Conclusions via unique predictions obtained despite unidentifiability – new definitions and a general method

It is often predicted that model‐based data analysis will revolutionize biology, just as it has physics and engineering. A widely used tool within such analysis is hypothesis testing, which focuses on model rejections. However, the fact that a systems biology model is non‐rejected is often a relatively weak statement, as such models usually are highly over‐parametrized with respect to the available data, and both parameters and predictions may therefore be arbitrarily uncertain. For this reason, we formally define and analyse the concept of a core prediction. A core prediction is a uniquely identified property that must be fulfilled if the given model structure is to explain the data, even if the individual parameters are non‐uniquely identified. It is shown that such a prediction is as strong a conclusion as a rejection. Furthermore, a new method for core prediction analysis is introduced, which is beneficial for the uncertainty of specific model properties, as the method only characterizes the space of acceptable parameters in the relevant directions. This avoids the curse of dimensionality associated with the generic characterizations used by previously proposed methods. Analysis on examples shows that the new method is comparable to profile likelihood with regard to practical identifiability, and thus generalizes profile likelihood to the more general problem of observability. If used, the concepts and methods presented herein make it possible to distinguish between a conclusion and a mere suggestion, which hopefully will contribute to a more justified confidence in systems biology analyses.