Tumour growth: An approach to calibrate parameters of a multiphase porous media model based on in vitro observations of Neuroblastoma spheroid growth in a hydrogel microenvironment.

To unravel processes that lead to the growth of solid tumours, it is necessary to link knowledge of cancer biology with the physical properties of the tumour and its interaction with the surrounding microenvironment. Our understanding of the underlying mechanisms is however still imprecise. We therefore developed computational physics-based models, which incorporate the interaction of the tumour with its surroundings based on the theory of porous media. However, the experimental validation of such models represents a challenge to its clinical use as a prognostic tool. This study combines a physics-based model with in vitro experiments based on microfluidic devices used to mimic a three-dimensional tumour microenvironment. By conducting a global sensitivity analysis, we identify the most influential input parameters and infer their posterior distribution based on Bayesian calibration. The resulting probability density is in agreement with the scattering of the experimental data and thus validates the proposed workflow. This study demonstrates the huge challenges associated with determining precise parameters with usually only limited data for such complex processes and models, but also demonstrates in general how to indirectly characterise the mechanical properties of neuroblastoma spheroids that cannot feasibly be measured experimentally.

Global sensitivity analysis based on Gaussian-process metamodelling for complex biomechanical problems.

Biomechanical models often need to describe very complex systems, organs or diseases, and hence also include a large number of parameters. One of the attractive features of physics-based models is that in those models (most) parameters have a clear physical meaning. Nevertheless, the determination of these parameters is often very elaborate and costly and shows a large scatter within the population. Hence, it is essential to identify the most important parameters (worth the effort) for a particular problem at hand. In order to distinguish parameters which have a significant influence on a specific model output from non-influential parameters, we use sensitivity analysis, in particular the Sobol method as a global variance-based method. However, the Sobol method requires a large number of model evaluations, which is prohibitive for computationally expensive models. We therefore employ Gaussian processes as a metamodel for the underlying full model. Metamodelling introduces further uncertainty, which we also quantify. We demonstrate the approach by applying it to two different problems: nanoparticle-mediated drug delivery in a complex, multiphase tumour-growth model, and arterial growth and remodelling. Even relatively small numbers of evaluations of the full model suffice to identify the influential parameters in both cases and to separate them from non-influential parameters. The approach also allows the quantification of higher-order interaction effects. We thus show that a variance-based global sensitivity analysis is feasible for complex, computationally expensive biomechanical models. Different aspects of sensitivity analysis are covered including a transparent declaration of the uncertainties involved in the estimation process. Such a global sensitivity analysis not only helps to massively reduce costs for experimental determination of parameters but is also highly beneficial for inverse analysis of such complex models.