Sensitivity analysis for drug effect study: An NF-κB pathway example

Abstract

The complexity of biological signaling networks, especially the uncertainties associated with the model parameters, present challenges for understanding the behavior of such networks and hence hamper the translation of the modeling study into drug development process. Sensitivity analysis can help to determine which parameters are the "key drivers" of the model's output. How to tailor the sensitivity study under drug perturbation based on the knowledge of available existing or potential drugs are considered in this paper. The goal is to evaluate the drug effect on the signaling pathway modeled by kinetic rate changes. Through an example simulation study of the response of NF-κB pathway to two drugs, it is observed that new or modified sensitivity analysis methods may be necessary for the purpose of drug effect study. In addition, the new method may also help us determine whether combination therapy can yield significant synergism when compared to their individual drug effect.