The genomes of Darwin's primroses reveal chromosome-scale adaptive introgression and differential permeability of species boundaries.

Introgression is an important source of genetic variation that can determine species adaptation to environmental conditions. Yet, definitive evidence of the genomic and adaptive implications of introgression in nature remains scarce. The widespread hybrid zones of Darwin's primroses (Primula elatior, Primula veris, and Primula vulgaris) provide a unique natural laboratory for studying introgression in flowering plants and the varying permeability of species boundaries. Through analysis of 650 genomes, we provide evidence of an introgressed genomic region likely to confer adaptive advantage in conditions of soil toxicity. We also document unequivocal evidence of chloroplast introgression, an important precursor to species-wide chloroplast capture. Finally, we provide the first evidence that the S-locus supergene, which controls heterostyly in primroses, does not introgress in this clade. Our results contribute novel insights into the adaptive role of introgression and demonstrate the importance of extensive genomic and geographical sampling for illuminating the complex nature of species boundaries.

Different molecular changes underlie the same phenotypic transition: Origins and consequences of independent shifts to homostyly within species.

The repeated transition from outcrossing to selfing is a key topic in evolutionary biology. However, the molecular basis of such shifts has been rarely examined due to lack of knowledge of the genes controlling these transitions. A classic example of mating system transition is the repeated shift from heterostyly to homostyly. Occurring in 28 angiosperm families, heterostyly is characterized by the reciprocal position of male and female sexual organs in two (or three) distinct, usually self-incompatible floral morphs. Conversely, homostyly is characterized by a single, self-compatible floral morph with reduced separation of male and female organs, facilitating selfing. Here, we investigate the origins of homostyly in Primula vulgaris and its microevolutionary consequences by integrating surveys of the frequency of homostyles in natural populations, DNA sequence analyses of the gene controlling the position of female sexual organs (CYPᵀ), and microsatellite genotyping of both progeny arrays and natural populations characterized by varying frequencies of homostyles. As expected, we found that homostyles displace short-styled individuals, but long-style morphs are maintained at low frequencies within populations. We also demonstrated that homostyles repeatedly evolved from short-styled individuals in association with different types of loss-of-function mutations in CYPᵀ. Additionally, homostyly triggers a shift to selfing, promoting increased inbreeding within and genetic differentiation among populations. Our results elucidate the causes and consequences of repeated transitions to homostyly within species, and the putative mechanisms precluding its fixation in P. vulgaris. This study represents a benchmark for future analyses of losses of heterostyly in other angiosperms.

Whole-genome analyses disentangle reticulate evolution of primroses in a biodiversity hotspot.

Biodiversity hotspots, such as the Caucasus mountains, provide unprecedented opportunities for understanding the evolutionary processes that shape species diversity and richness. Therefore, we investigated the evolution of Primula sect. Primula, a clade with a high degree of endemism in the Caucasus. We performed phylogenetic and network analyses of whole-genome resequencing data from the entire nuclear genome, the entire chloroplast genome, and the entire heterostyly supergene. The different characteristics of the genomic partitions and the resulting phylogenetic incongruences enabled us to disentangle evolutionary histories resulting from tokogenetic vs cladogenetic processes. We provide the first phylogeny inferred from the heterostyly supergene that includes all species of Primula sect. Primula. Our results identified recurrent admixture at deep nodes between lineages in the Caucasus as the cause of non-monophyly in Primula. Biogeographic analyses support the 'out-of-the-Caucasus' hypothesis, emphasizing the importance of this hotspot as a cradle for biodiversity. Our findings provide novel insights into causal processes of phylogenetic discordance, demonstrating that genome-wide analyses from partitions with contrasting genetic characteristics and broad geographic sampling are crucial for disentangling the diversification of species-rich clades in biodiversity hotspots.

Comparative transcriptomics reveals commonalities and differences in the genetic underpinnings of a floral dimorphism.

Distyly, a floral dimorphism associated with heteromorphic self-incompatibility and controlled by the S-locus supergene, evolved independently multiple times. Comparative analyses of the first transcriptome atlas for the main distyly model, Primula veris, with other distylous species produced the following findings. A set of 53 constitutively expressed genes in P. veris did not include any of the housekeeping genes commonly used to normalize gene expression in qPCR experiments. The S-locus gene CYPT acquired its role in controlling style elongation via a change in expression profile. Comparison of genes differentially expressed between floral morphs revealed that brassinosteroids and auxin are the main hormones controlling style elongation in P. veris and Fagopyrum esculentum, respectively. Furthermore, shared biochemical pathways might underlie the expression of distyly in the distantly related P. veris, F. esculentum and Turnera subulata, suggesting a degree of correspondence between evolutionary convergence at phenotypic and molecular levels. Finally, we provide the first evidence supporting the previously proposed hypothesis that distyly supergenes of distantly related species evolved via the recruitment of genes related to the phytochrome-interacting factor (PIF) signaling network. To conclude, this is the first study that discovered homologous genes involved in the control of distyly in distantly related taxa.

