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Background Estimating the health effects of multi-pollutant mixtures is of increasing interest in environmental epidemiology. Recently, a new approach for estimating the health effects of mixtures, Bayesian kernel machine regression (BKMR), has been developed. This method estimates the multivariable exposure-response function in a flexible and parsimonious way, conducts variable selection on the (potentially high-dimensional) vector of exposures, and allows for a grouped variable selection approach that can accommodate highly correlated exposures. However, the application of this novel method has been limited by a lack of available software, the need to derive interpretable output in a computationally efficient manner, and the inability to apply the method to non-continuous outcome variables. Methods This paper addresses these limitations by (i) introducing an open-source software package in the R programming language, the bkmr R package, (ii) demonstrating methods for visualizing high-dimensional exposure-response functions, and for estimating scientifically relevant summaries, (iii) illustrating a probit regression implementation of BKMR for binary outcomes, and (iv) describing a fast version of BKMR that utilizes a Gaussian predictive process approach. All of the methods are illustrated using fully reproducible examples with the provided R code. Results Applying the methods to a continuous outcome example illustrated the ability of the BKMR implementation to estimate the health effects of multi-pollutant mixtures in the context of a highly nonlinear, biologically-based dose-response function, and to estimate overall, single-exposure, and interactive health effects. The Gaussian predictive process method led to a substantial reduction in the runtime, without a major decrease in accuracy. In the setting of a larger number of exposures and a dichotomous outcome, the probit BKMR implementation was able to correctly identify the variables included in the exposure-response function and yielded interpretable quantities on the scale of a latent continuous outcome or on the scale of the outcome probability. Conclusions This newly developed software, integrated suite of tools, and extended methodology makes BKMR accessible for use across a broad range of epidemiological applications in which multiple risk factors have complex effects on health.

Prior research suggests that United States governmental sources documenting the number of law-enforcement-related deaths (i.e., fatalities due to injuries inflicted by law enforcement officers) undercount these incidents. The National Vital Statistics System (NVSS), administered by the federal government and based on state death certificate data, identifies such deaths by assigning them diagnostic codes corresponding to \"legal intervention\" in accordance with the International Classification of Diseases-10th Revision (ICD-10). Newer, nongovernmental databases track law-enforcement-related deaths by compiling news media reports and provide an opportunity to assess the magnitude and determinants of suspected NVSS underreporting. Our a priori hypotheses were that underreporting by the NVSS would exceed that by the news media sources, and that underreporting rates would be higher for decedents of color versus white, decedents in lower versus higher income counties, decedents killed by non-firearm (e.g., Taser) versus firearm mechanisms, and deaths recorded by a medical examiner versus coroner. We created a new US-wide dataset by matching cases reported in a nongovernmental, news-media-based dataset produced by the newspaper The Guardian, The Counted, to identifiable NVSS mortality records for 2015. We conducted 2 main analyses for this cross-sectional study: (1) an estimate of the total number of deaths and the proportion unreported by each source using capture-recapture analysis and (2) an assessment of correlates of underreporting of law-enforcement-related deaths (demographic characteristics of the decedent, mechanism of death, death investigator type [medical examiner versus coroner], county median income, and county urbanicity) in the NVSS using multilevel logistic regression. We estimated that the total number of law-enforcement-related deaths in 2015 was 1,166 (95% CI: 1,153, 1,184). There were 599 deaths reported in The Counted only, 36 reported in the NVSS only, 487 reported in both lists, and an estimated 44 (95% CI: 31, 62) not reported in either source. The NVSS documented 44.9% (95% CI: 44.2%, 45.4%) of the total number of deaths, and The Counted documented 93.1% (95% CI: 91.7%, 94.2%). In a multivariable mixed-effects logistic model that controlled for all individual- and county-level covariates, decedents injured by non-firearm mechanisms had higher odds of underreporting in the NVSS than those injured by firearms (odds ratio [OR]: 68.2; 95% CI: 15.7, 297.5; p < 0.01), and underreporting was also more likely outside of the highest-income-quintile counties (OR for the lowest versus highest income quintile: 10.1; 95% CI: 2.4, 42.8; p < 0.01). There was no statistically significant difference in the odds of underreporting in the NVSS for deaths certified by coroners compared to medical examiners, and the odds of underreporting did not vary by race/ethnicity. One limitation of our analyses is that we were unable to examine the characteristics of cases that were unreported in The Counted. The media-based source, The Counted, reported a considerably higher proportion of law-enforcement-related deaths than the NVSS, which failed to report a majority of these incidents. For the NVSS, rates of underreporting were higher in lower income counties and for decedents killed by non-firearm mechanisms. There was no evidence suggesting that underreporting varied by death investigator type (medical examiner versus coroner) or race/ethnicity.

