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Abstract Background Schistosomiasis is endemic in 54 countries, but has one of the lowest coverages by mass drug administration of all helminth diseases. However, with increasing drug availability through donation, the World Health Organisation has set a goal of increasing coverage to 75 % of at-risk children in endemic countries and elimination in some regions. In this paper, we assess the impact on schistosomiasis of the WHO goals in terms of control and elimination. Methods We use an age-structured deterministic model of schistosome transmission in a human community and the effect of mass drug administration. The model is fitted to baseline data from a longitudinal re-infection study in Kenya and validated against the subsequent re-infection data. We examine the impact on host worm burden of the current treatment trend, extrapolated to meet the WHO goals, and its sensitivity to uncertainty in important parameters. We assess the feasibility of achieving elimination. Results Model results show that the current treatment trend, extrapolated to the WHO goals, is able to greatly reduce host worm burdens. If coverage is continued at the same level beyond 2020, elimination is possible for low to moderate transmission settings, where transmission intensity is defined by the basic reproduction number, R0. Low levels of adult coverage have a significant impact on worm burden in all settings. Model validation against the re-infection survey demonstrates that the age-structured model is able to match post-treatment data well in terms of egg output, but that some details of re-infection among school children and young adults are not currently well represented. Conclusions Our work suggests that the current WHO treatment goals should be successful in bringing about a major reduction in schistosome infection in treated communities. If continued over a 15 year period, they are likely to result in elimination, at least in areas with lower transmission.

Abstract Background It is the aim of the World Health Organisation to eliminate soil-transmitted helminths (STH) as a health problem in children. To this end, the goal is to increase anthelmintic treatment coverage for soil transmitted helminths to reach 75 % in pre-school aged and school aged children by 2020 in endemic countries. In this paper, we use mathematical models to investigate the impact of achieving this goal on the burdens of Ascaris lumbricoides, Trichuris trichuria and hookworm. Methods We employ a deterministic fully age-structured model of STH transmission and mass drug administration to examine the changes in worm burden in response to the known and projected coverage trends in children up to 2020 and beyond. Parameters are estimated from worm expulsion data and age intensity profiles before treatment using maximum likelihood methods. Model validation is performed using reinfection studies for Ascaris and analyses are conducted to assess the sensitivity of the predicted outcomes to variation in parameter estimates including transmission intensity (R0), children’s contributions to the pool of infective stages and drug coverage levels. Results The impact of the required increase in coverage trends are quite different across the three species. Ascaris burdens are reduced dramatically by 2020 with elimination predicted within studied the setting a further 10 years. For Trichuris and hookworm, however, impact is more limited, due to issues of drug efficacy (Trichuris) and distribution of worms in the population (hookworm). Sensitivity analysis indicates that results are largely robust. However, validation against Ascaris data indicates that assumptions concerning re-infection among children may have to be revised. Conclusions The 2020 coverage target is predicted to have a major impact on Ascaris levels by 2020. However, there is evidence from model validation that Ascaris in children is more resilient to treatment than currently assumed in the model. Broader coverage across all age classes is required to break transmission for hookworm and alternative dual drug treatment approaches are needed for Trichuris.

Human mobility contributes to the spatial dynamics of many infectious diseases, and understanding these dynamics helps us to determine the most effective ways to intervene and plan surveillance. In this paper, we describe a novel transmission model for the spatial dynamics of hookworm, a parasitic worm which is a common infection across sub-Saharan Africa, East Asia and the Pacific islands. We fit our model, with and without mobility, to data obtained from a sub-county in Kenya, and validate the model's predictions against the decline in prevalence observed over the course of a clustered randomized control trial evaluating methods of administering mass chemotherapy. We find that our model which incorporates human mobility is able to reproduce the observed patterns in decline of prevalence during the TUMIKIA trial, and additionally, that the widespread bounce-back of infection may be possible over many years, depending on the rates of people movement between villages. The results have important implications for the design of mass chemotherapy programmes for the elimination of human helminth transmission. This article is part of the theme issue 'Challenges and opportunities in the fight against neglected tropical diseases: a decade from the London Declaration on NTDs'.

Much effort has been devoted by the World Health Organization (WHO) to eliminate soil-transmitted helminth (STH) infections by 2030 using mass drug administration targeted at particular risk groups alongside the availability to access water, sanitation and hygiene services. The targets set by the WHO for the control of helminth infections are typically defined in terms of the prevalence of infection, whereas the standard formulation of STH transmission models typically describe dynamic changes in the mean-worm burden. We develop a prevalence-based deterministic model to investigate the transmission dynamics of soil-transmitted helminthiasis in humans, subject to continuous exposure to infection over time. We analytically determine local stability criteria for all equilibria and find bifurcation points. Our model predicts that STH infection will either be eliminated (if the initial prevalence value, y(0), is sufficiently small) or remain endemic (if y(0) is sufficiently large), with the two stable points of endemic infection and parasite eradication separated by a transmission breakpoint. Two special cases of the model are analysed: (1) the distribution of the STH parasites in the host population is highly aggregated following a negative binomial distribution, and (2) no density-dependent effects act on the parasite population. We find that disease extinction is always possible for Case (1), but it is not so for Case (2) if y(0) is sufficiently large. However, by introducing stochastic perturbation into the deterministic model, we discover that chance effects can lead to outcomes not predicted by the deterministic model alone, with outcomes highly dependent on the degree of worm clumping, k. Specifically, we show that if the reproduction number and clumping are sufficiently bounded, then stochasticity will cause the parasite to die out. It follows that control of soil-transmitted helminths will be more difficult if the worm distribution tends towards clumping., Competing Interests: The authors have declared that no competing interests exist.

The disease burden attributable to opportunistic pathogens depends on their prevalence in asymptomatic colonisation and the rate at which they progress to cause symptomatic disease. Increases in infections caused by commensals can result from the emergence of "hyperinvasive" strains. Such pathogens can be identified through quantifying progression rates using matched samples of typed microbes from disease cases and healthy carriers. This study describes Bayesian models for analysing such datasets, implemented in an RStan package (https://github.com/nickjcroucher/progressionEstimation). The models converged on stable fits that accurately reproduced observations from meta-analyses of Streptococcus pneumoniae datasets. The estimates of invasiveness, the progression rate from carriage to invasive disease, in cases per carrier per year correlated strongly with the dimensionless values from meta-analysis of odds ratios when sample sizes were large. At smaller sample sizes, the Bayesian models produced more informative estimates. This identified historically rare but high-risk S. pneumoniae serotypes that could be problematic following vaccine-associated disruption of the bacterial population. The package allows for hypothesis testing through model comparisons with Bayes factors. Application to datasets in which strain and serotype information were available for S. pneumoniae found significant evidence for within-strain and within-serotype variation in invasiveness. The heterogeneous geographical distribution of these genotypes is therefore likely to contribute to differences in the impact of vaccination in between locations. Hence genomic surveillance of opportunistic pathogens is crucial for quantifying the effectiveness of public health interventions, and enabling ongoing meta-analyses that can identify new, highly invasive variants., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: AL was funded by an investigator-initiated grant to NJC from GlaxoSmithKline (https://www.gsk.com/en-gb/home/), who manufacture the PCV10 vaccine. NJC has consulted for Pfizer (https://www.pfizer.com/), who manufacture the PCV13 and PCV20 vaccines.

Schistosomiasis causes severe morbidity in many countries with endemic infection with the schistosome digenean parasites in Africa and Asia. To control and eliminate the disease resulting from infection, regular mass drug administration (MDA) is used, with a focus on school-aged children (SAC; 5-14 years of age). In some high transmission settings, the World Health Organization (WHO) also recommends the inclusion of at-risk adults in MDA treatment programmes. The question of whether ecology (age-dependant exposure) or immunity (resistance to reinfection), or some combination of both, determines the form of observed convex age-intensity profile is still unresolved, but there is a growing body of evidence that the human hosts acquire some partial level of immunity after a long period of repeated exposure to infection. In the majority of past research modelling schistosome transmission and the impact of MDA programmes, the effect of acquired immunity has not been taken into account. Past work has been based on the assumption that age-related contact rates generate convex horizontal age-intensity profiles. In this paper, we use an individual based stochastic model of transmission and MDA impact to explore the effect of acquired immunity in defined MDA programmes. Compared with scenarios with no immunity, we find that acquired immunity makes the MDA programme less effective with a slower decrease in the prevalence of infection. Therefore, the time to achieve morbidity control and elimination as a public health problem is longer than predicted by models with just age-related exposure and no build-up of immunity. The level of impact depends on the baseline prevalence prior to treatment (the magnitude of the basic reproductive number R0) and the treatment frequency, among other factors. We find that immunity has a larger impact within moderate to high transmission settings such that it is very unlikely to achieve morbidity and transmission control employing current MDA programmes., Competing Interests: The authors have declared that no competing interests exist.

