Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - TAXINOMISIS (A multidisciplinary approach for the stratification of patients with carotid artery disease)

Teaser

Carotid artery disease, the primary trigger of ischaemic cerebrovascular events including stroke, causes major morbidity, mortality and healthcare costs worldwide. Still, treatment is based on criteria established in the 90s that do not take into account the molecular...

Summary

Carotid artery disease, the primary trigger of ischaemic cerebrovascular events including stroke, causes major morbidity, mortality and healthcare costs worldwide. Still, treatment is based on criteria established in the 90s that do not take into account the molecular evolution we have witnessed since, nor the introduction of new medication, leading to remarkably high unnecessary surgical treatment while missing most patients at risk. TAXINOMISIS will provide novel disease mechanism-based stratification for carotid artery disease patients to address the needs for stratified and personalised therapeutic interventions in the current era. TAXINOMISIS will deliver, as a main outcome, a software platform, which can perform the risk stratification.

TAXINOMISIS has the following six objectives:
-To characterize the mechanisms mediating carotid artery disease in the present era and current patient domain, and identify susceptibility and protection factors of plaque symptomatology through the exploitation of longitudinal cohorts and biobanks, deep cell profiling and multi-omics of carotid atherosclerosis.
-To apply systems biomedicine approaches, in order to define distinct disease endotypes and generate molecular fingerprints of high versus low risk states encompassing existing and novel circulatory biomarkers, to assist patient stratification and disease prognosis.
-To integrate computational multilevel models with agent based models and develop a risk stratification tool, to assist patient stratification and clinical decision making.
-To develop novel pharmacogenomics solutions for carotid artery disease based on an innovative lab-on-a-chip technology to refine patient stratification and support personalized medical treatment.
-To evaluate the effectiveness of the new risk stratification model and the lab-on-a-chip device in an international multicentre clinical study setting.
-To assess the commercialization opportunities through cost effectiveness analysis and review of the ethical and regulatory implications of the new risk stratification tool versus the current practices and guidelines.

The benefits for society are:
- The establishment of new computational models for patient stratification to assist clinical decision-making.
- The acceleration of the biomedical and clinical research results to medical use.
- The improved cost-effectiveness of the new approach compared to established clinical practices.
- The new research and innovation opportunities for small or medium-sized enterprises.

TAXINOMISIS project officially started as of 1st of January 2018. The consortium consists of 16 partners from 10 countries.

Work performed

WP1:
-Plaque phenotyping for all plaques that underwent bulk RNA sequencing (n= +/- 700)
-Sequencing data and QC
-First exploratory results of RNA signatures for differences between symptomatic and asymptomatic patients
-Clear patterns in the RNA expression data, grouping patients
-Data obtained regarding clinical presentation (asymptomatic, TIA, stroke, amaurosis fugax), risk factors and medication and other relevant patient characteristics
-Plaque characterization of all newly included plaques used to execute single cell sequencing
-Cellular composition of fresh plaque specimens from patients undergoing CEA using CyTOF
-Prevalence of T cells (CD4 and CD8) making up between 36 to 60% of the CD45+ population of the plaque with myeloid cells constituting the second majority with percentages ranging from 10 to 30% of all CD45+cells

WP2:
-Comprehensive clinical, biochemical and molecular data including omics from the AtheroExpress cohort
-Various methodologies (dimensionality reduction (PCA, t-SNE) and Feature Selection methods (FS) to visualize data, reduce noise and improve analyses)
-Unsupervised clustering analysis techniques (K-means and Hierarchical clustering)
-Assessmnent of the significance of the clusters generated
-Asymptomatic patients may share plaque characteristics similar to patients with amaurosis fugax
-More fibrous lesions are observed in patients who are asymptomatic or suffer from amaurosis fugax
-Patients with a TIA or stroke more often reveal lipid rich lesions
-Circulating biomarkers associated with asymptomatic or symptomatic patients

WP3:
-Review of the literature and available commercial software solutions
-3D vessel reconstruction and plaque characterization methodologies for carotid MRI, CT and US imaging
-MRI: Semi-automatic approaches using hybrid models of image processing methods together with supervised machine learning techniques
-CT: Calibration of an already existing methodology for the 3D reconstruction of coronary arteries for carotid arteries
-Annotation tools for MRI, CT and US imaging modalities
-Image quality control
-Guidelines for Duplex image acquisition
-Development of the agent based model of plaque progression
-Linkage between the NIVEL database, the UMCU Athero-Express cohort and the DIS health insurance claims database
-Conceptual framework and a first description of the overall architecture of the risk stratification tool


WP4:
-Informative pharmacogenetic markers for patient stratification and personalized treatment based on the literature
-PCR chips allowing singleplex and multiplex qPCR on chip in a single heated cavity
-PC-driven temperature controller with a custom user interface so parameters can easily be adjusted during PCR optimization
-The single cavity PCR chips were further used to optimize the on-chip PCR using TaqMan probe assays for the suite of SNPs.
- The activity of 14 commercial SNP assay was tested on the qPCR Lightcycler benchtop reference
-On-chip testing (aliquots of the assays together with three DNA samples)
-Optimization of the on-chip PCR master mix and the temperature cycling profile
-Different designs for advanced multiplex PCR chips
-A novel processing workflow was established to enable the fabrication of the advanced open fluidics multi-cavity chip designs
-A physical clamp was designed that has an elastic protrusion fitting into the central channel of the chip, thereby avoiding cross-contamination between the different cavities
-Thermal simulations using COMSOL Multiphysics

WP5:
-Clinical trial protocol
-Submission of the protocol in www.clinicaltrials.gov (study ID: NCT03495830)
-Ethical Approval obtained for all clinical centers
-244 patients have been enrolled
-electronic Case Report Form development

WP6:
-Clinical centers monitored by ESCVS
-Ethical and Legal issues addressed by the clinical study protocol

WP7:
-Communication and dissemination strategy (v1)
-Exploitation strategy (v1)

Final results

TAXINOMISIS solution has innovative and distinctive characteristics which rely on the ability to stratify vulnerable plaques based on the information collected from a large population of carotid artery disease patients. The business model supports the way in which TAXINOMISIS software platform can be proposed to the market and it is built on three distinctive factors which are:
• A tool to profile the patient’s plaque phenotypes and endotypes that will be implemented through state-of-the-art computational and mathematical models and algorithms
• A data stratification tool to stratify the patients according to their disease risk
• A lab-on-a-chip tool to improve risk stratification of patients through pharmacogenomics

Website & more info

More info: https://taxinomisis-project.eu/.