When predicting physical phenomena through simulation, quantification of the total uncertainty due to multiple sources is as crucial as making sure the underlying numerical model is accurate. Possible sources include irreducible uncertainty due to noise in the data, uncertainty induced by insufficient data or inadequate parameterization and uncertainty related to the use of misspecified model equations. In addition, recently proposed approaches provide flexible ways to combine information from data with full or partial satisfaction of equations that typically encode physical principles. Physics-based regularization interacts in non-trivial ways with aleatoric, epistemic and model-form uncertainty and their combination, and a better understanding of this interaction is needed to improve the predictive performance of physics-informed digital twins that operate under real conditions. To better understand this interaction, with a specific focus on biological and physiological models, this study investigates the decomposition of total uncertainty in the estimation of states and parameters of a differential system simulated with MC X-TFC, a new physics-informed approach for uncertainty quantification based on random projections and Monte Carlo sampling. After an introductory comparison between approaches for physics-informed estimation, MC X-TFC is applied to a six-compartment stiff ODE system, the CVSim-6 model, developed in the context of human physiology. The system is first analysed by progressively removing data while estimating an increasing number of parameters, and subsequently by investigating total uncertainty under model-form misspecification of nonlinear resistance in the pulmonary compartment. In particular, we focus on the interaction between the formulation of the discrepancy term and quantification of model-form uncertainty, and show how additional physics can help in the estimation process. The method demonstrates robustness and efficiency in estimating unknown states and parameters, even with limited, sparse and noisy data. It also offers great flexibility in integrating data with physics for improved estimation, even in cases of model misspecification.This article is part of the theme issue 'Uncertainty quantification for healthcare and biological systems (Part 1)'.
