Search

The incidence of vertebral fragility fracture is increased by the presence of preexisting pathologies such as metastatic disease. Computational tools could support the fracture prediction and consequently the decision of the best medical treatment. Anyway, validation is required to use these tools in clinical practice. To address this necessity, in this study subject-specific homogenized finite element models of single vertebrae were generated from micro CT images for both healthy and metastatic vertebrae and validated against experimental data. More in detail, spine segments were tested under compression and imaged with micro CT. The displacements field could be extracted for each vertebra singularly using the digital volume correlation full-field technique. Homogenized finite element models of each vertebra could hence be built from the micro CT images, applying boundary conditions consistent with the experimental displacements at the endplates. Numerical and experimental displacements and strains fields were eventually compared. In addition, the outcomes of a micro CT based homogenized model were compared to the ones of a clinical-CT based model. Good agreement between experimental and computational displacement fields, both for healthy and metastatic vertebrae, was found. Comparison between micro CT based and clinical-CT based outcomes showed strong correlations. Furthermore, models were able to qualitatively identify the regions which experimentally showed the highest strain concentration. In conclusion, the combination of experimental full-field technique and the in-silico modelling allowed the development of a promising pipeline for validation of fracture risk predictors, although further improvements in both fields are needed to better analyse quantitatively the post-yield behaviour of the vertebra.

Vertebral fractures prediction in clinics lacks of accuracy. The most used scores have limitations in distinguishing between subjects at risk or not. Finite element (FE) models generated from computed tomography (CT) of these patients may improve the predictive capability. Many models have already been proposed but the most of them considered the single vertebral body, excluding from the analysis the role of the inter-vertebral discs in the distribution of the load through the spine. Multi-vertebral models instead allow to examine more complex boundary condition. However, CT scans do not provide subject-specif information about the material properties of the disc. Consequently, the goal of the study was to validate a multi-vertebral FE model with subject specific modelling of the vertebral bone and population-based properties assigned to the disc, idealizing them with a linear isotropic material. Boundary condition were assigned in order to reproduce an experimental test performed on the same specimen and recorded using digital image correlation technique (DIC). FE and DIC strains on the vertebral surfaces are compared point-wise. Young's modulus values in the range 25-30 MPa allowed to achieve a comparable order of magnitude between experimental and computational data. However, the two distribution remained strongly different. To conclude, subject-specific material properties need to be assigned also to the discs as well as to the vertebrae to achieve acceptable accuracy in the assessment of the fracture risk., Comment: 18 pages, 6 figures submitted to Biomechanics and Modeling in Mechanobiology

The idea of a systematic digital representation of the entire known human pathophysiology, which we could call the Virtual Human Twin, has been around for decades. To date, most research groups focused instead on developing highly specialised, highly focused patient-specific models able to predict specific quantities of clinical relevance. While it has facilitated harvesting the low-hanging fruits, this narrow focus is, in the long run, leaving some significant challenges that slow the adoption of digital twins in healthcare. This position paper lays the conceptual foundations for developing the Virtual Human Twin (VHT). The VHT is intended as a distributed and collaborative infrastructure, a collection of technologies and resources (data, models) that enable it, and a collection of Standard Operating Procedures (SOP) that regulate its use. The VHT infrastructure aims to facilitate academic researchers, public organisations, and the biomedical industry in developing and validating new digital twins in healthcare solutions with the possibility of integrating multiple resources if required by the specific context of use. Healthcare professionals and patients can also use the VHT infrastructure for clinical decision support or personalised health forecasting. As the European Commission launched the EDITH coordination and support action to develop a roadmap for the development of the Virtual Human Twin, this position paper is intended as a starting point for the consensus process and a call to arms for all stakeholders.

The term "In Silico Trial" indicates the use of computer modelling and simulation to evaluate the safety and efficacy of a medical product, whether a drug, a medical device, a diagnostic product or an advanced therapy medicinal product. Predictive models are positioned as new methodologies for the development and the regulatory evaluation of medical products. New methodologies are qualified by regulators such as FDA and EMA through formal processes, where a first step is the definition of the Context of Use (CoU), which is a concise description of how the new methodology is intended to be used in the development and regulatory assessment process. As In Silico Trials are a disruptively innovative class of new methodologies, it is important to have a list of possible CoUs highlighting potential applications for the development of the relative regulatory science. This review paper presents the result of a consensus process that took place in the InSilicoWorld Community of Practice, an online forum for experts in in silico medicine. The experts involved identified 46 descriptions of possible CoUs which were organised into a candidate taxonomy of nine CoU categories. Examples of 31 CoUs were identified in the available literature; the remaining 15 should, for now, be considered speculative., Comment: Submitted to IEEE JOURNAL OF BIOMEDICAL AND HEALTH INFORMATICS

