Investigating the use of routine malaria surveillance data to evaluate the effectiveness of pyrethroid vector control interventions

Malaria control is increasingly being tailored to local needs, this is especially necessary in humanitarian settings where resources are poor. Pyrethroids are the most widely used class of insecticides for mosquito control. Using them effectively requires measuring their epidemiological impact and understanding how this is reduced by the emergence of pyrethroid resistance in mosquitoes. In the first two chapters of this thesis, I consider how we could measure the impact of pyrethroids using the prevalence of infection in pregnant women, a potentially cheaper and more reliable alternative to clinical incidence or prevalence in children. In Chapter 2, I fit a Bayesian regression model to show that the malaria burden measured at hospitals near internally displaced populations is higher than the regional average. In Chapter 3, I demonstrate that the prevalence of infection in pregnant women and the clinical incidence in children change together over time. Collecting routine data from pregnant women seems promising as a measure for assessing malaria burden trends. In the second half of the thesis I explore the impact of different pyrethroid-based interventions in a variety of contexts. In Chapter 4, I expand an existing mathematical model of malaria transmission to predict the impact of distributing emanators (a type of spatial repellent) where insecticidal nets are not commonplace. In Chapter 5, I establish how outdoor evening biting could sustain transmission in places where insecticidal nets are used but residual transmission remains. In Chapter 6, I investigate a sub-lethal effect of pyrethroid bed nets that I call temporary feeding inhibition, mosquitoes that are exposed to pyrethroids do not die but are unable to bite humans for a short while afterwards. Together the work shows how statistical and transmission dynamics models can be used to understand the efficacy of vector control interventions and measure their effectiveness in the field.Open Acces

Recent approaches in computational modelling for controlling pathogen threats.

In this review, we assess the status of computational modelling of pathogens. We focus on three disparate but interlinked research areas that produce models with very different spatial and temporal scope. First, we examine antimicrobial resistance (AMR). Many mechanisms of AMR are not well understood. As a result, it is hard to measure the current incidence of AMR, predict the future incidence, and design strategies to preserve existing antibiotic effectiveness. Next, we look at how to choose the finite number of bacterial strains that can be included in a vaccine. To do this, we need to understand what happens to vaccine and non-vaccine strains after vaccination programmes. Finally, we look at within-host modelling of antibody dynamics. The SARS-CoV-2 pandemic produced huge amounts of antibody data, prompting improvements in this area of modelling. We finish by discussing the challenges that persist in understanding these complex biological systems

The transmissibility of novel Coronavirus in the early stages of the 2019-20 outbreak in Wuhan: Exploring initial point-source exposure sizes and durations using scenario analysis.

Background: The current novel coronavirus outbreak appears to have originated from a point-source exposure event at Huanan seafood wholesale market in Wuhan, China. There is still uncertainty around the scale and duration of this exposure event. This has implications for the estimated transmissibility of the coronavirus and as such, these potential scenarios should be explored.   Methods: We used a stochastic branching process model, parameterised with available data where possible and otherwise informed by the 2002-2003 Severe Acute Respiratory Syndrome (SARS) outbreak, to simulate the Wuhan outbreak. We evaluated scenarios for the following parameters: the size, and duration of the initial transmission event, the serial interval, and the reproduction number (R0). We restricted model simulations based on the number of observed cases on the 25th of January, accepting samples that were within a 5% interval on either side of this estimate. Results: Using a pre-intervention SARS-like serial interval suggested a larger initial transmission event and a higher R0 estimate. Using a SARs-like serial interval we found that the most likely scenario produced an R0 estimate between 2-2.7 (90% credible interval (CrI)). A pre-intervention SARS-like serial interval resulted in an R0 estimate between 2-3 (90% CrI). There were other plausible scenarios with smaller events sizes and longer duration that had comparable R0 estimates. There were very few simulations that were able to reproduce the observed data when R0 was less than 1. Conclusions: Our results indicate that an R0 of less than 1 was highly unlikely unless the size of the initial exposure event was much greater than currently reported. We found that R0 estimates were comparable across scenarios with decreasing event size and increasing duration. Scenarios with a pre-intervention SARS-like serial interval resulted in a higher R0 and were equally plausible to scenarios with SARs-like serial intervals

