Carolyne Ndila

Reappraisal of known malaria resistance loci in a large multicenter study

Many human genetic associations with resistance to malaria have been reported, but few have been reliably replicated. We collected data on 11,890 cases of severe malaria due to Plasmodium falciparum and 17,441 controls from 12 locations in Africa, Asia and Oceania. We tested 55 SNPs in 27 loci previously reported to associate with severe malaria. There was evidence of association at P < 1 × 10−4 with the HBB, ABO, ATP2B4, G6PD and CD40LG loci, but previously reported associations at 22 other loci did not replicate in the multicenter analysis. The large sample size made it possible to identify authentic genetic effects that are heterogeneous across populations or phenotypes, with a striking example being the main African form of G6PD deficiency, which reduced the risk of cerebral malaria but increased the risk of severe malarial anemia. The finding that G6PD deficiency has opposing effects on different fatal complications of P. falciparum infection indicates that the evolutionary origins of this common human genetic disorder are more complex than previously supposed.

Bacteraemia in Kenyan children with sickle-cell anaemia: a retrospective cohort and case–control study

Summary Background In sub-Saharan Africa, more than 90% of children with sickle-cell anaemia die before the diagnosis can be made. The causes of death are poorly documented, but bacterial sepsis is probably important. We examined the risk of invasive bacterial diseases in children with sickle-cell anaemia. Methods This study was undertaken in a rural area on the coast of Kenya, with a case–control approach. We undertook blood cultures on all children younger than 14 years who were admitted from within a defined study area to Kilifi District Hospital between Aug 1, 1998, and March 31, 2008; those with bacteraemia were defined as cases. We used two sets of controls: children recruited by random sampling in the same area into several studies undertaken between Sept 1, 1998, and Nov 30, 2005; and those born consecutively within the area between May 1, 2006, and April 30, 2008. Cases and controls were tested for sickle-cell anaemia retrospectively. Findings We detected 2157 episodes of bacteraemia in 38 441 admissions (6%). 1749 of these children with bacteraemia (81%) were typed for sickle-cell anaemia, of whom 108 (6%) were positive as were 89 of 13 492 controls (1%). The organisms most commonly isolated from children with sickle-cell anaemia were Streptococcus pneumoniae (44/108 isolates; 41%), non-typhi Salmonella species (19/108; 18%), Haemophilus influenzae type b (13/108; 12%), Acinetobacter species (seven of 108; 7%), and Escherichia coli (seven of 108; 7%). The age-adjusted odds ratio for bacteraemia in children with sickle-cell anaemia was 26·3 (95% CI 14·5–47·6), with the strongest associations for S pneumoniae (33·0, 17·4–62·8), non-typhi Salmonella species (35·5, 16·4–76·8), and H influenzae type b (28·1, 12·0–65·9). Interpretation The organisms causing bacteraemia in African children with sickle-cell anaemia are the same as those in developed countries. Introduction of conjugate vaccines against S pneumoniae and H influenzae into the childhood immunisation schedules of African countries could substantially affect survival of children with sickle-cell anaemia. Funding Wellcome Trust, UK.

High mortality from Plasmodium falciparum malaria in children living with sickle cell anemia on the coast of Kenya.

Although malaria is widely considered a major cause of death in young children born with sickle cell anemia (SCA) in sub-Saharan Africa, this is poorly quantified. We attempted to investigate this question through 4 large case-control analyses involving 7164 children living on the coast of Kenya. SCA was associated with an increased risk of admission to hospital both with nonmalaria diseases in general (odds ratio [OR] = 4.17; 95% confidence interval [CI], 1.95-8.92; P < .001) and with invasive bacterial diseases in particular (OR = 8.73; 95% CI, 4.51-16.89; P < .001). We found no evidence for a strongly increased risk of either uncomplicated malaria (OR = 0.43; 95% CI, 0.09-2.10; P = .30) or malaria complicated by a range of well-described clinical features of severity (OR = 0.80; 95% CI, 0.25-2.51; P = .70) overall; nevertheless, mortality was considerably higher among SCA than non-SCA children hospitalized with malaria. Our findings highlight both the central role that malaria plays in the high early mortality seen in African children with SCA and the urgent need for better quantitative data. Meanwhile, our study confirms the importance of providing all children living with SCA in malaria-endemic areas with effective prophylaxis.