Many studies have reported significant associations between exposure to PM(2.5) and hospital admissions, but all have focused on the effects of short-term exposure. In addition all these studies have relied on a limited number of PM(2.5) monitors in their study regions, which introduces exposure error, and excludes rural and suburban populations from locations in which monitors are not available, reducing generalizability and potentially creating selection bias. Using our novel prediction models for exposure combining land use regression with physical measurements (satellite aerosol optical depth) we investigated both the long and short term effects of PM(2.5) exposures on hospital admissions across New-England for all residents aged 65 and older. We performed separate Poisson regression analysis for each admission type: all respiratory, cardiovascular disease (CVD), stroke and diabetes. Daily admission counts in each zip code were regressed against long and short-term PM(2.5) exposure, temperature, socio-economic data and a spline of time to control for seasonal trends in baseline risk. We observed associations between both short-term and long-term exposure to PM(2.5) and hospitalization for all of the outcomes examined. In example, for respiratory diseases, for every 10-µg/m(3) increase in short-term PM(2.5) exposure there is a 0.70 percent increase in admissions (CI = 0.35 to 0.52) while concurrently for every 10-µg/m(3) increase in long-term PM(2.5) exposure there is a 4.22 percent increase in admissions (CI = 1.06 to 4.75). As with mortality studies, chronic exposure to particles is associated with substantially larger increases in hospital admissions than acute exposure and both can be detected simultaneously using our exposure models.

Both short- and long-term exposures to fine particulate matter (≤ 2.5 μm; PM2.5) are associated with mortality. However, whether the associations exist at levels below the new U.S. Environmental Protection Agency (EPA) standards (12 μg/m3 of annual average PM2.5, 35 μg/m3 daily) is unclear. In addition, it is not clear whether results from previous time series studies (fit in larger cities) and cohort studies (fit in convenience samples) are generalizable. We estimated the effects of low-concentration PM2.5 on mortality. High resolution (1 km × 1 km) daily PM2.5 predictions, derived from satellite aerosol optical depth retrievals, were used. Poisson regressions were applied to a Medicare population (≥ 65 years of age) in New England to simultaneously estimate the acute and chronic effects of exposure to PM2.5, with mutual adjustment for short- and long-term exposure, as well as for area-based confounders. Models were also restricted to annual concentrations < 10 μg/m3 or daily concentrations < 30 μg/m3. PM2.5 was associated with increased mortality. In the study cohort, 2.14% (95% CI: 1.38, 2.89%) and 7.52% (95% CI: 1.95, 13.40%) increases were estimated for each 10-μg/m3 increase in short- (2 day) and long-term (1 year) exposure, respectively. The associations held for analyses restricted to low-concentration PM2.5 exposure, and the corresponding estimates were 2.14% (95% CI: 1.34, 2.95%) and 9.28% (95% CI: 0.76, 18.52%). Penalized spline models of long-term exposure indicated a larger effect for mortality in association with exposures ≥ 6 μg/m3 versus those < 6 μg/m3. In contrast, the association between short-term exposure and mortality appeared to be linear across the entire exposure distribution. Using a mutually adjusted model, we estimated significant acute and chronic effects of PM2.5 exposure below the current U.S. EPA standards. These findings suggest that improving air quality with even lower PM2.5 than currently allowed by U.S. EPA standards may benefit public health. Shi L, Zanobetti A, Kloog I, Coull BA, Koutrakis P, Melly SJ, Schwartz JD. 2016. Low-concentration PM2.5 and mortality: estimating acute and chronic effects in a population-based study. Environ Health Perspect 124:46-52; http://dx.doi.org/10.1289/ehp.1409111.

