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

Fluid Model Checking of Timed Properties

We address the problem of verifying timed properties of Markovian models of large populations of interacting agents, modelled as finite state automata. In particular, we focus on time-bounded properties of (random) individual agents specified by Deterministic Timed Automata (DTA) endowed with a single clock. Exploiting ideas from fluid approximation, we estimate the satisfaction probability of the DTA properties by reducing it to the computation of the transient probability of a subclass of Time-Inhomogeneous Markov Renewal Processes with exponentially and deterministically-timed transitions, and a small state space. For this subclass of models, we show how to derive a set of Delay Differential Equations (DDE), whose numerical solution provides a fast and accurate estimate of the satisfaction probability. In the paper, we also prove the asymptotic convergence of the approach, and exemplify the method on a simple epidemic spreading model. Finally, we also show how to construct a system of DDEs to efficiently approximate the average number of agents that satisfy the DTA specification

Noise Reduction in Complex Biological Switches

Cells operate in noisy molecular environments via complex regulatory networks. It is possible to understand how molecular counts are related to noise in specific networks, but it is not generally clear how noise relates to network complexity, because different levels of complexity also imply different overall number of molecules. For a fixed function, does increased network complexity reduce noise, beyond the mere increase of overall molecular counts? If so, complexity could provide an advantage counteracting the costs involved in maintaining larger networks. For that purpose, we investigate how noise affects multistable systems, where a small amount of noise could lead to very different outcomes; thus we turn to biochemical switches. Our method for comparing networks of different structure and complexity is to place them in conditions where they produce exactly the same deterministic function. We are then in a good position to compare their noise characteristics relatively to their identical deterministic traces. We show that more complex networks are better at coping with both intrinsic and extrinsic noise. Intrinsic noise tends to decrease with complexity, and extrinsic noise tends to have less impact. Our findings suggest a new role for increased complexity in biological networks, at parity of function

Bounding Mean First Passage Times in Population Continuous-Time Markov Chains

We consider the problem of bounding mean first passage times and reachability probabilities for the class of population continuous-time Markov chains, which capture stochastic interactions between groups of identical agents. The quantitative analysis of such models is notoriously difficult since typically neither state-based numerical approaches nor methods based on stochastic sampling give efficient and accurate results. Here, we propose a novel approach that leverages techniques from martingale theory and stochastic processes to generate constraints on the statistical moments of first passage time distributions. These constraints induce a semi-definite program that can be used to compute exact bounds on reachability probabilities and mean first passage times without numerically solving the transient probability distribution of the process or sampling from it. We showcase the method on some test examples and tailor it to models exhibiting multimodality, a class of particularly challenging scenarios from biology

Model Checking Markov Population Models by Central Limit Approximation

In this paper we investigate the use of Central Limit Approximation of Continuous Time Markov Chains to verify collective properties of large population models, describing the interaction of many similar individual agents. More precisely, we specify properties in terms of individual agents by means of deterministic timed automata with a single global clock (which cannot be reset), and then use the Central Limit Approximation to estimate the probability that a given fraction of agents satisfies the local specification