deployed in the networks generated is also ongoing. These tools are addressed in order of increasing biological insight and interpretability, from identification of likely driver nodes, to rule-based network causal inference, to finally Mendelian randomization coupled with machine learning, and will lead to the characterization of new, potentially causative, mechanisms involved.
The development of purpose-built human cell-based and animal models for the evaluation of causality of novel factors and pathways identified is in progress. New genetically modified mice needed to address the project's hypotheses are under development.
For the Identification of novel biomarkers for the diagnosis, prognosis and monitoring of CVD-depression co/multimorbidities, a novel and computationally efficient methodology has been developed and is used to analyze medical data from the Ludwigshafen Risk and Cardiovascular Health (LURIC) cohort.
Regulatory and ethical aspects of the project, including Ethics approval forms, establishment of an Ethics Advisory Board, access rights, compliance with the GDPR etc, have also been effectively dealt with during this period. Various dissemination, exploitation and awareness activities have been implemented and include a project website, videos and interviews of TO_AITION researchers, an electronic newsletter, social media accounts, printed material, awareness-raising activities from the European Society of Cardiology, and others.
Finally, an efficient management structure dealing with contractual, financial and legal administration, as well as day to day management is employed.
First, the TO_AITION cloud platform has been implemented, enabling data storage and processing of the many datasets of the project. Harmonization activities of the various cohorts’ datasets, rendering data in a similar format so that they can be analyzed together, have also taken place. There has also been enrichment of the Athero-Express Biobank Study with the OLINK® proteomics technology, providing new data for circulating biomarkers for about 700 patients.
For the analysis of the various cohorts, numerous methodologies are employed, and new analytical and computational models, and pipelines, are under development. The construction of multiplex disease networks, the identification of shared risk markers common to both CVD outcomes and depression, and the uncovering of synergistic associations within disease networks and markers linked to multimorbidity is ongoing. Initial analyses have been performed using datasets from the NESDA, HELIUS, LIFELINES, LURIC and YFS studies.
Work to implement and evaluate a range of causal inference methods deployed in the networks generated is also ongoing. These tools are addressed in order of increasing biological insight and interpretability, from identification of likely driver nodes, to rule-based network causal inference, to finally Mendelian randomization coupled with machine learning, and will lead to the characterization of new, potentially causative, mechanisms involved.
The development of purpose-built human cell-based and animal models for the evaluation of causality of novel factors and pathways identified is in progress. New genetically modified mice needed to address the project's hypotheses are under development.
For the Identification of novel biomarkers for the diagnosis, prognosis and monitoring of CVD-depression co/multimorbidities, a novel and computationally efficient methodology has been developed and is used to analyze medical data from the Ludwigshafen Risk and Cardiovascular Health (LURIC) cohort.
Regulatory and ethical aspects of the project, including Ethics approval forms, establishment of an Ethics Advisory Board, access rights, compliance with the GDPR etc, have also been effectively dealt with during this period. Various dissemination, exploitation and awareness activities have been implemented and include a project website, videos and interviews of TO_AITION researchers, an electronic newsletter, social media accounts, printed material, awareness-raising activities from the European Society of Cardiology, and others.
Finally, an efficient management structure dealing with contractual, financial and legal administration, as well as day to day management is employed.
TO_AITION aims to rationally change our current understanding of the causative mechanisms driving CVD-depression co/multimorbidities, unravelling patients’ complexity, improving the diagnosis, monitoring and management of these diseases, and opening up new avenues of research and new opportunities for potential prophylactic and therapeutic intervention.
To achieve its ambitious yet realistic targets, TO_AITION takes several bold steps beyond the state-of-the-art in all of its objectives, and will lead to multiple advances in the field, many of groundbreaking nature, including:
-The epidemiology of CVD-depression co/multimorbidity: risk, susceptibility factors and disease trajectories
-The current knowledge on the heterogeneity of depression and its relationship to the development of CVD comorbidity and outcomes
-The characterization of novel CVD-depression multimorbidity phenotypes and pathobiological states
-The unwinding of novel causative mechanisms driving CVD-depression co/multimorbidity
-The identification of novel biomarkers for CVD-depression multimorbidity and development of a new biomarker test
-The development of innovative predictive multi-scale models of disease risk for improved patient stratification and management
By exploring unique longitudinal cohorts, biobanks and registries of individuals with co/multimorbidities, and existing multi-omics data, and defining disease phenotypes and pathobiological states, the project
This will bring about a step-change in the way patients are stratified, proposing patient stratification on the basis of the underlying pathobiology and presence or risk of co/multimorbidity. It will also characterize causative mechanisms of co/multimorbidity, supporting the development of disease mechanism-based targeted interventions for CVD-depression co/multimorbidities of improved efficacy, predictable drug-drug interactions and reduced side effects.
This will thus lead to earlier diagnosis and better treatment of CVD-depression co/multimorbidities, and improved healthcare of patients, while promoting research and innovation, and supporting the development and growth of relevant biotechnology and pharmaceutical industries, particularly small or medium-sized enterprises (SMEs).
To achieve its ambitious yet realistic targets, TO_AITION takes several bold steps beyond the state-of-the-art in all of its objectives, and will lead to multiple advances in the field, many of groundbreaking nature, including:
-The epidemiology of CVD-depression co/multimorbidity: risk, susceptibility factors and disease trajectories
-The current knowledge on the heterogeneity of depression and its relationship to the development of CVD comorbidity and outcomes
-The characterization of novel CVD-depression multimorbidity phenotypes and pathobiological states
-The unwinding of novel causative mechanisms driving CVD-depression co/multimorbidity
-The identification of novel biomarkers for CVD-depression multimorbidity and development of a new biomarker test
-The development of innovative predictive multi-scale models of disease risk for improved patient stratification and management
By exploring unique longitudinal cohorts, biobanks and registries of individuals with co/multimorbidities, and existing multi-omics data, and defining disease phenotypes and pathobiological states, the project
This will bring about a step-change in the way patients are stratified, proposing patient stratification on the basis of the underlying pathobiology and presence or risk of co/multimorbidity. It will also characterize causative mechanisms of co/multimorbidity, supporting the development of disease mechanism-based targeted interventions for CVD-depression co/multimorbidities of improved efficacy, predictable drug-drug interactions and reduced side effects.
This will thus lead to earlier diagnosis and better treatment of CVD-depression co/multimorbidities, and improved healthcare of patients, while promoting research and innovation, and supporting the development and growth of relevant biotechnology and pharmaceutical industries, particularly small or medium-sized enterprises (SMEs).