register interest

Déirdre Hollingsworth

Research Area: Global Health
Technology Exchange: Bioinformatics and Computational biology
Scientific Themes: Tropical Medicine & Global Health and Immunology & Infectious Disease

Deirdre is an infectious disease epidemiologist who uses mathematical models and statistical analyses to study the evolution and transmission dynamics of infectious diseases with the aim of informing the design of more effective control interventions. She is particularly interested in neglected tropical diseases, a group of diseases which cause suffering amongst the poorest populations of the world. She leads the NTD Modelling Consortium, an international network of neglected tropical disease modellers. 

Her research foci are lymphatic filariasis, visceral leishmaniasis and a group of intestinal worms (soil transmitted helminths or STHs) which affect a large number of children and adults in low income settings. She has ongoing interests in the transmission and evolution of HIV in both Africa and European/North American settings as well as malaria and influenza.

Name Department Institution Country
Wirichada Pan-ngum Tropical Medicine Oxford University, Bangkok Thailand
Pareek M, Eborall HC, Wobi F, Ellis KS, Kontopantelis E, Zhang F, Baggaley R, Hollingsworth TD, Baines D, Patel H et al. 2019. Community-based testing of migrants for infectious diseases (COMBAT-ID): impact, acceptability and cost-effectiveness of identifying infectious diseases among migrants in primary care: protocol for an interrupted time-series, qualitative and health economic analysis. BMJ Open, 9 (3), pp. e029188. | Show Abstract | Read more

BACKGROUND: Migration is a major global driver of population change. Certain migrants may be at increased risk of infectious diseases, including tuberculosis (TB), HIV, hepatitis B and hepatitis C, and have poorer outcomes. Early diagnosis and management of these infections can reduce morbidity, mortality and onward transmission and is supported by national guidelines. To date, screening initiatives have been sporadic and focused on individual diseases; systematic routine testing of migrant groups for multiple infections is rarely undertaken and its impact is unknown. We describe the protocol for the evaluation of acceptability, effectiveness and cost-effectiveness of an integrated approach to screening migrants for a range of infectious diseases in primary care. METHODS AND ANALYSIS: We will conduct a mixed-methods study which includes an observational cohort with interrupted time-series analysis before and after the introduction of routine screening of migrants for infectious diseases (latent TB, HIV, hepatitis B and hepatitis C) when first registering with primary care within Leicester, UK. We will assess trends in the monthly number and rate of testing and diagnosis for latent TB, HIV, hepatitis B and hepatitis C to determine the effect of the policy change using segmented regression analyses at monthly time-points. Concurrently, we will undertake an integrated qualitative sub-study to understand the views of migrants and healthcare professionals to the new testing policy in primary care. Finally, we will evaluate the cost-effectiveness of combined infection testing for migrants in primary care. ETHICS AND DISSEMINATION: The study has received HRA and NHS approvals for both the interrupted time-series analysis (16/SC/0127) and the qualitative sub-study (16/EM/0159). For the interrupted time-series analysis we will only use fully anonymised data. For the qualitative sub-study, we will gain written, informed, consent. Dissemination of the results will be through local and national meetings/conferences as well as publications in peer-reviewed journals.

Davis C, Hollingsworth D, Caudron Q, Irvine M. 2019. The use of mixture-density networks in the emulation of complex epidemiological individual-based models | Show Abstract | Read more

Complex, highly computational, individual-based models are abundant in epidemiology. For epidemics such as macro-parasitic diseases, detailed modelling of human behaviour and pathogen life-cycle are required in order to produce accurate results. This can often lead to models that are computationally-expensive to analyse and perform model fitting, and often require many simulation runs in order to build up sufficient statistics. Emulation can provide a more computationally-efficient output of the individual-based model, by approximating it using a statistical model. Previous work has used Gaussian processes in order to achieve this, but these can not deal with multi-modal, heavy-tailed, or discrete distributions. Here, we introduce the concept of a mixture density network (MDN) in its application in the emulation of epidemiological models. MDNs incorporate both a mixture model and a neural network to provide a flexible tool for emulating a variety of models and outputs. We develop an MDN emulation methodology and demonstrate its use on a number of simple models incorporating both normal, gamma and beta distribution outputs. We then explore its use on the stochastic SIR model to predict the final size distribution and infection dynamics. MDNs have the potential to faithfully reproduce multiple outputs of an individual-based model and allow for rapid analysis from a range of users. As such, an open-access library of the method has been released alongside this manuscript.

Hope EC, Crump RE, Hollingsworth TD, Smieszek T, Robotham JV, Pouwels KB. 2018. Identifying English Practices that Are High Antibiotic Prescribers Accounting for Comorbidities and Other Legitimate Medical Reasons for Variation. EClinicalMedicine, 6 pp. 36-41. | Show Abstract | Read more

Background: Seeing one's practice as a high antibiotic prescriber compared to general practices with similar patient populations can be one of the best motivators for change. Current comparisons are based on age-sex weighting of the practice population for expected prescribing rates (STAR-PU). Here, we investigate whether there is a need to additionally account for further potentially legitimate medical reasons for higher antibiotic prescribing. Methods: Publicly available data from 7376 general practices in England between April 2014 and March 2015 were used. We built two different negative binomial regression models to compare observed versus expected antibiotic dispensing levels per practice: one including comorbidities as covariates and another with the addition of smoking prevalence and deprivation. We compared the ranking of practices in terms of items prescribed per STAR-PU according to i) conventional STAR-PU methodology, ii) observed vs expected prescribing levels using the comorbidity model, and iii) observed vs expected prescribing levels using the full model. Findings: The median number of antibiotic items prescribed per practice per STAR-PU was 1.09 (25th-75th percentile, 0.92-1.25). 1133 practices (76.8% of 1476) were consistently identified as being in the top 20% of high antibiotic prescribers. However, some practices that would be classified as high prescribers using the current STAR-PU methodology would not be classified as high prescribers if comorbidity was accounted for (n = 269, 18.2%) and if additionally smoking prevalence and deprivation were accounted for (n = 312, 21.1%). Interpretation: Current age-sex weighted comparisons of antibiotic prescribing rates in England are fair for many, but not all practices. This new metric that accounts for legitimate medical reasons for higher antibiotic prescribing may have more credibility among general practitioners and, thus, more likely to be acted upon. Outstanding Questions: Findings of this study indicate that the antibiotic prescribing metric by which practices are measured (and need to implement interventions determined) may be inadequate, and therefore raises the question of how they should be measured. Substantial variation between practices remains after accounting for comorbidities, deprivation and smoking. There is a need for a better understanding of why such variation remains and, more importantly, what can be done to reduce it. While antibiotics are more frequently indicated in patients with comorbidities, it is unclear to what extent antibiotic prescribing can be lowered among that patient population and how this could be achieved.

Chapman LAC, Morgan ALK, Adams ER, Bern C, Medley GF, Hollingsworth TD. 2018. Age trends in asymptomatic and symptomatic Leishmania donovani infection in the Indian subcontinent: A review and analysis of data from diagnostic and epidemiological studies. PLoS Negl Trop Dis, 12 (12), pp. e0006803. | Show Abstract | Read more

BACKGROUND: Age patterns in asymptomatic and symptomatic infection with Leishmania donovani, the causative agent of visceral leishmaniasis (VL) in the Indian subcontinent (ISC), are currently poorly understood. Age-stratified serology and infection incidence have been used to assess transmission levels of other diseases, which suggests that they may also be of use for monitoring and targeting control programmes to achieve elimination of VL and should be included in VL transmission dynamic models. We therefore analysed available age-stratified data on both disease incidence and prevalence of immune markers with the aim of collating the currently available data, estimating rates of infection, and informing modelling and future data collection. METHODOLOGY/PRINCIPAL FINDINGS: A systematic literature search yielded 13 infection prevalence and 7 VL incidence studies meeting the inclusion criteria. Statistical tests were performed to identify trends by age, and according to diagnostic cut-off. Simple reversible catalytic models with age-independent and age-dependent infection rates were fitted to the prevalence data to estimate infection and reversion rates, and to test different hypotheses about the origin of variation in these rates. Most of the studies showed an increase in infection prevalence with age: from ≲10% seroprevalence (<20% Leishmanin skin test (LST) positivity) for 0-10-year-olds to >10% seroprevalence (>20% LST-positivity) for 30-40-year-olds, but overall prevalence varied considerably between studies. VL incidence was lower amongst 0-5-year-olds than older age groups in most studies; most showing a peak in incidence between ages 5 and 20. The age-independent catalytic model provided the best overall fit to the infection prevalence data, but the estimated rates for the less parsimonious age-dependent model were much closer to estimates from longitudinal studies, suggesting that infection rates may increase with age. CONCLUSIONS/SIGNIFICANCE: Age patterns in asymptomatic infection prevalence and VL incidence in the ISC vary considerably with geographical location and time period. The increase in infection prevalence with age and peaked age-VL-incidence distribution may be due to lower exposure to infectious sandfly bites in young children, but also suggest that acquired immunity to the parasite increases with age. However, poor standardisation of serological tests makes it difficult to compare data from different studies and draw firm conclusions about drivers of variation in observed age patterns.

Fowler AC, Hollingsworth TD. 2018. Correction to: The Dynamics of Ascaris lumbricoides Infections. Bull Math Biol, 80 (10), pp. 2787. | Show Abstract | Read more

In the original article, the second author's name was incorrect in the metadata. The given name is T. Déirdre, and the family name is Hollingsworth.

Pinsent A, Hollingsworth TD. 2018. Optimising sampling regimes and data collection to inform surveillance for trachoma control. PLoS Negl Trop Dis, 12 (10), pp. e0006531. | Show Abstract | Read more

It is estimated that 190 million individuals are at risk of blindness from trachoma, and that control by mass drug administration (MDA) is reducing this risk in many populations. Programs are monitored using prevalence of follicular trachoma disease (TF) in children. However, as programs progress to low prevalence there are challenges interpreting this indirect measure of infection. PCR and sero-surveillance are being considered as complementary tools to monitor low-level transmission, but there are questions on how they can be most effectively used. We use a previously-published, mathematical model to explore the dynamic relationship between TF and PCR throughout a control program and a sero-catalytic model to evaluate the utility of two cross-sectional sero-surveys for estimating sero-conversion rates. The simulations show that whilst PCR is more sensitive than TF at detecting infection, the probability of detecting at least one positive individual declines during an MDA program more quickly for PCR than for TF (for the same sample size). Towards the end of a program there is a moderate chance of a random sample showing both low PCR prevalence and higher TF prevalence, which may contribute to the lack of correlation observed in epidemiological studies. We also show that conducting two cross-sectional sero-surveys 10 years apart can provide more precise and accurate estimation of epidemiological parameters than a single survey, supporting previous findings that whilst serology holds great promise, multiple cross-sections from the same community are needed to generate the most valuable information about transmission. These results highlight that the quantitative dynamics of infection and disease should be included alongside the many logistical and practical factors to be considered in designing a monitoring and evaluation strategy at the operational research level, in order to help subsequently inform data collection for individual country programs. Whilst our simulations provide some insight, they also highlight that some level of longitudinal, individual-level data on reinfection and disease may be needed to monitor elimination progress.

Chapman LAC, Jewell CP, Spencer SEF, Pellis L, Datta S, Chowdhury R, Bern C, Medley GF, Hollingsworth TD. 2018. The role of case proximity in transmission of visceral leishmaniasis in a highly endemic village in Bangladesh. PLoS Negl Trop Dis, 12 (10), pp. e0006453. | Show Abstract | Read more

BACKGROUND: Visceral leishmaniasis (VL) is characterised by a high degree of spatial clustering at all scales, and this feature remains even with successful control measures. VL is targeted for elimination as a public health problem in the Indian subcontinent by 2020, and incidence has been falling rapidly since 2011. Current control is based on early diagnosis and treatment of clinical cases, and blanket indoor residual spraying of insecticide (IRS) in endemic villages to kill the sandfly vectors. Spatially targeting active case detection and/or IRS to higher risk areas would greatly reduce costs of control, but its effectiveness as a control strategy is unknown. The effectiveness depends on two key unknowns: how quickly transmission risk decreases with distance from a VL case and how much asymptomatically infected individuals contribute to transmission. METHODOLOGY/PRINCIPAL FINDINGS: To estimate these key parameters, a spatiotemporal transmission model for VL was developed and fitted to geo-located epidemiological data on 2494 individuals from a highly endemic village in Mymensingh, Bangladesh. A Bayesian inference framework that could account for the unknown infection times of the VL cases, and missing symptom onset and recovery times, was developed to perform the parameter estimation. The parameter estimates obtained suggest that, in a highly endemic setting, VL risk decreases relatively quickly with distance from a case-halving within 90m-and that VL cases contribute significantly more to transmission than asymptomatic individuals. CONCLUSIONS/SIGNIFICANCE: These results suggest that spatially-targeted interventions may be effective for limiting transmission. However, the extent to which spatial transmission patterns and the asymptomatic contribution vary with VL endemicity and over time is uncertain. In any event, interventions would need to be performed promptly and in a large radius (≥300m) around a new case to reduce transmission risk.

Michael E, Sharma S, Smith ME, Touloupou P, Giardina F, Prada JM, Stolk WA, Hollingsworth D, de Vlas SJ. 2018. Quantifying the value of surveillance data for improving model predictions of lymphatic filariasis elimination. PLoS Negl Trop Dis, 12 (10), pp. e0006674. | Show Abstract | Read more

BACKGROUND: Mathematical models are increasingly being used to evaluate strategies aiming to achieve the control or elimination of parasitic diseases. Recently, owing to growing realization that process-oriented models are useful for ecological forecasts only if the biological processes are well defined, attention has focused on data assimilation as a means to improve the predictive performance of these models. METHODOLOGY AND PRINCIPAL FINDINGS: We report on the development of an analytical framework to quantify the relative values of various longitudinal infection surveillance data collected in field sites undergoing mass drug administrations (MDAs) for calibrating three lymphatic filariasis (LF) models (EPIFIL, LYMFASIM, and TRANSFIL), and for improving their predictions of the required durations of drug interventions to achieve parasite elimination in endemic populations. The relative information contribution of site-specific data collected at the time points proposed by the WHO monitoring framework was evaluated using model-data updating procedures, and via calculations of the Shannon information index and weighted variances from the probability distributions of the estimated timelines to parasite extinction made by each model. Results show that data-informed models provided more precise forecasts of elimination timelines in each site compared to model-only simulations. Data streams that included year 5 post-MDA microfilariae (mf) survey data, however, reduced each model's uncertainty most compared to data streams containing only baseline and/or post-MDA 3 or longer-term mf survey data irrespective of MDA coverage, suggesting that data up to this monitoring point may be optimal for informing the present LF models. We show that the improvements observed in the predictive performance of the best data-informed models may be a function of temporal changes in inter-parameter interactions. Such best data-informed models may also produce more accurate predictions of the durations of drug interventions required to achieve parasite elimination. SIGNIFICANCE: Knowledge of relative information contributions of model only versus data-informed models is valuable for improving the usefulness of LF model predictions in management decision making, learning system dynamics, and for supporting the design of parasite monitoring programmes. The present results further pinpoint the crucial need for longitudinal infection surveillance data for enhancing the precision and accuracy of model predictions of the intervention durations required to achieve parasite elimination in an endemic location.

