Current dichotomous metrics obscure trends in severe and extreme child growth failure.

Historically, the prevalence of child growth failure (CGF) has been tracked dichotomously as the proportion of children more than 2 SDs below the median of the World Health Organization growth standards. However, this conventional "thresholding" approach fails to recognize child growth as a spectrum and obscures trends in populations with the highest rates of CGF. Our analysis presents the first ever estimates of entire distributions of HAZ, WHZ, and WAZ for each of 204 countries and territories from 1990 to 2020 for children less than 5 years old by age group and sex. This approach reflects the continuous nature of CGF, allows us to more comprehensively assess shrinking or widening disparities over time, and reveals otherwise hidden trends that disproportionately affect the most vulnerable populations.

Mapping global variation in human mobility.

The geographic variation of human movement is largely unknown, mainly due to a lack of accurate and scalable data. Here we describe global human mobility patterns, aggregated from over 300 million smartphone users. The data cover nearly all countries and 65% of Earth's populated surface, including cross-border movements and international migration. This scale and coverage enable us to develop a globally comprehensive human movement typology. We quantify how human movement patterns vary across sociodemographic and environmental contexts and present international movement patterns across national borders. Fitting statistical models, we validate our data and find that human movement laws apply at 10 times shorter distances and movement declines 40% more rapidly in low-income settings. These results and data are made available to further understanding of the role of human movement in response to rapid demographic, economic and environmental changes.

Vector bionomics and vectorial capacity as emergent properties of mosquito behaviors and ecology.

Mosquitoes are important vectors for pathogens that infect humans and other vertebrate animals. Some aspects of adult mosquito behavior and mosquito ecology play an important role in determining the capacity of vector populations to transmit pathogens. Here, we re-examine factors affecting the transmission of pathogens by mosquitoes using a new approach. Unlike most previous models, this framework considers the behavioral states and state transitions of adult mosquitoes through a sequence of activity bouts. We developed a new framework for individual-based simulation models called MBITES (Mosquito Bout-based and Individual-based Transmission Ecology Simulator). In MBITES, it is possible to build models that simulate the behavior and ecology of adult mosquitoes in exquisite detail on complex resource landscapes generated by spatial point processes. We also developed an ordinary differential equation model which is the Kolmogorov forward equations for models developed in MBITES under a specific set of simplifying assumptions. While mosquito infection and pathogen development are one possible part of a mosquito's state, that is not our main focus. Using extensive simulation using some models developed in MBITES, we show that vectorial capacity can be understood as an emergent property of simple behavioral algorithms interacting with complex resource landscapes, and that relative density or sparsity of resources and the need to search can have profound consequences for mosquito populations' capacity to transmit pathogens.

Model-based assessment of public health impact and cost-effectiveness of dengue vaccination following screening for prior exposure.

The tetravalent dengue vaccine CYD-TDV (Dengvaxia) is the first licensed vaccine against dengue, but recent findings indicate an elevated risk of severe disease among vaccinees without prior dengue virus (DENV) exposure. The World Health Organization currently recommends CYD-TDV only for individuals with serological confirmation of past DENV exposure. Our objective was to evaluate the potential health impact and cost-effectiveness of vaccination following serological screening. To do so, we used an agent-based model to simulate DENV transmission with and without vaccination over a 10-year timeframe. Across a range of values for the proportion of vaccinees with prior DENV exposure, we projected the proportion of symptomatic and hospitalized cases averted as a function of the sensitivity and specificity of serological screening. Scenarios about the cost-effectiveness of screening and vaccination were chosen to be representative of Brazil and the Philippines. We found that public health impact depended primarily on sensitivity in high-transmission settings and on specificity in low-transmission settings. Cost-effectiveness could be achievable from the perspective of a public payer provided that sensitivity and the value of a disability-adjusted life-year were both high, but only in high-transmission settings. Requirements for reducing relative risk and achieving cost-effectiveness from an individual perspective were more restricted, due to the fact that those who test negative pay for screening but receive no benefit. Our results predict that cost-effectiveness could be achieved only in high-transmission areas of dengue-endemic countries with a relatively high per capita GDP, such as Panamá (13,680 USD), Brazil (8,649 USD), México (8,201 USD), or Thailand (5,807 USD). In conclusion, vaccination with CYD-TDV following serological screening could have a positive impact in some high-transmission settings, provided that screening is highly specific (to minimize individual harm), at least moderately sensitive (to maximize population benefit), and sufficiently inexpensive (depending on the setting).

