Ethical dilemma arises from optimizing interventions for epidemics in heterogeneous populations.

Interventions to mitigate the spread of infectious diseases, while succeeding in their goal, have economic and social costs associated with them. These limit the duration and intensity of the interventions. We study a class of interventions which reduce the reproduction number and find the optimal strength of the intervention which minimizes the final epidemic size for an immunity inducing infection. The intervention works by eliminating the overshoot part of an epidemic, and avoids a second wave of infections. We extend the framework by considering a heterogeneous population and find that the optimal intervention can pose an ethical dilemma for decision and policymakers. This ethical dilemma is shown to be analogous to the trolley problem. We apply this optimization strategy to real-world contact data and case fatality rates from three pandemics to underline the importance of this ethical dilemma in real-world scenarios.

Towards Inferring Network Properties from Epidemic Data.

Epidemic propagation on networks represents an important departure from traditional mass-action models. However, the high-dimensionality of the exact models poses a challenge to both mathematical analysis and parameter inference. By using mean-field models, such as the pairwise model (PWM), the high-dimensionality becomes tractable. While such models have been used extensively for model analysis, there is limited work in the context of statistical inference. In this paper, we explore the extent to which the PWM with the susceptible-infected-recovered (SIR) epidemic can be used to infer disease- and network-related parameters. Data from an epidemics can be loosely categorised as being population level, e.g., daily new cases, or individual level, e.g., recovery times. To understand if and how network inference is influenced by the type of data, we employed the widely-used MLE approach for population-level data and dynamical survival analysis (DSA) for individual-level data. For scenarios in which there is no model mismatch, such as when data are generated via simulations, both methods perform well despite strong dependence between parameters. In contrast, for real-world data, such as foot-and-mouth, H1N1 and COVID19, whereas the DSA method appears fairly robust to potential model mismatch and produces parameter estimates that are epidemiologically plausible, our results with the MLE method revealed several issues pertaining to parameter unidentifiability and a lack of robustness to exact knowledge about key quantities such as population size and/or proportion of under reporting. Taken together, however, our findings suggest that network-based mean-field models can be used to formulate approximate likelihoods which, coupled with an efficient inference scheme, make it possible to not only learn about the parameters of the disease dynamics but also that of the underlying network.

Finding influential nodes in networks using pinning control: Centrality measures confirmed with electrochemical oscillators.

The spatiotemporal organization of networks of dynamical units can break down resulting in diseases (e.g., in the brain) or large-scale malfunctions (e.g., power grid blackouts). Re-establishment of function then requires identification of the optimal intervention site from which the network behavior is most efficiently re-stabilized. Here, we consider one such scenario with a network of units with oscillatory dynamics, which can be suppressed by sufficiently strong coupling and stabilizing a single unit, i.e., pinning control. We analyze the stability of the network with hyperbolas in the control gain vs coupling strength state space and identify the most influential node (MIN) as the node that requires the weakest coupling to stabilize the network in the limit of very strong control gain. A computationally efficient method, based on the Moore-Penrose pseudoinverse of the network Laplacian matrix, was found to be efficient in identifying the MIN. In addition, we have found that in some networks, the MIN relocates when the control gain is changed, and thus, different nodes are the most influential ones for weakly and strongly coupled networks. A control theoretic measure is proposed to identify networks with unique or relocating MINs. We have identified real-world networks with relocating MINs, such as social and power grid networks. The results were confirmed in experiments with networks of chemical reactions, where oscillations in the networks were effectively suppressed through the pinning of a single reaction site determined by the computational method.

Necessary and sufficient conditions for exact closures of epidemic equations on configuration model networks.

We prove that it is possible to obtain the exact closure of SIR pairwise epidemic equations on a configuration model network if and only if the degree distribution follows a Poisson, binomial, or negative binomial distribution. The proof relies on establishing the equivalence, for these specific degree distributions, between the closed pairwise model and a dynamical survival analysis (DSA) model that was previously shown to be exact. Specifically, we demonstrate that the DSA model is equivalent to the well-known edge-based Volz model. Using this result, we also provide reductions of the closed pairwise and Volz models to a single equation that involves only susceptibles. This equation has a useful statistical interpretation in terms of times to infection. We provide some numerical examples to illustrate our results.

Synchronization, clustering, and weak chimeras in a densely coupled transcription-based oscillator model for split circadian rhythms.

