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Lloyd, A. L.

Publications and source records attributed to Lloyd, A. L..

9 recordsLinked to original sources

Spatial confinement of gene drives: Assessing risk of failure using global sensitivity analysis

Gene drives allow pest populations to be genetically modified to reduce their harm on agriculture and human health. The genetic modification, or payload, spreads within a target population at rates exceeding normal Mendelian inheritance. While gene drives have demonstrated immense potential in laboratory populations, they present unique challenges. Foremost among these challenges is spatial confinement, or ensuring that the payload remains confined to target populations. However, there is an inherent tension between gene drive spread and spatial confinement: increasing the spreading efficiency of a gene drive increases the risk of escape, while engineering confinement mechanisms increases the risk of gene drive extinction. In this work, we explore spatial outcomes in gene drives designed for spatial confinement and the dependence of these outcomes on target organism dispersal and payload fitness cost. We use a stochastic spatial model to compute the probability of failure for each gene drive, and use techniques from global sensitivity analysis to quantify the contribution of dispersal and fitness cost to variance in gene drive performance. Our findings reveal how spatial outcomes are affected by key parameters, and how this sensitivity varies tremendously between different gene drives. These spatial properties can be used to classify gene drive behavior and are useful to determine suitability for a particular application.

evolutionary biology↗

How population control of pests is modulated by density dependence: The perspective of genetic biocontrol

Managing pest species relies critically on mechanisms that regulate population dynamics, particularly those factors that change with population size. These density-dependent factors can help or hinder control efforts and are especially relevant considering recent advances in genetic techniques that allow for precise manipulation of the timing and sex-specificity of a control. Despite this importance, density dependence is often poorly characterized owing to limited data and an incomplete understanding of developmental ecology. To address this issue, we construct and analyze a mathematical model of a pest population with a general control under a wide range of density dependence scenarios. Using this model, we investigate how control performance is affected by the strength of density dependence. By modifying the timing and sex-specificity of the control, we tailor our analysis to simulate different pest control strategies, including conventional and genetic biocontrol methods. We pay particular attention to the latter as case studies by extending the baseline model to include genetic dynamics. Finally, we clarify past work on the dynamics of mechanistic models with density dependence. As expected, we find substantial differences in control performance for differing strengths of density dependence, with populations exhibiting strong density dependence being most resilient to suppression. However, these results change with the size and timing of the control load, as well as the target sex. Interestingly, we also find that population invasion by certain genetic biocontrol strategies is affected by the strength of density dependence. While the model is parameterized using the life history traits of the yellow fever mosquito, Aedes aegypti, the principles developed here apply to many pest species. We conclude by discussing what this means for pest population suppression moving forward.

ecology↗

Extensions of mean-field approximations for environmentally-transmitted pathogen networks

Many pathogens spread via environmental transmission, without requiring host- to-host direct contact. While models for environmental transmission exist, many are simply constructed intuitively with structures analogous to standard models for direct transmission. As model insights are generally sensitive to the underlying model assumptions, it is important that we are able understand the details and consequences of these assumptions. We construct a simple network model for an environmentally-transmitted pathogen and rigorously derive systems of ordinary differential equations (ODEs) based on different assumptions. We explore two key assumptions, namely homogeneity and independence, and demonstrate that relaxing these assumptions can lead to more accurate ODE approximations. We compare these ODE models to a stochastic implementation of the network model over a variety of parameters and network structures, demonstrating that with fewer restrictive assumptions we are able to achieve higher accuracy in our approximations and highlighting more precisely the errors produced by each assumption. We show that less restrictive assumptions lead to more complicated systems of ODEs and the potential for unstable solutions. Due to the rigour of our derivation, we are able to identify the reason behind these errors and propose potential resolutions.

microbiology↗

Fusing an agent-based model of mosquito population dynamics with a statistical reconstruction of spatio-temporal abundance patterns

