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BMC Syst Biol. 2018 Jun 14;12(1):68. doi: 10.1186/s12918-018-0586-6.

Principal process analysis of biological models.

Author information

1
Université Côte d'Azur, Inria, INRA, CNRS, UPMC Univ Paris 06, Biocore team, Sophia Antipolis, France. stefano.casagranda01@gmail.com.
2
Université Côte d'Azur, Inria, INRA, CNRS, UPMC Univ Paris 06, Biocore team, Sophia Antipolis, France.
3
Université Côte d'Azur, INRA, CNRS, ISA, Sophia Antipolis, France.
4
Univ. Grenoble Alpes, Inria, Grenoble, 38000, France.

Abstract

BACKGROUND:

Understanding the dynamical behaviour of biological systems is challenged by their large number of components and interactions. While efforts have been made in this direction to reduce model complexity, they often prove insufficient to grasp which and when model processes play a crucial role. Answering these questions is fundamental to unravel the functioning of living organisms.

RESULTS:

We design a method for dealing with model complexity, based on the analysis of dynamical models by means of Principal Process Analysis. We apply the method to a well-known model of circadian rhythms in mammals. The knowledge of the system trajectories allows us to decompose the system dynamics into processes that are active or inactive with respect to a certain threshold value. Process activities are graphically represented by Boolean and Dynamical Process Maps. We detect model processes that are always inactive, or inactive on some time interval. Eliminating these processes reduces the complex dynamics of the original model to the much simpler dynamics of the core processes, in a succession of sub-models that are easier to analyse. We quantify by means of global relative errors the extent to which the simplified models reproduce the main features of the original system dynamics and apply global sensitivity analysis to test the influence of model parameters on the errors.

CONCLUSION:

The results obtained prove the robustness of the method. The analysis of the sub-model dynamics allows us to identify the source of circadian oscillations. We find that the negative feedback loop involving proteins PER, CRY, CLOCK-BMAL1 is the main oscillator, in agreement with previous modelling and experimental studies. In conclusion, Principal Process Analysis is a simple-to-use method, which constitutes an additional and useful tool for analysing the complex dynamical behaviour of biological systems.

KEYWORDS:

Biological networks; Circadian clock; Dynamical systems; Model reduction; Parameter sensitivity analysis; Process analysis

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