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Propensity score methods, such as subclassification, are a common approach to control for confounding when estimating causal effects in non-randomized studies. Propensity score subclassification groups individuals into subclasses based on their propensity score values. Effect estimates are obtained within each subclass and then combined by weighting by the proportion of observations in each subclass. Combining subclass-specific estimates by weighting by the inverse variance is a promising alternative approach; a similar strategy is used in meta-analysis for its efficiency. We use simulation to compare performance of each of the two methods while varying (i) the number of subclasses, (ii) extent of propensity score overlap between the treatment and control groups (i.e., positivity), (iii) incorporation of survey weighting, and (iv) presence of heterogeneous treatment effects across subclasses. Both methods perform well in the absence of positivity violations and with a constant treatment effect with weighting by the inverse variance performing slightly better. Weighting by the proportion in subclass performs better in the presence of heterogeneous treatment effects across subclasses. We apply these methods to an illustrative example estimating the effect of living in a disadvantaged neighborhood on risk of past-year anxiety and depressive disorders among U.S. urban adolescents. This example entails practical positivity violations but no evidence of treatment effect heterogeneity. In this case, weighting by the inverse variance when combining across propensity score subclasses results in more efficient estimates that ultimately change inference. Copyright © 2016 John Wiley & Sons, Ltd., Competing Interests: The authors claim no conflicts of interest., (Copyright © 2016 John Wiley & Sons, Ltd.)

A substitution estimator can be used to predict how shifts in population exposures might change health. We illustrated this method by estimating how an upper limit on alcohol outlet density might alter binge drinking in the New York Social Environment Study (n = 4000), and provided statistical code and sample data. The largest differences in binge drinking were for an upper limit of 70 outlets per square mile; there was a -0.7% difference in binge drinking prevalence for New York City overall (95% confidence interval [CI] = -0.2%, -1.3%) and a -2.4% difference in binge drinking prevalence for the subset of communities the intervention modified (95% CI = -0.5%, -4.0%). A substitution estimator is a flexible tool for estimating population intervention parameters and improving the translation of public health research results to practitioners.

Suicide is a leading cause of premature mortality. Aspects of the social environment such as incidents of violence in the community may induce psychological distress and affect suicidality, but these determinants are not well understood. We conducted an ecological study using California vital statistics records, geocoded to address of the decedent, to examine whether proximity to homicide was associated with the occurrence of suicide in urban census tracts. For each urban tract (N = 7194) and each month in 2012, we assessed homicides in the tract or within buffer zones around the tract with a 1-month lag. We estimated two risk difference parameters that capture how suicide risk is related to differences in homicide exposure. Proximity to homicides was negatively associated with suicide occurrence after controlling for demographic factors, seasonality, and other confounders. Estimates suggest that the absence of homicides would be associated with a 4.2 % higher number of tract-months with one or more suicides (95 % confidence interval 2.2-6.0). This relationship was stronger in tracts that were wealthier, older, and less civically engaged. Results were robust to a wide variety of sensitivity tests. Contrary to expectations, we identified a consistent negative association of proximity to homicide with suicide occurrence. It may be that a homicide deters or distracts from suicidality or that aggression or hopelessness may be expressed as inward or outward directed violence in different settings. Further investigation is needed to identify the drivers of this association., Competing Interests: Compliance with Ethical Standards Study Approval This study was approved by the State of California and University of California, Berkeley Committees for the Protection of Human Subjects.This study was approved by the State of California and University of California, Berkeley Committees for the Protection of Human Subjects. Funding The authors acknowledge the following funding sources: NICHD/NIH Office of the Director DP2HD080350; Robert Wood Johnson Health and Society Scholars Program; and the University of California, Berkeley Committee on Research.