Trends and patterns of disparities in diabetes and chronic kidney disease mortality among US counties, 1980-2014.

INTRODUCTION: Diabetes and chronic kidney diseases are associated with a large health burden in the USA and globally. OBJECTIVE: To estimate age-standardized mortality rates by county from diabetes mellitus and chronic kidney disease. DESIGN AND SETTING: Validated small area estimation models were applied to de-identified death records from the National Center for Health Statistics (NCHS) and population counts from the census bureau, NCHS, and the Human Mortality Database to estimate county-level mortality rates from 1980 to 2014 from diabetes mellitus and chronic kidney disease (CKD). EXPOSURES: County of residence. MAIN OUTCOMES AND MEASURES: Age-standardized mortality rates by county, year, sex, and cause. RESULTS: Between 1980 and 2014, 2,067,805 deaths due to diabetes were recorded in the USA. The mortality rate due to diabetes increased by 33.6% (95% UI: 26.5%-41.3%) between 1980 and 2000 and then declined by 26.4% (95% UI: 22.8%-30.0%) between 2000 and 2014. Counties with very high mortality rates were found along the southern half of the Mississippi river and in parts of South and North Dakota, while very low rates were observed in central Colorado, and select counties in the Midwest, California, and southern Florida. A total of 1,659,045 deaths due to CKD were recorded between 1980 and 2014 (477,332 due to diabetes mellitus, 1,056,150 due to hypertension, 122,795 due to glomerulonephritis, and 2,768 due to other causes). CKD mortality varied among counties with very low mortality rates observed in central Colorado as well as some counties in southern Florida, California, and Great Plains states. High mortality rates from CKD were observed in counties throughout much of the Deep South, and a cluster of counties with particularly high rates was observed around the Mississippi river. CONCLUSIONS AND RELEVANCE: This study found large inequalities in diabetes and CKD mortality among US counties. The findings provide insights into the root causes of this variation and call for improvements in risk factors, access to medical care, and quality of medical care.

Rates of niche and phenotype evolution lag behind diversification in a temperate radiation.

Environmental change can create opportunities for increased rates of lineage diversification, but continued species accumulation has been hypothesized to lead to slowdowns via competitive exclusion and niche partitioning. Such density-dependent models imply tight linkages between diversification and trait evolution, but there are plausible alternative models. Little is known about the association between diversification and key ecological and phenotypic traits at broad phylogenetic and spatial scales. Do trait evolutionary rates coincide with rates of diversification, are there lags among these rates, or is diversification niche-neutral? To address these questions, we combine a deeply sampled phylogeny for a major flowering plant clade-Saxifragales-with phenotype and niche data to examine temporal patterns of evolutionary rates. The considerable phenotypic and habitat diversity of Saxifragales is greatest in temperate biomes. Global expansion of these habitats since the mid-Miocene provided ecological opportunities that, with density-dependent adaptive radiation, should result in simultaneous rate increases for diversification, niche, and phenotype, followed by decreases with habitat saturation. Instead, we find that these rates have significantly different timings, with increases in diversification occurring at the mid-Miocene Climatic Optimum (∼15 Mya), followed by increases in niche and phenotypic evolutionary rates by ∼5 Mya; all rates increase exponentially to the present. We attribute this surprising lack of temporal coincidence to initial niche-neutral diversification followed by ecological and phenotypic divergence coincident with more extreme cold and dry habitats that proliferated into the Pleistocene. A lack of density-dependence contrasts with investigations of other cosmopolitan lineages, suggesting alternative patterns may be common in the diversification of temperate lineages.

A Phylogenomic Perspective on Evolution and Discordance in the Alpine-Arctic Plant Clade Micranthes (Saxifragaceae).

