COVID-19 has shown that the consequences of a pandemic are wider-reaching than cases and deaths. Morbidity and mortality are important direct costs, but infectious diseases generate other direct and indirect benefits and costs as the economy responds to these shocks: some people lose, others gain and people modify their behaviours in ways that redistribute these benefits and costs. These additional effects feedback on health outcomes to create a complicated interdependent system of health and non-health outcomes. As a result, interventions primarily intended to reduce the burden of disease can have wider societal and economic effects and more complicated and unintended, but possibly not anticipable, system-level influences on the epidemiological dynamics themselves. Capturing these effects requires a systems approach that encompasses more direct health outcomes. Towards this end, in this article we discuss the importance of integrating epidemiology and economic models, setting out the key challenges which such a merging of epidemiology and economics presents. We conclude that understanding people’s behaviour in the context of interventions is key to developing a more complete and integrated economic-epidemiological approach; and a wider perspective on the benefits and costs of interventions (and who these fall upon) will help society better understand how to respond to future pandemics.

Since the beginning of the COVID-19 pandemic, the reproduction number [Formula: see text] has become a popular epidemiological metric used to communicate the state of the epidemic. At its most basic, [Formula: see text] is defined as the average number of secondary infections caused by one primary infected individual. [Formula: see text] seems convenient, because the epidemic is expanding if [Formula: see text] and contracting if [Formula: see text]. The magnitude of [Formula: see text] indicates by how much transmission needs to be reduced to control the epidemic. Using [Formula: see text] in a naïve way can cause new problems. The reasons for this are threefold: (1) There is not just one definition of [Formula: see text] but many, and the precise definition of [Formula: see text] affects both its estimated value and how it should be interpreted. (2) Even with a particular clearly defined [Formula: see text], there may be different statistical methods used to estimate its value, and the choice of method will affect the estimate. (3) The availability and type of data used to estimate [Formula: see text] vary, and it is not always clear what data should be included in the estimation. In this review, we discuss when [Formula: see text] is useful, when it may be of use but needs to be interpreted with care, and when it may be an inappropriate indicator of the progress of the epidemic. We also argue that careful definition of [Formula: see text], and the data and methods used to estimate it, can make [Formula: see text] a more useful metric for future management of the epidemic.

In March 2020 mathematics became a key part of the scientific advice to the UK government on the pandemic response to COVID-19. Mathematical and statistical modelling provided critical information on the spread of the virus and the potential impact of different interventions. The unprecedented scale of the challenge led the epidemiological modelling community in the UK to be pushed to its limits. At the same time, mathematical modellers across the country were keen to use their knowledge and skills to support the COVID-19 modelling effort. However, this sudden great interest in epidemiological modelling needed to be coordinated to provide much-needed support, and to limit the burden on epidemiological modellers already very stretched for time. In this paper we describe three initiatives set up in the UK in spring 2020 to coordinate the mathematical sciences research community in supporting mathematical modelling of COVID-19. Each initiative had different primary aims and worked to maximise synergies between the various projects. We reflect on the lessons learnt, highlighting the key roles of pre-existing research collaborations and focal centres of coordination in contributing to the success of these initiatives. We conclude with recommendations about important ways in which the scientific research community could be better prepared for future pandemics. This manuscript was submitted as part of a theme issue on "Modelling COVID-19 and Preparedness for Future Pandemics".

Mathematical models provide a rational basis to inform how, where and when to control disease. Assuming an accurate spatially explicit simulation model can be fitted to spread data, it is straightforward to use it to test the performance of a range of management strategies. However, the typical complexity of simulation models and the vast set of possible controls mean that only a small subset of all possible strategies can ever be tested. An alternative approach-optimal control theory-allows the best control to be identified unambiguously. However, the complexity of the underpinning mathematics means that disease models used to identify this optimum must be very simple. We highlight two frameworks for bridging the gap between detailed epidemic simulations and optimal control theory: open-loop and model predictive control. Both these frameworks approximate a simulation model with a simpler model more amenable to mathematical analysis. Using an illustrative example model, we show the benefits of using feedback control, in which the approximation and control are updated as the epidemic progresses. Our work illustrates a new methodology to allow the insights of optimal control theory to inform practical disease management strategies, with the potential for application to diseases of humans, animals and plants. This article is part of the theme issue 'Modelling infectious disease outbreaks in humans, animals and plants: epidemic forecasting and control'. This theme issue is linked with the earlier issue 'Modelling infectious disease outbreaks in humans, animals and plants: approaches and important themes'.

