Predictions of COVID-19 dynamics in the UK: Short-term forecasting and analysis of potential exit strategies.

Efforts to suppress transmission of SARS-CoV-2 in the UK have seen non-pharmaceutical interventions being invoked. The most severe measures to date include all restaurants, pubs and cafes being ordered to close on 20th March, followed by a "stay at home" order on the 23rd March and the closure of all non-essential retail outlets for an indefinite period. Government agencies are presently analysing how best to develop an exit strategy from these measures and to determine how the epidemic may progress once measures are lifted. Mathematical models are currently providing short and long term forecasts regarding the future course of the COVID-19 outbreak in the UK to support evidence-based policymaking. We present a deterministic, age-structured transmission model that uses real-time data on confirmed cases requiring hospital care and mortality to provide up-to-date predictions on epidemic spread in ten regions of the UK. The model captures a range of age-dependent heterogeneities, reduced transmission from asymptomatic infections and produces a good fit to the key epidemic features over time. We simulated a suite of scenarios to assess the impact of differing approaches to relaxing social distancing measures from 7th May 2020 on the estimated number of patients requiring inpatient and critical care treatment, and deaths. With regard to future epidemic outcomes, we investigated the impact of reducing compliance, ongoing shielding of elder age groups, reapplying stringent social distancing measures using region based triggers and the role of asymptomatic transmission. We find that significant relaxation of social distancing measures from 7th May onwards can lead to a rapid resurgence of COVID-19 disease and the health system being quickly overwhelmed by a sizeable, second epidemic wave. In all considered age-shielding based strategies, we projected serious demand on critical care resources during the course of the pandemic. The reintroduction and release of strict measures on a regional basis, based on ICU bed occupancy, results in a long epidemic tail, until the second half of 2021, but ensures that the health service is protected by reintroducing social distancing measures for all individuals in a region when required. Our work confirms the effectiveness of stringent non-pharmaceutical measures in March 2020 to suppress the epidemic. It also provides strong evidence to support the need for a cautious, measured approach to relaxation of lockdown measures, to protect the most vulnerable members of society and support the health service through subduing demand on hospital beds, in particular bed occupancy in intensive care units.

Spectral density-based and measure-preserving ABC for partially observed diffusion processes. An illustration on Hamiltonian SDEs.

Approximate Bayesian computation (ABC) has become one of the major tools of likelihood-free statistical inference in complex mathematical models. Simultaneously, stochastic differential equations (SDEs) have developed to an established tool for modelling time-dependent, real-world phenomena with underlying random effects. When applying ABC to stochastic models, two major difficulties arise: First, the derivation of effective summary statistics and proper distances is particularly challenging, since simulations from the stochastic process under the same parameter configuration result in different trajectories. Second, exact simulation schemes to generate trajectories from the stochastic model are rarely available, requiring the derivation of suitable numerical methods for the synthetic data generation. To obtain summaries that are less sensitive to the intrinsic stochasticity of the model, we propose to build up the statistical method (e.g. the choice of the summary statistics) on the underlying structural properties of the model. Here, we focus on the existence of an invariant measure and we map the data to their estimated invariant density and invariant spectral density. Then, to ensure that these model properties are kept in the synthetic data generation, we adopt measure-preserving numerical splitting schemes. The derived property-based and measure-preserving ABC method is illustrated on the broad class of partially observed Hamiltonian type SDEs, both with simulated data and with real electroencephalography data. The derived summaries are particularly robust to the model simulation, and this fact, combined with the proposed reliable numerical scheme, yields accurate ABC inference. In contrast, the inference returned using standard numerical methods (Euler-Maruyama discretisation) fails. The proposed ingredients can be incorporated into any type of ABC algorithm and directly applied to all SDEs that are characterised by an invariant distribution and for which a measure-preserving numerical method can be derived.

The Jacobi diffusion process as a neuronal model.

The Jacobi process is a stochastic diffusion characterized by a linear drift and a special form of multiplicative noise which keeps the process confined between two boundaries. One example of such a process can be obtained as the diffusion limit of the Stein's model of membrane depolarization which includes both excitatory and inhibitory reversal potentials. The reversal potentials create the two boundaries between which the process is confined. Solving the first-passage-time problem for the Jacobi process, we found closed-form expressions for mean, variance, and third moment that are easy to implement numerically. The first two moments are used here to determine the role played by the parameters of the neuronal model; namely, the effect of multiplicative noise on the output of the Jacobi neuronal model with input-dependent parameters is examined in detail and compared with the properties of the generic Jacobi diffusion. It appears that the dependence of the model parameters on the rate of inhibition turns out to be of primary importance to observe a change in the slope of the response curves. This dependence also affects the variability of the output as reflected by the coefficient of variation. It often takes values larger than one, and it is not always a monotonic function in dependency on the rate of excitation.

Accuracy of rate coding: When shorter time window and higher spontaneous activity help.

It is widely accepted that neuronal firing rates contain a significant amount of information about the stimulus intensity. Nevertheless, theoretical studies on the coding accuracy inferred from the exact spike counting distributions are rare. We present an analysis based on the number of observed spikes assuming the stochastic perfect integrate-and-fire model with a change point, representing the stimulus onset, for which we calculate the corresponding Fisher information to investigate the accuracy of rate coding. We analyze the effect of changing the duration of the time window and the influence of several parameters of the model, in particular the level of the presynaptic spontaneous activity and the level of random fluctuation of the membrane potential, which can be interpreted as noise of the system. The results show that the Fisher information is nonmonotonic with respect to the length of the observation period. This counterintuitive result is caused by the discrete nature of the count of spikes. We observe also that the signal can be enhanced by noise, since the Fisher information is nonmonotonic with respect to the level of spontaneous activity and, in some cases, also with respect to the level of fluctuation of the membrane potential.