Background: Soil-transmitted helminths (STHs) are a major cause of poor health in low- and middle-income countries. In particular, hookworm is known to cause anaemia in children and women of reproductive age (WRA). One goal of the World Health Organization's (WHO) 2030 roadmap for neglected tropical diseases is to reduce STH-related morbidity in WRA. As a minimal intervention, the WHO recommends deworming adolescent girls annually during human papilloma virus vaccination programmes and WRA during pregnancy and lactation. These routine interventions are low cost and can be implemented even by the most basic health services in endemic countries. In this study we use a cohort model to investigate the potential impact on STH-related morbidity in WRA., Results: Annual deworming treatment of adolescent girls reduces the prevalence of moderate- and heavy-intensity infections in this age group by up to 60% in moderate transmission settings and by 12-27% in high transmission settings. Treatment of WRA during pregnancy and lactation on its own has a small (< 20%) but significant effect on morbidity although it does not lead to the achievement of the morbidity target (< 2% moderate- to high-intensity infections) in this age group. However, depending on the age-intensity profile of infection, which may vary geographically, and assumptions on the density-dependence of egg production by fertilised female worms, continued school-based treatment may be able to reduce the force of infection acting on WRA, both through an indirect effect on the overall population-based force of infection and via reducing the burden of infection as children age and move into the WRA age classes. As a result, morbidity in WRA may be eliminated., Conclusion: While deworming during pregnancy and lactation does not lead to the achievement of the morbidity target in WRA and its efficacy may vary by setting, it is still expected to be beneficial for maternity and child health. Monitoring of any WRA-based intervention is recommended to evaluate its effectiveness.

Predicting the effect of different programmes designed to control both the morbidity induced by helminth infections and parasite transmission is greatly facilitated by the use of mathematical models of transmission and control impact. In such models, it is essential to account for the many sources of uncertainty - natural, or otherwise - to ensure robustness in prediction and to accurately depict variation around an expected outcome. In this paper, we investigate how well the standard deterministic models match the predictions made using individual-based stochastic simulations. We also explore how well concepts which derive from deterministic models, such as 'breakpoints' in transmission, apply in the stochastic world. Employing an individual-based stochastic model framework we also investigate how transmission and control are affected by the migration of infected people into a defined community. To give our study focus we consider the control of soil-transmitted helminths (STH) by mass drug administration (MDA), though our methodology is readily applicable to the other helminth species such as the schistosome parasites and the filarial worms. We show it is possible to theoretically define a 'stochastic breakpoint' where much noise surrounds the expected deterministic breakpoint. We also discuss the concept of the 'interruption of transmission' independent of the 'breakpoint' concept where analyses of model behaviour illustrate the current limitations of deterministic models to account for the 'fade-out' or transmission extinction behaviour in simulations. Our analysis of migration confirms a relationship between the critical infected human migration rate scale (i.e., order of magnitude) per unit of time and the death rate of infective stages that are released into the free-living environment. This relationship is shown to determine the likelihood that control activities aim at chemotherapeutic treatment of the human host will eliminate transmission. The development of a new stochastic simulation code for STH in the form of a publicly-available open-source python package which includes features to incorporate many population stratifications, different control interventions including mass drug administration (with defined frequency, coverage levels and compliance patterns) and inter-village human migration is also described., (Copyright © 2021. Published by Elsevier B.V.)

We present a general framework which describes the systematic (binary) scenario of individuals either taking treatment or not for any reason, over the course of mass drug administration (MDA)-which we refer to as 'adherence' and 'non-adherence'. The probability models developed can be informed by observed adherence behaviour as well as employed to explore how different patterns influence the impact of MDA programmes, by the use of mathematical models of transmission and control. We demonstrate the interpretative value of the developed probability model employing a dataset collected in the TUMIKIA project, a randomised trial of deworming strategies to control soil-transmitted helminths (STH) by MDA conducted in coastal Kenya. We stratify our analysis by age and sex, although the framework which we introduce here may be readily adapted to accommodate other stratifications. Our findings include the detection of specific patterns of non-adherence in all age groups to varying extents. This is particularly apparent in men of ages 30+. We then demonstrate the use of the probability model in stochastic individual-based simulations by running two example forecasts for the elimination of STH transmission employing MDA within the TUMIKIA trial setting with different adherence patterns. This suggested a substantial reduction in the probability of elimination (between 23-43%) when comparing observed adherence patterns with an assumption of independence, with important implications for programmes. The results here demonstrate the considerable impact and utility of considering non-adherence on the success of MDA programmes to control neglected tropical diseases (NTDs)., Competing Interests: No authors have competing interests. RMA was a former non-executive director of GlaxoSmithKline.

Background: The DeWorm3 project is an ongoing cluster-randomised trial assessing the feasibility of interrupting the transmission of soil-transmitted helminths (STH) through mass drug administration (MDA) using study sites in India, Malawi and Benin. In this article, we describe an approach which uses a combination of statistical and mathematical methods to forecast the outcome of the trial with respect to its stated goal of reducing the prevalence of infection to below 2%., Methods: Our approach is first to define the local patterns of transmission within each study site, which is achieved by statistical inference of key epidemiological parameters using the baseline epidemiological measures of age-related prevalence and intensity of STH infection which have been collected by the DeWorm3 trials team. We use these inferred parameters to calibrate an individual-based stochastic simulation of the trial at the cluster and study site level, which is subsequently run to forecast the future prevalence of STH infections. The simulator takes into account both the uncertainties in parameter estimation and the variability inherent in epidemiological and demographic processes in the simulator. We interpret the forecast results from our simulation with reference to the stated goal of the DeWorm3 trial, to achieve a target of [Formula: see text] prevalence at a point 24 months post-cessation of MDA., Results: Simulated output predicts that the two arms will be distinguishable from each other in all three country sites at the study end point. In India and Malawi, measured prevalence in the intervention arm is below the threshold with a high probability (90% and 95%, respectively), but in Benin the heterogeneity between clusters prevents the arm prevalence from being reduced below the threshold value. At the level of individual study arms within each site, heterogeneity among clusters leads to a very low probability of achieving complete elimination in an intervention arm, yielding a post-study scenario with widespread elimination but a few 'hot spot' areas of persisting STH transmission., Conclusions: Our results suggest that geographical heterogeneities in transmission intensity and worm aggregation have a large impact on the effect of MDA. It is important to accurately assess cluster-level, or even smaller scale, heterogeneities in factors which influence transmission and aggregation for a clearer perspective on projecting the outcomes of MDA control of STH and other neglected tropical diseases.

Background: Schistosomiasis remains an endemic parasitic disease causing much morbidity and, in some cases, mortality. The World Health Organization (WHO) has outlined strategies and goals to combat the burden of disease caused by schistosomiasis. The first goal is morbidity control, which is defined by achieving less than 5% prevalence of heavy intensity infection in school-aged children (SAC). The second goal is elimination as a public health problem (EPHP), achieved when the prevalence of heavy intensity infection in SAC is reduced to less than 1%. Mass drug administration (MDA) of praziquantel is the main strategy for control. However, there is limited availability of praziquantel, particularly in Africa where there is high prevalence of infection. It is therefore important to explore whether the WHO goals can be achieved using the current guidelines for treatment based on targeting SAC and, in some cases, adults. Previous modelling work has largely focused on Schistosoma mansoni, which in advance cases can cause liver and spleen enlargement. There has been much less modelling of the transmission of Schistosoma haematobium, which in severe cases can cause kidney damage and bladder cancer. This lack of modelling has largely been driven by limited data availability and challenges in interpreting these data., Results: In this paper, using an individual-based stochastic model and age-intensity profiles of S. haematobium from two different communities, we calculate the probability of achieving the morbidity and EPHP goals within 15 years of treatment under the current WHO treatment guidelines. We find that targeting SAC only can achieve the morbidity goal for all transmission settings, regardless of the burden of infection in adults. The EPHP goal can be achieved in low transmission settings, but in some moderate to high settings community-wide treatment is needed., Conclusions: We show that the key determinants of achieving the WHO goals are the precise form of the age-intensity of infection profile and the baseline SAC prevalence. Additionally, we find that the higher the burden of infection in adults, the higher the chances that adults need to be included in the treatment programme to achieve EPHP.

