Imperial College London

Professor Sir Roy Anderson FRS, FMedSci

Faculty of MedicineSchool of Public Health

Professor in Infectious Disease Epidemiology
 
 
 
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Contact

 

+44 (0)20 7594 3399roy.anderson Website

 
 
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Assistant

 

Mrs Clare Mylchreest +44 (0)7766 331 301

 
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Location

 

LG35Norfolk PlaceSt Mary's Campus

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Summary

 

Publications

Publication Type
Year
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506 results found

Clarke NE, Dinh N-N, Traub RJ, Clements ACA, Halton K, Anderson RM, Gray DJ, Coffeng LE, Kaldor JM, Nery SVet al., 2019, A cluster-randomised controlled trial comparing school and community-based deworming for soil transmitted helminth control in school-age children: the CoDe-STH trial protocol, BMC INFECTIOUS DISEASES, Vol: 19

Journal article

Toor J, Truscott JE, Werkman M, Turner HC, Phillips AE, King CH, Medley GF, Anderson RMet al., 2019, Determining post-treatment surveillance criteria for predicting the elimination of Schistosoma mansoni transmission, Parasites and Vectors, Vol: 12, ISSN: 1756-3305

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

Journal article

Truscott JE, Ower AK, Werkman M, Halliday K, Oswald WE, Gichuki PM, Mcharo C, Brooker S, Njenga SM, Mwandariwo C, Walson JL, Pullan R, Anderson Ret al., 2019, Heterogeneity in transmission parameters of hookworm infection within the baseline data from the TUMIKIA study in Kenya, Parasites and Vectors, Vol: 12, ISSN: 1756-3305

BACKGROUND: As many countries with endemic soil-transmitted helminth (STH) burdens achieve high coverage levels of mass drug administration (MDA) to treat school-aged and pre-school-aged children, understanding the detailed effects of MDA on the epidemiology of STH infections is desirable in formulating future policies for morbidity and/or transmission control. Prevalence and mean intensity of infection are characterized by heterogeneity across a region, leading to uncertainty in the impact of MDA strategies. In this paper, we analyze this heterogeneity in terms of factors that govern the transmission dynamics of the parasite in the host population. RESULTS: Using data from the TUMIKIA study in Kenya (cluster STH prevalence range at baseline: 0-63%), we estimated these parameters and their variability across 120 population clusters in the study region, using a simple parasite transmission model and Gibbs-sampling Monte Carlo Markov chain techniques. We observed great heterogeneity in R0 values, with estimates ranging from 1.23 to 3.27, while k-values (which vary inversely with the degree of parasite aggregation within the human host population) range from 0.007 to 0.29 in a positive association with increasing prevalence. The main finding of this study is the increasing trend for greater parasite aggregation as prevalence declines to low levels, reflected in the low values of the negative binomial parameter k in clusters with low hookworm prevalence. Localized climatic and socioeconomic factors are investigated as potential drivers of these observed epidemiological patterns. CONCLUSIONS: Our results show that lower prevalence is associated with higher degrees of aggregation and hence prevalence alone is not a good indicator of transmission intensity. As a consequence, approaches to MDA and monitoring and evaluation of community infection status may need to be adapted as transmission elimination is aimed for by targeted treatment approaches.

Journal article

Halliday KE, Oswald WE, Mcharo C, Beaumont E, Gichuki PM, Kepha S, Witek-McManus SS, Matendechero SH, El-Busaidy H, Muendo R, Chiguzo AN, Cano J, Karanja MW, Musyoka LW, Safari TK, Mutisya LN, Muye IJ, Sidigu MA, Anderson RM, Allen E, Brooker SJ, Mwandawiro CS, Njenga SM, Pullan RLet al., 2019, Community-level epidemiology of soil-transmitted helminths in the context of school-based deworming: Baseline results of a cluster randomised trial on the coast of Kenya., PLoS Negl Trop Dis, Vol: 13

TRIAL REGISTRATION: ClinicalTrials.gov NCT02397772.

