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Causal network inference using biochemical kinetics.

ABSTRACT: Networks are widely used as structural summaries of biochemical systems. Statistical estimation of networks is usually based on linear or discrete models. However, the dynamics of biochemical systems are generally non-linear, suggesting that suitable non-linear formulations may offer gains with respect to causal network inference and aid in associated prediction problems.We present a general framework for network inference and dynamical prediction using time course data that is rooted in non-linear biochemical kinetics. This is achieved by considering a dynamical system based on a chemical reaction graph with associated kinetic parameters. Both the graph and kinetic parameters are treated as unknown; inference is carried out within a Bayesian framework. This allows prediction of dynamical behavior even when the underlying reaction graph itself is unknown or uncertain. Results, based on (i) data simulated from a mechanistic model of mitogen-activated protein kinase signaling and (ii) phosphoproteomic data from cancer cell lines, demonstrate that non-linear formulations can yield gains in causal network inference and permit dynamical prediction and uncertainty quantification in the challenging setting where the reaction graph is unknown.MATLAB R2014a software is available to download from warwick.ac.uk/chrisoates.Supplementary data are available at Bioinformatics online.

SUBMITTER: Oates CJ

PROVIDER: S-EPMC4147905 | biostudies-other | 2014 Sep

REPOSITORIES: biostudies-other

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Causal network inference using biochemical kinetics.

Oates Chris J CJ Dondelinger Frank F Bayani Nora N Korkola James J Gray Joe W JW Mukherjee Sach S

Bioinformatics (Oxford, England) 20140901 17

<h4>Motivation</h4>Networks are widely used as structural summaries of biochemical systems. Statistical estimation of networks is usually based on linear or discrete models. However, the dynamics of biochemical systems are generally non-linear, suggesting that suitable non-linear formulations may offer gains with respect to causal network inference and aid in associated prediction problems.<h4>Results</h4>We present a general framework for network inference and dynamical prediction using time co ...[more]

PMID: 25161235

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Project description:Biological systems contain a large number of molecules that have diverse interactions. A fruitful path to understanding these systems is to represent them with interaction networks, and then describe flow processes in the network with a dynamic model. Boolean modeling, the simplest discrete dynamic modeling framework for biological networks, has proven its value in recapitulating experimental results and making predictions. A first step and major roadblock to the widespread use of Boolean networks in biology is the laborious network inference and construction process. Here we present a streamlined network inference method that combines the discovery of a parsimonious network structure and the identification of Boolean functions that determine the dynamics of the system. This inference method is based on a causal logic analysis method that associates a logic type (sufficient or necessary) to node-pair relationships (whether promoting or inhibitory). We use the causal logic framework to assimilate indirect information obtained from perturbation experiments and infer relationships that have not yet been documented experimentally. We apply this inference method to a well-studied process of hormone signaling in plants, the signaling underlying abscisic acid (ABA)-induced stomatal closure. Applying the causal logic inference method significantly reduces the manual work typically required for network and Boolean model construction. The inferred model agrees with the manually curated model. We also test this method by re-inferring a network representing epithelial to mesenchymal transition based on a subset of the information that was initially used to construct the model. We find that the inference method performs well for various likely scenarios of inference input information. We conclude that our method is an effective approach toward inference of biological networks and can become an efficient step in the iterative process between experiments and computations.

Dataset Information

Causal network inference using biochemical kinetics.

Publications

Causal network inference using biochemical kinetics.

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