Proper lumping in systems biology models.

An algorithm for automatic order reduction of models defined by large systems of differential equations is presented. The algorithm was developed with systems biology models in mind and the motivation behind it is to develop mechanistic pharmacokinetic/pharmacodynamic models from already available systems biology models. The approach used for model reduction is proper lumping of the system's states and is based on a search through the possible combinations of lumps. To avoid combinatorial explosion, a heuristic, greedy search strategy is employed and comparison with the full exhaustive search provides evidence that it performs well. The method takes advantage of an apparent property of this kind of systems that lumps remain consistent over different levels of order reduction. Advantages of the method presented include: the variables and parameters of the reduced model retain a specific physiological meaning; the algorithm is automatic and easy to use; it can be used for nonlinear models and can handle parameter uncertainty and constraints. The algorithm was applied to a model of NF-B signalling pathways in order to demonstrate its use and performance. Significant reduction was achieved for the example model, while agreement with the original model was proportional to the size of the reduced model, as expected. The results of the model reduction were compared with a published, intuitively reduced model of NF-B signalling pathways and were found to be in agreement, in terms of the identified key species for the system's kinetic behaviour. The method may provide useful insights which are complementary to the intuitive reduction approach, especially in large systems.