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Zhang and Goutsias BMC Bioinformatics 2010, 11:246 /1471-2105/11/246 R E S E A R C H A R T I C L E Open Access Research article A comparison of approximation techniques for variance-based sensitivity analysis of biochemical reaction systems Hong-Xuan Zhang and John Goutsias* Abstract Background: Sensitivity analysis is an indispensable tool for the analysis of complex systems. In a recent paper, we have introduced a thermodynamically consistent variance-based sensitivity analysis approach for studying the robustness and fragility properties of biochemical reaction systems under uncertainty in the standard chemical potentials of the activated complexes of the reactions and the standard chemical potentials of the molecular species. In that approach, key sensitivity indices were estimated by Monte Carlo sampling, which is computationally very demanding and impractical for large biochemical reaction systems. Computationally efficient algorithms are needed to make variance-based sensitivity analysis applicable to realistic cellular networks, modeled by biochemical reaction systems that consist of a large number of reactions and molecular species. Results: We present four techniques, derivative approximation (DA), polynomial approximation (PA), Gauss-Hermite integration (GHI), and orthonormal Hermite approximation (OHA), for analytically approximating the variance-based sensitivity indices associated with a biochemical reaction system. By using a well-known model of the mitogen- activated protein kinase signaling cascade as a case study, we numerically compare the approximation quality of these techniques against traditional Monte Carlo sampling. Our results indicate that, although DA is computationally the most attractive technique, special care should be exercised when using it for sensitivity analysis, since it may only be