Background: Studies have shown that children with cancer globally lack access to palliative care. Little is known regarding physicians' perceptions of palliative care, treatment access, and self-reported competence in providing palliative care., Procedure: Members of the Global Neuroblastoma Network (online tumor board) were surveyed. Eighty-three respondents met inclusion criteria; 53 (64%) completed the survey., Results: Most respondents trained in high-income countries (HIC) but practice in low- and middle-income countries (LMIC), and care for more than five patients with neuroblastoma annually. WHO Essential Medicines in palliative care varied in availability, with incomplete access across LMIC centers. Nonpharmacologic therapies were inconsistently available. Contrary to international definitions, 17% of respondents inappropriately considered palliative care as that initiated only after curative therapy is stopped. Mean physician competence composite score (Likert scale 1-5, 5 = very competent) in providing symptomatic relief and palliative care across phases of care was 2.93 (95% CI 2.71-3.22). Physicians reported significantly greater competence in symptom management during cure-directed therapy than during end-of-life (P = 0.02) or when patients are actively dying (P = 0.007). Practicing in HIC, prior palliative care training, having access to radiotherapy, and not having to turn patients away due to bed shortages were significantly predictive of perceived competence in providing palliative care at end of life., Conclusions: An international sample identified gaps in treatment and palliative care service availability, in understanding the definition of palliative care, and in self-reported competence in providing palliative care. Increased perceived competence was associated with training, which supports the need for increased palliative care education and advocacy, especially in LMIC., (© 2016 Wiley Periodicals, Inc.)

Matching methods are common in studies across many disciplines. However, there is limited evidence on how to optimally combine matching with subsequent analysis approaches to minimize bias and maximize efficiency for the quantity of interest. We conducted simulations to compare the performance of a wide variety of matching methods and analysis approaches in terms of bias, variance, and mean squared error (MSE). We then compared these approaches in an applied example of an employment training program. The results indicate that combining full matching with double robust analysis performed best in both the simulations and the applied example, particularly when combined with machine learning estimation methods. To reduce bias, current guidelines advise researchers to select the technique with the best post-matching covariate balance, but this work finds that such an approach does not always minimize mean squared error (MSE). These findings have important implications for future research utilizing matching. To minimize MSE, investigators should consider additional diagnostics, and use of simulations tailored to the study of interest to identify the optimal matching and analysis combination.

Background: Recent outbreaks of measles in the Americas have received news and popular attention, noting the importance of vaccination to population health. To estimate the potential increase in immunization coverage and reduction in days at risk if every opportunity to vaccinate a child was used, we analyzed vaccination histories of children 11-59 months of age from large household surveys in Mesoamerica., Methods: Our study included 22,234 children aged less than 59 months in El Salvador, Guatemala, Honduras, Mexico, Nicaragua, and Panama. Child vaccination cards were used to calculate coverage of measles, mumps, and rubella (MMR) and to compute the number of days lived at risk. A child had a missed opportunity for vaccination if their card indicated a visit for vaccinations at which the child was not caught up to schedule for MMR. A Cox proportional hazards model was used to compute the hazard ratio associated with the reduction in days at risk, accounting for missed opportunities., Results: El Salvador had the highest proportion of children with a vaccine card (91.2%) while Nicaragua had the lowest (76.5%). Card MMR coverage ranged from 44.6% in Mexico to 79.6% in Honduras while potential coverage accounting for missed opportunities ranged from 70.8% in Nicaragua to 96.4% in El Salvador. Younger children were less likely to have a missed opportunity. In Panama, children from households with higher expenditure were more likely to have a missed opportunity for MMR vaccination compared to the poorest (OR 1.62, 95% CI: 1.06-2.47). In Nicaragua, compared to children of mothers with no education, children of mothers with primary education and secondary education were less likely to have a missed opportunity (OR 0.46, 95% CI: 0.24-0.88 and OR 0.25, 95% CI: 0.096-0.65, respectively). Mean days at risk for MMR ranged from 158 in Panama to 483 in Mexico while potential days at risk ranged from 92 in Panama to 239 in El Salvador., Conclusions: Our study found high levels of missed opportunities for immunizing children in Mesoamerica. Our findings cause great concern, as they indicate that families are bringing their children to health facilities, but these children are not receiving all appropriate vaccinations during visits. This points to serious problems in current immunization practices and protocols in poor areas in Mesoamerica. Our study calls for programs to ensure that vaccines are available and that health professionals use every opportunity to vaccinate a child.

