in-silico-clinical-trials-for-cardiovascular-disease

<em>In Silico</em> Clinical Trials for Cardiovascular Disease

The SILICOFCM project mainly aims to develop a computational platform for in silico clinical trials of familial cardiomyopathies (FCMs). The unique ...

Bioengineering Research and Development Center BioIRC

University of Kragujevac

One of the critical components of the respiratory drug delivery is the manner in which the inhaled aerosol is deposited in respiratory tract compartments. Depending on formulation properties, device characteristics and breathing pattern, only a certain fraction of the dose will reach the target site in the lungs, while the rest of the drug will deposit in the inhalation device or in the mouth-throat region. The aim of this study was to link the Computational fluid dynamics (CFD) with physiologically-based pharmacokinetic (PBPK) modelling in order to predict aerolisolization of different dry powder formulations, and estimate concomitant in vivo deposition and absorption of amiloride hydrochloride. Drug physicochemical properties were experimentally determined and used as inputs for the CFD simulations of particle flow in the generated 3D geometric model of Aerolizer® dry powder inhaler (DPI). CFD simulations were used to simulate air flow through Aerolizer® inhaler and Discrete Phase Method (DPM) was used to simulate aerosol particles deposition within the fluid domain. The simulated values for the percent emitted dose were comparable to the values obtained using Andersen cascade impactor (ACI). However, CFD predictions indicated that aerosolized DPI have smaller particle size and narrower size distribution than assumed based on ACI measurements. Comparison with the literature in vivo data revealed that the constructed drug-specific PBPK model was able to capture amiloride absorption pattern following oral and inhalation administration. The PBPK simulation results, based on the CFD generated particle distribution data as input, illustrated the influence of formulation properties on the expected drug plasma concentration profiles. The model also predicted the influence of potential changes in physiological parameters on the extent of inhaled amiloride absorption. Overall, this study demonstrated the potential of the combined CFD-PBPK approach to model inhaled drug bioperformance, and suggested that CFD generated results might serve as input for the prediction of drug deposition pattern in vivo.

Coupled in silico platform: Computational fluid dynamics (CFD) and physiologically-based pharmacokinetic (PBPK) modelling.

This paper presents the improved technique for classification of the type of lumbar discus hernia based on fuzzy logic. The reduced mobility of the foot is one of the symptoms of the disease that occurs because of the displaced discs in the space of two vertebrae. This fact was used for non-invasive discus hernia diagnosis by measuring force values from four sensors placed on both feet (first, second and fourth metatarsal head as well as the heel). Hardware and software systems were constructed for the doctor to perform the measurements and have a graphical representation during the measuring procedure. The procedure included measuring force values of 18 subjects during normal standing, standing on forefeet and heels. All subjects were diagnosed by a specialist with either L4/L5 or L5/S1 discus hernia. Filtering and further preprocessing of acquired values included separation of forefeet and heel segments that were used as inputs to fuzzy system. The results showed that the accuracy of such a fuzzy system was around 72%, and the proposed system correctly recognizes healthy individuals. Obtained information about forces on characteristic points on the foot represents useful data in diagnosis which further can be processed in order to be a supportive tool to doctors.

Non-invasive improved technique for lumbar discus hernia classification based on fuzzy logic.

The aim of this work was to investigate effects of the formulation factors on tablet printability as well as to optimize and predict extended drug release from cross-linked polymeric ibuprofen printlets using an artificial neural network (ANN). Printlets were printed using digital light processing (DLP) technology from formulations containing polyethylene glycol diacrylate, polyethylene glycol, and water in concentrations according to D-optimal mixture design and 0.1% ww riboflavin and 5% w/w ibuprofen. It was observed that with higher water content longer exposure time was required for successful printing. For understanding the effects of excipients and printing parameters on drug dissolution rate in DLP printlets two different neural networks were developed with using two commercially available softwares. After comparison of experimental and predicted values of in vitro dissolution at the corresponding time points for optimized formulation, the R experimental vs. predicted value was 0.9811 (neural network 1) and 0.9960 (neural network 2). According to difference  and similarity factor  ( = 14.30 and  = 52.15) neural network 1 with supervised multilayer perceptron, backpropagation algorithm, and linear activation function gave a similar dissolution profile to obtained experimental results, indicating that adequate ANN is able to set out an input-output relationship in DLP printing of pharmaceutics.