Imputation-Based Meta-Analysis of Severe Malaria in Three African Populations

Combining data from genome-wide association studies (GWAS) conducted at different locations, using genotype imputation and fixed-effects meta-analysis, has been a powerful approach for dissecting complex disease genetics in populations of European ancestry. Here we investigate the feasibility of applying the same approach in Africa, where genetic diversity, both within and between populations, is far more extensive. We analyse genome-wide data from approximately 5,000 individuals with severe malaria and 7,000 population controls from three different locations in Africa. Our results show that the standard approach is well powered to detect known malaria susceptibility loci when sample sizes are large, and that modern methods for association analysis can control the potential confounding effects of population structure. We show that pattern of association around the haemoglobin S allele differs substantially across populations due to differences in haplotype structure. Motivated by these observations we consider new approaches to association analysis that might prove valuable for multicentre GWAS in Africa: we relax the assumptions of SNP–based fixed effect analysis; we apply Bayesian approaches to allow for heterogeneity in the effect of an allele on risk across studies; and we introduce a region-based test to allow for heterogeneity in the location of causal alleles.

Cause-specific childhood mortality in Africa and Asia: evidence from INDEPTH health and demographic surveillance system sites

Background Because most deaths in Africa and Asia are not well documented, estimates of mortality are often made using scanty data. The INDEPTH Network works to alleviate this problem by collating detailed individual data from defined Health and Demographic Surveillance sites. By registering all deaths over time and carrying out verbal autopsies to determine cause of death across many such sites, using standardised methods, the Network seeks to generate population-based mortality statistics that are not otherwise available. Objective To build a large standardised mortality database from African and Asian sites, detailing the relevant methods, and use it to describe cause-specific mortality patterns. Design Individual demographic and verbal autopsy (VA) data from 22 INDEPTH sites were collated into a standardised database. The INDEPTH 2013 population was used for standardisation. The WHO 2012 VA standard and the InterVA-4 model were used for assigning cause of death. Results A total of 111,910 deaths occurring over 12,204,043 person-years (accumulated between 1992 and 2012) were registered across the 22 sites, and for 98,429 of these deaths (88.0%) verbal autopsies were successfully completed. There was considerable variation in all-cause mortality between sites, with most of the differences being accounted for by variations in infectious causes as a proportion of all deaths. Conclusions This dataset documents individual deaths across Africa and Asia in a standardised way, and on an unprecedented scale. While INDEPTH sites are not constructed to constitute a representative sample, and VA may not be the ideal method of determining cause of death, nevertheless these findings represent detailed mortality patterns for parts of the world that are severely under-served in terms of measuring mortality. Further papers explore details of mortality patterns among children and specifically for NCDs, external causes, pregnancy-related mortality, malaria, and HIV/AIDS. Comparisons will also be made where possible with other findings on mortality in the same regions. Findings presented here and in accompanying papers support the need for continued work towards much wider implementation of universal civil registration of deaths by cause on a worldwide basis.Background Because most deaths in Africa and Asia are not well documented, estimates of mortality are often made using scanty data. The INDEPTH Network works to alleviate this problem by collating detailed individual data from defined Health and Demographic Surveillance sites. By registering all deaths over time and carrying out verbal autopsies to determine cause of death across many such sites, using standardised methods, the Network seeks to generate population-based mortality statistics that are not otherwise available. Objective To build a large standardised mortality database from African and Asian sites, detailing the relevant methods, and use it to describe cause-specific mortality patterns. Design Individual demographic and verbal autopsy (VA) data from 22 INDEPTH sites were collated into a standardised database. The INDEPTH 2013 population was used for standardisation. The WHO 2012 VA standard and the InterVA-4 model were used for assigning cause of death. Results A total of 111,910 deaths occurring over 12,204,043 person-years (accumulated between 1992 and 2012) were registered across the 22 sites, and for 98,429 of these deaths (88.0%) verbal autopsies were successfully completed. There was considerable variation in all-cause mortality between sites, with most of the differences being accounted for by variations in infectious causes as a proportion of all deaths. Conclusions This dataset documents individual deaths across Africa and Asia in a standardised way, and on an unprecedented scale. While INDEPTH sites are not constructed to constitute a representative sample, and VA may not be the ideal method of determining cause of death, nevertheless these findings represent detailed mortality patterns for parts of the world that are severely under-served in terms of measuring mortality. Further papers explore details of mortality patterns among children and specifically for NCDs, external causes, pregnancy-related mortality, malaria, and HIV/AIDS. Comparisons will also be made where possible with other findings on mortality in the same regions. Findings presented here and in accompanying papers support the need for continued work towards much wider implementation of universal civil registration of deaths by cause on a worldwide basis.