Background Numerous methods exist to analyze complex environmental mixtures in health studies. As an illustration of the different uses of mixture methods, we employed methods geared toward distinct research questions concerning persistent organic chemicals (POPs) as a mixture and leukocyte telomere length (LTL) as an outcome. Methods With information on 18 POPs and LTL among 1,003 U.S. adults (NHANES, 2001–2002), we used unsupervised methods including clustering to identify profiles of similarly exposed participants, and Principal Component Analysis (PCA) and Exploratory Factor Analysis (EFA) to identify common exposure patterns. We also employed supervised learning techniques, including penalized, weighted quantile sum (WQS), and Bayesian kernel machine (BKMR) regressions, to identify potentially toxic agents, and characterize nonlinear associations, interactions, and the overall mixture effect. Results Clustering separated participants into high, medium, and low POP exposure groups; longer log-LTL was found among those with high exposure. The first PCA component represented overall POP exposure and was positively associated with log-LTL. Two EFA factors, one representing furans and the other PCBs 126 and 118, were positively associated with log-LTL. Penalized regression methods selected three congeners in common (PCB 126, PCB 118, and furan 2,3,4,7,8-pncdf) as potentially toxic agents. WQS found a positive overall effect of the POP mixture and identified six POPs as potentially toxic agents (furans 1,2,3,4,6,7,8-hxcdf, 2,3,4,7,8-pncdf, and 1,2,3,6,7,8-hxcdf, and PCBs 99, 126, 169). BKMR found a positive linear association with furan 2,3,4,7,8-pncdf, suggestive evidence of linear associations with PCBs 126 and 169, and a positive overall effect of the mixture, but no interactions among congeners. Conclusions Using different methods, we identified patterns of POP exposure, potentially toxic agents, the absence of interaction, and estimated the overall mixture effect. These applications and results may serve as a guide for mixture method selection based on specific research questions.

BackgroundKnowing the geographical and temporal variation in radon concentrations is essential for assessing residential exposure to radon, the leading cause of lung cancer in never-smokers in the United States. Tens of millions of short-term radon measurements, which normally last 2 to 4 days, have been conducted during the past decades. However, these massive short-term measurements have not been commonly used in exposure assessment because of the conflicting evidence regarding their correlation with long-term measurements, the gold standard of assessing long-term radon exposure.ObjectiveWe aim to evaluate the extent to which a long-term radon measurement can be predicted by a collocated short-term radon measurement under different conditions.MethodsWe compiled a national dataset of 2245 pairs of collocated short- and long-term measurements, analyzed the predictability of long-term measurements with stratified linear regression and bootstrapping resampling.ResultsWe found that the extent to which a long-term measurement can be predicted by the collocated short-term measurement was a joint function of two factors: the temporal difference in starting dates between two measurements and the length of the long-term measurement. Short-term measurements, jointly with other factors, could explain up to 79% (0.95 Confidence Interval [CI]: 0.73–0.84) of the variance in seasonal radon concentrations and could explain up to 67% (0.95 CI: 0.52–0.81) of the variance in annual radon concentrations. The large proportions of variance explained suggest that short-term measurement can be used as convenient proxy for seasonal radon concentrations. Accurate annual radon estimation entails averaging multiple short-term measurements in different seasons.SignificanceOur findings will facilitate the usage of abundant short-term radon measurements, which have been obtained but was previously underutilized in assessing residential radon exposure.Impact statementTens of millions of short-term radon measurements have been conducted but underutilized in assessing residential exposure to radon, the greatest cause of lung cancer in non-smokers. We investigate the correlations between collocated short- and long-term measurements in 2245 U.S. buildings and find that short-term measurements can explain ~75% of the variance in subsequent long-term measurements in the same buildings. Our results can facilitate the usage of massive short-term radon measurements that have been conducted to estimate the spatial and longitudinal distribution of radon concentrations, which can be used in epidemiological studies to quantify the health effects of radon.