Seroepidemiological monitoring of population immunity to vaccine-preventable diseases is critical to prevent future outbreaks. Dried blood spots (DBS), drops of capillary blood dried on filter paper, are an affordable, minimally invasive alternative to venipuncture for collecting blood in field settings. However, few proven methods exist to analyze DBS for the presence of protective antibodies. This study validates a novel technique for measuring measles-specific immunoglobulin G (IgG) in capillary DBS using a commercial ELISA. The predictive performance of a new method for analyzing DBS was tested by comparing matched serum and DBS samples from 50 children. The accuracy, precision, and reliability of the procedure were evaluated, and the optimal cut points to classify positive and negative samples were determined. The method was then applied to 1,588 DBS collected during a large survey of children in Mexico and Nicaragua. Measles-specific IgG in serum samples were 62% negative, 10% equivocal, and 28% positive. In comparisons with matched serum, DBS results were 100% sensitive and 96 · 8% specific, and agreed in 46 of 50 (92%) cases. The inter-assay and intra-assay coefficients of variation from kit-provided controls were greater than desired (24.8% and 8.4%, respectively). However, in predictive simulations the average misclassification was only 3.9%. Procedures were found to be acceptable to surveyors and participants. Analyzing DBS collected in low-resources settings is a feasible and accurate means of measuring population immunity to measles and should be used to generate objective measures of health status and health system performance., (© 2015 Wiley Periodicals, Inc.)

Background: Individual income and poverty are associated with poor health outcomes. The poor face unique challenges related to access, education, financial capacity, environmental effects, and other factors that threaten their health outcomes., Methods: We examined the variation in the health outcomes and health behaviors among the poorest quintile in eight countries of Mesoamerica using data from the Salud Mesomérica 2015 baseline household surveys. We used multivariable logistic regression to measure the association between delivering a child in a health facility and select household and maternal characteristics, including education and measures of wealth., Results: Health indicators varied greatly between geographic segments. Controlling for other demographic characteristics, women with at least secondary education were more likely to have an in-facility delivery compared to women who had not attended school (OR: 3.20, 95 % confidence interval [CI]: 2.56-3.99, respectively). Similarly, women from households with the highest expenditure were more likely to deliver in a health facility compared to those from the lowest expenditure households (OR 3.06, 95 % CI: 2.43-3.85). Household assets did not impact these associations. Moreover, we found that commonly-used definitions of poverty do not align with the disparities in health outcomes observed in these communities., Conclusions: Although poverty measured by expenditure or wealth is associated with health disparities or health outcomes, a composite indicator of health poverty based on coverage is more likely to focus attention on health problems and solutions. Our findings call for the public health community to define poverty by health coverage measures rather than income or wealth. Such a health-poverty metric is more likely to generate attention and mobilize targeted action by the health communities than our current definition of poverty.

Timely and accurate measurement of population protection against measles is critical for decision-making and prevention of outbreaks. However, little is known about how survey-based estimates of immunization (crude coverage) compare to the seroprevalence of antibodies (effective coverage), particularly in low-resource settings. In poor areas of Mexico and Nicaragua, we used household surveys to gather information on measles immunization from child health cards and caregiver recall. We also collected dried blood spots (DBS) from children aged 12 to 23 months to compare crude and effective coverage of measles immunization. We used survey-weighted logistic regression to identify individual, maternal, household, community, and health facility characteristics that predict gaps between crude coverage and effective coverage. We found that crude coverage was significantly higher than effective coverage (83% versus 68% in Mexico; 85% versus 50% in Nicaragua). A large proportion of children (19% in Mexico; 43% in Nicaragua) had health card documentation of measles immunization but lacked antibodies. These discrepancies varied from 0% to 100% across municipalities in each country. In multivariate analyses, card-positive children in Mexico were more likely to lack antibodies if they resided in urban areas or the jurisdiction of De Los Llanos. In contrast, card-positive children in Nicaragua were more likely to lack antibodies if they resided in rural areas or the North Atlantic region, had low weight-for-age, or attended health facilities with a greater number of refrigerators. Findings highlight that reliance on child health cards to measure population protection against measles is unwise. We call for the evaluation of immunization programs using serological methods, especially in poor areas where the cold chain is likely to be compromised. Identification of within-country variation in effective coverage of measles immunization will allow researchers and public health professionals to address challenges in current immunization programs.