Defining the relationship between infection prevalence and clinical incidence of Plasmodium falciparum malaria.

In many countries health system data remain too weak to accurately enumerate Plasmodium falciparum malaria cases. In response, cartographic approaches have been developed that link maps of infection prevalence with mathematical relationships to predict the incidence rate of clinical malaria. Microsimulation (or 'agent-based') models represent a powerful new paradigm for defining such relationships; however, differences in model structure and calibration data mean that no consensus yet exists on the optimal form for use in disease-burden estimation. Here we develop a Bayesian statistical procedure combining functional regression-based model emulation with Markov Chain Monte Carlo sampling to calibrate three selected microsimulation models against a purpose-built data set of age-structured prevalence and incidence counts. This allows the generation of ensemble forecasts of the prevalence-incidence relationship stratified by age, transmission seasonality, treatment level and exposure history, from which we predict accelerating returns on investments in large-scale intervention campaigns as transmission and prevalence are progressively reduced.

Bioeconomic analysis of child-targeted subsidies for artemisinin combination therapies: a cost-effectiveness analysis.

The Affordable Medicines Facility for malaria (AMFm) was conceived as a global market-based mechanism to increase access to effective malaria treatment and prolong effectiveness of artemisinin. Although results from a pilot implementation suggested that the subsidy was effective in increasing access to high-quality artemisinin combination therapies (ACTs), the Global Fund has converted AMFm into a country-driven mechanism whereby individual countries could choose to fund the subsidy from within their country envelopes. Because the initial costs of the subsidy in the pilot countries was higher than expected, countries are also exploring alternatives to a universal subsidy, such as subsidizing only child doses. We examined the incremental cost-effectiveness of a child-targeted policy using an age-structured bioeconomic model of malaria from the provider perspective. Because the vast majority of malaria deaths occur in children, targeting children could potentially improve the cost-effectiveness of the subsidy, though it would avert significantly fewer deaths. However, the benefits of a child-targeted subsidy (i.e. deaths averted) are eroded as leakage (i.e. older individuals taking young child-targeted doses) increases, with few of the benefits of a universal subsidy gained (i.e. reductions in overall prevalence). Although potentially more cost-effective, a child-targeted subsidy must contain measures to reduce the possibility of leakage.

Improving pandemic influenza risk assessment.

Assessing the pandemic risk posed by specific non-human influenza A viruses is an important goal in public health research. As influenza virus genome sequencing becomes cheaper, faster, and more readily available, the ability to predict pandemic potential from sequence data could transform pandemic influenza risk assessment capabilities. However, the complexities of the relationships between virus genotype and phenotype make such predictions extremely difficult. The integration of experimental work, computational tool development, and analysis of evolutionary pathways, together with refinements to influenza surveillance, has the potential to transform our ability to assess the risks posed to humans by non-human influenza viruses and lead to improved pandemic preparedness and response.

Malaria burden and control in Bangladesh and prospects for elimination: an epidemiological and economic assessment.