The number of pathogenic threats to plant, animal and human health is increasing. Controlling the spread of such threats is costly and often resources are limited. A key challenge facing decision makers is how to allocate resources to control the different threats in order to achieve the least amount of damage from the collective impact. In this paper we consider the allocation of limited resources across n independent target populations to treat pathogens whose spread is modelled using the susceptible–infected–susceptible model. Using mathematical analysis of the systems dynamics, we show that for effective disease control, with a limited budget, treatment should be focused on a subset of populations, rather than attempting to treat all populations less intensively. The choice of populations to treat can be approximated by a knapsack-type problem. We show that the knapsack closely approximates the exact optimum and greatly outperforms a number of simpler strategies. A key advantage of the knapsack approximation is that it provides insight into the way in which the economic and epidemiological dynamics affect the optimal allocation of resources. In particular using the knapsack approximation to apportion control takes into account two important aspects of the dynamics: the indirect interaction between the populations due to the shared pool of limited resources and the dependence on the initial conditions.

The real options approach provides a powerful tool for determining the optimal time at which to adopt disease control measures given uncertainty about the future spread of an invading pest/pathogen. We consider the management of disease invasions in the natural environment typified by woodlands. Previous studies considered the timing of control from the point of view of a central planner, for example a governmental decision making body. However, decisions regarding the deployment of control measures in the landscape are typically taken by individual land managers. Woodlands provide both marketable benefits, such as timber, and non-marketable benefits, for example biodiversity. The relative importance placed on these types of benefit depends on the land purpose, which is determined by a managers’ objectives. We investigate how management objectives influence the optimal timing of control adoption. Our results show that differences in objectives lead managers to exercise the option to control at different times, and potentially never adopt disease control. Since infection can spread from one region to another, managers who do not adopt control therefore transfer the risk of infection to other managers within the landscape. For landscapes composed of managers with divergent objectives, this creates conflict due to the transferable externality (the disease). We show targeted subsidies can reduce differences in the timing of control adoption between managers with divergent objectives. Both lump-sum subsidies and annual subsidies bring forward the adoption of control strategies, causing them to be implemented over a wider range of infection proportions in an individual woodland. However, the two types of subsidy have opposite effects on the decision to suspend control. Annual subsidies delay suspension and extend the region over which control continues to be implemented. In contrast, lump-sum subsidies slightly reduce the region over which control continues to be implemented. For high proportions of infection, this implies that a lump-sum subsidy can induce a value-maximising manager to suspend control earlier: the opposite effect to that presumably intended. Our results have important implications for national decision making bodies and suggest that incentives may need to be targeted at specific groups to ensure a coherent response to disease control.

The real options approach has been used within environmental economics to investigate the impact of uncertainty on the optimal timing of control measures to minimise the impacts of invasive species, including pests and diseases. Previous studies typically model the growth in infected area using geometric Brownian motion (GBM). The advantage of this simple approach is that it allows for closed form solutions. However, such a process does not capture the mechanisms underlying the spread of infection. In particular the GBM assumption does not respect the natural upper boundary of the system, which is determined by the maximum size of the host species, nor the deceleration in the rate of infection as this boundary is approached. We show how the stochastic process describing the growth in infected area can be derived from the characteristics of the spread of infection. If the model used does not appropriately capture uncertainty in infection dynamics, then the excessive delay before treatment implies that the full value of the option to treat is not realised. Indeed, when uncertainty is high or the disease is fast spreading, ignoring the mechanisms of infection spread can lead to control never being deployed. Thus the results presented here have important implications for the way in which the real options approach is applied to determine optimal timing of disease control given uncertainty in future disease progression.