Many studies have reported the associations between long-term exposure to PM2.5 and increased risk of death. However, to our knowledge, none has used a causal modeling approach or controlled for long-term temperature exposure, and few have used a general population sample. We estimated the causal effects of long-term PM2.5 exposure on mortality and tested the effect modifications by seasonal temperatures, census tract-level socioeconomic variables, and county-level health conditions. We applied a variant of the difference-in-differences approach, which serves to approximate random assignment of exposure across the population and hence estimate a causal effect. Specifically, we estimated the association between long-term exposure to PM2.5 and mortality while controlling for geographical differences using dummy variables for each census tract in New Jersey, a state-wide time trend using dummy variables for each year from 2004 to 2009, and mean summer and winter temperatures for each tract in each year. This approach assumed that no variable changing differentially over time across space other than seasonal temperatures confounded the association. For each interquartile range (2 μg/m3) increase in annual PM2.5, there was a 3.0% [95% confidence interval (CI): 0.2, 5.9%] increase in all natural-cause mortality for the whole population, with similar results for people > 65 years old [3.5% (95% CI: 0.1, 6.9%)] and people ≤ 65 years old [3.1% (95% CI: -1.8, 8.2%)]. The mean summer temperature and the mean winter temperature in a census tract significantly modified the effects of long-term exposure to PM2.5 on mortality. We observed a higher percentage increase in mortality associated with PM2.5 in census tracts with more blacks, lower home value, or lower median income. Under the assumption of the difference-in-differences approach, we identified a causal effect of long-term PM2.5 exposure on mortality that was modified by seasonal temperatures and ecological socioeconomic status. Wang Y, Kloog I, Coull BA, Kosheleva A, Zanobetti A, Schwartz JD. 2016. Estimating causal effects of long-term PM2.5 exposure on mortality in New Jersey. Environ Health Perspect 124:1182-1188; http://dx.doi.org/10.1289/ehp.1409671.

BACKGROUND:Many studies have reported associations between ambient particulate matter (PM) and adverse health effects, focused on either short-term (acute) or long-term (chronic) PM exposures. For chronic effects, the studied cohorts have rarely been representative of the population. We present a novel exposure model combining satellite aerosol optical depth and land-use data to investigate both the long- and short-term effects of PM2.5 exposures on population mortality in Massachusetts, United States, for the years 2000–2008. METHODS:All deaths were geocoded. We performed two separate analysesa time-series analysis (for short-term exposure) where counts in each geographic grid cell were regressed against cell-specific short-term PM2.5 exposure, temperature, socioeconomic data, lung cancer rates (as a surrogate for smoking), and a spline of time (to control for season and trends). In addition, for long-term exposure, we performed a relative incidence analysis using two long-term exposure metricsregional 10 × 10 km PM2.5 predictions and local deviations from the cell average based on land use within 50 m of the residence. We tested whether these predicted the proportion of deaths from PM-related causes (cardiovascular and respiratory diseases). RESULTS:For short-term exposure, we found that for every 10-µg/m increase in PM 2.5 exposure there was a 2.8% increase in PM-related mortality (95% confidence interval [CI] = 2.0–3.5). For the long-term exposure at the grid cell level, we found an odds ratio (OR) for every 10-µg/m increase in long-term PM2.5 exposure of 1.6 (CI = 1.5–1.8) for particle-related diseases. Local PM2.5 had an OR of 1.4 (CI = 1.3–1.5), which was independent of and additive to the grid cell effect. CONCLUSIONS:We have developed a novel PM2.5 exposure model based on remote sensing data to assess both short- and long-term human exposures. Our approach allows us to gain spatial resolution in acute effects and an assessment of long-term effects in the entire population rather than a selective sample from urban locations.

