Accelerating Progress Towards the 2030 Neglected Tropical Diseases Targets: How Can Quantitative Modeling Support Programmatic Decisions?

Over the past decade, considerable progress has been made in the control, elimination, and eradication of neglected tropical diseases (NTDs). Despite these advances, most NTD programs have recently experienced important setbacks; for example, NTD interventions were some of the most frequently and severely impacted by service disruptions due to the coronavirus disease 2019 (COVID-19) pandemic. Mathematical modeling can help inform selection of interventions to meet the targets set out in the NTD road map 2021-2030, and such studies should prioritize questions that are relevant for decision-makers, especially those designing, implementing, and evaluating national and subnational programs. In September 2022, the World Health Organization hosted a stakeholder meeting to identify such priority modeling questions across a range of NTDs and to consider how modeling could inform local decision making. Here, we summarize the outputs of the meeting, highlight common themes in the questions being asked, and discuss how quantitative modeling can support programmatic decisions that may accelerate progress towards the 2030 targets.

A generation of junior faculty is at risk from the impacts of COVID-19.

For junior investigators starting their independent careers, the challenges of the Coronavirus Disease 2019 (COVID-19) pandemic extend beyond lost time and are career threatening. Without intervention, academic science could lose a generation of talent.

Emergence of SARS-CoV-2 Delta Variant and Effect of Nonpharmaceutical Interventions, British Columbia, Canada.

In British Columbia, Canada, initial growth of the SARS-CoV-2 Delta variant was slower than that reported in other jurisdictions. Delta became the dominant variant (>50% prevalence) within ≈7-13 weeks of first detection in regions within the United Kingdom and United States. In British Columbia, it remained at <10% of weekly incident COVID-19 cases for 13 weeks after first detection on March 21, 2021, eventually reaching dominance after 17 weeks. We describe the growth of Delta variant cases in British Columbia during March 1-June 30, 2021, and apply retrospective counterfactual modeling to examine factors for the initially low COVID-19 case rate after Delta introduction, such as vaccination coverage and nonpharmaceutical interventions. Growth of COVID-19 cases in the first 3 months after Delta emergence was likely limited in British Columbia because additional nonpharmaceutical interventions were implemented to reduce levels of contact at the end of March 2021, soon after variant emergence.

Assessing the impact of lateral flow testing strategies on within-school SARS-CoV-2 transmission and absences: A modelling study.

Rapid testing strategies that replace the isolation of close contacts through the use of lateral flow device tests (LFTs) have been suggested as a way of controlling SARS-CoV-2 transmission within schools that maintain low levels of pupil absences. We developed an individual-based model of a secondary school formed of exclusive year group bubbles (five year groups, with 200 pupils per year) to assess the likely impact of strategies using LFTs in secondary schools over the course of a seven-week half-term on transmission, absences, and testing volume, compared to a policy of isolating year group bubbles upon a pupil returning a positive polymerase chain reaction (PCR) test. We also considered the sensitivity of results to levels of participation in rapid testing and underlying model assumptions. While repeated testing of year group bubbles following case detection is less effective at reducing infections than a policy of isolating year group bubbles, strategies involving twice weekly mass testing can reduce infections to lower levels than would occur under year group isolation. By combining regular testing with serial contact testing or isolation, infection levels can be reduced further still. At high levels of pupil participation in lateral flow testing, strategies replacing the isolation of year group bubbles with testing substantially reduce absences, but require a high volume of testing. Our results highlight the conflict between the goals of minimising within-school transmission, minimising absences and minimising testing burden. While rapid testing strategies can reduce school transmission and absences, they may lead to a large number of daily tests.

Approximating steady state distributions for household structured epidemic models.