Journal article

McRae-McKee K, Chinedu T, Udeh-Momoh CT, Price G, Sumali Bajaj S, de Jager CA, Scott D, Hadjichrysanthou C, McNaughton E, Bracoud L, Ahmadi-Abhari S, De Wolf F, Anderson R, Middleton Let al., 2019, Perspective: Clinical relevance of the dichotomous classification of Alzheimer’s disease biomarkers: Should there be a “grey zone”?, Alzheimers & Dementia, ISSN: 1552-5260

Journal article

Kura K, Truscott JE, Toor J, Anderson RMet al., 2019, Modelling the impact of a Schistosoma mansoni vaccine and mass drug administration to achieve morbidity control and transmission elimination, PLoS Neglected Tropical Diseases, Vol: 13, Pages: 1-21, ISSN: 1935-2727

Mass drug administration (MDA) is, and has been, the principal method for the control of the schistosome helminths. Using MDA only is unlikely to eliminate the infection in areas of high transmission and the implementation of other measures such as reduced water contact improved hygiene and sanitation are required. Ideally a vaccine is needed to ensure long term benefits and eliminate the need for repeated drug treatment since infection does not seem to induce lasting protective immunity. Currently, a candidate vaccine is under trial in a baboon animal model, and very encouraging results have been reported. In this paper, we develop an individual-based stochastic model to evaluate the effect of a vaccine with similar properties in humans to those recorded in baboons in achieving the World Health Organization (WHO) goals of morbidity control and elimination as a public health problem in populations living in a variety of transmission settings. MDA and vaccination assuming different durations of protection and coverage levels, alone or in combination, are examined as treatment strategies to reach the WHO goals of the elimination of morbidity and mortality in the coming decade. We find that the efficacy of a vaccine as an adjunct or main control tool will depend critically on a number of factors including the average duration of protection it provides, vaccine efficacy and the baseline prevalence prior to immunization. In low prevalence settings, simulations suggest that the WHO goals can be achieved for all treatment strategies. In moderate prevalence settings, a vaccine that provides 5 years of protection, can achieve both goals within 15 years of treatment. In high prevalence settings, by vaccinating at age 1, 6 and 11 we can achieve the morbidity control with a probability of nearly 0.89 but we cannot achieve elimination as a public health problem goal. A combined vaccination and MDA treatment plan has the greatest chance of achieving the WHO goals in the shorter t

Journal article

Giardina F, Coffeng LE, Farrell SH, Vegvari C, Werkman M, Truscott JE, Anderson RM, de Vlas SJet al., 2019, Sampling strategies for monitoring and evaluation of morbidity targets for soil-transmitted helminths, PLoS Neglected Tropical Diseases, Vol: 13, ISSN: 1935-2727

BackgroundThe current World Health Organization (WHO) target for the three major soil-transmitted helminth (STH) infections is to reduce prevalence of moderate-to-heavy infections to below 1% by 2020. In terms of monitoring and evaluation (M&E), the current WHO guidelines for control of STHs recommend evaluation of infection levels in school-age children (SAC) after five to six years of preventive chemotherapy (PC), using the standard Kato-Katz faecal smear. Here, we assess the predictive performance of various sampling designs for the evaluation of the morbidity target.Methodology/Principal findingsUsing two mathematical models for STH transmission and control, we simulate how the number of villages and SAC sampled affect the ability of survey results in sentinel villages to predict the achievement of the morbidity target in PC implementation units (e.g. districts). As PC is stopped when the prevalence of infection in SAC in sentinel villages is less than 1%, we estimate the positive predictive value (PPV) of this indicator for meeting the morbidity target in the whole district. The PPV varies by species and PC strategy, and it is generally higher in areas with lower pre-control prevalence. Sampling a fixed number of SAC spread out over 10 instead of 5 sentinel villages may increase the PPV by up to 20 percentage points. If every SAC in a village is tested, a higher number of villages may increase the PPV by up to 80 percentage points. Increasing the proportion of SAC tested per village does not result in a relevant increase of PPV.Conclusions/SignificanceAlthough the WHO guidelines provide a combined strategy to control the three STH species, the efficacy of PC strategies clearly differs by species. There is added value in considering more villages within implementation units for M&E of morbidity targets, the extent varying by STH species. A better understanding of pre- and post-control local STH prevalence levels is essential for an adequate M&E strat

Journal article

Pullan RL, Halliday KE, Oswald WE, Mcharo C, Beaumont E, Kepha S, Witek-McManus S, Gichuki PM, Allen E, Drake T, Pitt C, Matendechero SH, Gwayi-Chore M-C, Anderson RM, Njenga SM, Brooker SJ, Mwandawiro CSet al., 2019, Effects, equity, and cost of school-based and community-wide treatment strategies for soil-transmitted helminths in Kenya: a cluster-randomised controlled trial, LANCET, Vol: 393, Pages: 2039-2050, ISSN: 0140-6736

Journal article

McRae-McKee K, Evans S, Hadjichrysanthou C, Wong MM, de Wolf F, Anderson RMet al., 2019, Combining hippocampal volume metrics to better understand Alzheimer's disease progression in at-risk individuals, Scientific Reports, Vol: 9, ISSN: 2045-2322