The mosquito Aedes aegypti is the vector of a number of medically-important viruses, including dengue virus, yellow virus, chikungunya virus, and Zika virus, and as such vector control is a key approach to managing the diseases they cause. Understanding the impact of vector control on these diseases is aided by first understanding its impact on Ae. aegypti population dynamics. A number of detail-rich models have been developed to couple the dynamics of the immature and adult stages of Ae. aegypti. The numerous assumptions of these models enable them to realistically characterize impacts of mosquito control, but they also constrain the ability of such models to reproduce empirical patterns that do not conform to the models behavior. In contrast, statistical models afford sufficient flexibility to extract nuanced signals from noisy data, yet they have limited ability to make predictions about impacts of mosquito control on disease caused by pathogens that the mosquitoes transmit without extensive data on mosquitoes and disease. Here, we demonstrate how the differing strengths of mechanistic realism and statistical flexibility can be fused into a single model. Our analysis utilizes data from 176,352 household-level Ae. aegypti aspirator collections conducted during 1999-2011 in Iquitos, Peru. The key step in our approach is to calibrate a single parameter of the model to spatio-temporal abundance patterns predicted by a generalized additive model (GAM). In effect, this calibrated parameter absorbs residual variation in the abundance time-series not captured by other features of the mechanistic model. We then used this calibrated parameter and the literature-derived parameters in the agent-based model to explore Ae. aegypti population dynamics and the impact of insecticide spraying to kill adult mosquitoes. The baseline abundance predicted by the agent-based model closely matched that predicted by the GAM. Following spraying, the agent-based model predicted that mosquito abundance rebounds within about two months, commensurate with recent experimental data from Iquitos. Our approach was able to accurately reproduce abundance patterns in Iquitos and produce a realistic response to adulticide spraying, while retaining sufficient flexibility to be applied across a range of settings. Author SummaryThe mosquito Aedes aegypti is the vector for a number of the most medically important viruses, including dengue, Zika, chikungunya, and yellow fever. Understanding the population dynamics of this mosquito, and how those dynamics might respond to vector control interventions, is critical to inform the deployment of such interventions. One of the best ways to gain this understanding is through modeling of population dynamics. Such models are often categorizes as either statistical or dynamical, and each of these approaches has advantages and disadvantages - for instance, statistical models may more closely match patterns observed in empirical data, while dynamical models are better able to predict the impact of counterfactual situations such as vector control strategies. In this paper, we present an approach which fuses these two approaches in order to gain the advantages of both: it fits empirical data on Aedes aegypti population dynamics well, while producing realistic responses to vector control interventions. Our approach has the potential to inform and improve the deployment of vector control interventions, and, when used in concert with and epidemiological model, to help reduce the burden of the diseases spread by such vectors.

ecology↗

A critical assessment of the detailed Aedes aegypti simulation model Skeeter Buster 2 using field experiments of indoor insecticidal control in Iquitos, Peru

The importance of mosquitoes in human pathogen transmission has motivated major research efforts into mosquito biology in pursuit of more effective vector control measures. Aedes aegypti is a particular concern in tropical urban areas, where it is the primary vector of numerous flaviviruses, including the yellow fever, Zika, and dengue viruses. With an anthropophilic habit, Ae. aegypti prefers houses, human blood meals, and ovipositioning in water-filled containers. We hypothesized that this relatively simple ecological niche should allow us to predict the impacts of insecticidal control measures on mosquito populations. To do this, we use Skeeter Buster 2 (SB2), a stochastic, spatially explicit, mechanistic model of Ae. aegypti population biology. SB2 builds on Skeeter Buster, which reproduced equilibrium dynamics of Ae. aegypti in Iquitos, Peru. Our goal was to predict the response of mosquito populations to perturbations by indoor insecticidal spraying and widespread destructive insect surveys. To evaluate SB2, we conducted two field experiments in Iquitos, Peru: a smaller pilot study in 2013 (S-2013) followed by a larger experiment in 2014 (L-2014). Here, we compare model predictions with (pre-viously reported) empirical results from these experiments. In both simulated and empirical populations, repeated spraying yielded substantial yet temporary reductions in adult densities. The proportional effects of spraying were broadly comparable between simulated and empirical results, but we found noteworthy differences. In particular, SB2 consistently over-estimated the proportion of nulliparous females and the proportion of containers holding immature mosquitoes. We also observed less temporal variation in simulated surveys of adult abundance relative to corresponding empirical observations. Our results indicate the presence of ecological heterogeneities or sampling processes not effectively represented by SB2. Although additional empirical research could further improve the accuracy and precision of SB2, our results under-score the importance of non-linear dynamics in the response of Ae. aegypti populations to perturbations, and suggest general limits to the fine-grained predictability of its population dynamics over space and time.

ecology↗

Evolution of Knockdown Resistance Haplotypes in Response to Pyrethroid Selection in Aedes aegypti

This study describes the evolution of knockdown resistance (kdr) haplotypes in Aedes aegypti in response to pyrethroid insecticide use over the course of 18 years in Iquitos, Peru. Based on the duration and intensiveness of sampling ([~]10,000 samples), this is the most thorough study of kdr population genetics in Ae. aegypti to date within a city. We provide evidence for the direct connection between programmatic citywide pyrethroid spraying and the increase in frequency of specific kdr haplotypes by identifying two evolutionary events in the population. The relatively high selection coefficients, even under infrequent insecticide pressure, emphasizes how quickly populations can evolve. The observed rapid increase in frequency of resistance alleles might have been aided by the incomplete dominance of resistance-conferring alleles over corresponding susceptibility alleles. In addition to dramatic temporal shifts, spatial suppression experiments reveal that genetic heterogeneity existed not only at the citywide scale, but also on a very fine scale within the city.