The synchronization dynamics for the circadian gene expression in the suprachiasmatic nucleus is investigated using a transcriptional circadian clock gene oscillator model. With global coupling in constant dark (DD) conditions, the model exhibits a one-cluster phase synchronized state, in dim light (dim LL), bistability between one- and two-cluster states and in bright LL, a two-cluster state. The two-cluster phase synchronized state, where some oscillator pairs synchronize in-phase, and some anti-phase, can explain the splitting of the circadian clock, i.e., generation of two bouts of daily activities with certain species, e.g., with hamsters. The one- and two-cluster states can be reached by transferring the animal from DD or bright LL to dim LL, i.e., the circadian synchrony has a memory effect. The stability of the one- and two-cluster states was interpreted analytically by extracting phase models from the ordinary differential equation models. In a modular network with two strongly coupled oscillator populations with weak intragroup coupling, with appropriate initial conditions, one group is synchronized to the one-cluster state and the other group to the two-cluster state, resulting in a weak-chimera state. Computational modeling suggests that the daily rhythms in sleep-wake depend on light intensity acting on bilateral networks of suprachiasmatic nucleus (SCN) oscillators. Addition of a network heterogeneity (coupling between the left and right SCN) allowed the system to exhibit chimera states. The simulations can guide experiments in the circadian rhythm research to explore the effect of light intensity on the complexities of circadian desynchronization.

On Parameter Identifiability in Network-Based Epidemic Models.

Modelling epidemics on networks represents an important departure from classical compartmental models which assume random mixing. However, the resulting models are high-dimensional and their analysis is often out of reach. It turns out that mean-field models, low-dimensional systems of differential equations, whose variables are carefully chosen expected quantities from the exact model provide a good approximation and incorporate explicitly some network properties. Despite the emergence of such mean-field models, there has been limited work on investigating whether these can be used for inference purposes. In this paper, we consider network-based mean-field models and explore the problem of parameter identifiability when observations about an epidemic are available. Making use of the analytical tractability of most network-based mean-field models, e.g. explicit analytical expressions for leading eigenvalue and final epidemic size, we set up the parameter identifiability problem as finding the solution or solutions of a system of coupled equations. More precisely, subject to observing/measuring growth rate and final epidemic size, we seek to identify parameter values leading to these measurements. We are particularly concerned with disentangling transmission rate from the network density. To do this, we give a condition for practical identifiability and we find that except for the simplest model, parameters cannot be uniquely determined, that is, they are practically unidentifiable. This means that there exist multiple solutions (a manifold of infinite measure) which give rise to model output that is close to the data. Identifying, formalising and analytically describing this problem should lead to a better appreciation of the complexity involved in fitting models with many parameters to data.

Optimal phase-selective entrainment of heterogeneous oscillator ensembles.

We develop a framework to design optimal entrainment signals that entrain an ensemble of heterogeneous nonlinear oscillators, described by phase models, at desired phases. We explicitly take into account heterogeneity in both oscillation frequency and the type of oscillators characterized by different Phase Response Curves. The central idea is to leverage the Fourier series representation of periodic functions to decode a phase-selective entrainment task into a quadratic program. We demonstrate our approach using a variety of phase models, where we entrain the oscillators into distinct phase patterns. Also, we show how the generalizability gained from our formulation enables us to meet a wide range of design objectives and constraints, such as minimum-power, fast entrainment, and charge-balanced controls.

Synchronization of Belousov-Zhabotinsky oscillators with electrochemical coupling in a spontaneous process.

A passive electrochemical coupling approach is proposed to induce spontaneous synchronization between chemical oscillators. The coupling exploits the potential difference between a catalyst redox couple in the Belousov-Zhabotinsky (BZ) reaction, without external feedback, to induce surface reactions that impact the kinetics of the bulk system. The effect of coupling in BZ oscillators under batch condition is characterized using phase synchronization measures. Although the frequency of the oscillators decreases nonlinearly over time, by a factor of 2 or more within 100 cycles, the coupling is strong enough to maintain synchronization. In such a highly drifting system, the Gibbs-Shannon entropy of the cyclic phase difference distribution can be used to quantify the coupling effect. We extend the Oregonator BZ model to account for the drifting natural frequencies in batch condition and for electrochemical coupling, and numerical simulations of the effect of acid concentration on synchronization patterns are in agreement with the experiments. Because of the passive nature of coupling, the proposed coupling scheme can open avenues for designing pattern recognition and neuromorphic computation systems using chemical reactions in a spontaneous process.

Emergent hypernetworks in weakly coupled oscillators.

Networks of weakly coupled oscillators had a profound impact on our understanding of complex systems. Studies on model reconstruction from data have shown prevalent contributions from hypernetworks with triplet and higher interactions among oscillators, in spite that such models were originally defined as oscillator networks with pairwise interactions. Here, we show that hypernetworks can spontaneously emerge even in the presence of pairwise albeit nonlinear coupling given certain triplet frequency resonance conditions. The results are demonstrated in experiments with electrochemical oscillators and in simulations with integrate-and-fire neurons. By developing a comprehensive theory, we uncover the mechanism for emergent hypernetworks by identifying appearing and forbidden frequency resonant conditions. Furthermore, it is shown that microscopic linear (difference) coupling among units results in coupled mean fields, which have sufficient nonlinearity to facilitate hypernetworks. Our findings shed light on the apparent abundance of hypernetworks and provide a constructive way to predict and engineer their emergence.

