Stochastic amplification in epidemics

The role of stochasticity and its interplay with nonlinearity are central current issues in studies of the complex population patterns observed in nature, including the pronounced oscillations of wildlife and infectious diseases. The dynamics of childhood diseases have provided influential case studies to develop and test mathematical models with practical application to epidemiology, but are also of general relevance to the central question of whether simple nonlinear systems can explain and predict the complex temporal and spatial patterns observed in nature outside laboratory conditions. Here, we present a stochastic theory for the major dynamical transitions in epidemics from regular to irregular cycles, which relies on the discrete nature of disease transmission and low spatial coupling. The full spectrum of stochastic fluctuations is derived analytically to show how the amplification of noise varies across these transitions. The changes in noise amplification and coherence appear robust to seasonal forcing, questioning the role of seasonality and its interplay with deterministic components of epidemiological models. Childhood diseases are shown to fall into regions of parameter space of high noise amplification. This type of "endogenous" stochastic resonance may be relevant to population oscillations in nonlinear ecological systems in general.     

Noise, nonlinearity and seasonality: the epidemics of whooping cough revisited

Understanding the mechanisms that generate oscillations in the incidence of childhood infectious diseases has preoccupied epidemiologists and population ecologists for nearly two centuries. This body of work has generated simple yet powerful explanations for the epidemics of measles and chickenpox, while the dynamics of other infectious diseases, such as whooping cough, have proved more challenging to decipher. A number of authors have, in recent years, proposed that the noisy and somewhat irregular epidemics of whooping cough may arise due to stochasticity and its interaction with nonlinearity in transmission and seasonal variation in contact rates. The reason underlying the susceptibility of whooping cough dynamics to noise and the precise nature of its transient dynamics remain poorly understood. Here we use household data on the incubation period in order to parametrize more realistic distributions of the latent and infectious periods. We demonstrate that previously reported phenomena result from transients following the interaction between the stable annual attractor and unstable multiennial solutions.     

Optimal control of epidemics in metapopulations

Little is known about how best to deploy scarce resources for disease control when epidemics occur in different but interconnected regions. We use a combination of optimal control methods and epidemiological theory for metapopulations to address this problem. We consider what strategy should be used if the objective is to minimize the discounted number of infected individuals during the course of an epidemic. We show, for a system with two interconnected regions and an epidemic in which infected individuals recover and can be reinfected, that equalizing infection in the two regions is the worst possible strategy in minimizing the total level of infection. Treatment should instead be preferentially directed at the region with the lower level of infection, treating the other subpopulation only when there is resource left over. The same strategy holds with preferential treatments of regions with lower levels of infection when quarantine is introduced.     

Constructing the effect of alternative intervention strategies on historic epidemics.

Data from historical epidemics provide a vital and sometimes under-used resource from which to devise strategies for future control of disease. Previous methods for retrospective analysis of epidemics, in which alternative interventions are compared, do not make full use of the information; by using only partial information on the historical trajectory, augmentation of control may lead to predictions of a paradoxical increase in disease. Here we introduce a novel statistical approach that takes full account of the available information in constructing the effect of alternative intervention strategies in historic epidemics. The key to the method lies in identifying a suitable mapping between the historic and notional outbreaks, under alternative control strategies. We do this by using the Sellke construction as a latent process linking epidemics. We illustrate the application of the method with two examples. First, using temporal data for the common human cold, we show the improvement under the new method in the precision of predictions for different control strategies. Second, we show the generality of the method for retrospective analysis of epidemics by applying it to a spatially extended arboreal epidemic in which we demonstrate the relative effectiveness of host culling strategies that differ in frequency and spatial extent. Some of the inferential and philosophical issues that arise are discussed along with the scope of potential application of the new method.     

Modelling control of epidemics spreading by long-range interactions

We have studied the spread of epidemics characterized by a mixture of local and non-local interactions. The infection spreads on a two-dimensional lattice with the fixed nearest neighbour connections. In addition, long-range dynamical links are formed by moving agents (vectors). Vectors perform random walks, with step length distributed according to a thick-tail distribution. Two distributions are considered in this paper, an α-stable distribution describing self-similar vector movement, yet characterized by an infinite variance and an exponential power characterized by a large but finite variance. Such long-range interactions are hard to track and make control of epidemics very difficult. We also allowed for cryptic infection, whereby an infected individual on the lattice can be infectious prior to showing any symptoms of infection or disease. To account for such cryptic spread, we considered a control strategy in which not only detected, i.e. symptomatic, individuals but also all individuals within a certain control neighbourhood are treated upon the detection of disease. We show that it is possible to eradicate the disease by using such purely local control measures, even in the presence of long-range jumps. In particular, we show that the success of local control and the choice of the optimal strategy depend in a non-trivial way on the dispersal patterns of the vectors. By characterizing these patterns using the stability index of the α-stable distribution to change the power-law behaviour or the exponent characterizing the decay of an exponential power distribution, we show that infection can be successfully contained using relatively small control neighbourhoods for two limiting cases for long-distance dispersal and for vectors that are much more limited in their dispersal range.     

