Simon I. Hay; Emelda A. Okiro; Peter W. Gething; Anand P. Patil; Andrew J. Tatem; Carlos A. Guerra; Robert W. Snow

“ The epidemiology of malaria makes surveillance-based methods of estimating its disease burden problematic. Cartographic approaches have provided alternative malaria burden estimates, but there remains widespread misunderstanding about their derivation and fidelity. The aims of this study are to present a new cartographic technique and its application for deriving global clinical burden estimates of Plasmodium falciparum malaria for 2007, and to compare these estimates and their likely precision with those derived under existing surveillance-based approaches. ”

“ Cartographic approaches to burden estimation provide a globally consistent measure of malaria morbidity of known fidelity, and they represent the only plausible method in those malaria-endemic countries with nonfunctional national surveillance. Unacceptable uncertainty in the clinical burden of malaria in only four countries confounds our ability to evaluate needs and monitor progress toward international targets for malaria control at the global scale. National prevalence surveys in each nation would reduce this uncertainty profoundly. ”

“ Globally, this is likely to be of particular utility in those areas of low and unstable transmission where surveillance capabilities are often more robust and correspondingly where prevalence data are often rare as the number of people needed to be sampled to find infections is prohibitive [5] .
The malaria clinical burden estimates presented in this paper are driven by the underlying model of global prevalence [22] . This global malaria map is, to our knowledge, the first evidence-based attempt to define populations at risk of different levels of parasite transmission. ”

“ There is no perfect post-hoc correction to compensate for poor malaria surveillance. Both methods using routine HMIS adjusted for nonattendance, poor reporting, and inadequate diagnostics, and those presented here, have limitations with respect to coverage and quality of the input data for each model, and with respect to underlying modelling assumptions. Both approaches to burden estimation result in wide margins of confidence and the inevitable plea from any such analysis is for accurate national reporting systems or more empirical epidemiological data. ”

“ To combine the uncertainty from both models, each realisation of the uncertainty map was used as input into a realisation of the endemicity–incidence model to obtain a realisation of a 5×5 km resolution incidence map. This was downscaled to 1×1 km resolution and multiplied with the 2007 population surface to obtain, for every grid square, a realisation of the number of clinical cases in 2007. By repeating this procedure for every model realisation, a set of 250,000 burden values was generated for every grid square, approximating a complete posterior distribution for the estimates. ”

“ In completely independent work, the final estimate for malaria mortality in India in 2006, taken from the “million deaths” verbal autopsy study was approximately 200,000 deaths (Dhingra N, et al., unpublished data) . Assuming a conservative case fatality rate of only one per 1,000 [81] , [82] , this would lead to a morbidity estimate much closer to those retrieved using cartographic techniques—somewhere in the region of 200 million cases. ”

“ Defining Malaria Incidence in Areas of Unstable P. falciparum Malaria Transmission
We estimate that almost one billion people were living in areas where P. falciparum transmission was unstable in 2007 [21] (Figure 2) . Defining annualized disease risk in these areas from empirical data is difficult, as epidemiological investigations for research or survey purposes are rare. Nevertheless, in computing disease burdens it is important to impute some measure of completeness of formal malaria reporting within these marginal, unstable transmission areas. ”

“ This increase in the parasitic burden causes malaria's characteristic symptoms—debilitating and recurring fevers and chills. Infected red blood cells also release gametocytes, which infect mosquitoes when they take a blood meal. In the mosquito, the gametocytes multiply and develop into sporozoites, thus completing the parasite's life cycle. Malaria can be prevented by controlling the mosquitoes that spread the parasite and by avoiding mosquito bites. Effective treatment with antimalarial drugs also helps to reduce malaria transmission. ”

“ This method requires an understanding of the basic clinical epidemiology of P. falciparum malaria, its relationship to transmission intensity and the use of empirical, longitudinal observations in populations exposed to different conditions of transmission. However, these empirical studies of clinical incidence are not without their own caveats [23] . Longitudinal surveillance over a complete annual malaria transmission cycle within the same cohort is likely to underestimate the “natural” risk of disease given the ethical need to treat effectively all detected infections or clinical events. ”

“ We have not stratified incidence by age nor considered any of the consequential morbid events, sequelae, or mortality. Systematic biases in the identification of the extent of stable and unstable transmission would clearly impact estimates, and developing the datasets and techniques to address this problem is an important avenue for future work. Nor have we modelled uncertainty in HMIS reporting in unstable and low-stable transmission zones, and this might be possible with a methodological hybrid combining higher spatial resolution HMIS facility data with geostatistical techniques [88] . ”

“ India remains a massive source of uncertainty in our cartography-based estimates (Results and Protocol S2) , contributing over three-quarters (76%) of the uncertainty range in the global incidence estimates. It is therefore important to explore ancillary evidence for the plausibility of these cartographic estimates of 102 (31–187) million compared to the much smaller estimate derived from surveillance-based techniques: 10.65 (9.00–12.41) million [69] .
A wide range of factors can reduce the accuracy of surveillance data. ”

“ Estimating the disease burden posed by malaria is an important public health challenge [1] – [2] . The clinical consequences of Plasmodium falciparum infection have several features that confound traditional approaches to disease burden and disability measurement [3] , [4] . First, not all infections result in progression to disease, notably in areas of stable transmission [5] , where populations have acquired clinical immunity [6] . ”