BACKGROUND: Malaria is endemic in 13 of 64 districts in Bangladesh. About 14 million people are at risk. Some evidence suggests that the prevalence of malaria in Bangladesh has decreased since the the Global Fund to Fight AIDS, Tuberculosis and Malaria started to support the National Malaria Control Program (NMCP) in 2007. We did an epidemiological and economic assessment of malaria control in Bangladesh. METHODS: We obtained annually reported, district-level aggregated malaria case data and information about disbursed funds from the NMCP. We used a Poisson regression model to examine the associations between total malaria, severe malaria, malaria-attributable mortality, and insecticide-treated net coverage. We identified and mapped malaria hotspots using the Getis-Ord Gi* statistic. We estimated the cost-effectiveness of the NMCP by estimating the cost per confirmed case, cost per treated case, and cost per person of insecticide-treated net coverage. FINDINGS: During the study period (from Jan 1, 2008, to Dec 31, 2012) there were 285,731 confirmed malaria cases. Malaria decreased from 6.2 cases per 1000 population in 2008, to 2.1 cases per 1000 population in 2012. Prevalence of all malaria decreased by 65% (95% CI 65-66), severe malaria decreased by 79% (78-80), and malaria-associated mortality decreased by 91% (83-95). By 2012, there was one insecticide-treated net for every 2.6 individuals (SD 0.20). Districts with more than 0.5 insecticide-treated nets per person had a decrease in prevalence of 21% (95% CI 19-23) for all malaria, 25% (17-32) for severe malaria, and 76% (35-91) for malaria-associated mortality among all age groups. Malaria hotspots remained in the highly endemic districts in the Chittagong Hill Tracts. The cost per diagnosed case was US$0.39 (SD 0.02) and per treated case was $0.51 (0.27); $0.05 (0.04) was invested per person per year for health education and $0.68 (0.30) was spent per person per year for insecticide-treated net coverage. INTERPRETATION: Malaria elimination is an achievable prospect in Bangladesh and failure to push for elimination nearly ensures a resurgence of disease. Consistent financing is needed to avoid resurgence and maintain elimination goals. FUNDING: None.

Measuring changes in Plasmodium falciparum transmission: precision, accuracy and costs of metrics.

As malaria declines in parts of Africa and elsewhere, and as more countries move towards elimination, it is necessary to robustly evaluate the effect of interventions and control programmes on malaria transmission. To help guide the appropriate design of trials to evaluate transmission-reducing interventions, we review 11 metrics of malaria transmission, discussing their accuracy, precision, collection methods and costs and presenting an overall critique. We also review the nonlinear scaling relationships between five metrics of malaria transmission: the entomological inoculation rate, force of infection, sporozoite rate, parasite rate and the basic reproductive number, R0. Our chapter highlights that while the entomological inoculation rate is widely considered the gold standard metric of malaria transmission and may be necessary for measuring changes in transmission in highly endemic areas, it has limited precision and accuracy and more standardised methods for its collection are required. In areas of low transmission, parasite rate, seroconversion rates and molecular metrics including MOI and mFOI may be most appropriate. When assessing a specific intervention, the most relevant effects will be detected by examining the metrics most directly affected by that intervention. Future work should aim to better quantify the precision and accuracy of malaria metrics and to improve methods for their collection.

Urbanization and the global malaria recession.

BACKGROUND: The past century has seen a significant contraction in the global extent of malaria transmission, resulting in over 50 countries being declared malaria free, and many regions of currently endemic countries eliminating the disease. Moreover, substantial reductions in transmission have been seen since 1900 in those areas that remain endemic today. Recent work showed that this malaria recession was unlikely to have been driven by climatic factors, and that control measures likely played a significant role. It has long been considered, however, that economic development, and particularly urbanization, has also been a causal factor. The urbanization process results in profound socio-economic and landscape changes that reduce malaria transmission, but the magnitude and extent of these effects on global endemicity reductions are poorly understood. METHODS: Global data at subnational spatial resolution on changes in malaria transmission intensity and urbanization trends over the past century were combined to examine the relationships seen over a range of spatial and temporal scales. RESULTS/CONCLUSIONS: A consistent pattern of increased urbanization coincident with decreasing malaria transmission and elimination over the past century was found. Whilst it remains challenging to untangle whether this increased urbanization resulted in decreased transmission, or that malaria reductions promoted development, the results point to a close relationship between the two, irrespective of national wealth. The continuing rapid urbanization in malaria-endemic regions suggests that such malaria declines are likely to continue, particularly catalyzed by increasing levels of direct malaria control.