The increased availability of large phylogenomic datasets is often accompanied by difficulties in disentangling and harnessing the data. These difficulties may be enhanced for species resulting from reticulate evolution and/or rapid radiations producing large-scale discordance. As a result, there is a need for methods to investigate discordance, and in turn, use this conflict to inform and aid in downstream analyses. Therefore, we drew upon multiple analytical tools to investigate the evolution of Micranthes (Saxifragaceae), a clade of primarily arctic-alpine herbs impacted by reticulate and rapid radiations. To elucidate the evolution of Micranthes we sought near-complete taxon sampling with multiple accessions per species and assembled extensive nuclear (518 putatively single copy loci) and plastid (95 loci) datasets. In addition to a robust phylogeny for Micranthes, this research shows that genetic discordance presents a valuable opportunity to develop hypotheses about its underlying causes, such as hybridization, polyploidization, and range shifts. Specifically, we present a multi-step approach that incorporates multiple checks points for paralogy, including reciprocally blasting targeted genes against transcriptomes, running paralogy checks during the assembly step, and grouping genes into gene families to look for duplications. We demonstrate that a thorough assessment of discordance can be a source of evidence for evolutionary processes that were not adequately captured by a bifurcating tree model, and helped to clarify processes that have structured the evolution of Micranthes.

Progress toward eliminating TB and HIV deaths in Brazil, 2001-2015: a spatial assessment.

BACKGROUND: Brazil has high burdens of tuberculosis (TB) and HIV, as previously estimated for the 26 states and the Federal District, as well as high levels of inequality in social and health indicators. We improved the geographic detail of burden estimation by modelling deaths due to TB and HIV and TB case fatality ratios for the more than 5400 municipalities in Brazil. METHODS: This ecological study used vital registration data from the national mortality information system and TB case notifications from the national communicable disease notification system from 2001 to 2015. Mortality due to TB and HIV was modelled separately by cause and sex using a Bayesian spatially explicit mixed effects regression model. TB incidence was modelled using the same approach. Results were calibrated to the Global Burden of Disease Study 2016. Case fatality ratios were calculated for TB. RESULTS: There was substantial inequality in TB and HIV mortality rates within the nation and within states. National-level TB mortality in people without HIV infection declined by nearly 50% during 2001 to 2015, but HIV mortality declined by just over 20% for males and 10% for females. TB and HIV mortality rates for municipalities in the 90th percentile nationally were more than three times rates in the 10th percentile, with nearly 70% of the worst-performing municipalities for male TB mortality and more than 75% for female mortality in 2001 also in the worst decile in 2015. The same municipality ranking metric for HIV was observed to be between 55% and 61%. Within states, the TB mortality rate ratios by sex for municipalities in the worst decile versus the best decile varied from 1.4 to 2.9, and HIV varied from 1.4 to 4.2. The World Health Organization target case fatality rate for TB of less than 10% was achieved in 9.6% of municipalities for males versus 38.4% for females in 2001 and improved to 38.4% and 56.6% of municipalities for males versus females, respectively, by 2014. CONCLUSIONS: Mortality rates in municipalities within the same state exhibited nearly as much relative variation as within the nation as a whole. Monitoring the mortality burden at this level of geographic detail is critical for guiding precision public health responses.

The future of cold-adapted plants in changing climates: Micranthes (Saxifragaceae) as a case study.

Research has shown species undergoing range contractions and/or northward and higher elevational movements as a result of changing climates. Here, we evaluate how the distribution of a group of cold-adapted plant species with similar evolutionary histories changes in response to warming climates. We selected 29 species of Micranthes (Saxifragaceae) representing the mountain and Arctic biomes of the Northern Hemisphere. For this analysis, 24,755 data points were input into ecological niche models to assess both present fundamental niches and predicted future ranges under climate change scenarios. Comparisons were made across the Northern Hemisphere between all cold-adapted Micranthes, including Arctic species, montane species, and species defined as narrow endemics. Under future climate change models, 72% of the species would occupy smaller geographical areas than at present. This loss of habitat is most pronounced in Arctic species in general, but is also prevalent in species restricted to higher elevations in mountains. Additionally, narrowly endemic species restricted to high elevations were more susceptible to habitat loss than those species found at lower elevations. Using a large dataset and modeling habitat suitability at a global scale, our results empirically model the threats to cold-adapted species as a result of warming climates. Although Arctic and alpine biomes share many underlying climate similarities, such as cold and short growing seasons, our results confirm that species in these climates have varied responses to climate change and that key abiotic variables differ between these two habitats.

Trends and Patterns of Geographic Variation in Mortality From Substance Use Disorders and Intentional Injuries Among US Counties, 1980-2014.