To date nearly all clinical trials of Alzheimer’s disease (AD) therapies have failed. These failures are, at least in part, attributable to poor endpoint choice and to inadequate recruitment criteria. Recently, focus has shifted to targeting at-risk populations in the preclinical stages of AD thus improved predictive markers for identifying individuals likely to progress to AD are crucial to help inform the sample of individuals to be recruited into clinical trials. We focus on hippocampal volume (HV) and assess the added benefit of combining HV and rate of hippocampal atrophy over time in relation to disease progression. Following the cross-validation of previously published estimates of the predictive value of HV, we consider a series of combinations of HV metrics and show that a combination of HV and rate of hippocampal atrophy characterises disease progression better than either measure individually. Furthermore, we demonstrate that the risk of disease progression associated with HV metrics does not differ significantly between clinical states. HV and rate of hippocampal atrophy should therefore be used in tandem when describing AD progression in at-risk individuals. Analyses also suggest that the effects of HV metrics are constant across the continuum of the early stages of the disease.

Journal article

Løchen A, Anderson RM, 2019, Dynamic transmission models and economic evaluations of pneumococcal conjugate vaccines: a quality appraisal and limitations., Clin Microbiol Infect

BACKGROUND: Of over 90 serotypes of Streptococcus pneumoniae, only seven were included in the first pneumococcal conjugate vaccine (PCV). While PCV reduced the disease incidence, in part because of a herd immunity effect, a replacement effect was observed whereby disease was increasingly caused by serotypes not included in the vaccine. Dynamic transmission models can account for these effects to describe post-vaccination scenarios, whereas economic evaluations can enable decision-makers to compare vaccines of increasing valency for implementation. AIM: The aim of this review was to examine epidemiological and economic models and their assumptions for their potential contributions to future research and immunisation policy. SOURCES: Pubmed, Scopus, Ovid, ISI Web of Knowledge, Centre of Reviews and Dissemination (CRD) databases were searched. CONTENT: Twenty-three dynamic transmission models and 21 economic models were retrieved and reviewed. Published models employed various templates, revealing several key uncertainties regarding the biology and epidemiology of pneumococcal infection. While models suggested that PCVs will reduce the burden of disease, the extent to which they are predicted to do so depended on various assumptions regarding features of pneumococcal infection and epidemiology that governed PCV cost-effectiveness as well. Such features include the duration of protection and competitive interactions between serotypes, which are unclear at present, but which directly relate to herd immunity and serotype replacement. IMPLICATIONS: Economic evaluations are not typically based on transmission dynamic models and hence omit indirect herd immunity effects. The two tools could be used in conjunction to inform decision-makers on vaccine implementation, but so far there have been few attempts to build economic evaluations on transmission dynamic models, and none in this field. Future directions for research could include studies to evaluate key parameters for the

Journal article

Easton AV, Quiñones M, Vujkovic-Cvijin I, Oliveira RG, Kepha S, Odiere MR, Anderson RM, Belkaid Y, Nutman TBet al., 2019, The impact of anthelmintic treatment on human gut microbiota based on cross-sectional and pre- and postdeworming comparisons in Western Kenya, mBio, Vol: 10, ISSN: 2150-7511

Murine studies suggest that the presence of some species of intestinal helminths is associated with changes in host microbiota composition and diversity. However, studies in humans have produced varied conclusions, and the impact appears to vary widely depending on the helminth species present. To demonstrate how molecular approaches to the human gut microbiome can provide insights into the complex interplay among disparate organisms, DNA was extracted from cryopreserved stools collected from residents of 5 rural Kenyan villages prior to and 3 weeks and 3 months following albendazole (ALB) therapy. Samples were analyzed by quantitative PCR (qPCR) for the presence of 8 species of intestinal parasites and by MiSeq 16S rRNA gene sequencing. Based on pretreatment results, the presence of neither Ascaris lumbricoides nor Necator americanus infection significantly altered the overall diversity of the microbiota in comparison with age-matched controls. Following ALB therapy and clearance of soil-transmitted helminths (STH), there were significant increases in the proportion of the microbiota made up by Clostridiales (P = 0.0002; average fold change, 0.57) and reductions in the proportion made up by Enterobacteriales (P = 0.0004; average fold change, -0.58). There was a significant posttreatment decrease in Chao1 richness, even among individuals who were uninfected pretreatment, suggesting that antimicrobial effects must be considered in any posttreatment setting. Nevertheless, the helminth-associated changes in Clostridiales and Enterobacteriales suggest that clearance of STH, and of N. americanus in particular, alters the gut microbiota.IMPORTANCE The gut microbiome is an important factor in human health. It is affected by what we eat, what medicines we take, and what infections we acquire. In turn, it affects the way we absorb nutrients and whether we have excessive intestinal inflammation. Intestinal worms may have an important