Optimization and Prediction of Ibuprofen Release from 3D DLP Printlets Using Artificial Neural Networks.

The aim of this research was to investigate the best methodology for disc hernia diagnosis using foot force measurements from the designed platform. Based on the subjective neurological examination that examines muscle weakness on the nerve endings of the skin area on feet and concludes about origins of nerve roots between spine discs, a platform for objective recordings of the aforementioned muscle weakness has been designed. The dataset included 33 patients with pre-diagnosed L4/L5 and L5/S1 disc hernia on the left or the right side, confirmed with the MRI scanning and neurological exam. We have implemented 5 different classifiers that were found to be the most suitable for smaller dataset and investigated the accuracy of classification depending on the normalization method, linearity/non-linearity of the algorithm, and dataset splitting variation (32-1, 31-2, 30-3, 29-4 patients for training and testing, respectively). The classifier is able to distinguish between four different diagnoses L4/L5 on the left side, L4/L5 on the right side, L5/S1 on the left side and L5/S1 on the right side, as well as to recognize healthy subjects (without disc herniation). The results show that non-linear algorithms achieved better accuracy in comparison to tested linear classifiers, suggesting the expected non-linear connection between the foot force values and the level of disc herniation. Two algorithms with highest accuracy turned out to be Decision Tree and Naïve Bayes, depending on the normalization method. The system is also able to record and recognize improvements in muscle weakness after surgical operation and physical therapy.

A comparison of classifiers in biomedical signal processing as a decision support system in disc hernia diagnosis.

 Systems Medicine is a novel approach to medicine, that is, an interdisciplinary field that considers the human body as a system, composed of multiple parts and of complex relationships at multiple levels, and further integrated into an environment. Exploring Systems Medicine implies understanding and combining concepts coming from diametral different fields, including medicine, biology, statistics, modeling and simulation, and data science. Such heterogeneity leads to semantic issues, which may slow down implementation and fruitful interaction between these highly diverse fields.  In this review, we collect and explain more than100 terms related to Systems Medicine. These include both modeling and data science terms and basic systems medicine terms, along with some synthetic definitions, examples of applications, and lists of relevant references.  This glossary aims at being a first aid kit for the Systems Medicine researcher facing an unfamiliar term, where he/she can get a first understanding of them, and, more importantly, examples and references for digging into the topic.

An Early Stage Researcher's Primer on Systems Medicine Terminology.

Although ML has been studied for different epidemiological and clinical issues as well as for survival prediction of COVID-19, there is a noticeable shortage of literature dealing with ML usage in prediction of disease severity changes through the course of the disease. In that way, predicting disease progression from mild towards moderate, severe and critical condition, would help not only to respond in a timely manner to prevent lethal results, but also to minimize the number of patients in hospitals where this is not necessary.

Artificial intelligence approach towards assessment of condition of COVID-19 patients - Identification of predictive biomarkers associated with severity of clinical condition and disease progression.

