Evaluating quasi-experimental approaches for estimating epidemiological efficacy of non-randomised field trials: applications in Wolbachia interventions for dengue.

BACKGROUND: Wolbachia symbiosis in Aedes aegypti is an emerging biocontrol measure against dengue. However, assessing its real-world efficacy is challenging due to the non-randomised, field-based nature of most intervention studies. This research re-evaluates the spatial-temporal impact of Wolbachia interventions on dengue incidence using a large battery of quasi-experimental methods and assesses each method's validity. METHODS: A systematic search for Wolbachia intervention data was conducted via PUBMED. Efficacy was reassessed using commonly-used quasi-experimental approaches with extensive robustness checks, including geospatial placebo tests and a simulation study. Intervention efficacies across multiple study sites were computed using high-resolution aggregations to examine heterogeneities across sites and study periods. We further designed a stochastic simulation framework to assess the methods' ability to estimate intervention efficacies (IE). RESULTS: Wolbachia interventions in Singapore, Malaysia, and Brazil significantly decreased dengue incidence, with reductions ranging from 48.17% to 69.19%. IEs varied with location and duration. Malaysia showed increasing efficacy over time, while Brazil exhibited initial success with subsequent decline, hinting at operational challenges. Singapore's strategy was highly effective despite partial saturation. Simulations identified Synthetic Control Methods (SCM) and its variant, count Synthetic Control Method (cSCM), as superior in precision, with the smallest percentage errors in efficacy estimation. These methods also demonstrated robustness in placebo tests. CONCLUSIONS: Wolbachia interventions exhibit consistent protective effects against dengue. SCM and cSCM provided the most precise and robust estimates of IEs, validated across simulated and real-world settings.

Modeling insect growth regulators for pest management.

Insect growth regulators (IGRs) have been developed as effective control measures against harmful insect pests to disrupt their normal development. This study is to propose a mathematical model to evaluate the cost-effectiveness of IGRs for pest management. The key features of the model include the temperature-dependent growth of insects and realistic impulsive IGRs releasing strategies. The impulsive releases are carefully modeled by counting the number of implements during an insect's temperature-dependent development duration, which introduces a surviving probability determined by a product of terms corresponding to each release. Dynamical behavior of the model is illustrated through dynamical system analysis and a threshold-type result is established in terms of the net reproduction number. Further numerical simulations are performed to quantitatively evaluate the effectiveness of IGRs to control populations of harmful insect pests. It is interesting to observe that the time-changing environment plays an important role in determining an optimal pest control scheme with appropriate release frequencies and time instants.

More pests but less pesticide applications: Ambivalent effect of landscape complexity on conservation biological control.

In agricultural landscapes, the amount and organization of crops and semi-natural habitats (SNH) have the potential to promote a bundle of ecosystem services due to their influence on ecological community at multiple spatio-temporal scales. SNH are relatively undisturbed and are often source of complementary resources and refuges, therefore supporting more diverse and abundant natural pest enemies. However, the nexus of SNH proportion and organization with pest suppression is not trivial. It is thus crucial to understand how the behavior of pest and natural enemy species, the underlying landscape structure, and their interaction, may influence conservation biological control (CBC). Here, we develop a generative stochastic landscape model to simulate realistic agricultural landscape compositions and configurations of fields and linear elements. Generated landscapes are used as spatial support over which we simulate a spatially explicit predator-prey dynamic model. We find that increased SNH presence boosts predator populations by sustaining high predator density that regulates and keeps pest density below the pesticide application threshold. However, predator presence over all the landscape helps to stabilize the pest population by keeping it under this threshold, which tends to increase pest density at the landscape scale. In addition, the joint effect of SNH presence and predator dispersal ability among hedge and field interface results in a stronger pest regulation, which also limits pest growth. Considering properties of both fields and linear elements, such as local structure and geometric features, provides deeper insights for pest regulation; for example, hedge presence at crop field boundaries clearly strengthens CBC. Our results highlight that the integration of species behaviors and traits with landscape structure at multiple scales is necessary to provide useful insights for CBC.

Species diversity and food web structure jointly shape natural biological control in agricultural landscapes.