Lepper HC, Prada JM, Davis EL, Gunawardena SA, Hollingsworth TD. 2018. Complex interactions in soil-transmitted helminth co-infections from a cross-sectional study in Sri Lanka. Trans R Soc Trop Med Hyg, 112 (8), pp. 397-404. | Show Abstract | Read more

Background: Co-infection with multiple soil-transmitted helminth (STH) species is common in communities with a high STH prevalence. The life histories of STH species share important characteristics, particularly in the gut, and there is the potential for interaction, but evidence on whether interactions may be facilitating or antagonistic are limited. Methods: Data from a pretreatment cross-sectional survey of STH egg deposition in a tea plantation community in Sri Lanka were analysed to evaluate patterns of co-infection and changes in egg deposition. Results: There were positive associations between Trichuris trichiura (whipworm) and both Necator americanus (hookworm) and Ascaris lumbricoides (roundworm), but N. americanus and Ascaris were not associated. N. americanus and Ascaris infections had lower egg depositions when they were in single infections than when they were co-infecting. There was no clear evidence of a similar effect of co-infection in Trichuris egg deposition. Conclusions: Associations in prevalence and egg deposition in STH species may vary, possibly indicating that effects of co-infection are species dependent. We suggest that between-species interactions that differ by species could explain these results, but further research in different populations is needed to support this theory.

Dyson L, Hollingsworth TD. 2018. Diagnosing risk factors alongside mass drug administration using serial diagnostic tests-which test first? Trans R Soc Trop Med Hyg, 112 (7), pp. 342-348. | Show Abstract | Read more

Background: When tests are used in series to determine individual risk factors and infection status in a mass drug administration (MDA), the diagnostics, test order and subsequent treatment decisions (the testing algorithm) affect population-level treatment coverage and cost, but there is no existing framework for evaluating which algorithm optimizes any given outcome. Methods: We present a mathematical tool (with spreadsheet implementation) to analyse the effect of test ordering, illustrated using treatment for onchocerciasis in an area where high-burden Loa loa co-infections present a known risk factor. Results: The prevalence of the infection and risk factor have a non-linear impact on the optimal ordering of tests. Testing for the MDA infection first always leaves more infected people untreated but fewer people with the risk factor being misclassified. The cost of the treatment given to infected individuals with the risk factor does not affect which algorithm is more cost effective. Conclusions: For a given test and treat algorithm and its costs, the correct strategy depends on the expected prevalence. In most cases, when the apparent prevalence of the target infection is greater than the apparent prevalence of the risk factor, it is cheaper to do the risk factor test first, and vice versa.

Lietman TM, Pinsent A, Liu F, Deiner M, Hollingsworth TD, Porco TC. 2018. Models of Trachoma Transmission and Their Policy Implications: From Control to Elimination. Clin Infect Dis, 66 (suppl_4), pp. S275-S280. | Show Abstract | Read more

Despite great progress in eliminating trachoma from the majority of worldwide districts, trachoma control seems to have stalled in some endemic districts. Can mathematical models help suggest the way forward? We review specific achievements of models in trachoma control in the past. Models showed that, even with incomplete coverage, mass drug administration could eliminate disease through a spillover effect, somewhat analogous to how incomplete vaccine campaigns can eliminate disease through herd protection. Models also suggest that elimination can always be achieved if enough people are treated often enough with an effective enough drug. Other models supported the idea that targeting ages at highest risk or continued improvements in hygiene and sanitation can contribute meaningfully to trachoma control. Models of intensive targeting of a core group may point the way to final eradication even in areas with substantial transmission and within-community heterogeneity.

Stolk WA, Prada JM, Smith ME, Kontoroupis P, de Vos AS, Touloupou P, Irvine MA, Brown P, Subramanian S, Kloek M et al. 2018. Are Alternative Strategies Required to Accelerate the Global Elimination of Lymphatic Filariasis? Insights From Mathematical Models. Clin Infect Dis, 66 (suppl_4), pp. S260-S266. | Show Abstract | Read more

Background: With the 2020 target year for elimination of lymphatic filariasis (LF) approaching, there is an urgent need to assess how long mass drug administration (MDA) programs with annual ivermectin + albendazole (IA) or diethylcarbamazine + albendazole (DA) would still have to be continued, and how elimination can be accelerated. We addressed this using mathematical modeling. Methods: We used 3 structurally different mathematical models for LF transmission (EPIFIL, LYMFASIM, TRANSFIL) to simulate trends in microfilariae (mf) prevalence for a range of endemic settings, both for the current annual MDA strategy and alternative strategies, assessing the required duration to bring mf prevalence below the critical threshold of 1%. Results: Three annual MDA rounds with IA or DA and good coverage (≥65%) are sufficient to reach the threshold in settings that are currently at mf prevalence <4%, but the required duration increases with increasing mf prevalence. Switching to biannual MDA or employing triple-drug therapy (ivermectin, diethylcarbamazine, and albendazole [IDA]) could reduce program duration by about one-third. Optimization of coverage reduces the time to elimination and is particularly important for settings with a history of poorly implemented MDA (low coverage, high systematic noncompliance). Conclusions: Modeling suggests that, in several settings, current annual MDA strategies will be insufficient to achieve the 2020 LF elimination targets, and programs could consider policy adjustment to accelerate, guided by recent monitoring and evaluation data. Biannual treatment and IDA hold promise in reducing program duration, provided that coverage is good, but their efficacy remains to be confirmed by more extensive field studies.

Medley GF, Blok DJ, Crump RE, Hollingsworth TD, Galvani AP, Ndeffo-Mbah ML, Porco TC, Richardus JH. 2018. Policy Lessons From Quantitative Modeling of Leprosy. Clin Infect Dis, 66 (suppl_4), pp. S281-S285. | Show Abstract | Read more

Recent mathematical and statistical modeling of leprosy incidence data provides estimates of the current undiagnosed population and projections of diagnosed cases, as well as ongoing transmission. Furthermore, modeling studies have been used to evaluate the effectiveness of proposed intervention strategies, such as postleprosy exposure prophylaxis and novel diagnostics, relative to current approaches. Such modeling studies have revealed both a slow decline of new cases and a substantial pool of undiagnosed infections. These findings highlight the need for active case detection, particularly targeting leprosy foci, as well as for continued research into innovative accurate, rapid, and cost-effective diagnostics. As leprosy incidence continues to decline, targeted active case detection primarily in foci and connected areas will likely become increasingly important.

Le Rutte EA, Chapman LAC, Coffeng LE, Ruiz-Postigo JA, Olliaro PL, Adams ER, Hasker EC, Boelaert MC, Hollingsworth TD, Medley GF, de Vlas SJ. 2018. Policy Recommendations From Transmission Modeling for the Elimination of Visceral Leishmaniasis in the Indian Subcontinent. Clin Infect Dis, 66 (suppl_4), pp. S301-S308. | Show Abstract | Read more

Background: Visceral leishmaniasis (VL) has been targeted by the World Health Organization (WHO) and 5 countries in the Indian subcontinent for elimination as a public health problem. To achieve this target, the WHO has developed guidelines consisting of 4 phases of different levels of interventions, based on vector control through indoor residual spraying of insecticide (IRS) and active case detection (ACD). Mathematical transmission models of VL are increasingly used for planning and assessing the efficacy of interventions and evaluating the intensity and timescale required to achieve the elimination target. Methods: This paper draws together the key policy-relevant conclusions from recent transmission modeling of VL, and presents new predictions for VL incidence under the interventions recommended by the WHO using the latest transmission models. Results: The model predictions suggest that the current WHO guidelines should be sufficient to reach the elimination target in areas that had medium VL endemicities (up to 5 VL cases per 10000 population per year) prior to the start of interventions. However, additional interventions, such as extending the WHO attack phase (intensive IRS and ACD), may be required to bring forward elimination in regions with high precontrol endemicities, depending on the relative infectiousness of different disease stages. Conclusions: The potential hurdle that asymptomatic and, in particular, post-kala-azar dermal leishmaniasis cases may pose to reaching and sustaining the target needs to be addressed. As VL incidence decreases, the pool of immunologically naive individuals will grow, creating the potential for new outbreaks.

Rock KS, Ndeffo-Mbah ML, Castaño S, Palmer C, Pandey A, Atkins KE, Ndung'u JM, Hollingsworth TD, Galvani A, Bever C et al. 2018. Assessing Strategies Against Gambiense Sleeping Sickness Through Mathematical Modeling. Clin Infect Dis, 66 (suppl_4), pp. S286-S292. | Show Abstract | Read more

Background: Control of gambiense sleeping sickness relies predominantly on passive and active screening of people, followed by treatment. Methods: Mathematical modeling explores the potential of 3 complementary interventions in high- and low-transmission settings. Results: Intervention strategies that included vector control are predicted to halt transmission most quickly. Targeted active screening, with better and more focused coverage, and enhanced passive surveillance, with improved access to diagnosis and treatment, are both estimated to avert many new infections but, when used alone, are unlikely to halt transmission before 2030 in high-risk settings. Conclusions: There was general model consensus in the ranking of the 3 complementary interventions studied, although with discrepancies between the quantitative predictions due to differing epidemiological assumptions within the models. While these predictions provide generic insights into improving control, the most effective strategy in any situation depends on the specific epidemiology in the region and the associated costs.

Hollingsworth TD. 2018. Counting Down the 2020 Goals for 9 Neglected Tropical Diseases: What Have We Learned From Quantitative Analysis and Transmission Modeling? Clin Infect Dis, 66 (suppl_4), pp. S237-S244. | Show Abstract | Read more

The control of neglected tropical diseases (NTDs) has received huge investment in recent years, leading to large reductions in morbidity. In 2012, the World Health Organization set ambitious targets for eliminating many of these diseases as a public health problem by 2020, an aspiration that was supported by donations of treatments, intervention materials, and funding committed by a broad partnership of stakeholders in the London Declaration on NTDs. Alongside these efforts, there has been an increasing role for quantitative analysis and modeling to support the achievement of these goals through evaluation of the likely impact of interventions, the factors that could undermine these achievements, and the role of new diagnostics and treatments in reducing transmission. In this special issue, we aim to summarize those insights in an accessible way. This article acts as an introduction to the special issue, outlining key concepts in NTDs and insights from modeling as we approach 2020.

Irvine MA, Hollingsworth TD. 2018. Kernel-density estimation and approximate Bayesian computation for flexible epidemiological model fitting in Python. Epidemics, 25 pp. 80-88. | Show Abstract | Read more

Fitting complex models to epidemiological data is a challenging problem: methodologies can be inaccessible to all but specialists, there may be challenges in adequately describing uncertainty in model fitting, the complex models may take a long time to run, and it can be difficult to fully capture the heterogeneity in the data. We develop an adaptive approximate Bayesian computation scheme to fit a variety of epidemiologically relevant data with minimal hyper-parameter tuning by using an adaptive tolerance scheme. We implement a novel kernel density estimation scheme to capture both dispersed and multi-dimensional data, and directly compare this technique to standard Bayesian approaches. We then apply the procedure to a complex individual-based simulation of lymphatic filariasis, a human parasitic disease. The procedure and examples are released alongside this article as an open access library, with examples to aid researchers to rapidly fit models to data. This demonstrates that an adaptive ABC scheme with a general summary and distance metric is capable of performing model fitting for a variety of epidemiological data. It also does not require significant theoretical background to use and can be made accessible to the diverse epidemiological research community.

Cooper AJ, Hollingsworth TD. 2018. The impact of seasonality on the dynamics and control of Ascaris lumbricoides infections. J Theor Biol, 453 pp. 96-107. | Show Abstract | Read more

Intestinal nematode infections affect a huge proportion of the world's population. Increasingly these infections, particularly amongst the poorest communities, are controlled through mass drug treatment programs. Seasonal variations of climate and behaviour in these regions can be significant, but their impact on the dynamics of infection and implications for the effectiveness of any mass drug treatment program (a pulsed reduction in worm burden in hosts) is not clearly understood. Here the effect of seasonality on the dynamics of the soil-based helminth, Ascaris lumbricoides, is investigated using a reformulated version of the Anderson-May model for macro-parasitic infections. Explicit analytical expressions are obtained for the stable oscillatory solution over the annual cycle, which provides a means of relating times of peak numbers of eggs, larvae and mature worms to seasonal variations. Numerical and analytical techniques are then used to consider the impact of seasonality on the optimal timing of drug treatment. Our results show that there is a relatively large window for the timing of optimal treatment, and the impact of repeated annual mass drug treatments can be substantially improved if they are timed to coincide with the months when the number of eggs and larvae are at their lowest - minimising reinfection. In terms of a more measurable quantity, in our example this corresponds to the months when the seasonal temperature is highest. Multiple annual treatments at (or close to) the optimal time each year are predicted to achieve local elimination in the community, whereas treatment at other times has a more limited impact. A key finding is that even for pronounced seasonality, perturbations in mean worm burden, and hence seasonal variation in observed egg output, may be small, potentially explaining why seasonal effects have been overlooked. Taken together these results suggest that seasonality of soil-transmitted helminths requires further experimental, field and mathematical study if the impact for mass drug administration programs is to be exploited.

Bundy DAP, Appleby LJ, Bradley M, Croke K, Hollingsworth TD, Pullan R, Turner HC, de Silva N. 2018. 100 Years of Mass Deworming Programmes: A Policy Perspective From the World Bank's Disease Control Priorities Analyses. Adv Parasitol, 100 pp. 127-154. | Show Abstract | Read more

For more than 100 years, countries have used mass drug administration as a public health response to soil-transmitted helminth infection. The series of analyses published as Disease Control Priorities is the World Bank's vehicle for exploring the cost-effectiveness and value for money of public health interventions. The first edition was published in 1993 as a technical supplement to the World Bank's World Development Report Investing in Health where deworming was used as an illustrative example of value for money in treating diseases with relatively low morbidity but high prevalence. Over the second (2006) and now third (2017) editions deworming has been an increasingly persuasive example to use for this argument. The latest analyses recognize the negative impact of intestinal worm infection on human capital in poor communities and document a continuing decline in worm infection as a result of the combination of high levels of mass treatment and ongoing economic development trends in poor communities.

Gedge LM, Bettis AA, Bradley MH, Hollingsworth TD, Turner HC. 2018. Economic evaluations of lymphatic filariasis interventions: a systematic review and research needs. Parasit Vectors, 11 (1), pp. 75. | Show Abstract | Read more

In 2000, the World Health Organization established the Global Programme to Eliminate Lymphatic Filariasis (GPELF), with the goal of eliminating the disease as a public health problem by 2020. Since the start of the programme, a cumulative total of 6.2 billion treatments have been delivered to affected populations - with more than 556 million people treated in 2015 alone. In this paper, we perform a rigorous systematic review of the economic evaluations of lymphatic filariasis interventions have been conducted. We demonstrate that the standard interventions to control lymphatic filariasis are consistently found to be highly cost-effective. This finding has important implications for advocacy groups and potential funders. However, there are several important inconsistencies and research gaps that need to be addressed as we move forward towards the 2020 elimination goals. One of the most important identified research gaps was a lack of evaluation of new interventions specifically targeting areas co-endemic with onchocerciasis and Loa loa - which could become a major barrier to achieving elimination.

Irvine MA, Kazura JW, Hollingsworth TD, Reimer LJ. 2018. Understanding heterogeneities in mosquito-bite exposure and infection distributions for the elimination of lymphatic filariasis. Proc Biol Sci, 285 (1871), pp. 20172253-20172253. | Show Abstract | Read more

It is well known that individuals in the same community can be exposed to a highly variable number of mosquito bites. This heterogeneity in bite exposure has consequences for the control of vector-borne diseases because a few people may be contributing significantly to transmission. However, very few studies measure sources of heterogeneity in a way which is relevant to decision-making. We investigate the relationship between two classic measures of heterogeneity, spatial and individual, within the context of lymphatic filariasis, a parasitic mosquito-borne disease. Using infection and mosquito-bite data for five villages in Papua New Guinea, we measure biting characteristics to model what impact bed-nets have had on control of the disease. We combine this analysis with geospatial modelling to understand the spatial relationship between disease indicators and nightly mosquito bites. We found a weak association between biting and infection heterogeneity within villages. The introduction of bed-nets increased biting heterogeneity, but the reduction in mean biting more than compensated for this, by reducing prevalence closer to elimination thresholds. Nightly biting was explained by a spatial heterogeneity model, while parasite load was better explained by an individual heterogeneity model. Spatial and individual heterogeneity are qualitatively different with profoundly different policy implications.