The release of metal particles and ions due to wear and corrosion is one of the main underlying reasons for the long-term complications of implantable metallic implants. The rather short-term focus of the established  biocompatibility tests cannot take into account such effects. Corrosion behavior of metallic implants mostly investigated in  body-like environments for long time periods and their coupling with long-term  experiments are not practical. Mathematical modeling and modeling the corrosion mechanisms of metals and alloys is receiving a considerable attention to make predictions in particular for long term applications by decreasing the required experimental duration. By using such  approaches, the corrosion conditions for later stages can be mimicked immediately in i experiments. For this end, we have developed a mathematical model for multi-pit corrosion based on Cellular Automata (CA). The model consists of two sub-models, corrosion initialization and corrosion progression, each driven by a set of rules. The model takes into account several environmental factors (pH, temperature, potential difference, etc.), as well as stochastic component, present in phenomena such as corrosion. The selection of NiTi was based on the risk of Ni release from the implant surface as it leads to immune reactions. We have also performed experiments with Nickel Titanium (NiTi) shape memory alloys. The images both from simulation and experiments can be analyzed using a set of statistical methods, also investigated in this paper (mean corrosion, standard deviation, entropy etc.). For more widespread implementation, both simulation model, as well as analysis of output images are implemented as a web tool. Described methodology could be applied to any metal provided that the parameters for the model are available. Such tool can help biomedical researchers to test their new metallic implant systems at different time points with respect to ion release and corrosion and couple the obtained information directly with  tests.

An  Corrosion Model for Biomedical Applications for Coupling With  Biocompatibility Tests for Estimation of Long-Term Effects.

Since the outbreak of coronavirus disease-2019 (COVID-19), the whole world has taken interest in the mechanisms of its spread and development. Mathematical models have been valuable instruments for the study of the spread and control of infectious diseases. For that purpose, we propose a two-way approach in modeling COVID-19 spread: a susceptible, exposed, infected, recovered, deceased (SEIRD) model based on differential equations and a long short-term memory (LSTM) deep learning model. The SEIRD model is a compartmental epidemiological model with included components: susceptible, exposed, infected, recovered, deceased. In the case of the SEIRD model, official statistical data available online for countries of Belgium, Netherlands, and Luxembourg (Benelux) in the period of March 15 2020 to March 15 2021 were used. Based on them, we have calculated key parameters and forward them to the epidemiological model, which will predict the number of infected, deceased, and recovered people. Results show that the SEIRD model is able to accurately predict several peaks for all the three countries of interest, with very small root mean square error (RMSE), except for the mild cases (maximum RMSE was 240.79 ± 90.556), which can be explained by the fact that no official data were available for mild cases, but this number was derived from other statistics. On the other hand, LSTM represents a special kind of recurrent neural network structure that can comparatively learn long-term temporal dependencies. Results show that LSTM is capable of predicting several peaks based on the position of previous peaks with low values of RMSE. Higher values of RMSE are observed in the number of infected cases in Belgium (RMSE was 535.93) and Netherlands (RMSE was 434.28), and are expected because of thousands of people getting infected per day in those countries. In future studies, we will extend the models to include mobility information, variants of concern, as well as a medical intervention, etc. A prognostic model could help us predict epidemic peaks. In that way, we could react in a timely manner by introducing new or tightening existing measures before the health system is overloaded.

Epidemiological Predictive Modeling of COVID-19 Infection: Development, Testing, and Implementation on the Population of the Benelux Union.

In vitro assessment of dry powders for inhalation (DPIs) aerodynamic performance is an inevitable test in DPI development. However, contemporary trends in drug development also implicate the use of in silico methods, e.g., computational fluid dynamics (CFD) coupled with discrete phase modeling (DPM). The aim of this study was to compare the designed CFD-DPM outcomes with the results of three in vitro methods for aerodynamic assessment of solid lipid microparticle DPIs. The model was able to simulate particle-to-wall sticking and estimate fractions of particles that stick or bounce off the inhaler's wall; however, we observed notable differences between the in silico and in vitro results. The predicted emitted fractions (EFs) were comparable to the in vitro determined EFs, whereas the predicted fine particle fractions (FPFs) were generally lower than the corresponding in vitro values. In addition, CFD-DPM predicted higher mass median aerodynamic diameter (MMAD) in comparison to the in vitro values. The outcomes of different in vitro methods also diverged, implying that these methods are not interchangeable. Overall, our results support the utility of CFD-DPM in the DPI development, but highlight the need for additional improvements in these models to capture all the key processes influencing aerodynamic performance of specific DPIs.

Tijana Sustersic

Bioengineering Research and Development Center BioIRC

In Silico Clinical Trials for Cardiovascular Disease