31 results found
Vegvari C, Baggaley R, Gon G, et al., 2023, Do current maternal health staffing and bed occupancy benchmarks work in practice? Results from a simulation model, BMJ Public Health
Anderson RM, Cano J, Hollinsworth TD, et al., 2023, Responding to the cuts in UK AID to neglected tropical diseases control programmes in Africa, TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE, Vol: 117, Pages: 237-239, ISSN: 0035-9203
Borlase A, Le Rutte EA, Castano S, et al., 2022, Evaluating and mitigating the potential indirect effect of COVID-19 on control programmes for seven neglected tropical diseases: a modelling study, LANCET GLOBAL HEALTH, Vol: 10, Pages: E1600-E1611, ISSN: 2214-109X
Vegvari C, Abbott S, Ball F, et al., 2022, Commentary on the use of the reproduction number <i>R</i> during the COVID-19 pandemic, STATISTICAL METHODS IN MEDICAL RESEARCH, Vol: 31, Pages: 1675-1685, ISSN: 0962-2802
Anderson RM, Vegvari C, Hollingsworth TD, et al., 2021, The SARS-CoV-2 pandemic: remaining uncertainties in our understanding of the epidemiology and transmission dynamics of the virus, and challenges to be overcome, INTERFACE FOCUS, Vol: 11, ISSN: 2042-8898
Hardwick RJ, Vegvari C, Collyer B, et al., 2021, Spatial scales in human movement between reservoirs of infection, JOURNAL OF THEORETICAL BIOLOGY, Vol: 524, ISSN: 0022-5193
Vegvari C, Giardina F, Malizia V, et al., 2021, Impact of Key Assumptions About the Population Biology of Soil-Transmitted Helminths on the Sustainable Control of Morbidity, CLINICAL INFECTIOUS DISEASES, Vol: 72, Pages: S188-S194, ISSN: 1058-4838
Vegvari C, Giardina F, Bajaj S, et al., 2021, Deworming women of reproductive age during adolescence and pregnancy: what is the impact on morbidity from soil-transmitted helminths infection?, PARASITES & VECTORS, Vol: 14, ISSN: 1756-3305
Toor J, Adams ER, Aliee M, et al., 2021, Predicted impact of COVID-19 on neglected tropical disease programs and the opportunity for innovation, Clinical Infectious Diseases, Vol: 72, Pages: 1463-1466, ISSN: 1058-4838
Due to the COVID-19 pandemic, many key neglected tropical disease (NTD) activities have been postponed. This hindrance comes at a time when the NTDs are progressing towards their ambitious goals for 2030. Mathematical modelling on several NTDs, namely gambiense sleeping sickness, lymphatic filariasis, onchocerciasis, schistosomiasis, soil-transmitted helminthiases (STH), trachoma, and visceral leishmaniasis, shows that the impact of this disruption will vary across the diseases. Programs face a risk of resurgence, which will be fastest in high-transmission areas. Furthermore, of the mass drug administration diseases, schistosomiasis, STH, and trachoma are likely to encounter faster resurgence. The case-finding diseases (gambiense sleeping sickness and visceral leishmaniasis) are likely to have fewer cases being detected but may face an increasing underlying rate of new infections. However, once programs are able to resume, there are ways to mitigate the impact and accelerate progress towards the 2030 goals.
Malizia V, Giardina F, Vegvari C, et al., 2021, Modelling the impact of COVID-19-related control programme interruptions on progress towards the WHO 2030 target for soil-transmitted helminths, Transactions of the Royal Society of Tropical Medicine and Hygiene, Vol: 115, Pages: 253-260, ISSN: 0035-9203
BACKGROUND: On 1 April 2020, the WHO recommended an interruption of all activities for the control of neglected tropical diseases, including soil-transmitted helminths (STH), in response to the COVID-19 pandemic. This paper investigates the impact of this disruption on the progress towards the WHO 2030 target for STH. METHODS: We used two stochastic individual-based models to simulate the impact of missing one or more preventive chemotherapy (PC) rounds in different endemicity settings. We also investigated the extent to which this impact can be lessened by mitigation strategies, such as semiannual or community-wide PC. RESULTS: Both models show that without a mitigation strategy, control programmes will catch up by 2030, assuming that coverage is maintained. The catch-up time can be up to 4.5 y after the start of the interruption. Mitigation strategies may reduce this time by up to 2 y and increase the probability of achieving the 2030 target. CONCLUSIONS: Although a PC interruption will only temporarily impact the progress towards the WHO 2030 target, programmes are encouraged to restart as soon as possible to minimise the impact on morbidity. The implementation of suitable mitigation strategies can turn the interruption into an opportunity to accelerate progress towards reaching the target.
