Spatial modelling for population replacement of mosquito vectors at continental scale.

Malaria is one of the deadliest vector-borne diseases in the world. Researchers are developing new genetic and conventional vector control strategies to attempt to limit its burden. Novel control strategies require detailed safety assessment to ensure responsible and successful deployments. Anopheles gambiae sensu stricto (s.s.) and Anopheles coluzzii, two closely related subspecies within the species complex Anopheles gambiae sensu lato (s.l.), are among the dominant malaria vectors in sub-Saharan Africa. These two subspecies readily hybridise and compete in the wild and are also known to have distinct niches, each with spatially and temporally varying carrying capacities driven by precipitation and land use factors. We model the spread and persistence of a population-modifying gene drive system in these subspecies across sub-Saharan Africa by simulating introductions of genetically modified mosquitoes across the African mainland and its offshore islands. We explore transmission of the gene drive between the two subspecies that arise from different hybridisation mechanisms, the effects of both local dispersal and potential wind-aided migration to the spread, and the development of resistance to the gene drive. Given the best current available knowledge on the subspecies' life histories, we find that an introduced gene drive system with typical characteristics can plausibly spread from even distant offshore islands to the African mainland with the aid of wind-driven migration, with resistance beginning to take over within a decade. Our model accounts for regional to continental scale mechanisms, and demonstrates a range of realistic dynamics including the effect of prevailing wind on spread and spatio-temporally varying carrying capacities for subspecies. As a result, it is well-placed to answer future questions relating to mosquito gene drives as important life history parameters become better understood.

Predicting the spread and persistence of genetically modified dominant sterile male mosquitoes.

BACKGROUND: Reproductive containment provides an opportunity to implement a staged-release strategy for genetic control of malaria vectors, in particular allowing predictions about the spread and persistence of (self-limiting) sterile and male-biased strains to be compared to outcomes before moving to (self-sustaining) gene-drive strains. METHODS: In this study, we: (i) describe a diffusion-advection-reaction model of the spread and persistence of a single cohort of male mosquitoes; (ii) elicit informative prior distributions for model parameters, for wild-type (WT) and genetically modified dominant sterile strains (DSM); (iii) estimate posterior distributions for WT strains using data from published mark-recapture-release (MRR) experiments, with inference performed through the Delayed-Rejection Adaptive Metropolis algorithm; and (iv) weight prior distributions, in order to make predictions about genetically modified strains using Bayes factors calculated for the WT strains. RESULTS: If a single cohort of 5000 genetically modified dominant sterile male mosquitoes are released at the same location as previous MRR experiments with their WT counterparts, there is a 90% probability that the expected number of released mosquitoes will fall to < 1 in 10 days, and that by 12 days there will be a 99% probability that no mosquitoes will be found more than 150 m from the release location. CONCLUSIONS: Spread and persistence models should form a key component of risk assessments of novel genetic control strategies for malaria vectors. Our predictions, used in an independent risk assessment, suggest that genetically modified sterile male mosquitoes will remain within the locality of the release site, and that they will persist for a very limited amount of time. Data gathered following the release of these mosquitoes will enable us to test the accuracy of these predictions and also provide a means to update parameter distributions for genetic strains in a coherent (Bayesian) framework. We anticipate this will provide additional insights about how to conduct probabilistic risk assessments of stage-released genetically modified mosquitoes.

Quantifying the risk of vector-borne disease transmission attributable to genetically modified vectors.

The relative risk of disease transmission caused by the potential release of transgenic vectors, such as through sterile insect technique or gene drive systems, is assessed with comparison with wild-type vectors. The probabilistic risk framework is demonstrated with an assessment of the relative risk of lymphatic filariasis, malaria and o'nyong'nyong arbovirus transmission by mosquito vectors to human hosts given a released transgenic strain of Anopheles coluzzii carrying a dominant sterile male gene construct. Harm is quantified by a logarithmic loss function that depends on the causal risk ratio, which is a quotient of basic reproduction numbers derived from mathematical models of disease transmission. The basic reproduction numbers are predicted to depend on the number of generations in an insectary colony and the number of backcrosses between the transgenic and wild-type lineages. Analogous causal risk ratios for short-term exposure to a single cohort release are also derived. These causal risk ratios were parametrized by probabilistic elicitations, and updated with experimental data for adult vector mortality. For the wild-type, high numbers of insectary generations were predicted to reduce the number of infectious human cases compared with uncolonized wild-type. Transgenic strains were predicted to produce fewer infectious cases compared with the uncolonized wild-type.

Modelling competition between hybridising subspecies.