Davis EL, Danon L, Prada JM, Gunawardena SA, Truscott JE, Vlaminck J, Anderson RM, Levecke B, Morgan ER, Hollingsworth TD. 2018. Seasonally timed treatment programs for Ascaris lumbricoides to increase impact-An investigation using mathematical models. PLoS Negl Trop Dis, 12 (1), pp. e0006195. | Show Abstract | Read more

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.

Prada JM, Touloupou P, Adriko M, Tukahebwa EM, Lamberton PHL, Hollingsworth TD. 2018. Understanding the relationship between egg- and antigen-based diagnostics of Schistosoma mansoni infection pre- and post-treatment in Uganda. Parasit Vectors, 11 (1), pp. 21. | Show Abstract | Read more

BACKGROUND: Schistosomiasis is a major socio-economic and public health problem in many sub-Saharan African countries. After large mass drug administration (MDA) campaigns, prevalence of infection rapidly returns to pre-treatment levels. The traditional egg-based diagnostic for schistosome infections, Kato-Katz, is being substituted in many settings by circulating antigen recognition-based diagnostics, usually the point-of-care circulating cathodic antigen test (CCA). The relationship between these diagnostics is poorly understood, particularly after treatment in both drug-efficacy studies and routine monitoring. RESULTS: We created a model of schistosome infections to better understand and quantify the relationship between these two egg- and adult worm antigen-based diagnostics. We focused particularly on the interpretation of "trace" results after CCA testing. Our analyses suggest that CCA is generally a better predictor of prevalence, particularly after treatment, and that trace CCA results are typically associated with truly infected individuals. CONCLUSIONS: Even though prevalence rises to pre-treatment levels only six months after MDAs, our model suggests that the average intensity of infection is much lower, and is probably in part due to a small burden of surviving juveniles from when the treatment occurred. This work helps to better understand CCA diagnostics and the interpretation of post-treatment prevalence estimations.

Jervis S, Chapman LAC, Dwivedi S, Karthick M, Das A, Le Rutte EA, Courtenay O, Medley GF, Banerjee I, Mahapatra T et al. 2017. Variations in visceral leishmaniasis burden, mortality and the pathway to care within Bihar, India. Parasit Vectors, 10 (1), pp. 601. | Show Abstract | Read more

BACKGROUND: Visceral leishmaniasis (VL) has been targeted by the WHO for elimination as a public health problem (< 1 case/10,000 people/year) in the Indian sub-continent (ISC) by 2020. Bihar State in India, which accounts for the majority of cases in the ISC, remains a major target for this elimination effort. However, there is considerable spatial, temporal and sub-population variation in occurrence of the disease and the pathway to care, which is largely unexplored and a threat to achieving the target. METHODS: Data from 6081 suspected VL patients who reported being clinically diagnosed during 2012-2013 across eight districts in Bihar were analysed. Graphical comparisons and Chi-square tests were used to determine differences in the burden of identified cases by season, district, age and sex. Log-linear regression models were fitted to onset (of symptoms)-to-diagnosis and onset-to-treatment waiting times to estimate their associations with age, sex, district and various socio-economic factors (SEFs). Logistic regression models were used to identify factors associated with mortality. RESULTS: Comparisons of VL caseloads suggested an annual cycle peaking in January-March. A 17-fold variation in the burden of identified cases across districts and under-representation of young children (0-5 years) relative to age-specific populations in Bihar were observed. Women accounted for a significantly lower proportion of the reported cases than men (41 vs 59%, P < 0.0001). Age, district of residence, house wall materials, caste, treatment cost, travelling for diagnosis and the number of treatments for symptoms before diagnosis were identified as correlates of waiting times. Mortality was associated with age, district of residence, onset-to-treatment waiting time, treatment duration, cattle ownership and cost of diagnosis. CONCLUSIONS: The distribution of VL in Bihar is highly heterogeneous, and reported caseloads and associated mortality vary significantly across different districts, posing different challenges to the elimination campaign. Socio-economic factors are important correlates of these differences, suggesting that elimination will require tailoring to population and sub-population circumstances.

Bundy DAP, de Silva N, Horton S, Patton GC, Schultz L, Jamison DT, Disease Control Priorities-3 Child and Adolescent Health and Development Authors Group. 2018. Investment in child and adolescent health and development: key messages from Disease Control Priorities, 3rd Edition. Lancet, 391 (10121), pp. 687-699. | Show Abstract | Read more

The realisation of human potential for development requires age-specific investment throughout the 8000 days of childhood and adolescence. Focus on the first 1000 days is an essential but insufficient investment. Intervention is also required in three later phases: the middle childhood growth and consolidation phase (5-9 years), when infection and malnutrition constrain growth, and mortality is higher than previously recognised; the adolescent growth spurt (10-14 years), when substantial changes place commensurate demands on good diet and health; and the adolescent phase of growth and consolidation (15-19 years), when new responses are needed to support brain maturation, intense social engagement, and emotional control. Two cost-efficient packages, one delivered through schools and one focusing on later adolescence, would provide phase-specific support across the life cycle, securing the gains of investment in the first 1000 days, enabling substantial catch-up from early growth failure, and leveraging improved learning from concomitant education investments.

Dyson L, Marks M, Crook OM, Sokana O, Solomon AW, Bishop A, Mabey DCW, Hollingsworth TD. 2018. Targeted Treatment of Yaws With Household Contact Tracing: How Much Do We Miss? Am J Epidemiol, 187 (4), pp. 837-844. | Show Abstract | Read more

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.

Turner HC, Toor J, Hollingsworth TD, Anderson RM. 2018. Economic Evaluations of Mass Drug Administration: The Importance of Economies of Scale and Scope. Clin Infect Dis, 66 (8), pp. 1298-1303. | Show Abstract | Read more

It is recognized that changing the current approaches for the control of the neglected tropical diseases will be needed to reach the World Health Organization's (WHO) 2020 goals. Consequently, it is important that economic evaluations of the alternative approaches are conducted. A vital component of such evaluations is the issue of how the intervention's costs should be incorporated. We discuss this issue-focusing on mass drug administration. We argue that the common approach of assuming an intervention's cost per treatment is constant, regardless of the number of individuals treated, is a misleading way to consider the delivery costs of mass drug administration due to the occurrence of economies/diseconomies of scale and scope. Greater care and consideration are required when the costs are incorporated into such analyses. Without this, these economic evaluations could potentially lead to incorrect policy recommendations.

Baggaley RF, Irvine MA, Leber W, Cambiano V, Figueroa J, McMullen H, Anderson J, Santos AC, Terris-Prestholt F, Miners A et al. 2017. Cost-effectiveness of screening for HIV in primary care: a health economics modelling analysis. Lancet HIV, 4 (10), pp. e465-e474. | Show Abstract | Read more

BACKGROUND: Early HIV diagnosis reduces morbidity, mortality, the probability of onward transmission, and their associated costs, but might increase cost because of earlier initiation of antiretroviral treatment (ART). We investigated this trade-off by estimating the cost-effectiveness of HIV screening in primary care. METHODS: We modelled the effect of the four-times higher diagnosis rate observed in the intervention arm of the RHIVA2 randomised controlled trial done in Hackney, London (UK), a borough with high HIV prevalence (≥0·2% adult prevalence). We constructed a dynamic, compartmental model representing incidence of infection and the effect of screening for HIV in general practices in Hackney. We assessed cost-effectiveness of the RHIVA2 trial by fitting model diagnosis rates to the trial data, parameterising with epidemiological and behavioural data from the literature when required, using trial testing costs and projecting future costs of treatment. FINDINGS: Over a 40 year time horizon, incremental cost-effectiveness ratios were £22 201 (95% credible interval 12 662-132 452) per quality-adjusted life-year (QALY) gained, £372 207 (268 162-1 903 385) per death averted, and £628 874 (434 902-4 740 724) per HIV transmission averted. Under this model scenario, with UK cost data, RHIVA2 would reach the upper National Institute for Health and Care Excellence cost-effectiveness threshold (about £30 000 per QALY gained) after 33 years. Scenarios using cost data from Canada (which indicate prolonged and even higher health-care costs for patients diagnosed late) suggest this threshold could be reached in as little as 13 years. INTERPRETATION: Screening for HIV in primary care has important public health benefits as well as clinical benefits. We predict it to be cost-effective in the UK in the medium term. However, this intervention might be cost-effective far sooner, and even cost-saving, in settings where long-term health-care costs of late-diagnosed patients in high-prevalence regions are much higher (≥60%) than those of patients diagnosed earlier. Screening for HIV in primary care is cost-effective and should be promoted. FUNDING: NHS City and Hackney, UK Department of Health, National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care.

Steinmann P, Reed SG, Mirza F, Hollingsworth TD, Richardus JH. 2017. Innovative tools and approaches to end the transmission of Mycobacterium leprae. Lancet Infect Dis, 17 (9), pp. e298-e305. | Show Abstract | Read more

Leprosy control has seen little innovation and only limited progress in the past decade. However, research on the disease has increased and important innovations are underway. Here, we comment on efforts to develop tools and approaches to detect leprosy and to stop the transmission of Mycobacterium leprae, the causative bacillus of the disease. The tracing and screening of contacts of known patients with leprosy promises to strengthen early diagnosis, while preventive chemotherapy will reduce the risk of contacts developing the disease by 50-60% within 2 years of administration. Until now, diagnosis has been mainly based on the presence of signs and symptoms, but efforts are underway to develop inexpensive, reliable, point-of-care tests to diagnose infection. Development of a leprosy-specific vaccine that boosts long-lasting T-cell responses is also a research objective. As for launching a programme to interrupt transmission, two interlinked tools-epidemiological modelling and the concept of an investment case-are being developed to explore the feasibility and costs of such a programme and its overall effect on individuals and society. We believe that sustained innovation is needed and that only a combination of tools and approaches holds promise to end M leprae transmission.

Irvine MA, Stolk WA, Smith ME, Subramanian S, Singh BK, Weil GJ, Michael E, Hollingsworth TD. 2017. Effectiveness of a triple-drug regimen for global elimination of lymphatic filariasis: a modelling study. Lancet Infect Dis, 17 (4), pp. 451-458. | Show Abstract | Read more

BACKGROUND: Lymphatic filariasis is targeted for elimination as a public health problem by 2020. The principal approach used by current programmes is annual mass drug administration with two pairs of drugs with a good safety profile. However, one dose of a triple-drug regimen (ivermectin, diethylcarbamazine, and albendazole) has been shown to clear the transmissible stage of the helminth completely in treated individuals. The aim of this study was to use modelling to assess the potential value of mass drug administration with the triple-drug regimen for accelerating elimination of lymphatic filariasis in different epidemiological settings. METHODS: We used three different transmission models to compare the number of rounds of mass drug administration needed to achieve a prevalence of microfilaraemia less than 1% with the triple-drug regimen and with current two-drug regimens. FINDINGS: In settings with a low baseline prevalence of lymphatic filariasis (5%), the triple-drug regimen reduced the number of rounds of mass drug administration needed to reach the target prevalence by one or two rounds, compared with the two-drug regimen. For areas with higher baseline prevalence (10-40%), the triple-drug regimen strikingly reduced the number of rounds of mass drug administration needed, by about four or five, but only at moderate-to-high levels of population coverage (>65%) and if systematic non-adherence to mass drug administration was low. INTERPRETATION: Simulation modelling suggests that the triple-drug regimen has potential to accelerate the elimination of lymphatic filariasis if high population coverage of mass drug administration can be achieved and if systematic non-adherence with mass drug administration is low. Future work will reassess these estimates in light of more clinical trial data and to understand the effect on an individual country's programme. FUNDING: Bill & Melinda Gates Foundation.

Smith ME, Singh BK, Irvine MA, Stolk WA, Subramanian S, Hollingsworth TD, Michael E. 2017. Predicting lymphatic filariasis transmission and elimination dynamics using a multi-model ensemble framework. Epidemics, 18 pp. 16-28. | Show Abstract | Read more

Mathematical models of parasite transmission provide powerful tools for assessing the impacts of interventions. Owing to complexity and uncertainty, no single model may capture all features of transmission and elimination dynamics. Multi-model ensemble modelling offers a framework to help overcome biases of single models. We report on the development of a first multi-model ensemble of three lymphatic filariasis (LF) models (EPIFIL, LYMFASIM, and TRANSFIL), and evaluate its predictive performance in comparison with that of the constituents using calibration and validation data from three case study sites, one each from the three major LF endemic regions: Africa, Southeast Asia and Papua New Guinea (PNG). We assessed the performance of the respective models for predicting the outcomes of annual MDA strategies for various baseline scenarios thought to exemplify the current endemic conditions in the three regions. The results show that the constructed multi-model ensemble outperformed the single models when evaluated across all sites. Single models that best fitted calibration data tended to do less well in simulating the out-of-sample, or validation, intervention data. Scenario modelling results demonstrate that the multi-model ensemble is able to compensate for variance between single models in order to produce more plausible predictions of intervention impacts. Our results highlight the value of an ensemble approach to modelling parasite control dynamics. However, its optimal use will require further methodological improvements as well as consideration of the organizational mechanisms required to ensure that modelling results and data are shared effectively between all stakeholders.

Dyson L, Stolk WA, Farrell SH, Hollingsworth TD. 2017. Measuring and modelling the effects of systematic non-adherence to mass drug administration. Epidemics, 18 pp. 56-66. | Show Abstract | Read more

It is well understood that the success or failure of a mass drug administration campaign critically depends on the level of coverage achieved. To that end coverage levels are often closely scrutinised during campaigns and the response to underperforming campaigns is to attempt to improve coverage. Modelling work has indicated, however, that the quality of the coverage achieved may also have a significant impact on the outcome. If the coverage achieved is likely to miss similar people every round then this can have a serious detrimental effect on the campaign outcome. We begin by reviewing the current modelling descriptions of this effect and introduce a new modelling framework that can be used to simulate a given level of systematic non-adherence. We formalise the likelihood that people may miss several rounds of treatment using the correlation in the attendance of different rounds. Using two very simplified models of the infection of helminths and non-helminths, respectively, we demonstrate that the modelling description used and the correlation included between treatment rounds can have a profound effect on the time to elimination of disease in a population. It is therefore clear that more detailed coverage data is required to accurately predict the time to disease elimination. We review published coverage data in which individuals are asked how many previous rounds they have attended, and show how this information may be used to assess the level of systematic non-adherence. We note that while the coverages in the data found range from 40.5% to 95.5%, still the correlations found lie in a fairly narrow range (between 0.2806 and 0.5351). This indicates that the level of systematic non-adherence may be similar even in data from different years, countries, diseases and administered drugs.

Hollingsworth TD, Medley GF. 2017. Learning from multi-model comparisons: Collaboration leads to insights, but limitations remain. Epidemics, 18 pp. 1-3. | Read more

Le Rutte EA, Chapman LAC, Coffeng LE, Jervis S, Hasker EC, Dwivedi S, Karthick M, Das A, Mahapatra T, Chaudhuri I et al. 2017. Elimination of visceral leishmaniasis in the Indian subcontinent: a comparison of predictions from three transmission models. Epidemics, 18 pp. 67-80. | Show Abstract | Read more

We present three transmission models of visceral leishmaniasis (VL) in the Indian subcontinent (ISC) with structural differences regarding the disease stage that provides the main contribution to transmission, including models with a prominent role of asymptomatic infection, and fit them to recent case data from 8 endemic districts in Bihar, India. Following a geographical cross-validation of the models, we compare their predictions for achieving the WHO VL elimination targets with ongoing treatment and vector control strategies. All the transmission models suggest that the WHO elimination target (<1 new VL case per 10,000 capita per year at sub-district level) is likely to be met in Bihar, India, before or close to 2020 in sub-districts with a pre-control incidence of 10 VL cases per 10,000 people per year or less, when current intervention levels (60% coverage of indoor residual spraying (IRS) of insecticide and a delay of 40days from onset of symptoms to treatment (OT)) are maintained, given the accuracy and generalizability of the existing data regarding incidence and IRS coverage. In settings with a pre-control endemicity level of 5/10,000, increasing the effective IRS coverage from 60 to 80% is predicted to lead to elimination of VL 1-3 years earlier (depending on the particular model), and decreasing OT from 40 to 20days to bring elimination forward by approximately 1year. However, in all instances the models suggest that L. donovani transmission will continue after 2020 and thus that surveillance and control measures need to remain in place until the longer-term aim of breaking transmission is achieved.