Validating physician-certified verbal autopsy and probabilistic modeling (InterVA) approaches to verbal autopsy interpretation using hospital causes of adult deaths

BackgroundThe most common method for determining cause of death is certification by physicians based either on available medical records, or where such data are not available, through verbal autopsy (VA). The physician-certification approach is costly and inconvenient; however, recent work shows the potential of a computer-based probabilistic model (InterVA) to interpret verbal autopsy data in a more convenient, consistent, and rapid way. In this study we validate separately both physician-certified verbal autopsy (PCVA) and the InterVA probabilistic model against hospital cause of death (HCOD) in adults dying in a district hospital on the coast of Kenya.MethodsBetween March 2007 and June 2010, VA interviews were conducted for 145 adult deaths that occurred at Kilifi District Hospital. The VA data were reviewed by a physician and the cause of death established. A range of indicators (including age, gender, physical signs and symptoms, pregnancy status, medical history, and the circumstances of death) from the VA forms were included in the InterVA for interpretation. Cause-specific mortality fractions (CSMF), Cohens kappa (κ) statistic, receiver operating characteristic (ROC) curves, sensitivity, specificity, and positive predictive values were applied to compare agreement between PCVA, InterVA, and HCOD.ResultsHCOD, InterVA, and PCVA yielded the same top five underlying causes of adult deaths. The InterVA overestimated tuberculosis as a cause of death compared to the HCOD. On the other hand, PCVA overestimated diabetes. Overall, CSMF for the five major cause groups by the InterVA, PCVA, and HCOD were 70%, 65%, and 60%, respectively. PCVA versus HCOD yielded a higher kappa value (κ = 0.52, 95% confidence interval [CI]: 0.48, 0.54) than the InterVA versus HCOD which yielded a kappa (κ) value of 0.32 (95% CI: 0.30, 0.38). Overall, (κ) agreement across the three methods was 0.41 (95% CI: 0.37, 0.48). The areas under the ROC curves were 0.82 for InterVA and 0.88 for PCVA. The observed sensitivities and specificities across the five major causes of death varied from 43% to 100% and 87% to 99%, respectively, for the InterVA/PCVA against the HCOD.ConclusionBoth the InterVA and PCVA compared well with the HCOD at a population level and determined the top five underlying causes of death in the rural community of Kilifi. We hope that our study, albeit small, provides new and useful data that will stimulate further definitive work on methods of interpreting VA data.

HIV/AIDS-related mortality in Africa and Asia: evidence from INDEPTH health and demographic surveillance system sites.

Background As the HIV/AIDS pandemic has evolved over recent decades, Africa has been the most affected region, even though a large proportion of HIV/AIDS deaths have not been documented at the individual level. Systematic application of verbal autopsy (VA) methods in defined populations provides an opportunity to assess the mortality burden of the pandemic from individual data. Objective To present standardised comparisons of HIV/AIDS-related mortality at sites across Africa and Asia, including closely related causes of death such as pulmonary tuberculosis (PTB) and pneumonia. Design Deaths related to HIV/AIDS were extracted from individual demographic and VA data from 22 INDEPTH sites across Africa and Asia. VA data were standardised to WHO 2012 standard causes of death assigned using the InterVA-4 model. Between-site comparisons of mortality rates were standardised using the INDEPTH 2013 standard population. Results The dataset covered a total of 10,773 deaths attributed to HIV/AIDS, observed over 12,204,043 person-years. HIV/AIDS-related mortality fractions and mortality rates varied widely across Africa and Asia, with highest burdens in eastern and southern Africa, and lowest burdens in Asia. There was evidence of rapidly declining rates at the sites with the heaviest burdens. HIV/AIDS mortality was also strongly related to PTB mortality. On a country basis, there were strong similarities between HIV/AIDS mortality rates at INDEPTH sites and those derived from modelled estimates. Conclusions Measuring HIV/AIDS-related mortality continues to be a challenging issue, all the more so as anti-retroviral treatment programmes alleviate mortality risks. The congruence between these results and other estimates adds plausibility to both approaches. These data, covering some of the highest mortality observed during the pandemic, will be an important baseline for understanding the future decline of HIV/AIDS.Background As the HIV/AIDS pandemic has evolved over recent decades, Africa has been the most affected region, even though a large proportion of HIV/AIDS deaths have not been documented at the individual level. Systematic application of verbal autopsy (VA) methods in defined populations provides an opportunity to assess the mortality burden of the pandemic from individual data. Objective To present standardised comparisons of HIV/AIDS-related mortality at sites across Africa and Asia, including closely related causes of death such as pulmonary tuberculosis (PTB) and pneumonia. Design Deaths related to HIV/AIDS were extracted from individual demographic and VA data from 22 INDEPTH sites across Africa and Asia. VA data were standardised to WHO 2012 standard causes of death assigned using the InterVA-4 model. Between-site comparisons of mortality rates were standardised using the INDEPTH 2013 standard population. Results The dataset covered a total of 10,773 deaths attributed to HIV/AIDS, observed over 12,204,043 person-years. HIV/AIDS-related mortality fractions and mortality rates varied widely across Africa and Asia, with highest burdens in eastern and southern Africa, and lowest burdens in Asia. There was evidence of rapidly declining rates at the sites with the heaviest burdens. HIV/AIDS mortality was also strongly related to PTB mortality. On a country basis, there were strong similarities between HIV/AIDS mortality rates at INDEPTH sites and those derived from modelled estimates. Conclusions Measuring HIV/AIDS-related mortality continues to be a challenging issue, all the more so as anti-retroviral treatment programmes alleviate mortality risks. The congruence between these results and other estimates adds plausibility to both approaches. These data, covering some of the highest mortality observed during the pandemic, will be an important baseline for understanding the future decline of HIV/AIDS.