evolutionary biology↗

Mathematical modeling of genetic pest management through female lethality with independently segregating alleles

Many novel genetic approaches are under development to combat insect pests. One genetic strategy aims to suppress or locally eliminate a species through large, repeated releases of genetically engineered strains that render female offspring unviable under field conditions. Strains with this female-killing (FK) characteristic have been developed either with all of the molecular components in a single construct or with the components in two constructs inserted at independently assorting loci. Strains with two constructs are typically considered to be only of value as research tools and for producing solely male offspring in rearing factories which are subsequently sterilized by radiation before release. A concern with the two-construct strains is that once released, the two constructs would become separated and therefore non-functional. The only FK strains that have been released in the field without sterilization are single-construct strains. Here, we use a population genetics model with density dependence to evaluate the relative effectiveness of female killing approaches based on single- and two-construct arrangements. We find that, in general, the single-construct arrangement results in slightly faster population suppression, but the two-construct arrangement can eventually cause stronger suppression and cause local elimination with a smaller release size. Based on our results, there is no a priori reason that males carrying two independently segregating constructs need to be sterilized prior to release. In some cases, a fertile release would be more efficient for population suppression.Competing Interest StatementThe authors have declared no competing interest.View Full Text

evolutionary biology↗

Efficacy of Aedes aegypti control by indoor Ultra Low Volume (ULV) insecticide spraying in Iquitos, Peru

BackgroundAedes aegypti is a primary vector of dengue, chikungunya, Zika, and urban yellow fever viruses. Indoor, ultra low volume (ULV) space spraying with pyrethroid insecticides is the main approach used for Ae. aegypti emergency control in many countries. Given the widespread use of this method, the lack of large-scale experiments or detailed evaluations of municipal spray programs is problematic.\n\nMethodology/Principal FindingsTwo experimental evaluations of non-residual, indoor ULV pyrethroid spraying were conducted in Iquitos, Peru. In each, a central sprayed sector was surrounded by an unsprayed buffer sector. In 2013, spray and buffer sectors included 398 and 765 houses, respectively. Spraying reduced the mean number of adults captured per house by ~83 percent relative to the pre-spray baseline survey. In the 2014 experiment, sprayed and buffer sectors included 1,117 and 1,049 houses, respectively. Here, the sprayed sectors number of adults per house was reduced ~64 percent relative to baseline. Parity surveys in the sprayed sector during the 2014 spray period indicated an increase in the proportion of very young females. We also evaluated impacts of a 2014 citywide spray program by the local Ministry of Health, which reduced adult populations by ~60 percent. In all cases, adult densities returned to near-baseline levels within one month.\n\nConclusions/SignificanceOur results demonstrate that densities of adult Ae. aegypti can be reduced by experimental and municipal spraying programs. The finding that adult densities return to approximately pre-spray densities in less than a month is similar to results from previous, smaller scale experiments. Our results demonstrate that ULV spraying is best viewed as having a short-term entomological effect. The epidemiological impact of ULV spraying will need evaluation in future trials that measure capacity of insecticide spraying to reduce disease transmission.

epidemiology↗

Invasion and migration of self-limiting gene drives: a comparative analysis

Recent advances in research on gene drives have produced genetic constructs that could theoretically spread a desired gene (payload) into all populations of a species, with a single release in one place. This attribute has advantages, but also comes with risks and ethical concerns. There has been a call for research on gene drive systems that are spatially and/or temporally self-limiting. Here we use a population genetics model to compare the expected characteristics of three spatially self-limiting gene drive systems: one-locus underdominance, two-locus underdominance, and daisy-chain drives. We find large differences between these gene drives in the minimum release size required for successfully driving a payload into a population. The daisy-chain system is the most efficient, requiring the smallest release, followed by the two-locus underdominance system, and then the one-locus underdominance system. However, when the target population exchanges migrants with a non-target population, the gene drives requiring smaller releases suffer from higher risks of unintended spread. For payloads that incur relatively low fitness costs (up to 30%), a simple daisy-chain drive is practically incapable of remaining localized, even with migration rates as low as 0.5% per generation. The two-locus underdominance system can achieve localized spread under a broader range of migration rates and of payload fitness costs, while the one-locus underdominance system largely remains localized. We also find differences in the extent of population alteration and in the permanence of the alteration achieved by the three gene drives. The two-locus underdominance system does not always spread the payload to fixation, even after successful drive, while the daisy-chain system can, for a small set of parameter values, achieve a temporally-limited spread of the payload. These differences could affect the suitability of each gene drive for specific applications. Note: This manuscript has been accepted for publication in the journal Evolutionary Applications and is pending publication. We suggest that any reference to or quotation of this article should be made with this recognition.

bioengineering↗