Quantifying Aggregated Uncertainty in Plasmodium falciparum Malaria Prevalence and Populations at Risk via Efficient Space-Time Geostatistical Joint Simulation

Risk maps estimating the spatial distribution of infectious diseases are required to guide public health policy from local to global scales. The advent of model-based geostatistics (MBG) has allowed these maps to be generated in a formal statistical framework, providing robust metrics of map uncertainty that enhances their utility for decision-makers. In many settings, decision-makers require spatially aggregated measures over large regions such as the mean prevalence within a country or administrative region, or national populations living under different levels of risk. Existing MBG mapping approaches provide suitable metrics of local uncertainty—the fidelity of predictions at each mapped pixel—but have not been adapted for measuring uncertainty over large areas, due largely to a series of fundamental computational constraints. Here the authors present a new efficient approximating algorithm that can generate for the first time the necessary joint simulation of prevalence values across the very large prediction spaces needed for global scale mapping. This new approach is implemented in conjunction with an established model for P. falciparum allowing robust estimates of mean prevalence at any specified level of spatial aggregation. The model is used to provide estimates of national populations at risk under three policy-relevant prevalence thresholds, along with accompanying model-based measures of uncertainty. By overcoming previously unchallenged computational barriers, this study illustrates how MBG approaches, already at the forefront of infectious disease mapping, can be extended to provide large-scale aggregate measures appropriate for decision-makers

Modelling the global constraints of temperature on transmission of Plasmodium falciparum and P. vivax

<p>Abstract</p> <p>Background</p> <p>Temperature is a key determinant of environmental suitability for transmission of human malaria, modulating endemicity in some regions and preventing transmission in others. The spatial modelling of malaria endemicity has become increasingly sophisticated and is now central to the global scale planning, implementation, and monitoring of disease control and regional efforts towards elimination, but existing efforts to model the constraints of temperature on the malaria landscape at these scales have been simplistic. Here, we define an analytical framework to model these constraints appropriately at fine spatial and temporal resolutions, providing a detailed dynamic description that can enhance large scale malaria cartography as a decision-support tool in public health.</p> <p>Results</p> <p>We defined a dynamic biological model that incorporated the principal mechanisms of temperature dependency in the malaria transmission cycle and used it with fine spatial and temporal resolution temperature data to evaluate time-series of temperature suitability for transmission of <it>Plasmodium falciparum </it>and <it>P. vivax </it>throughout an average year, quantified using an index proportional to the basic reproductive number. Time-series were calculated for all 1 km resolution land pixels globally and were summarised to create high-resolution maps for each species delineating those regions where temperature precludes transmission throughout the year. Within suitable zones we mapped for each pixel the number of days in which transmission is possible and an integrated measure of the intensity of suitability across the year. The detailed evaluation of temporal suitability dynamics provided by the model is visualised in a series of accompanying animations.</p> <p>Conclusions</p> <p>These modelled products, made available freely in the public domain, can support the refined delineation of populations at risk; enhance endemicity mapping by offering a detailed, dynamic, and biologically driven alternative to the ubiquitous empirical incorporation of raw temperature data in geospatial models; and provide a rich spatial and temporal platform for future biological modelling studies.</p

Refining the Global Spatial Limits of Dengue Virus Transmission by Evidence-Based Consensus

Background: Dengue is a growing problem both in its geographical spread and in its intensity, and yet current global distribution remains highly uncertain. Challenges in diagnosis and diagnostic methods as well as highly variable national health systems mean no single data source can reliably estimate the distribution of this disease. As such, there is a lack of agreement on national dengue status among international health organisations. Here we bring together all available information on dengue occurrence using a novel approach to produce an evidence consensus map of the disease range that highlights nations with an uncertain dengue status. Methods/Principle Findings: A baseline methodology was used to assess a range of evidence for each country. In regions where dengue status was uncertain, additional evidence types were included to either clarify dengue status or confirm that it is unknown at this time. An algorithm was developed that assesses evidence quality and consistency, giving each country an evidence consensus score. Using this approach, we were able to generate a contemporary global map of national-level dengue status that assigns a relative measure of certainty and identifies gaps in the available evidence

Defining the relationship between Plasmodium falciparum parasite rate and clinical disease: statistical models for disease burden estimation