Journal article

Truscott JE, Dunn JC, Papaiakovou M, Schaer F, Werkman M, Littlewood DTJ, Walson JL, Anderson RMet al., 2019, Calculating the prevalence of soil-transmitted helminth infection through pooling of stool samples: Choosing and optimizing the pooling strategy, PLoS Neglected Tropical Diseases, Vol: 13, ISSN: 1935-2727

Prevalence is a common epidemiological measure for assessing soil-transmitted helminthburden and forms the basis for much public-health decision-making. Standard diagnostictechniques are based on egg detection in stool samples through microscopy and these techniques are known to have poor sensitivity for individuals with low infection intensity, leadingto poor sensitivity in low prevalence populations. PCR diagnostic techniques offer very highsensitivities even at low prevalence, but at a greater cost for each diagnostic test in terms ofequipment needed and technician time and training. Pooling of samples can allow prevalence to be estimated while minimizing the number of tests performed. We develop a modelof the relative cost of pooling to estimate prevalence, compared to the direct approach oftesting all samples individually. Analysis shows how expected relative cost depends on boththe underlying prevalence in the population and the size of the pools constructed. A criticalprevalence level (approx. 31%) above which pooling is never cost effective, independent ofpool size. When no prevalence information is available, there is no basis on which to choosebetween pooling and testing all samples individually. We recast our model of relative cost ina Bayesian framework in order to investigate how prior information about prevalence in agiven population can be used to inform the decision to choose either pooling or full testing.Results suggest that if prevalence is below 10%, a relatively small exploratory prevalencesurvey (10–15 samples) can be sufficient to give a high degree of certainty that pooling maybe relatively cost effective.

Journal article

Dunn JC, Bettis AA, Wyine NY, Lwin AMM, Tun A, Maung NS, Anderson RMet al., 2019, Soil-transmitted helminth reinfection four and six months after mass drug administration: Results from the delta region of Myanmar, PLoS Neglected Tropical Diseases, Vol: 13, ISSN: 1935-2727

BackgroundMass drug administration (MDA), targeted at school-aged children (SAC) is the method recommended by the World Health Organization for the control of morbidity induced by soil-transmitted helminth (STH) infection in endemic countries. However, MDA does not prevent reinfection between treatment rounds and research suggests that only treating SAC will not be sufficient to bring prevalence to low levels and possibly interrupt transmission of STH. In countries with endemic infection, such as Myanmar, the coverage, who is targeted, and rates of reinfection will determine how effective MDA is in suppressing transmission in the long-term.Methods/principal findingsIn this paper, data from an epidemiological study on STH, comprising three surveys conducted between June 2015 and June 2016 in the delta region of Myanmar, are analysed to determine how STH prevalence and intensity in the study community changes over the course of a year, including reinfection after two MDA rounds in which the whole study sample (all age groups, n = 523) were treated with albendazole. Prevalence in the first survey (August 2015) was 27.92% for any STH, 5.54% for Ascaris lumbricoides, 17.02% for Trichuris trichiura and 9.75% for hookworm. Over the year (survey one to survey three), prevalence of any STH decreased by 8.99% (P < 0.001) and mean EPG significantly decreased for T. trichiura (P < 0.01) and hookworm (P < 0.001). Risk ratios (RRs) for a four-month reinfection period (August to December) were statistically significant and were below one, indicating that STH prevalence had not bounced back to the prevalence levels recorded immediately prior to the last round of treatment (any STH RR = 0.67, 95% CI 0.56–0.81; A. lumbricoides RR = 0.31, 95% CI 0.16–0.59; T. trichiura RR = 0.70, 95% CI 0.55–0.88; hookworm RR = 0.69, 95% CI 0.50–0.95). The only statistically significant RR for the six-month reinfection period (December to June) was for A. lumbricoides

Journal article

Anderson RM, Hadjichrysanthou C, Evans S, McRae-McKee K, Wong MMet al., 2019, Unsuccessful trials of therapies for Alzheimer's disease Reply, LANCET, Vol: 393, Pages: 29-30, ISSN: 0140-6736

Journal article

Anderson RM, Hadjichrysanthou C, Evans S, McRae-McKee K, Wong MMet al., 2019, Unsuccessful trials of therapies for Alzheimer's disease - Authors' reply, Lancet, Vol: 393, Pages: 29-30, ISSN: 0140-6736

