An unbiased sensitivity analysis reveals important parameters controlling periodicity of circadian clock

To assess the importance of model parameters in kinetic models, sensitivity analysis is generally employed to provide key measures. However, it is quite often that no information is available for a significant number of parameters in biochemical models. Therefore, the results of sensitivity analysis that heavily rely on the accuracy of parameters are largely ambiguous. In this study, we propose a computational approach to determine the relative importance of parameters controlling the performance of the circadian clock in Drosophila. While previous attempts to sensitivity analysis largely depend on the knowledge of model parameters which are generally unknown, our study depicts a consistent picture of sensitivity assessment for a large number of parameters, even when the values of these parameters are not available in vivo. The resulting parametric sensitivity analysis suggests that PER/TIM negative loop is critical to maintain the stable periodicity of the circadian clock, which is consistent to the previously experimental and computational findings. Furthermore, our analysis generates a rich hypothesis of important parameters in the circadian clock that can be further tested experimentally. This approach can also be extended to assess the sensitivity of parameters in any biochemical system where a large number of parameters have unknown values.