When intuition falters: repeated testing accuracy during an epidemic

Widespread, repeated testing using rapid antigen tests to proactively detect asymptomatic SARS-CoV-2 infections has been a promising yet controversial topic during the COVID-19 pandemic. Concerns have been raised over whether currently authorized lateral flow tests are sufficiently sensitive and specific to detect enough infections to impact transmission whilst minimizing unnecessary isolation of false positives. These concerns have often been illustrated using simple, textbook calculations of positivity rates and positive predictive value assuming fixed values for sensitivity, specificity and prevalence. However, we argue that evaluating repeated testing strategies requires the consideration of three additional factors: new infections continue to arise depending on the incidence rate, isolating positive individuals reduces prevalence in the tested population, and each infected individual is tested multiple times during their infection course. We provide a simple mathematical model with an online interface to illustrate how these three factors impact test positivity rates and the number of isolating individuals over time. These results highlight the potential pitfalls of using inappropriate textbook-style calculations to evaluate statistics arising from repeated testing strategies during an epidemic

A systematic review of sample size estimation accuracy on power in malaria cluster randomised trials measuring epidemiological outcomes.

INTRODUCTION: Cluster randomised trials (CRTs) are the gold standard for measuring the community-wide impacts of malaria control tools. CRTs rely on well-defined sample size estimations to detect statistically significant effects of trialled interventions, however these are often predicted poorly by triallists. Here, we review the accuracy of predicted parameters used in sample size calculations for malaria CRTs with epidemiological outcomes. METHODS: We searched for published malaria CRTs using four online databases in March 2022. Eligible trials included those with malaria-specific epidemiological outcomes which randomised at least six geographical clusters to study arms. Predicted and observed sample size parameters were extracted by reviewers for each trial. Pair-wise Spearman's correlation coefficients (rs) were calculated to assess the correlation between predicted and observed control-arm outcome measures and effect sizes (relative percentage reductions) between arms. Among trials which retrospectively calculated an estimate of heterogeneity in cluster outcomes, we recalculated study power according to observed trial estimates. RESULTS: Of the 1889 records identified and screened, 108 articles were eligible and comprised of 71 malaria CRTs. Among 91.5% (65/71) of trials that included sample size calculations, most estimated cluster heterogeneity using the coefficient of variation (k) (80%, 52/65) which were often predicted without using prior data (67.7%, 44/65). Predicted control-arm prevalence moderately correlated with observed control-arm prevalence (rs: 0.44, [95%CI: 0.12,0.68], p-value < 0.05], with 61.2% (19/31) of prevalence estimates overestimated. Among the minority of trials that retrospectively calculated cluster heterogeneity (20%, 13/65), empirical values contrasted with those used in sample size estimations and often compromised study power. Observed effect sizes were often smaller than had been predicted at the sample size stage (72.9%, 51/70) and were typically higher in the first, compared to the second, year of trials. Overall, effect sizes achieved by malaria interventions tested in trials decreased between 1995 and 2021. CONCLUSIONS: Study findings reveal sample size parameters in malaria CRTs were often inaccurate and resulted in underpowered studies. Future trials must strive to obtain more representative epidemiological sample size inputs to ensure interventions against malaria are adequately evaluated. REGISTRATION: This review is registered with PROSPERO (CRD42022315741)

Estimating the infection and case fatality ratio for coronavirus disease (COVID-19) using age-adjusted data from the outbreak on the Diamond Princess cruise ship, February 2020.

Adjusting for delay from confirmation to death, we estimated case and infection fatality ratios (CFR, IFR) for coronavirus disease (COVID-19) on the Diamond Princess ship as 2.6% (95% confidence interval (CI): 0.89-6.7) and 1.3% (95% CI: 0.38-3.6), respectively. Comparing deaths on board with expected deaths based on naive CFR estimates from China, we estimated CFR and IFR in China to be 1.2% (95% CI: 0.3-2.7) and 0.6% (95% CI: 0.2-1.3), respectively