Journal article

Hadjichrysanthou C, McRae-McKee K, Evans S, de Wolf F, Anderson RMet al., 2018, Potential factors associated with cognitive improvement of individuals diagnosed with mild cognitive impairment or dementia in longitudinal studies, Journal of Alzheimer's Disease, Vol: 66, Pages: 587-600, ISSN: 1387-2877

Despite the progressive nature of Alzheimer’s disease and other dementias, it is observed that many individuals that are diagnosed with mild cognitive impairment (MCI) in one clinical assessment, may return back to normal cognition (CN) in a subsequent assessment. Less frequently, such ‘back-transitions’ are also observed in people that had already been diagnosed with later stages of dementia. In this study, an analysis was performed on two longitudinal cohort datasets provided by 1) the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and 2) the National Alzheimer’s Coordinating Centre (NACC). The focus is on the observed improvement of individuals’ clinical condition recorded in these datasets to explore potential associations with different factors. It is shown that, in both datasets, transitions from MCI to CN are significantly associated with younger age, better cognitive function, and the absence of ApoE ɛ4 alleles. Better cognitive function and in some cases the absence of ApoE ɛ4 alleles are also significantly associated with transitions from types of dementia to less severe clinical states. The effect of gender and education is not clear-cut in these datasets, although highly educated people who reach MCI tend to be more likely to show an improvement in their clinical state. The potential effect of other factors such as changes in symptoms of depression is also discussed. Although improved clinical outcomes can be associated with many factors, better diagnostic tools are required to provide insight into whether such improvements are a result of misdiagnosis, and if they are not, whether they are linked to improvements in the underlying neuropathological condition.

Journal article

Toor J, Turner HC, Truscott JE, Werkman M, Phillips AE, Alsallaq R, Medley GF, King CH, Anderson RMet al., 2018, The design of schistosomiasis monitoring and evaluation programmes: The importance of collecting adult data to inform treatment strategies for Schistosoma mansoni, PLoS Neglected Tropical Diseases, Vol: 12, ISSN: 1935-2727

Monitoring and evaluation (M&E) programmes are used to collect data which are required to assess the impact of current interventions on their progress towards achieving the World Health Organization (WHO) goals of morbidity control and elimination as a public health problem for schistosomiasis. Prevalence and intensity of infection data are typically collected from school-aged children (SAC) as they are relatively easy to sample and are thought to be most likely to be infected by schistosome parasites. However, adults are also likely to be infected. We use three different age-intensity profiles of infection for Schistosoma mansoni with low, moderate and high burdens of infection in adults to investigate how the age distribution of infection impacts the mathematical model generated recommendations of the preventive chemotherapy coverage levels required to achieve the WHO goals. We find that for moderate prevalence regions, regardless of the burden of infection in adults, treating SAC only may achieve the WHO goals. However, for high prevalence regions with a high burden of infection in adults, adult treatment is required to meet the WHO goals. Hence, we show that the optimal treatment strategy for a defined region requires consideration of the burden of infection in adults as it cannot be based solely on the prevalence of infection in SAC. Although past epidemiological data have informed mathematical models for the transmission and control of schistosome infections, more accurate and detailed data are required from M&E programmes to accurately determine the optimal treatment strategy for a defined region. We highlight the importance of collecting prevalence and intensity of infection data from a broader age-range, specifically the inclusion of adult data at baseline (prior to treatment) and throughout the treatment programme if possible, rather than SAC only, to accurately determine the treatment strategy for a defined region. Furthermore, we discuss addition

Journal article

Werkman M, Toor J, Vegvari C, Wright JE, Truscott JE, Asbjornsdottir KH, Means AR, Walson JL, Anderson RMet al., 2018, Defining stopping criteria for ending randomized clinical trials that investigate the interruption of transmission of soil-transmitted helminths employing mass drug administration, PLoS Neglected Tropical Diseases, Vol: 12, ISSN: 1935-2727