Agent-Based Models are a powerful class of computational models widely used to simulate complex phenomena in many different application areas. However, one of the most critical aspects, poorly investigated in the literature, regards an important step of the model credibility assessment: solution verification. This study overcomes this limitation by proposing a general verification framework for Agent-Based Models that aims at evaluating the numerical errors associated with the model. A step-by-step procedure, which consists of two main verification studies (deterministic and stochastic model verification), is described in detail and applied to a specific mission critical scenario: the quantification of the numerical approximation error for UISS-TB, an ABM of the human immune system developed to predict the progression of pulmonary tuberculosis. Results provide indications on the possibility to use the proposed model verification workflow to systematically identify and quantify numerical approximation errors associated with UISS-TB and, in general, with any other ABMs.

SARS-CoV-2 is a severe respiratory infection that infects humans. Its outburst entitled it as a pandemic emergence. To get a grip on this, outbreak specific preventive and therapeutic interventions are urgently needed. It must be said that, until now, there are no existing vaccines for coronaviruses. To promptly and rapidly respond to pandemic events, the application of in silico trials can be used for designing and testing medicines against SARS-CoV-2 and speed-up the vaccine discovery pipeline, predicting any therapeutic failure and minimizing undesired effects. Here, we present an in silico platform that showed to be in very good agreement with the latest literature in predicting SARS- CoV-2 dynamics and related immune system host response. Moreover, it has been used to predict the outcome of one of the latest suggested approach to design an effective vaccine, based on monoclonal antibody. UISS is then potentially ready to be used as an in silico trial platform to predict the outcome of vaccination strategy against SARS-CoV-2., Comment: 8 pages, 7 figures

EC funded STriTuVaD project aims to test, through a phase IIb clinical trial, two of the most advanced therapeutic vaccines against tuberculosis. In parallel, we have extended the Universal Immune System Simulator to include all relevant determinants of such clinical trial, to establish its predictive accuracy against the individual patients recruited in the trial, to use it to generate digital patients and predict their response to the HRT being tested, and to combine them to the observations made on physical patients using a new in silico-augmented clinical trial approach that uses a Bayesian adaptive design. This approach, where found effective could drastically reduce the cost of innovation in this critical sector of public healthcare. One of the most challenging task is to develop a methodology to reproduce biological diversity of the subjects that have to be simulated, i.e., provide an appropriate strategy for the generation of libraries of digital patients. This has been achieved through the the creation of the initial immune system repertoire in a stochastic way, and though the identification of a "vector of features" that combines both biological and pathophysiological parameters that personalize the digital patient to reproduce the physiology and the pathophysiology of the subject., Comment: 5 pages

Tuberculosis (TB) is one of the deadliest diseases worldwide, with 1,5 million fatalities every year along with potential devastating effects on society, families and individuals. To address this alarming burden, vaccines can play a fundamental role, even though to date no fully effective TB vaccine really exists. Current treatments involve several combinations of antibiotics administered to TB patients for up to two years, leading often to financial issues and reduced therapy adherence. Along with this, the development and spread of drug-resistant TB strains is another big complicating matter. Faced with these challenges, there is an urgent need to explore new vaccination strategies in order to boost immunity against tuberculosis and shorten the duration of treatment. Computational modeling represents an extraordinary way to simulate and predict the outcome of vaccination strategies, speeding up the arduous process of vaccine pipeline development and relative time to market. Here, we present EU - funded STriTuVaD project computational platform able to predict the artificial immunity induced by RUTI and ID93/GLA-SE, two specific tuberculosis vaccines. Such an in silico trial will be validated through a phase 2b clinical trial. Moreover, STriTuVaD computational framework is able to inform of the reasons for failure should the vaccinations strategies against M. tuberculosis under testing found not efficient, which will suggest possible improvements., Comment: 5 pages

Different research communities have developed various approaches to assess the credibility of predictive models. Each approach usually works well for a specific type of model, and under some epistemic conditions that are normally satisfied within that specific research domain. Some regulatory agencies recently started to consider evidences of safety and efficacy on new medical products obtained using computer modelling and simulation (which is referred to as In Silico Trials); this has raised the attention in the computational medicine research community on the regulatory science aspects of this emerging discipline. But this poses a foundational problem: in the domain of biomedical research the use of computer modelling is relatively recent, without a widely accepted epistemic framing for problem of model credibility. Also, because of the inherent complexity of living organisms, biomedical modellers tend to use a variety of modelling methods, sometimes mixing them in the solution of a single problem. In such context merely adopting credibility approaches developed within other research community might not be appropriate. In this position paper we propose a theoretical framing for the problem of assessing the credibility of a predictive models for In Silico Trials, which accounts for the epistemic specificity of this research field and is general enough to be used for different type of models., Comment: 11 pages