Importance: Substance use disorders, including alcohol use disorders and drug use disorders, and intentional injuries, including self-harm and interpersonal violence, are important causes of early death and disability in the United States. Objective: To estimate age-standardized mortality rates by county from alcohol use disorders, drug use disorders, self-harm, and interpersonal violence in the United States. Design and Setting: Validated small-area estimation models were applied to deidentified death records from the National Center for Health Statistics (NCHS) and population counts from the US Census Bureau, NCHS, and the Human Mortality Database to estimate county-level mortality rates from 1980 to 2014 for alcohol use disorders, drug use disorders, self-harm, and interpersonal violence. Exposures: County of residence. Main Outcomes and Measures: Age-standardized mortality rates by US county (N = 3110), year, sex, and cause. Results: Between 1980 and 2014, there were 2 848 768 deaths due to substance use disorders and intentional injuries recorded in the United States. Mortality rates from alcohol use disorders (n = 256 432), drug use disorders (n = 542 501), self-harm (n = 1 289 086), and interpersonal violence (n = 760 749) varied widely among counties. Mortality rates decreased for alcohol use disorders, self-harm, and interpersonal violence at the national level between 1980 and 2014; however, over the same period, the percentage of counties in which mortality rates increased for these causes was 65.4% for alcohol use disorders, 74.6% for self-harm, and 6.6% for interpersonal violence. Mortality rates from drug use disorders increased nationally and in every county between 1980 and 2014, but the relative increase varied from 8.2% to 8369.7%. Relative and absolute geographic inequalities in mortality, as measured by comparing the 90th and 10th percentile among counties, decreased for alcohol use disorders and interpersonal violence but increased substantially for drug use disorders and self-harm between 1980 and 2014. Conclusions and Relevance: Mortality due to alcohol use disorders, drug use disorders, self-harm, and interpersonal violence varied widely among US counties, both in terms of levels of mortality and trends. These estimates may be useful to inform efforts to target prevention, diagnosis, and treatment to improve health and reduce inequalities.

Pseudo-parallel patterns of disjunctions in an Arctic-alpine plant lineage.

Disjunct distributions have intrigued biologists for centuries. Investigating these biogeographic patterns provides insight into speciation and biodiversity at multiple spatial and phylogenetic scales. Some disjunctions have been intensively studied, yet others have been largely overlooked and remain poorly understood. Among the lesser-known disjunction patterns is that between the mountain ranges of western North America. Flora and fauna endemic to the mountains of this region provide important systems for investigating causes and results of disjunctions, given the relatively recent geological formation of this area and the intense climatic fluctuations that have occurred since its formation. In Micranthes (Saxifragaceae), which has high rates of montane endemism, two species, M. bryophora and M. tolmiei, show this biogeographical pattern. By reconstructing a time-calibrated phylogeny based on 518 low-copy nuclear markers and including multiple populations of each species from the Coast Ranges, Cascades, Sierra Nevada, and Rocky Mountains, this study provides a biogeographical and temporal framework for the evolution of Micranthes in western North America. Strongly supported east-west differentiated clades are recovered for M. bryophora and M. tolmiei in both maximum likelihood and coalescent-based species tree reconstructions. Biogeographic analysis suggests different patterns of dispersal for both taxa and the dating analyses recovered contrasting ages for each clade. Due to both the different geographic patterns and the timing of the initial diversification of each taxon corresponding to different geologic and climatic events, the disjunction patterns shown for these taxa are suggested to be an example of biogeographical pseudocongruence.

Mapping local variation in educational attainment across Africa.

Educational attainment for women of reproductive age is linked to reduced child and maternal mortality, lower fertility and improved reproductive health. Comparable analyses of attainment exist only at the national level, potentially obscuring patterns in subnational inequality. Evidence suggests that wide disparities between urban and rural populations exist, raising questions about where the majority of progress towards the education targets of the Sustainable Development Goals is occurring in African countries. Here we explore within-country inequalities by predicting years of schooling across five by five kilometre grids, generating estimates of average educational attainment by age and sex at subnational levels. Despite marked progress in attainment from 2000 to 2015 across Africa, substantial differences persist between locations and sexes. These differences have widened in many countries, particularly across the Sahel. These high-resolution, comparable estimates improve the ability of decision-makers to plan the precisely targeted interventions that will be necessary to deliver progress during the era of the Sustainable Development Goals.

Mapping child growth failure in Africa between 2000 and 2015.

Insufficient growth during childhood is associated with poor health outcomes and an increased risk of death. Between 2000 and 2015, nearly all African countries demonstrated improvements for children under 5 years old for stunting, wasting, and underweight, the core components of child growth failure. Here we show that striking subnational heterogeneity in levels and trends of child growth remains. If current rates of progress are sustained, many areas of Africa will meet the World Health Organization Global Targets 2025 to improve maternal, infant and young child nutrition, but high levels of growth failure will persist across the Sahel. At these rates, much, if not all of the continent will fail to meet the Sustainable Development Goal target-to end malnutrition by 2030. Geospatial estimates of child growth failure provide a baseline for measuring progress as well as a precision public health platform to target interventions to those populations with the greatest need, in order to reduce health disparities and accelerate progress.