Background: Soil-transmitted helminths (STH) are intestinal parasites estimated to infect over 1.5 billion people. Current treatment programmes are aimed at morbidity control through school-based deworming programmes (targeting school-aged children, SAC) and treating women of reproductive age (WRA), as these two groups are believed to record the highest morbidity. More recently, however, the potential for interrupting transmission by treating entire communities has been receiving greater emphasis and the feasibility of such programmes are now under investigation in randomised clinical trials through the Bill & Melinda Gates Foundation funded DeWorm3 studies. Helminth parasites are known to be highly aggregated within human populations, with a small minority of individuals harbouring most worms. Empirical evidence from the TUMIKIA project in Kenya suggests that aggregation may increase significantly after anthelminthic treatment., Methods: A stochastic, age-structured, individual-based simulation model of parasite transmission is employed to better understand the factors that might induce this pattern. A simple probabilistic model based on compounded negative binomial distributions caused by age-dependencies in both treatment coverage and exposure to infection is also employed to further this understanding., Results: Both approaches confirm helminth aggregation is likely to increase post-mass drug administration as measured by a decrease in the value of the negative binomial aggregation parameter, k. Simple analytical models of distribution compounding describe the observed patterns well., Conclusions: The helminth aggregation that was observed in the field was replicated with our stochastic individual-based model. Further work is required to generalise the probabilistic model to take account of the respective sensitivities of different diagnostics on the presence or absence of infection.

Background: Soil-transmitted helminth (STH) infections affect predominantly socio-economically disadvantaged populations in sub-Saharan Africa, East Asia and the Americas. Previous mathematical modelling studies have evaluated optimal intervention strategies to break STH transmission in clusters of villages. These studies assumed that villages are closed independent units with no movement of people in or out of communities. Here we examine how human population movement, for example, of seasonal migrant labourers, affect the outcome of mass drug administration (MDA) programmes., Results: We used a stochastic individual-based metapopulation model to analyse the impact of human population movement at varying rates on STH elimination efforts. Specifically, we looked at seasonal clumped movement events of infected individuals into a village. We showed that even if on average 75% of the entire resident population within a village are treated, an annual rate of 2-3% of the population arriving from an untreated source village can reduce the probability of STH elimination to less than 50% in high-prevalence settings. If a village is infection-free, an annual movement rate of 2-3% from an infected source village imposes a risk of re-introduction of STH of 75% or higher, unless the prevalence in the source village is less than 20%. Even a single arrival of 2-3% of the population can impose a risk of re-introducing STH of 50% or greater depending on the prevalence in the source village. The risk of re-introduction also depends on both the age group of moving individuals and STH species, since the pattern of cross-sectional age-prevalence and age-intensity profiles of infection in the human host are species-specific., Conclusions: Planning for STH elimination programmes should account for human mobility patterns in defined regions. We recommend that individuals arriving from areas with ongoing STH transmission should receive preventive chemotherapy for STHs. This can most easily be implemented if migration is seasonal and overlaps with treatment rounds, e.g. seasonal migrant labour. Moreover, transmission hotspots in or near treatment clusters should be eliminated, for example, by implementing appropriate water, sanitation and hygiene (WASH) measures and targeting treatment to individuals living in hotspots.

Background: As many countries with endemic soil-transmitted helminth (STH) burdens achieve high coverage levels of mass drug administration (MDA) to treat school-aged and pre-school-aged children, understanding the detailed effects of MDA on the epidemiology of STH infections is desirable in formulating future policies for morbidity and/or transmission control. Prevalence and mean intensity of infection are characterized by heterogeneity across a region, leading to uncertainty in the impact of MDA strategies. In this paper, we analyze this heterogeneity in terms of factors that govern the transmission dynamics of the parasite in the host population., Results: Using data from the TUMIKIA study in Kenya (cluster STH prevalence range at baseline: 0-63%), we estimated these parameters and their variability across 120 population clusters in the study region, using a simple parasite transmission model and Gibbs-sampling Monte Carlo Markov chain techniques. We observed great heterogeneity in R 0 values, with estimates ranging from 1.23 to 3.27, while k-values (which vary inversely with the degree of parasite aggregation within the human host population) range from 0.007 to 0.29 in a positive association with increasing prevalence. The main finding of this study is the increasing trend for greater parasite aggregation as prevalence declines to low levels, reflected in the low values of the negative binomial parameter k in clusters with low hookworm prevalence. Localized climatic and socioeconomic factors are investigated as potential drivers of these observed epidemiological patterns., Conclusions: Our results show that lower prevalence is associated with higher degrees of aggregation and hence prevalence alone is not a good indicator of transmission intensity. As a consequence, approaches to MDA and monitoring and evaluation of community infection status may need to be adapted as transmission elimination is aimed for by targeted treatment approaches.

Background: The World Health Organization (WHO) has set elimination (interruption of transmission) as an end goal for schistosomiasis. However, there is currently little guidance on the monitoring and evaluation strategy required once very low prevalence levels have been reached to determine whether elimination or resurgence of the disease will occur after stopping mass drug administration (MDA) treatment., Methods: We employ a stochastic individual-based model of Schistosoma mansoni transmission and MDA impact to determine a prevalence threshold, i.e. prevalence of infection, which can be used to determine whether elimination or resurgence will occur after stopping treatment with a given probability. Simulations are run for treatment programmes with varying probabilities of achieving elimination and for settings where adults harbour low to high burdens of infection. Prevalence is measured based on using a single Kato-Katz on two samples per individual. We calculate positive predictive values (PPV) using PPV ≥ 0.9 as a reliable measure corresponding to ≥ 90% certainty of elimination. We analyse when post-treatment surveillance should be carried out to predict elimination. We also determine the number of individuals across a single community (of 500-1000 individuals) that should be sampled to predict elimination., Results: We find that a prevalence threshold of 1% by single Kato-Katz on two samples per individual is optimal for predicting elimination at two years (or later) after the last round of MDA using a sample size of 200 individuals across the entire community (from all ages). This holds regardless of whether the adults have a low or high burden of infection relative to school-aged children., Conclusions: Using a prevalence threshold of 0.5% is sufficient for surveillance six months after the last round of MDA. However, as such a low prevalence can be difficult to measure in the field using Kato-Katz, we recommend using 1% two years after the last round of MDA. Higher prevalence thresholds of 2% or 5% can be used but require waiting over four years for post-treatment surveillance. Although, for treatment programmes where elimination is highly likely, these higher thresholds could be used sooner. Additionally, switching to more sensitive diagnostic techniques, will allow for a higher prevalence threshold to be employed.

Background: The strategy of pooling stool specimens has been extensively used in the field of parasitology in order to facilitate the screening of large numbers of samples whilst minimizing the prohibitive cost of single sample analysis. The aim of this study was to develop a standardized reproducible pooling protocol for stool samples, validated between two different laboratories, without jeopardizing the sensitivity of the quantitative polymerase chain reaction (qPCR) assays employed for the detection of soil-transmitted helminths (STHs). Two distinct experimental phases were recruited. First, the sensitivity and specificity of the established protocol was assessed by real-time PCR for each one of the STHs. Secondly, agreement and reproducibility of the protocol between the two different laboratories were tested. The need for multiple stool sampling to avoid false negative results was also assessed. Finally, a cost exercise was conducted which included labour cost in low- and high-wage settings, consumable cost, prevalence of a single STH species, and a simple distribution pattern of the positive samples in pools to estimate time and money savings suggested by the strategy., Results: The sensitivity of the pooling method was variable among the STH species but consistent between the two laboratories. Estimates of specificity indicate a 'pooling approach' can yield a low frequency of 'missed' infections. There were no significant differences regarding the execution of the protocol and the subsequent STH detection between the two laboratories, which suggests in most cases the protocol is reproducible by adequately trained staff. Finally, given the high degree of agreement, there appears to be little or no need for multiple sampling of either individuals or pools., Conclusions: Our results suggest that the pooling protocol developed herein is a robust and efficient strategy for the detection of STHs in 'pools-of-five'. There is notable complexity of the pool preparation to ensure even distribution of helminth DNA throughout. Therefore, at a given setting, cost of labour among other logistical and epidemiological factors, is the more concerning and determining factor when choosing pooling strategies, rather than losing sensitivity and/or specificity of the molecular assay or the method.