<p>Abstract</p> <p>Background</p> <p>Clinical malaria has proven an elusive burden to enumerate. Many cases go undetected by routine disease recording systems. Epidemiologists have, therefore, frequently defaulted to actively measuring malaria in population cohorts through time. Measuring the clinical incidence of malaria longitudinally is labour-intensive and impossible to undertake universally. There is a need, therefore, to define a relationship between clinical incidence and the easier and more commonly measured index of infection prevalence: the "parasite rate". This relationship can help provide an informed basis to define malaria burdens in areas where health statistics are inadequate.</p> <p>Methods</p> <p>Formal literature searches were conducted for <it>Plasmodium falciparum </it>malaria incidence surveys undertaken prospectively through active case detection at least every 14 days. The data were abstracted, standardized and geo-referenced. Incidence surveys were time-space matched with modelled estimates of infection prevalence derived from a larger database of parasite prevalence surveys and modelling procedures developed for a global malaria endemicity map. Several potential relationships between clinical incidence and infection prevalence were then specified in a non-parametric Gaussian process model with minimal, biologically informed, prior constraints. Bayesian inference was then used to choose between the candidate models.</p> <p>Results</p> <p>The suggested relationships with credible intervals are shown for the Africa and a combined America and Central and South East Asia regions. In both regions clinical incidence increased slowly and smoothly as a function of infection prevalence. In Africa, when infection prevalence exceeded 40%, clinical incidence reached a plateau of 500 cases per thousand of the population <it>per annum</it>. In the combined America and Central and South East Asia regions, this plateau was reached at 250 cases per thousand of the population <it>per annum</it>. A temporal volatility model was also incorporated to facilitate a closer description of the variance in the observed data.</p> <p>Conclusion</p> <p>It was possible to model a relationship between clinical incidence and <it>P. falciparum </it>infection prevalence but the best-fit models were very noisy reflecting the large variance within the observed opportunistic data sample. This continuous quantification allows for estimates of the clinical burden of <it>P. falciparum </it>of known confidence from wherever an estimate of <it>P. falciparum </it>prevalence is available.</p

The risks of malariainfection in Kenya in 2009

BACKGROUND: To design an effective strategy for the control of malaria requires a map of infection and disease risks to select appropriate suites of interventions. Advances in model based geo-statistics and malaria parasite prevalence data assemblies provide unique opportunities to redefine national Plasmodium falciparum risk distributions. Here we present a new map of malaria risk for Kenya in 2009. METHODS: Plasmodium falciparum parasite rate data were assembled from cross-sectional community based surveys undertaken from 1975 to 2009. Details recorded for each survey included the month and year of the survey, sample size, positivity and the age ranges of sampled population. Data were corrected to a standard age-range of two to less than 10 years (PfPR2-10) and each survey location was geo-positioned using national and on-line digital settlement maps. Ecological and climate covariates were matched to each PfPR2-10 survey location and examined separately and in combination for relationships to PfPR2-10. Significant covariates were then included in a Bayesian geostatistical spatial-temporal framework to predict continuous and categorical maps of mean PfPR2-10 at a 1 x 1 km resolution across Kenya for the year 2009. Model hold-out data were used to test the predictive accuracy of the mapped surfaces and distributions of the posterior uncertainty were mapped. RESULTS: A total of 2,682 estimates of PfPR2-10 from surveys undertaken at 2,095 sites between 1975 and 2009 were selected for inclusion in the geo-statistical modeling. The covariates selected for prediction were urbanization; maximum temperature; precipitation; enhanced vegetation index; and distance to main water bodies. The final Bayesian geo-statistical model had a high predictive accuracy with mean error of -0.15% PfPR2-10; mean absolute error of 0.38% PfPR2-10; and linear correlation between observed and predicted PfPR2-10 of 0.81. The majority of Kenya's 2009 population (35.2 million, 86.3%) reside in areas where predicted PfPR2-10 is less than 5%; conversely in 2009 only 4.3 million people (10.6%) lived in areas where PfPR2-10 was predicted to be &gt; or =40% and were largely located around the shores of Lake Victoria. CONCLUSION: Model based geo-statistical methods can be used to interpolate malaria risks in Kenya with precision and our model shows that the majority of Kenyans live in areas of very low P. falciparum risk. As malaria interventions go to scale effectively tracking epidemiological changes of risk demands a rigorous effort to document infection prevalence in time and space to remodel risks and redefine intervention priorities over the next 10-15 years

Refining the global spatial limits of dengue virus transmission by evidence-based consensus.