Trends and Patterns of Differences in Infectious Disease Mortality Among US Counties, 1980-2014.

Importance: Infectious diseases are mostly preventable but still pose a public health threat in the United States, where estimates of infectious diseases mortality are not available at the county level. Objective: To estimate age-standardized mortality rates and trends by county from 1980 to 2014 from lower respiratory infections, diarrheal diseases, HIV/AIDS, meningitis, hepatitis, and tuberculosis. Design and Setting: This study used deidentified death records from the National Center for Health Statistics (NCHS) and population counts from the US Census Bureau, NCHS, and the Human Mortality Database. Validated small-area estimation models were applied to these data to estimate county-level infectious disease mortality rates. Exposures: County of residence. Main Outcomes and Measures: Age-standardized mortality rates of lower respiratory infections, diarrheal diseases, HIV/AIDS, meningitis, hepatitis, and tuberculosis by county, year, and sex. Results: Between 1980 and 2014, there were 4 081 546 deaths due to infectious diseases recorded in the United States. In 2014, a total of 113 650 (95% uncertainty interval [UI], 108 764-117 942) deaths or a rate of 34.10 (95% UI, 32.63-35.38) deaths per 100 000 persons were due to infectious diseases in the United States compared to a total of 72 220 (95% UI, 69 887-74 712) deaths or a rate of 41.95 (95% UI, 40.52-43.42) deaths per 100 000 persons in 1980, an overall decrease of 18.73% (95% UI, 14.95%-23.33%). Lower respiratory infections were the leading cause of infectious diseases mortality in 2014 accounting for 26.87 (95% UI, 25.79-28.05) deaths per 100 000 persons (78.80% of total infectious diseases deaths). There were substantial differences among counties in death rates from all infectious diseases. Lower respiratory infection had the largest absolute mortality inequality among counties (difference between the 10th and 90th percentile of the distribution, 24.5 deaths per 100 000 persons). However, HIV/AIDS had the highest relative mortality inequality between counties (10.0 as the ratio of mortality rate in the 90th and 10th percentile of the distribution). Mortality from meningitis and tuberculosis decreased over the study period in all US counties. However, diarrheal diseases were the only cause of infectious diseases mortality to increase from 2000 to 2014, reaching a rate of 2.41 (95% UI, 0.86-2.67) deaths per 100 000 persons, with many counties of high mortality extending from Missouri to the northeastern region of the United States. Conclusions and Relevance: Between 1980 and 2014, there were declines in mortality from most categories of infectious diseases, with large differences among US counties. However, over this time there was an increase in mortality for diarrheal diseases.

Variation in life expectancy and mortality by cause among neighbourhoods in King County, WA, USA, 1990-2014: a census tract-level analysis for the Global Burden of Disease Study 2015.

BACKGROUND: Health outcomes are known to vary at both the country and local levels, but trends in mortality across a detailed and comprehensive set of causes have not been previously described at a very local level. Life expectancy in King County, WA, USA, is in the 95th percentile among all counties in the USA. However, little is known about how life expectancy and mortality from different causes of death vary at a local, neighbourhood level within this county. In this analysis, we estimated life expectancy and cause-specific mortality within King County to describe spatial trends, quantify disparities in mortality, and assess the contribution of each cause of death to overall disparities in all-cause mortality. METHODS: We applied established so-called garbage code redistribution algorithms and small area estimation methods to death registration data for King County to estimate life expectancy, cause-specific mortality rates, and years of life lost (YLL) rates from 152 causes of death for 397 census tracts from Jan 1, 1990, to Dec 31, 2014. We used the cause list developed for the Global Burden of Disease 2015 study for this analysis. Deaths were tabulated by age group, sex, census tract, and cause of death. We used Bayesian mixed-effects regression models to estimate mortality overall and from each cause. FINDINGS: Between 1990 and 2014, life expectancy in King County increased by 5·4 years (95% uncertainty interval [UI] 5·0-5·7) among men (from 74·0 years [73·7-74·3] to 79·3 years [79·1-79·6]) and by 3·4 years (3·0-3·7) among women (from 80·0 years [79·7-80·2] to 83·3 years [83·1-83·5]). In 2014, life expectancy ranged from 68·4 years (95% UI 66·9-70·1) to 86·7 years (85·0-88·2) for men and from 73·6 years (71·6-75·5) to 88·4 years (86·9-89·9) for women among census tracts within King County. Rates of YLL by cause also varied substantially among census tracts for each cause of death. Geographical areas with relatively high and relatively low YLL rates differed by cause. In general, causes of death responsible for more YLLs overall also contributed more significantly to geographical inequality within King County. However, certain causes contributed more to inequality than to overall YLLs. INTERPRETATION: This census tract-level analysis of life expectancy and cause-specific YLL rates highlights important differences in health among neighbourhoods in King County that are masked by county-level estimates. Efforts to improve population health in King County should focus on reducing geographical inequality, by targeting those health conditions that contribute the most to overall YLLs and to inequality. This analysis should be replicated in other locations to more fully describe fine-grained local-level variation in population health and contribute to efforts to improve health while reducing inequalities. FUNDING: John W Stanton and Theresa E Gillespie.

