Dataset Information

Identification of marginal causal relationships in gene networks from observational and interventional expression data.

ABSTRACT: Causal network inference is an important methodological challenge in biology as well as other areas of application. Although several causal network inference methods have been proposed in recent years, they are typically applicable for only a small number of genes, due to the large number of parameters to be estimated and the limited number of biological replicates available. In this work, we consider the specific case of transcriptomic studies made up of both observational and interventional data in which a single gene of biological interest is knocked out. We focus on a marginal causal estimation approach, based on the framework of Gaussian directed acyclic graphs, to infer causal relationships between the knocked-out gene and a large set of other genes. In a simulation study, we found that our proposed method accurately differentiates between downstream causal relationships and those that are upstream or simply associative. It also enables an estimation of the total causal effects between the gene of interest and the remaining genes. Our method performed very similarly to a classical differential analysis for experiments with a relatively large number of biological replicates, but has the advantage of providing a formal causal interpretation. Our proposed marginal causal approach is computationally efficient and may be applied to several thousands of genes simultaneously. In addition, it may help highlight subsets of genes of interest for a more thorough subsequent causal network inference. The method is implemented in an R package called MarginalCausality (available on GitHub).

SUBMITTER: Monneret G

PROVIDER: S-EPMC5354375 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Publications

Identification of marginal causal relationships in gene networks from observational and interventional expression data.

Monneret Gilles G Jaffrézic Florence F Rau Andrea A Zerjal Tatiana T Nuel Grégory G

PloS one 20170316 3

Causal network inference is an important methodological challenge in biology as well as other areas of application. Although several causal network inference methods have been proposed in recent years, they are typically applicable for only a small number of genes, due to the large number of parameters to be estimated and the limited number of biological replicates available. In this work, we consider the specific case of transcriptomic studies made up of both observational and interventional da ...[more]

PMID: 28301504

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Project description:BACKGROUND: In recent years, there has been great interest in using transcriptomic data to infer gene regulatory networks. For the time being, methodological development in this area has primarily made use of graphical Gaussian models for observational wild-type data, resulting in undirected graphs that are not able to accurately highlight causal relationships among genes. In the present work, we seek to improve the estimation of causal effects among genes by jointly modeling observational transcriptomic data with arbitrarily complex intervention data obtained by performing partial, single, or multiple gene knock-outs or knock-downs. RESULTS: Using the framework of causal Gaussian Bayesian networks, we propose a Markov chain Monte Carlo algorithm with a Mallows proposal model and analytical likelihood maximization to sample from the posterior distribution of causal node orderings, and in turn, to estimate causal effects. The main advantage of the proposed algorithm over previously proposed methods is its flexibility to accommodate any kind of intervention design, including partial or multiple knock-out experiments. Using simulated data as well as data from the Dialogue for Reverse Engineering Assessments and Methods (DREAM) 2007 challenge, the proposed method was compared to two alternative approaches: one requiring a complete, single knock-out design, and one able to model only observational data. CONCLUSIONS: The proposed algorithm was found to perform as well as, and in most cases better, than the alternative methods in terms of accuracy for the estimation of causal effects. In addition, multiple knock-outs proved to contribute valuable additional information compared to single knock-outs. Finally, the simulation study confirmed that it is not possible to estimate the causal ordering of genes from observational data alone. In all cases, we found that the inclusion of intervention experiments enabled more accurate estimation of causal regulatory relationships than the use of wild-type data alone.

Dataset Information

Identification of marginal causal relationships in gene networks from observational and interventional expression data.

Publications

Identification of marginal causal relationships in gene networks from observational and interventional expression data.

Similar Datasets

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