Background: The current World Health Organization (WHO) target for the three major soil-transmitted helminth (STH) infections is to reduce prevalence of moderate-to-heavy infections to below 1% by 2020. In terms of monitoring and evaluation (M&E), the current WHO guidelines for control of STHs recommend evaluation of infection levels in school-age children (SAC) after five to six years of preventive chemotherapy (PC), using the standard Kato-Katz faecal smear. Here, we assess the predictive performance of various sampling designs for the evaluation of the morbidity target., Methodology/principal Findings: Using two mathematical models for STH transmission and control, we simulate how the number of villages and SAC sampled affect the ability of survey results in sentinel villages to predict the achievement of the morbidity target in PC implementation units (e.g. districts). As PC is stopped when the prevalence of infection in SAC in sentinel villages is less than 1%, we estimate the positive predictive value (PPV) of this indicator for meeting the morbidity target in the whole district. The PPV varies by species and PC strategy, and it is generally higher in areas with lower pre-control prevalence. Sampling a fixed number of SAC spread out over 10 instead of 5 sentinel villages may increase the PPV by up to 20 percentage points. If every SAC in a village is tested, a higher number of villages may increase the PPV by up to 80 percentage points. Increasing the proportion of SAC tested per village does not result in a relevant increase of PPV., Conclusions/significance: Although the WHO guidelines provide a combined strategy to control the three STH species, the efficacy of PC strategies clearly differs by species. There is added value in considering more villages within implementation units for M&E of morbidity targets, the extent varying by STH species. A better understanding of pre- and post-control local STH prevalence levels is essential for an adequate M&E strategy including the definition of morbidity targets at the appropriate geographical scale., Competing Interests: The authors have declared that no competing interests exist.

Mass drug administration (MDA) is, and has been, the principal method for the control of the schistosome helminths. Using MDA only is unlikely to eliminate the infection in areas of high transmission and the implementation of other measures such as reduced water contact improved hygiene and sanitation are required. Ideally a vaccine is needed to ensure long term benefits and eliminate the need for repeated drug treatment since infection does not seem to induce lasting protective immunity. Currently, a candidate vaccine is under trial in a baboon animal model, and very encouraging results have been reported. In this paper, we develop an individual-based stochastic model to evaluate the effect of a vaccine with similar properties in humans to those recorded in baboons in achieving the World Health Organization (WHO) goals of morbidity control and elimination as a public health problem in populations living in a variety of transmission settings. MDA and vaccination assuming different durations of protection and coverage levels, alone or in combination, are examined as treatment strategies to reach the WHO goals of the elimination of morbidity and mortality in the coming decade. We find that the efficacy of a vaccine as an adjunct or main control tool will depend critically on a number of factors including the average duration of protection it provides, vaccine efficacy and the baseline prevalence prior to immunization. In low prevalence settings, simulations suggest that the WHO goals can be achieved for all treatment strategies. In moderate prevalence settings, a vaccine that provides 5 years of protection, can achieve both goals within 15 years of treatment. In high prevalence settings, by vaccinating at age 1, 6 and 11 we can achieve the morbidity control with a probability of nearly 0.89 but we cannot achieve elimination as a public health problem goal. A combined vaccination and MDA treatment plan has the greatest chance of achieving the WHO goals in the shorter term., Competing Interests: The authors have declared that no competing interests exist.

Prevalence is a common epidemiological measure for assessing soil-transmitted helminth burden and forms the basis for much public-health decision-making. Standard diagnostic techniques are based on egg detection in stool samples through microscopy and these techniques are known to have poor sensitivity for individuals with low infection intensity, leading to poor sensitivity in low prevalence populations. PCR diagnostic techniques offer very high sensitivities even at low prevalence, but at a greater cost for each diagnostic test in terms of equipment needed and technician time and training. Pooling of samples can allow prevalence to be estimated while minimizing the number of tests performed. We develop a model of the relative cost of pooling to estimate prevalence, compared to the direct approach of testing all samples individually. Analysis shows how expected relative cost depends on both the underlying prevalence in the population and the size of the pools constructed. A critical prevalence level (approx. 31%) above which pooling is never cost effective, independent of pool size. When no prevalence information is available, there is no basis on which to choose between pooling and testing all samples individually. We recast our model of relative cost in a Bayesian framework in order to investigate how prior information about prevalence in a given population can be used to inform the decision to choose either pooling or full testing. Results suggest that if prevalence is below 10%, a relatively small exploratory prevalence survey (10-15 samples) can be sufficient to give a high degree of certainty that pooling may be relatively cost effective., Competing Interests: The authors have declared that no competing interests exist.

Monitoring and evaluation (M&E) programmes are used to collect data which are required to assess the impact of current interventions on their progress towards achieving the World Health Organization (WHO) goals of morbidity control and elimination as a public health problem for schistosomiasis. Prevalence and intensity of infection data are typically collected from school-aged children (SAC) as they are relatively easy to sample and are thought to be most likely to be infected by schistosome parasites. However, adults are also likely to be infected. We use three different age-intensity profiles of infection for Schistosoma mansoni with low, moderate and high burdens of infection in adults to investigate how the age distribution of infection impacts the mathematical model generated recommendations of the preventive chemotherapy coverage levels required to achieve the WHO goals. We find that for moderate prevalence regions, regardless of the burden of infection in adults, treating SAC only may achieve the WHO goals. However, for high prevalence regions with a high burden of infection in adults, adult treatment is required to meet the WHO goals. Hence, we show that the optimal treatment strategy for a defined region requires consideration of the burden of infection in adults as it cannot be based solely on the prevalence of infection in SAC. Although past epidemiological data have informed mathematical models for the transmission and control of schistosome infections, more accurate and detailed data are required from M&E programmes to accurately determine the optimal treatment strategy for a defined region. We highlight the importance of collecting prevalence and intensity of infection data from a broader age-range, specifically the inclusion of adult data at baseline (prior to treatment) and throughout the treatment programme if possible, rather than SAC only, to accurately determine the treatment strategy for a defined region. Furthermore, we discuss additional epidemiological data, such as individual longitudinal adherence to treatment, that should ideally be collected in M&E programmes., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: RMA is a Non-Executive Director of GlaxoSmithKline (GSK). GSK played no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The other authors have no competing interests.

The current World Health Organization strategy to address soil-transmitted helminth (STH) infections in children is based on morbidity control through routine deworming of school and pre-school aged children. However, given that transmission continues to occur as a result of persistent reservoirs of infection in untreated individuals (including adults) and in the environment, in many settings such a strategy will need to be continued for very extended periods of time, or until social, economic and environmental conditions result in interruption of transmission. As a result, there is currently much discussion surrounding the possibility of accelerating the interruption of transmission using alternative strategies of mass drug administration (MDA). However, the feasibility of achieving transmission interruption using MDA remains uncertain due to challenges in sustaining high MDA coverage levels across entire communities. The DeWorm3 trial, designed to test the feasibility of interrupting STH transmission, is currently ongoing. In DeWorm3, three years of high treatment coverage-indicated by mathematical models as necessary for breaking transmission-will be followed by two years of surveillance. Given the fast reinfection (bounce-back) rates of STH, a two year no treatment period is regarded as adequate to assess whether bounce-back or transmission interruption have occurred in a given location. In this study, we investigate if criteria to determine whether transmission interruption is unlikely can be defined at earlier timepoints. A stochastic, individual-based simulation model is employed to simulate core aspects of the DeWorm3 community-based cluster-randomized trial. This trial compares a control arm (annual treatment of children alone with MDA) with an intervention arm (community-wide biannual treatment with MDA). Simulations were run for each scenario for both Ascaris lumbricoides and hookworm (Necator americanus). A range of threshold prevalences measured at six months after the last round of MDA and the impact of MDA coverage levels were evaluated to see if the likelihood of bounce-back or elimination could reliably be assessed at that point, rather than after two years of subsequent surveillance. The analyses suggest that all clusters should be assessed for transmission interruption after two years of surveillance, unless transmission interruption can be effectively ruled out through evidence of low treatment coverage. Models suggest a tight range of homogenous prevalence estimates following high coverage MDA across clusters which do not allow for discrimination between bounce back or transmission interruption within 24 months following cessation of MDA., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: RMA is non-executive member of the board of GlaxoSmithKline (GSK). GlaxoSmithKline played no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This does not alter our adherence to all PLOS policies on sharing data and materials.