BACKGROUND: Dengue is a growing problem both in its geographical spread and in its intensity, and yet current global distribution remains highly uncertain. Challenges in diagnosis and diagnostic methods as well as highly variable national health systems mean no single data source can reliably estimate the distribution of this disease. As such, there is a lack of agreement on national dengue status among international health organisations. Here we bring together all available information on dengue occurrence using a novel approach to produce an evidence consensus map of the disease range that highlights nations with an uncertain dengue status. METHODS/PRINCIPAL FINDINGS: A baseline methodology was used to assess a range of evidence for each country. In regions where dengue status was uncertain, additional evidence types were included to either clarify dengue status or confirm that it is unknown at this time. An algorithm was developed that assesses evidence quality and consistency, giving each country an evidence consensus score. Using this approach, we were able to generate a contemporary global map of national-level dengue status that assigns a relative measure of certainty and identifies gaps in the available evidence. CONCLUSION: The map produced here provides a list of 128 countries for which there is good evidence of dengue occurrence, including 36 countries that have previously been classified as dengue-free by the World Health Organization and/or the US Centers for Disease Control. It also identifies disease surveillance needs, which we list in full. The disease extents and limits determined here using evidence consensus, marks the beginning of a five-year study to advance the mapping of dengue virus transmission and disease risk. Completion of this first step has allowed us to produce a preliminary estimate of population at risk with an upper bound of 3.97 billion people. This figure will be refined in future work

Plasmodium vivax Malaria Endemicity in Indonesia in 2010

BACKGROUND: Plasmodium vivax imposes substantial morbidity and mortality burdens in endemic zones. Detailed understanding of the contemporary spatial distribution of this parasite is needed to combat it. We used model based geostatistics (MBG) techniques to generate a contemporary map of risk of Plasmodium vivax malaria in Indonesia in 2010. METHODS: Plasmodium vivax Annual Parasite Incidence data (2006-2008) and temperature masks were used to map P. vivax transmission limits. A total of 4,658 community surveys of P. vivax parasite rate (PvPR) were identified (1985-2010) for mapping quantitative estimates of contemporary endemicity within those limits. After error-checking a total of 4,457 points were included into a national database of age-standardized 1-99 year old PvPR data. A Bayesian MBG procedure created a predicted PvPR(1-99) endemicity surface with uncertainty estimates. Population at risk estimates were derived with reference to a 2010 human population surface. RESULTS: We estimated 129.6 million people in Indonesia lived at risk of P. vivax transmission in 2010. Among these, 79.3% inhabited unstable transmission areas and 20.7% resided in stable transmission areas. In western Indonesia, the predicted P. vivax prevalence was uniformly low. Over 70% of the population at risk in this region lived on Java and Bali islands, where little malaria transmission occurs. High predicted prevalence areas were observed in the Lesser Sundas, Maluku and Papua. In general, prediction uncertainty was relatively low in the west and high in the east. CONCLUSION: Most Indonesians living with endemic P. vivax experience relatively low risk of infection. However, blood surveys for this parasite are likely relatively insensitive and certainly do not detect the dormant liver stage reservoir of infection. The prospects for P. vivax elimination would be improved with deeper understanding of glucose-6-phosphate dehydrogenase deficiency (G6PDd) distribution, anti-relapse therapy practices and manageability of P. vivax importation risk, especially in Java and Bali

The dominant Anopheles vectors of human malaria in the Americas: occurrence data, distribution maps and bionomic précis

Background: An increasing knowledge of the global risk of malaria shows that the nations of the Americans have the lowest levels of Plasmodium falciparum and P. vivax endemicity worldwide, sustained, in part, by substantive integrated vector control. To help maintain and better target these efforts, knowledge of the contemporary distribution of each of the dominant vector species (DVS) of human malaria is needed, alongside a comprehensive understanding of the ecology and behaviour of each species.Results: A database of contemporary occurrence data for 41 of the DVS of human malaria was compiled from intensive searches of the formal and informal literature. The results for the nine DVS of the Americas are described in detail here. Nearly 6000 occurrence records were gathered from 25 countries in the region and were complemented by a synthesis of published expert opinion range maps, refined further by a technical advisory group of medical entomologists. A suite of environmental and climate variables of suspected relevance to anopheline ecology were also compiled from open access sources. These three sets of data were then combined to produce predictive species range maps using the Boosted Regression Tree method. The predicted geographic extent for each of the following species (or species complex*) are provided: Anopheles (Nyssorhynchus) albimanus Wiedemann, 1820, An. (Nys.) albitaris*, An. (Nys.) aquasalis Curry, 1932, An. (Nys.) darlingi Root, 1926, An. (Anopheles) freeborni Aitken, 1939, An. (Nys.) marajoara Galvāo & Damasceno, 1942, An. (Nys.) nuneztovari*, An. (Ano.) pseudopunctipennis* and An. (Ano.) quadrimaculatus Say, 1824. A bionomics review summarising ecology and behaviour relevant to the the control of each of these species was also compiled.Conclusions: The distribution maps and bionomics review should both be considered as a starting point in an ongoing process of (i) describing the distributions of these DVS (since the opportunistic samples of occurrence data assembled can be substantially improved) and (ii) documenting their contemporary bionomics (since intervention and control pressures can act to modify behavioural traits). This is the first in a series of three articles describing the distribution of the 41 global DVS worldwide. The remaining two publications will describe those vectors found in (i) Africa, Europe and the Middle East and (ii) in Asia. All geographic distribution maps are being made available in the public domain according to the open access principles of the Malaria Atlas Project