Household-structured infectious disease models consider the increased transmission potential between individuals of the same household when compared with two individuals in different households. Accounting for these heterogeneities in transmission enables control measures to be more effectively planned. Ideally, pre-control data may be used to fit such a household-structured model at an endemic steady state, before making dynamic forward-predictions under different proposed strategies. However, this requires the accurate calculation of the steady states for the full dynamic model. We observe that steady state SIS dynamics with household structure cannot necessarily be described by the master equation for a single household, instead requiring consideration of the full system. However, solving the full system of equations becomes increasingly computationally intensive, particularly for higher-dimensional models. We compare two approximations to the full system: the single household master equation; and a proposed alternative method, using the Fokker-Planck equation. Moment closure is another commonly used method, but for more complicated systems, the equations quickly become unwieldy and very difficult to derive. In comparison, using the master equation for a single household is easily implementable, however it can be quite inaccurate. In this paper we compare these methods in terms of accuracy and ease of implementation. We find that there are regions of parameter space in which each method outperforms the other, and that these regions of parameter space can be characterised by the infection prevalence, or by the correlation between household states.

Exploring the role of the potential surface in the behaviour of early warning signals.

The theory of critical slowing down states that a system displays increasing relaxation times as it approaches a critical transition. These changes can be seen in statistics generated from timeseries data, which can be used as early warning signals of a transition. Such early warning signals would be of value for emerging infectious diseases or to understand when an endemic disease is close to elimination. However, in applications to a variety of epidemiological models there is frequent disagreement with the general theory of critical slowing down, with some indicators performing well on prevalence data but not when applied to incidence data. Furthermore, the alternative theory of critical speeding up predicts contradictory behaviour of early warning signals prior to some stochastic transitions. To investigate the possibility of observing critical speeding up in epidemiological models we characterise the behaviour of common early warning signals in terms of a system's potential surface and noise around a quasi-steady state. We then describe a method to obtain these key features from timeseries data, taking as a case study a version of the SIS model, adapted to demonstrate either critical slowing down or critical speeding up. We show this method accurately reproduces the analytic potential surface and diffusion function, and that these results can be used to determine the behaviour of early warning signals and correctly identify signs of both critical slowing down and critical speeding up.

Modelling optimal vaccination strategy for SARS-CoV-2 in the UK.

The COVID-19 outbreak has highlighted our vulnerability to novel infections. Faced with this threat and no effective treatment, in line with many other countries, the UK adopted enforced social distancing (lockdown) to reduce transmission-successfully reducing the reproductive number R below one. However, given the large pool of susceptible individuals that remain, complete relaxation of controls is likely to generate a substantial further outbreak. Vaccination remains the only foreseeable means of both containing the infection and returning to normal interactions and behaviour. Here, we consider the optimal targeting of vaccination within the UK, with the aim of minimising future deaths or quality adjusted life year (QALY) losses. We show that, for a range of assumptions on the action and efficacy of the vaccine, targeting older age groups first is optimal and may be sufficient to stem the epidemic if the vaccine prevents transmission as well as disease.

A network modelling approach to assess non-pharmaceutical disease controls in a worker population: An application to SARS-CoV-2.

As part of a concerted pandemic response to protect public health, businesses can enact non-pharmaceutical controls to minimise exposure to pathogens in workplaces and premises open to the public. Amendments to working practices can lead to the amount, duration and/or proximity of interactions being changed, ultimately altering the dynamics of disease spread. These modifications could be specific to the type of business being operated. We use a data-driven approach to parameterise an individual-based network model for transmission of SARS-CoV-2 amongst the working population, stratified into work sectors. The network is comprised of layered contacts to consider the risk of spread in multiple encounter settings (workplaces, households, social and other). We analyse several interventions targeted towards working practices: mandating a fraction of the population to work from home; using temporally asynchronous work patterns; and introducing measures to create 'COVID-secure' workplaces. We also assess the general role of adherence to (or effectiveness of) isolation and test and trace measures and demonstrate the impact of all these interventions across a variety of relevant metrics. The progress of the epidemic can be significantly hindered by instructing a significant proportion of the workforce to work from home. Furthermore, if required to be present at the workplace, asynchronous work patterns can help to reduce infections when compared with scenarios where all workers work on the same days, particularly for longer working weeks. When assessing COVID-secure workplace measures, we found that smaller work teams and a greater reduction in transmission risk reduced the probability of large, prolonged outbreaks. Finally, following isolation guidance and engaging with contact tracing without other measures is an effective tool to curb transmission, but is highly sensitive to adherence levels. In the absence of sufficient adherence to non-pharmaceutical interventions, our results indicate a high likelihood of SARS-CoV-2 spreading widely throughout a worker population. Given the heterogeneity of demographic attributes across worker roles, in addition to the individual nature of controls such as contact tracing, we demonstrate the utility of a network model approach to investigate workplace-targeted intervention strategies and the role of test, trace and isolation in tackling disease spread.