Superinfection and the evolution of resistance to antimalarial drugs.

A major issue in the control of malaria is the evolution of drug resistance. Ecological theory has demonstrated that pathogen superinfection and the resulting within-host competition influences the evolution of specific traits. Individuals infected with Plasmodium falciparum are consistently infected by multiple parasites; however, while this probably alters the dynamics of resistance evolution, there are few robust mathematical models examining this issue. We developed a general theory for modelling the evolution of resistance with host superinfection and examine: (i) the effect of transmission intensity on the rate of resistance evolution; (ii) the importance of different biological costs of resistance; and (iii) the best measure of the frequency of resistance. We find that within-host competition retards the ability and slows the rate at which drug-resistant parasites invade, particularly as the transmission rate increases. We also find that biological costs of resistance that reduce transmission are less important than reductions in the duration of drug-resistant infections. Lastly, we find that random sampling of the population for resistant parasites is likely to significantly underestimate the frequency of resistance. Considering superinfection in mathematical models of antimalarial drug resistance may thus be important for generating accurate predictions of interventions to contain resistance.

Malaria resurgence: a systematic review and assessment of its causes.

BACKGROUND: Considerable declines in malaria have accompanied increased funding for control since the year 2000, but historical failures to maintain gains against the disease underscore the fragility of these successes. Although malaria transmission can be suppressed by effective control measures, in the absence of active intervention malaria will return to an intrinsic equilibrium determined by factors related to ecology, efficiency of mosquito vectors, and socioeconomic characteristics. Understanding where and why resurgence has occurred historically can help current and future malaria control programmes avoid the mistakes of the past. METHODS: A systematic review of the literature was conducted to identify historical malaria resurgence events. All suggested causes of these events were categorized according to whether they were related to weakened malaria control programmes, increased potential for malaria transmission, or technical obstacles like resistance. RESULTS: The review identified 75 resurgence events in 61 countries, occurring from the 1930s through the 2000s. Almost all resurgence events (68/75 = 91%) were attributed at least in part to the weakening of malaria control programmes for a variety of reasons, of which resource constraints were the most common (39/68 = 57%). Over half of the events (44/75 = 59%) were attributed in part to increases in the intrinsic potential for malaria transmission, while only 24/75 (32%) were attributed to vector or drug resistance. CONCLUSIONS: Given that most malaria resurgences have been linked to weakening of control programmes, there is an urgent need to develop practical solutions to the financial and operational threats to effectively sustaining today's successful malaria control programmes.

Preventing the reintroduction of malaria in Mauritius: a programmatic and financial assessment.

Sustaining elimination of malaria in areas with high receptivity and vulnerability will require effective strategies to prevent reestablishment of local transmission, yet there is a dearth of evidence about this phase. Mauritius offers a uniquely informative history, with elimination of local transmission in 1969, re-emergence in 1975, and second elimination in 1998. Towards this end, Mauritius's elimination and prevention of reintroduction (POR) programs were analyzed via a comprehensive review of literature and government documents, supplemented by program observation and interviews with policy makers and program personnel. The impact of the country's most costly intervention, a passenger screening program, was assessed quantitatively using simulation modeling.On average, Mauritius spent $4.43 per capita per year (pcpy) during its second elimination campaign from 1982 to 1988. The country currently spends $2.06 pcpy on its POR program that includes robust surveillance, routine vector control, and prompt and effective treatment and response. Thirty-five percent of POR costs are for a passenger screening program. Modeling suggests that the estimated 14% of imported malaria infections identified by this program reduces the annual risk of indigenous transmission by approximately 2%. Of cases missed by the initial passenger screening program, 49% were estimated to be identified by passive or reactive case detection, leaving an estimated 3.1 unidentified imported infections per 100,000 inhabitants per year.The Mauritius experience indicates that ongoing intervention, strong leadership, and substantial predictable funding are critical to consistently prevent the reestablishment of malaria. Sustained vigilance is critical considering Mauritius's enabling conditions. Although the cost of POR is below that of elimination, annual per capita spending remains at levels that are likely infeasible for countries with lower overall health spending. Countries currently embarking on elimination should quantify and plan for potentially similar POR operations and costs.