Baggaley RF, Vegvari C, Dimala CA, et al., 2021, Health economic analyses of latent tuberculosis infection screening and preventive treatment among people living with HIV in lower tuberculosis incidence settings: a systematic review., Wellcome Open Res, Vol: 6, ISSN: 2398-502X
Introduction: In lower tuberculosis (TB) incidence countries (<100 cases/100,000/year), screening and preventive treatment (PT) for latent TB infection (LTBI) among people living with HIV (PLWH) is often recommended, yet guidelines advising which groups to prioritise for screening can be contradictory and implementation patchy. Evidence of LTBI screening cost-effectiveness may improve uptake and health outcomes at reasonable cost. Methods: Our systematic review assessed cost-effectiveness estimates of LTBI screening/PT strategies among PLWH in lower TB incidence countries to identify model-driving inputs and methodological differences. Databases were searched 1980-2020. Studies including health economic evaluation of LTBI screening of PLWH in lower TB incidence countries (<100 cases/100,000/year) were included. Results: Of 2,644 articles screened, nine studies were included. Cost-effectiveness estimates of LTBI screening/PT for PLWH varied widely, with universal screening/PT found highly cost-effective by some studies, while only targeting to high-risk groups (such as those from mid/high TB incidence countries) deemed cost-effective by others. Cost-effectiveness of strategies screening all PLWH from studies published in the past five years varied from US$2828 to US$144,929/quality-adjusted life-year gained (2018 prices). Study quality varied, with inconsistent reporting of methods and results limiting comparability of studies. Cost-effectiveness varied markedly by screening guideline, with British HIV Association guidelines more cost-effective than NICE guidelines in the UK. Discussion: Cost-effectiveness studies of LTBI screening/PT for PLWH in lower TB incidence settings are scarce, with large variations in methods and assumptions used, target populations and screening/PT strategies evaluated. The limited evidence suggests LTBI screening/PT may be cost-effective for some PLWH groups but further research is required, particularly on strategies targeting scree
Anderson RM, Vegvari C, Truscott J, et al., 2020, Challenges in creating herd immunity to SARS-CoV-2 infection by mass vaccination, The Lancet, Vol: 396, Pages: 1614-1616, ISSN: 0140-6736
Malizia V, Giardina F, Vegvari C, et al., 2020, Modelling the impact of COVID-19-related control programme interruptions on progress towards the WHO 2030 target for soil-transmitted helminths
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>On the 1<jats:sup>st</jats:sup> of April 2020, the World Health Organization (WHO) recommended an interruption of all neglected tropical disease control programmes, including soil-transmitted helminths (STH), in response to the COVID-19 pandemic. This paper investigates the impact of this disruption on the achieved progress towards the WHO 2030 target for STH.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We used two stochastic individual-based models to simulate the impact of missing one or more preventive chemotherapy (PC) rounds in different endemicity settings. We also investigate the extent to which the impact can be lessened by mitigation strategies, such as semi-annual or community-wide PC.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Both models show that even without a mitigation strategy, control programmes will catch up by 2030. The catch-up time is limited to a maximum of 4.5 years after the interruption. Mitigations strategies may reduce this catch-up time by up to two years and can even increase the probability of achieving the 2030 target.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Though a PC interruption will only temporarily impact the progress towards the WHO 2030 target, programmes are encouraged to restart as soon as possible to minimise the impact on morbidity. The implementation of suitable mitigation strategies can turn the interruption into an opportunity to accelerate the progress toward reaching the target.</jats:p></jats:sec>