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.

An analysis of school absences in England during the COVID-19 pandemic.

BACKGROUND: The introduction of SARS-CoV-2, the virus that causes COVID-19 infection, in the UK in early 2020, resulted in the introduction of several control policies to reduce disease spread. As part of these restrictions, schools were closed to all pupils in March (except for vulnerable and key worker children), before re-opening to certain year groups in June. Finally, all school children returned to the classroom in September. METHODS: Here, we analyse data on school absences in late 2020 as a result of COVID-19 infection and how that varied through time as other measures in the community were introduced. We utilise data from the Department for Education Educational Settings database and examine how pupil and teacher absences change in both primary and secondary schools. RESULTS: Our results show that absences as a result of COVID-19 infection rose steadily following the re-opening of schools in September. Cases in teachers declined during the November lockdown, particularly in regions previously in tier 3, the highest level of control at the time. Cases in secondary school pupils increased for the first 2 weeks of the November lockdown, before decreasing. Since the introduction of the tier system, the number of absences with confirmed infection in primary schools was observed to be (markedly) lower than that in secondary schools. In December, we observed a large rise in the number of absences per school in secondary school settings in the South East and London, but such rises were not observed in other regions or in primary school settings. We conjecture that the increased transmissibility of the new variant in these regions may have contributed to this rise in secondary school cases. Finally, we observe a positive correlation between cases in the community and cases in schools in most regions, with weak evidence suggesting that cases in schools lag behind cases in the surrounding community. CONCLUSIONS: We conclude that there is no significant evidence to suggest that schools are playing a substantial role in driving spread in the community and that careful monitoring may be required as schools re-open to determine the effect associated with open schools upon community incidence.

Prospects for detecting early warning signals in discrete event sequence data: Application to epidemiological incidence data.

Early warning signals (EWS) identify systems approaching a critical transition, where the system undergoes a sudden change in state. For example, monitoring changes in variance or autocorrelation offers a computationally inexpensive method which can be used in real-time to assess when an infectious disease transitions to elimination. EWS have a promising potential to not only be used to monitor infectious diseases, but also to inform control policies to aid disease elimination. Previously, potential EWS have been identified for prevalence data, however the prevalence of a disease is often not known directly. In this work we identify EWS for incidence data, the standard data type collected by the Centers for Disease Control and Prevention (CDC) or World Health Organization (WHO). We show, through several examples, that EWS calculated on simulated incidence time series data exhibit vastly different behaviours to those previously studied on prevalence data. In particular, the variance displays a decreasing trend on the approach to disease elimination, contrary to that expected from critical slowing down theory; this could lead to unreliable indicators of elimination when calculated on real-world data. We derive analytical predictions which can be generalised for many epidemiological systems, and we support our theory with simulated studies of disease incidence. Additionally, we explore EWS calculated on the rate of incidence over time, a property which can be extracted directly from incidence data. We find that although incidence might not exhibit typical critical slowing down properties before a critical transition, the rate of incidence does, presenting a promising new data type for the application of statistical indicators.

Modeling Treatment Strategies to Inform Yaws Eradication.

Yaws is a neglected tropical disease targeted for eradication by 2030. To achieve eradication, finding and treating asymptomatic infections as well as clinical cases is crucial. The proposed plan, the Morges strategy, involves rounds of total community treatment (i.e., treating the whole population) and total targeted treatment (TTT) (i.e., treating clinical cases and contacts). However, modeling and empirical work suggests asymptomatic infections often are not found in the same households as clinical cases, reducing the utility of household-based contact tracing for a TTT strategy. We use a model fitted to data from the Solomon Islands to predict the likelihood of elimination of transmission under different intervention schemes and levels of systematic nontreatment resulting from the intervention. Our results indicate that implementing additional treatment rounds through total community treatment is more effective than conducting additional rounds of treatment of at-risk persons through TTT.

