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An important goal of environmental epidemiology is to quantify the complex health risks posed by a wide array of environmental exposures. In analyses focusing on a smaller number of exposures within a mixture, flexible models like Bayesian kernel machine regression (BKMR) are appealing because they allow for non-linear and non-additive associations among mixture components. However, this flexibility comes at the cost of low power and difficult interpretation, particularly in exposomic analyses when the number of exposures is large. We propose a flexible framework that allows for separate selection of additive and non-additive effects, unifying additive models and kernel machine regression. The proposed approach yields increased power and simpler interpretation when there is little evidence of interaction. Further, it allows users to specify separate priors for additive and non-additive effects, and allows for tests of non-additive interaction. We extend the approach to the class of multiple index models, in which the special case of kernel machine-distributed lag models are nested. We apply the method to motivating data from a subcohort of the Human Early Life Exposome (HELIX) study containing 65 mixture components grouped into 13 distinct exposure classes.

Exposure to environmental pollutants during the gestational period can significantly impact infant health outcomes, such as birth weight and neurological development. Identifying critical windows of susceptibility, which are specific periods during pregnancy when exposure has the most profound effects, is essential for developing targeted interventions. Distributed lag models (DLMs) are widely used in environmental epidemiology to analyze the temporal patterns of exposure and their impact on health outcomes. However, traditional DLMs focus on modeling the conditional mean, which may fail to capture heterogeneity in the relationship between predictors and the outcome. Moreover, when modeling the distribution of health outcomes like gestational birthweight, it is the extreme quantiles that are of most clinical relevance. We introduce two new quantile distributed lag model (QDLM) estimators designed to address the limitations of existing methods by leveraging smoothness and shape constraints, such as unimodality and concavity, to enhance interpretability and efficiency. We apply our QDLM estimators to the Colorado birth cohort data, demonstrating their effectiveness in identifying critical windows of susceptibility and informing public health interventions.

Maternal exposure to air pollution during pregnancy has a substantial public health impact. Epidemiological evidence supports an association between maternal exposure to air pollution and low birth weight. A popular method to estimate this association while identifying windows of susceptibility is a distributed lag model (DLM), which regresses an outcome onto exposure history observed at multiple time points. However, the standard DLM framework does not allow for modification of the association between repeated measures of exposure and the outcome. We propose a distributed lag interaction model that allows modification of the exposure-time-response associations across individuals by including an interaction between a continuous modifying variable and the exposure history. Our model framework is an extension of a standard DLM that uses a cross-basis, or bi-dimensional function space, to simultaneously describe both the modification of the exposure-response relationship and the temporal structure of the exposure data. Through simulations, we showed that our model with penalization out-performs a standard DLM when the true exposure-time-response associations vary by a continuous variable. Using a Colorado, USA birth cohort, we estimated the association between birth weight and ambient fine particulate matter air pollution modified by an area-level metric of health and social adversities from Colorado EnviroScreen., Comment: 41 pages, 4 figures, 2 tables

The COVID-19 infection fatality rate (IFR) is the proportion of individuals infected with SARS-CoV-2 who subsequently die. As COVID-19 disproportionately affects older individuals, age-specific IFR estimates are imperative to facilitate comparisons of the impact of COVID-19 between locations and prioritize distribution of scare resources. However, there lacks a coherent method to synthesize available data to create estimates of IFR and seroprevalence that vary continuously with age and adequately reflect uncertainties inherent in the underlying data. In this paper we introduce a novel Bayesian hierarchical model to estimate IFR as a continuous function of age that acknowledges heterogeneity in population age structure across locations and accounts for uncertainty in the estimates due to seroprevalence sampling variability and the imperfect serology test assays. Our approach simultaneously models test assay characteristic, serology, and death data, where the serology and death data are often available only for binned age groups. Information is shared across locations through hierarchical modeling to improve estimation of the parameters with limited data. Modeling data from 26 developing country locations during the first year of the COVID-19 pandemic, we found seroprevalence did not change dramatically with age, and the IFR at age 60 was above the high-income country benchmark for most locations.

