An iterative identification procedure for dynamic modeling of biochemical networks.
BACKGROUND
Mathematical models provide abstract representations of the information gained from experimental observations on the structure and function of a particular biological system. Conferring a predictive character on a given mathematical formulation often relies on determining a number of non-measurable parameters that largely condition the model's response. These parameters can be identified by fitting the model to experimental data. However, this fit can only be accomplished when identifiability can be guaranteed.


RESULTS
We propose a novel iterative identification procedure for detecting and dealing with the lack of identifiability. The procedure involves the following steps: 1) performing a structural identifiability analysis to detect identifiable parameters; 2) globally ranking the parameters to assist in the selection of the most relevant parameters; 3) calibrating the model using global optimization methods; 4) conducting a practical identifiability analysis consisting of two (a priori and a posteriori) phases aimed at evaluating the quality of given experimental designs and of the parameter estimates, respectively and 5) optimal experimental design so as to compute the scheme of experiments that maximizes the quality and quantity of information for fitting the model.


CONCLUSIONS
The presented procedure was used to iteratively identify a mathematical model that describes the NF-kappaB regulatory module involving several unknown parameters. We demonstrated the lack of identifiability of the model under typical experimental conditions and computed optimal dynamic experiments that largely improved identifiability properties.
Balsa-Canto
Eva
E
Bioprocess Engineering Group, Spanish National Research Council, IIM-CSIC, 36208 Vigo-Spain. ebalsa@iim.csic.es
Alonso
Antonio A
AA
Banga
Julio R
JR
D000465:Algorithms; D003198:Computer Simulation; D005786:Gene Expression Regulation / Q000502:physiology*; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D016328:NF-kappa B