In silico trials for treatment of acute ischemic stroke: Design and implementation

Claire Miller,Raymond M Padmos,Max Van Der Kolk,Tamás I Józsa,Noor Samuels,Yidan Xue,Stephen J Payne,Alfons G Hoekstra

doi:10.1016/j.compbiomed.2021.104802

Claire Miller, Raymond M Padmos + Show 6 more

Open Access

https://doi.org/10.1016/j.compbiomed.2021.104802

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Abstract

An in silico trial simulates a disease and its corresponding therapies on a cohort of virtual patients to support the development and evaluation of medical devices, drugs, and treatment. In silico trials have the potential to refine, reduce cost, and partially replace current in vivo studies, namely clinical trials and animal testing. We present the design and implementation of an in silico trial for treatment of acute ischemic stroke. We propose an event-based modelling approach for the simulation of a disease and injury, where changes to the state of the system (the events) are assumed to be instantaneous. Using this approach we are able to combine a diverse set of models, spanning multiple time scales, to model acute ischemic stroke, treatment, and resulting brain tissue injury. The in silico trial is designed to be modular to aid development and reproducibility. It provides a comprehensive framework for application to any potential in silico trial. A statistical population model is used to generate cohorts of virtual patients. Patient functional outcomes are also predicted with a statistical model, using treatment and injury results and the patient's clinical parameters. We demonstrate the functionality of the event-based modelling approach and trial framework by running proof of concept in silico trials. The proof of concept trials simulate the same cohort of patients twice: once with successful treatment (successful recanalisation) and once with unsuccessful treatment (unsuccessful treatment). Ways to overcome some of the challenges and difficulties in setting up such an in silico trial are discussed, such as validation and computational limitations.

Highlights

Research and development of novel medical devices, drugs, and treatments is expensive—the average cost to bring a new drug to market has been estimated at 1–2.5 billion US dollars [1,2]
In this paper we present our event-based modelling approach and the in silico trial (IST) framework, developed based on the strategy described in the INSIST white paper [28]
We have presented a comprehensive framework, using an eventbased modelling approach, for an in silico trial (IST), and applied it to acute ischemic stroke (AIS)

Summary

Introduction

Research and development of novel medical devices, drugs, and treatments is expensive—the average cost to bring a new drug to market has been estimated at 1–2.5 billion US dollars [1,2]. Clinical trial failure contributes to the increasing costs and can result in abandoned products, often without a clear understanding of the reason for the failure [3,4]. Clinical trials for higher prevalence dis eases, with high participation, often only capture the average popula tion, thereby missing important effects occurring in only a small percentage of the population. This can lead to unforeseen side-effects when the product is brought to market. Clinical trials for low prevalence diseases can struggle to recruit the requisite number of patients, making development of treatments for these diseases economically infeasible

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