In environmental health research there is often interest in the effect of an exposure on a health outcome assessed on the same day and several subsequent days or lags. Distributed lag nonlinear models (DLNM) are a well-established statistical framework for estimating an exposure-lag-response function. We propose methods to allow for prior information to be incorporated into DLNMs. First, we impose a monotonicity constraint in the exposure-response at lagged time periods which matches with knowledge on how biological mechanisms respond to increased levels of exposures. Second, we introduce variable selection into the DLNM to identify lagged periods of susceptibility with respect to the outcome of interest. The variable selection approach allows for direct application of informative priors on which lags have nonzero association with the outcome. We propose a tree-of-trees model that uses two layers of trees: one for splitting the exposure time frame and one for fitting exposure-response functions over different time periods. We introduce a zero-inflated alternative to the tree splitting prior in Bayesian additive regression trees to allow for lag selection and the addition of informative priors. We develop a computational approach for efficient posterior sampling and perform a comprehensive simulation study to compare our method to existing DLNM approaches. We apply our method to estimate time-lagged extreme temperature relationships with mortality during summer or winter in Chicago, IL., Comment: 29 pages, 5 figures, 2 tables

Exposure to air pollution is associated with increased morbidity and mortality. Recent technological advancements permit the collection of time-resolved personal exposure data. Such data are often incomplete with missing observations and exposures below the limit of detection, which limit their use in health effects studies. In this paper we develop an infinite hidden Markov model for multiple asynchronous multivariate time series with missing data. Our model is designed to include covariates that can inform transitions among hidden states. We implement beam sampling, a combination of slice sampling and dynamic programming, to sample the hidden states, and a Bayesian multiple imputation algorithm to impute missing data. In simulation studies, our model excels in estimating hidden states and state-specific means and imputing observations that are missing at random or below the limit of detection. We validate our imputation approach on data from the Fort Collins Commuter Study. We show that the estimated hidden states improve imputations for data that are missing at random compared to existing approaches. In a case study of the Fort Collins Commuter Study, we describe the inferential gains obtained from our model including improved imputation of missing data and the ability to identify shared patterns in activity and exposure among repeated sampling days for individuals and among distinct individuals.

A key goal of environmental health research is to assess the risk posed by mixtures of pollutants. As epidemiologic studies of mixtures can be expensive to conduct, it behooves researchers to incorporate prior knowledge about mixtures into their analyses. This work extends the Bayesian multiple index model (BMIM), which assumes the exposure-response function is a non-parametric function of a set of linear combinations of pollutants formed with a set of exposure-specific weights. The framework is attractive because it combines the flexibility of response-surface methods with the interpretability of linear index models. We propose three strategies to incorporate prior toxicological knowledge into construction of indices in a BMIM: (a) constraining index weights, (b) structuring index weights by exposure transformations, and (c) placing informative priors on the index weights. We propose a novel prior specification that combines spike-and-slab variable selection with informative Dirichlet distribution based on relative potency factors often derived from previous toxicological studies. In simulations we show that the proposed priors improve inferences when prior information is correct and can protect against misspecification suffered by naive toxicological models when prior information is incorrect. Moreover, different strategies may be mixed-and-matched for different indices to suit available information (or lack thereof). We demonstrate the proposed methods on an analysis of data from the National Health and Nutrition Examination Survey and incorporate prior information on relative chemical potencies obtained from toxic equivalency factors available in the literature.

Children's health studies support an association between maternal environmental exposures and children's birth outcomes. A common goal is to identify critical windows of susceptibility--periods during gestation with increased association between maternal exposures and a future outcome. The timing of the critical windows and magnitude of the associations are likely heterogeneous across different levels of individual, family, and neighborhood characteristics. Using an administrative Colorado birth cohort we estimate the individualized relationship between weekly exposures to fine particulate matter (PM$_{2.5}$) during gestation and birth weight. To achieve this goal, we propose a statistical learning method combining distributed lag models and Bayesian additive regression trees to estimate critical windows at the individual level and identify characteristics that induce heterogeneity from a high-dimensional set of potential modifying factors. We find evidence of heterogeneity in the PM$_{2.5}$-birth weight relationship, with some mother-child dyads showing a 3 times larger decrease in birth weight for an IQR increase in exposure (5.9 to 8.5 $\mu g/m^3$ PM$_{2.5}$) compared to the population average. Specifically, we find increased susceptibility for non-Hispanic mothers who are either younger, have higher body mass index or lower educational attainment. Our case study is the first precision health study of critical windows., Comment: 37 pages, 6 figures, 3 tables