Exposure to chemical mixtures is recognized as the real-life scenario in all populations, needing new statistical methods that can assess their complex effects. We aimed to assess the joint effect of in utero exposure to arsenic, manganese, and lead on children's neurodevelopment. We employed a novel statistical approach, Bayesian kernel machine regression (BKMR), to study the joint effect of coexposure to arsenic, manganese, and lead on neurodevelopment using an adapted Bayley Scale of Infant and Toddler Development™. Third Edition, in 825 mother-child pairs recruited into a prospective birth cohort from two clinics in the Pabna and Sirajdikhan districts of Bangladesh. Metals were measured in cord blood using inductively coupled plasma-mass spectrometry. Analyses were stratified by clinic due to differences in exposure profiles. In the Pabna district, which displayed high manganese levels [interquartile range (IQR): 4.8, 18 μg/dl], we found a statistically significant negative effect of the mixture of arsenic, lead, and manganese on cognitive score when cord blood metals concentrations were all above the 60th percentile (As≥0.7 μg/dl, Mn≥6.6 μg/dl, Pb≥4.2 μg/dl) compared to the median (As=0.5 μg/dl, Mn=5.8 μg/dl, Pb=3.1 μg/dl). Evidence of a nonlinear effect of manganese was found. A change in log manganese from the 25th to the 75th percentile when arsenic and manganese were at the median was associated with a decrease in cognitive score of −0.3 (−0.5, −0.1) standard deviations. Our study suggests that arsenic might be a potentiator of manganese toxicity. Employing a novel statistical method for the study of the health effects of chemical mixtures, we found evidence of neurotoxicity of the mixture, as well as potential synergism between arsenic and manganese. https://doi.org/10.1289/EHP614.

Emerging evidence suggests that perfluoroalkyl substances (PFASs) are endocrine disruptors and may contribute to the etiology of type 2 diabetes (T2D), but this hypothesis needs to be clarified in prospective human studies. Our objective was to examine the associations between PFAS exposures and subsequent incidence of T2D in the Nurses' Health Study II (NHSII). In addition, we aimed to evaluate potential demographic and lifestyle determinants of plasma PFAS concentrations. A prospective nested case-control study of T2D was conducted among participants who were free of diabetes, cardiovascular disease, and cancer in 1995-2000 [(mean±SD): 45.3±4.4 y) of age]. We identified and ascertained 793 incident T2D cases through 2011 (mean±SD) years of follow-up: 6.7±3.7 y). Each case was individually matched to a control (on age, month and fasting status at sample collection, and menopausal status and hormone replacement therapy). Plasma concentrations of five major PFASs, including perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexanesulfonate, perfluorononanoic acid, and perfluorodecanoic acid were measured. Odds ratios (ORs) of T2D by PFAS tertiles were estimated by conditional logistic regression. Shorter breastfeeding duration and higher intake of certain foods, such as seafood and popcorn, were significantly associated with higher plasma concentrations of PFASs among controls. After multivariate adjustment for T2D risk factors, including body mass index, family history, physical activity, and other covariates, higher plasma concentrations of PFOS and PFOA were associated with an elevated risk of T2D. Comparing extreme tertiles of PFOS or PFOA, ORs were 1.62 (95% CI: 1.09, 2.41; =0.02) and 1.54 (95% CI: 1.04, 2.28; =0.03), respectively. Other PFASs were not clearly associated with T2D risk. Background exposures to PFASs in the late 1990s were associated with higher T2D risk during the following years in a prospective case-control study of women from the NHSII. These findings support a potential diabetogenic effect of PFAS exposures. https://doi.org/10.1289/EHP2619.