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.
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.
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.
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.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Satellite-derived aerosol optical depth (AOD) measurements have the potential to provide spatiotemporally resolved predictions of both long and short-term exposures, but previous studies have ...generally shown moderate predictive power and lacked detailed high spatio- temporal resolution predictions across large domains. We aimed at extending our previous work by validating our model in another region with different geographical and metrological characteristics, and incorporating fine scale land use regression and nonrandom missingness to better predict PM2.5 concentrations for days with or without satellite AOD measures. We start by calibrating AOD data for 2000–2008 across the Mid-Atlantic. We used mixed models regressing PM2.5 measurements against day-specific random intercepts, and fixed and random AOD and temperature slopes. We used inverse probability weighting to account for nonrandom missingness of AOD, nested regions within days to capture spatial variation in the daily calibration, and introduced a penalization method that reduces the dimensionality of the large number of spatial and temporal predictors without selecting different predictors in different locations. We then take advantage of the association between grid-cell specific AOD values and PM2.5 monitoring data, together with associations between AOD values in neighboring grid cells to develop grid cell predictions when AOD is missing. Finally to get local predictions (at the resolution of 50 m), we regressed the residuals from the predictions for each monitor from these previous steps against the local land use variables specific for each monitor. “Out-of-sample” 10-fold cross-validation was used to quantify the accuracy of our predictions at each step. For all days without AOD values, model performance was excellent (mean “out-of-sample” R 2 = 0.81, year-to-year variation 0.79–0.84). Upon removal of outliers in the PM2.5 monitoring data, the results of the cross validation procedure was even better (overall mean ”out of sample” R 2 of 0.85). Further, cross validation results revealed no bias in the predicted concentrations (Slope of observed vs predicted = 0.97–1.01). Our model allows one to reliably assess short-term and long-term human exposures in order to investigate both the acute and effects of ambient particles, respectively.
Land use regression (LUR) models provide good estimates of spatially resolved long-term exposures, but are poor at capturing short term exposures. Satellite-derived Aerosol Optical Depth (AOD) ...measurements have the potential to provide spatio-temporally resolved predictions of both long and short term exposures, but previous studies have generally showed relatively low predictive power. Our objective was to extend our previous work on day-specific calibrations of AOD data using ground PM₂.₅ measurements by incorporating commonly used LUR variables and meteorological variables, thus benefiting from both the spatial resolution from the LUR models and the spatio-temporal resolution from the satellite models. Later we use spatial smoothing to predict PM₂.₅ concentrations for day/locations with missing AOD measures. We used mixed models with random slopes for day to calibrate AOD data for 2000–2008 across New-England with monitored PM₂.₅ measurements. We then used a generalized additive mixed model with spatial smoothing to estimate PM₂.₅ in location–day pairs with missing AOD, using regional measured PM₂.₅, AOD values in neighboring cells, and land use. Finally, local (100 m) land use terms were used to model the difference between grid cell prediction and monitored value to capture very local traffic particles. Out-of-sample ten-fold cross-validation was used to quantify the accuracy of our predictions. For days with available AOD data we found high out-of-sample R² (mean out-of-sample R² = 0.830, year to year variation 0.725–0.904). For days without AOD values, our model performance was also excellent (mean out-of-sample R² = 0.810, year to year variation 0.692–0.887). Importantly, these R² are for daily, rather than monthly or yearly, values. Our model allows one to assess short term and long-term human exposures in order to investigate both the acute and chronic effects of ambient particles, respectively.
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.
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CEKLJ, DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Weather impacts on the chemical composition of PM2.5 varies significantly over space and time given the diversity of particle components and the complex mechanisms governing particle formation and ...removal. In this study, we employed generalized additive models (GAMs) to estimate weather-associated changes in PM2.5 composition in the US during 1988–2017. We considered seven components of ambient PM2.5, which included elemental carbon (EC), organic carbon (OC), nitrate, sulfate, sodium, ammonium, and silicon. The impact of long-term weather changes on each PM2.5 component was defined in our study as “weather penalty”. During our study period, temperature increased in four regions, including the Industrial Midwest and Northeast during the warm and cold season; and Upper Midwest and West in the cold season. Wind speed decreased in the both seasons. Relative humidity increased in the warm season and decreased in the cold season. The weather changes between 1988 and 2017 were associated with most PM2.5 components during both warm and cold seasons. The direction and the magnitude of the weather penalty varied considerably over the space and season. In the warm season, our findings suggest a nationwide weather penalty for EC, OC, nitrate, sulfate, sodium, ammonium, and silicon of 0.04, 0.21, 0.04, 0.35, −0.01, 0.05, and 0.01 μg/m3, respectively. In the cold season, the estimated total penalty was 0.04, 0.21, 0.06, 0.04, −0.01, −0.02, and 0.02 μg/m3, respectively.
•The West demonstrated the highest weather penalty on nitrate.•Our results indicate minimal influences of weather changes on sulfate in the cold season.•The weather penalties for sodium were negative in all coastal regions.•Weather penalties on silicon were positive in all regions in both warm and cold seasons.
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.
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.
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.
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.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
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CEKLJ, DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
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