Celma CC, Beard S, Douglas A, et al., 2020, Retrospective analysis on confirmation rates for referred positive rotavirus samples in England, 2016 to 2017: implications for diagnosis and surveillance, Eurosurveillance, Vol: 25, Pages: 1-8, ISSN: 1025-496X
BackgroundRapid diagnostic tests are commonly used by hospital laboratories in England to detect rotavirus (RV), and results are used to inform clinical management and support national surveillance of the infant rotavirus immunisation programme since 2013. In 2017, the Public Health England (PHE) national reference laboratory for enteric viruses observed that the presence of RV could not be confirmed by PCR in a proportion of RV-positive samples referred for confirmatory detection.AimWe aimed to compare the positivity rate of detection methods used by hospital laboratories with the PHE confirmatory test rate.MethodsRotavirus specimens testing positive at local hospital laboratories were re-tested at the PHE national reference laboratory using a PCR test. Confirmatory results were compared to original results from the PHE laboratory information management system.ResultsHospital laboratories screened 70.1% (2,608/3,721) of RV samples using immunochromatographic assay (IC) or rapid tests, 15.5% (578/3,721) using enzyme immunoassays (EIA) and 14.4% (535/3,721) using PCR. Overall, 1,011/3,721 (27.2%) locally RV-positive samples referred to PHE in 2016 and 2017 failed RV detection using the PHE reference laboratory PCR test. Confirmation rates were 66.9% (1,746/2,608) for the IC tests, 87.4% (505/578) for the EIA and 86.4% (465/535) for the PCR assays. Seasonal confirmation rate discrepancies were also evident for IC tests.ConclusionsThis report highlights high false positive rates with the most commonly used RV screening tests and emphasises the importance of implementing verified confirmatory tests for RV detections. This has implications for clinical diagnosis and national surveillance.
Anderson RM, Hollingsworth TD, Baggaley RF, et al., 2020, COVID-19 spread in the UK: the end of the beginning?, LANCET, Vol: 396, Pages: 587-590, ISSN: 0140-6736
Vegvari C, Giardina F, Bajaj S, et al., 2020, Deworming Women of Reproductive Age During Adolescence and Pregnancy: What is the Impact on Morbidity From Soil-transmitted Helminths Infection?
<jats:title>Abstract</jats:title> <jats:p><jats:bold>Background: </jats:bold>Soil-transmitted helminths (STHs) are a major cause of poor health in low- and middle-income countries. In particular, hookworm is known to cause anaemia in children and women of reproductive age (WRA). One goal of the World Health Organization’s (WHO) 2030 roadmap for neglected tropical diseases is to reduce STH-related morbidity in WRA. As a minimal intervention the WHO recommends deworming adolescent girls annually during human papilloma virus vaccination programmes and women of reproductive age (WRA) during pregnancy and lactation. These routine interventions are low cost can be implemented even from the most basic health services in endemic countries. In this study we use a cohort model to investigate the potential impact on STH-related morbidity in WRA.<jats:bold>Results:</jats:bold> We find that annual deworming of adolescent girls reduces morbidity in a similar way treatment programmes for pre-school-age and school-age children (pSAC and SAC). Treatment of WRA during pregnancy and lactation on its own has a small but significant effect on morbidity although it does not achieve the morbidity target (<2% moderate-to-high intensity infections) in this age group. However, depending on the age-intensity profile of infection, which may vary geographically, and assumptions on the density-dependence of egg production by fertilised female worms, continued school-based treatment may be able to reduce the force of infection acting on WRA, both through an indirect effect on the overall population based force of infection and via reducing the burden of infection as children age and move into the WRA age classes. As a result, morbidity in WRA may be eliminated.<jats:bold>Conclusion:</jats:bold> While deworming during pregnancy and lactation does not achieve the morbidity target in WRA and its efficacy may vary by setting
Hardwick RJ, Vegvari C, Truscott JE, et al., 2020, The 'breakpoint' of soil-transmitted helminths with infected human migration, JOURNAL OF THEORETICAL BIOLOGY, Vol: 486, ISSN: 0022-5193