Searching for the most cost-effective strategy for controlling epidemics spreading on regular and small-world networks

We present a combined epidemiological and economic model for control of diseases spreading on local and small-world networks. The disease is characterized by a pre-symptomatic infectious stage that makes detection and control of cases more difficult. The effectiveness of local (ring-vaccination or culling) and global control strategies is analysed by comparing the net present values of the combined cost of preventive treatment and illness. The optimal strategy is then selected by minimizing the total cost of the epidemic. We show that three main strategies emerge, with treating a large number of individuals (global strategy, GS), treating a small number of individuals in a well-defined neighbourhood of a detected case (local strategy) and allowing the disease to spread unchecked (null strategy, NS). The choice of the optimal strategy is governed mainly by a relative cost of palliative and preventive treatments. If the disease spreads within the well-defined neighbourhood, the local strategy is optimal unless the cost of a single vaccine is much higher than the cost associated with hospitalization. In the latter case, it is most cost-effective to refrain from prevention. Destruction of local correlations, either by long-range (small-world) links or by inclusion of many initial foci, expands the range of costs for which the NS is most cost-effective. The GS emerges for the case when the cost of prevention is much lower than the cost of treatment and there is a substantial non-local component in the disease spread. We also show that local treatment is only desirable if the disease spreads on a small-world network with sufficiently few long-range links; otherwise it is optimal to treat globally. In the mean-field case, there are only two optimal solutions, to treat all if the cost of the vaccine is low and to treat nobody if it is high. The basic reproduction ratio, R₀, does not depend on the rate of responsive treatment in this case and the disease always invades (but might be stopped afterwards). The details of the local control strategy, and in particular the optimal size of the control neighbourhood, are determined by the epidemiology of the disease. The properties of the pathogen might not be known in advance for emerging diseases, but the broad choice of the strategy can be made based on economic analysis only.     

Modelling the long-term dynamics of pre-vaccination pertussis

The dynamics of strongly immunizing childhood infections is still not well understood. Although reports of successful modelling of several data records can be found in the previous literature, the key determinants of the observed temporal patterns have not yet been clearly identified. In particular, different models of immunity waning and degree of protection applied to disease- and vaccine-induced immunity have been debated in the previous literature on pertussis. Here, we study the effect of disease-acquired immunity on the long-term patterns of pertussis prevalence. We compare five minimal models, all of which are stochastic, seasonally forced, well-mixed models of infection, based on susceptible–infective–recovered dynamics in a closed population. These models reflect different assumptions about the immune response of naive hosts, namely total permanent immunity, immunity waning, immunity waning together with immunity boosting, reinfection of recovered and repeat infection after partial immunity waning. The power spectra of the output prevalence time series characterize the long-term dynamics of the models. For epidemiological parameters consistent with published data, the power spectra show quantitative and even qualitative differences, which can be used to test their assumptions by comparison with ensembles of several-decades-long pre-vaccination data records. We illustrate this strategy on two publicly available historical datasets.     

A farewell to R: time-series models for tracking and forecasting epidemics

The time-dependent reproduction number, R_t, is a key metric used by epidemiologists to assess the current state of an outbreak of an infectious disease. This quantity is usually estimated using time-series observations on new infections combined with assumptions about the distribution of the serial interval of transmissions. Bayesian methods are often used with the new cases data smoothed using a simple, but to some extent arbitrary, moving average. This paper describes a new class of time-series models, estimated by classical statistical methods, for tracking and forecasting the growth rate of new cases and deaths. Very few assumptions are needed and those that are made can be tested. Estimates of R_t, together with their standard deviations, are obtained as a by-product.     

Inferring the reproduction number using the renewal equation in heterogeneous epidemics

Real-time estimation of the reproduction number has become the focus of modelling groups around the world as the SARS-CoV-2 pandemic unfolds. One of the most widely adopted means of inference of the reproduction number is via the renewal equation, which uses the incidence of infection and the generation time distribution. In this paper, we derive a multi-type equivalent to the renewal equation to estimate a reproduction number which accounts for heterogeneity in transmissibility including through asymptomatic transmission, symptomatic isolation and vaccination. We demonstrate how use of the renewal equation that misses these heterogeneities can result in biased estimates of the reproduction number. While the bias is small with symptomatic isolation, it can be much larger with asymptomatic transmission or transmission from vaccinated individuals if these groups exhibit substantially different generation time distributions to unvaccinated symptomatic transmitters, whose generation time distribution is often well defined. The bias in estimate becomes larger with greater population size or transmissibility of the poorly characterized group. We apply our methodology to Ebola in West Africa in 2014 and the SARS-CoV-2 in the UK in 2020–2021.     

