Stochastic shielding and edge importance for Markov chains with timescale separation

Deena R Schmidt, Roberto F Galán and Peter J Thomas

PLOS Computational Biology, 2018, vol. 14, issue 6, 1-35

Abstract: Nerve cells produce electrical impulses (“spikes”) through the coordinated opening and closing of ion channels. Markov processes with voltage-dependent transition rates capture the stochasticity of spike generation at the cost of complex, time-consuming simulations. Schmandt and Galán introduced a novel method, based on the stochastic shielding approximation, as a fast, accurate method for generating approximate sample paths with excellent first and second moment agreement to exact stochastic simulations. We previously analyzed the mathematical basis for the method’s remarkable accuracy, and showed that for models with a Gaussian noise approximation, the stationary variance of the occupancy at each vertex in the ion channel state graph could be written as a sum of distinct contributions from each edge in the graph. We extend this analysis to arbitrary discrete population models with first-order kinetics. The resulting decomposition allows us to rank the “importance” of each edge’s contribution to the variance of the current under stationary conditions. In most cases, transitions between open (conducting) and closed (non-conducting) states make the greatest contributions to the variance, but there are exceptions. In a 5-state model of the nicotinic acetylcholine receptor, at low agonist concentration, a pair of “hidden” transitions (between two closed states) makes a greater contribution to the variance than any of the open-closed transitions. We exhaustively investigate this “edge importance reversal” phenomenon in simplified 3-state models, and obtain an exact formula for the contribution of each edge to the variance of the open state. Two conditions contribute to reversals: the opening rate should be faster than all other rates in the system, and the closed state leading to the opening rate should be sparsely occupied. When edge importance reversal occurs, current fluctuations are dominated by a slow noise component arising from the hidden transitions.Author summary: Discrete state, continuous time Markov processes occur throughout cell biology, neuroscience, and ecology, representing the random dynamics of processes transitioning among multiple locations or states. Complexity reduction for such models aims to capture the essential dynamics and stochastic properties via a simpler representation, with minimal loss of accuracy. Classical approaches, such as aggregation of nodes and elimination of fast variables, lead to reduced models that are no longer Markovian. Stochastic shielding provides an alternative approach by simplifying the description of the noise driving the process, while preserving the Markov property, by removing from the model those fluctuations that are not directly observable. We previously applied the stochastic shielding approximation to several Markov processes arising in neuroscience and processes on random graphs. Here we explore the range of validity of stochastic shielding for processes with nonuniform stationary probabilities and multiple timescales, including ion channels with “bursty” dynamics. We show that stochastic shielding is robust to the introduction of timescale separation, for a class of simple networks, but it can break down for more complex systems with three distinct timescales. We also show that our related edge importance measure remains valid for arbitrary networks regardless of multiple timescales.

Date: 2018
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1006206

DOI: 10.1371/journal.pcbi.1006206

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