The problem of detrending when analysing potential indicators of disease elimination.

As we strive towards the elimination of many burdensome diseases, the question of when intervention efforts may cease is increasingly important. It can be very difficult to know when prevalences are low enough that the disease will die out without further intervention, particularly for diseases that lack accurate tests. The consequences of stopping an intervention prematurely can put back elimination efforts by decades. Critical slowing down theory predicts that as a dynamical system moves through a critical transition, deviations from the steady state return increasingly slowly. We study two potential indicators of disease elimination predicted by this theory, and investigate their response using a simple stochastic model. We compare our dynamical predictions to simulations of the fluctuation variance and coefficient of variation as the system moves through the transition to elimination. These comparisons demonstrate that the primary challenge facing the analysis of early warning signs in timeseries data is that of accurately 'detrending' the signal, in order to preserve the statistical properties of the fluctuations. We show here that detrending using the mean of even just four realisations of the process can give a significant improvement when compared to using a moving window average. Taking this idea further, we consider a 'metapopulation' model of an endemic disease, in which infection spreads in various separated areas with some movement between the subpopulations. We successfully predict the behaviour of both variance and the coefficient of variation in a metapopulation by using information from the other subpopulations to detrend the system.

A chemotactic model of trunk neural crest cell migration.

Trunk neural crest cells follow a common ventral migratory pathway but are distributed into two distinct locations to form discrete sympathetic and dorsal root ganglia along the vertebrate axis. Although fluorescent cell labeling and time-lapse studies have recorded complex trunk neural crest cell migratory behaviors, the signals that underlie this dynamic patterning remain unclear. The absence of molecular information has led to a number of mechanistic hypotheses for trunk neural crest cell migration. Here, we review recent data in support of three distinct mechanisms of trunk neural crest cell migration and develop and simulate a computational model based on chemotactic signaling. We show that by integrating the timing and spatial location of multiple chemotactic signals, trunk neural crest cells may be accurately positioned into two distinct targets that correspond to the sympathetic and dorsal root ganglia. In doing so, we honor the contributions of Wilhelm His to his identification of the neural crest and extend the observations of His and others to better understand a complex question in neural crest cell biology.

Targeted Treatment of Yaws With Household Contact Tracing: How Much Do We Miss?

Yaws is a disabling bacterial infection found primarily in warm and humid tropical areas. The World Health Organization strategy mandates an initial round of total community treatment (TCT) with single-dose azithromycin followed either by further TCT or active case-finding and treatment of cases and their contacts (the Morges strategy). We sought to investigate the effectiveness of the Morges strategy. We employed a stochastic household model to study the transmission of infection using data collected from a pre-TCT survey conducted in the Solomon Islands. We used this model to assess the proportion of asymptomatic infections that occurred in households without active cases. This analysis indicated that targeted treatment of cases and their household contacts would miss a large fraction of asymptomatic infections (65%-100%). This fraction was actually higher at lower prevalences. Even assuming that all active cases and their households were successfully treated, our analysis demonstrated that at all prevalences present in the data set, up to 90% of (active and asymptomatic) infections would not be treated under household-based contact tracing. Mapping was undertaken as part of the study "Epidemiology of Yaws in the Solomon Islands and the Impact of a Trachoma Control Programme," in September-October 2013.

Multiscale mechanisms of cell migration during development: theory and experiment.

Long-distance cell migration is an important feature of embryonic development, adult morphogenesis and cancer, yet the mechanisms that drive subpopulations of cells to distinct targets are poorly understood. Here, we use the embryonic neural crest (NC) in tandem with theoretical studies to evaluate model mechanisms of long-distance cell migration. We find that a simple chemotaxis model is insufficient to explain our experimental data. Instead, model simulations predict that NC cell migration requires leading cells to respond to long-range guidance signals and trailing cells to short-range cues in order to maintain a directed, multicellular stream. Experiments confirm differences in leading versus trailing NC cell subpopulations, manifested in unique cell orientation and gene expression patterns that respond to non-linear tissue growth of the migratory domain. Ablation experiments that delete the trailing NC cell subpopulation reveal that leading NC cells distribute all along the migratory pathway and develop a leading/trailing cellular orientation and gene expression profile that is predicted by model simulations. Transplantation experiments and model predictions that move trailing NC cells to the migratory front, or vice versa, reveal that cells adopt a gene expression profile and cell behaviors corresponding to the new position within the migratory stream. These results offer a mechanistic model in which leading cells create and respond to a cell-induced chemotactic gradient and transmit guidance information to trailing cells that use short-range signals to move in a directional manner.