There is clear empirical evidence that environmental conditions can influence Ascaris spp. free-living stage development and host reinfection, but the impact of these differences on human infections, and interventions to control them, is variable. A new model framework reflecting four key stages of the A. lumbricoides life cycle, incorporating the effects of rainfall and temperature, is used to describe the level of infection in the human population alongside the environmental egg dynamics. Using data from South Korea and Nigeria, we conclude that settings with extreme fluctuations in rainfall or temperature could exhibit strong seasonal transmission patterns that may be partially masked by the longevity of A. lumbricoides infections in hosts; we go on to demonstrate how seasonally timed mass drug administration (MDA) could impact the outcomes of control strategies. For the South Korean setting the results predict a comparative decrease of 74.5% in mean worm days (the number of days the average individual spend infected with worms across a 12 month period) between the best and worst MDA timings after four years of annual treatment. The model found no significant seasonal effect on MDA in the Nigerian setting due to a narrower annual temperature range and no rainfall dependence. Our results suggest that seasonal variation in egg survival and maturation could be exploited to maximise the impact of MDA in certain settings.

Current control strategies for soil-transmitted helminths (STH) emphasize morbidity control through mass drug administration (MDA) targeting preschool- and school-age children, women of childbearing age and adults in certain high-risk occupations such as agricultural laborers or miners. This strategy is effective at reducing morbidity in those treated but, without massive economic development, it is unlikely it will interrupt transmission. MDA will therefore need to continue indefinitely to maintain benefit. Mathematical models suggest that transmission interruption may be achievable through MDA alone, provided that all age groups are targeted with high coverage. The DeWorm3 Project will test the feasibility of interrupting STH transmission using biannual MDA targeting all age groups. Study sites (population ≥80,000) have been identified in Benin, Malawi and India. Each site will be divided into 40 clusters, to be randomized 1:1 to three years of twice-annual community-wide MDA or standard-of-care MDA, typically annual school-based deworming. Community-wide MDA will be delivered door-to-door, while standard-of-care MDA will be delivered according to national guidelines. The primary outcome is transmission interruption of the STH species present at each site, defined as weighted cluster-level prevalence ≤2% by quantitative polymerase chain reaction (qPCR), 24 months after the final round of MDA. Secondary outcomes include the endline prevalence of STH, overall and by species, and the endline prevalence of STH among children under five as an indicator of incident infections. Secondary analyses will identify cluster-level factors associated with transmission interruption. Prevalence will be assessed using qPCR of stool samples collected from a random sample of cluster residents at baseline, six months after the final round of MDA and 24 months post-MDA. A smaller number of individuals in each cluster will be followed with annual sampling to monitor trends in prevalence and reinfection throughout the trial., Trial Registration: ClinicalTrials.gov NCT03014167.

In recent years, an increased focus has been placed upon the possibility of the elimination of soil-transmitted helminth (STH) transmission using various interventions including mass drug administration. The primary diagnostic tool recommended by the WHO is the detection of STH eggs in stool using the Kato-Katz (KK) method. However, detecting infected individuals using this method becomes increasingly difficult as the intensity of infection decreases. Newer techniques, such as qPCR, have been shown to have greater sensitivity than KK, especially at low prevalence. However, the impact of using qPCR on elimination thresholds is yet to be investigated. In this paper, we aim to quantify how the sensitivity of these two diagnostic tools affects the optimal prevalence threshold at which to declare the interruption of transmission with a defined level of confidence. A stochastic, individual-based STH transmission model was used in this study to simulate the transmission dynamics of Ascaris and hookworm. Data from a Kenyan deworming study were used to parameterize the diagnostic model which was based on egg detection probabilities. The positive and negative predictive values (PPV and NPV) were calculated to assess the quality of any given threshold, with the optimal threshold value taken to be that at which both were maximised. The threshold prevalence of infection values for declaring elimination of Ascaris transmission were 6% and 12% for KK and qPCR respectively. For hookworm, these threshold values are lower at 0.5% and 2% respectively. Diagnostic tests with greater sensitivity are becoming increasingly important as we approach the elimination of STH transmission in some regions of the world. For declaring the elimination of transmission, using qPCR to diagnose STH infection results in the definition of a higher prevalence, than when KK is used.

Background: There is an increased focus on whether mass drug administration (MDA) programmes alone can interrupt the transmission of soil-transmitted helminths (STH). Mathematical models can be used to model these interventions and are increasingly being implemented to inform investigators about expected trial outcome and the choice of optimum study design. One key factor is the choice of threshold for detecting elimination. However, there are currently no thresholds defined for STH regarding breaking transmission., Methods: We develop a simulation of an elimination study, based on the DeWorm3 project, using an individual-based stochastic disease transmission model in conjunction with models of MDA, sampling, diagnostics and the construction of study clusters. The simulation is then used to analyse the relationship between the study end-point elimination threshold and whether elimination is achieved in the long term within the model. We analyse the quality of a range of statistics in terms of the positive predictive values (PPV) and how they depend on a range of covariates, including threshold values, baseline prevalence, measurement time point and how clusters are constructed., Results: End-point infection prevalence performs well in discriminating between villages that achieve interruption of transmission and those that do not, although the quality of the threshold is sensitive to baseline prevalence and threshold value. Optimal post-treatment prevalence threshold value for determining elimination is in the range 2% or less when the baseline prevalence range is broad. For multiple clusters of communities, both the probability of elimination and the ability of thresholds to detect it are strongly dependent on the size of the cluster and the size distribution of the constituent communities. Number of communities in a cluster is a key indicator of probability of elimination and PPV. Extending the time, post-study endpoint, at which the threshold statistic is measured improves PPV value in discriminating between eliminating clusters and those that bounce back., Conclusions: The probability of elimination and PPV are very sensitive to baseline prevalence for individual communities. However, most studies and programmes are constructed on the basis of clusters. Since elimination occurs within smaller population sub-units, the construction of clusters introduces new sensitivities for elimination threshold values to cluster size and the underlying population structure. Study simulation offers an opportunity to investigate key sources of sensitivity for elimination studies and programme designs in advance and to tailor interventions to prevailing local or national conditions.

Background: There is currently no vaccine available to protect humans against infection with the schistosome digenean parasites, although candidate formulations for Schistosoma mansoni are under trial in animal models, including rodents and primates. Current strategies for the control of infection are based on mass drug administration (MDA) targeted at school-aged children of age 5 to 14 years. This approach is unlikely to eliminate exposure to infection except in settings with very low levels of transmission., Methods: A deterministic mathematical model for the transmission dynamics of the parasite is described and employed to investigate community level outcomes. The model is defined to encompass two different delivery strategies for the vaccination of the population, namely, infant (cohort) and mass vaccination. However, in this paper the focus is on vaccination delivered in a cohort immunisation programme where infants are immunised within the first year of life before acquiring infection. An analysis of the parasite's transmission dynamics following the administration of a partially protective vaccine is presented. The vaccine acts on parasite mortality, fecundity or/and establishment., Results: A vaccine with an efficacy of over 60% can interrupt transmission in low and moderate transmission settings. In higher transmission intensity areas, greater efficacy or higher infant vaccination coverage is required. Candidate vaccines that act either on parasite mortality, fecundity or establishment within the human host, can be similarly effective. In all cases, however, the duration of protection is important. The community level impact of vaccines with all modes of action, declines if vaccine protection is of a very short duration. However, durations of protection of 5-10 years or more are sufficient, with high coverage and efficacy levels, to halt transmission. The time taken to break transmission may be 18 years or more after the start of the cohort vaccination, depending on the intensity of the transmission in a defined location., Conclusions: The analyses provide support for the proposition that even a partially efficacious vaccine could be of great value in reducing the burden of schistosome infections in endemic regions and hopefully could provide a template for the elimination of parasite transmission.

