A non-homogeneous dynamic Bayesian network with sequentially coupled interaction parameters for applications in systems and synthetic biology

An important and challenging problem in systems biology is the inference of gene regulatory networks from short non-stationary time series of transcriptional profiles. A popular approach that has been widely applied to this end is based on dynamic Bayesian networks (DBNs), although traditional homogeneous DBNs fail to model the non-stationarity and time-varying nature of the gene regulatory processes. Various authors have therefore recently proposed combining DBNs with multiple changepoint processes to obtain time varying dynamic Bayesian networks (TV-DBNs). However, TV-DBNs are not without problems. Gene expression time series are typically short, which leaves the model over-flexible, leading to over-fitting or inflated inference uncertainty. In the present paper, we introduce a Bayesian regularization scheme that addresses this difficulty. Our approach is based on the rationale that changes in gene regulatory processes appear gradually during an organism's life cycle or in response to a changing environment, and we have integrated this notion in the prior distribution of the TV-DBN parameters. We have extensively tested our regularized TV-DBN model on synthetic data, in which we have simulated short non-homogeneous time series produced from a system subject to gradual change. We have then applied our method to real-world gene expression time series, measured during the life cycle of Drosophila melanogaster, under artificially generated constant light condition in Arabidopsis thaliana, and from a synthetically designed strain of Saccharomyces cerevisiae exposed to a changing environment

Bayesian regularization of non-homogeneous dynamic Bayesian networks by globally coupling interaction parameters

To relax the homogeneity assumption of classical dynamic Bayesian networks (DBNs), various recent studies have combined DBNs with multiple changepoint processes. The underlying assumption is that the parameters associated with time series segments delimited by multiple changepoints are a priori independent. Under weak regularity conditions, the parameters can be integrated out in the likelihood, leading to a closed-form expression of the marginal likelihood. However, the assumption of prior independence is unrealistic in many real-world applications, where the segment-specific regulatory relationships among the interdependent quantities tend to undergo gradual evolutionary adaptations. We therefore propose a Bayesian coupling scheme to introduce systematic information sharing among the segment-specific interaction parameters. We investigate the effect this model improvement has on the network reconstruction accuracy in a reverse engineering context, where the objective is to learn the structure of a gene regulatory network from temporal gene expression profiles

Hubbard chain with a Kondo impurity

A Bethe Ansatz solution of a (modified) Hubbard chain with a Kondo impurity of arbitrary spin S at a highly symmetric line of parameter space is proposed and explored. Our results confirm the existence of a strong-coupling (line of) fixed-point(s) with ferromagnetic Kondo coupling as first hypothetized by Furusaki and Nagaosa on the basis of perturbative renormalization group calculations. For on-site Hubbard repulsion and ferromagnetic Kondo exchange, the ground state has spin S-1/2, i.e., is a singlet when S=1/2. The contributions of the impurity to the magnetic susceptibility and low-temperature specific heat are discussed. While the Wilson ratio is unity in the half-filled band, it is found to be a function of density and interaction away from half-filling.Comment: 5 pages, Revte

Network Reconstruction with Realistic Models

We extend a recently proposed gradient-matching method for inferring interactions in complex systems described by differential equations in various respects: improved gradient inference, evaluation of the influence of the prior on kinetic parameters, comparative evaluation of two model selection paradigms: marginal likelihood versus DIC (divergence information criterion), comparative evaluation of different numerical procedures for computing the marginal likelihood, extension of the methodology from protein phosphorylation to transcriptional regulation, based on a realistic simulation of the underlying molecular processes with Markov jump processes

Targeting Bayes factors with direct-path non-equilibrium thermodynamic integration

Thermodynamic integration (TI) for computing marginal likelihoods is based on an inverse annealing path from the prior to the posterior distribution. In many cases, the resulting estimator suffers from high variability, which particularly stems from the prior regime. When comparing complex models with differences in a comparatively small number of parameters, intrinsic errors from sampling fluctuations may outweigh the differences in the log marginal likelihood estimates. In the present article, we propose a thermodynamic integration scheme that directly targets the log Bayes factor. The method is based on a modified annealing path between the posterior distributions of the two models compared, which systematically avoids the high variance prior regime. We combine this scheme with the concept of non-equilibrium TI to minimise discretisation errors from numerical integration. Results obtained on Bayesian regression models applied to standard benchmark data, and a complex hierarchical model applied to biopathway inference, demonstrate a significant reduction in estimator variance over state-of-the-art TI methods