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Despite improved treatment, a large portion of patients with acute ischemic stroke due to a large vessel occlusion have poor functional outcome. Further research exploring novel treatments and better patient selection has therefore been initiated. The feasibility of new treatments and optimized patient selection are commonly tested in extensive and expensive randomized clinical trials. in-silico trials, computer-based simulation of randomized clinical trials, have been proposed to aid clinical trials. In this white paper, we present our vision and approach to set up in-silico trials focusing on treatment and selection of patients with an acute ischemic stroke. The INSIST project (IN-Silico trials for treatment of acute Ischemic STroke, www.insist-h2020.eu) is a collaboration of multiple experts in computational science, cardiovascular biology, biophysics, biomedical engineering, epidemiology, radiology, and neurology. INSIST will generate virtual populations of acute ischemic stroke patients based on anonymized data from the recent stroke trials and registry, and build on the existing and emerging in-silico models for acute ischemic stroke, its treatment (thrombolysis and thrombectomy) and the resulting perfusion changes. These models will be used to design a platform for in-silico trials that will be validated with existing data and be used to provide a proof of concept of the potential efficacy of this emerging technology. The platform will be used for preliminary evaluation of the potential suitability and safety of medication, new thrombectomy device configurations and methods to select patient subpopulations for better treatment outcome. This could allow generating, exploring and refining relavant hypotheses on potential causal pathways (which may follow from the evidence obtained from clinical trials) and improving clinical trial design. Importantly, the findings of the in-silico trials will require validation under the controlled settings of randomized clinical trials.

In-silico clinical platforms have been recently used as a new revolutionary path for virtual patients (VP) generation and further analysis, such as, drug development. Advanced individualized models have been developed to enhance flexibility and reliability of the virtual patient cohorts. This study focuses on the implementation and comparison of three different methodologies for generating virtual data for in-silico clinical trials. Towards this direction, three computational methods, namely: (i) the multivariate log-normal distribution (logMVND), (ii) the supervised tree ensembles, and (iii) the unsupervised tree ensembles are deployed and evaluated against their performance towards the generation of high-quality virtual data using the goodness of fit (gof) and the dataset correlation matrix as performance evaluation measures. Our results reveal the dominance of the tree ensembles towards the generation of virtual data with similar distributions (avg. gof values less than 0.2) and correlation patterns (avg. difference less than 0.03)., Pre-Final version, Presented in 2020 42nd Annual International Conference of the IEEE Engineering in Medicine & Biology Society (EMBC)

Background: In type 1 diabetes (T1D) research, in-silico clinical trials (ISCTs) have proven effective in accelerating the development of new therapies. However, published simulators lack a realistic description of some aspects of patient lifestyle which can remarkably affect glucose control. In this paper, we develop a mathematical description of meal carbohydrates (CHO) amount and timing, with the aim to improve the meal generation module in the T1D Patient Decision Simulator (T1D-PDS) published in Vettoretti et al. Methods: Data of 32 T1D subjects under free-living conditions for 4874 days were used. Univariate probability density function (PDF) parametric models with different candidate shapes were fitted, individually, against sample distributions of: CHO amounts of breakfast (CHOB), lunch (CHOL), dinner (CHOD), and snack (CHOS); breakfast timing (TB); and time between breakfast-lunch (TBL) and between lunch-dinner (TLD). Furthermore, a support vector machine (SVM) classifier was developed to predict the occurrence of a snack in future fixed-length time windows. Once embedded inside the T1D-PDS, an ISCT was performed. Results: Resulting PDF models were: gamma (CHOB, CHOS), lognormal (CHOL, TB), loglogistic (CHOD), and generalized-extreme-values (TBL, TLD). The SVM showed a classification accuracy of 0.8 over the test set. The distributions of simulated meal data were not statistically different from the distributions of the real data used to develop the models (α = 0.05). Conclusions: The models of meal amount and timing variability developed are suitable for describing real data. Their inclusion in modules that describe patient behavior in the T1D-PDS can permit investigators to perform more realistic, reliable, and insightful ISCTs.