Distributed lag models are useful in environmental epidemiology as they allow the user to investigate critical windows of exposure, defined as the time period during which exposure to a pollutant adversely affects health outcomes. Recent studies have focused on estimating the health effects of a large number of environmental exposures, or an environmental mixture, on health outcomes. In such settings, it is important to understand which environmental exposures affect a particular outcome, while acknowledging the possibility that different exposures have different critical windows. Further, in the studies of environmental mixtures, it is important to identify interactions among exposures, and to account for the fact that this interaction may occur between two exposures having different critical windows. Exposure to one exposure early in time could cause an individual to be more or less susceptible to another exposure later in time. We propose a Bayesian model to estimate the temporal effects of a large number of exposures on an outcome. We use spike-and-slab priors and semiparametric distributed lag curves to identify important exposures and exposure interactions, and discuss extensions with improved power to detect harmful exposures. We then apply these methods to estimate the effects of exposure to multiple air pollutants during pregnancy on birthweight from vital records in Colorado.

Maternal exposure to environmental chemicals during pregnancy can alter birth and children's health outcomes. Research seeks to identify critical windows, time periods when the exposures can change future health outcomes, and estimate the exposure-response relationship. Existing statistical approaches focus on estimation of the association between maternal exposure to a single environmental chemical observed at high-temporal resolution, such as weekly throughout pregnancy, and children's health outcomes. Extending to multiple chemicals observed at high temporal resolution poses a dimensionality problem and statistical methods are lacking. We propose a tree-based model for mixtures of exposures that are observed at high temporal resolution. The proposed approach uses an additive ensemble of structured tree-pairs that define structured main effects and interactions between time-resolved predictors and variable selection to select out of the model predictors not correlated with the outcome. We apply our method in a simulation and the analysis of the relationship between five exposures measured weekly throughout pregnancy and resulting birth weight in a Denver, Colorado birth cohort. We identified critical windows during which fine particulate matter, sulfur dioxide, and temperature are negatively associated with birth weight and an interaction between fine particulate matter and temperature. Software is made available in the R package dlmtree., Comment: 22 pages, 3 figures, 3 tables

An important goal of environmental health research is to assess the risk posed by mixtures of environmental exposures. Two popular classes of models for mixtures analyses are response-surface methods and exposure-index methods. Response-surface methods estimate high-dimensional surfaces and are thus highly flexible but difficult to interpret. In contrast, exposure-index methods decompose coefficients from a linear model into an overall mixture effect and individual index weights; these models yield easily interpretable effect estimates and efficient inferences when model assumptions hold, but, like most parsimonious models, incur bias when these assumptions do not hold. In this paper we propose a Bayesian multiple index model framework that combines the strengths of each, allowing for non-linear and non-additive relationships between exposure indices and a health outcome, while reducing the dimensionality of the exposure vector and estimating index weights with variable selection. This framework contains response-surface and exposure-index models as special cases, thereby unifying the two analysis strategies. This unification increases the range of models possible for analyzing environmental mixtures and health, allowing one to select an appropriate analysis from a spectrum of models varying in flexibility and interpretability. In an analysis of the association between telomere length and 18 organic pollutants in the National Health and Nutrition Examination Survey (NHANES), the proposed approach fits the data as well as more complex response-surface methods and yields more interpretable results.

In studies of maternal exposure to air pollution a children's health outcome is regressed on exposures observed during pregnancy. The distributed lag nonlinear model (DLNM) is a statistical method commonly implemented to estimate an exposure-time-response function when it is postulated the exposure effect is nonlinear. Previous implementations of the DLNM estimate an exposure-time-response surface parameterized with a bivariate basis expansion. However, basis functions such as splines assume smoothness across the entire exposure-time-response surface, which may be unrealistic in settings where the exposure is associated with the outcome only in a specific time window. We propose a framework for estimating the DLNM based on Bayesian additive regression trees. Our method operates using a set of regression trees that each assume piecewise constant relationships across the exposure-time space. In a simulation, we show that our model outperforms spline-based models when the exposure-time surface is not smooth, while both methods perform similarly in settings where the true surface is smooth. Importantly, the proposed approach is lower variance and more precisely identifies critical windows during which exposure is associated with a future health outcome. We apply our method to estimate the association between maternal exposure to PM$_{2.5}$ and birth weight in a Colorado USA birth cohort., Comment: 31 pages, 1 table, 4 figures

