No abstract

A signalling pathway is a sequence of chemical reactions initiated by a stimulus which in turn affects a receptor, and then through some intermediate steps cascades down to the final cell response. Based on the technique of flow cytometry, samples of cell-by-cell measurements are collected under each experimental condition, resulting in a collection of interventional data (assuming no latent variables are involved). Usually several external interventions are applied at different points of the pathway, the ultimate aim being the structural recovery of the underlying signalling network which we model as a causal Directed Acyclic Graph (DAG) using intervention calculus. The advantage of using interventional data, rather than purely observational one, is that identifiability of the true data generating DAG is enhanced. More technically a Markov equivalence class of DAGs, whose members are statistically indistinguishable based on observational data alone, can be further decomposed, using additional interventional data, into smaller distinct Interventional Markov equivalence classes. We present a Bayesian methodology for structural learning of Interventional Markov equivalence classes based on observational and interventional samples of multivariate Gaussian observations. Our approach is objective, meaning that it is based on default parameter priors requiring no personal elicitation; some flexibility is however allowed through a tuning parameter which regulates sparsity in the prior on model space. Based on an analytical expression for the marginal likelihood of a given Interventional Essential Graph, and a suitable MCMC scheme, our analysis produces an approximate posterior distribution on the space of Interventional Markov equivalence classes, which can be used to provide uncertainty quantification for features of substantive scientific interest, such as the posterior probability of inclusion of selected edges, or paths.

We assume that multivariate observational data are generated from a distribution whose conditional independencies are encoded in a Directed Acyclic Graph (DAG). For any given DAG, the causal effect of a variable onto another one can be evaluated through intervention calculus. A DAG is typically not identifiable from observational data alone. However, its Markov equivalence class (a collection of DAGs) can be estimated from the data. As a consequence, for the same intervention a set of causal effects, one for each DAG in the equivalence class, can be evaluated. In this paper, we propose a fully Bayesian methodology to make inference on the causal effects of any intervention in the system. Main features of our method are: (a) both uncertainty on the equivalence class and the causal effects are jointly modeled; (b) priors on the parameters of the modified Cholesky decomposition of the precision matrices across all DAG models are constructively assigned starting from a unique prior on the complete (unrestricted) DAG; (c) an efficient algorithm to sample from the posterior distribution on graph space is adopted; (d) an objective Bayes approach, requiring virtually no user specification, is used throughout. We demonstrate the merits of our methodology in simulation studies, wherein comparisons with current state‐of‐the‐art procedures turn out to be highly satisfactory. Finally we examine a real data set of gene expressions for Arabidopsis thaliana.

Graphical modeling represents an established methodology for identifying complex dependencies in biological networks, as exemplified in the study of co‐expression, gene regulatory, and protein interaction networks. The available observations often exhibit an intrinsic heterogeneity, which impacts on the network structure through the modification of specific pathways for distinct groups, such as disease subtypes. We propose to infer the resulting multiple graphs jointly in order to benefit from potential similarities across groups; on the other hand our modeling framework is able to accommodate group idiosyncrasies. We consider directed acyclic graphs (DAGs) as network structures, and develop a Bayesian method for structural learning of multiple DAGs. We explicitly account for Markov equivalence of DAGs, and propose a suitable prior on the collection of graph spaces that induces selective borrowing strength across groups. The resulting inference allows in particular to compute the posterior probability of edge inclusion, a useful summary for representing flow directions within the network. Finally, we detail a simulation study addressing the comparative performance of our method, and present an analysis of two protein networks together with a substantive interpretation of our findings.

We consider a binary response which is potentially affected by a set of continuous variables. Of special interest is the causal effect on the response due to an intervention on a specific variable. The latter can be meaningfully determined on the basis of observational data through suitable assumptions on the data generating mechanism. In particular we assume that the joint distribution obeys the conditional independencies (Markov properties) inherent in a Directed Acyclic Graph (DAG), and the DAG is given a causal interpretation through the notion of interventional distribution. We propose a DAG-probit model where the response is generated by discretization through a random threshold of a continuous latent variable and the latter, jointly with the remaining continuous variables, has a distribution belonging to a zero-mean Gaussian model whose covariance matrix is constrained to satisfy the Markov properties of the DAG; the latter is assigned a DAG-Wishart prior through the corresponding Cholesky parameters. Our model leads to a natural definition of causal effect conditionally on a given DAG. Since the DAG which generates the observations is unknown, we present an efficient MCMC algorithm whose target is the posterior distribution on the space of DAGs, the Cholesky parameters of the concentration matrix, and the threshold linking the response to the latent. Our end result is a Bayesian Model Averaging estimate of the causal effect which incorporates parameter, as well as model, uncertainty. The methodology is assessed using simulation experiments and applied to a gene expression data set originating from breast cancer stem cells.