Dynamical compensation and structural identifiability of biological models: Analysis, implications, and reconciliation

The concept of dynamical compensation has been recently introduced to describe the ability of a biological system to keep its output dynamics unchanged in the face of varying parameters. However, the original definition of dynamical compensation amounts to lack of structural identifiability. This is relevant if model parameters need to be estimated, as is often the case in biological modelling. Care should we taken when using an unidentifiable model to extract biological insight: the estimated values of structurally unidentifiable parameters are meaningless, and model predictions about unmeasured state variables can be wrong. Taking this into account, we explore alternative definitions of dynamical compensation that do not necessarily imply structural unidentifiability. Accordingly, we show different ways in which a model can be made identifiable while exhibiting dynamical compensation. Our analyses enable the use of the new concept of dynamical compensation in the context of parameter identification, and reconcile it with the desirable property of structural identifiability.Author summary: A robust behaviour is a desirable feature in many biological systems. The study of mechanisms capable of maintaining the transient response unchanged despite environmental disturbances has recently motivated the introduction of a new concept: Dynamical Compensation (DC). However, the original definition of DC with respect to a parameter amounts to structural unidentifiability of that parameter, which means that it cannot be estimated by measuring the model output. Since most biological models have unknown parameters that need to be estimated, DC can be considered a negative property for the purpose of model identification. In this paper we reconcile these two conflicting views by proposing a new definition of DC that captures its intended biological meaning (i.e. robustness, which should be a systemic property, intrinsic to the dynamics) while making it distinct from structural unidentifiability (which is a modelling property that depends on decisions made by the modeller, such as the choice of model outputs or unknown parameters, and on experimental constraints). Our definition enables a model to have DC with respect to a structurally identifiable parameter, thus increasing the applicability of the concept.