Dynamic survival analysis for non-Markovian epidemic models.

We present a new method for analysing stochastic epidemic models under minimal assumptions. The method, dubbed dynamic survival analysis (DSA), is based on a simple yet powerful observation, namely that population-level mean-field trajectories described by a system of partial differential equations may also approximate individual-level times of infection and recovery. This idea gives rise to a certain non-Markovian agent-based model and provides an agent-level likelihood function for a random sample of infection and/or recovery times. Extensive numerical analyses on both synthetic and real epidemic data from foot-and-mouth disease in the UK (2001) and COVID-19 in India (2020) show good accuracy and confirm the method's versatility in likelihood-based parameter estimation. The accompanying software package gives prospective users a practical tool for modelling, analysing and interpreting epidemic data with the help of the DSA approach.

The impact of spatial and social structure on an SIR epidemic on a weighted multilayer network.

A key factor in the transmission of infectious diseases is the structure of disease transmitting contacts. In the context of the current COVID-19 pandemic and with some data based on the Hungarian population we develop a theoretical epidemic model (susceptible-infected-removed, SIR) on a multilayer network. The layers include the Hungarian household structure, with population divided into children, adults and elderly, as well as schools and workplaces, some spatial embedding and community transmission due to sharing communal spaces, service and public spaces. We investigate the sensitivity of the model (via the time evolution and final size of the epidemic) to the different contact layers and we map out the relation between peak prevalence and final epidemic size. When compared to the classic compartmental model and for the same final epidemic size, we find that epidemics on multilayer network lead to higher peak prevalence meaning that the risk of overwhelming the health care system is higher. Based on our model we found that keeping cliques/bubbles in school as isolated as possible has a major effect while closing workplaces had a mild effect as long as workplaces are of relatively small size.

Publisher's Note: Entropy of weighted recurrence plots [Phys. Rev. E 90, 042919 (2014)].

This corrects the article DOI: 10.1103/PhysRevE.90.042919.

The Impact of Contact Structure and Mixing on Control Measures and Disease-Induced Herd Immunity in Epidemic Models: A Mean-Field Model Perspective.

The contact structure of a population plays an important role in transmission of infection. Many 'structured models' capture aspects of the contact pattern through an underlying network or a mixing matrix. An important observation in unstructured models of a disease that confers immunity is that once a fraction [Formula: see text] has been infected, the residual susceptible population can no longer sustain an epidemic. A recent observation of some structured models is that this threshold can be crossed with a smaller fraction of infected individuals, because the disease acts like a targeted vaccine, preferentially immunising higher-risk individuals who play a greater role in transmission. Therefore, a limited 'first wave' may leave behind a residual population that cannot support a second wave once interventions are lifted. In this paper, we set out to investigate this more systematically. While networks offer a flexible framework to model contact patterns explicitly, they suffer from several shortcomings: (i) high-fidelity network models require a large amount of data which can be difficult to harvest, and (ii) very few, if any, theoretical contact network models offer the flexibility to tune different contact network properties within the same framework. Therefore, we opt to systematically analyse a number of well-known mean-field models. These are computationally efficient and provide good flexibility in varying contact network properties such as heterogeneity in the number contacts, clustering and household structure or differentiating between local and global contacts. In particular, we consider the question of herd immunity under several scenarios. When modelling interventions as changes in transmission rates, we confirm that in networks with significant degree heterogeneity, the first wave of the epidemic confers herd immunity with significantly fewer infections than equivalent models with less or no degree heterogeneity. However, if modelling the intervention as a change in the contact network, then this effect may become much more subtle. Indeed, modifying the structure disproportionately can shield highly connected nodes from becoming infected during the first wave and therefore make the second wave more substantial. We strengthen this finding by using an age-structured compartmental model parameterised with real data and comparing lockdown periods implemented either as a global scaling of the mixing matrix or age-specific structural changes. Overall, we find that results regarding (disease-induced) herd immunity levels are strongly dependent on the model, the duration of the lockdown and how the lockdown is implemented in the model.

Asymmetry-induced isolated fully synchronized state in coupled oscillator populations.

A symmetry-breaking mechanism is investigated that creates bistability between fully and partially synchronized states in oscillator networks. Two populations of oscillators with unimodal frequency distribution and different amplitudes, in the presence of weak global coupling, are shown to simplify to a modular network with asymmetrical coupling. With increasing the coupling strength, a synchronization transition is observed with an isolated fully synchronized state. The results are interpreted theoretically in the thermodynamic limit and confirmed in experiments with chemical oscillators.

Synchronization in populations of electrochemical bursting oscillators with chaotic slow dynamics.