Coffeng L, Malizia V, Vegvari C, et al., 2019, Impact of different sampling schemes for decision making in soil-transmitted helminthiasis control programs, Journal of Infectious Diseases, Vol: 221, Pages: S531-S538, ISSN: 0022-1899
Starting and stopping preventive chemotherapy (PC) for soil-transmitted helminthiasis is typically based on the prevalence of infection as measured by Kato-Katz (KK) fecal smears. Kato-Katz-based egg counts can vary highly over repeated stool samples and smears. Consequentially, the sensitivity of KK-based surveys depends on the number of stool samples per person and the number of smears per sample. Given finite resources, collecting multiple samples and/or smears means screening fewer individuals, thereby lowering the statistical precision of prevalence estimates. Using population-level data from various epidemiological settings, we assessed the performance of different sampling schemes executed within the confines of the same budget. We recommend the use of single-slide KK for determining prevalence of moderate-to-heavy intensity infection and policy decisions for starting and continuing PC; more sensitive sampling schemes may be required for policy decisions involving stopping PC. Our findings highlight that guidelines should include specific guidance on sampling schemes.
Vegvari C, Truscott JE, Kura K, et al., 2019, Human population movement can impede the elimination of soil-transmitted helminth transmission in regions with heterogeneity in mass drug administration coverage and transmission potential between villages: a metapopulation analysis, Parasites and Vectors, Vol: 12, Pages: 1-12, ISSN: 1756-3305
BackgroundSoil-transmitted helminth (STH) infections affect predominantly socio-economically disadvantaged populations in sub-Saharan Africa, East Asia and the Americas. Previous mathematical modelling studies have evaluated optimal intervention strategies to break STH transmission in clusters of villages. These studies assumed that villages are closed independent units with no movement of people in or out of communities. Here we examine how human population movement, for example, of seasonal migrant labourers, affect the outcome of mass drug administration (MDA) programmes.ResultsWe used a stochastic individual-based metapopulation model to analyse the impact of human population movement at varying rates on STH elimination efforts. Specifically, we looked at seasonal clumped movement events of infected individuals into a village. We showed that even if on average 75% of the entire resident population within a village are treated, an annual rate of 2–3% of the population arriving from an untreated source village can reduce the probability of STH elimination to less than 50% in high-prevalence settings. If a village is infection-free, an annual movement rate of 2–3% from an infected source village imposes a risk of re-introduction of STH of 75% or higher, unless the prevalence in the source village is less than 20%. Even a single arrival of 2–3% of the population can impose a risk of re-introducing STH of 50% or greater depending on the prevalence in the source village. The risk of re-introduction also depends on both the age group of moving individuals and STH species, since the pattern of cross-sectional age-prevalence and age-intensity profiles of infection in the human host are species-specific.ConclusionsPlanning for STH elimination programmes should account for human mobility patterns in defined regions. We recommend that individuals arriving from areas with ongoing STH transmission should receive preventive chemotherapy for STHs. This can mos
Vegvari C, Truscott J, Kura K, et al., 2019, IMPACT OF POPULATION MOVEMENT BETWEEN VILLAGES ON THE LIKELIHOOD OF BREAKING TRANSMISSION OF SOIL-TRANSMITTED HELMINTHS, Publisher: OXFORD UNIV PRESS, Pages: S53-S54, ISSN: 0035-9203
Giardina F, Coffeng LE, Farrell SH, et 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
Imtiaz R, Campbell SJ, Vegvari C, et al., 2019, Insights from quantitative analysis and mathematical modelling on the proposed who 2030 goals for soil-transmitted helminths., Gates Open Research, Vol: 3