Land-use change and agricultural intensification concurrently impact natural enemy (e.g., parasitoid) communities and their associated ecosystem services (ESs), i.e., biological pest control. However, the extent to which (on-farm) parasitoid diversity and food webs mediate landscape-level influences on biological control remains poorly understood. Here, drawing upon a 3-year study of quantitative parasitoid-hyperparasitoid trophic networks from 25 different agro-landscapes, we assess the cascading effects of landscape composition, species diversity and trophic network structure on ecosystem functionality (i.e., parasitism, hyperparasitism). Path analysis further reveals cascaded effects leading to biological control of a resident crop pest, i.e., Aphis gossypii. Functionality is dictated by (hyper)parasitoid diversity, with its effects modulated by food web generality and vulnerability. Non-crop habitat cover directly benefits biological control, whereas secondary crop cover indirectly lowers hyperparasitism. Our work underscores a need to simultaneously account for on-farm biodiversity and trophic interactions when investigating ESs within dynamic agro-landscapes.

Biological control of the Asian chestnut gall wasp in Portugal: Insights from a mathematical model.

In recent years, the Asian gall wasp Dryocosmus kuriphilus has invaded chestnut trees and significantly affected the Portuguese chestnut production. Studies in other countries, such as Japan or Italy, have shown that the parasitoid Torymus sinensis can successfully achieve biological control of D. kuriphilus. Mathematical models help us to understand the dynamics of the interaction between the pest D. kuriphilus and its parasitoid T. sinensis and, consequently, they can help to implement measures that enhance crop pest management. In this work, the evolution of the density of D. kuriphilus and T. sinensis across time and space is studied through the numerical solution of models that include parameters based on observations made in Portugal. Simultaneous releases of the parasitoid are simulated at various locations and at different times. The results indicate that, in the case of a small and homogeneous orchard, biological control can be effective, but, in the case of extensive domains, the pest control is much more difficult to achieve. In order for biological control to be efficient, it is necessary to implement, in each chestnut-producing region, a collective strategy based on the annual monitoring of infestation levels.

Reduced competence to arboviruses following the sustainable invasion of Wolbachia into native Aedes aegypti from Southeastern Brazil.

Field release of Wolbachia-infected Aedes aegypti has emerged as a promising solution to manage the transmission of dengue, Zika and chikungunya in endemic areas across the globe. Through an efficient self-dispersing mechanism, and the ability to induce virus-blocking properties, Wolbachia offers an unmatched potential to gradually modify wild Ae. aegypti populations turning them unsuitable disease vectors. Here we describe a proof-of-concept field trial carried out in a small community of Niterói, greater Rio de Janeiro, Brazil. Following the release of Wolbachia-infected eggs, we report here a successful invasion and long-term establishment of the bacterium across the territory, as denoted by stable high-infection indexes (> 80%). We have also demonstrated that refractoriness to dengue and Zika viruses, either thorough oral-feeding or intra-thoracic saliva challenging assays, was maintained over the adaptation to the natural environment of Southeastern Brazil. These findings further support Wolbachia's ability to invade local Ae. aegypti populations and impair disease transmission, and will pave the way for future epidemiological and economic impact assessments.

Challenges of automation and scale: Bioinformatics and the evaluation of proteins to support genetically modified product safety assessments.

Bioinformatic analyses of protein sequences play an important role in the discovery and subsequent safety assessment of insect control proteins in Genetically Modified (GM) crops. Due to the rapid adoption of high-throughput sequencing methods over the last decade, the number of protein sequences in GenBank and other public databases has increased dramatically. Many of these protein sequences are the product of whole genome sequencing efforts, coupled with automated protein sequence prediction and annotation pipelines. Published genome sequencing studies provide a rich and expanding foundation of new source organisms and proteins for insect control or other desirable traits in GM products. However, data generated by automated pipelines can also confound regulatory safety assessments that employ bioinformatics. Largely this issue does not arise due to underlying sequence, but rather its annotation or associated metadata, and the downstream integration of that data into existing repositories. Observations made during bioinformatic safety assessments are described.

Dynamics of a two-sex model for the population ecology of dengue mosquitoes in the presence of Wolbachia.