Presynaptic Spontaneous Activity Enhances the Accuracy of Latency Coding.

The time to the first spike after stimulus onset typically varies with the stimulation intensity. Experimental evidence suggests that neural systems use such response latency to encode information about the stimulus. We investigate the decoding accuracy of the latency code in relation to the level of noise in the form of presynaptic spontaneous activity. Paradoxically, the optimal performance is achieved at a nonzero level of noise and suprathreshold stimulus intensities. We argue that this phenomenon results from the influence of the spontaneous activity on the stabilization of the membrane potential in the absence of stimulation. The reported decoding accuracy improvement represents a novel manifestation of the noise-aided signal enhancement.

Approximation of the first passage time density of a Wiener process to an exponentially decaying boundary by two-piecewise linear threshold. Application to neuronal spiking activity.

The first passage time density of a diffusion process to a time varying threshold is of primary interest in different fields. Here, we consider a Brownian motion in presence of an exponentially decaying threshold to model the neuronal spiking activity. Since analytical expressions of the first passage time density are not available, we propose to approximate the curved boundary by means of a continuous two-piecewise linear threshold. Explicit expressions for the first passage time density towards the new boundary are provided. First, we introduce different approximating linear thresholds. Then, we describe how to choose the optimal one minimizing the distance to the curved boundary, and hence the error in the corresponding passage time density. Theoretical means, variances and coefficients of variation given by our method are compared with empirical quantities from simulated data. Moreover, a further comparison with firing statistics derived under the assumption of a small amplitude of the time-dependent change in the threshold, is also carried out. Finally, maximum likelihood and moment estimators of the parameters of the model are derived and applied on simulated data.

A review of the methods for neuronal response latency estimation.

Neuronal response latency is usually vaguely defined as the delay between the stimulus onset and the beginning of the response. It contains important information for the understanding of the temporal code. For this reason, the detection of the response latency has been extensively studied in the last twenty years, yielding different estimation methods. They can be divided into two classes, one of them including methods based on detecting an intensity change in the firing rate profile after the stimulus onset and the other containing methods based on detection of spikes evoked by the stimulation using interspike intervals and spike times. The aim of this paper is to present a review of the main techniques proposed in both classes, highlighting their advantages and shortcomings.

Parameter inference from hitting times for perturbed Brownian motion.

A latent internal process describes the state of some system, e.g. the social tension in a political conflict, the strength of an industrial component or the health status of a person. When this process reaches a predefined threshold, the process terminates and an observable event occurs, e.g. the political conflict finishes, the industrial component breaks down or the person dies. Imagine an intervention, e.g., a political decision, maintenance of a component or a medical treatment, is initiated to the process before the event occurs. How can we evaluate whether the intervention had an effect? To answer this question we describe the effect of the intervention through parameter changes of the law governing the internal process. Then, the time interval between the start of the process and the final event is divided into two subintervals: the time from the start to the instant of intervention, denoted by S, and the time between the intervention and the threshold crossing, denoted by R. The first question studied here is: What is the joint distribution of (S,R)? The theoretical expressions are provided and serve as a basis to answer the main question: Can we estimate the parameters of the model from observations of S and R and compare them statistically? Maximum likelihood estimators are calculated and applied on simulated data under the assumption that the process before and after the intervention is described by the same type of model, i.e. a Brownian motion, but with different parameters. Also covariates and handling of censored observations are incorporated into the statistical model, and the method is illustrated on lung cancer data.

Identification of noisy response latency.

In many physical systems there is a time delay before an applied input (stimulation) has an impact on the output (response), and the quantification of this delay is of paramount interest. If the response can only be observed on top of an indistinguishable background signal, the estimation can be highly unreliable, unless the background signal is accounted for in the analysis. In fact, if the background signal is ignored, however small it is compared to the response and however large the delay is, the estimate of the time delay will go to zero for any reasonable estimator when increasing the number of observations. Here we propose a unified concept of response latency identification in event data corrupted by a background signal. It is done in the context of information transfer within a neural system, more specifically on spike trains from single neurons. The estimators are compared on simulated data and the most suitable for specific situations are recommended.

Detecting dependencies between spike trains of pairs of neurons through copulas.

The dynamics of a neuron are influenced by the connections with the network where it lies. Recorded spike trains exhibit patterns due to the interactions between neurons. However, the structure of the network is not known. A challenging task is to investigate it from the analysis of simultaneously recorded spike trains. We develop a non-parametric method based on copulas, that we apply to simulated data according to different bivariate Leaky Integrate and Fire models. The method discerns dependencies determined by the surrounding network, from those determined by direct interactions between the two neurons. Furthermore, the method recognizes the presence of delays in the spike propagation. This article is part of a Special Issue entitled "Neural Coding".

Leaky integrate and fire models coupled through copulas: association properties of the interspike intervals.

We propose a model able to describe the Interspike Intervals of two or more neurons subject to common inputs from the network. The single neuron dynamic is described through a classical Leaky Integrate and Fire model, but the model also catches the joint behavior of two neurons resorting to the use of copulas. Copulas are mathematical objects largely used to describe dependencies laws. Synchronous and delayed dependencies are considered by means of a set of examples. Results are discussed making use of crosscorrelograms.