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Guido Sanguinetti

Publications and source records attributed to Guido Sanguinetti.

48 records · Page 3Linked to original sources
arXiv2015

Comparison of different moment-closure approximations for stochastic chemical kinetics

In recent years moment-closure approximations (MA) of the chemical master equation have become a popular method for the study of stochastic effects in chemical reaction systems. Several different MA methods have been proposed and applied in the literature, but it remains unclear how they perform with respect to each other. In this paper we study the normal, Poisson, log-normal and central-moment-neglect MAs by applying them to understand the stochastic properties of chemical systems whose deterministic rate equations show the properties of bistability, ultrasensitivity and oscillatory behaviour. Our results suggest that the normal MA is favourable over the other studied MAs. In particular we found that (i) the size of the region of parameter space where a closure gives physically meaningful results, e.g. positive mean and variance, is considerably larger for the normal closure than for the other three closures; (ii) the accuracy of the predictions of the four closures (relative to simulations using the stochastic simulation algorithm) is comparable in those regions of parameter space where all closures give physically meaningful results; (iii) the Poisson and log-normal MAs are not uniquely defined for systems involving conservation laws in molecule numbers. We also describe the new software package MOCA which enables the automated numerical analysis of various MA methods in a graphical user interface and which was used to perform the comparative analysis presented in this paper. MOCA allows the user to develop novel closure methods and can treat polynomial, non-polynomial, as well as time-dependent propensity functions, thus being applicable to virtually any chemical reaction system.

q-bio.QM↗
arXiv2015

Sparse Approximate Inference for Spatio-Temporal Point Process Models

Spatio-temporal point process models play a central role in the analysis of spatially distributed systems in several disciplines. Yet, scalable inference remains computa- tionally challenging both due to the high resolution modelling generally required and the analytically intractable likelihood function. Here, we exploit the sparsity structure typical of (spatially) discretised log-Gaussian Cox process models by using approximate message-passing algorithms. The proposed algorithms scale well with the state dimension and the length of the temporal horizon with moderate loss in distributional accuracy. They hence provide a flexible and faster alternative to both non-linear filtering-smoothing type algorithms and to approaches that implement the Laplace method or expectation propagation on (block) sparse latent Gaussian models. We infer the parameters of the latent Gaussian model using a structured variational Bayes approach. We demonstrate the proposed framework on simulation studies with both Gaussian and point-process observations and use it to reconstruct the conflict intensity and dynamics in Afghanistan from the WikiLeaks Afghan War Diary.

stat.ML↗
arXiv2015

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.

eess.SY↗
arXiv2015

Validity conditions for moment closure approximations in stochastic chemical kinetics

Approximations based on moment-closure (MA) are commonly used to obtain estimates of the mean molecule numbers and of the variance of fluctuations in the number of molecules of chemical systems. The advantage of this approach is that it can be far less computationally expensive than exact stochastic simulations of the chemical master equation. Here we numerically study the conditions under which the MA equations yield results reflecting the true stochastic dynamics of the system. We show that for bistable and oscillatory chemical systems with deterministic initial conditions, the solution of the MA equations can be interpreted as a valid approximation to the true moments of the CME, only when the steady-state mean molecule numbers obtained from the chemical master equation fall within a certain finite range. The same validity criterion for monostable systems implies that the steady-state mean molecule numbers obtained from the chemical master equation must be above a certain threshold. For mean molecule numbers outside of this range of validity, the MA equations lead to either qualitatively wrong oscillatory dynamics or to unphysical predictions such as negative variances in the molecule numbers or multiple steady-state moments of the stationary distribution as the initial conditions are varied. Our results clarify the range of validity of the MA approach and show that pitfalls in the interpretation of the results can only be overcome through the systematic comparison of the solutions of the MA equations of a certain order with those of higher orders.

q-bio.MN↗
arXiv2014

M3D: a kernel-based test for shape changes in methylation profiles

DNA methylation is an intensely studied epigenetic mark implicated in many biological processes of direct clinical relevance. While sequencing based technologies are increasingly allowing high resolution measurements of DNA methylation, statistical modelling of such data is still challenging. In particular, statistical identification of differentially methylated regions across different conditions poses unresolved challenges in accounting for spatial correlations within the statistical testing procedure. We propose a non-parametric, kernel-based method, M3D, to detect higher-order changes in methylation profiles, such as shape, across pre-defined regions. The test statistic explicitly accounts for differences in coverage levels between samples, thus handling in a principled way a major confounder in the analysis of methylation data. Empirical tests on real and simulated data sets show an increased power compared to established methods, as well as considerable robustness with respect to coverage and replication levels. Code is implemented in R, and is freely available via Bioconductor package M3D.