The release of Wolbachia-infected mosquitoes into the population of wild mosquitoes is one of the promising biological control method for combating the population abundance of mosquitoes that cause deadly diseases, such as dengue. In this study, a new two-sex mathematical model for the population ecology of dengue mosquitoes and disease is designed and used to assess the population-level impact of the periodic release of Wolbachia-infected mosquitoes. Rigorous analysis of the model, which incorporates many of the lifecycle features of dengue disease and the cytoplasmic incompatibility property of Wolbachia bacterium in mosquitoes, reveal that the disease-free equilibrium of the model is locally-asymptotically stable whenever a certain epidemiological threshold, known as the reproduction number of the model (denoted by R0W), is less than unity. The model is shown, using centre manifold theory, to undergo the phenomenon of backward bifurcation at R0W=1. The consequence of this bifurcation is that Wolbachia may not persist, or dengue disease may not be effectively-controlled, when R0W is less than unity. Such persistence and elimination will depend on the initial sizes of the sub-populations of the model. Two mechanisms were identified for which the backward bifurcation phenomenon can be removed. When backward bifurcation does not occur, the associated non-trivial disease-free equilibrium is shown to be globally-asymptotically stable when the reproduction number of the model is less than unity. Numerical simulations, using data relevant to dengue transmission dynamics in northern Queensland, Australia, shows that releasing Wolbachia-infected mosquitoes every three weeks, for a one-year duration, can lead to the effective control of the population abundance of the local wild mosquitoes, and that such effective control increases with increasing number of Wolbachia-infected mosquitoes released (resulting in the reduction of over 90% of the wild mosquito population from their baseline values). Furthermore, simulations show that releasing only adult male Wolbachia-infected mosquitoes provide more beneficial population-level impact (in terms of reducing the population abundance of the wild mosquitoes), in comparison to releasing adult female Wolbachia-infected mosquitoes. Increasing the frequency of Wolbachia release (e.g., from the default release frequency of every three weeks to weekly) does not significantly affect the effectiveness of the Wolbachia-based control program in curtailing the local abundance of the wild mosquitoes. Finally, it was shown that the cytoplasmic incompatibility property of Wolbachia bacterium does not significantly affect the effectiveness of the Wolbachia-based mosquito control strategy implemented in the community.

Weed biological control in low- and middle-income countries.

Invasive alien plants have a significant impact on biodiversity, crop and pasture production, human and animal health, water resources, and economic development. As most low- and middle-income countries do not have the resources to actively manage invasive plants, many have intentionally introduced biological control agents to help manage their most important weeds. Some of these introductions have resulted in the successful control of numerous weeds such as Chromolaena odorata, Mimosa diplotricha, Pistia stratiotes, and Salvinia molesta. These successes are partly due to the reliance on biological control agents that have been tested and utilized elsewhere. However, despite the successes in weed biological control to date, many low- and middle-income countries are reluctant to pursue weed biological control, due to poor perceptions of biological control and lack of capacity. This results in missed opportunities to manage many weeds cost-effectively, and in so doing, increasing production costs and a dependency on herbicides.

Bifurcation analysis of a wild and sterile mosquito model.

The bifurcation of an ordinary differential equation model describing interaction of the wild and the released sterile mosquitoes is analyzed. It is shown that the model undergoes a sequence of bifurcations including saddle-node bifurcation, supercritical Hopf bifurcation, subcritical Hopf bifurcation, homoclinic bifurcation and Bogdanov-Takens bifurcation. We also find that the model displays monostable, bistable or tristable dynamics. This analysis suggests that the densities of the initial wild mosquitoes and the released sterile ones determine the asymptotic states of both populations. This study may give an insight into the estimation number of the released sterile mosquitoes.

Establishing Wolbachia in the wild mosquito population: The effects of wind and critical patch size.

Releasing mosquitoes with Wolbachia into the wild mosquito population is becoming the very promising strategy to control mosquito-borne infections. To investigate the effects of wind and critical patch size on the Wolbachia establishment in the wild mosquito population, in this paper, we propose a diffusion-reaction-advection system in a heterogeneous environment. By studying the related eigenvalue problems, we derive various conditions under which Wolbachia can fully establish in the entire wild mosquito population. Our findings may provide some useful insights on designing practical releasing strategies to control the mosquito population.

Effectiveness of augmentative biological control depends on landscape context.

Biological pest control by natural enemies is an important component of sustainable crop production. Among biological control approaches, natural enemy augmentation is an effective alternative when naturally occurring enemies are not sufficiently abundant or effective. However, it remains unknown whether the effectiveness of augmentative biocontrol varies along gradients of landscape composition, and how the interactions with resident enemies may modulate the collective impact on pest suppression. By combining field and lab experiments, we evaluated how landscape composition influenced the effectiveness of predator augmentation, and the consequences on pest abundance, plant damage, and crop biomass. We show for the first time that the effectiveness of predator augmentation is landscape-dependent. In complex landscapes, with less cropland area, predator augmentation increased predation rates, reduced pest abundance and plant damage, and increased crop biomass. By contrast, predator releases in simple landscapes had a negative effect on pest control, increasing plant damage and reducing crop biomass. Results from the lab experiment further suggested that landscape simplification can lead to greater interference among predators, causing a decrease in predator foraging efficiency. Our results indicate that landscape composition influence the effectiveness of augmentative biocontrol by modulating interactions between the introduced predators and the local enemy community.

