Periodic Reporting for period 4 - TAXINOMISIS (A multidisciplinary approach for the stratification of patients with carotid artery disease)
Periodo di rendicontazione: 2022-07-01 al 2023-12-31
The TAXINOMISIS project aims to provide novel disease mechanism-based stratification for carotid artery disease patients to address the need for stratified and personalised therapeutic interventions in the current era. TAXINOMISIS established a rational new approach for the stratification of carotid artery disease patients by unwinding the pathobiology that underlies carotid artery disease, discriminating distinct disease mechanism-driven states (endotypes) and measurable biological indicators (biomarkers), and developed a multiscale risk stratification tool. The TAXINOMISIS risk stratification tool has combined clinical and personalized data, plaque and cerebral image processing and haemodynamics, with computer models and simulations for plaque growth, risk for rupture and novel biomarkers for high versus low risk states. It has been validated following ASME V&V 40, an FDA-recognized standard that provides a risk framework to establish the credibility requirements of a computational model. This is accompanied by the development of a novel pharmacogenomics solution showing how an individual's genetic inheritance affects the body's response to drugs. Specifically, the TAXINOMISIS lab-on-a-chip technology is a miniature platform that can manipulate and analyze small volumes of fluids which can refine patient stratification and personalized medical treatment. The evaluation of the new risk stratification model and the lab-on-a-chip device was performed through a multicenter clinical study. The assessment of the commercialization opportunities through cost effectiveness analysis and review of the ethical and regulatory issues versus the current practices and guidelines were among the objectives of TAXINOMISIS.
The introduction of a novel computational tool for patient risk stratification to assist clinical decision-making introduces a new way of patient monitoring and treatment, providing more accurate, predictive and timely decisions, which might support better intervention, reduce the health costs and contribute to the patients’ Quality of Life. The molecular mechanisms, the new endotypes, the unique pattern or representation of a molecule's chemical structure and properties (molecular fingerprints) for high risk, the risk stratification tool and the lab on chip emphasize the improved cost-effectiveness of the new approach and the new research and innovation opportunities for SMEs in the transition to new more personalized medicine principles.
The introduction of a novel computational tool for patient risk stratification to assist clinical decision-making introduces a new way of patient monitoring and treatment, providing more accurate, predictive and timely decisions, which might support better intervention, reduce the health costs and contribute to the patients’ Quality of Life. The molecular mechanisms, the new endotypes, the unique pattern or representation of a molecule's chemical structure and properties (molecular fingerprints) for high risk, the risk stratification tool and the lab on chip emphasize the improved cost-effectiveness of the new approach and the new research and innovation opportunities for SMEs in the transition to new more personalized medicine principles.
TAXINOMISIS combined expertise in multidisciplinary areas to provide new knowledge on the clinical, biological and engineering domains. From a biological point of view, cellular composition of plaque specimens was assessed using mass cytometry (a novel platform for high-dimensional phenotypic and functional analysis of single cells) revealing a prevalence of T cells and myeloid cells. Ceramides and phosphatidylcholines were identified as potential markers for high-risk patients. Cardiovascular disease-related proteins in plasma extracellular vesicles (cell-derived membrane-surrounded vesicles that carry bioactive molecules and deliver them to recipient cells) were associated with major adverse cardiovascular events. Five new endotypes were defined by clustering atherosclerotic plaque and plasma patient samples into biologically and clinically relevant disease subtypes namely fibrous, inflammatory, lipo-necrotic, fibro-inflammatory, and fibro-productive. Lipo-necrotic and fibro-inflammatory were associated with high risk, inflammatory with intermediate risk and fibrous and fibro-productive with low risk.
TAXINOMISIS developed two tools: the risk stratification tool and the lab-on-a chip. The risk stratification tool is a user-friendly, cloud-based platform addressing the standard of care gaps in risk stratification and decision making. Risk assessment is provided using machine learning algorithms, computational fluid dynamics and predictive modeling. The platform considers various data such as personal information, blood exams, medication, and imaging data and was validated using data from 345 patients participating in the TAXINOMISIS observational clinical study. The risk stratification tool is based on a 3-level approach defined by clinical experts. The first level utilizes cutting-edge machine learning algorithms to predict more accurately an individual's risk of carotid artery disease. The second level leverages the power of computational fluid dynamics to simulate blood flow. The calculation of wall shear stress enhances the understanding of the mechanical forces contributing to plaque buildup. The third level uses computational models to simulate the progression of plaque over time allowing clinicians to forecast plaque growth and identify high risk patients.