Trends and Patterns of Differences in Chronic Respiratory Disease Mortality Among US Counties, 1980-2014.

Importance: Chronic respiratory diseases are an important cause of death and disability in the United States. Objective: To estimate age-standardized mortality rates by county from chronic respiratory diseases. Design, Setting, and Participants: Validated small area estimation models were applied to deidentified death records from the National Center for Health Statistics and population counts from the US Census Bureau, National Center for Health Statistics, and Human Mortality Database to estimate county-level mortality rates from 1980 to 2014 for chronic respiratory diseases. Exposure: County of residence. Main Outcomes and Measures: Age-standardized mortality rates by county, year, sex, and cause. Results: A total of 4 616 711 deaths due to chronic respiratory diseases were recorded in the United States from January 1, 1980, through December 31, 2014. Nationally, the mortality rate from chronic respiratory diseases increased from 40.8 (95% uncertainty interval [UI], 39.8-41.8) deaths per 100 000 population in 1980 to a peak of 55.4 (95% UI, 54.1-56.5) deaths per 100 000 population in 2002 and then declined to 52.9 (95% UI, 51.6-54.4) deaths per 100 000 population in 2014. This overall 29.7% (95% UI, 25.5%-33.8%) increase in chronic respiratory disease mortality from 1980 to 2014 reflected increases in the mortality rate from chronic obstructive pulmonary disease (by 30.8% [95% UI, 25.2%-39.0%], from 34.5 [95% UI, 33.0-35.5] to 45.1 [95% UI, 43.7-46.9] deaths per 100 000 population), interstitial lung disease and pulmonary sarcoidosis (by 100.5% [95% UI, 5.8%-155.2%], from 2.7 [95% UI, 2.3-4.2] to 5.5 [95% UI, 3.5-6.1] deaths per 100 000 population), and all other chronic respiratory diseases (by 42.3% [95% UI, 32.4%-63.8%], from 0.51 [95% UI, 0.48-0.54] to 0.73 [95% UI, 0.69-0.78] deaths per 100 000 population). There were substantial differences in mortality rates and changes in mortality rates over time among counties, and geographic patterns differed by cause. Counties with the highest mortality rates were found primarily in central Appalachia for chronic obstructive pulmonary disease and pneumoconiosis; widely dispersed throughout the Southwest, northern Great Plains, New England, and South Atlantic for interstitial lung disease; along the southern half of the Mississippi River and in Georgia and South Carolina for asthma; and in southern states from Mississippi to South Carolina for other chronic respiratory diseases. Conclusions and Relevance: Despite recent declines in mortality from chronic respiratory diseases, mortality rates in 2014 remained significantly higher than in 1980. Between 1980 and 2014, there were important differences in mortality rates and changes in mortality by county, sex, and particular chronic respiratory disease type. These estimates may be helpful for informing efforts to improve prevention, diagnosis, and treatment.

Inequalities in Life Expectancy Among US Counties, 1980 to 2014: Temporal Trends and Key Drivers.