Global temperature constraints on Aedes aegypti and Ae. albopictus persistence and competence for dengue virus transmission.

BACKGROUND: Dengue is a disease that has undergone significant expansion over the past hundred years. Understanding what factors limit the distribution of transmission can be used to predict current and future limits to further dengue expansion. While not the only factor, temperature plays an important role in defining these limits. Previous attempts to analyse the effect of temperature on the geographic distribution of dengue have not considered its dynamic intra-annual and diurnal change and its cumulative effects on mosquito and virus populations. METHODS: Here we expand an existing modelling framework with new temperature-based relationships to model an index proportional to the basic reproductive number of the dengue virus. This model framework is combined with high spatial and temporal resolution global temperature data to model the effects of temperature on Aedes aegypti and Ae. albopictus persistence and competence for dengue virus transmission. RESULTS: Our model predicted areas where temperature is not expected to permit transmission and/or Aedes persistence throughout the year. By reanalysing existing experimental data our analysis indicates that Ae. albopictus, often considered a minor vector of dengue, has comparable rates of virus dissemination to its primary vector, Ae. aegypti, and when the longer lifespan of Ae. albopictus is considered its competence for dengue virus transmission far exceeds that of Ae. aegypti. CONCLUSIONS: These results can be used to analyse the effects of temperature and other contributing factors on the expansion of dengue or its Aedes vectors. Our finding that Ae. albopictus has a greater capacity for dengue transmission than Ae. aegypti is contrary to current explanations for the comparative rarity of dengue transmission in established Ae. albopictus populations. This suggests that the limited capacity of Ae. albopictus to transmit DENV is more dependent on its ecology than vector competence. The recommendations, which we explicitly outlined here, point to clear targets for entomological investigation

Geographical variation in \u3ci\u3ePlasmodium vivax\u3c/i\u3e relapse

Background: Plasmodium vivax has the widest geographic distribution of the human malaria parasites and nearly 2.5 billion people live at risk of infection. The control of P. vivax in individuals and populations is complicated by its ability to relapse weeks to months after initial infection. Strains of P. vivax from different geographical areas are thought to exhibit varied relapse timings. In tropical regions strains relapse quickly (three to six weeks), whereas those in temperate regions do so more slowly (six to twelve months), but no comprehensive assessment of evidence has been conducted. Here observed patterns of relapse periodicity are used to generate predictions of relapse incidence within geographic regions representative of varying parasite transmission. Methods: A global review of reports of P. vivax relapse in patients not treated with a radical cure was conducted. Records of time to first P. vivax relapse were positioned by geographic origin relative to expert opinion regions of relapse behaviour and epidemiological zones. Mixed-effects meta-analysis was conducted to determine which geographic classification best described the data, such that a description of the pattern of relapse periodicity within each region could be described. Model outputs of incidence and mean time to relapse were mapped to illustrate the global variation in relapse. Results: Differences in relapse periodicity were best described by a historical geographic classification system used to describe malaria transmission zones based on areas sharing zoological and ecological features. Maps of incidence and time to relapse showed high relapse frequency to be predominant in tropical regions and prolonged relapse in temperate areas. Conclusions: The results indicate that relapse periodicity varies systematically by geographic region and are categorized by nine global regions characterized by similar malaria transmission dynamics. This indicates that relapse may be an adaptation evolved to exploit seasonal changes in vector survival and therefore optimize transmission. Geographic patterns in P. vivax relapse are important to clinicians treating individual infections, epidemiologists trying to infer P. vivax burden, and public health officials trying to control and eliminate the disease in human populations