Each data point itself is the bulk average of a large number of cells, and so it is assumed that the sample average from this large collection of cells is normally distributed with mean equal to the popula tion average, but that the standard deviation can vary with time. Individual samples are assumed to be indepen Parameter values were estimated by minimizing sellekchem the a cost function based on the goodness of fit between model and data. Two objective functions were used, one which computed the normalized sum of squares error, between the model simulations at parameter set, y, and observed data points yobs, where i indexes the n time points at which data was collected. A second objective function used the chi square test statistic com puted from Fishers method, an adaptation of the moment matching algorithm proposed in.

The simulated concentrations of NF B and IKK were nor malized to their respective concentrations at 20 min and 5 min to allow direct comparison with experimental data. Optimization was performed using the fmincon constrained minimization algorithm from the Matlab Optimization Toolbox. Lower and upper bounds for the parameter values were taken from the available literature, as specified in Additional file 1. The normalized first order sensitivity coefficients of the system, dent across experiment replicates and identically distrib uted with regard to their respective time points. This is justified since all samples are collected from independent cell populations.

Under these assumptions, a two sided one sample t test can be used to compare the population mean from the model simulations corresponding to a specific set of parameters, to the sample mean from ni experimental samples collected at time ti. The null hypothesis that the two are consistent is rejected at a significance level a if the p value corresponding to the ith t statistic is pi a. Fishers method combines the information from the individual test results to test the shared null hypothesis that all the ni experimental samples come from cell populations whose time evolution of the population average is given by the kinetic model. The test statistic for Fishers method is computed by combining each independent test as follows, n where yi is a system output andj is the jth rate para meter, were solved using the CVODES forward sensitiv ity solver from the SUNDIALS 2. 4.

0 software suite. Sensitivity scores were also assigned based on the time averaged integral of the normalized sensitivity magnitudes, The biological literature represents the repository of bio logical knowledge. The ever increasing scientific litera ture now available electronically and the exponential growth of large scale molecular data AV-951 have prompted active research in biological text mining and information extraction to facilitate literature based curation of mole cular databases and biomedical ontologies.