A framework for assessing the feasibility of malaria elimination.

The recent scale-up of malaria interventions, the ensuing reductions in the malaria burden, and reinvigorated discussions about global eradication have led many countries to consider malaria elimination as an alternative to maintaining control measures indefinitely. Evidence-based guidance to help countries weigh their options is thus urgently needed. A quantitative feasibility assessment that balances the epidemiological situation in a region, the strength of the public health system, the resource constraints, and the status of malaria control in neighboring areas can serve as the basis for robust, long-term strategic planning. Such a malaria elimination feasibility assessment was recently prepared for the Minister of Health in Zanzibar. Based on the Zanzibar experience, a framework is proposed along three axes that assess the technical requirements to achieve and maintain elimination, the operational capacity of the malaria programme and the public health system to meet those requirements, and the feasibility of funding the necessary programmes over time. Key quantitative and qualitative metrics related to each component of the assessment are described here along with the process of collecting data and interpreting the results. Although further field testing, validation, and methodological improvements will be required to ensure applicability in different epidemiological settings, the result is a flexible, rational methodology for weighing different strategic options that can be applied in a variety of contexts to establish data-driven strategic plans.

Climate change and the global malaria recession.

The current and potential future impact of climate change on malaria is of major public health interest. The proposed effects of rising global temperatures on the future spread and intensification of the disease, and on existing malaria morbidity and mortality rates, substantively influence global health policy. The contemporary spatial limits of Plasmodium falciparum malaria and its endemicity within this range, when compared with comparable historical maps, offer unique insights into the changing global epidemiology of malaria over the last century. It has long been known that the range of malaria has contracted through a century of economic development and disease control. Here, for the first time, we quantify this contraction and the global decreases in malaria endemicity since approximately 1900. We compare the magnitude of these changes to the size of effects on malaria endemicity proposed under future climate scenarios and associated with widely used public health interventions. Our findings have two key and often ignored implications with respect to climate change and malaria. First, widespread claims that rising mean temperatures have already led to increases in worldwide malaria morbidity and mortality are largely at odds with observed decreasing global trends in both its endemicity and geographic extent. Second, the proposed future effects of rising temperatures on endemicity are at least one order of magnitude smaller than changes observed since about 1900 and up to two orders of magnitude smaller than those that can be achieved by the effective scale-up of key control measures. Predictions of an intensification of malaria in a warmer world, based on extrapolated empirical relationships or biological mechanisms, must be set against a context of a century of warming that has seen marked global declines in the disease and a substantial weakening of the global correlation between malaria endemicity and climate.

Should new antimalarial drugs be subsidized?

Malaria kills over a million people each year. The loss of chloroquine due to the spread of parasite resistance is largely responsible for the resurgence of malaria. A new class of antimalarial drugs called artemisinins are available, but are unaffordable to most people in malaria-endemic countries and may quickly face the same fate as chloroquine unless they are combined with a partner drug. Subsidies for artemisinin combination treatments may be warranted on second-best grounds as they deter use of single-ingredient drugs, for which externalities from the risk of resistance evolution are larger. Furthermore, by expanding total effective drug use, subsidies reduce infection transmission externalities among individuals. However, use of combination treatments could still lead to drug resistance and the subsidies themselves entail welfare consequences. This paper develops a conceptual and numerical framework for understanding the conditions under which subsidies for artemisinin combinations can be justified on economic efficiency grounds.