We investigate the synchronization of coupled electrochemical bursting oscillators using the electrodissolution of iron in sulfuric acid. The dynamics of a single oscillator consisted of slow chaotic oscillations interrupted by a burst of fast spiking, generating a multiple time-scale dynamical system. A wavelet analysis first decomposed the time series data from each oscillator into a fast and a slow component, and the corresponding phases were also obtained. The phase synchronization of the fast and slow dynamics was analyzed as a function of electrical coupling imposed by an external coupling resistance. For two oscillators, a progressive transition was observed: With increasing coupling strength, first, the fast bursting intervals overlapped, which was followed by synchronization of the fast spiking, and finally, the slow chaotic oscillations synchronized. With a population of globally coupled 25 oscillators, the coupling eliminated the fast dynamics, and only the synchronization of the slow dynamics can be observed. The results demonstrated the complexities of synchronization with bursting oscillations that could be useful in other systems with multiple time-scale dynamics, in particular, in neuronal networks.

Random heterogeneity outperforms design in network synchronization.

A widely held assumption on network dynamics is that similar components are more likely to exhibit similar behavior than dissimilar ones and that generic differences among them are necessarily detrimental to synchronization. Here, we show that this assumption does not generally hold in oscillator networks when communication delays are present. We demonstrate, in particular, that random parameter heterogeneity among oscillators can consistently rescue the system from losing synchrony. This finding is supported by electrochemical-oscillator experiments performed on a multielectrode array network. Remarkably, at intermediate levels of heterogeneity, random mismatches are more effective in promoting synchronization than parameter assignments specifically designed to facilitate identical synchronization. Our results suggest that, rather than being eliminated or ignored, intrinsic disorder in technological and biological systems can be harnessed to help maintain coherence required for function.

Optimal timing of one-shot interventions for epidemic control.

The interventions and outcomes in the ongoing COVID-19 pandemic are highly varied. The disease and the interventions both impose costs and harm on society. Some interventions with particularly high costs may only be implemented briefly. The design of optimal policy requires consideration of many intervention scenarios. In this paper we investigate the optimal timing of interventions that are not sustainable for a long period. Specifically, we look at at the impact of a single short-term non-repeated intervention (a "one-shot intervention") on an epidemic and consider the impact of the intervention's timing. To minimize the total number infected, the intervention should start close to the peak so that there is minimal rebound once the intervention is stopped. To minimise the peak prevalence, it should start earlier, leading to initial reduction and then having a rebound to the same prevalence as the pre-intervention peak rather than one very large peak. To delay infections as much as possible (as might be appropriate if we expect improved interventions or treatments to be developed), earlier interventions have clear benefit. In populations with distinct subgroups, synchronized interventions are less effective than targeting the interventions in each subcommunity separately.

Coherent Dynamics Enhanced by Uncorrelated Noise.

Synchronization is a widespread phenomenon observed in physical, biological, and social networks, which persists even under the influence of strong noise. Previous research on oscillators subject to common noise has shown that noise can actually facilitate synchronization, as correlations in the dynamics can be inherited from the noise itself. However, in many spatially distributed networks, such as the mammalian circadian system, the noise that different oscillators experience can be effectively uncorrelated. Here, we show that uncorrelated noise can in fact enhance synchronization when the oscillators are coupled. Strikingly, our analysis also shows that uncorrelated noise can be more effective than common noise in enhancing synchronization. We first establish these results theoretically for phase and phase-amplitude oscillators subject to either or both additive and multiplicative noise. We then confirm the predictions through experiments on coupled electrochemical oscillators. Our findings suggest that uncorrelated noise can promote rather than inhibit coherence in natural systems and that the same effect can be harnessed in engineered systems.

Key questions for modelling COVID-19 exit strategies.

Combinations of intense non-pharmaceutical interventions (lockdowns) were introduced worldwide to reduce SARS-CoV-2 transmission. Many governments have begun to implement exit strategies that relax restrictions while attempting to control the risk of a surge in cases. Mathematical modelling has played a central role in guiding interventions, but the challenge of designing optimal exit strategies in the face of ongoing transmission is unprecedented. Here, we report discussions from the Isaac Newton Institute 'Models for an exit strategy' workshop (11-15 May 2020). A diverse community of modellers who are providing evidence to governments worldwide were asked to identify the main questions that, if answered, would allow for more accurate predictions of the effects of different exit strategies. Based on these questions, we propose a roadmap to facilitate the development of reliable models to guide exit strategies. This roadmap requires a global collaborative effort from the scientific community and policymakers, and has three parts: (i) improve estimation of key epidemiological parameters; (ii) understand sources of heterogeneity in populations; and (iii) focus on requirements for data collection, particularly in low-to-middle-income countries. This will provide important information for planning exit strategies that balance socio-economic benefits with public health.