Turner HC, Bettis AA, Dunn JC, Whitton JM, Hollingsworth TD, Fleming FM, Anderson RM. 2017. Economic Considerations for Moving beyond the Kato-Katz Technique for Diagnosing Intestinal Parasites As We Move Towards Elimination. Trends Parasitol, 33 (6), pp. 435-443. | Show Abstract | Read more

While the need for more sensitive diagnostics for intestinal helminths is well known, the cost of developing and implementing new tests is considered relatively high compared to the Kato-Katz technique. Here, we review the reported costs of performing the Kato-Katz technique. We also outline several economic arguments we believe highlight the need for further investment in alternative diagnostics, and considerations that should be made when comparing their costs. In our opinion, we highlight that, without new diagnostic methods, it will be difficult for policy makers to make the most cost-effective decisions and that the potentially higher unit costs of new methods can be outweighed by the long-term programmatic benefits they have (such as the ability to detect the interruption of transmission).

Irvine MA, Hollingsworth TD. 2017. Making Transmission Models Accessible to End-Users: The Example of TRANSFIL. PLoS Negl Trop Dis, 11 (2), pp. e0005206. | Read more

Koukounari A, Hollingsworth TD. 2017. A strengthening evidence-base for mass deworming, but questions remain. Lancet, 389 (10066), pp. 231-233. | Read more

Deol A, Webster JP, Walker M, Basáñez M-G, Hollingsworth TD, Fleming FM, Montresor A, French MD. 2016. Development and evaluation of a Markov model to predict changes in schistosomiasis prevalence in response to praziquantel treatment: a case study of Schistosoma mansoni in Uganda and Mali. Parasit Vectors, 9 (1), pp. 543. | Show Abstract | Read more

BACKGROUND: Understanding whether schistosomiasis control programmes are on course to control morbidity and potentially switch towards elimination interventions would benefit from user-friendly quantitative tools that facilitate analysis of progress and highlight areas not responding to treatment. This study aimed to develop and evaluate such a tool using large datasets collected during Schistosomiasis Control Initiative-supported control programmes. METHODS: A discrete-time Markov model was developed using transition probability matrices parameterized with control programme longitudinal data on Schistosoma mansoni obtained from Uganda and Mali. Four matrix variants (A-D) were used to compare different data types for parameterization: A-C from Uganda and D from Mali. Matrix A used data at baseline and year 1 of the control programme; B used year 1 and year 2; C used baseline and year 1 from selected districts, and D used baseline and year 1 Mali data. Model predictions were tested against 3 subsets of the Uganda dataset: dataset 1, the full 4-year longitudinal cohort; dataset 2, from districts not used to parameterize matrix C; dataset 3, cross-sectional data, and dataset 4, from Mali as an independent dataset. RESULTS: The model parameterized using matrices A, B and D predicted similar infection dynamics (overall and when stratified by infection intensity). Matrices A-D successfully predicted prevalence in each follow-up year for low and high intensity categories in dataset 1 followed by dataset 2. Matrices A, B and D yielded similar and close matches to dataset 1 with marginal discrepancies when comparing model outputs against datasets 2 and 3. Matrix C produced more variable results, correctly estimating fewer data points. CONCLUSION: Model outputs closely matched observed values and were a useful predictor of the infection dynamics of S. mansoni when using longitudinal and cross-sectional data from Uganda. This also held when the model was tested with data from Mali. This was most apparent when modelling overall infection and in low and high infection intensity areas. Our results indicate the applicability of this Markov model approach as countries aim at reaching their control targets and potentially move towards the elimination of schistosomiasis.

Turner HC, Truscott JE, Bettis AA, Hollingsworth TD, Brooker SJ, Anderson RM. 2016. Analysis of the population-level impact of co-administering ivermectin with albendazole or mebendazole for the control and elimination of Trichuris trichiura. Parasite Epidemiol Control, 1 (2), pp. 177-187. | Show Abstract | Read more

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.

Irvine MA, Njenga SM, Gunawardena S, Wamae CN, Cano J, Brooker SJ, Hollingsworth TD. 2016. Understanding the relationship between prevalence of microfilariae and antigenaemia using a model of lymphatic filariasis infection. Trans R Soc Trop Med Hyg, 110 (5), pp. 317. | Read more

Marshall JM, Touré M, Ouédraogo AL, Ndhlovu M, Kiware SS, Rezai A, Nkhama E, Griffin JT, Hollingsworth TD, Doumbia S et al. 2016. Key traveller groups of relevance to spatial malaria transmission: a survey of movement patterns in four sub-Saharan African countries. Malar J, 15 (1), pp. 200. | Show Abstract | Read more

BACKGROUND: As malaria prevalence declines in many parts of the world due to widescale control efforts and as drug-resistant parasites begin to emerge, a quantitative understanding of human movement is becoming increasingly relevant to malaria control. However, despite its importance, significant knowledge gaps remain regarding human movement, particularly in sub-Saharan Africa. METHODS: A quantitative survey of human movement patterns was conducted in four countries in sub-Saharan Africa: Mali, Burkina Faso, Zambia, and Tanzania, with three to five survey locations chosen in each country. Questions were included on demographic and trip details, malaria risk behaviour, children accompanying travellers, and mobile phone usage to enable phone signal data to be better correlated with movement. A total of 4352 individuals were interviewed and 6411 trips recorded. RESULTS: A cluster analysis of trips highlighted two distinct traveller groups of relevance to malaria transmission: women travelling with children (in all four countries) and youth workers (in Mali). Women travelling with children were more likely to travel to areas of relatively high malaria prevalence in Mali (OR = 4.46, 95% CI = 3.42-5.83), Burkina Faso (OR = 1.58, 95% CI = 1.23-1.58), Zambia (OR = 1.50, 95% CI = 1.20-1.89), and Tanzania (OR = 2.28, 95% CI = 1.71-3.05) compared to other travellers. They were also more likely to own bed nets in Burkina Faso (OR = 1.77, 95% CI = 1.25-2.53) and Zambia (OR = 1.74, 95% CI = 1.34 2.27), and less likely to own a mobile phone in Mali (OR = 0.50, 95% CI = 0.39-0.65), Burkina Faso (OR = 0.39, 95% CI = 0.30-0.52), and Zambia (OR = 0.60, 95% CI = 0.47-0.76). Malian youth workers were more likely to travel to areas of relatively high malaria prevalence (OR = 23, 95% CI = 17-31) and for longer durations (mean of 70 days cf 21 days, p < 0.001) compared to other travellers. CONCLUSIONS: Women travelling with children were a remarkably consistent traveller group across all four countries surveyed. They are expected to contribute greatly towards spatial malaria transmission because the children they travel with tend to have high parasite prevalence. Youth workers were a significant traveller group in Mali and are expected to contribute greatly to spatial malaria transmission because their movements correlate with seasonal rains and hence peak mosquito densities. Interventions aimed at interrupting spatial transmission of parasites should consider these traveller groups.

Fowler AC, Hollingsworth TD. 2015. Simple Approximations for Epidemics with Exponential and Fixed Infectious Periods. Bull Math Biol, 77 (8), pp. 1539-1555. | Show Abstract | Read more

Analytical approximations have generated many insights into the dynamics of epidemics, but there is only one well-known approximation which describes the dynamics of the whole epidemic. In addition, most of the well-known approximations for different aspects of the dynamics are for the classic susceptible-infected-recovered model, in which the infectious period is exponentially distributed. Whilst this assumption is useful, it is somewhat unrealistic. Equally reasonable assumptions are that the infectious period is finite and fixed or that there is a distribution of infectious periods centred round a nonzero mean. We investigate the effect of these different assumptions on the dynamics of the epidemic by deriving approximations to the whole epidemic curve. We show how the well-known sech-squared approximation for the infective population in 'weak' epidemics (where the basic reproduction rate R₀ ≈ 1) can be extended to the case of an arbitrary distribution of infectious periods having finite second moment, including as examples fixed and gamma-distributed infectious periods. Further, we show how to approximate the time course of a 'strong' epidemic, where R₀ ≫ 1, demonstrating the importance of estimating the infectious period distribution early in an epidemic.

Fowler AC, Hollingsworth TD. 2016. The Dynamics of Ascaris lumbricoides Infections. Bull Math Biol, 78 (4), pp. 815-833. | Show Abstract | Read more

The Anderson-May model of human parasite infections and specifically that for the intestinal worm Ascaris lumbricoides is reconsidered, with a view to deriving the observed characteristic negative binomial distribution which is frequently found in human communities. The means to obtaining this result lies in reformulating the continuous Anderson-May model as a stochastic process involving two essential populations, the density of mature worms in the gut, and the density of mature eggs in the environment. The resulting partial differential equation for the generating function of the joint probability distribution of eggs and worms can be partially solved in the appropriate limit where the worm lifetime is much greater than that of the mature eggs in the environment. Allowing for a mean field nonlinearity, and for egg immigration from neighbouring communities, a negative binomial worm distribution can be predicted, whose parameters are determined by those in the continuous Anderson-May model; this result assumes no variability in predisposition to the infection.

Turner HC, Truscott JE, Fleming FM, Hollingsworth TD, Brooker SJ, Anderson RM. 2016. Cost-effectiveness of scaling up mass drug administration for the control of soil-transmitted helminths: a comparison of cost function and constant costs analyses. Lancet Infect Dis, 16 (7), pp. 838-846. | Show Abstract | Read more

BACKGROUND: The coverage of mass drug administration (MDA) for neglected tropical diseases, such as the soil-transmitted helminths (STHs), needs to rapidly expand to meet WHO's 2020 targets. We aimed to compare use of a cost function to take into account economies of scale to the standard method of assuming a constant cost per treatment when investigating the cost and cost-effectiveness of scaling up a STH MDA programme targeting Ascaris lumbricoides. METHODS: We fitted a cost function describing how the costs of MDA change with scale to empirical cost data and incorporated it into a STH transmission model. Using this cost function, we investigated the consequences of taking into account economies of scale on the projected cost-effectiveness of STH control, by comparison with the standard method of assuming a constant cost per treatment. The cost function was fitted to economic cost data collected as part of a school-based deworming programme in Uganda using maximum likelihood methods. We used the model to investigate the total reduction in the overall worm burden, the total number of prevalent infection case-years averted, and the total number of heavy infection case-years averted. For each year, we calculated the effectiveness as the difference between the worm burden or number of cases and the number in absence of treatment. FINDINGS: When using the cost function, the cost-effectiveness of STH control markedly increased as the programme was scaled up. By contrast, the standard method (constant cost per treatment) undervalued this and generated misleading conclusions. For example, when scaling up control in the projected district from 10% to 75% coverage of at-risk school-age children, the cost-effectiveness in terms of prevention of heavy burden infections was projected to increase by over 70% when using the cost function, but decrease by 18% when assuming a constant cost per treatment. INTERPRETATION: The current exclusion of economies of scale in most economic analyses must be addressed if the most cost-effective policies for the control of neglected tropical diseases are to be formulated. These findings are also relevant to other large-scale disease interventions. FUNDING: GlaxoSmithKline, Bill & Melinda Gates Foundation, Partnership for Child Development, and Wellcome Trust.

Irvine MA, Njenga SM, Gunawardena S, Njeri Wamae C, Cano J, Brooker SJ, Hollingsworth TD. 2016. Understanding the relationship between prevalence of microfilariae and antigenaemia using a model of lymphatic filariasis infection. Trans R Soc Trop Med Hyg, 110 (2), pp. 118-124. | Show Abstract | Read more

BACKGROUND: Lymphatic filariasis is a debilitating neglected tropical disease that affects impoverished communities. Rapid diagnostic tests of antigenaemia are a practical alternative to parasitological tests of microfilaraemia for mapping and surveillance. However the relationship between these two methods of measuring burden has previously been difficult to interpret. METHODS: A statistical model of the distribution of worm burden and microfilariae (mf) and resulting antigenaemic and mf prevalence was developed and fitted to surveys of two contrasting sentinel sites undergoing interventions. The fitted model was then used to explore the relationship in various pre- and post-intervention scenarios. RESULTS: The model had good quantitative agreement with the data and provided estimates of the reduction in mf output due to treatment. When extrapolating the results to a range of prevalences there was good qualitative agreement with published data. CONCLUSIONS: The observed relationship between antigenamic and mf prevalence is a natural consequence of the relationship between prevalence and intensity of adult worms and mf production. The method described here allows the estimation of key epidemiological parameters and consequently gives insight into the efficacy of an intervention programme.

Cameron MM, Acosta-Serrano A, Bern C, Boelaert M, den Boer M, Burza S, Chapman LAC, Chaskopoulou A, Coleman M, Courtenay O et al. 2016. Understanding the transmission dynamics of Leishmania donovani to provide robust evidence for interventions to eliminate visceral leishmaniasis in Bihar, India. Parasit Vectors, 9 (1), pp. 25. | Show Abstract | Read more

Visceral Leishmaniasis (VL) is a neglected vector-borne disease. In India, it is transmitted to humans by Leishmania donovani-infected Phlebotomus argentipes sand flies. In 2005, VL was targeted for elimination by the governments of India, Nepal and Bangladesh by 2015. The elimination strategy consists of rapid case detection, treatment of VL cases and vector control using indoor residual spraying (IRS). However, to achieve sustained elimination of VL, an appropriate post elimination surveillance programme should be designed, and crucial knowledge gaps in vector bionomics, human infection and transmission need to be addressed. This review examines the outstanding knowledge gaps, specifically in the context of Bihar State, India.The knowledge gaps in vector bionomics that will be of immediate benefit to current control operations include better estimates of human biting rates and natural infection rates of P. argentipes, with L. donovani, and how these vary spatially, temporally and in response to IRS. The relative importance of indoor and outdoor transmission, and how P. argentipes disperse, are also unknown. With respect to human transmission it is important to use a range of diagnostic tools to distinguish individuals in endemic communities into those who: 1) are to going to progress to clinical VL, 2) are immune/refractory to infection and 3) have had past exposure to sand flies.It is crucial to keep in mind that close to elimination, and post-elimination, VL cases will become infrequent, so it is vital to define what the surveillance programme should target and how it should be designed to prevent resurgence. Therefore, a better understanding of the transmission dynamics of VL, in particular of how rates of infection in humans and sand flies vary as functions of each other, is required to guide VL elimination efforts and ensure sustained elimination in the Indian subcontinent. By collecting contemporary entomological and human data in the same geographical locations, more precise epidemiological models can be produced. The suite of data collected can also be used to inform the national programme if supplementary vector control tools, in addition to IRS, are required to address the issues of people sleeping outside.

