Reply to Comment on “Sloppy models, parameter uncertainty, and the role of experimental design"

Abstract

We welcome the commentary from Chachra, Transtrum, and Sethna1 regarding our paper “Sloppy models, parameter uncertainty, and the role of experimental design,”2 as their intriguing work shaped our thinking in this area.3 Sethna and colleagues introduced the notion of sloppy models, in which the uncertainty in the values of some combinations of parameters is many orders of magnitude greater than others.4 In our work we explored the extent to which large parameter uncertainties are an intrinsic characteristic of systems biology network models, or whether uncertainties are instead closely related to the collection of experiments used for model estimation. We were gratified to find the latter result –– that parameters are in principle knowable, which is important for the field of systems biology. The work also showed that small parameter uncertainties can be achieved and that the process can be greatly accelerated by using computational experimental design approaches5–9 deployed to select sets of experiments that effectively exercise the system in complementary directions.