The current World Health Organization strategy to address soil-transmitted helminth (STH) infections in children is based on morbidity control through routine deworming of school and pre-school aged children. However, given that transmission continues to occur as a result of persistent reservoirs of infection in untreated individuals (including adults) and in the environment, in many settings such a strategy will need to be continued for very extended periods of time, or until social, economic and environmental conditions result in interruption of transmission. As a result, there is currently much discussion surrounding the possibility of accelerating the interruption of transmission using alternative strategies of mass drug administration (MDA). However, the feasibility of achieving transmission interruption using MDA remains uncertain due to challenges in sustaining high MDA coverage levels across entire communities. The DeWorm3 trial, designed to test the feasibility of interrupting STH transmission, is currently ongoing. In DeWorm3, three years of high treatment coverage—indicated by mathematical models as necessary for breaking transmission—will be followed by two years of surveillance. Given the fast reinfection (bounce-back) rates of STH, a two year no treatment period is regarded as adequate to assess whether bounce-back or transmission interruption have occurred in a given location. In this study, we investigate if criteria to determine whether transmission interruption is unlikely can be defined at earlier timepoints. A stochastic, individual-based simulation model is employed to simulate core aspects of the DeWorm3 community-based cluster-randomized trial. This trial compares a control arm (annual treatment of children alone with MDA) with an intervention arm (community-wide biannual treatment with MDA). Simulations were run for each scenario for both Ascaris lumbricoides and hookworm (Necator americanus). A range of threshold prevalences meas

Journal article

Ower AK, Hadjichrysanthou C, Gras L, Goudsmit J, Anderson RM, de Wolf F, Alzheimers Disease Neuroimaging Initiativeet al., 2018, Temporal association patterns and dynamics of amyloid-β and tau in Alzheimer's disease, European Journal of Epidemiology, Vol: 33, Pages: 657-666, ISSN: 0393-2990

The elusive relationship between underlying pathology and clinical disease hampers diagnosis of Alzheimer's disease (AD) and preventative intervention development. We seek to understand the relationship between two classical AD biomarkers, amyloid-β1-42 (Aβ1-42) and total-tau (t-tau), and define their trajectories across disease development, as defined by disease onset at diagnosis of mild cognitive impairment (MCI). Using longitudinal data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we performed a correlation analysis of biomarkers CSF Aβ1-42 and t-tau, and longitudinal quantile analysis. Using a mixed effects model, with MCI onset as an anchor, we develop linear trajectories to describe the rate of change across disease development. These trajectories were extended through the incorporation of data from cognitively normal, healthy adults (aged 20-62 years) from the literature, to fit sigmoid curves by means of non-linear least squares estimators, to create curves encompassing the 50 years prior to MCI onset. A strong right-angled relationship between the biomarkers Aβ1-42 and t-tau is detected, implying a highly non-linear relationship. The rate of change of Aβ1-42 is correlated with the baseline concentration per quantile, reflecting a reduction in the rate of loss across disease within subjects. Regression models reveal significant amyloid loss relative to MCI onset (- 2.35 pg/mL/year), compared to minimal loss relative to AD onset (- 0.97 pg/mL/year). Tau accumulates consistently relative to MCI and AD onset, (2.05 pg/mL/year) and (2.46 pg/mL/year), respectively. The fitted amyloid curve shows peak loss of amyloid 8.06 years prior to MCI diagnosis, while t-tau exhibits peak accumulation 14.17 years following MCI diagnosis, with the upper limit not yet reached 30 years post diagnosis. Biomarker trajectories aid unbiased, objective assessment of disease progression. Q

Journal article

Toor J, Alsallaq R, Truscott JE, Turner HC, Werkman M, Gurarie D, King CH, Anderson RMet al., 2018, Are We on Our Way to Achieving the 2020 Goals for Schistosomiasis Morbidity Control Using Current World Health Organization Guidelines?, CLINICAL INFECTIOUS DISEASES, Vol: 66, Pages: S245-S252, ISSN: 1058-4838

BackgroundSchistosomiasis remains an endemic parasitic disease affecting millions of people around the world. The World Health Organization (WHO) has set goals of controlling morbidity to be reached by 2020, along with elimination as a public health problem in certain regions by 2025. Mathematical models of parasite transmission and treatment impact have been developed to assist in controlling the morbidity caused by schistosomiasis. These models can inform and guide implementation policy for mass drug administration programs, and help design monitoring and evaluation activities.MethodsWe use these models to predict whether the guidelines set by the WHO are on track for achieving their 2020 goal for the control of morbidity, specifically for Schistosoma mansoni. We examine whether programmatic adaptations; namely increases in treatment coverage and/or expansion to adult inclusion in treatment, will improve the likelihood of reaching the WHO goals.ResultsWe find that in low-prevalence settings, the goals are likely to be attainable under current WHO guidelines, but in moderate to high-prevalence settings, the goals are less likely to be achieved unless treatment coverage is increased and expanded to at least 85% for school-aged children and 40% for adults.ConclusionsTo improve the likelihood of reaching the WHO goals, programmatic adaptations are required, particularly for moderate- to high-prevalence settings. Furthermore, improvements in adherence to treatment, potential development of candidate vaccines, and enhanced snail control and WASH (water, sanitation, and hygiene) measures will all assist in achieving the goals.