Importance: Understanding the major health problems in the United States and how they are changing over time is critical for informing national health policy., Objectives: To measure the burden of diseases, injuries, and leading risk factors in the United States from 1990 to 2010 and to compare these measurements with those of the 34 countries in the Organisation for Economic Co-operation and Development (OECD) countries., Design: We used the systematic analysis of descriptive epidemiology of 291 diseases and injuries, 1160 sequelae of these diseases and injuries, and 67 risk factors or clusters of risk factors from 1990 to 2010 for 187 countries developed for the Global Burden of Disease 2010 Study to describe the health status of the United States and to compare US health outcomes with those of 34 OECD countries. Years of life lost due to premature mortality (YLLs) were computed by multiplying the number of deaths at each age by a reference life expectancy at that age. Years lived with disability (YLDs) were calculated by multiplying prevalence (based on systematic reviews) by the disability weight (based on population-based surveys) for each sequela; disability in this study refers to any short- or long-term loss of health. Disability-adjusted life-years (DALYs) were estimated as the sum of YLDs and YLLs. Deaths and DALYs related to risk factors were based on systematic reviews and meta-analyses of exposure data and relative risks for risk-outcome pairs. Healthy life expectancy (HALE) was used to summarize overall population health, accounting for both length of life and levels of ill health experienced at different ages., Results: US life expectancy for both sexes combined increased from 75.2 years in 1990 to 78.2 years in 2010; during the same period, HALE increased from 65.8 years to 68.1 years. The diseases and injuries with the largest number of YLLs in 2010 were ischemic heart disease, lung cancer, stroke, chronic obstructive pulmonary disease, and road injury. Age-standardized YLL rates increased for Alzheimer disease, drug use disorders, chronic kidney disease, kidney cancer, and falls. The diseases with the largest number of YLDs in 2010 were low back pain, major depressive disorder, other musculoskeletal disorders, neck pain, and anxiety disorders. As the US population has aged, YLDs have comprised a larger share of DALYs than have YLLs. The leading risk factors related to DALYs were dietary risks, tobacco smoking, high body mass index, high blood pressure, high fasting plasma glucose, physical inactivity, and alcohol use. Among 34 OECD countries between 1990 and 2010, the US rank for the age-standardized death rate changed from 18th to 27th, for the age-standardized YLL rate from 23rd to 28th, for the age-standardized YLD rate from 5th to 6th, for life expectancy at birth from 20th to 27th, and for HALE from 14th to 26th., Conclusions and Relevance: From 1990 to 2010, the United States made substantial progress in improving health. Life expectancy at birth and HALE increased, all-cause death rates at all ages decreased, and age-specific rates of years lived with disability remained stable. However, morbidity and chronic disability now account for nearly half of the US health burden, and improvements in population health in the United States have not kept pace with advances in population health in other wealthy nations.

Background: Non-fatal health outcomes from diseases and injuries are a crucial consideration in the promotion and monitoring of individual and population health. The Global Burden of Disease (GBD) studies done in 1990 and 2000 have been the only studies to quantify non-fatal health outcomes across an exhaustive set of disorders at the global and regional level. Neither effort quantified uncertainty in prevalence or years lived with disability (YLDs)., Methods: Of the 291 diseases and injuries in the GBD cause list, 289 cause disability. For 1160 sequelae of the 289 diseases and injuries, we undertook a systematic analysis of prevalence, incidence, remission, duration, and excess mortality. Sources included published studies, case notification, population-based cancer registries, other disease registries, antenatal clinic serosurveillance, hospital discharge data, ambulatory care data, household surveys, other surveys, and cohort studies. For most sequelae, we used a Bayesian meta-regression method, DisMod-MR, designed to address key limitations in descriptive epidemiological data, including missing data, inconsistency, and large methodological variation between data sources. For some disorders, we used natural history models, geospatial models, back-calculation models (models calculating incidence from population mortality rates and case fatality), or registration completeness models (models adjusting for incomplete registration with health-system access and other covariates). Disability weights for 220 unique health states were used to capture the severity of health loss. YLDs by cause at age, sex, country, and year levels were adjusted for comorbidity with simulation methods. We included uncertainty estimates at all stages of the analysis., Findings: Global prevalence for all ages combined in 2010 across the 1160 sequelae ranged from