Cause and Cure of Sloppiness in Ordinary Differential Equation Models

TL;DR

This paper investigates the origins of sloppiness in ODE models of biochemical networks, linking it to model structure and experimental design, and proposes strategies to mitigate it using optimal experimental design.

Contribution

It identifies the structural causes of sloppiness and introduces design strategies to reduce it in biochemical ODE models.

Findings

Sloppiness arises from model topology and experimental design.

Optimal experimental design can produce non-sloppy models.

Strategies to circumvent sloppiness improve model reliability.

Abstract

Data-based mathematical modeling of biochemical reaction networks, e.g. by nonlinear ordinary differential equation (ODE) models, has been successfully applied. In this context, parameter estimation and uncertainty analysis is a major task in order to assess the quality of the description of the system by the model. Recently, a broadened eigenvalue spectrum of the Hessian matrix of the objective function covering orders of magnitudes was observed and has been termed as sloppiness. In this work, we investigate the origin of sloppiness from structures in the sensitivity matrix arising from the properties of the model topology and the experimental design. Furthermore, we present strategies using optimal experimental design methods in order to circumvent the sloppiness issue and present non-sloppy designs for a benchmark model.