Journal article

Farrell SH, Coffeng LE, Truscott JE, Werkman M, Toor J, de Vlas SJ, Anderson RMet al., 2018, Investigating the Effectiveness of Current and Modified World Health Organization Guidelines for the Control of Soil-Transmitted Helminth Infections, CLINICAL INFECTIOUS DISEASES, Vol: 66, Pages: S253-S259, ISSN: 1058-4838

BackgroundConsiderable efforts have been made to better understand the effectiveness of large-scale preventive chemotherapy therapy for the control of morbidity caused by infection with soil-transmitted helminths (STHs): Ascaris lumbricoides, Trichuris trichiura, and the 2 hookworm species, Necator americanus and Ancylostoma duodenale. Current World Health Organization (WHO) guidelines for STH control include mass drug administration (MDA) programs based on prevalence measurements, aiming at reducing morbidity in pre–school-aged children (pre-SAC) and school-aged children (SAC) by lowering the prevalence of moderate- to heavy-intensity infections to <1%.MethodsWe project the likely impact of following the current WHO guidelines and assess whether the WHO morbidity goals will be achieved across a range of transmission settings. We also investigate modifications that could be made to the current WHO treatment guidelines, and project their potential impacts in achieving morbidity and transmission control.ResultsWhile the standard guidelines are sufficient at low transmission levels, community-wide treatment (ie, involving pre-SAC, SAC, and adults) is essential if WHO morbidity goals are to be met in moderate- to high-transmission settings. Moreover, removing the recommendation of decreasing the treatment frequency at midline (5–6 years after the start of MDA) further improves the likelihood of achieving morbidity control in SAC.ConclusionsWe meld analyses based on 2 mathematical models of parasite transmission and control by MDA for the dominant STH species, to generate a unified treatment approach applicable across all settings, regardless of which STH infection is most common. We recommend clearly defined changes to the current WHO guidelines.

Journal article

Savioli L, Albonico M, Daumerie D, Lo NC, Stothard JR, Asaolu S, Tchuente LAT, Anderson RMet al., 2018, Review of the 2017 WHO Guideline: Preventive chemotherapy to control soil-transmitted helminth infections in at-risk population groups. An opportunity lost in translation, PLOS NEGLECTED TROPICAL DISEASES, Vol: 12, ISSN: 1935-2735

Journal article

Turner HC, Toor J, Hollingsworth TD, Anderson RMet al., 2018, Economic evaluations of mass drug administration: the importance of economies of scale and scope, Clinical Infectious Diseases, Vol: 66, Pages: 1298-1303, ISSN: 1058-4838

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.

Journal article

Wright JE, Werkman M, Dunn J, Anderson Ret al., 2018, Current epidemiological evidence for predisposition to high or low intensity human helminth infection: a systematic review, Parasites & Vectors, Vol: 11, ISSN: 1756-3305

Background: The human helminth infections include ascariasis, trichuriasis, hookworm infections, schistosomiasis,lymphatic filariasis (LF) and onchocerciasis. It is estimated that almost 2 billion people worldwide are infected withhelminths. Whilst the WHO treatment guidelines for helminth infections are mostly aimed at controlling morbidity,there has been a recent shift with some countries moving towards goals of disease elimination through mass drugadministration, especially for LF and onchocerciasis. However, as prevalence is driven lower, treating entire populationsmay no longer be the most efficient or cost-effective strategy. Instead, it may be beneficial to identify individuals ordemographic groups who are persistently infected, often termed as being “predisposed” to infection, and targettreatment at them.Methods: The authors searched Embase, MEDLINE, Global Health, and Web of Science for all English language, humanbasedpapers investigating predisposition to helminth infections published up to October 31st, 2017. Thevarying definitions used to describe predisposition, and the statistical tests used to determine its presence, are summarised.Evidence for predisposition is presented, stratified by helminth species, and risk factors for predisposition to infection areidentified and discussed.Results: In total, 43 papers were identified, summarising results from 34 different studies in 23 countries. Consistentevidence of predisposition to infection with certain species of human helminth was identified. Children were regularlyfound to experience greater predisposition to Ascaris lumbricoides, Schistosoma mansoni and S. haematobium than adults.Females were found to be more predisposed to A. lumbricoides infection than were males. Household clustering ofinfection was identified for A. lumbricoides, T. trichiura and S. japonicum. Ascaris lumbricoides and T. trichiura also showedevidence of familial predisposition. Whilst strong evidence for predisposition

Journal article

Farrell SH, Anderson RM, 2018, Helminth lifespan interacts with noncompliance in reducing the effectiveness of anthelmintic treatment, PARASITES & VECTORS, Vol: 11, ISSN: 1756-3305