Adult non-communicable disease mortality in Africa and Asia: evidence from INDEPTH Health and Demographic Surveillance System sites

Background Mortality from non-communicable diseases (NCDs) is a major global issue, as other categories of mortality have diminished and life expectancy has increased. The World Health Organizations Member States have called for a 25% reduction in premature NCD mortality by 2025, which can only be achieved by substantial reductions in risk factors and improvements in the management of chronic conditions. A high burden of NCD mortality among much older people, who have survived other hazards, is inevitable. The INDEPTH Network collects detailed individual data within defined Health and Demographic Surveillance sites. By registering deaths and carrying out verbal autopsies to determine cause of death across many such sites, using standardised methods, the Network seeks to generate population-based mortality statistics that are not otherwise available. Objective To describe patterns of adult NCD mortality from INDEPTH Network sites across Africa and Asia, according to the WHO 2012 verbal autopsy (VA) cause categories, with separate consideration of premature (15–64 years) and older (65+ years) NCD mortality. Design All adult deaths at INDEPTH sites are routinely registered and followed up with VA interviews. For this study, VA archives were transformed into the WHO 2012 VA standard format and processed using the InterVA-4 model to assign cause of death. Routine surveillance data also provide person-time denominators for mortality rates. Results A total of 80,726 adult (over 15 years) deaths were documented over 7,423,497 person-years of observation. NCDs were attributed as the cause for 35.6% of these deaths. Slightly less than half of adult NCD deaths occurred in the 15–64 age group. Detailed results are presented by age and sex for leading causes of NCD mortality. Per-site rates of NCD mortality were significantly correlated with rates of HIV/AIDS-related mortality. Conclusions These findings present important evidence on the distribution of NCD mortality across a wide range of African and Asian settings. This comes against a background of global concern about the burden of NCD mortality, especially among adults aged under 70, and provides an important baseline for future work.Background Mortality from non-communicable diseases (NCDs) is a major global issue, as other categories of mortality have diminished and life expectancy has increased. The World Health Organizations Member States have called for a 25% reduction in premature NCD mortality by 2025, which can only be achieved by substantial reductions in risk factors and improvements in the management of chronic conditions. A high burden of NCD mortality among much older people, who have survived other hazards, is inevitable. The INDEPTH Network collects detailed individual data within defined Health and Demographic Surveillance sites. By registering deaths and carrying out verbal autopsies to determine cause of death across many such sites, using standardised methods, the Network seeks to generate population-based mortality statistics that are not otherwise available. Objective To describe patterns of adult NCD mortality from INDEPTH Network sites across Africa and Asia, according to the WHO 2012 verbal autopsy (VA) cause categories, with separate consideration of premature (15-64 years) and older (65+ years) NCD mortality. Design All adult deaths at INDEPTH sites are routinely registered and followed up with VA interviews. For this study, VA archives were transformed into the WHO 2012 VA standard format and processed using the InterVA-4 model to assign cause of death. Routine surveillance data also provide person-time denominators for mortality rates. Results A total of 80,726 adult (over 15 years) deaths were documented over 7,423,497 person-years of observation. NCDs were attributed as the cause for 35.6% of these deaths. Slightly less than half of adult NCD deaths occurred in the 15-64 age group. Detailed results are presented by age and sex for leading causes of NCD mortality. Per-site rates of NCD mortality were significantly correlated with rates of HIV/AIDS-related mortality. Conclusions These findings present important evidence on the distribution of NCD mortality across a wide range of African and Asian settings. This comes against a background of global concern about the burden of NCD mortality, especially among adults aged under 70, and provides an important baseline for future work.

