Learning and Designing Stochastic Processes from Logical Constraints

Stochastic processes offer a flexible mathematical formalism to model and reason about systems. Most analysis tools, however, start from the premises that models are fully specified, so that any parameters controlling the system's dynamics must be known exactly. As this is seldom the case, many methods have been devised over the last decade to infer (learn) such parameters from observations of the state of the system. In this paper, we depart from this approach by assuming that our observations are {\it qualitative} properties encoded as satisfaction of linear temporal logic formulae, as opposed to quantitative observations of the state of the system. An important feature of this approach is that it unifies naturally the system identification and the system design problems, where the properties, instead of observations, represent requirements to be satisfied. We develop a principled statistical estimation procedure based on maximising the likelihood of the system's parameters, using recent ideas from statistical machine learning. We demonstrate the efficacy and broad applicability of our method on a range of simple but non-trivial examples, including rumour spreading in social networks and hybrid models of gene regulation

Transcriptional delay stabilizes bistable gene networks

Transcriptional delay can significantly impact the dynamics of gene networks. Here we examine how such delay affects bistable systems. We investigate several stochastic models of bistable gene networks and find that increasing delay dramatically increases the mean residence times near stable states. To explain this, we introduce a non-Markovian, analytically tractable reduced model. The model shows that stabilization is the consequence of an increased number of failed transitions between stable states. Each of the bistable systems that we simulate behaves in this manner

Relative Stability of Network States in Boolean Network Models of Gene Regulation in Development

Progress in cell type reprogramming has revived the interest in Waddington's concept of the epigenetic landscape. Recently researchers developed the quasi-potential theory to represent the Waddington's landscape. The Quasi-potential U(x), derived from interactions in the gene regulatory network (GRN) of a cell, quantifies the relative stability of network states, which determine the effort required for state transitions in a multi-stable dynamical system. However, quasi-potential landscapes, originally developed for continuous systems, are not suitable for discrete-valued networks which are important tools to study complex systems. In this paper, we provide a framework to quantify the landscape for discrete Boolean networks (BNs). We apply our framework to study pancreas cell differentiation where an ensemble of BN models is considered based on the structure of a minimal GRN for pancreas development. We impose biologically motivated structural constraints (corresponding to specific type of Boolean functions) and dynamical constraints (corresponding to stable attractor states) to limit the space of BN models for pancreas development. In addition, we enforce a novel functional constraint corresponding to the relative ordering of attractor states in BN models to restrict the space of BN models to the biological relevant class. We find that BNs with canalyzing/sign-compatible Boolean functions best capture the dynamics of pancreas cell differentiation. This framework can also determine the genes' influence on cell state transitions, and thus can facilitate the rational design of cell reprogramming protocols.Comment: 24 pages, 6 figures, 1 tabl

A stroboscopic averaging algorithm for highly oscillatory delay problems

We propose and analyze a heterogenous multiscale method for the efficient integration of constant-delay differential equations subject to fast periodic forcing. The stroboscopic averaging method (SAM) suggested here may provide approximations with \(\mathcal{O}(H^2+1/\Omega^2)\) errors with a computational effort that grows like \(H^{-1}\) (the inverse of the stepsize), uniformly in the forcing frequency Omega

Optimal Path to Epigenetic Switching

We use large deviation methods to calculate rates of noise-induced transitions between states in multistable genetic networks. We analyze a synthetic biochemical circuit, the toggle switch, and compare the results to those obtained from a numerical solution of the master equation.Comment: 5 pages. 2 figures, uses revtex 4. PR-E reviewed for publicatio

Mean-Field approximation and Quasi-Equilibrium reduction of Markov Population Models

Markov Population Model is a commonly used framework to describe stochastic systems. Their exact analysis is unfeasible in most cases because of the state space explosion. Approximations are usually sought, often with the goal of reducing the number of variables. Among them, the mean field limit and the quasi-equilibrium approximations stand out. We view them as techniques that are rooted in independent basic principles. At the basis of the mean field limit is the law of large numbers. The principle of the quasi-equilibrium reduction is the separation of temporal scales. It is common practice to apply both limits to an MPM yielding a fully reduced model. Although the two limits should be viewed as completely independent options, they are applied almost invariably in a fixed sequence: MF limit first, QE-reduction second. We present a framework that makes explicit the distinction of the two reductions, and allows an arbitrary order of their application. By inverting the sequence, we show that the double limit does not commute in general: the mean field limit of a time-scale reduced model is not the same as the time-scale reduced limit of a mean field model. An example is provided to demonstrate this phenomenon. Sufficient conditions for the two operations to be freely exchangeable are also provided

Modeling delayed processes in biological systems

Delayed processes are ubiquitous in biological systems and are often characterized by delay differential equations (DDEs) and their extension to include stochastic effects. DDEs do not explicitly incorporate intermediate states associated with a delayed process but instead use an estimated average delay time. In an effort to examine the validity of this approach, we study systems with significant delays by explicitly incorporating intermediate steps. We show by that such explicit models often yield significantly different equilibrium distributions and transition times as compared to DDEs with deterministic delay values. Additionally, different explicit models with qualitatively different dynamics can give rise to the same DDEs revealing important ambiguities. We also show that DDE-based predictions of oscillatory behavior may fail for the corresponding explicit model