Importance: Examining life expectancy by county allows for tracking geographic disparities over time and assessing factors related to these disparities. This information is potentially useful for policy makers, clinicians, and researchers seeking to reduce disparities and increase longevity. Objective: To estimate annual life tables by county from 1980 to 2014; describe trends in geographic inequalities in life expectancy and age-specific risk of death; and assess the proportion of variation in life expectancy explained by variation in socioeconomic and race/ethnicity factors, behavioral and metabolic risk factors, and health care factors. Design, Setting, and Participants: Annual county-level life tables were constructed using small area estimation methods from deidentified death records from the National Center for Health Statistics (NCHS), and population counts from the US Census Bureau, NCHS, and the Human Mortality Database. Measures of geographic inequality in life expectancy and age-specific mortality risk were calculated. Principal component analysis and ordinary least squares regression were used to examine the county-level association between life expectancy and socioeconomic and race/ethnicity factors, behavioral and metabolic risk factors, and health care factors. Exposures: County of residence. Main Outcomes and Measures: Life expectancy at birth and age-specific mortality risk. Results: Counties were combined as needed to create stable units of analysis over the period 1980 to 2014, reducing the number of areas analyzed from 3142 to 3110. In 2014, life expectancy at birth for both sexes combined was 79.1 (95% uncertainty interval [UI], 79.0-79.1) years overall, but differed by 20.1 (95% UI, 19.1-21.3) years between the counties with the lowest and highest life expectancy. Absolute geographic inequality in life expectancy increased between 1980 and 2014. Over the same period, absolute geographic inequality in the risk of death decreased among children and adolescents, but increased among older adults. Socioeconomic and race/ethnicity factors, behavioral and metabolic risk factors, and health care factors explained 60%, 74%, and 27% of county-level variation in life expectancy, respectively. Combined, these factors explained 74% of this variation. Most of the association between socioeconomic and race/ethnicity factors and life expectancy was mediated through behavioral and metabolic risk factors. Conclusions and Relevance: Geographic disparities in life expectancy among US counties are large and increasing. Much of the variation in life expectancy among counties can be explained by a combination of socioeconomic and race/ethnicity factors, behavioral and metabolic risk factors, and health care factors. Policy action targeting socioeconomic factors and behavioral and metabolic risk factors may help reverse the trend of increasing disparities in life expectancy in the United States.

Trends and Patterns of Geographic Variation in Cardiovascular Mortality Among US Counties, 1980-2014.

IMPORTANCE: In the United States, regional variation in cardiovascular mortality is well-known but county-level estimates for all major cardiovascular conditions have not been produced. OBJECTIVE: To estimate age-standardized mortality rates from cardiovascular diseases by county. DESIGN AND SETTING: Deidentified death records from the National Center for Health Statistics and population counts from the US Census Bureau, the National Center for Health Statistics, and the Human Mortality Database from 1980 through 2014 were used. Validated small area estimation models were used to estimate county-level mortality rates from all cardiovascular diseases, including ischemic heart disease, cerebrovascular disease, ischemic stroke, hemorrhagic stroke, hypertensive heart disease, cardiomyopathy, atrial fibrillation and flutter, rheumatic heart disease, aortic aneurysm, peripheral arterial disease, endocarditis, and all other cardiovascular diseases combined. EXPOSURES: The 3110 counties of residence. MAIN OUTCOMES AND MEASURES: Age-standardized cardiovascular disease mortality rates by county, year, sex, and cause. RESULTS: From 1980 to 2014, cardiovascular diseases were the leading cause of death in the United States, although the mortality rate declined from 507.4 deaths per 100 000 persons in 1980 to 252.7 deaths per 100 000 persons in 2014, a relative decline of 50.2% (95% uncertainty interval [UI], 49.5%-50.8%). In 2014, cardiovascular diseases accounted for more than 846 000 deaths (95% UI, 827-865 thousand deaths) and 11.7 million years of life lost (95% UI, 11.6-11.9 million years of life lost). The gap in age-standardized cardiovascular disease mortality rates between counties at the 10th and 90th percentile declined 14.6% from 172.1 deaths per 100 000 persons in 1980 to 147.0 deaths per 100 000 persons in 2014 (posterior probability of decline >99.9%). In 2014, the ratio between counties at the 90th and 10th percentile was 2.0 for ischemic heart disease (119.1 vs 235.7 deaths per 100 000 persons) and 1.7 for cerebrovascular disease (40.3 vs 68.1 deaths per 100 000 persons). For other cardiovascular disease causes, the ratio ranged from 1.4 (aortic aneurysm: 3.5 vs 5.1 deaths per 100 000 persons) to 4.2 (hypertensive heart disease: 4.3 vs 17.9 deaths per 100 000 persons). The largest concentration of counties with high cardiovascular disease mortality extended from southeastern Oklahoma along the Mississippi River Valley to eastern Kentucky. Several cardiovascular disease conditions were clustered substantially outside the South, including atrial fibrillation (Northwest), aortic aneurysm (Midwest), and endocarditis (Mountain West and Alaska). The lowest cardiovascular mortality rates were found in the counties surrounding San Francisco, California, central Colorado, northern Nebraska, central Minnesota, northeastern Virginia, and southern Florida. CONCLUSIONS AND RELEVANCE: Substantial differences exist between county ischemic heart disease and stroke mortality rates. Smaller differences exist for diseases of the myocardium, atrial fibrillation, aortic and peripheral arterial disease, rheumatic heart disease, and endocarditis.

Trends and Patterns of Disparities in Cancer Mortality Among US Counties, 1980-2014.