In addition, a lab-on-a-chip device was developed and tested. Thirteen different single nucleotide polymorphisms (a variation at a single position in a DNA sequence among individuals) were detected which are relevant for patient treatment. The single nucleotide polymorphisms’ detection was based on quantitative polymerase chain reaction, a technique that combines amplification of a target DNA sequence with quantification of the concentration of that DNA species in the reaction.
The regulatory roadmap of TAXINOMISIS was defined. The risk stratification tool was categorized as class IIb according to Regulation (EU) 2017/745 on medical devices. The lab-on-a-chip was categorized as class A (instrument) according to Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices.
The TAXINOMISIS results were disseminated and communicated using Journal and conference publications, exhibitions, demonstrations to experts, social media, and videos. Exploitation and commercialization activities included market analysis, Intellectual Property Rights and a business model. Also, a patent has been submitted.
TAXINOMISIS developed two tools: the risk stratification tool and the lab-on-a chip. The risk stratification tool is a user-friendly, cloud-based platform addressing the standard of care gaps in risk stratification and decision making. Risk assessment is provided using machine learning algorithms, computational fluid dynamics and predictive modeling. The platform considers various data such as personal information, blood exams, medication, and imaging data and was validated using data from 345 patients participating in the TAXINOMISIS observational clinical study. The risk stratification tool is based on a 3-level approach defined by clinical experts. The first level utilizes cutting-edge machine learning algorithms to predict more accurately an individual's risk of carotid artery disease. The second level leverages the power of computational fluid dynamics to simulate blood flow. The calculation of wall shear stress enhances the understanding of the mechanical forces contributing to plaque buildup. The third level uses computational models to simulate the progression of plaque over time allowing clinicians to forecast plaque growth and identify high risk patients.
In addition, a lab-on-a-chip device was developed and tested. Thirteen different single nucleotide polymorphisms (a variation at a single position in a DNA sequence among individuals) were detected which are relevant for patient treatment. The single nucleotide polymorphisms’ detection was based on quantitative polymerase chain reaction, a technique that combines amplification of a target DNA sequence with quantification of the concentration of that DNA species in the reaction.
The regulatory roadmap of TAXINOMISIS was defined. The risk stratification tool was categorized as class IIb according to Regulation (EU) 2017/745 on medical devices. The lab-on-a-chip was categorized as class A (instrument) according to Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices.
The TAXINOMISIS results were disseminated and communicated using Journal and conference publications, exhibitions, demonstrations to experts, social media, and videos. Exploitation and commercialization activities included market analysis, Intellectual Property Rights and a business model. Also, a patent has been submitted.
The clinical practice in carotid artery disease is based on the guidelines of the European Society for Vascular Surgery which often fall short in terms of predictive accuracy and comprehensiveness, they rarely cater to the individual characteristics of each patient and screening for asymptomatic patients is not recommended. TAXINOMISIS managed to characterize the gene expression profile (which specific genes from the entire genome are being expressed in particular cells at any given time) of symptomatic and asymptomatic patients, to determine the cellular composition of atherosclerotic plaques, to assess the predictive value of ceramides and extracellular vesicle biomarkers in carotid artery disease, to identify five new endotypes and circulating biomarkers (whole cells, such as circulating tumour cells, subcellular extracellular vesicles and cell-free factors such as DNA, RNA and proteins) associated with plaque erosion and rupture. A computational multilevel platform for risk stratification and decision making was introduced, which can improve monitoring and treatment assisting in the avoidance of clinical exams and unnecessary treatments, through an accurate predictive approach, which might lead to timely and more efficient intervention. The platform has demonstrated wide acceptance by the experts and cost benefits for the healthcare system. The platform is accompanied by a newly developed lab-on-a-chip to improve patients’ risk stratification through pharmacogenomics.