Resistance to malaria through structural variation of red blood cell invasion receptors

Structural variants are mapped that are correlated with a reduced risk of severe malaria. Pathogens select for genomic variants Large-scale deletions and duplications of genes, referred to as structural variants (SVs), are common within the human genome and have been linked to disease. Examining a genomic region that appears to confer a selective benefit, Leffler et al. used fine mapping to identify a specific SV that reduces the risk of severe malaria by an estimated 40% (see the Perspective by Winzeler). Data from African individuals revealed that populations harbor different SVs in this region. Furthermore, by dissecting a highly complex genomic region, the authors identified the likely causal element. This element encodes hybrid genes that affect glycophorin proteins, which are used by the malarial parasite in infection and are associated with resistance to severe disease. Science, this issue p. eaam6393; see also p. 1122 INTRODUCTION Malaria parasites cause human disease by invading and replicating inside red blood cells. In the case of Plasmodium falciparum, this can lead to severe forms of malaria that are a major cause of childhood mortality in Africa. This species of parasite enters the red blood cell through interactions with surface proteins including the glycophorins GYPA and GYPB, which determine the polymorphic MNS blood group system. In a recent genome-wide association study, we identified alleles associated with protection against severe malaria near the cluster of genes encoding these invasion receptors. RATIONALE Investigation of genetic variants at this locus and their relation to severe malaria is challenging because of the high sequence similarity between the neighboring glycophorin genes and the relative lack of available sequence data capturing the genetic diversity of sub-Saharan Africa. To better assess whether variation in the glycophorin genes could explain the signal of association, we generated additional sequence data from sub-Saharan African populations and developed an analytical approach to characterize structural variation at this complex locus. RESULTS Using 765 newly sequenced human genomes from 10 African ethnic groups along with data from the 1000 Genomes Project, we generated a reference panel of haplotypes across the glycophorin region. In addition to single-nucleotide polymorphisms and short indels, we assayed large copy number variants (CNVs) using sequencing read depth and uncovered extensive structural diversity. By imputing from this reference panel into 4579 severe malaria cases and 5310 controls from three African populations, we found that a complex CNV, here called DUP4, is associated with resistance to severe malaria and fully explains the previously reported signal of association. In our sample, DUP4 is present only in east Africa, and this localization, as well as the extent of similarity between DUP4 haplotypes, suggests that it has recently increased in frequency, presumably under natural selection due to malaria. To evaluate the potential functional consequences of this structural variant, we analyzed high-coverage sequence-read data from multiple individuals to generate a model of the DUP4 chromosome structure. The DUP4 haplotype contains five glycophorin genes, including two hybrid genes that juxtapose the extracellular domain of GYPB with the transmembrane and intracellular domains of GYPA. Noting that these predicted hybrids are characteristic of the Dantu antigen in the MNS blood group system, we sequenced a Dantu positive individual and confirmed that DUP4 is the molecular basis of the Dantu NE blood group variant. CONCLUSION Although a role for GYPA and GYPB in parasite invasion is well known, a direct link between glycophorin polymorphisms and clinical susceptibility to malaria has been elusive. Here we have provided a systematic catalog of CNVs, describing structural diversity that may have functional importance at this locus. Our results identify a specific variant that encodes hybrid glycophorin proteins and is associated with protection against severe malaria. This discovery calls for further work to determine how this particular molecular rearrangement affects parasite invasion and the red blood cell response and may lead us toward new parasite vulnerabilities that can be utilized in future interventions against this deadly disease. A structural variant creating hybrid glycophorin genes is associated with protection from severe malaria. The reference haplotype carries three glycophorin genes, two of which (GYPA and GYPB) are expressed as proteins on the red blood cell surface. The malaria-protective haplotype carries five glycophorin genes, including two hybrid genes that encode the Dantu blood group antigen and are composed of a GYPB extracellular domain and GYPA intracellular domain. These glycophorins serve as receptors for malaria-parasite ligands during red blood cell invasion. The malaria parasite Plasmodium falciparum invades human red blood cells by a series of interactions between host and parasite surface proteins. By analyzing genome sequence data from human populations, including 1269 individuals from sub-Saharan Africa, we identify a diverse array of large copy-number variants affecting the host invasion receptor genes GYPA and GYPB. We find that a nearby association with severe malaria is explained by a complex structural rearrangement involving the loss of GYPB and gain of two GYPB-A hybrid genes, which encode a serologically distinct blood group antigen known as Dantu. This variant reduces the risk of severe malaria by 40% and has recently increased in frequency in parts of Kenya, yet it appears to be absent from west Africa. These findings link structural variation of red blood cell invasion receptors with natural resistance to severe malaria.

