Figure 4

Hierarchical analysis of the uncertain dynamics of the JAK2/STAT5 signaling pathway. We made use of the linking between the graph view and the line plots, as well as the linking between different line plots, to perform a hierarchical analysis of the dynamic attributes of the JAK2/STAT5 signaling pathway (A). We studied the three layers of the BRN: the output layer (B), which includes the measured quantities; the state layer (C), which includes the states of the different chemical species; and the flux layer (D), which uniquely describes the changes in the states and the dynamics of outputs. The stack of graph views (A) illustrates the animation of the graph, where the states and fluxes at a particular time point are mapped to the color of the nodes and links respectively. The line plots (B)-(E) depict the median (full line) and the 90% Bayesian confidence interval (semitransparent area). Starting from the animation, the hierarchical analysis reveals that the output trajectories (B), which are fitted to the experimental data (dots), are the most well determined properties of the systems. The uncertainties in the states (C) that determine a certain output are in general much larger. Furthermore, different combinations of fluxes can yield roughly the same state trajectories, which in general results in a further increase of the uncertainties in the fluxes (D). However, for the JAK2/STAT5 signaling pathway this increase in uncertainty cannot be observed, probably, because the fluxes are constrained by molecular conservation laws. Variations in one flux must be compensated by another flux, resulting in significant flux-flux correlation (E). Complementary to the analysis of individual experimental data, the comparison across experiments provides information about the relative importance and role of certain mechanisms.