Recent network evolution increases the potential for large epidemics in the British cattle population.

Following the foot and mouth disease epidemic in Great Britain (GB) in 2001, livestock movement bans were replaced with mandatory periods of standstill for livestock moving between premises. It was anticipated that these movement restrictions would limit each individual's contact networks, the extent of livestock movements and thus the spread of future disease outbreaks. However, the effect of behaviour changes on the global network in adapting to these restrictions is currently unknown. Here, we take a novel approach using GB cattle movement data to construct week-by-week contact networks between animal holdings (AH) to explore the evolution of the network since this policy was introduced, the first time network theory has been used for this purpose. We show that the number of AH moving cattle as part of the giant strong component (GSC), representing the region of maximal connectivity, has been increasing linearly over time. This is of epidemiological significance as the size of the GSC indicates the number of holdings potentially exposed to disease, thus giving a lower bound of maximum epidemic size. Therefore, despite restriction of cattle movements, emergent behaviour in this self-organizing system has potentially increased the size of infectious disease epidemics within the cattle industry.     

Misinformation can prevent the suppression of epidemics

The effectiveness of non-pharmaceutical interventions, such as mask-wearing and social distancing, as control measures for pandemic disease relies upon a conscientious and well-informed public who are aware of and prepared to follow advice. Unfortunately, public health messages can be undermined by competing misinformation and conspiracy theories, spread virally through communities that are already distrustful of expert opinion. In this article, we propose and analyse a simple model of the interaction between disease spread and awareness dynamics in a heterogeneous population composed of both trusting individuals who seek better quality information and will take precautionary measures, and distrusting individuals who reject better quality information and have overall riskier behaviour. We show that, as the density of the distrusting population increases, the model passes through a phase transition to a state in which major outbreaks cannot be suppressed. Our work highlights the urgent need for effective interventions to increase trust and inform the public.     

Coordination of gene expression noise with cell size: analytical results for agent-based models of growing cell populations

The chemical master equation and the Gillespie algorithm are widely used to model the reaction kinetics inside living cells. It is thereby assumed that cell growth and division can be modelled through effective dilution reactions and extrinsic noise sources. We here re-examine these paradigms through developing an analytical agent-based framework of growing and dividing cells accompanied by an exact simulation algorithm, which allows us to quantify the dynamics of virtually any intracellular reaction network affected by stochastic cell size control and division noise. We find that the solution of the chemical master equation—including static extrinsic noise—exactly agrees with the agent-based formulation when the network under study exhibits stochastic concentration homeostasis, a novel condition that generalizes concentration homeostasis in deterministic systems to higher order moments and distributions. We illustrate stochastic concentration homeostasis for a range of common gene expression networks. When this condition is not met, we demonstrate by extending the linear noise approximation to agent-based models that the dependence of gene expression noise on cell size can qualitatively deviate from the chemical master equation. Surprisingly, the total noise of the agent-based approach can still be well approximated by extrinsic noise models.     

Characterizing the dynamics of rubella relative to measles: the role of stochasticity

Rubella is a completely immunizing and mild infection in children. Understanding its behaviour is of considerable public health importance because of congenital rubella syndrome, which results from infection with rubella during early pregnancy and may entail a variety of birth defects. The recurrent dynamics of rubella are relatively poorly resolved, and appear to show considerable diversity globally. Here, we investigate the behaviour of a stochastic seasonally forced susceptible–infected–recovered model to characterize the determinants of these dynamics and illustrate patterns by comparison with measles. We perform a systematic analysis of spectra of stochastic fluctuations around stable attractors of the corresponding deterministic model and compare them with spectra from full stochastic simulations in large populations. This approach allows us to quantify the effects of demographic stochasticity and to give a coherent picture of measles and rubella dynamics, explaining essential differences in the recurrent patterns exhibited by these diseases. We discuss the implications of our findings in the context of vaccination and changing birth rates as well as the persistence of these two childhood infections.     