Background: Systematic non-compliance to chemotherapeutic treatment among a portion of the eligible population is thought to be a major obstacle to the elimination of helminth infections by mass drug administration (MDA). MDA for helminths is repeated at defined intervals such as yearly or every 2 years, as a consequence of the inability of the human host to develop fully protective immunity to reinfection. As such, how an individual complies to these repeated rounds of MDA can have a significant impact on parasite transmission. The importance of this factor is poorly understood at present. Few epidemiological studies have examined longitudinal trends in compliance in the many communities in areas of endemic helminth infection that are undergoing MDA. Reducing systematic non-compliance will obviously increase the number of individuals treated, but it may also alter the dynamics of parasite transmission., Methods: Here we develop an individual-based stochastic model of helminth transmission and MDA treatment to investigate how different patterns of compliance influence the impact of MDA for two groups of helminths, the soil transmitted nematode infections and the schistosome parasites. We study the effect of several alternative treatment and compliance patterns on the dynamics of transmission., Results: We find that the impact of different compliance patterns, ranging from random treatment at each round of chemotherapy to systematic non-compliance by a proportion of the population, is very dependent on both transmission intensity in a defined setting and the type of infection that the treatment is targeted at. Systematic non-compliance has a greater impact on the potential for elimination of Schistosoma mansoni transmission by intensive MDA, than it does on Ascaris lumbricoides., Conclusions: We discuss the implications of our findings for the prioritisation of resources in MDA programmes and for monitoring and evaluation programme design. The key message generated by the analyses is that great care must be taken to record individual longitudinal patterns of compliance at each round of MDA as opposed to just recording overall coverage.

Background: Current WHO guidelines for soil-transmitted helminth (STH) control focus on mass drug administration (MDA) targeting preschool-aged (pre-SAC) and school-aged children (SAC), with the goal of eliminating STH as a public health problem amongst children. Recently, attention and funding has turned towards the question whether MDA alone can result in the interruption of transmission for STH. The lymphatic filariasis (LF) elimination programme, have been successful in reaching whole communities. There is the possibility of building upon the infrastructure created for these LF-programmes to enhance the control of STH. Using hookworm as an example, we explore what further MDA coverage might be required to induce interruption of transmission for hookworm in the wake of a successful LF programme., Results: Analyses based on the model of STH transmission and MDA impact predict the effects of previous LF control by MDA over five years, on a defined baseline prevalence of STH in an area with a defined transmission intensity (the basic reproductive number R 0 ). If the LF MDA programme achieved a high coverage (70, 70 and 60% for pre-SAC, SAC and adults, respectively) we expect that in communities with a hookworm prevalence of 15%, after 5 years of LF control, the intrinsic R 0 value in that setting is 2.47. By contrast, if lower LF coverages were achieved (40, 40 and 30% for pre-SAC, SAC and adults, respectively), with the same prevalence of 15% at baseline (after 5 years of LF MDA), the intrinsic hookworm R 0 value is predicted to be 1.67. The intrinsic R 0 value has a large effect on the expected successes of follow-up STH programmes post LF MDA. Consequently, the outcomes of identical programmes may differ between these communities., Conclusion: To design the optimal MDA intervention to eliminate STH infections, it is vital to have information on historical MDA programmes and baseline prevalence to estimate the intrinsic transmission intensity for the defined setting (R 0 ). The baseline prevalence alone is not sufficient to inform policy for the control of STH, post cessation of LF MDA, since this will be highly dependent on the intensity and effectiveness of past programmes and the intrinsic transmission intensity of the dominant STH species in any given setting.

Background: The majority of schistosomiasis control programmes focus on targeting school-aged children. Expanding the use of community-wide mass treatment to reach more adults is under consideration. However, it should be noted that this would require a further increase in programmatic resources, international aid, and commitment for the provision of praziquantel. Consequently, it is important to understand (i) where a change of strategy would have the greatest benefit, and (ii) how generalisable the conclusions of field trials and analytical studies based on mathematical models investigating the impact of community-wide mass treatment, are to a broad range of settings., Methods: In this paper, we employ a previously described deterministic fully age-structured schistosomiasis transmission model and evaluate the benefit of community-wide mass treatment both in terms of controlling morbidity and eliminating transmission for Schistosoma mansoni, across a wide range of epidemiological settings and programmatic scenarios. This included variation in the baseline relative worm pre-control burden in adults, the overall level of transmission in defined settings, choice of effectiveness metric (basing morbidity calculations on prevalence or intensity), the level of school enrolment and treatment compliance., Results: Community-wide mass treatment was found to be more effective for controlling the transmission of schistosome parasites than using a school-based programme only targeting school-aged children. However, in the context of morbidity control, the potential benefit of switching to community-wide mass treatment was highly variable across the different scenarios analysed. In contrast, for areas where the goal is to eliminate transmission, the projected benefit of community-wide mass treatment was more consistent., Conclusion: Whether community-wide mass treatment is appropriate will depend on the local epidemiological setting (i.e. the relative pre-control burden in adults and transmission intensity), and whether the goal is morbidity control or eliminating transmission. This has important implications regarding the generalisability of cost-effectiveness analyses of schistosomiasis interventions. Our results indicate that areas with poor school-enrolment/coverage could benefit more from community-wide treatment of praziquantel and should potentially be prioritised for any change in strategy. This work highlights the importance of not over-generalising conclusions and policy in this area, but of basing decisions on high quality epidemiological data and quantitative analyses of the impact of interventions in a range of settings.

The predictions of two mathematical models describing the transmission dynamics of schistosome infection and the impact of mass drug administration are compared. The models differ in their description of the dynamics of the parasites within the host population and in their representation of the stages of the parasite lifecycle outside of the host. Key parameters are estimated from data collected in northern Mozambique from 2011 to 2015. This type of data set is valuable for model validation as treatment prior to the study was minimal. Predictions from both models are compared with each other and with epidemiological observations. Both models have difficulty matching both the intensity and prevalence of disease in the datasets and are only partially successful at predicting the impact of treatment. The models also differ from each other in their predictions, both quantitatively and qualitatively, of the long-term impact of 10 years' school-based mass drug administration. We trace the dynamical differences back to basic assumptions about worm aggregation, force of infection and the dynamics of the parasite in the snail population in the two models and suggest data which could discriminate between them. We also discuss limitations with the datasets used and ways in which data collection could be improved., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

The predictions of two mathematical models of the transmission dynamics of Ascaris lumbricoides and hookworm infection and the impact of mass drug administration (MDA) are compared, using data from India. One model has an age structured partial differential equation (PDE) deterministic framework for the distribution of parasite numbers per host and sexual mating. The second model is an individual-based stochastic model. Baseline data acquired prior to treatment are used to estimate key transmission parameters, and forward projections are made, given the known MDA population coverage. Predictions are compared with observed post-treatment epidemiological patterns. The two models could equally well predict the short-term impact of deworming on A. lumbricoides and hookworm infection levels, despite being fitted to different subsets and/or summary statistics of the data. As such, the outcomes give confidence in their use as aids to policy formulation for the use of PCT to control A. lumbricoides and hookworm infection. The models further largely agree in a qualitative sense on the added benefit of semi-annual vs. annual deworming and targeting of the entire population vs. only children, as well as the potential for interruption of transmission. Further, this study also illustrates that long-term predictions are sensitive to modelling assumptions about which age groups contribute most to transmission, which depends on human demography and age-patterns in exposure and contribution to the environmental reservoir of infection, the latter being notoriously difficult to empirically quantify., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Soil-transmitted helminth (STH) infections are predominately controlled by providing children with preventive chemotherapy with either albendazole or mebendazole. However, neither has a high efficacy against Trichuris trichiura . This low efficacy limits the overall effectiveness of the current STH control programmes against T. trichiura . It has been demonstrated that co-administering ivermectin with albendazole or mebendazole significantly increases the efficacy of current treatments, which may increase the overall effectiveness of control programmes., Methods: Using a STH transmission mathematical model, we evaluated the potential impact of co-administering ivermectin with albendazole or mebendazole to treat T. trichiura within a preventive chemotherapy programme targeting children (2-15 year olds). We evaluated the impact in terms of reduction in prevalent infections, mean worm burden, and prevalence of heavy infections., Results: Although the current treatment strategy reduced T. trichiura worm burden and prevalence of heavy infections, due to their poor efficacy the long term impact of preventive chemotherapy for children was smaller compared to the other STH. Co-administering ivermectin increased the projected impact of the preventive chemotherapy programme in terms of all three of the explored metrics, practically in high transmission settings. Furthermore, ivermectin co-administration greatly increased the feasibility of and timeframe for breaking transmission., Conclusions: Co-administering ivermectin notably increased the projected impact of preventive chemotherapy in high transmission settings and increased the feasibility for breaking transmission. This has important implications for control programmes, some of which may be shifting focus from morbidity control to interruption of transmission, and some of which may be logistically unable to provide preventive chemotherapy twice a year as recommended. However, the benefit of co-administering ivermectin is limited by the fact that 2-5 year olds are often ineligible to receive treatment.