fewer than one case per 1 million people to 350,000 cases per 1 million people. Prevalence and severity of health loss were weakly correlated (correlation coefficient -0·37). In 2010, there were 777 million YLDs from all causes, up from 583 million in 1990. The main contributors to global YLDs were mental and behavioural disorders, musculoskeletal disorders, and diabetes or endocrine diseases. The leading specific causes of YLDs were much the same in 2010 as they were in 1990: low back pain, major depressive disorder, iron-deficiency anaemia, neck pain, chronic obstructive pulmonary disease, anxiety disorders, migraine, diabetes, and falls. Age-specific prevalence of YLDs increased with age in all regions and has decreased slightly from 1990 to 2010. Regional patterns of the leading causes of YLDs were more similar compared with years of life lost due to premature mortality. Neglected tropical diseases, HIV/AIDS, tuberculosis, malaria, and anaemia were important causes of YLDs in sub-Saharan Africa., Interpretation: Rates of YLDs per 100,000 people have remained largely constant over time but rise steadily with age. Population growth and ageing have increased YLD numbers and crude rates over the past two decades. Prevalences of the most common causes of YLDs, such as mental and behavioural disorders and musculoskeletal disorders, have not decreased. Health systems will need to address the needs of the rising numbers of individuals with a range of disorders that largely cause disability but not mortality. Quantification of the burden of non-fatal health outcomes will be crucial to understand how well health systems are responding to these challenges. Effective and affordable strategies to deal with this rising burden are an urgent priority for health systems in most parts of the world., Funding: Bill & Melinda Gates Foundation., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Quantification of the disease burden caused by different risks informs prevention by providing an account of health loss different to that provided by a disease-by-disease analysis. No complete revision of global disease burden caused by risk factors has been done since a comparative risk assessment in 2000, and no previous analysis has assessed changes in burden attributable to risk factors over time., Methods: We estimated deaths and disability-adjusted life years (DALYs; sum of years lived with disability [YLD] and years of life lost [YLL]) attributable to the independent effects of 67 risk factors and clusters of risk factors for 21 regions in 1990 and 2010. We estimated exposure distributions for each year, region, sex, and age group, and relative risks per unit of exposure by systematically reviewing and synthesising published and unpublished data. We used these estimates, together with estimates of cause-specific deaths and DALYs from the Global Burden of Disease Study 2010, to calculate the burden attributable to each risk factor exposure compared with the theoretical-minimum-risk exposure. We incorporated uncertainty in disease burden, relative risks, and exposures into our estimates of attributable burden., Findings: In 2010, the three leading risk factors for global disease burden were high blood pressure (7·0% [95% uncertainty interval 6·2-7·7] of global DALYs), tobacco smoking including second-hand smoke (6·3% [5·5-7·0]), and alcohol use (5·5% [5·0-5·9]). In 1990, the leading risks were childhood underweight (7·9% [6·8-9·4]), household air pollution from solid fuels (HAP; 7·0% [5·6-8·3]), and tobacco smoking including second-hand smoke (6·1% [5·4-6·8]). Dietary risk factors and physical inactivity collectively accounted for 10·0% (95% UI 9·2-10·8) of global DALYs in 2010, with the most prominent dietary risks being diets low in fruits and those high in sodium. Several risks that primarily affect childhood communicable diseases, including unimproved water and sanitation and childhood micronutrient deficiencies, fell in rank between 1990 and 2010, with unimproved water and sanitation accounting for 0·9% (0·4-1·6) of global DALYs in 2010. However, in most of sub-Saharan Africa childhood underweight, HAP, and non-exclusive and discontinued breastfeeding were the leading risks in 2010, while HAP was the leading risk in south Asia. The leading risk factor in Eastern Europe, most of Latin America, and southern sub-Saharan Africa in 2010 was alcohol use; in most of Asia, North Africa and Middle East, and central Europe it was high blood pressure. Despite declines, tobacco smoking including second-hand smoke remained the leading risk in high-income north America and western Europe. High body-mass index has increased globally and it is the leading risk in Australasia and southern Latin America, and also ranks high in other high-income regions, North Africa and Middle East, and Oceania., Interpretation: Worldwide, the contribution of different risk factors to disease burden has changed substantially, with a shift away from risks for communicable diseases in children towards those for non-communicable diseases in adults. These changes are related to the ageing population, decreased mortality among children younger than 5 years, changes in cause-of-death composition, and changes in risk factor