A continuation technique for maximum likelihood estimators in biological models

Abstract: Estimating model parameters is a crucial step in mathematical modelling and typically involves minimizing the disagreement between model predictions and experimental data. This calibration data can change throughout a study, particularly if modelling is performed simultaneously with the calibration experiments, or during an on-going public health crisis as in the case of the COVID-19 pandemic. Consequently, the optimal parameter set, or maximal likelihood estimator (MLE), is a function of the experimental data set. Here, we develop a numerical technique to predict the evolution of the MLE as a function of the experimental data. We show that, when considering perturbations from an initial data set, our approach is significantly more computationally efficient that re-fitting model parameters while resulting in acceptable model fits to the updated data. We use the continuation technique to develop an explicit functional relationship between fit model parameters and experimental data that can be used to measure the sensitivity of the MLE to experimental data. We then leverage this inverse sensitivity analysis to select between model fits with similar information criteria, \textit{a priori} determine the experimental measurements to which the MLE is most sensitive, and suggest additional experiment measurements that can resolve parameter uncertainty.