Malaria mortality in Africa and Asia: evidence from INDEPTH health and demographic surveillance system sites

Background Malaria continues to be a major cause of infectious disease mortality in tropical regions. However, deaths from malaria are most often not individually documented, and as a result overall understanding of malaria epidemiology is inadequate. INDEPTH Network members maintain population surveillance in Health and Demographic Surveillance System sites across Africa and Asia, in which individual deaths are followed up with verbal autopsies. Objective To present patterns of malaria mortality determined by verbal autopsy from INDEPTH sites across Africa and Asia, comparing these findings with other relevant information on malaria in the same regions. Design From a database covering 111,910 deaths over 12,204,043 person-years in 22 sites, in which verbal autopsy data were handled according to the WHO 2012 standard and processed using the InterVA-4 model, over 6,000 deaths were attributed to malaria. The overall period covered was 1992–2012, but two-thirds of the observations related to 2006–2012. These deaths were analysed by site, time period, age group and sex to investigate epidemiological differences in malaria mortality. Results Rates of malaria mortality varied by 1:10,000 across the sites, with generally low rates in Asia (one site recording no malaria deaths over 0.5 million person-years) and some of the highest rates in West Africa (Nouna, Burkina Faso: 2.47 per 1,000 person-years). Childhood malaria mortality rates were strongly correlated with Malaria Atlas Project estimates of Plasmodium falciparum parasite rates for the same locations. Adult malaria mortality rates, while lower than corresponding childhood rates, were strongly correlated with childhood rates at the site level. Conclusions The wide variations observed in malaria mortality, which were nevertheless consistent with various other estimates, suggest that population-based registration of deaths using verbal autopsy is a useful approach to understanding the details of malaria epidemiology.Background Malaria continues to be a major cause of infectious disease mortality in tropical regions. However, deaths from malaria are most often not individually documented, and as a result overall understanding of malaria epidemiology is inadequate. INDEPTH Network members maintain population surveillance in Health and Demographic Surveillance System sites across Africa and Asia, in which individual deaths are followed up with verbal autopsies. Objective To present patterns of malaria mortality determined by verbal autopsy from INDEPTH sites across Africa and Asia, comparing these findings with other relevant information on malaria in the same regions. Design From a database covering 111,910 deaths over 12,204,043 person-years in 22 sites, in which verbal autopsy data were handled according to the WHO 2012 standard and processed using the InterVA-4 model, over 6,000 deaths were attributed to malaria. The overall period covered was 1992-2012, but two-thirds of the observations related to 2006-2012. These deaths were analysed by site, time period, age group and sex to investigate epidemiological differences in malaria mortality. Results Rates of malaria mortality varied by 1:10,000 across the sites, with generally low rates in Asia (one site recording no malaria deaths over 0.5 million person-years) and some of the highest rates in West Africa (Nouna, Burkina Faso: 2.47 per 1,000 person-years). Childhood malaria mortality rates were strongly correlated with Malaria Atlas Project estimates of Plasmodium falciparum parasite rates for the same locations. Adult malaria mortality rates, while lower than corresponding childhood rates, were strongly correlated with childhood rates at the site level. Conclusions The wide variations observed in malaria mortality, which were nevertheless consistent with various other estimates, suggest that population-based registration of deaths using verbal autopsy is a useful approach to understanding the details of malaria epidemiology.