1. Sensitivity analysis of signaling pathway models based on discrete-time measurements
- Author
-
Jaroslaw Smieja and Malgorzata Kardynska
- Subjects
0301 basic medicine ,Control and Optimization ,lcsh:T58.5-58.64 ,Computer science ,lcsh:Information technology ,lcsh:Mathematics ,lcsh:QA1-939 ,signaling pathways ,03 medical and health sciences ,030104 developmental biology ,Discrete time and continuous time ,sensitivity analysis ,Control and Systems Engineering ,Modeling and Simulation ,measurement uncertainty ,discretetime measurements ,Measurement uncertainty ,Sensitivity (control systems) ,Signal transduction ,Biological system - Abstract
The paper is focused on sensitivity analysis of large-scale models of biological systems that describe dynamics of the so called signaling pathways. These systems are continuous in time but their models are based on discrete-time measurements. Therefore, if sensitivity analysis is used as a tool supporting model development and evaluation of its quality, it should take this fact into account. Such models are usually very complex and include many parameters difficult to estimate in an experimental way. Changes of many of those parameters have little effect on model dynamics, and therefore they are called sloppy. In contrast, other parameters, when changed, lead to substantial changes in model responses and these are called stiff parameters. While this is a well-known fact, and there are methods to discern sloppy parameters from the stiff ones, they have not been utilized, so far, to create parameter rankings and quantify the influence of single parameter changes on system time responses. These single parameter changes are particularly important in analysis of signalling pathways, because they may pinpoint parameters, associated with the processes to be targeted at the molecular level in laboratory experiments. In the paper we present a new, original method of creating parameter rankings, based on an Hessian of a cost function which describes the fit of the model to a discrete experimental data. Its application is explained with simple dynamical systems, representing two typical dynamics exhibited by the signaling pathways.
- Published
- 2017