The Limitations of Model-Based Experimental Design and Parameter Estimation in Sloppy Systems

We explore the relationship among experimental design, parameter estimation, and systematic error in sloppy models. We show that the approximate nature of mathematical models poses challenges for experimental design in sloppy models. In many models of complex biological processes it is unknown what are the relevant physical mechanisms that must be included to explain system behaviors. As a consequence, models are often overly complex, with many practically unidentifiable parameters. Furthermore, which mechanisms are relevant/irrelevant vary among experiments. By selecting complementary experiments, experimental design may inadvertently make details that were ommitted from the model become relevant. When this occurs, the model will have a large systematic error and fail to give a good fit to the data. We use a simple hyper-model of model error to quantify a model’s discrepancy and apply it to two models of complex biological processes (EGFR signaling and DNA repair) with optimally selected experiments. We find that although parameters may be accurately estimated, the discrepancy in the model renders it less predictive than it was in the sloppy regime where systematic error is small. We introduce the concept of a sloppy system–a sequence of models of increasing complexity that become sloppy in the limit of microscopic accuracy. We explore the limits of accurate parameter estimation in sloppy systems and argue that identifying underlying mechanisms controlling system behavior is better approached by considering a hierarchy of models of varying detail rather than focusing on parameter estimation in a single model.Author Summary: Sloppy models are often unidentifiable, i.e., characterized by many parameters that are poorly constrained by experimental data. Many models of complex biological systems are sloppy, which has prompted considerable debate about the identifiability of parameters and methods of selecting optimal experiments to infer parameter values. We explore how the approximate nature of models affects the prospect for accurate parameter estimates and model predictivity in sloppy models when using optimal experimental design. We find that sloppy models may no longer give a good fit to data generated from “optimal” experiments. In this case, the model has much less predictive power than it did before optimal experimental selection. We use a simple hyper-model of model error to quantify the model’s discrepancy from the physical system and discuss the potential limits of accurate parameter estimation in sloppy systems.