In many applications there is interest in estimating the relation between a predictor and an outcome when the relation is known to be monotone or otherwise constrained due to the physical processes involved. We consider one such application--inferring time-resolved aerosol concentration from a low-cost differential pressure sensor. The objective is to estimate a monotone function and make inference on the scaled first derivative of the function. We proposed Bayesian nonparametric monotone regression which uses a Bernstein polynomial basis to construct the regression function and puts a Dirichlet process prior on the regression coefficients. The base measure of the Dirichlet process is a finite mixture of a mass point at zero and a truncated normal. This construction imposes monotonicity while clustering the basis functions. Clustering the basis functions reduces the parameter space and allows the estimated regression function to be linear. With the proposed approach we can make closed-formed inference on the derivative of the estimated function including full quantification of uncertainty. In a simulation study the proposed method performs similar to other monotone regression approaches when the true function is wavy but performs better when the true function is linear. We apply the method to estimate time-resolved aerosol concentration with a newly-developed portable aerosol monitor. The R package bnmr is made available to implement the method.

Exposures to environmental chemicals during gestation can alter health status later in life. Most studies of maternal exposure to chemicals during pregnancy have focused on a single chemical exposure observed at high temporal resolution. Recent research has turned to focus on exposure to mixtures of multiple chemicals, generally observed at a single time point. We consider statistical methods for analyzing data on chemical mixtures that are observed at a high temporal resolution. As motivation, we analyze the association between exposure to four ambient air pollutants observed weekly throughout gestation and birth weight in a Boston-area prospective birth cohort. To explore patterns in the data, we first apply methods for analyzing data on (1) a single chemical observed at high temporal resolution, and (2) a mixture measured at a single point in time. We highlight the shortcomings of these approaches for temporally-resolved data on exposure to chemical mixtures. Second, we propose a novel method, a Bayesian kernel machine regression distributed lag model (BKMR-DLM), that simultaneously accounts for nonlinear associations and interactions among time-varying measures of exposure to mixtures. BKMR-DLM uses a functional weight for each exposure that parameterizes the window of susceptibility corresponding to that exposure within a kernel machine framework that captures non-linear and interaction effects of the multivariate exposure on the outcome. In a simulation study, we show that the proposed method can better estimate the exposure-response function and, in high signal settings, can identify critical windows in time during which exposure has an increased association with the outcome. Applying the proposed method to the Boston birth cohort data, we find evidence of a negative association between organic carbon and birth weight and that nitrate modifies the organic carbon, ...

Epidemiological research supports an association between maternal exposure to air pollution during pregnancy and adverse children's health outcomes. Advances in exposure assessment and statistics allow for estimation of both critical windows of vulnerability and exposure effect heterogeneity. Simultaneous estimation of windows of vulnerability and effect heterogeneity can be accomplished by fitting a distributed lag model (DLM) stratified by subgroup. However, this can provide an incomplete picture of how effects vary across subgroups because it does not allow for subgroups to have the same window but different within-window effects or to have different windows but the same within-window effect. Because the timing of some developmental processes are common across subpopulations of infants while for others the timing differs across subgroups, both scenarios are important to consider when evaluating health risks of prenatal exposures. We propose a new approach that partitions the DLM into a constrained functional predictor that estimates windows of vulnerability and a scalar effect representing the within-window effect directly. The proposed method allows for heterogeneity in only the window, only the within-window effect, or both. In a simulation study we show that a model assuming a shared component across groups results in lower bias and mean squared error for the estimated windows and effects when that component is in fact constant across groups. We apply the proposed method to estimate windows of vulnerability in the association between prenatal exposures to fine particulate matter and each of birth weight and asthma incidence, and estimate how these associations vary by sex and maternal obesity status, in a Boston-area prospective pre-birth cohort study.

Climate change is expected to alter the distribution of ambient ozone levels and temperatures which, in turn, may impact public health. Much research has focused on the effect of short-term ozone exposures on mortality and morbidity while controlling for temperature as a confounder, but less is known about the joint effects of ozone and temperature. The extent of the health effects of changing ozone levels and temperatures will depend on whether these effects are additive or synergistic. In this paper we propose a spatial, semi-parametric model to estimate the joint ozone-temperature risk surfaces in 95 US urban areas. Our methodology restricts the ozone-temperature risk surfaces to be monotone in ozone and allows for both nonadditive and nonlinear effects of ozone and temperature. We use data from the National Mortality and Morbidity Air Pollution Study (NMMAPS) and show that the proposed model fits the data better than additive linear and nonlinear models. We then examine the synergistic effect of ozone and temperature both nationally and locally and find evidence of a nonlinear ozone effect and an ozone-temperature interaction at higher temperatures and ozone concentrations., Comment: Published in at http://dx.doi.org/10.1214/14-AOAS754 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org)