Soil-transmitted helminths (STHs) are a group of parasitic worms that infect humans, causing a wide spectrum of disease, notably anaemia, growth retardation, and delayed cognitive development. The three main STHs are Ascaris lumbricoides, Trichuris trichiura and hookworm (Necator americanus and Ancylostoma duodenale). Approximately 1.5 billion people are infected with STHs worldwide. The World Health Organization goal for 2030 is morbidity control, defined as reaching <2% prevalence of medium-to-high intensity infections in preschool-age children and school-age children (SAC). Treatment guidelines for achieving this goal have been recommended. The Neglected Tropical Diseases Modelling Consortium has developed mathematical and statistical models to quantify, predict, and evaluate the impact of control measures on STHs. These models show that the morbidity target can be achieved following current guidelines in moderate prevalence settings (20-50% in SAC). In high prevalence settings, semi-annual preventive chemotherapy (PC) ideally including adults, or at least women of reproductive age, is required. For T. trichiura, dual therapy with albendazole and ivermectin is required. In general, stopping PC is not possible without infection resurgence, unless effective measures for improved access to water, hygiene, and sanitation have been implemented, or elimination of transmission has been achieved. Current diagnostic methods are based on egg counts in stool samples, but these are known to have poor sensitivity at low prevalence levels. A target threshold for novel, more sensitive diagnostics should be defined relative to currently preferred diagnostics (Kato-Katz). Our analyses identify the extent of systematic non-access to treatment and the individual patterns of compliance over multiple rounds of treatment as the biggest unknowns and the main impediment to reaching the target. Moreover, the link between morbidity and infection intensity has not been fully elucidated.
Vegvari C, Hardwick R, Truscott J, et al., 2019, RELEVANT SPATIAL SCALE FOR EVALUATION UNITS FOR ELIMINATION PROGRAMS FOR SOIL-TRANSMITTED HELMINTHS GIVEN GEOGRAPHY OF SETTLEMENTS AND HUMAN MOVEMENT, 68th Annual Meeting of the American-Society-for-Tropical-Medicine-and-Hygiene (ASTMH), Publisher: AMER SOC TROP MED & HYGIENE, Pages: 618-618, ISSN: 0002-9637
Werkman M, Toor J, Vegvari C, et 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
Vegvari C, Kura K, Truscott J, et al., 2018, MIGRATION AND LOCAL MOVEMENT CAN IMPEDE ELIMINATION EFFORTS OF SOIL-TRANSMITTED HELMINTHS (STH) BY MASS DRUG ADMINISTRATION (MDA), 67th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTHM), Publisher: AMER SOC TROP MED & HYGIENE, Pages: 239-239, ISSN: 0002-9637
Lawrence E, Vegvari C, Ower A, et al., 2017, A Systematic Review of Longitudinal Studies Which Measure Alzheimer's Disease Biomarkers, JOURNAL OF ALZHEIMERS DISEASE, Vol: 59, Pages: 1359-1379, ISSN: 1387-2877
Alzheimer’s disease (AD) is a progressive and fatal neurodegenerative disease, with no effective treatment orcure. A gold standard therapy would be treatment to slow or halt disease progression; however, knowledge of causationin the early stages of AD is very limited. In order to determine effective endpoints for possible therapies, a number ofquantitative surrogate markers of disease progression have been suggested, including biochemical and imaging biomarkers.The dynamics of these various surrogate markers over time, particularly in relation to disease development, are, however,not well characterized. We reviewed the literature for studies that measured cerebrospinal fluid or plasma amyloid-andtau, or took magnetic resonance image or fluorodeoxyglucose/Pittsburgh compound B-positron electron tomography scans,in longitudinal cohort studies. We summarized the properties of the major cohort studies in various countries, commonlyused diagnosis methods and study designs. We have concluded that additional studies with repeat measures over time in arepresentative population cohort are needed to address the gap in knowledge of AD progression. Based on our analysis, wesuggest directions in which research could move in order to advance our understanding of this complex disease, includingrepeat biomarker measurements, standardization and increased sample sizes.
