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Inference of a Boolean Network From Causal Logic Implications

ABSTRACT: 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.

SUBMITTER: Maheshwari P

PROVIDER: S-EPMC9246059 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundGene regulatory network inference remains a challenging problem in systems biology despite the numerous approaches that have been proposed. When substantial knowledge on a gene regulatory network is already available, supervised network inference is appropriate. Such a method builds a binary classifier able to assign a class (Regulation/No regulation) to an ordered pair of genes. Once learnt, the pairwise classifier can be used to predict new regulations. In this work, we explore the framework of Markov Logic Networks (MLN) that combine features of probabilistic graphical models with the expressivity of first-order logic rules.ResultsWe propose to learn a Markov Logic network, e.g. a set of weighted rules that conclude on the predicate "regulates", starting from a known gene regulatory network involved in the switch proliferation/differentiation of keratinocyte cells, a set of experimental transcriptomic data and various descriptions of genes all encoded into first-order logic. As training data are unbalanced, we use asymmetric bagging to learn a set of MLNs. The prediction of a new regulation can then be obtained by averaging predictions of individual MLNs. As a side contribution, we propose three in silico tests to assess the performance of any pairwise classifier in various network inference tasks on real datasets. A first test consists of measuring the average performance on balanced edge prediction problem; a second one deals with the ability of the classifier, once enhanced by asymmetric bagging, to update a given network. Finally our main result concerns a third test that measures the ability of the method to predict regulations with a new set of genes. As expected, MLN, when provided with only numerical discretized gene expression data, does not perform as well as a pairwise SVM in terms of AUPR. However, when a more complete description of gene properties is provided by heterogeneous sources, MLN achieves the same performance as a black-box model such as a pairwise SVM while providing relevant insights on the predictions.ConclusionsThe numerical studies show that MLN achieves very good predictive performance while opening the door to some interpretability of the decisions. Besides the ability to suggest new regulations, such an approach allows to cross-validate experimental data with existing knowledge.

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Inference of a Boolean Network From Causal Logic Implications

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