Calibration methods to fit parameters within complex biological models

Mathematical and computational models of biological systems are increasingly complex, typically comprised of hybrid multi-scale methods such as ordinary differential equations, partial differential equations, agent-based and rule-based models, etc. These mechanistic models concurrently simulate detail at resolutions of whole host, multi-organ, organ, tissue, cellular, molecular, and genomic dynamics. Lacking analytical and numerical methods, solving complex biological models requires iterative parameter sampling-based approaches to establish appropriate ranges of model parameters that capture corresponding experimental datasets. However, these models typically comprise large numbers of parameters and therefore large degrees of freedom. Thus, fitting these models to multiple experimental datasets over time and space presents significant challenges. In this work we undertake the task of reviewing, testing, and advancing calibration practices across models and dataset types to compare methodologies for model calibration. Evaluating the process of calibrating models includes weighing strengths and applicability of each approach as well as standardizing calibration methods. Our work compares the performance of our model agnostic Calibration Protocol (CaliPro) with approximate Bayesian computing (ABC) to highlight strengths, weaknesses, synergies, and differences among these methods. We also present next-generation updates to CaliPro. We explore several model implementations and suggest a decision tree for selecting calibration approaches to match dataset types and modeling constraints.