Macpherson EE, Adams ER, Bockarie MJ, Hollingsworth TD, Kelly-Hope LA, Lehane M, Kovacic V, Harrison RA, Paine MJ, Reimer LJ, Torr SJ. 2015. Mass Drug Administration and beyond: how can we strengthen health systems to deliver complex interventions to eliminate neglected tropical diseases? BMC Proc, 9 (Suppl 10), pp. S7. | Show Abstract | Read more

Achieving the 2020 goals for Neglected Tropical Diseases (NTDs) requires scale-up of Mass Drug Administration (MDA) which will require long-term commitment of national and global financing partners, strengthening national capacity and, at the community level, systems to monitor and evaluate activities and impact. For some settings and diseases, MDA is not appropriate and alternative interventions are required. Operational research is necessary to identify how existing MDA networks can deliver this more complex range of interventions equitably. The final stages of the different global programmes to eliminate NTDs require eliminating foci of transmission which are likely to persist in complex and remote rural settings. Operational research is required to identify how current tools and practices might be adapted to locate and eliminate these hard-to-reach foci. Chronic disabilities caused by NTDs will persist after transmission of pathogens ceases. Development and delivery of sustainable services to reduce the NTD-related disability is an urgent public health priority. LSTM and its partners are world leaders in developing and delivering interventions to control vector-borne NTDs and malaria, particularly in hard-to-reach settings in Africa. Our experience, partnerships and research capacity allows us to serve as a hub for developing, supporting, monitoring and evaluating global programmes to eliminate NTDs.

Hollingsworth TD, Langley I, Nokes DJ, Macpherson EE, McGivern G, Adams ER, Bockarie MJ, Mortimer K, Reimer LJ, Squire B et al. 2015. Infectious disease and health systems modelling for local decision making to control neglected tropical diseases. BMC Proc, 9 (Suppl 10), pp. S6. | Show Abstract | Read more

Most neglected tropical diseases (NTDs) have complex life cycles and are challenging to control. The "2020 goals" of control and elimination as a public health programme for a number of NTDs are the subject of significant international efforts and investments. Beyond 2020 there will be a drive to maintain these gains and to push for true local elimination of transmission. However, these diseases are affected by variations in vectors, human demography, access to water and sanitation, access to interventions and local health systems. We therefore argue that there will be a need to develop local quantitative expertise to support elimination efforts. If available now, quantitative analyses would provide updated estimates of the burden of disease, assist in the design of locally appropriate control programmes, estimate the effectiveness of current interventions and support 'real-time' updates to local operations. Such quantitative tools are increasingly available at an international scale for NTDs, but are rarely tailored to local scenarios. Localised expertise not only provides an opportunity for more relevant analyses, but also has a greater chance of developing positive feedback between data collection and analysis by demonstrating the value of data. This is essential as rational program design relies on good quality data collection. It is also likely that if such infrastructure is provided for NTDs there will be an additional impact on the health system more broadly. Locally tailored quantitative analyses can help achieve sustainable and effective control of NTDs, but also underpin the development of local health care systems.

Reimer LJ, Adams ER, Paine MJ, Ranson H, Coleman M, Thomsen EK, MacPherson EE, Hollingsworth TD, Kelly-Hope LA, Bockarie MJ et al. 2015. Fit for purpose: do we have the right tools to sustain NTD elimination? BMC Proc, 9 (Suppl 10), pp. S5. | Show Abstract | Read more

Priorities for NTD control programmes will shift over the next 10-20 years as the elimination phase reaches the 'end game' for some NTDs, and the recognition that the control of other NTDs is much more problematic. The current goal of scaling up programmes based on preventive chemotherapy (PCT) will alter to sustaining NTD prevention, through sensitive surveillance and rapid response to resurgence. A new suite of tools and approaches will be required for both PCT and Intensive Disease Management (IDM) diseases in this timeframe to enable disease endemic countries to: 1. Sensitively and sustainably survey NTD transmission and prevalence in order to identify and respond quickly to resurgence. 2. Set relevant control targets based not only on epidemiological indicators but also entomological and ecological metrics and use decision support technology to help meet those targets. 3. Implement verified and cost-effective tools to prevent transmission throughout the elimination phase. Liverpool School of Tropical Medicine (LSTM) and partners propose to evaluate and implement existing tools from other disease systems as well as new tools in the pipeline in order to support endemic country ownership in NTD decision-making during the elimination phase and beyond.

Medley GF, Hollingsworth TD, Olliaro PL, Adams ER. 2015. Health-seeking behaviour, diagnostics and transmission dynamics in the control of visceral leishmaniasis in the Indian subcontinent. Nature, 528 (7580), pp. S102-S108. | Show Abstract | Read more

Countries in the Indian subcontinent have committed to reducing the incidence of kala-azar, a clinical manifestation of visceral leishmaniasis, to below 1 in 10,000 by 2020. We address the role of timing of use and accuracy of diagnostics in kala-azar control and elimination. We use empirical data on health-seeking behaviour and health-system performance from the Indian state of Bihar, Bangladesh and Nepal to parameterize a mathematical model. Diagnosis of cases is key to case management, control and surveillance. Treatment of cases prevents onward transmission, and we show that the differences in time to diagnosis in these three settings explain the observed differences in incidence. Shortening the time from health-care seeking to diagnosis is likely to lead to dramatic reductions in incidence in Bihar, bringing the incidence down to the levels seen in Bangladesh and Nepal. The results emphasize the importance of maintaining population and health-system awareness, particularly as transmission and disease incidence decline. We explore the possibility of diagnosing patients before the onset of clinical kala-azar (before 14 days fever), and show that this could have a marked impact on incidence, even for a moderately sensitive test. However, limited specificity (that results in false positives) is a major barrier to such a strategy. Diagnostic tests of high specificity used at an early stage of active infection, even if sensitivity is only moderate, could have a key role in the control of kala-azar, and prevent its resurgence when paired with the passive health-care system and tests of high sensitivity, such as the test for rK39 antibody response.

Hollingsworth TD, Adams ER, Anderson RM, Atkins K, Bartsch S, Basáñez M-G, Behrend M, Blok DJ, Chapman LAC, Coffeng L et al. 2015. Quantitative analyses and modelling to support achievement of the 2020 goals for nine neglected tropical diseases. Parasit Vectors, 8 (1), pp. 630. | Show Abstract | Read more

Quantitative analysis and mathematical models are useful tools in informing strategies to control or eliminate disease. Currently, there is an urgent need to develop these tools to inform policy to achieve the 2020 goals for neglected tropical diseases (NTDs). In this paper we give an overview of a collection of novel model-based analyses which aim to address key questions on the dynamics of transmission and control of nine NTDs: Chagas disease, visceral leishmaniasis, human African trypanosomiasis, leprosy, soil-transmitted helminths, schistosomiasis, lymphatic filariasis, onchocerciasis and trachoma. Several common themes resonate throughout these analyses, including: the importance of epidemiological setting on the success of interventions; targeting groups who are at highest risk of infection or re-infection; and reaching populations who are not accessing interventions and may act as a reservoir for infection,. The results also highlight the challenge of maintaining elimination 'as a public health problem' when true elimination is not reached. The models elucidate the factors that may be contributing most to persistence of disease and discuss the requirements for eventually achieving true elimination, if that is possible. Overall this collection presents new analyses to inform current control initiatives. These papers form a base from which further development of the models and more rigorous validation against a variety of datasets can help to give more detailed advice. At the moment, the models' predictions are being considered as the world prepares for a final push towards control or elimination of neglected tropical diseases by 2020.

Chapman LAC, Dyson L, Courtenay O, Chowdhury R, Bern C, Medley GF, Hollingsworth TD. 2015. Quantification of the natural history of visceral leishmaniasis and consequences for control. Parasit Vectors, 8 (1), pp. 521. | Show Abstract | Read more

BACKGROUND: Visceral leishmaniasis has been targeted for elimination as a public health problem (less than 1 case per 10,000 people per year) in the Indian sub-continent by 2017. However, there is still a high degree of uncertainty about the natural history of the disease, in particular about the duration of asymptomatic infection and the proportion of asymptomatically infected individuals that develop clinical visceral leishmaniasis. Quantifying these aspects of the disease is key for guiding efforts to eliminate visceral leishmaniasis and maintaining elimination once it is reached. METHODS: Data from a detailed epidemiological study in Bangladesh in 2002-2004 was analysed to estimate key epidemiological parameters. The role of diagnostics in determining the probability and rate of progression to clinical disease was estimated by fitting Cox proportional hazards models. A multi-state Markov model of the natural history of visceral leishmaniasis was fitted to the data to estimate the asymptomatic infection period and the proportion of asymptomatic individuals going on to develop clinical symptoms. RESULTS: At the time of the study, individuals were taking several months to be diagnosed with visceral leishmaniasis, leading to many opportunities for ongoing transmission. The probability of progression to clinical disease was strongly associated with initial seropositivity and even more strongly with seroconversion, with most clinical symptoms developing within a year. The estimated average durations of asymptomatic infection and symptomatic infection for our model of the natural history are 147 days (95 % CI 130-166) and 140 days (95 % CI 123-160), respectively, and are significantly longer than previously reported estimates. We estimate from the data that 14.7 % (95 % CI 12.6-20.0 %) of asymptomatic individuals develop clinical symptoms-a greater proportion than previously estimated. CONCLUSIONS: Extended periods of asymptomatic infection could be important for visceral leishmaniasis transmission, but this depends critically on the relative infectivity of asymptomatic and symptomatic individuals to sandflies. These estimates could be informed by similar analysis of other datasets. Our results highlight the importance of reducing times from onset of symptoms to diagnosis and treatment to reduce opportunities for transmission.

Irvine MA, Reimer LJ, Njenga SM, Gunawardena S, Kelly-Hope L, Bockarie M, Hollingsworth TD. 2015. Modelling strategies to break transmission of lymphatic filariasis--aggregation, adherence and vector competence greatly alter elimination. Parasit Vectors, 8 (1), pp. 547. | Show Abstract | Read more

BACKGROUND: With ambitious targets to eliminate lymphatic filariasis over the coming years, there is a need to identify optimal strategies to achieve them in areas with different baseline prevalence and stages of control. Modelling can assist in identifying what data should be collected and what strategies are best for which scenarios. METHODS: We develop a new individual-based, stochastic mathematical model of the transmission of lymphatic filariasis. We validate the model by fitting to a first time point and predicting future timepoints from surveillance data in Kenya and Sri Lanka, which have different vectors and different stages of the control programme. We then simulate different treatment scenarios in low, medium and high transmission settings, comparing once yearly mass drug administration (MDA) with more frequent MDA and higher coverage. We investigate the potential impact that vector control, systematic non-compliance and different levels of aggregation have on the dynamics of transmission and control. RESULTS: In all settings, increasing coverage from 65 to 80 % has a similar impact on control to treating twice a year at 65 % coverage, for fewer drug treatments being distributed. Vector control has a large impact, even at moderate levels. The extent of aggregation of parasite loads amongst a small portion of the population, which has been estimated to be highly variable in different settings, can undermine the success of a programme, particularly if high risk sub-communities are not accessing interventions. CONCLUSION: Even moderate levels of vector control have a large impact both on the reduction in prevalence and the maintenance of gains made during MDA, even when parasite loads are highly aggregated, and use of vector control is at moderate levels. For the same prevalence, differences in aggregation and adherence can result in very different dynamics. The novel analysis of a small amount of surveillance data and resulting simulations highlight the need for more individual level data to be analysed to effectively tailor programmes in the drive for elimination.

Drake LJ, Singh S, Mishra CK, Sinha A, Kumar S, Bhushan R, Hollingsworth TD, Appleby LJ, Kumar R, Sharma K et al. 2015. Bihar's Pioneering School-Based Deworming Programme: Lessons Learned in Deworming over 17 Million Indian School-Age Children in One Sustainable Campaign. PLoS Negl Trop Dis, 9 (11), pp. e0004106. | Read more

Turner HC, Truscott JE, Bettis AA, Shuford KV, Dunn JC, Hollingsworth TD, Brooker SJ, Anderson RM. 2015. An economic evaluation of expanding hookworm control strategies to target the whole community. Parasit Vectors, 8 (1), pp. 570. | Show Abstract | Read more

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.

Moraga P, Cano J, Baggaley RF, Gyapong JO, Njenga SM, Nikolay B, Davies E, Rebollo MP, Pullan RL, Bockarie MJ et al. 2015. Modelling the distribution and transmission intensity of lymphatic filariasis in sub-Saharan Africa prior to scaling up interventions: integrated use of geostatistical and mathematical modelling. Parasit Vectors, 8 (1), pp. 560. | Show Abstract | Read more

BACKGROUND: Lymphatic filariasis (LF) is one of the neglected tropical diseases targeted for global elimination. The ability to interrupt transmission is, partly, influenced by the underlying intensity of transmission and its geographical variation. This information can also help guide the design of targeted surveillance activities. The present study uses a combination of geostatistical and mathematical modelling to predict the prevalence and transmission intensity of LF prior to the implementation of large-scale control in sub-Saharan Africa. METHODS: A systematic search of the literature was undertaken to identify surveys on the prevalence of Wuchereria bancrofti microfilaraemia (mf), based on blood smears, and on the prevalence of antigenaemia, based on the use of an immuno-chromatographic card test (ICT). Using a suite of environmental and demographic data, spatiotemporal multivariate models were fitted separately for mf prevalence and ICT-based prevalence within a Bayesian framework and used to make predictions for non-sampled areas. Maps of the dominant vector species of LF were also developed. The maps of predicted prevalence and vector distribution were linked to mathematical models of the transmission dynamics of LF to infer the intensity of transmission, quantified by the basic reproductive number (R0). RESULTS: The literature search identified 1267 surveys that provide suitable data on the prevalence of mf and 2817 surveys that report the prevalence of antigenaemia. Distinct spatial predictions arose from the models for mf prevalence and ICT-based prevalence, with a wider geographical distribution when using ICT-based data. The vector distribution maps demonstrated the spatial variation of LF vector species. Mathematical modelling showed that the reproduction number (R0) estimates vary from 2.7 to 30, with large variations between and within regions. CONCLUSIONS: LF transmission is highly heterogeneous, and the developed maps can help guide intervention, monitoring and surveillance strategies as countries progress towards LF elimination.

Brooker SJ, Mwandawiro CS, Halliday KE, Njenga SM, Mcharo C, Gichuki PM, Wasunna B, Kihara JH, Njomo D, Alusala D et al. 2015. Interrupting transmission of soil-transmitted helminths: a study protocol for cluster randomised trials evaluating alternative treatment strategies and delivery systems in Kenya. BMJ Open, 5 (10), pp. e008950. | Show Abstract | Read more

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.

Medley GF, Hollingsworth TD. 2015. MDA helminth control: more questions than answers. Lancet Glob Health, 3 (10), pp. e583-e584. | Read more

Anderson RM, Turner HC, Truscott JE, Hollingsworth TD, Brooker SJ. 2015. Should the Goal for the Treatment of Soil Transmitted Helminth (STH) Infections Be Changed from Morbidity Control in Children to Community-Wide Transmission Elimination? PLoS Negl Trop Dis, 9 (8), pp. e0003897. | Read more

Turner HC, Truscott JE, Hollingsworth TD, Bettis AA, Brooker SJ, Anderson RM. 2015. Cost and cost-effectiveness of soil-transmitted helminth treatment programmes: systematic review and research needs. Parasit Vectors, 8 (1), pp. 355. | Show Abstract | Read more

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.

Hollingsworth TD, Pilcher CD, Hecht FM, Deeks SG, Fraser C. 2015. High Transmissibility During Early HIV Infection Among Men Who Have Sex With Men-San Francisco, California. J Infect Dis, 211 (11), pp. 1757-1760. | Show Abstract | Read more

We estimate the relative transmission rate in early versus later infection among men who have sex with men (MSM) in San Francisco, California, by studying the characteristics of a sample of transmitters, recruited through newly diagnosed, recently infected MSM between 1996 and 2009. Of 36 transmitters identified, 9 were determined on the basis of testing history and serologic testing to have been recently infected. The unadjusted odds ratio of transmitting during early infection was 15.2 (95% confidence interval [CI], 6.3-33.4; P < .001); the odds ratio was 8.9 (95% CI, 4.1-19.4) after adjustment for self-reported antiretroviral treatment. This high transmissibility could be due to both high infectiousness and high rates of sex partner change or concurrent partnerships.