Vegvari C, Hadjichrysanthou C, Cauët E, et al., 2016, How Can Viral Dynamics Models Inform Endpoint Measures in Clinical Trials of Therapies for Acute Viral Infections?, PLOS One, Vol: 11, ISSN: 1932-6203
Acute viral infections pose many practical challenges for the accurate assessment of the impact of novel therapies on viral growth and decay. Using the example of influenza A, we illustrate how the measurement of infection-related quantities that determine the dynamics of viral load within the human host, can inform investigators on the course and severity of infection and the efficacy of a novel treatment. We estimated the values of key infection-related quantities that determine the course of natural infection from viral load data, using Markov Chain Monte Carlo methods. The data were placebo group viral load measurements collected during volunteer challenge studies, conducted by Roche, as part of the oseltamivir trials. We calculated the values of the quantities for each patient and the correlations between the quantities, symptom severity and body temperature. The greatest variation among individuals occurred in the viral load peak and area under the viral load curve. Total symptom severity correlated positively with the basic reproductive number. The most sensitive endpoint for therapeutic trials with the goal to cure patients is the duration of infection. We suggest laboratory experiments to obtain more precise estimates of virological quantities that can supplement clinical endpoint measurements.
Vegvari C, Cauët E, Hadjichrysanthou C, et al., 2016, Using Clinical Trial Simulators to Analyse the Sources of Variance in Clinical Trials of Novel Therapies for Acute Viral Infections., PLOS One, Vol: 11, ISSN: 1932-6203
BACKGROUND: About 90% of drugs fail in clinical development. The question is whether trials fail because of insufficient efficacy of the new treatment, or rather because of poor trial design that is unable to detect the true efficacy. The variance of the measured endpoints is a major, largely underestimated source of uncertainty in clinical trial design, particularly in acute viral infections. We use a clinical trial simulator to demonstrate how a thorough consideration of the variability inherent in clinical trials of novel therapies for acute viral infections can improve trial design. METHODS AND FINDINGS: We developed a clinical trial simulator to analyse the impact of three different types of variation on the outcome of a challenge study of influenza treatments for infected patients, including individual patient variability in the response to the drug, the variance of the measurement procedure, and the variance of the lower limit of quantification of endpoint measurements. In addition, we investigated the impact of protocol variation on clinical trial outcome. We found that the greatest source of variance was inter-individual variability in the natural course of infection. Running a larger phase II study can save up to $38 million, if an unlikely to succeed phase III trial is avoided. In addition, low-sensitivity viral load assays can lead to falsely negative trial outcomes. CONCLUSIONS: Due to high inter-individual variability in natural infection, the most important variable in clinical trial design for challenge studies of potential novel influenza treatments is the number of participants. 100 participants are preferable over 50. Using more sensitive viral load assays increases the probability of a positive trial outcome, but may in some circumstances lead to false positive outcomes. Clinical trial simulations are powerful tools to identify the most important sources of variance in clinical trials and thereby help improve trial design.
Hadjichrysanthou C, Cauët E, Lawrence E, et al., 2016, Understanding the within-host dynamics of influenza A virus: from theory to clinical implications, Journal of the Royal Society Interface, Vol: 13, ISSN: 1742-5689
Mathematical models have provided important insights into acute viral dynamics within individual patients. In this paper, we study the simplest target cell-limited models to investigate the within-host dynamics of influenza A virus infection in humans. Despite the biological simplicity of the models, we show how these can be used to understand the severity of the infection and the key attributes of possible immunotherapy and antiviral drugs for the treatment of infection at different times post infection. Through an analytic approach, we derive and estimate simple summary biological quantities that can provide novel insights into the infection dynamics and the definition of clinical endpoints. We focus on nine quantities, including the area under the viral load curve, peak viral load, the time to peak viral load and the level of cell death due to infection. Using Markov chain Monte Carlo methods, we fitted the models to data collected from 12 untreated volunteers who participated in two clinical studies that tested the antiviral drugs oseltamivir and zanamivir. Based on the results, we also discuss various difficulties in deriving precise estimates of the parameters, even in the very simple models considered, when experimental data are limited to viral load measures and/or there is a limited number of viral load measurements post infection.
Vegvari C, Foley R, 2014, Competition and Culture Change in Prehistoric Socio-Environmental Systems, Computer Applications and Quantitative Methods in Archaeology 2013
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