Background: The WHO treatment guidelines for the soil-transmitted helminths (STH) focus on targeting children for the control of morbidity induced by heavy infections. However, unlike the other STHs, the majority of hookworm infections are harboured by adults. This untreated burden may have important implications for controlling both hookworm's morbidity and transmission. This is particularly significant in the context of the increased interest in investigating STH elimination strategies., Methods: We used a deterministic STH transmission model and parameter estimates derived from field epidemiological studies to evaluate the impact of child-targeted (2-14 year olds) versus community-wide treatment against hookworm in terms of preventing morbidity and the timeframe for breaking transmission. Furthermore, we investigated how mass treatment may influence the long-term programmatic costs of preventive chemotherapy for hookworm., Results: The model projected that a large proportion of the overall morbidity due to hookworm was unaffected by the current child-targeted strategy. Furthermore, driving worm burdens to levels low enough to potentially break transmission was only possible when using community-wide treatment. Due to these projected reductions in programme duration, it was possible for community-wide treatment to generate cost savings - even if it notably increases the annual distribution costs., Conclusions: Community-wide treatment is notably more cost-effective for controlling hookworm's morbidity and transmission than the current child-targeted strategies and could even be cost-saving in many settings in the longer term. These calculations suggest that it is not optimum to treat using the same treatment strategies as other STH. Hookworm morbidity and transmission control require community-wide treatment.

Background: It is the aim of the World Health Organisation to eliminate soil-transmitted helminths (STH) as a health problem in children. To this end, the goal is to increase anthelmintic treatment coverage for soil transmitted helminths to reach 75 % in pre-school aged and school aged children by 2020 in endemic countries. In this paper, we use mathematical models to investigate the impact of achieving this goal on the burdens of Ascaris lumbricoides, Trichuris trichuria and hookworm., Methods: We employ a deterministic fully age-structured model of STH transmission and mass drug administration to examine the changes in worm burden in response to the known and projected coverage trends in children up to 2020 and beyond. Parameters are estimated from worm expulsion data and age intensity profiles before treatment using maximum likelihood methods. Model validation is performed using reinfection studies for Ascaris and analyses are conducted to assess the sensitivity of the predicted outcomes to variation in parameter estimates including transmission intensity (R0), children's contributions to the pool of infective stages and drug coverage levels., Results: The impact of the required increase in coverage trends are quite different across the three species. Ascaris burdens are reduced dramatically by 2020 with elimination predicted within studied the setting a further 10 years. For Trichuris and hookworm, however, impact is more limited, due to issues of drug efficacy (Trichuris) and distribution of worms in the population (hookworm). Sensitivity analysis indicates that results are largely robust. However, validation against Ascaris data indicates that assumptions concerning re-infection among children may have to be revised., Conclusions: The 2020 coverage target is predicted to have a major impact on Ascaris levels by 2020. However, there is evidence from model validation that Ascaris in children is more resilient to treatment than currently assumed in the model. Broader coverage across all age classes is required to break transmission for hookworm and alternative dual drug treatment approaches are needed for Trichuris.

Background: Schistosomiasis is endemic in 54 countries, but has one of the lowest coverages by mass drug administration of all helminth diseases. However, with increasing drug availability through donation, the World Health Organisation has set a goal of increasing coverage to 75 % of at-risk children in endemic countries and elimination in some regions. In this paper, we assess the impact on schistosomiasis of the WHO goals in terms of control and elimination., Methods: We use an age-structured deterministic model of schistosome transmission in a human community and the effect of mass drug administration. The model is fitted to baseline data from a longitudinal re-infection study in Kenya and validated against the subsequent re-infection data. We examine the impact on host worm burden of the current treatment trend, extrapolated to meet the WHO goals, and its sensitivity to uncertainty in important parameters. We assess the feasibility of achieving elimination., Results: Model results show that the current treatment trend, extrapolated to the WHO goals, is able to greatly reduce host worm burdens. If coverage is continued at the same level beyond 2020, elimination is possible for low to moderate transmission settings, where transmission intensity is defined by the basic reproduction number, R0. Low levels of adult coverage have a significant impact on worm burden in all settings. Model validation against the re-infection survey demonstrates that the age-structured model is able to match post-treatment data well in terms of egg output, but that some details of re-infection among school children and young adults are not currently well represented., Conclusions: Our work suggests that the current WHO treatment goals should be successful in bringing about a major reduction in schistosome infection in treated communities. If continued over a 15 year period, they are likely to result in elimination, at least in areas with lower transmission.

Introduction: In recent years, an unprecedented emphasis has been given to the control of neglected tropical diseases, including soil-transmitted helminths (STHs). The mainstay of STH control is school-based deworming (SBD), but mathematical modelling has shown that in all but very low transmission settings, SBD is unlikely to interrupt transmission, and that new treatment strategies are required. This study seeks to answer the question: is it possible to interrupt the transmission of STH, and, if so, what is the most cost-effective treatment strategy and delivery system to achieve this goal?, Methods and Analysis: Two cluster randomised trials are being implemented in contrasting settings in Kenya. The interventions are annual mass anthelmintic treatment delivered to preschool- and school-aged children, as part of a national SBD programme, or to entire communities, delivered by community health workers. Allocation to study group is by cluster, using predefined units used in public health provision-termed community units (CUs). CUs are randomised to one of three groups: receiving either (1) annual SBD; (2) annual community-based deworming (CBD); or (3) biannual CBD. The primary outcome measure is the prevalence of hookworm infection, assessed by four cross-sectional surveys. Secondary outcomes are prevalence of Ascaris lumbricoides and Trichuris trichiura, intensity of species infections and treatment coverage. Costs and cost-effectiveness will be evaluated. Among a random subsample of participants, worm burden and proportion of unfertilised eggs will be assessed longitudinally. A nested process evaluation, using semistructured interviews, focus group discussions and a stakeholder analysis, will investigate the community acceptability, feasibility and scale-up of each delivery system., Ethics and Dissemination: Study protocols have been reviewed and approved by the ethics committees of the Kenya Medical Research Institute and National Ethics Review Committee, and London School of Hygiene and Tropical Medicine. The study has a dedicated web site., Trial Registration Number: NCT02397772., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: In this time of rapidly expanding mass drug administration (MDA) coverage and the new commitments for soil-transmitted helminth (STH) control, it is essential that resources are allocated in an efficient manner to have the greatest impact. However, many questions remain regarding how best to deliver STH treatment programmes; these include which age-groups should be targeted and how often. To perform further analyses to investigate what the most cost-effective control strategies are in different settings, accurate cost data for targeting different age groups at different treatment frequencies (in a range of settings) are essential., Methods: Using the electronic databases PubMed, MEDLINE, and ISI Web of Knowledge, we perform a systematic review of costing studies and cost-effectiveness evaluations for potential STH treatment strategies. We use this review to highlight research gaps and outline the key future research needs., Results: We identified 29 studies reporting costs of STH treatment and 17 studies that investigated its cost-effectiveness. The majority of these pertained to programmes only targeting school-aged children (SAC), with relatively few studies investigating alternative preventive chemotherapy (PCT) treatment strategies. The methods of cost data collection, analysis and reporting were highly variable among the different studies. Only four of the costing studies were found to have high applicability for use in forthcoming economic evaluations. There are also very few studies quantifying the costs of increasing the treatment frequency., Conclusions: The absence of cost data and inconsistencies in the collection and analysis methods constitutes a major research gap for STH control. Detailed and accurate costs of targeting different age groups or increasing treatment frequency will be essential to formulate cost-effective public health policy. Defining the most cost-effective control strategies in different settings is of high significance during this period of expanding MDA coverage and new resource commitments for STH control.