“ It is not possible to provide an evidence-based under-reporting correction factor that is specific for every national malaria information system. We have therefore elected to use a single worst-case rate of 10-fold under-reporting across all countries. We hence assume for all unstable areas a uniform incidence of 0.1 case per 1,000 PA, with a lower confidence bound of zero and an upper confidence bound assuming a 10-fold under-reporting rate ”

“ To estimate stable transmission intensity, a Bayesian space-time geostatistical modelling framework was developed to interpolate empirical estimates of age-corrected parasite prevalence derived from 7,953 community surveys undertaken between 1985 and 2008 across 83 malaria-endemic countries. This model has been described in detail elsewhere [22] and its output allows for a continuous, urban-adjusted, contemporary estimate of parasite prevalence in children aged from 2 up to 10 years (PfPR2–10) at a pixel spatial resolution of 5×5 km for the year 2007 (Figure 2) . ”

“ For this or any other malaria control initiative to be effective, however, an accurate picture of the global clinical burden of malaria (how many people become ill because of malaria and where they live) is needed so that resources can be concentrated where they will have the most impact. Estimates of the global burden of many infectious diseases are obtained using data collected by national surveillance systems. ”

“ Low rates of care-seeking for malaria in the formal health sector, unreliable diagnoses, poor record keeping, and inefficient data transfer and collation systems can all combine to make the number of cases formally reported a small fraction of the true number of cases in a population. ”

“ Finally, we have not considered the impact of scaled or partial coverage of interventions aimed at preventing infection, because we feel this is reflected in the parasite prevalence surface [22] . The one exception is the use of failing monotherapy because recrudescent cases will not be reflected in our endemicity–incidence relationship based on active case detection with effective treatment and thus, where this poses a significant threat, our estimates will be even greater underestimates. ”

“ It is clear that investing in radically improved surveillance and/or nationally representative malariometric surveys would substantially increase the fidelity of national and, by extension, global burden estimates. Because there are regional differences in the uncertain relationship between transmission intensity and disease outcome [23] , more information derived from active case detection studies would improve the precision in our estimates of disease incidence within these transmission ranges. ”

“ Crucially, the joint simulation framework allows modelled uncertainty to be aggregated across regions to provide our final credible intervals for country and region-specific burden estimates, a procedure that is not possible using the per-pixel prediction approaches currently pervasive in disease mapping. ”

“ The single largest difference between previous work and the present iteration of P. falciparum disease burden estimation is that neither previous approach was based upon an empirically defined risk map of malaria transmission [22] . Comparing estimates derived using these different techniques, over various time periods, is not a sound basis for investigating trends and should be avoided. ”

“ Defining P. falciparum Clinical Incidence in Areas of Reliable Case Detection
Paradoxically, where the incidence of clinical malaria events are rare, their rapid detection and notification becomes increasingly important as part of national malaria control strategies, demanding more sophisticated surveillance [35] , [34] – [36] . This is particularly true for countries aiming to attain or maintain WHO accredited elimination status [37] – [38] . ”

“ Finally, they note that improvements in the national prevalence surveys in India, Nigeria, the Democratic Republic of the Congo, and Myanmar would greatly reduce the uncertainty associated with their estimate of the global clinical burden of malaria, an observation that should encourage efforts to improve malaria surveillance in these countries. ”

“ Opportunities for further reducing uncertainty in clinical burden estimates by hybridizing alternative burden estimation procedures are also evaluated.
Please see later in the article for the Editors' Summary==Abstract== Editors' Summary
Background
Malaria is a major global public-health problem. Nearly half the world's population is at risk of malaria, and Plasmodium falciparum malaria—the deadliest form of the disease—causes about one million deaths each year. Malaria is a parasitic disease that is transmitted to people through the bite of an infected mosquito. ”

“ These insects inject a parasitic form known as sporozoites into people, where they replicate briefly inside liver cells. The liver cells then release merozoites (another parasitic form) , which invade red blood cells. ”

“ The dashed lines separate the Americas, Africa+, and the CSE Asia region, respectively, from left to right. The seven countries with thick blue borders have very low P. falciparum burden and reliable national health information systems.Global human population density in 2007.Human population density [25] in persons per km2 is displayed on a logarithmic colour scale within the limits of P. falciparum transmission. ”

“ Global Rural-Urban Mapping Project;HMIS: health management information systems;MAP: Malaria Atlas Project;PA: per annum;PAR: population at risk;PHC: primary health centre;PfAPI: P. falciparum annual parasite incidence;PfMEC: P. falciparum malaria endemic country;PfPR: P. falciparum parasite rate;SEARO: South East Asian Regional Office;WHO: World Health Organization;WPRO: Western Pacific Regional Office
References 1 2 3 4 Snow, RW ”

“ Pozzi, F & Hay, SI (2006) , “Determining global population distribution: methods, applications and data.”, Adv Parasitol 62: 119–156, 16647969, pmid:16647969 ↑ , 2006 ↑ Hay, SI; Noor, AM; Nelson, A & Tatem, AJ (2005) , “The accuracy of human population maps for public health application.”, Trop Med Int Health 10: 1073–1086, 16185243, pmid:16185243 1 2 Macdonald, G (1957) , Local features of malaria., London: Oxford University Press, pp. 63–99 The epidemiology and control of malaria ↑ Mouchet, J ”