BackgroundThe success of mass drug administration programmes targeting the soil-transmitted helminths and schistosome parasites is in part dependent on compliance to treatment at sequential rounds of mass drug administration (MDA). The impact of MDA is vulnerable to systematic non-compliance, defined as a portion of the eligible population remaining untreated over successive treatment rounds. The impact of systematic non-compliance on helminth transmission dynamics - and thereby on the number of treatment rounds required to interrupt transmission - is dependent on the parasitic helminth being targeted by MDA.ResultsHere, we investigate the impact of adult parasite lifespan in the human host and other factors that determine the magnitude of the basic reproductive number R 0 , on the number of additional treatment rounds required in a target population, using mathematical models of Ascaris lumbricoides and Schistosoma mansoni transmission incorporating systematic non-compliance. Our analysis indicates a strong interaction between helminth lifespan and the impact of systematic non-compliance on parasite elimination, and confirms differences in its impact between Ascaris and the schistosome parasites in a streamlined model structure.ConclusionsOur analysis suggests that achieving reductions in the level of systematic non-compliance may be of particular benefit in mass drug administration programmes treating the longer-lived helminth parasites, and highlights the need for improved data collection in understanding the impact of compliance.

Journal article

Hadjichrysanthou C, Ower AK, de Wolf F, Anderson RMet al., 2018, The development of a stochastic mathematical model of Alzheimer's disease to help improve the design of clinical trials of potential treatments, PLOS ONE, Vol: 13, ISSN: 1932-6203

Alzheimer’sdisease(AD)is a neurodegenerative disordercharacterisedbya slowprogres-sivedeteriorationof cognitivecapacity.Drugsareurgentlyneededforthetreatmentof ADandunfortunatelyalmostallclinicaltrialsof ADdrugcandidateshavefailedor beendiscon-tinuedto date.Mathematical,computationalandstatisticaltoolscanbeemployedin theconstructionof clinicaltrialsimulatorsto assistin theimprovementof trialdesignandenhancethechancesof successof potentialnewtherapies.Basedontheanalysisof a setof clinicaldataprovidedbytheAlzheimer’sDiseaseNeuroimagingInitiative(ADNI)wedevelopeda simplestochasticmathematicalmodelto simulatethedevelopmentandpro-gressionof Alzheimer’sin a longitudinalcohortstudy.Weshowhowthismodellingframe-workcouldbeusedto assesstheeffectandthechancesof successof hypotheticaltreatmentsthatareadministeredat differentstagesanddelaydiseasedevelopment.Wedemonstratethatthedetectionof thetrueefficacyof anADtreatmentcanbeverychalleng-ing,evenif thetreatmentis highlyeffective.Animportantreasonbehindtheinabilitytodetectsignalsof efficacyin a clinicaltrialin thistherapyareacouldbethehighbetween-andwithin-individualvariabilityin themeasurement of diagnosticmarkersandendpoints,whichconsequentlyresultsin themisdiagnosisof anindividual’sdiseasestate.

Journal article

Asbjornsdottir KH, Rao Ajjampur SS, Anderson R, Bailey R, Gardiner I, Halliday KE, Ibikounle M, Kalua K, Kang G, Littlewood DTJ, Luty AJF, Rubin Means A, Oswald W, Pullan RL, Sarkar R, Schar F, Szpiro A, Truscott J, Werkman M, Yard E, Walson JLet al., 2018, Assessing the feasibility of interrupting the transmission of soil-transmitted helminths through mass drug administration: The DeWorm3 cluster randomized trial protoco, PLoS Neglected Tropical Diseases, Vol: 12, ISSN: 1935-2727

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

Journal article

Davis EL, Danon L, Prada JM, Gunawardena SA, Truscott JE, Vlaminck J, Anderson RM, Levecke B, Morgan ER, Hollingsworth TDet al., 2018, Seasonally timed treatment programs for Ascaris lumbricoides to increase impact-An investigation using mathematical models, PLOS NEGLECTED TROPICAL DISEASES, Vol: 12, ISSN: 1935-2735

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.

Journal article

Werkman M, Wright JE, Truscott JE, Easton AV, Oliveira RG, Toor J, Ower A, Ásbjörnsdóttir KH, Means AR, Farrell SH, Walson JL, Anderson RMet al., 2018, Testing for soil-transmitted helminth transmission elimination: Analysing the impact of the sensitivity of different diagnostic tools., PLoS Neglected Tropical Diseases, Vol: 12, ISSN: 1935-2727

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

Journal article

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