Rock KS, le Rutte EA, de Vlas SJ, Adams ER, Medley GF, Hollingsworth TD. 2015. Uniting mathematics and biology for control of visceral leishmaniasis. Trends Parasitol, 31 (6), pp. 251-259. | Show Abstract | Read more

The neglected tropical disease (NTD) visceral leishmaniasis (VL) has been targeted by the WHO for elimination as a public health problem on the Indian subcontinent by 2017 or earlier. To date there is a surprising scarcity of mathematical models capable of capturing VL disease dynamics, which are widely considered central to planning and assessing the efficacy of interventions. The few models that have been developed are examined, highlighting the necessity for better data to parameterise and fit these and future models. In particular, the characterisation and infectiousness of the different disease stages will be crucial to elimination. Modelling can then assist in establishing whether, when, and how the WHO VL elimination targets can be met.

Baggaley RF, Hollingsworth TD. 2015. Brief report: HIV-1 transmissions during asymptomatic infection: exploring the impact of changes in HIV-1 viral load due to coinfections. J Acquir Immune Defic Syndr, 68 (5), pp. 594-598. | Show Abstract | Read more

High HIV-1 plasma viral loads (PVLs) in sub-Saharan Africa, partly because of high rates of coinfection, may have been one of the drivers of the "explosive" epidemics seen in that region. Using a previously published framework of infectiousness and survival, we estimate the excess onward HIV-1 transmission events (secondary infections) resulting from coinfection-induced changes in PVL during asymptomatic HIV-1 infection. For every 100 HIV-infected people, each suffering 1 episode of tuberculosis infection, there are 4.9 (2.7th-97.5th percentile: 0.2-21.5) excess onward HIV-1 transmission events attributable to this coinfection. Other estimates are malaria 0.4 (0.0-2.0), soil-transmitted helminths 3.1 (0.1-14.9), schistosomiasis 8.5 (0.2-38.6), filariasis 13.3 (0.3-89.2), syphilis 0.1 (0.0-1.6), herpes simplex virus 4.0 (0.0-24.2), and gonorrhea 2.1 (0.1-8.0) transmissions. If these higher PVLs confer a shorter life expectancy and higher infectiousness, then their impact on transmission is, in general, reduced. For most HIV-1 coinfections, the duration of a single infection is too short and/or the associated PVL elevation is too modest to contribute substantially to onward HIV-1 transmission.

Heesterbeek H, Anderson RM, Andreasen V, Bansal S, De Angelis D, Dye C, Eames KTD, Edmunds WJ, Frost SDW, Funk S et al. 2015. Modeling infectious disease dynamics in the complex landscape of global health. Science, 347 (6227), pp. aaa4339. | Show Abstract | Read more

Despite some notable successes in the control of infectious diseases, transmissible pathogens still pose an enormous threat to human and animal health. The ecological and evolutionary dynamics of infections play out on a wide range of interconnected temporal, organizational, and spatial scales, which span hours to months, cells to ecosystems, and local to global spread. Moreover, some pathogens are directly transmitted between individuals of a single species, whereas others circulate among multiple hosts, need arthropod vectors, or can survive in environmental reservoirs. Many factors, including increasing antimicrobial resistance, increased human connectivity and changeable human behavior, elevate prevention and control from matters of national policy to international challenge. In the face of this complexity, mathematical models offer valuable tools for synthesizing information to understand epidemiological patterns, and for developing quantitative evidence for decision-making in global health.

Metcalf CJE, Andreasen V, Bjørnstad ON, Eames K, Edmunds WJ, Funk S, Hollingsworth TD, Lessler J, Viboud C, Grenfell BT. 2015. Seven challenges in modeling vaccine preventable diseases. Epidemics, 10 pp. 11-15. | Show Abstract | Read more

Vaccination has been one of the most successful public health measures since the introduction of basic sanitation. Substantial mortality and morbidity reductions have been achieved via vaccination against many infections, and the list of diseases that are potentially controllable by vaccines is growing steadily. We introduce key challenges for modeling in shaping our understanding and guiding policy decisions related to vaccine preventable diseases.

Hollingsworth TD, Pulliam JRC, Funk S, Truscott JE, Isham V, Lloyd AL. 2015. Seven challenges for modelling indirect transmission: vector-borne diseases, macroparasites and neglected tropical diseases. Epidemics, 10 pp. 16-20. | Show Abstract | Read more

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.

Klepac P, Funk S, Hollingsworth TD, Metcalf CJE, Hampson K. 2015. Six challenges in the eradication of infectious diseases. Epidemics, 10 pp. 97-101. | Show Abstract | Read more

Eradication and elimination are increasingly a part of the global health agenda. Once control measures have driven infection to low levels, the ecology of disease may change posing challenges for eradication efforts. These challenges vary from identifying pockets of susceptibles, improving monitoring during and after the endgame, to quantifying the economics of disease eradication versus sustained control, all of which are shaped and influenced by processes of loss of immunity, susceptible build-up, emergence of resistance, population heterogeneities and non-compliance with control measures. Here we discuss how modelling can be used to address these challenges.

Lessler J, Edmunds WJ, Halloran ME, Hollingsworth TD, Lloyd AL. 2015. Seven challenges for model-driven data collection in experimental and observational studies. Epidemics, 10 pp. 78-82. | Show Abstract | Read more

Infectious disease models are both concise statements of hypotheses and powerful techniques for creating tools from hypotheses and theories. As such, they have tremendous potential for guiding data collection in experimental and observational studies, leading to more efficient testing of hypotheses and more robust study designs. In numerous instances, infectious disease models have played a key role in informing data collection, including the Garki project studying malaria, the response to the 2009 pandemic of H1N1 influenza in the United Kingdom and studies of T-cell immunodynamics in mammals. However, such synergies remain the exception rather than the rule; and a close marriage of dynamic modeling and empirical data collection is far from the norm in infectious disease research. Overcoming the challenges to using models to inform data collection has the potential to accelerate innovation and to improve practice in how we deal with infectious disease threats.

Griffin JT, Hollingsworth TD, Reyburn H, Drakeley CJ, Riley EM, Ghani AC. 2015. Gradual acquisition of immunity to severe malaria with increasing exposure. Proc Biol Sci, 282 (1801), pp. 20142657. | Show Abstract | Read more

Previous analyses have suggested that immunity to non-cerebral severe malaria due to Plasmodium falciparum is acquired after only a few infections, whereas longitudinal studies show that some children experience multiple episodes of severe disease, suggesting that immunity may not be acquired so quickly. We fitted a mathematical model for the acquisition and loss of immunity to severe disease to the age distribution of severe malaria cases stratified by symptoms from a range of transmission settings in Tanzania, combined with data from several African countries on the age distribution and overall incidence of severe malaria. We found that immunity to severe disease was acquired more gradually with exposure than previously thought. The model also suggests that physiological changes, rather than exposure, may alter the symptoms of disease with increasing age, suggesting that a later age at infection would be associated with a higher proportion of cases presenting with cerebral malaria regardless of exposure. This has consequences for the expected pattern of severe disease as transmission changes. Careful monitoring of the decline in immunity associated with reduced transmission will therefore be needed to ensure rebound epidemics of severe and fatal malaria are avoided.

Truscott J, Hollingsworth TD, Anderson R. 2014. Modeling the interruption of the transmission of soil-transmitted helminths by repeated mass chemotherapy of school-age children. PLoS Negl Trop Dis, 8 (12), pp. e3323. | Show Abstract | Read more

BACKGROUND: The control or elimination of neglected tropical diseases has recently become the focus of increased interest and funding from international agencies through the donation of drugs. Resources are becoming available for the treatment of soil-transmitted helminth (STH) infection through school-based deworming strategies. However, little research has been conducted to assess the impact of STH treatment that could be used to guide the design of efficient elimination programs. METHODOLOGY: We construct and analyse an age-structured model of STH population dynamics under regular treatment. We investigate the potential for elimination with finite rounds of treatment, and how this depends on the value of the basic reproductive number R0 and treatment frequency. PRINCIPAL FINDINGS: Analysis of the model indicates that its behaviour is determined by key parameter groupings describing the basic reproduction number and the fraction of it attributable to the treated group, the timescale of material in the environment and the frequency and efficacy of treatment. Mechanisms of sexual reproduction and persistence of infectious material in the environment are found to be much more important in the context of elimination than in the undisturbed baseline scenario. For a given rate of drug use, sexual reproduction dictates that less frequent, higher coverage treatment is more effective. For a given treatment coverage level, the lifespan of infectious material in the environment places a limit on the effectiveness of increased treatment frequency. CONCLUSIONS: Our work suggests that for models to capture the dynamics of parasite burdens in populations under regular treatment as elimination is approached, they need to include the effects of sexual reproduction among parasites and the dynamics infectious material in the reservoir. The interaction of these two mechanisms has a strong effect on optimum treatment strategies, both in terms of how frequently to treat and for how long.

Pinsent A, Read JM, Griffin JT, Smith V, Gething PW, Ghani AC, Pasvol G, Hollingsworth TD. 2014. Risk factors for UK Plasmodium falciparum cases. Malar J, 13 (1), pp. 298. | Show Abstract | Read more

BACKGROUND: An increasing proportion of malaria cases diagnosed in UK residents with a history of travel to malaria endemic areas are due to Plasmodium falciparum. METHODS: In order to identify travellers at most risk of acquiring malaria a proportional hazards model was used to estimate the risk of acquiring malaria stratified by purpose of travel and age whilst adjusting for entomological inoculation rate (EIR) and duration of stay in endemic countries. RESULTS: Travellers visiting friends and relatives and business travellers were found to have significantly higher hazard of acquiring malaria (adjusted hazard ratio (HR) relative to that of holiday makers 7.4, 95% CI 6.4-8.5, p < 0. 0001 and HR 3.4, 95% CI 2.9-3.8, p < 0. 0001, respectively). All age-groups were at lower risk than children aged 0-15 years. CONCLUSIONS: These estimates of the increased risk for business travellers and those visiting friends and relatives should be used to inform programmes to improve awareness of the risks of malaria when travelling.

Truscott JE, Hollingsworth TD, Brooker SJ, Anderson RM. 2014. Can chemotherapy alone eliminate the transmission of soil transmitted helminths? Parasit Vectors, 7 (1), pp. 266. | Show Abstract | Read more

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.

Anderson R, Truscott J, Hollingsworth TD. 2014. The coverage and frequency of mass drug administration required to eliminate persistent transmission of soil-transmitted helminths. Philos Trans R Soc Lond B Biol Sci, 369 (1645), pp. 20130435. | Show Abstract | Read more

A combination of methods, including mathematical model construction, demographic plus epidemiological data analysis and parameter estimation, are used to examine whether mass drug administration (MDA) alone can eliminate the transmission of soil-transmitted helminths (STHs). Numerical analyses suggest that in all but low transmission settings (as defined by the magnitude of the basic reproductive number, R0), the treatment of pre-school-aged children (pre-SAC) and school-aged children (SAC) is unlikely to drive transmission to a level where the parasites cannot persist. High levels of coverage (defined as the fraction of an age group effectively treated) are required in pre-SAC, SAC and adults, if MDA is to drive the parasite below the breakpoint under which transmission is eliminated. Long-term solutions to controlling helminth infections lie in concomitantly improving the quality of the water supply, sanitation and hygiene (WASH). MDA, however, is a very cost-effective tool in long-term control given that most drugs are donated free by the pharmaceutical industry for poor regions of the world. WASH interventions, by lowering the basic reproductive number, can facilitate the ability of MDA to interrupt transmission.

Fraser C, Lythgoe K, Leventhal GE, Shirreff G, Hollingsworth TD, Alizon S, Bonhoeffer S. 2014. Virulence and pathogenesis of HIV-1 infection: an evolutionary perspective. Science, 343 (6177), pp. 1243727. | Show Abstract | Read more

Why some individuals develop AIDS rapidly whereas others remain healthy without treatment for many years remains a central question of HIV research. An evolutionary perspective reveals an apparent conflict between two levels of selection on the virus. On the one hand, there is rapid evolution of the virus in the host, and on the other, new observations indicate the existence of virus factors that affect the virulence of infection whose influence persists over years in infected individuals and across transmission events. Here, we review recent evidence that shows that viral genetic factors play a larger role in modulating disease severity than anticipated. We propose conceptual models that reconcile adaptive evolution at both levels of selection. Evolutionary analysis provides new insight into HIV pathogenesis.

Anderson RM, Truscott JE, Pullan RL, Brooker SJ, Hollingsworth TD. 2013. How effective is school-based deworming for the community-wide control of soil-transmitted helminths? PLoS Negl Trop Dis, 7 (2), pp. e2027. | Show Abstract | Read more

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.

Baggaley RF, White RG, Hollingsworth TD, Boily M-C. 2013. Heterosexual HIV-1 infectiousness and antiretroviral use: systematic review of prospective studies of discordant couples. Epidemiology, 24 (1), pp. 110-121. | Show Abstract | Read more

BACKGROUND: Recent studies have estimated the reduction in HIV-1 infectiousness with antiretroviral therapy (ART), but high-quality studies such as randomized controlled trials, accompanied by rigorous adherence counseling, are likely to overestimate the effectiveness of treatment-as-prevention in real-life settings. METHODS: We attempted to summarize the effect of ART on HIV transmission by undertaking a systematic review and meta-analysis of HIV-1 infectiousness per heterosexual partnership (incidence rate and cumulative incidence over study follow-up) estimated from prospective studies of discordant couples. We used random-effects Poisson regression models to obtain summary estimates. When possible, the analyses were further stratified by direction of transmission (man-to-woman or woman-to-man) and economic setting (high- or low-income countries). Potential causes of heterogeneity of estimates were explored through subgroup analyses. RESULTS: Fifty publications were included. Nine allowed comparison between ART and non-ART users within studies (ART-stratified studies), in which summary incidence rates were 3.6/100 person-years (95% confidence interval = 2.0-6.5) and 0.2/100 person-years (0.07-0.7) for non-ART- and ART-using couples, respectively (P < 0.001), constituting a 91% (79-96%) reduction in per-partner HIV-1 incidence rate with ART use. The 41 studies that did not stratify by ART use provided estimates with high levels of heterogeneity (I statistic) and few reported levels of ART use, making interpretation difficult. Nevertheless, estimates tended to be lower with ART use. Infectiousness tended to be higher for low-income than high-income settings, but there was no clear pattern by direction of transmission (man-to-woman and woman-to-man). CONCLUSIONS: ART substantially reduces HIV-1 infectiousness within discordant couples, based on observational studies, and could play a major part in HIV-1 prevention efforts. However, the non-zero risk from partners receiving ART demonstrates that appropriate counseling and other risk-reduction strategies for discordant couples are still required. Additional estimates of ART effectiveness by adherence level from real-life settings will be important, especially for persons starting treatment early without symptoms.