Coalescent models for developmental biology and the spatio-temporal dynamics of growing tissues

Development is a process that needs to be tightly coordinated in both space and time. Cell tracking and lineage tracing have become important experimental techniques in developmental biology and allow us to map the fate of cells and their progeny. A generic feature of developing and homeostatic tissues that these analyses have revealed is that relatively few cells give rise to the bulk of the cells in a tissue; the lineages of most cells come to an end quickly. Computational and theoretical biologists/physicists have, in response, developed a range of modelling approaches, most notably agent-based modelling. These models seem to capture features observed in experiments, but can also become computationally expensive. Here, we develop complementary genealogical models of tissue development that trace the ancestry of cells in a tissue back to their most recent common ancestors. We show that with both bounded and unbounded growth simple, but universal scaling relationships allow us to connect coalescent theory with the fractal growth models extensively used in developmental biology. Using our genealogical perspective, it is possible to study bulk statistical properties of the processes that give rise to tissues of cells, without the need for large-scale simulations.     

The effect of network mixing patterns on epidemic dynamics and the efficacy of disease contact tracing

In networks, nodes may preferentially contact other nodes with similar (assortatively mixed) or dissimilar (disassortatively mixed) numbers of contacts. Different patterns of contact support different epidemic dynamics, potentially affecting the efficacy of control measures such as contact tracing, which aims to identify and isolate nodes with infectious contacts. We used stochastic simulations to investigate the effects of mixing patterns on epidemic dynamics and contact-tracing efficacy. For uncontrolled epidemics, outbreaks occur at lower infection rates for more assortatively mixed networks, with faster initial epidemic growth rate and shorter epidemic duration than for disassortatively mixed networks. Contact tracing performs better for assortative mixing where epidemic size is large and tracing rate low, but it performs better for disassortative mixing at higher contact rates. For assortatively mixed networks, disease spreads first to highly connected nodes, but this is balanced by contact tracing quickly identifying these same nodes. The converse is true for disassortative mixing, where both disease and tracing are less likely to target highly connected nodes. For small epidemics, contact tracing is more effective on disassortative networks due to the greater resilience of assortative networks to link removal. Multi-step contact tracing is more effective than single-step tracing for assortative mixing, but this effect is smaller for disassortatively mixed networks.     

Inference and uncertainty quantification of stochastic gene expression via synthetic models

Estimating uncertainty in model predictions is a central task in quantitative biology. Biological models at the single-cell level are intrinsically stochastic and nonlinear, creating formidable challenges for their statistical estimation which inevitably has to rely on approximations that trade accuracy for tractability. Despite intensive interest, a sweet spot in this trade-off has not been found yet. We propose a flexible procedure for uncertainty quantification in a wide class of reaction networks describing stochastic gene expression including those with feedback. The method is based on creating a tractable coarse-graining of the model that is learned from simulations, a synthetic model, to approximate the likelihood function. We demonstrate that synthetic models can substantially outperform state-of-the-art approaches on a number of non-trivial systems and datasets, yielding an accurate and computationally viable solution to uncertainty quantification in stochastic models of gene expression.     

A nonparametric probabilistic approach for quantifying uncertainties in low‐dimensional and high‐dimensional nonlinear models

A nonparametric probabilistic approach for modeling uncertainties in projection‐based, nonlinear, reduced‐order models is presented. When experimental data are available, this approach can also quantify uncertainties in the associated high‐dimensional models. The main underlying idea is twofold. First, to substitute the deterministic reduced‐order basis (ROB) with a stochastic counterpart. Second, to construct the probability measure of the stochastic reduced‐order basis (SROB) on a subset of a compact Stiefel manifold in order to preserve some important properties of a ROB. The stochastic modeling is performed so that the probability distribution of the constructed SROB depends on a small number of hyperparameters. These are determined by solving a reduced‐order statistical inverse problem. The mathematical properties of this novel approach for quantifying model uncertainties are analyzed through theoretical developments and numerical simulations. Its potential is demonstrated through several example problems from computational structural dynamics. Copyright © 2016 John Wiley & Sons, Ltd.     

Multi-scale modelling of the dynamics of cell colonies: insights into cell-adhesion forces and cancer invasion from in silico simulations

Studying the biophysical interactions between cells is crucial to understanding how normal tissue develops, how it is structured and also when malfunctions occur. Traditional experiments try to infer events at the tissue level after observing the behaviour of and interactions between individual cells. This approach assumes that cells behave in the same biophysical manner in isolated experiments as they do within colonies and tissues. In this paper, we develop a multi-scale multi-compartment mathematical model that accounts for the principal biophysical interactions and adhesion pathways not only at a cell–cell level but also at the level of cell colonies (in contrast to the traditional approach). Our results suggest that adhesion/separation forces between cells may be lower in cell colonies than traditional isolated single-cell experiments infer. As a consequence, isolated single-cell experiments may be insufficient to deduce important biological processes such as single-cell invasion after detachment from a solid tumour. The simulations further show that kinetic rates and cell biophysical characteristics such as pressure-related cell-cycle arrest have a major influence on cell colony patterns and can allow for the development of protrusive cellular structures as seen in invasive cancer cell lines independent of expression levels of pro-invasion molecules.