The notion of entropy is shared between statistics and thermodynamics, and is fundamental to both disciplines. This makes statistical problems particularly suitable for reaction network implementations. In this paper we show how to perform a statistical operation known as Information Projection or E projection with stochastic mass-action kinetics. Our scheme encodes desired conditional distributions as the equilibrium distributions of reaction systems. To our knowledge this is a first scheme to exploit the inherent stochasticity of reaction networks for information processing. We apply this to the problem of an artificial cell trying to infer its environment from partial observations.
In Gopalkrishnan @cite_2 , one of the present authors has proposed a molecular scheme to do Maximum Likelihood Estimation in Log-Linear models. The reaction networks employed in that work are essentially identical to the reaction networks employed in this work, modulo some minor technical differences. In that paper, the reaction networks were used to obtain M-projections (or reverse I-projections), and thereby to solve for Maximum Likelihood Estimators. In this paper, we obtain E-projections, and sample from conditional distributions. The results in that paper were purely at the level of deterministic mass-action kinetics. The results in this paper obtain at the level of stochastic behavior.
@cite_2
1184690218 2166918926 2963675110 2150055571
We propose a novel molecular computing scheme for statistical inference. We focus on the much-studied statistical inference problem of computing maximum likelihood estimators for log-linear models. Our scheme takes log-linear models to reaction systems, and the observed data to initial conditions, so that the corresponding equilibrium of each reaction system encodes the corresponding maximum likelihood estimator. The main idea is to exploit the coincidence between thermodynamic entropy and statistical entropy. We map a Maximum Entropy characterization of the maximum likelihood estimator onto a Maximum Entropy characterization of the equilibrium concentrations for the reaction system. This allows for an efficient encoding of the problem, and reveals that reaction networks are superbly suited to statistical inference tasks. Such a scheme may also provide a template to understanding how in vivo biochemical signaling pathways integrate extensive information about their environment and history. Recent work on molecular programming has explored new possibilities for computational abstractions with biomolecules, including logic gates, neural networks, and linear systems. In the future such abstractions might enable nanoscale devices that can sense and control the world at a molecular scale. Just as in macroscale robotics, it is critical that such devices can learn about their environment and reason under uncertainty. At this small scale, systems are typically modeled as chemical reaction networks. In this work, we develop a procedure that can take arbitrary probabilistic graphical models, represented as factor graphs over discrete random variables, and compile them into chemical reaction networks that implement inference. In particular, we show that marginalization based on sum-product message passing can be implemented in terms of reactions between chemical species whose concentrations represent probabilities. We show algebraically that the steady state concentration of these species correspond to the marginal distributions of the random variables in the graph and validate the results in simulations. As with standard sum-product inference, this procedure yields exact results for tree-structured graphs, and approximate solutions for loopy graphs. We propose a graphical model for representing networks of stochastic processes, the minimal generative model graph. It is based on reduced factorizations of the joint distribution over time. We show that under appropriate conditions, it is unique and consistent with another type of graphical model, the directed information graph, which is based on a generalization of Granger causality. We demonstrate how directed information quantifies Granger causality in a particular sequential prediction setting. We also develop efficient methods to estimate the topological structure from data that obviate estimating the joint statistics. One algorithm assumes upper bounds on the degrees and uses the minimal dimension statistics necessary. In the event that the upper bounds are not valid, the resulting graph is nonetheless an optimal approximation in terms of Kullback-Leibler (KL) divergence. Another algorithm uses near-minimal dimension statistics when no bounds are known, but the distribution satisfies a certain criterion. Analogous to how structure learning algorithms for undirected graphical models use mutual information estimates, these algorithms use directed information estimates. We characterize the sample-complexity of two plug-in directed information estimators and obtain confidence intervals. For the setting when point estimates are unreliable, we propose an algorithm that uses confidence intervals to identify the best approximation that is robust to estimation error. Last, we demonstrate the effectiveness of the proposed algorithms through the analysis of both synthetic data and real data from the Twitter network. In the latter case, we identify which news sources influence users in the network by merely analyzing tweet times. In the stochastic formulation of chemical reactions, the dynamics of the first M-order moments of the species populations generally do not form a closed system of differential equations, in the sense that the time-derivatives of first M-order moments generally depend on moments of order higher than M. However, for analysis purposes, these dynamics are often made to be closed by approximating the needed derivatives of the first M-order moments by nonlinear functions of the same moments. These functions are called the moment closure functions. Recent results have introduced the technique of derivative-matching, where the moment closure functions are obtained by first assuming that they exhibit a certain separable form, and then matching time derivatives of the exact (not closed) moment equations with that of the approximate (closed) equations for some initial time and set of initial conditions. However, for multi-species reactions these results have been restricted to second order truncations, i.e, M = 2. This paper extends these results by providing explicit formulas to construct moment closure functions for any arbitrary order of truncation M. We show that with increasing M the closed moment equations provide more accurate approximations to the exact moment equations. Striking features of these moment closure functions are that they are independent of the reaction parameters (reaction rates and stoichiometry) and moreover the dependence of higher-order moment on lower order ones is consistent with the population being jointly lognormally distributed. To illustrate the applicability of our results we consider a simple bi-molecular reaction. Moment estimates from a third order truncation are compared with estimates obtained from a large number of Monte Carlo simulations