q-bio.QM↗
arXiv2014

Smoothed Model Checking for Uncertain Continuous Time Markov Chains

We consider the problem of computing the satisfaction probability of a formula for stochastic models with parametric uncertainty. We show that this satisfaction probability is a smooth function of the model parameters. This enables us to devise a novel Bayesian statistical algorithm which performs statistical model checking simultaneously for all values of the model parameters from observations of truth values of the formula over individual runs of the model at isolated parameter values. This is achieved by exploiting the smoothness of the satisfaction function: by modelling explicitly correlations through a prior distribution over a space of smooth functions (a Gaussian Process), we can condition on observations at individual parameter values to construct an analytical approximation of the function itself. Extensive experiments on non-trivial case studies show that the approach is accurate and several orders of magnitude faster than naive parameter exploration with standard statistical model checking methods.

cs.LO↗
arXiv2014

The complex chemical Langevin equation

The chemical Langevin equation (CLE) is a popular simulation method to probe the stochastic dynamics of chemical systems. The CLE's main disadvantage is its break down in finite time due to the problem of evaluating square roots of negative quantities whenever the molecule numbers become sufficiently small. We show that this issue is not a numerical integration problem, rather in many systems it is intrinsic to all representations of the CLE. Various methods of correcting the CLE have been proposed which avoid its break down. We show that these methods introduce undesirable artefacts in the CLE's predictions. In particular, for unimolecular systems, these correction methods lead to CLE predictions for the mean concentrations and variance of fluctuations which disagree with those of the chemical master equation. We show that, by extending the domain of the CLE to complex space, break down is eliminated, and the CLE's accuracy for unimolecular systems is restored. Although the molecule numbers are generally complex, we show that the "complex CLE" predicts real-valued quantities for the mean concentrations, the moments of intrinsic noise, power spectra and first passage times, hence admitting a physical interpretation. It is also shown to provide a more accurate approximation of the chemical master equation of simple biochemical circuits involving bimolecular reactions than the various corrected forms of the real-valued CLE, the linear-noise approximation and a commonly used two moment-closure approximation.

q-bio.QM↗
arXiv2013

Learning Temporal Logical Properties Discriminating ECG models of Cardiac Arrhytmias

We present a novel approach to learn the formulae characterising the emergent behaviour of a dynamical system from system observations. At a high level, the approach starts by devising a statistical dynamical model of the system which optimally fits the observations. We then propose general optimisation strategies for selecting high support formulae (under the learnt model of the system) either within a discrete set of formulae of bounded complexity, or a parametric family of formulae. We illustrate and apply the methodology on an in-depth case study of characterising cardiac malfunction from electro-cardiogram data, where our approach enables us to quantitatively determine the diagnostic power of a formula in discriminating between different cardiac conditions.

cs.LO↗
arXiv2013

On the Robustness of Temporal Properties for Stochastic Models

Stochastic models such as Continuous-Time Markov Chains (CTMC) and Stochastic Hybrid Automata (SHA) are powerful formalisms to model and to reason about the dynamics of biological systems, due to their ability to capture the stochasticity inherent in biological processes. A classical question in formal modelling with clear relevance to biological modelling is the model checking problem. i.e. calculate the probability that a behaviour, expressed for instance in terms of a certain temporal logic formula, may occur in a given stochastic process. However, one may not only be interested in the notion of satisfiability, but also in the capacity of a system to mantain a particular emergent behaviour unaffected by the perturbations, caused e.g. from extrinsic noise, or by possible small changes in the model parameters. To address this issue, researchers from the verification community have recently proposed several notions of robustness for temporal logic providing suitable definitions of distance between a trajectory of a (deterministic) dynamical system and the boundaries of the set of trajectories satisfying the property of interest. The contributions of this paper are twofold. First, we extend the notion of robustness to stochastic systems, showing that this naturally leads to a distribution of robustness scores. By discussing two examples, we show how to approximate the distribution of the robustness score and its key indicators: the average robustness and the conditional average robustness. Secondly, we show how to combine these indicators with the satisfaction probability to address the system design problem, where the goal is to optimize some control parameters of a stochastic model in order to best maximize robustness of the desired specifications.

cs.LO↗
arXiv2013

A stochastic hybrid model of a biological filter

We present a hybrid model of a biological filter, a genetic circuit which removes fast fluctuations in the cell's internal representation of the extra cellular environment. The model takes the classic feed-forward loop (FFL) motif and represents it as a network of continuous protein concentrations and binary, unobserved gene promoter states. We address the problem of statistical inference and parameter learning for this class of models from partial, discrete time observations. We show that the hybrid representation leads to an efficient algorithm for approximate statistical inference in this circuit, and show its effectiveness on a simulated data set.

cs.LG↗
arXiv2013

Factored expectation propagation for input-output FHMM models in systems biology

We consider the problem of joint modelling of metabolic signals and gene expression in systems biology applications. We propose an approach based on input-output factorial hidden Markov models and propose a structured variational inference approach to infer the structure and states of the model. We start from the classical free form structured variational mean field approach and use a expectation propagation to approximate the expectations needed in the variational loop. We show that this corresponds to a factored expectation constrained approximate inference. We validate our model through extensive simulations and demonstrate its applicability on a real world bacterial data set.

stat.ML↗