Using non-smooth models to determine thresholds for microbial pest management.

Releasing infectious pests could successfully control and eventually maintain the number of pests below a threshold level. To address this from a mathematical point of view, two non-smooth microbial pest-management models with threshold policy are proposed and investigated in the present paper. First, we establish an impulsive model with state-dependent control to describe the cultural control strategies, including releasing infectious pests and spraying chemical pesticide. We examine the existence and stability of an order-1 periodic solution, the existence of order-k periodic solutions and chaotic phenomena of this model by analyzing the properties of the Poincaré map. Secondly, we establish and analyze a Filippov model. By examining the sliding dynamics, we investigate the global stability of both the pseudo-equilibria and regular equilibria. The findings suggest that we can choose appropriate threshold levels and control intensity to maintain the number of pests at or below the economic threshold. The modelling and control outcomes presented here extend the results for the system with impulsive interventions at fixed moments.

Biocontrol of rats in an urban environment in Southeast Asia using Sarcocystis singaporensis.

BACKGROUND: Upon request of the local administration a control campaign targeting commensal rats (Rattus rattus, R. exulans) was conducted in 30 sub-districts (villages) of the World Heritage town Luang Prabang, Northern Laos, using rat bait containing lethal quantities of the parasitic protist Sarcocystis singaporensis. The associated investigations assessed the short-term control efficacy, willingness of residents to co-operate (community approach), and temporal and spatial changes of the urban rat population in response to treatment. RESULTS: Biological rodent control significantly reduced rodent activity (percentage of positive tracking patches) in the town, from a mean of 25.3% (±12.8% SD) before (January-February) down to 8.0% (±4.4%) after (June) treatment. Reduction of rodent activity relative to three untreated villages was 83%. Similarly, residents observed significantly fewer rats on their properties after the campaign (mean percentage of households (HHs) per village with sightings), whereby reduction of sightings amounted to 57%. There was significant correlation between residents' observation rates and rodent activity. Among 94 rats trapped before and after treatment each, proportions of adult R. exulans and juvenile R. rattus were higher after rodent control, suggesting that a considerable part of the adult house rat population had been removed. Furthermore, a 5% post-campaign incidence of infection suggested that few rats had survived bait uptake. CONCLUSION: S. singaporensis may be used successfully as tactical biocontrol agent for culling of rats in urban environments. We propose additional components of a long-term rodent management strategy for the town, without which the impact of culling campaigns would be limited. © 2019 Society of Chemical Industry.

Dynamics of delayed mosquitoes populations models with two different strategies of releasing sterile mosquitoes.

To prevent the transmissions of mosquito-borne diseases (e.g., malaria, dengue fever), recent works have considered the problem of using the sterile insect technique to reduce or eradicate the wild mosquito population. It is important to consider how reproductive advantage of the wild mosquito population offsets the success of population replacement. In this work, we explore the interactive dynamics of the wild and sterile mosquitoes by incorporating the delay in terms of the growth stage of the wild mosquitoes. We analyze (both analytically and numerically) the role of time delay in two different ways of releasing sterile mosquitoes. Our results demonstrate that in the case of constant release rate, the delay does not affect the dynamics of the system and every solution of the system approaches to an equilibrium point; while in the case of the release rate proportional to the wild mosquito populations, the delay has a large effect on the dynamics of the system, namely, for some parameter ranges, when the delay is small, every solution of the system approaches to an equilibrium point; but as the delay increases, the solutions of the system exhibit oscillatory behavior via Hopf bifurcations. Numerical examples and bifurcation diagrams are also given to demonstrate rich dynamical features of the model in the latter release case.

Quantifying the survival uncertainty of Wolbachia-infected mosquitoes in a spatial model.

Artificial releases of Wolbachia-infected Aedes mosquitoes have been under study in the past yearsfor fighting vector-borne diseases such as dengue, chikungunya and zika.Several strains of this bacterium cause cytoplasmic incompatibility (CI) and can also affect their host's fecundity or lifespan, while highly reducing vector competence for the main arboviruses. We consider and answer the following questions: 1) what should be the initial condition (i.e. size of the initial mosquito population) to have invasion with one mosquito release source? We note that it is hard to have an invasion in such case. 2) How many release points does one need to have sufficiently high probability of invasion? 3) What happens if one accounts for uncertainty in the release protocol (e.g. unequal spacing among release points)? We build a framework based on existing reaction-diffusion models for the uncertainty quantification in this context,obtain both theoretical and numerical lower bounds for the probability of release successand give new quantitative results on the one dimensional case.