The importance of volume exclusion in modelling cellular migration.

The modelling of collective migration has traditionally been undertaken in a continuous framework, with little reference to the individual-level mechanisms that give rise to such a concerted movement. One factor whose importance is now coming to light is that the individuals themselves occupy space in the domain, thus obstructing others from moving past them (volume exclusion). In this work, we systematically derive continuous descriptions of cellular migration with volume exclusion for a wide range of individual-based mechanisms and in one, two and three dimensions. We also consider subpopulations of migrating individuals, which may have different characteristics, such as differing sizes and speeds of migration. We demonstrate that volume exclusion is of particular importance when biased movement is included, and thus conclude that volume exclusion may have its greatest effect when considering directed migratory mechanisms such as chemotaxis.

Noise-induced bistable states and their mean switching time in foraging colonies.

We investigate a type of bistability occurring in population systems where noise not only causes transitions between stable states, but also constructs the states themselves. We focus on the experimentally well-studied system of ants choosing between two food sources to illustrate the essential points, but the ideas are more general. The mean time for switching between the two bistable states of the system is calculated. This suggests a procedure for estimating, in a real system, the critical population size above which bistability ceases to occur.

Age-related changes in speed and mechanism of adult skeletal muscle stem cell migration.

Skeletal muscle undergoes a progressive age-related loss in mass and function. Preservation of muscle mass depends in part on satellite cells, the resident stem cells of skeletal muscle. Reduced satellite cell function may contribute to the age-associated decrease in muscle mass. Here, we focused on characterizing the effect of age on satellite cell migration. We report that aged satellite cells migrate at less than half the speed of young cells. In addition, aged cells show abnormal membrane extension and retraction characteristics required for amoeboid-based cell migration. Aged satellite cells displayed low levels of integrin expression. By deploying a mathematical model approach to investigate mechanism of migration, we have found that young satellite cells move in a random "memoryless" manner, whereas old cells demonstrate superdiffusive tendencies. Most importantly, we show that nitric oxide, a key regulator of cell migration, reversed the loss in migration speed and reinstated the unbiased mechanism of movement in aged satellite cells. Finally, we found that although hepatocyte growth factor increased the rate of aged satellite cell movement, it did not restore the memoryless migration characteristics displayed in young cells. Our study shows that satellite cell migration, a key component of skeletal muscle regeneration, is compromised during aging. However, we propose clinically approved drugs could be used to overcome these detrimental changes.

Spatio-temporal surveillance and early detection of SARS-CoV-2 variants of concern: a retrospective analysis.

The SARS-CoV-2 pandemic has been characterized by the repeated emergence of genetically distinct virus variants of increased transmissibility and immune evasion compared to pre-existing lineages. In many countries, their containment required the intervention of public health authorities and the imposition of control measures. While the primary role of testing is to identify infection, target treatment, and limit spread (through isolation and contact tracing), a secondary benefit is in terms of surveillance and the early detection of new variants. Here we study the spatial invasion and early spread of the Alpha, Delta and Omicron (BA.1 and BA.2) variants in England from September 2020 to February 2022 using the random neighbourhood covering (RaNCover) method. This is a statistical technique for the detection of aberrations in spatial point processes, which we tailored here to community PCR (polymerase-chain-reaction) test data where the TaqPath kit provides a proxy measure of the switch between variants. Retrospectively, RaNCover detected the earliest signals associated with the four novel variants that led to large infection waves in England. With suitable data our method therefore has the potential to rapidly detect outbreaks of future SARS-CoV-2 variants, thus helping to inform targeted public health interventions.