A new hierarchical approach to multi-level model abstraction for simplifying ODE models of biological networks and a case study: The G1/S Checkpoint/DNA damage signalling pathways of mammalian cell cycle

Abstract

Model reduction is an important topic in studies of biological systems. By reducing the complexity of large models through multi-level models while keeping the essence (biological meaning) of the model, model reduction can help answer many important questions about these systems. In this paper, we present a new reduction method based on hierarchical representation and a lumping approach. We used G1/S checkpoint pathway represented in Ordinary Differential Equations (ODE) in Iwamoto et al. (2011) as a case study to present this reduction method. The approach consists of two parts; the first part represents the biological network as a hierarchy (multiple levels) based on protein binding relations, which allowed us to model the biological network at different levels of abstraction. The second part applies different levels (level 1, 2 and 3) of lumping the species together depending on the level of the hierarchy, resulting in a reduced and transformed model for each level. The model at each level is a representation of the whole system and can address questions pertinent to that level. We develop and simulate reduced models for levels-1, 2 and 3 of lumping for the G1/S checkpoint pathway and evaluate the biological plausibility of the proposed method by comparing the results with the original ODE model of Iwamoto et al. (2011). The results for continuous dynamics of the G1/S checkpoint pathway with or without DNA-damage for reduced models of level- 1, 2 and 3 of lumping are in very good agreement and consistent with the original model results and with biological findings. Therefore, the reduced models (level-1, 2 and 3) can be used to study cell cycle progression in G1 and the effects of DNA damage on it. It is suitable for reducing complex ODE biological network models while retaining accurate continuous dynamics of the system. The 3 levels of the reduced models respectively achieved 20%, 26% and 31% reduction of the base model. Moreover, the reduced model is more efficient to run (30%, 44% and 52% time reduction for the three levels) and generate solutions than the original ODE model. Simplification of complex mathematical models is possible and the proposed reduction method has the potential to make an impact across many fields of biomedical research.