Pest demography critically determines the viability of synthetic gene drives for population control.

Synthetic gene drives offer a novel solution for the control of invasive alien species. CRISPR-based gene drives can positively bias their own inheritance, and comprise a DNA sequence that is replicated by homologous recombination. Since gene drives can be positioned to silence fertility or developmental genes, they could be used for population suppression. However, the production of resistant alleles following self-replication errors threatens the technology's viability for pest eradication in real-world applications. Further, a robust assessment of how pest demography impacts the expected progression of gene drives through populations is currently lacking. We used a deterministic, two-sex, birth-death model to investigate how demographic assumptions affect the efficiency of suppression drives for controlling invasive rodents on islands, for two different gene-drive strategies. We show that mass-action reproduction results in overly optimistic eradication outcomes when compared to the more realistic assumption of polygynous breeding. When polygyny was assumed, both gene-strategies failed due to the evolution of resistance unless a reproductive Allee effect (reduced reproductive rates at low population density) was also included; although model outcomes were highly sensitive to the strength of this effect. Increasing the size of the initial gene-drive introduction (up to 10% of carrying capacity) had little impact on population outcomes. Understanding the demography of a population targeted for eradication is critical before the viability of gene-drive suppression can be adequately assessed.

Diffusing wild type and sterile mosquitoes in an optimal control setting.

This paper develops an optimal control framework to investigate the introduction of sterile type mosquitoes to reduce the overal moquito population. As is well known, mosquitoes are vectors of disease. For instance the WHO lists, among other diseases, Malaria, Dengue Fever, Rift Valley Fever, Yellow Fever, Chikungunya Fever and Zika. [http://www.who.int/mediacentre/factsheets/fs387/en/ ] The goal is to establish the existence of a solution given an optimal sterilization protocol as well as to develop the corresponding optimal control representation to minimize the infiltrating mosquito population while minimizing fecundity and the number of sterile type mosquitoes introduced into the environment per unit time. This paper incorporates the diffusion of the mosquitoes into the controlled model and presents a number of numerical simulations.

Biological control with nonlocal interactions.

In this paper, we consider a three-species food chain model with ratio-dependent predation, where species u is preyed upon by species v, which in turn is preyed upon by species w. Our primary focus is on biological control, where the bottom species u is an important crop, and v is a pest that has infested the crop. The superpredator w is introduced into this pest-infested environment in an attempt to restore the system to a pest-free state. We assume that the species can behave nonlocally, where individuals will interact over a distance, and incorporate this nonlocality into the model. For this model, we consider two types of nonlocality: one where the crop species u competes nonlocally with itself, and the other where the superpredator w is assumed to be highly mobile and therefore preys upon the pest v in a nonlocal fashion. We examine how biological control can prove to be highly susceptible to noise, and can fail outright if the pest species is highly diffusive. We show, however, that control can be restored if the superpredator is sufficiently diffusive, and that robust partial control can occur if the superpredator behaves nonlocally. Since the superpredator is generally introduced artificially, our results point to properties of the superpredator which can lead to successful control.

Optimal control approach for establishing wMelPop Wolbachia infection among wild Aedes aegypti populations.

Wolbachia-based biocontrol has recently emerged as a potential method for prevention and control of dengue and other vector-borne diseases. Major vector species, such as Aedes aegypti females, when deliberately infected with Wolbachia become less capable of getting viral infections and transmitting the virus to human hosts. In this paper, we propose an explicit sex-structured population model that describes an interaction of uninfected (wild) male and female mosquitoes and those deliberately infected with wMelPop strain of Wolbachia in the same locality. This particular strain of Wolbachia is regarded as the best blocker of dengue and other arboviral infections. However, wMelPop strain of Wolbachia also causes the loss of individual fitness in Aedes aegypti mosquitoes. Our model allows for natural introduction of the decision (or control) variable, and we apply the optimal control approach to simulate wMelPop Wolbachia infestation of wild Aedes aegypti populations. The control action consists in continuous periodic releases of mosquitoes previously infected with wMelPop strain of Wolbachia in laboratory conditions. The ultimate purpose of control is to find a tradeoff between reaching the population replacement in minimum time and with minimum cost of the control effort. This approach also allows us to estimate the number of Wolbachia-carrying mosquitoes to be released in day-by-day control action. The proposed method of biological control is safe to human health, does not contaminate the environment, does not make harm to non-target species, and preserves their interaction with mosquitoes in the ecosystem.