The geographic niches of many species are dramatically changing as a result of environmental and anthropogenic impacts such as global climate change and the introduction of invasive species. In particular, genetically compatible subspecies that were once geographically separated are being reintroduced to one another. This is of concern for conservation, where rare or threatened subspecies could be bred out by hybridising with their more common relatives, and for commercial interests, where the stock or quality of desirable harvested species could be compromised. It is also relevant to disease ecology, where disease transmission is heterogeneous among subspecies and hybridisation may affect the rate and spatial spread of disease. We develop and investigate a mathematical model to combine competitive effects via the Lotka-Volterra model with hybridisation effects via mate choice. The species complex is structured into two classes: a subspecies of interest (named x), and other subspecies including any hybrids produced (named y). We show that in the absence of limit cycles the model has four possible equilibrium outcomes, representing every combination: total extinction, x-dominance (y extinct), y-dominance (x extinct), and at most a single coexistence equilibrium. We give conditions for which limit cycles cannot exist, then further show that the "total extinction" equilibrium is always unstable, that y-dominance is always stable, and that the other equilibria have stability depending on the model parameters. We demonstrate that both x-dominance and coexistence are achievable under a wide range of parameter values and initial conditions, which corresponds with empirical evidence of known competing-hybridising systems. We then briefly examine bifurcation behaviour. In particular, we note that a subcritical bifurcation is possible in which a "catastrophic" transition from x-dominance to y-dominance can occur, representing an invasion event. Finally, we briefly examine the common complication of time-varying carrying capacity, showing that such a case can make coexistence more likely.

Assessing privacy risks in population health publications using a checklist-based approach.

OBJECTIVE: Recent growth in the number of population health researchers accessing detailed datasets, either on their own computers or through virtual data centers, has the potential to increase privacy risks. In response, a checklist for identifying and reducing privacy risks in population health analysis outputs has been proposed for use by researchers themselves. In this study we explore the usability and reliability of such an approach by investigating whether different users identify the same privacy risks on applying the checklist to a sample of publications. METHODS: The checklist was applied to a sample of 100 academic population health publications distributed among 5 readers. Cohen's κ was used to measure interrater agreement. RESULTS: Of the 566 instances of statistical output types found in the 100 publications, the most frequently occurring were counts, summary statistics, plots, and model outputs. Application of the checklist identified 128 outputs (22.6%) with potential privacy concerns. Most of these were associated with the reporting of small counts. Among these identified outputs, the readers found no substantial actual privacy concerns when context was taken into account. Interrater agreement for identifying potential privacy concerns was generally good. CONCLUSION: This study has demonstrated that a checklist can be a reliable tool to assist researchers with anonymizing analysis outputs in population health research. This further suggests that such an approach may have the potential to be developed into a broadly applicable standard providing consistent confidentiality protection across multiple analyses of the same data.

Modelling hospital length of stay using convolutive mixtures distributions.

Length of hospital stay (LOS) is an important indicator of the hospital activity and management of health care. The skewness in the distribution of LOS poses problems in statistical modelling because it fails to adequately follow the usual traditional distribution of positive variables such as the log-normal distribution. We present in this paper a model using the convolution of two distributions, a technique well known in the signal processing community. The specificity of that model is that the variable of interest is considered to be the resulting sum of two random variables with different distributions. One of the variables features the patient-related factors in terms of their need to recover from their admission condition, while the other models the hospital management process such as the discharging process. Two estimation procedures are proposed. One is the classical maximum likelihood, while the other relates to the expectation-maximization algorithm. We present some results obtained by applying this model to a set of real data from a group of hospitals in Victoria (Australia). Copyright © 2016 John Wiley & Sons, Ltd.

Anonymization for outputs of population health and health services research conducted via an online data center.

OBJECTIVE: Online data centers (ODCs) are becoming increasingly popular for making health-related data available for research. Such centers provide good privacy protection during analysis by trusted researchers, but privacy concerns may still remain if the system outputs are not sufficiently anonymized. In this article, we propose a method for anonymizing analysis outputs from ODCs for publication in academic literature. METHODS: We use as a model system the Secure Unified Research Environment, an online computing system that allows researchers to access and analyze linked health-related data for approved studies in Australia. This model system suggests realistic assumptions for an ODC that, together with literature and practice reviews, inform our solution design. RESULTS: We propose a two-step approach to anonymizing analysis outputs from an ODC. A data preparation stage requires data custodians to apply some basic treatments to the dataset before making it available. A subsequent output anonymization stage requires researchers to use a checklist at the point of downloading analysis output. The checklist assists researchers with highlighting potential privacy concerns, then applying appropriate anonymization treatments. CONCLUSION: The checklist can be used more broadly in health care research, not just in ODCs. Ease of online publication as well as encouragement from journals to submit supplementary material are likely to increase both the volume and detail of analysis results publicly available, which in turn will increase the need for approaches such as the one suggested in this paper.