Bezemer D, de Wolf F, Boerlijst MC, van Sighem A, Hollingsworth D, Fraser C. 2012. 27 years of the HIV epidemic amongst men having sex with men in the Netherlands: An in depth mathematical model-based analysis (vol 2, pg 66, 2010) EPIDEMICS, 4 (3), pp. 170-170. | Read more

Anderson RM, Hollingsworth TD, Truscott J, Brooker S. 2012. Optimisation of mass chemotherapy to control soil-transmitted helminth infection (vol 379, pg 289, 2012) LANCET, 379 (9821), pp. 1102-1102. | Read more

Anderson RM, Hollingsworth TD, Truscott J, Brooker S. 2012. Department of Error The Lancet, 379 (9821), pp. 1102-1102. | Read more

Anderson R, Hollingsworth TD, Truscott J, Brooker S. 2012. Optimisation of mass chemotherapy to control soil-transmitted helminth infection. Lancet, 379 (9813), pp. 289-290. | Read more

Okell LC, Griffin JT, Kleinschmidt I, Hollingsworth TD, Churcher TS, White MJ, Bousema T, Drakeley CJ, Ghani AC. 2011. The potential contribution of mass treatment to the control of Plasmodium falciparum malaria. PLoS One, 6 (5), pp. e20179. | Show Abstract | Read more

Mass treatment as a means to reducing P. falciparum malaria transmission was used during the first global malaria eradication campaign and is increasingly being considered for current control programmes. We used a previously developed mathematical transmission model to explore both the short and long-term impact of possible mass treatment strategies in different scenarios of endemic transmission. Mass treatment is predicted to provide a longer-term benefit in areas with lower malaria transmission, with reduced transmission levels for at least 2 years after mass treatment is ended in a scenario where the baseline slide-prevalence is 5%, compared to less than one year in a scenario with baseline slide-prevalence at 50%. However, repeated annual mass treatment at 80% coverage could achieve around 25% reduction in infectious bites in moderate-to-high transmission settings if sustained. Using vector control could reduce transmission to levels at which mass treatment has a longer-term impact. In a limited number of settings (which have isolated transmission in small populations of 1000-10,000 with low-to-medium levels of baseline transmission) we find that five closely spaced rounds of mass treatment combined with vector control could make at least temporary elimination a feasible goal. We also estimate the effects of using gametocytocidal treatments such as primaquine and of restricting treatment to parasite-positive individuals. In conclusion, mass treatment needs to be repeated or combined with other interventions for long-term impact in many endemic settings. The benefits of mass treatment need to be carefully weighed against the risks of increasing drug selection pressure.

Hollingsworth TD, Klinkenberg D, Heesterbeek H, Anderson RM. 2011. Mitigation strategies for pandemic influenza A: balancing conflicting policy objectives. PLoS Comput Biol, 7 (2), pp. e1001076. | Show Abstract | Read more

Mitigation of a severe influenza pandemic can be achieved using a range of interventions to reduce transmission. Interventions can reduce the impact of an outbreak and buy time until vaccines are developed, but they may have high social and economic costs. The non-linear effect on the epidemic dynamics means that suitable strategies crucially depend on the precise aim of the intervention. National pandemic influenza plans rarely contain clear statements of policy objectives or prioritization of potentially conflicting aims, such as minimizing mortality (depending on the severity of a pandemic) or peak prevalence or limiting the socio-economic burden of contact-reducing interventions. We use epidemiological models of influenza A to investigate how contact-reducing interventions and availability of antiviral drugs or pre-pandemic vaccines contribute to achieving particular policy objectives. Our analyses show that the ideal strategy depends on the aim of an intervention and that the achievement of one policy objective may preclude success with others, e.g., constraining peak demand for public health resources may lengthen the duration of the epidemic and hence its economic and social impact. Constraining total case numbers can be achieved by a range of strategies, whereas strategies which additionally constrain peak demand for services require a more sophisticated intervention. If, for example, there are multiple objectives which must be achieved prior to the availability of a pandemic vaccine (i.e., a time-limited intervention), our analysis shows that interventions should be implemented several weeks into the epidemic, not at the very start. This observation is shown to be robust across a range of constraints and for uncertainty in estimates of both R(0) and the timing of vaccine availability. These analyses highlight the need for more precise statements of policy objectives and their assumed consequences when planning and implementing strategies to mitigate the impact of an influenza pandemic.

Fraser C, Hollingsworth TD. 2010. Interpretation of correlations in setpoint viral load in transmitting couples. AIDS, 24 (16), pp. 2596-2597. | Read more

Griffin JT, Hollingsworth TD, Okell LC, Churcher TS, White M, Hinsley W, Bousema T, Drakeley CJ, Ferguson NM, Basáñez M-G, Ghani AC. 2010. Reducing Plasmodium falciparum malaria transmission in Africa: a model-based evaluation of intervention strategies. PLoS Med, 7 (8), pp. e1000324-e1000324. | Show Abstract | Read more

BACKGROUND: Over the past decade malaria intervention coverage has been scaled up across Africa. However, it remains unclear what overall reduction in transmission is achievable using currently available tools. METHODS AND FINDINGS: We developed an individual-based simulation model for Plasmodium falciparum transmission in an African context incorporating the three major vector species (Anopheles gambiae s.s., An. arabiensis, and An. funestus) with parameters obtained by fitting to parasite prevalence data from 34 transmission settings across Africa. We incorporated the effect of the switch to artemisinin-combination therapy (ACT) and increasing coverage of long-lasting insecticide treated nets (LLINs) from the year 2000 onwards. We then explored the impact on transmission of continued roll-out of LLINs, additional rounds of indoor residual spraying (IRS), mass screening and treatment (MSAT), and a future RTS,S/AS01 vaccine in six representative settings with varying transmission intensity (as summarized by the annual entomological inoculation rate, EIR: 1 setting with low, 3 with moderate, and 2 with high EIRs), vector-species combinations, and patterns of seasonality. In all settings we considered a realistic target of 80% coverage of interventions. In the low-transmission setting (EIR approximately 3 ibppy [infectious bites per person per year]), LLINs have the potential to reduce malaria transmission to low levels (<1% parasite prevalence in all age-groups) provided usage levels are high and sustained. In two of the moderate-transmission settings (EIR approximately 43 and 81 ibppy), additional rounds of IRS with DDT coupled with MSAT could drive parasite prevalence below a 1% threshold. However, in the third (EIR = 46) with An. arabiensis prevailing, these interventions are insufficient to reach this threshold. In both high-transmission settings (EIR approximately 586 and 675 ibppy), either unrealistically high coverage levels (>90%) or novel tools and/or substantial social improvements will be required, although considerable reductions in prevalence can be achieved with existing tools and realistic coverage levels. CONCLUSIONS: Interventions using current tools can result in major reductions in P. falciparum malaria transmission and the associated disease burden in Africa. Reduction to the 1% parasite prevalence threshold is possible in low- to moderate-transmission settings when vectors are primarily endophilic (indoor-resting), provided a comprehensive and sustained intervention program is achieved through roll-out of interventions. In high-transmission settings and those in which vectors are mainly exophilic (outdoor-resting), additional new tools that target exophagic (outdoor-biting), exophilic, and partly zoophagic mosquitoes will be required.

Bezemer D, de Wolf F, Boerlijst MC, van Sighem A, Hollingsworth TD, Fraser C. 2010. 27 years of the HIV epidemic amongst men having sex with men in the Netherlands: an in depth mathematical model-based analysis. Epidemics, 2 (2), pp. 66-79. | Show Abstract | Read more

BACKGROUND: There has been increasing concern about a resurgent epidemic of HIV-1 amongst men having sex with men in the Netherlands, which has parallels with similar epidemics now occurring in many other countries. METHODS: A transmission model applicable to HIV-1 epidemics, including the use of antiretroviral therapy, is presented in a set of ordinary differential equations. The model is fitted by maximum likelihood to national HIV-1 and AIDS diagnosis data from 1980 to 2006, estimating parameters on average changes in unsafe sex and time to diagnosis. Robustness is studied with a detailed univariate sensitivity analysis, and a range of hypothetical scenarios are explored for the past and next decade. RESULTS: With a reproduction number around the epidemic threshold one, the HIV-1 epidemic amongst men having sex with men in the Netherlands is still not under control. Scenario analysis showed that in the absence of antiretroviral therapy limiting infectiousness in treated patients, the epidemic could have been more than double its current size. Ninety percent of new HIV transmissions are estimated to take place before diagnosis of the index case. Decreasing time from infection to diagnosis, which was 2.5 years on average in 2006, can prevent many future infections. CONCLUSIONS: Sexual risk behaviour amongst men having sex with men who are not aware of their infection is the most likely factor driving this epidemic.

Hollingsworth TD, Laeyendecker O, Shirreff G, Donnelly CA, Serwadda D, Wawer MJ, Kiwanuka N, Nalugoda F, Collinson-Streng A, Ssempijja V et al. 2010. HIV-1 transmitting couples have similar viral load set-points in Rakai, Uganda. PLoS Pathog, 6 (5), pp. e1000876. | Show Abstract | Read more

It has been hypothesized that HIV-1 viral load set-point is a surrogate measure of HIV-1 viral virulence, and that it may be subject to natural selection in the human host population. A key test of this hypothesis is whether viral load set-points are correlated between transmitting individuals and those acquiring infection. We retrospectively identified 112 heterosexual HIV-discordant couples enrolled in a cohort in Rakai, Uganda, in which HIV transmission was suspected and viral load set-point was established. In addition, sequence data was available to establish transmission by genetic linkage for 57 of these couples. Sex, age, viral subtype, index partner, and self-reported genital ulcer disease status (GUD) were known. Using ANOVA, we estimated the proportion of variance in viral load set-points which was explained by the similarity within couples (the 'couple effect'). Individuals with suspected intra-couple transmission (97 couples) had similar viral load set-points (p = 0.054 single factor model, p = 0.0057 adjusted) and the couple effect explained 16% of variance in viral loads (23% adjusted). The analysis was repeated for a subset of 29 couples with strong genetic support for transmission. The couple effect was the major determinant of viral load set-point (p = 0.067 single factor, and p = 0.036 adjusted) and the size of the effect was 27% (37% adjusted). Individuals within epidemiologically linked couples with genetic support for transmission had similar viral load set-points. The most parsimonious explanation is that this is due to shared characteristics of the transmitted virus, a finding which sheds light on both the role of viral factors in HIV-1 pathogenesis and on the evolution of the virus.

Shirreff G, Hollingsworth TD, Hanage WP, Fraser C. 2010. Modelling the between-host evolution of set-point viral load in HIV infection INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 14 pp. E79-E79. | Read more

Rhodes CJ, Hollingsworth TD. 2009. Variational data assimilation with epidemic models (vol 258, pg 591, 2009) JOURNAL OF THEORETICAL BIOLOGY, 260 (4), pp. 599-599. | Read more

Christophe Fraser, Christl AD, Cauchemez S, Hanage WP, Van Kerkhove MD, Hollingsworth TD, Griffin J, Baggaley RF, Jenkins HE, Lyons EJ et al. 2009. Response Science, 325 (5944), pp. 1072-1073.

Hollingsworth TD. 2009. Controlling infectious disease outbreaks: Lessons from mathematical modelling. J Public Health Policy, 30 (3), pp. 328-341. | Show Abstract | Read more

Epidemiological analysis and mathematical models are now essential tools in understanding the dynamics of infectious diseases and in designing public health strategies to contain them. They have provided fundamental concepts, such as the basic and effective reproduction number, generation times, epidemic growth rates, and the role of pre-symptomatic infectiousness, which are crucial in characterising infectious diseases. These concepts are outlined and their relevance in designing control policies for outbreaks is discussed. They are illustrated using examples from the 2003 severe acute respiratory syndrome outbreak, which was brought under control within a year, and from pandemic influenza planning, where mathematical models have been used extensively.

Fraser C, Donnelly CA, Cauchemez S, Hanage WP, Van Kerkhove MD, Hollingsworth TD, Griffin J, Baggaley RF, Jenkins HE, Lyons EJ et al. 2009. Influenza: Making Privileged Data Public Response SCIENCE, 325 (5944), pp. 1072-1073. | Read more

Fraser C, Donnelly CA, Cauchemez S, Hanage WP, Van Kerkhove MD, Hollingsworth TD, Griffin J, Baggaley RF, Jenkins HE, Lyons EJ et al. 2009. Pandemic potential of a strain of influenza A (H1N1): early findings. Science, 324 (5934), pp. 1557-1561. | Show Abstract | Read more

A novel influenza A (H1N1) virus has spread rapidly across the globe. Judging its pandemic potential is difficult with limited data, but nevertheless essential to inform appropriate health responses. By analyzing the outbreak in Mexico, early data on international spread, and viral genetic diversity, we make an early assessment of transmissibility and severity. Our estimates suggest that 23,000 (range 6000 to 32,000) individuals had been infected in Mexico by late April, giving an estimated case fatality ratio (CFR) of 0.4% (range: 0.3 to 1.8%) based on confirmed and suspected deaths reported to that time. In a community outbreak in the small community of La Gloria, Veracruz, no deaths were attributed to infection, giving an upper 95% bound on CFR of 0.6%. Thus, although substantial uncertainty remains, clinical severity appears less than that seen in the 1918 influenza pandemic but comparable with that seen in the 1957 pandemic. Clinical attack rates in children in La Gloria were twice that in adults (<15 years of age: 61%; >/=15 years: 29%). Three different epidemiological analyses gave basic reproduction number (R0) estimates in the range of 1.4 to 1.6, whereas a genetic analysis gave a central estimate of 1.2. This range of values is consistent with 14 to 73 generations of human-to-human transmission having occurred in Mexico to late April. Transmissibility is therefore substantially higher than that of seasonal flu, and comparable with lower estimates of R0 obtained from previous influenza pandemics.

Rhodes CJ, Hollingsworth TD. 2009. Variational data assimilation with epidemic models. J Theor Biol, 258 (4), pp. 591-602. | Show Abstract | Read more

Mathematical modelling is playing an increasing role in developing an understanding of the dynamics of communicable disease and assisting the construction and implementation of intervention strategies. The threat of novel emergent pathogens in human and animal hosts implies the requirement for methods that can robustly estimate epidemiological parameters and provide forecasts. Here, a technique called variational data assimilation is introduced as a means of optimally melding dynamic epidemic models with epidemiological observations and data to provide forecasts and parameter estimates. Using data from a simulated epidemic process the method is used to estimate the start time of an epidemic, to provide a forecast of future epidemic behaviour and estimate the basic reproductive ratio. A feature of the method is that it uses a basic continuous-time SIR model, which is often the first point of departure for epidemiological modelling during the early stages of an outbreak. The method is illustrated by application to data gathered during an outbreak of influenza in a school environment.

Baggaley RF, Griffin JT, Chapman R, Hollingsworth TD, Nagot N, Delany S, Mayaud P, de Wolf F, Fraser C, Ghani AC, Weiss HA. 2009. Estimating the public health impact of the effect of herpes simplex virus suppressive therapy on plasma HIV-1 viral load. AIDS, 23 (8), pp. 1005-1013. | Show Abstract | Read more

OBJECTIVE: Trials of herpes simplex virus (HSV) suppressive therapy among HSV-2/HIV-1-infected individuals have reported an impact on plasma HIV-1 viral loads (PVLs). Our aim was to estimate the population-level impact of suppressive therapy on female-to-male HIV-1 sexual transmission. DESIGN AND METHODS: By comparing prerandomization and postrandomization individual-level PVL data from the first two HSV suppressive therapy randomized controlled trials in sub-Saharan Africa, we estimated the effect of treatment on duration of asymptomatic infection and number of HIV-1 transmission events for each trial. RESULTS: Assuming that a reduction in PVL is accompanied by an increased duration of HIV-1 asymptomatic infection, 4-6 years of HSV suppressive therapy produce a 1-year increase in the duration of this stage. To avert one HIV-1 transmission requires 8.8 [95% confidence interval (CI), 5.9-14.9] and 11.4 (95% CI, 7.8-27.5) women to be treated from halfway through their HIV-1 asymptomatic period, using results from Burkina Faso and South African trials, respectively. Regardless of the timing of treatment initiation, 51.6 (95% CI, 30.4-137.0) and 66.5 (95% CI, 36.7-222.6) treatment-years are required to avert one HIV-1 infection. Distributions of set-point PVL values from sub-Saharan African populations suggest that unintended adverse consequences of therapy at the population level (i.e. increased HIV-1 transmission due to increased duration of infection) are unlikely to occur in these settings. CONCLUSION: HSV suppressive therapy may avert relatively few HIV-1 transmission events per person-year of treatment. Its use as a prevention intervention may be limited; however, further research into its effect on rate of CD4 cell count decline and the impact of higher dosing schedules is warranted.

