Inferring Regulatory Networks by Combining Perturbation Screens and Steady State Gene Expression Profiles

Reconstructing transcriptional regulatory networks is an important task in functional genomics. Data obtained from experiments that perturb genes by knockouts or RNA interference contain useful information for addressing this reconstruction problem. However, such data can be limited in size and/or are expensive to acquire. On the other hand, observational data of the organism in steady state (e.g. wild-type) are more readily available, but their informational content is inadequate for the task at hand. We develop a computational approach to appropriately utilize both data sources for estimating a regulatory network. The proposed approach is based on a three-step algorithm to estimate the underlying directed but cyclic network, that uses as input both perturbation screens and steady state gene expression data. In the first step, the algorithm determines causal orderings of the genes that are consistent with the perturbation data, by combining an exhaustive search method with a fast heuristic that in turn couples a Monte Carlo technique with a fast search algorithm. In the second step, for each obtained causal ordering, a regulatory network is estimated using a penalized likelihood based method, while in the third step a consensus network is constructed from the highest scored ones. Extensive computational experiments show that the algorithm performs well in reconstructing the underlying network and clearly outperforms competing approaches that rely only on a single data source. Further, it is established that the algorithm produces a consistent estimate of the regulatory network.Comment: 24 pages, 4 figures, 6 table

Identifiability and transportability in dynamic causal networks

In this paper we propose a causal analog to the purely observational Dynamic Bayesian Networks, which we call Dynamic Causal Networks. We provide a sound and complete algorithm for identification of Dynamic Causal Networks, namely, for computing the effect of an intervention or experiment, based on passive observations only, whenever possible. We note the existence of two types of confounder variables that affect in substantially different ways the identification procedures, a distinction with no analog in either Dynamic Bayesian Networks or standard causal graphs. We further propose a procedure for the transportability of causal effects in Dynamic Causal Network settings, where the result of causal experiments in a source domain may be used for the identification of causal effects in a target domain.Preprin

Causal Consistency of Structural Equation Models

Complex systems can be modelled at various levels of detail. Ideally, causal models of the same system should be consistent with one another in the sense that they agree in their predictions of the effects of interventions. We formalise this notion of consistency in the case of Structural Equation Models (SEMs) by introducing exact transformations between SEMs. This provides a general language to consider, for instance, the different levels of description in the following three scenarios: (a) models with large numbers of variables versus models in which the `irrelevant' or unobservable variables have been marginalised out; (b) micro-level models versus macro-level models in which the macro-variables are aggregate features of the micro-variables; (c) dynamical time series models versus models of their stationary behaviour. Our analysis stresses the importance of well specified interventions in the causal modelling process and sheds light on the interpretation of cyclic SEMs.Comment: equal contribution between Rubenstein and Weichwald; accepted manuscrip

Beyond Structural Causal Models: Causal Constraints Models

Structural Causal Models (SCMs) provide a popular causal modeling framework. In this work, we show that SCMs are not flexible enough to give a complete causal representation of dynamical systems at equilibrium. Instead, we propose a generalization of the notion of an SCM, that we call Causal Constraints Model (CCM), and prove that CCMs do capture the causal semantics of such systems. We show how CCMs can be constructed from differential equations and initial conditions and we illustrate our ideas further on a simple but ubiquitous (bio)chemical reaction. Our framework also allows to model functional laws, such as the ideal gas law, in a sensible and intuitive way.Comment: Published in Proceedings of the 35th Annual Conference on Uncertainty in Artificial Intelligence (UAI-19