Many of the challenges which face modellers of directly transmitted pathogens also arise when modelling the epidemiology of pathogens with indirect transmission--whether through environmental stages, vectors, intermediate hosts or multiple hosts. In particular, understanding the roles of different hosts, how to measure contact and infection patterns, heterogeneities in contact rates, and the dynamics close to elimination are all relevant challenges, regardless of the mode of transmission. However, there remain a number of challenges that are specific and unique to modelling vector-borne diseases and macroparasites. Moreover, many of the neglected tropical diseases which are currently targeted for control and elimination are vector-borne, macroparasitic, or both, and so this article includes challenges which will assist in accelerating the control of these high-burden diseases. Here, we discuss the challenges of indirect measures of infection in humans, whether through vectors or transmission life stages and in estimating the contribution of different host groups to transmission. We also discuss the issues of "evolution-proof" interventions against vector-borne disease., (Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Amongst the world's poorest populations, availability of anthelmintic treatments for the control of soil transmitted helminths (STH) by mass or targeted chemotherapy has increased dramatically in recent years. However, the design of community based treatment programmes to achieve the greatest impact on transmission is still open to debate. Questions include: who should be treated, how often should they be treated, how long should treatment be continued for?, Methods: Simulation and analysis of a dynamic transmission model and novel data analyses suggest refinements of the World Health Organization guidelines for the community based treatment of STH., Results: This analysis shows that treatment levels and frequency must be much higher, and the breadth of coverage across age classes broader than is typically the current practice, if transmission is to be interrupted by mass chemotherapy alone., Conclusions: When planning interventions to reduce transmission, rather than purely to reduce morbidity, current school-based interventions are unlikely to be enough to achieve the desired results.

Background: The London Declaration on neglected tropical diseases was based in part on a new World Health Organization roadmap to "sustain, expand and extend drug access programmes to ensure the necessary supply of drugs and other interventions to help control by 2020". Large drug donations from the pharmaceutical industry form the backbone to this aim, especially for soil-transmitted helminths (STHs) raising the question of how best to use these resources. Deworming for STHs is often targeted at school children because they are at greatest risk of morbidity and because it is remarkably cost-effective. However, the impact of school-based deworming on transmission in the wider community remains unclear., Methods: We first estimate the proportion of parasites targeted by school-based deworming using demography, school enrolment, and data from a small number of example settings where age-specific intensity of infection (either worms or eggs) has been measured for all ages. We also use transmission models to investigate the potential impact of this coverage on transmission for different mixing scenarios., Principal Findings: In the example settings <30% of the population are 5 to <15 years old. Combining this demography with the infection age-intensity profile we estimate that in one setting school children output as little as 15% of hookworm eggs, whereas in another setting they harbour up to 50% of Ascaris lumbricoides worms (the highest proportion of parasites for our examples). In addition, it is estimated that from 40-70% of these children are enrolled at school., Conclusions: These estimates suggest that, whilst school-based programmes have many important benefits, the proportion of infective stages targeted by school-based deworming may be limited, particularly where hookworm predominates. We discuss the consequences for transmission for a range of scenarios, including when infective stages deposited by children are more likely to contribute to transmission than those from adults.

Scrapie is a fatal transmissible spongiform encephalopathy (TSE) of sheep, endemic in the UK for centuries. Interest in the disease has been heightened over the last decade by the possibility of the related BSE being transmissible to and between sheep and a range of control interventions has been proposed and implemented. In this paper, we examined the effect of these policies and their components on observed case rate, susceptible allele frequency and R0 within the framework of a large simulation model of the British sheep population and its breeding and trading structure. We compared interventions with the natural fade-out of scrapie in the population through loss of susceptible genotypes in the absence of control. We compare the results of interventions with the natural course of the scrapie epidemic. Our model suggested that scrapie will persist in the national flock for 300-400 years with the impact on gene frequencies confined largely to high case-rate breeds, such as Shetland and Swaledale. We found the National Scrapie Plan (NSP) to be the most effective in terms of the removal of both susceptible genotypes and scrapie from the population. Complete eradication of scrapie can be achieved within 32 years (95% CI 23-43 years). The Compulsory Scrapie Flock Scheme (CSFS) is as effective as the NSP in reducing the observed case rate but has a limited impact on the frequencies of susceptible genotypes in the population overall. In combination with the NSP, eradication of scrapie is achieved >10 years faster. Of the components of the CSFS, the breeding and culling aspects are each almost as effective as the full policy, with trading restrictions contributing little. We have speculated on the impact of control measures on the possibility BSE infection within the national flock by examining their effect on flock R0 for BSE across different breeds.

SUMMARYScrapie is a fatal neurological disease of sheep which is endemic in the United Kingdom. It is one of the family of transmissible spongiform encephalopathies (TSEs) that includes BSE. In this paper, we developed a micro-simulation model for scrapie in the UK sheep population, incorporating the genetic and structural diversity of the population and infectious contact between flocks through trading. The simulation was fitted to epidemiological data from a range of sources. We found a detection/reporting probability of 16% (95% CI 12-17) for animals dying of scrapie. Prevalence of infected animals in the population was about 0.15%. Infected individuals were found in 9% of flocks overall, rising to 60% in Shetland and 75% in Swaledale flocks. Mean values of R0 for flocks varied with breed from 2.43 (Shetland) to 0.21 (Suffolk). We also examined the possible long-term persistence of scrapie in the UK flock in the absence of any intervention.

We use a spatially explicit, stochastic model to analyse the effectiveness of different scales of local control strategies in containing the long-term, multi-seasonal spread of a crop disease through a dynamically changing population of susceptible crops in which there is cryptic infection. The model distinguishes between susceptible, infested and symptomatic fields. It is motivated by rhizomania disease on sugar beet in the UK as an exemplar of a spatially structured and partially asymptomatic epidemic. Our results show the importance of matching the scales of local control strategies to prevent intensification and regional spread of disease with the inherent temporal and spatial scales of an epidemic. A simple field-scale containment strategy, whereby the susceptible crop is no longer grown on fields showing symptoms, fails for this system with cryptic infection because the locally applied control lags behind the epidemic. A farm-scale strategy, whereby growers respond to the disease status of neighbouring farms by transferring their quota for sugar beet to farmers in regions of reduced risk, succeeds. We conclude that a soil-borne pathogen such as rhizomania could be managed by movement of susceptible crops in the landscape using a strategy that matches the temporal and spatial scales of the epidemic and which take account of risk aversion among growers. We show some parallels and differences in effectiveness between a 'culling' strategy involving crop removal around emerging foci and the local deployment of partially resistant varieties that reduce amplification and transmission of inoculum. Some relationships between the control of plant and livestock diseases are briefly discussed.

The Australian population is becoming progressively older, placing significant pressure on both the supply of supported accommodation and health services. Collaboration between general practitioners and nurse practitioners over the care of people living in residential aged care facilities has the potential to promote continuity of care, decrease hospitalisations and readmissions, enhance patient satisfaction, reduce costs, enhance working relations between medicine and nursing, and improve residents' access to care. It will require improved communication and the overcoming of several attitudinal and organisational barriers.

ABSTRACT Rhizomania disease of sugar beet represents a major economic threat to the sugar industry in the United Kingdom. Here we use the UK rhizomania epidemic as an exemplar of a range of highly infectious spatially heterogeneous diseases. Using a spatially explicit stochastic model, we investigated the efficacy of a spectrum of possible control strategies, both locally reactive and national in character. These include the use of novel cultivars of beet with different responses to infection, changes in cultivation practice, and reactive containment policies at the farm scale. We show that strictly local responses, including a containment policy similar to that initially implemented in the United Kingdom in response to the disease, are largely ineffective in slowing the spread because they fail to match the natural scale of the epidemic. Larger spatial-scale processes are considerably more successful. We conclude that epidemics have intrinsic temporal and spatial scales that must be matched by any control strategy if it is to be both effective and efficient. We have generated probability distributions for the proportion of farms symptomatic. Over the course of the epidemic, such distributions develop a bimodality that we hypothesize to correspond to the matching of spatial heterogeneity in the susceptible population to the intrinsic scales of the epidemic.

Fluctuations in the natural environment introduce variability into the biological systems that exist within them. In this paper, we develop a model for the influence of random fluctuations in the environment on a simple epidemiological system. The model describes the infection of a dynamic host population by an environmentally sensitive pathogen and is based on the infection of sugar beet plants by the endoparasitic slime-mold vector Polymyxa betae. The infection process is switched on only when the temperature is above a critical value. We discuss some of the problems inherent in modeling such a system and analyze the resulting model by using asymptotic techniques to generate closed-form solutions for the mean and variance of the net amount of new inoculum produced within a season. In this way, the variance of temperature profile can be linked with that of the inoculum produced in a season and hence the risk of disease. We also examine the connection between the model developed in this paper and discrete Markov-chain models for weather.