Hollingsworth TD, Anderson RM, Fraser C. 2008. HIV-1 transmission, by stage of infection. J Infect Dis, 198 (5), pp. 687-693. | Show Abstract | Read more

BACKGROUND: The epidemiological impact of public health interventions targeted at reducing transmission of human immunodeficiency virus type 1 (HIV-1) during early or late-stage infection depends on the contribution of these disease stages to transmission within a particular epidemic. METHODS: Transmission hazards and durations of periods of high infectivity during primary, asymptomatic, and late-stage infection were estimated for HIV-1-serodiscordant heterosexual couples in Rakai, Uganda, by use of a robust probabilistic framework. RESULTS: Primary infection and late-stage infection were estimated to be 26 and 7 times, respectively, more infectious than asymptomatic infection. High infectiousness during primary infection was estimated to last for approximately 3 months after seroconversion, whereas high infectiousness during late-stage infection was estimated to be concentrated between 19 months and 10 months before death. CONCLUSIONS: Primary and late-stage HIV-1 infection are more infectious than previously estimated, but for shorter periods. In a homogeneous population, the asymptomatic stage of infection will typically contribute more to the net transmission of HIV-1 over the lifetime of an infected individual, because of its longer duration. The dependence of the relative contribution of infectious stages on patterns of sexual behavior and the phase of epidemics is discussed.

Bezemer D, de Wolf F, Boerlijst MC, van Sighem A, Hollingsworth TD, Prins M, Geskus RB, Gras L, Coutinho RA, Fraser C. 2008. A resurgent HIV-1 epidemic among men who have sex with men in the era of potent antiretroviral therapy. AIDS, 22 (9), pp. 1071-1077. | Show Abstract | Read more

OBJECTIVE: Reducing viral load, highly active antiretroviral therapy has the potential to limit onwards transmission of HIV-1 and thus help contain epidemic spread. However, increases in risk behaviour and resurgent epidemics have been widely reported post-highly active antiretroviral therapy. The aim of this study was to quantify the impact that highly active antiretroviral therapy had on the epidemic. DESIGN: We focus on the HIV-1 epidemic among men who have sex with men in the Netherlands, which has been well documented over the past 20 years within several long-standing national surveillance programs. METHODS: We used a mathematical model including highly active antiretroviral therapy use and estimated the changes in risk behaviour and diagnosis rate needed to explain annual data on HIV and AIDS diagnoses. RESULTS: We show that the reproduction number R(t), a measure of the state of the epidemic, declined early on from initial values above two and was maintained below one from 1985 to 2000. Since 1996, when highly active antiretroviral therapy became widely used, the risk behaviour rate has increased 66%, resulting in an increase of R(t) to 1.04 in the latest period 2000-2004 (95% confidence interval 0.98-1.09) near or just above the threshold for a self-sustaining epidemic. Hypothetical scenario analysis shows that the epidemiological benefits of highly active antiretroviral therapy and earlier diagnosis on incidence have been entirely offset by increases in the risk behaviour rate. CONCLUSION: We provide the first detailed quantitative analysis of the HIV epidemic in a well defined population and find a resurgent epidemic in the era of highly active antiretroviral therapy, most likely predominantly caused by increasing sexual risk behaviour.

Fraser C, Hollingsworth TD, Chapman R, de Wolf F, Hanage WP. 2007. Variation in HIV-1 set-point viral load: epidemiological analysis and an evolutionary hypothesis. Proc Natl Acad Sci U S A, 104 (44), pp. 17441-17446. | Show Abstract | Read more

The natural course of HIV-1 infection is characterized by a high degree of heterogeneity in viral load, not just within patients over time, but also between patients, especially during the asymptomatic stage of infection. Asymptomatic, or set-point, viral load has been shown to correlate with both decreased time to AIDS and increased infectiousness. The aim of this study is to characterize the epidemiological impact of heterogeneity in set-point viral load. By analyzing two cohorts of untreated patients, we quantify the relationships between both viral load and infectiousness and the duration of the asymptomatic infectious period. We find that, because both the duration of infection and infectiousness determine the opportunities for the virus to be transmitted, this suggests a trade-off between these contributions to the overall transmission potential. Some public health implications of variation in set-point viral load are discussed. We observe that set-point viral loads are clustered around those that maximize the transmission potential, and this leads us to hypothesize that HIV-1 could have evolved to optimize its transmissibility, a form of adaptation to the human host population. We discuss how this evolutionary hypothesis can be tested, review the evidence available to date, and highlight directions for future research.

Hollingsworth TD, Ferguson NM, Anderson RM. 2007. Frequent travelers and rate of spread of epidemics. Emerg Infect Dis, 13 (9), pp. 1288-1294. | Show Abstract | Read more

A small proportion of air travelers make disproportionately more journeys than the rest of travelers. They also tend to interact predominantly with other frequent travelers in hotels and airport lounges. This group has the potential to accelerate global spread of infectious respiratory diseases. Using an epidemiologic model, we simulated exportation of cases from severe acute respiratory syndrome-like and influenza-like epidemics in a population for which a small proportion travel more frequently than the rest. Our simulations show that frequent travelers accelerate international spread of epidemics only if they are infected early in an outbreak and the outbreak does not expand rapidly. If the epidemic growth rate is high, as is likely for pandemic influenza, heterogeneities in travel are frequently overwhelmed by the large number of infected persons in the majority population and the resulting high probability that some of these persons will take an international flight.

Hollingsworth TD, Ferguson NM, Anderson RM. 2006. Will travel restrictions control the international spread of pandemic influenza? Nat Med, 12 (5), pp. 497-499. | Read more

Cited:

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Scopus

Bianchi M, Boyle M, Hollingsworth D. 1999. A comparison of methods for trend estimation APPLIED ECONOMICS LETTERS, 6 (2), pp. 103-109. | Show Abstract | Read more

This paper analyses a number of methods for trend estimation focusing on their ability to pick up turning points quickly at the end of a series. An application to the Bank of England flows M4 series is provided which shows that some of the proposed methods may be more reliable than others for this task.

Hollingsworth TD. 2018. Counting Down the 2020 Goals for 9 Neglected Tropical Diseases: What Have We Learned From Quantitative Analysis and Transmission Modeling? Clin Infect Dis, 66 (suppl_4), pp. S237-S244. | Show Abstract | Read more

The control of neglected tropical diseases (NTDs) has received huge investment in recent years, leading to large reductions in morbidity. In 2012, the World Health Organization set ambitious targets for eliminating many of these diseases as a public health problem by 2020, an aspiration that was supported by donations of treatments, intervention materials, and funding committed by a broad partnership of stakeholders in the London Declaration on NTDs. Alongside these efforts, there has been an increasing role for quantitative analysis and modeling to support the achievement of these goals through evaluation of the likely impact of interventions, the factors that could undermine these achievements, and the role of new diagnostics and treatments in reducing transmission. In this special issue, we aim to summarize those insights in an accessible way. This article acts as an introduction to the special issue, outlining key concepts in NTDs and insights from modeling as we approach 2020.

Baggaley RF, Irvine MA, Leber W, Cambiano V, Figueroa J, McMullen H, Anderson J, Santos AC, Terris-Prestholt F, Miners A et al. 2017. Cost-effectiveness of screening for HIV in primary care: a health economics modelling analysis. Lancet HIV, 4 (10), pp. e465-e474. | Show Abstract | Read more

BACKGROUND: Early HIV diagnosis reduces morbidity, mortality, the probability of onward transmission, and their associated costs, but might increase cost because of earlier initiation of antiretroviral treatment (ART). We investigated this trade-off by estimating the cost-effectiveness of HIV screening in primary care. METHODS: We modelled the effect of the four-times higher diagnosis rate observed in the intervention arm of the RHIVA2 randomised controlled trial done in Hackney, London (UK), a borough with high HIV prevalence (≥0·2% adult prevalence). We constructed a dynamic, compartmental model representing incidence of infection and the effect of screening for HIV in general practices in Hackney. We assessed cost-effectiveness of the RHIVA2 trial by fitting model diagnosis rates to the trial data, parameterising with epidemiological and behavioural data from the literature when required, using trial testing costs and projecting future costs of treatment. FINDINGS: Over a 40 year time horizon, incremental cost-effectiveness ratios were £22 201 (95% credible interval 12 662-132 452) per quality-adjusted life-year (QALY) gained, £372 207 (268 162-1 903 385) per death averted, and £628 874 (434 902-4 740 724) per HIV transmission averted. Under this model scenario, with UK cost data, RHIVA2 would reach the upper National Institute for Health and Care Excellence cost-effectiveness threshold (about £30 000 per QALY gained) after 33 years. Scenarios using cost data from Canada (which indicate prolonged and even higher health-care costs for patients diagnosed late) suggest this threshold could be reached in as little as 13 years. INTERPRETATION: Screening for HIV in primary care has important public health benefits as well as clinical benefits. We predict it to be cost-effective in the UK in the medium term. However, this intervention might be cost-effective far sooner, and even cost-saving, in settings where long-term health-care costs of late-diagnosed patients in high-prevalence regions are much higher (≥60%) than those of patients diagnosed earlier. Screening for HIV in primary care is cost-effective and should be promoted. FUNDING: NHS City and Hackney, UK Department of Health, National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care.

Steinmann P, Reed SG, Mirza F, Hollingsworth TD, Richardus JH. 2017. Innovative tools and approaches to end the transmission of Mycobacterium leprae. Lancet Infect Dis, 17 (9), pp. e298-e305. | Show Abstract | Read more

Leprosy control has seen little innovation and only limited progress in the past decade. However, research on the disease has increased and important innovations are underway. Here, we comment on efforts to develop tools and approaches to detect leprosy and to stop the transmission of Mycobacterium leprae, the causative bacillus of the disease. The tracing and screening of contacts of known patients with leprosy promises to strengthen early diagnosis, while preventive chemotherapy will reduce the risk of contacts developing the disease by 50-60% within 2 years of administration. Until now, diagnosis has been mainly based on the presence of signs and symptoms, but efforts are underway to develop inexpensive, reliable, point-of-care tests to diagnose infection. Development of a leprosy-specific vaccine that boosts long-lasting T-cell responses is also a research objective. As for launching a programme to interrupt transmission, two interlinked tools-epidemiological modelling and the concept of an investment case-are being developed to explore the feasibility and costs of such a programme and its overall effect on individuals and society. We believe that sustained innovation is needed and that only a combination of tools and approaches holds promise to end M leprae transmission.

Irvine MA, Stolk WA, Smith ME, Subramanian S, Singh BK, Weil GJ, Michael E, Hollingsworth TD. 2017. Effectiveness of a triple-drug regimen for global elimination of lymphatic filariasis: a modelling study. Lancet Infect Dis, 17 (4), pp. 451-458. | Show Abstract | Read more

BACKGROUND: Lymphatic filariasis is targeted for elimination as a public health problem by 2020. The principal approach used by current programmes is annual mass drug administration with two pairs of drugs with a good safety profile. However, one dose of a triple-drug regimen (ivermectin, diethylcarbamazine, and albendazole) has been shown to clear the transmissible stage of the helminth completely in treated individuals. The aim of this study was to use modelling to assess the potential value of mass drug administration with the triple-drug regimen for accelerating elimination of lymphatic filariasis in different epidemiological settings. METHODS: We used three different transmission models to compare the number of rounds of mass drug administration needed to achieve a prevalence of microfilaraemia less than 1% with the triple-drug regimen and with current two-drug regimens. FINDINGS: In settings with a low baseline prevalence of lymphatic filariasis (5%), the triple-drug regimen reduced the number of rounds of mass drug administration needed to reach the target prevalence by one or two rounds, compared with the two-drug regimen. For areas with higher baseline prevalence (10-40%), the triple-drug regimen strikingly reduced the number of rounds of mass drug administration needed, by about four or five, but only at moderate-to-high levels of population coverage (>65%) and if systematic non-adherence to mass drug administration was low. INTERPRETATION: Simulation modelling suggests that the triple-drug regimen has potential to accelerate the elimination of lymphatic filariasis if high population coverage of mass drug administration can be achieved and if systematic non-adherence with mass drug administration is low. Future work will reassess these estimates in light of more clinical trial data and to understand the effect on an individual country's programme. FUNDING: Bill & Melinda Gates Foundation.

Medley GF, Hollingsworth TD, Olliaro PL, Adams ER. 2015. Health-seeking behaviour, diagnostics and transmission dynamics in the control of visceral leishmaniasis in the Indian subcontinent. Nature, 528 (7580), pp. S102-S108. | Show Abstract | Read more

Countries in the Indian subcontinent have committed to reducing the incidence of kala-azar, a clinical manifestation of visceral leishmaniasis, to below 1 in 10,000 by 2020. We address the role of timing of use and accuracy of diagnostics in kala-azar control and elimination. We use empirical data on health-seeking behaviour and health-system performance from the Indian state of Bihar, Bangladesh and Nepal to parameterize a mathematical model. Diagnosis of cases is key to case management, control and surveillance. Treatment of cases prevents onward transmission, and we show that the differences in time to diagnosis in these three settings explain the observed differences in incidence. Shortening the time from health-care seeking to diagnosis is likely to lead to dramatic reductions in incidence in Bihar, bringing the incidence down to the levels seen in Bangladesh and Nepal. The results emphasize the importance of maintaining population and health-system awareness, particularly as transmission and disease incidence decline. We explore the possibility of diagnosing patients before the onset of clinical kala-azar (before 14 days fever), and show that this could have a marked impact on incidence, even for a moderately sensitive test. However, limited specificity (that results in false positives) is a major barrier to such a strategy. Diagnostic tests of high specificity used at an early stage of active infection, even if sensitivity is only moderate, could have a key role in the control of kala-azar, and prevent its resurgence when paired with the passive health-care system and tests of high sensitivity, such as the test for rK39 antibody response.

Heesterbeek H, Anderson RM, Andreasen V, Bansal S, De Angelis D, Dye C, Eames KTD, Edmunds WJ, Frost SDW, Funk S et al. 2015. Modeling infectious disease dynamics in the complex landscape of global health. Science, 347 (6227), pp. aaa4339. | Show Abstract | Read more

Despite some notable successes in the control of infectious diseases, transmissible pathogens still pose an enormous threat to human and animal health. The ecological and evolutionary dynamics of infections play out on a wide range of interconnected temporal, organizational, and spatial scales, which span hours to months, cells to ecosystems, and local to global spread. Moreover, some pathogens are directly transmitted between individuals of a single species, whereas others circulate among multiple hosts, need arthropod vectors, or can survive in environmental reservoirs. Many factors, including increasing antimicrobial resistance, increased human connectivity and changeable human behavior, elevate prevention and control from matters of national policy to international challenge. In the face of this complexity, mathematical models offer valuable tools for synthesizing information to understand epidemiological patterns, and for developing quantitative evidence for decision-making in global health.

Fraser C, Lythgoe K, Leventhal GE, Shirreff G, Hollingsworth TD, Alizon S, Bonhoeffer S. 2014. Virulence and pathogenesis of HIV-1 infection: an evolutionary perspective. Science, 343 (6177), pp. 1243727. | Show Abstract | Read more

Why some individuals develop AIDS rapidly whereas others remain healthy without treatment for many years remains a central question of HIV research. An evolutionary perspective reveals an apparent conflict between two levels of selection on the virus. On the one hand, there is rapid evolution of the virus in the host, and on the other, new observations indicate the existence of virus factors that affect the virulence of infection whose influence persists over years in infected individuals and across transmission events. Here, we review recent evidence that shows that viral genetic factors play a larger role in modulating disease severity than anticipated. We propose conceptual models that reconcile adaptive evolution at both levels of selection. Evolutionary analysis provides new insight into HIV pathogenesis.

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