Beat-to-beat variability in repolarization (BVR) has been proposed as an arrhythmic risk marker for disease and pharmacological action. The mechanisms are unclear but BVR is thought to be a cell level manifestation of ion channel stochasticity, modulated by cell-to-cell differences in ionic conductances. In this study, we describe the construction of an experimentally-calibrated set of stochastic cardiac cell models that captures both BVR and cell-to-cell differences in BVR displayed in isolated canine action potential measurements using pharmacological agents. Simulated and experimental ranges of BVR are compared in control and under pharmacological inhibition, and the key ionic currents determining BVR under physiological and pharmacological conditions are identified. Results show that the 4-aminopyridine-sensitive transient outward potassium current, Ito1, is a fundamental driver of BVR in control and upon complete inhibition of the slow delayed rectifier potassium current, IKs. In contrast, IKs and the L-type calcium current, ICaL, become the major contributors to BVR upon inhibition of the fast delayed rectifier potassium current, IKr. This highlights both IKs and Ito1 as key contributors to repolarization reserve. Partial correlation analysis identifies the distribution of Ito1 channel numbers as an important independent determinant of the magnitude of BVR and drug-induced change in BVR in control and under pharmacological inhibition of ionic currents. Distributions in the number of IKs and ICaL channels only become independent determinants of the magnitude of BVR upon complete inhibition of IKr. These findings provide quantitative insights into the ionic causes of BVR as a marker for repolarization reserve, both under control condition and pharmacological inhibition.

The Wright-Fisher model is an Itô stochastic differential equation that was originally introduced to model genetic drift within finite populations and has recently been used as an approximation to ion channel dynamics within cardiac and neuronal cells. While analytic solutions to this equation remain within the interval [0,1], current numerical methods are unable to preserve such boundaries in the approximation. We present a new numerical method that guarantees approximations to a form of Wright-Fisher model, which includes mutation, remain within [0,1] for all time with probability one. Strong convergence of the method is proved and numerical experiments suggest that this new scheme converges with strong order 1/2. Extending this method to a multidimensional case, numerical tests suggest that the algorithm still converges strongly with order 1/2. Finally, numerical solutions obtained using this new method are compared to those obtained using the Euler-Maruyama method where the Wiener increment is resampled to ensure solutions remain within [0,1].

The behaviour of ion channels within cardiac and neuronal cells is intrinsically stochastic in nature. When the number of channels is small this stochastic noise is large and can have an impact on the dynamics of the system which is potentially an issue when modelling small neurons and drug block in cardiac cells. While exact methods correctly capture the stochastic dynamics of a system they are computationally expensive, restricting their inclusion into tissue level models and so approximations to exact methods are often used instead. The other issue in modelling ion channel dynamics is that the transition rates are voltage dependent, adding a level of complexity as the channel dynamics are coupled to the membrane potential. By assuming that such transition rates are constant over each time step, it is possible to derive a stochastic differential equation (SDE), in the same manner as for biochemical reaction networks, that describes the stochastic dynamics of ion channels. While such a model is more computationally efficient than exact methods we show that there are analytical problems with the resulting SDE as well as issues in using current numerical schemes to solve such an equation. We therefore make two contributions: develop a different model to describe the stochastic ion channel dynamics that analytically behaves in the correct manner and also discuss numerical methods that preserve the analytical properties of the model.

While the foundations of modern epidemiology are based upon deterministic models with homogeneous mixing, it is being increasingly realized that both spatial structure and stochasticity play major roles in shaping epidemic dynamics. The integration of these two confounding elements is generally ascertained through numerical simulation. Here, for the first time, we develop a more rigorous analytical understanding based on pairwise approximations to incorporate localized spatial structure and diffusion approximations to capture the impact of stochasticity. Our results allow us to quantify, analytically, the impact of network structure on the variability of an epidemic. Using the susceptible-infectious-susceptible framework for the infection dynamics, the pairwise stochastic model is compared with the stochastic homogeneous-mixing (mean-field) model-although to enable a fair comparison the homogeneous-mixing parameters are scaled to give agreement with the pairwise dynamics. At equilibrium, we show that the pairwise model always displays greater variation about the mean, although the differences are generally small unless the prevalence of infection is low. By contrast, during the early epidemic growth phase when the level of infection is increasing exponentially, the pairwise model generally shows less variation.