exposures. New evidence has led to changes in the magnitude of key risks including unimproved water and sanitation, vitamin A and zinc deficiencies, and ambient particulate matter pollution. The extent to which the epidemiological shift has occurred and what the leading risks currently are varies greatly across regions. In much of sub-Saharan Africa, the leading risks are still those associated with poverty and those that affect children., Funding: Bill & Melinda Gates Foundation., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Measuring disease and injury burden in populations requires a composite metric that captures both premature mortality and the prevalence and severity of ill-health. The 1990 Global Burden of Disease study proposed disability-adjusted life years (DALYs) to measure disease burden. No comprehensive update of disease burden worldwide incorporating a systematic reassessment of disease and injury-specific epidemiology has been done since the 1990 study. We aimed to calculate disease burden worldwide and for 21 regions for 1990, 2005, and 2010 with methods to enable meaningful comparisons over time., Methods: We calculated DALYs as the sum of years of life lost (YLLs) and years lived with disability (YLDs). DALYs were calculated for 291 causes, 20 age groups, both sexes, and for 187 countries, and aggregated to regional and global estimates of disease burden for three points in time with strictly comparable definitions and methods. YLLs were calculated from age-sex-country-time-specific estimates of mortality by cause, with death by standardised lost life expectancy at each age. YLDs were calculated as prevalence of 1160 disabling sequelae, by age, sex, and cause, and weighted by new disability weights for each health state. Neither YLLs nor YLDs were age-weighted or discounted. Uncertainty around cause-specific DALYs was calculated incorporating uncertainty in levels of all-cause mortality, cause-specific mortality, prevalence, and disability weights., Findings: Global DALYs remained stable from 1990 (2·503 billion) to 2010 (2·490 billion). Crude DALYs per 1000 decreased by 23% (472 per 1000 to 361 per 1000). An important shift has occurred in DALY composition with the contribution of deaths and disability among children (younger than 5 years of age) declining from 41% of global DALYs in 1990 to 25% in 2010. YLLs typically account for about half of disease burden in more developed regions (high-income Asia Pacific, western Europe, high-income North America, and Australasia), rising to over 80% of DALYs in sub-Saharan Africa. In 1990, 47% of DALYs worldwide were from communicable, maternal, neonatal, and nutritional disorders, 43% from non-communicable diseases, and 10% from injuries. By 2010, this had shifted to 35%, 54%, and 11%, respectively. Ischaemic heart disease was the leading cause of DALYs worldwide in 2010 (up from fourth rank in 1990, increasing by 29%), followed by lower respiratory infections (top rank in 1990; 44% decline in DALYs), stroke (fifth in 1990; 19% increase), diarrhoeal diseases (second in 1990; 51% decrease), and HIV/AIDS (33rd in 1990; 351% increase). Major depressive disorder increased from 15th to 11th rank (37% increase) and road injury from 12th to 10th rank (34% increase). Substantial heterogeneity exists in rankings of leading causes of disease burden among regions., Interpretation: Global disease burden has continued to shift away from communicable to non-communicable diseases and from premature death to years lived with disability. In sub-Saharan Africa, however, many communicable, maternal, neonatal, and nutritional disorders remain the dominant causes of disease burden. The rising burden from mental and behavioural disorders, musculoskeletal disorders, and diabetes will impose new challenges on health systems. Regional heterogeneity highlights the importance of understanding local burden of disease and setting goals and targets for the post-2015 agenda taking such patterns into account. Because of improved definitions, methods, and data, these results for 1990 and 2010 supersede all previously published Global Burden of Disease results., Funding: Bill & Melinda Gates Foundation., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Reliable and timely information on the leading causes of death in populations, and how these are changing, is a crucial input into health policy debates. In the Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010), we aimed to estimate annual deaths for the world and 21 regions between 1980 and 2010 for 235 causes, with uncertainty intervals (UIs), separately by age and sex., Methods: We attempted to identify all available data on causes of death for 187 countries from 1980 to 2010 from vital registration, verbal autopsy, mortality surveillance, censuses, surveys, hospitals, police records, and mortuaries. We assessed data quality for completeness, diagnostic accuracy, missing data, stochastic variations, and probable causes of death. We applied six different modelling strategies to estimate cause-specific mortality trends depending on the strength of the data. For 133 causes and three special aggregates we used the Cause of Death Ensemble model (CODEm) approach, which uses four