Introduction: Cancer is a leading cause of morbidity and mortality in the United States and results in a high economic burden. Objective: To estimate age-standardized mortality rates by US county from 29 cancers. Design and Setting: Deidentified death records from the National Center for Health Statistics (NCHS) and population counts from the Census Bureau, the NCHS, and the Human Mortality Database from 1980 to 2014 were used. Validated small area estimation models were used to estimate county-level mortality rates from 29 cancers: lip and oral cavity; nasopharynx; other pharynx; esophageal; stomach; colon and rectum; liver; gallbladder and biliary; pancreatic; larynx; tracheal, bronchus, and lung; malignant skin melanoma; nonmelanoma skin cancer; breast; cervical; uterine; ovarian; prostate; testicular; kidney; bladder; brain and nervous system; thyroid; mesothelioma; Hodgkin lymphoma; non-Hodgkin lymphoma; multiple myeloma; leukemia; and all other cancers combined. Exposure: County of residence. Main Outcomes and Measures: Age-standardized cancer mortality rates by county, year, sex, and cancer type. Results: A total of 19 511 910 cancer deaths were recorded in the United States between 1980 and 2014, including 5 656 423 due to tracheal, bronchus, and lung cancer; 2 484 476 due to colon and rectum cancer; 1 573 593 due to breast cancer; 1 077 030 due to prostate cancer; 1 157 878 due to pancreatic cancer; 209 314 due to uterine cancer; 421 628 due to kidney cancer; 487 518 due to liver cancer; 13 927 due to testicular cancer; and 829 396 due to non-Hodgkin lymphoma. Cancer mortality decreased by 20.1% (95% uncertainty interval [UI], 18.2%-21.4%) between 1980 and 2014, from 240.2 (95% UI, 235.8-244.1) to 192.0 (95% UI, 188.6-197.7) deaths per 100 000 population. There were large differences in the mortality rate among counties throughout the period: in 1980, cancer mortality ranged from 130.6 (95% UI, 114.7-146.0) per 100 000 population in Summit County, Colorado, to 386.9 (95% UI, 330.5-450.7) in North Slope Borough, Alaska, and in 2014 from 70.7 (95% UI, 63.2-79.0) in Summit County, Colorado, to 503.1 (95% UI, 464.9-545.4) in Union County, Florida. For many cancers, there were distinct clusters of counties with especially high mortality. The location of these clusters varied by type of cancer and were spread in different regions of the United States. Clusters of breast cancer were present in the southern belt and along the Mississippi River, while liver cancer was high along the Texas-Mexico border, and clusters of kidney cancer were observed in North and South Dakota and counties in West Virginia, Ohio, Indiana, Louisiana, Oklahoma, Texas, Alaska, and Illinois. Conclusions and Relevance: Cancer mortality declined overall in the United States between 1980 and 2014. Over this same period, there were important changes in trends, patterns, and differences in cancer mortality among US counties. These patterns may inform further research into improving prevention and treatment.

Distance to health services modifies the effect of an 11-valent pneumococcal vaccine on pneumonia risk among children less than 2 years of age in Bohol, Philippines.

Background: Both vaccine trials and surveillance studies typically use passive surveillance systems to monitor study outcomes, which may lead to under-reporting of study outcomes in areas with poor access to care. This detection bias can have an adverse effect on conventional estimates of pneumonia risk derived from vaccine trials. Methods: We conducted a secondary analysis of a randomized, placebo-controlled, double-blind vaccine trial that examined the efficacy of an 11-valent pneumococcal vaccine (PCV) among children less than 2 years of age in Bohol, Philippines. Trial data were linked to the residential location of each participant using a geographical information system. The study was conducted using 11 729 children who received three doses of any study vaccine (PCV11) or placebo. Multivariate Cox proportional hazards models were used to examine major risk factors for pneumonia diagnosis and the relationship between distance to Bohol Regional Hospital (BRH) and vaccination with PCV with risk for pneumonia diagnosis. Results: There was a significant interaction effect between distance from BRH and vaccination with PCV11 on pneumonia risk. Among children living 12 km from BRH, vaccination with PCV11 was associated with a decreased hazard ratio for radiographic pneumonia, compared with vaccination with the study placebo [0.57, 95% confidence interval (CI) 0.37-0.86). However, for children living 1 km from BRH, there was little difference in risk of radiographic pneumonia diagnosis between children vaccinated with PCV11 and those given the study placebo. Conclusion: Children living close to BRH had no documented reduction in the primary study outcome from PCV11, whereas those at greater distance experienced a substantial reduction. Because of detection bias caused by distance to BRH, in spatial analysis of vaccine trial results it may be necessary to adjust estimates of pneumonia risk and vaccine efficacy. Failure to consider the geographical dimension of trials may lead to underestimates of efficacy which might influence public health planning efforts.