families of statistical models testing a large set of different models using different permutations of covariates. Model ensembles were developed from these component models. We assessed model performance with rigorous out-of-sample testing of prediction error and the validity of 95% UIs. For 13 causes with low observed numbers of deaths, we developed negative binomial models with plausible covariates. For 27 causes for which death is rare, we modelled the higher level cause in the cause hierarchy of the GBD 2010 and then allocated deaths across component causes proportionately, estimated from all available data in the database. For selected causes (African trypanosomiasis, congenital syphilis, whooping cough, measles, typhoid and parathyroid, leishmaniasis, acute hepatitis E, and HIV/AIDS), we used natural history models based on information on incidence, prevalence, and case-fatality. We separately estimated cause fractions by aetiology for diarrhoea, lower respiratory infections, and meningitis, as well as disaggregations by subcause for chronic kidney disease, maternal disorders, cirrhosis, and liver cancer. For deaths due to collective violence and natural disasters, we used mortality shock regressions. For every cause, we estimated 95% UIs that captured both parameter estimation uncertainty and uncertainty due to model specification where CODEm was used. We constrained cause-specific fractions within every age-sex group to sum to total mortality based on draws from the uncertainty distributions., Findings: In 2010, there were 52·8 million deaths globally. At the most aggregate level, communicable, maternal, neonatal, and nutritional causes were 24·9% of deaths worldwide in 2010, down from 15·9 million (34·1%) of 46·5 million in 1990. This decrease was largely due to decreases in mortality from diarrhoeal disease (from 2·5 to 1·4 million), lower respiratory infections (from 3·4 to 2·8 million), neonatal disorders (from 3·1 to 2·2 million), measles (from 0·63 to 0·13 million), and tetanus (from 0·27 to 0·06 million). Deaths from HIV/AIDS increased from 0·30 million in 1990 to 1·5 million in 2010, reaching a peak of 1·7 million in 2006. Malaria mortality also rose by an estimated 19·9% since 1990 to 1·17 million deaths in 2010. Tuberculosis killed 1·2 million people in 2010. Deaths from non-communicable diseases rose by just under 8 million between 1990 and 2010, accounting for two of every three deaths (34·5 million) worldwide by 2010. 8 million people died from cancer in 2010, 38% more than two decades ago; of these, 1·5 million (19%) were from trachea, bronchus, and lung cancer. Ischaemic heart disease and stroke collectively killed 12·9 million people in 2010, or one in four deaths worldwide, compared with one in five in 1990; 1·3 million deaths were due to diabetes, twice as many as in 1990. The fraction of global deaths due to injuries (5·1 million deaths) was marginally higher in 2010 (9·6%) compared with two decades earlier (8·8%). This was driven by a 46% rise in deaths worldwide due to road traffic accidents (1·3 million in 2010) and a rise in deaths from falls. Ischaemic heart disease, stroke, chronic obstructive pulmonary disease (COPD), lower respiratory infections, lung cancer, and HIV/AIDS were the leading causes of death in 2010. Ischaemic heart disease, lower respiratory infections, stroke, diarrhoeal disease, malaria, and HIV/AIDS were the leading causes of years of life lost due to premature mortality (YLLs) in 2010, similar to what was estimated for 1990, except for HIV/AIDS and preterm birth complications. YLLs from lower respiratory infections and diarrhoea decreased by 45-54% since 1990; ischaemic heart disease and stroke YLLs increased by 17-28%. Regional variations in leading causes of death were substantial. Communicable, maternal, neonatal, and nutritional causes still accounted for 76% of premature mortality in sub-Saharan Africa in 2010. Age standardised death rates from some key disorders rose (HIV/AIDS, Alzheimer's disease, diabetes mellitus, and chronic kidney disease in particular), but for most diseases, death rates fell in the past two decades; including major vascular diseases, COPD, most forms of cancer, liver cirrhosis, and maternal disorders. For other conditions, notably malaria, prostate cancer, and injuries, little change was noted., Interpretation: Population growth, increased average age of the world's population, and largely decreasing age-specific, sex-specific, and cause-specific death rates combine to drive a broad shift from communicable, maternal, neonatal, and nutritional causes towards non-communicable diseases. Nevertheless, communicable, maternal, neonatal, and nutritional causes remain the dominant causes of YLLs in sub-Saharan Africa. Overlaid on this general pattern of the epidemiological transition, marked regional variation exists in many causes, such as interpersonal violence, suicide, liver cancer, diabetes, cirrhosis, Chagas disease, African trypanosomiasis, melanoma, and others. Regional heterogeneity highlights the importance of sound epidemiological assessments of the causes of death on a regular basis., Funding: Bill & Melinda Gates Foundation., (Copyright © 2012 Elsevier Ltd. All rights reserved.)