Search

Not accounting for competing events in survival analysis can lead to biased estimates, as individuals who die from other causes do not have the opportunity to develop the event of interest. Formal definitions and considerations for causal effects in the presence of competing risks have been published, but not for the mediation analysis setting. We propose, for the first time, an approach based on the path-specific effects framework to account for competing risks in longitudinal mediation analysis with time-to-event outcomes. We do so by considering the pathway through the competing event as another mediator, which is nested within our longitudinal mediator of interest. We provide a theoretical formulation and related definitions of the effects of interest based on the mediational g-formula, as well as a detailed description of the algorithm. We also present an application of our algorithm to data from the Strong Heart Study, a prospective cohort of American Indian adults. In this application, we evaluated the mediating role of the blood pressure trajectory (measured during three visits) on the association between arsenic and cadmium, in separate models, with time to cardiovascular disease, accounting for competing risks by death. Identifying the effects through different paths enables us to evaluate the impact of metals on the outcome of interest, as well as through competing risks, more transparently.

A key challenge in differential abundance analysis of microbial samples is that the counts for each sample are compositional, resulting in biased comparisons of the absolute abundance across study groups. Normalization-based differential abundance analysis methods rely on external normalization factors that account for the compositionality by standardizing the counts onto a common numerical scale. However, existing normalization methods have struggled at maintaining the false discovery rate in settings where the variance or compositional bias is large. This article proposes a novel framework for normalization that can reduce bias in differential abundance analysis by re-conceptualizing normalization as a group-level task. We present two normalization methods within the group-wise framework: group-wise relative log expression (G-RLE) and fold-truncated sum scaling (FTSS). G-RLE and FTSS achieve higher statistical power for identifying differentially abundant taxa than existing methods in model-based and synthetic data simulation settings, while maintaining the false discovery rate in challenging scenarios where existing methods suffer. The best results are obtained from using FTSS normalization with the differential abundance analysis method MetagenomeSeq. Code for implementing the methods and replicating the analysis can be found at our GitHub page (https://github.com/dclarkboucher/microbiome_groupwise_normalization).

Humans are exposed to complex mixtures of environmental pollutants rather than single chemicals, necessitating methods to quantify the health effects of such mixtures. Research on environmental mixtures provides insights into realistic exposure scenarios, informing regulatory policies that better protect public health. However, statistical challenges, including complex correlations among pollutants and nonlinear multivariate exposure-response relationships, complicate such analyses. A popular Bayesian semi-parametric Gaussian process regression framework (Coull et al., 2015) addresses these challenges by modeling exposure-response functions with Gaussian processes and performing feature selection to manage high-dimensional exposures while accounting for confounders. Originally designed for small to moderate-sized cohort studies, this framework does not scale well to massive datasets. To address this, we propose a divide-and-conquer strategy, partitioning data, computing posterior distributions in parallel, and combining results using the generalized median. While we focus on Gaussian process models for environmental mixtures, the proposed distributed computing strategy is broadly applicable to other Bayesian models with computationally prohibitive full-sample Markov Chain Monte Carlo fitting. We provide theoretical guarantees for the convergence of the proposed posterior distributions to those derived from the full sample. We apply this method to estimate associations between a mixture of ambient air pollutants and ~650,000 birthweights recorded in Massachusetts during 2001-2012. Our results reveal negative associations between birthweight and traffic pollution markers, including elemental and organic carbon and PM2.5, and positive associations with ozone and vegetation greenness.

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.

MCMC algorithms are frequently used to perform inference under a Bayesian modeling framework. Convergence diagnostics, such as traceplots, the Gelman-Rubin potential scale reduction factor, and effective sample size, are used to visualize mixing and determine how long to run the sampler. However, these classic diagnostics can be ineffective when the sample space of the algorithm is highly discretized (eg. Bayesian Networks or Dirichlet Process Mixture Models) or the sampler uses frequent non-Euclidean moves. In this article, we develop novel generalized convergence diagnostics produced by mapping the original space to the real-line while respecting a relevant distance function and then evaluating the convergence diagnostics on the mapped values. Simulated examples are provided that demonstrate the success of this method in identifying failures to converge that are missed or unavailable by other methods., Comment: 17 pages, 12 figures

Measurement error can often be harmful when estimating causal effects. Two scenarios in which this is the case are in the estimation of (a) the average treatment effect when confounders are measured with error and (b) the natural indirect effect when the exposure and/or confounders are measured with error. Methods adjusting for measurement error typically require external data or knowledge about the measurement error distribution. Here, we propose methodology not requiring any such information. Instead, we show that when the outcome regression is linear in the error-prone variables, consistent estimation of these causal effects can be recovered using constructed instrumental variables under certain conditions. These variables, which are functions of only the observed data, behave like instrumental variables for the error-prone variables. Using data from a study of the effects of prenatal exposure to heavy metals on growth and neurodevelopment in Bangladeshi mother-infant pairs, we apply our methodology to estimate (a) the effect of lead exposure on birth length while controlling for maternal protein intake, and (b) lead exposure's role in mediating the effect of maternal protein intake on birth length. Protein intake is calculated from food journal entries, and is suspected to be highly prone to measurement error., Comment: 72 pages, 4 figures

Monitoring small-area geographical population trends in opioid mortality has large scale implications to informing preventative resource allocation. A common approach to obtain small area estimates of opioid mortality is to use a standard disease mapping approach in which population-at-risk estimates are treated as fixed and known. Assuming fixed populations ignores the uncertainty surrounding small area population estimates, which may bias risk estimates and under-estimate their associated uncertainties. We present a Bayesian Spatial Berkson Error (BSBE) model to incorporate population-at-risk uncertainty within a disease mapping model. We compare the BSBE approach to the naive (treating denominators as fixed) using simulation studies to illustrate potential bias resulting from this assumption. We show the application of the BSBE model to obtain 2020 opioid mortality risk estimates for 159 counties in GA accounting for population-at-risk uncertainty. Utilizing our proposed approach will help to inform interventions in opioid related public health responses, policies, and resource allocation. Additionally, we provide a general framework to improve in the estimation and mapping of health indicators.

The estimation of the effect of environmental exposures and overall mixtures on a survival time outcome is common in environmental epidemiological studies. While advanced statistical methods are increasingly being used for mixture analyses, their applicability and performance for survival outcomes has yet to be explored. We identified readily available methods for analyzing an environmental mixture's effect on a survival outcome and assessed their performance via simulations replicating various real-life scenarios. Using prespecified criteria, we selected Bayesian Additive Regression Trees (BART), Cox Elastic Net, Cox Proportional Hazards (PH) with and without penalized splines, Gaussian Process Regression (GPR) and Multivariate Adaptive Regression Splines (MARS) to compare the bias and efficiency produced when estimating individual exposure, overall mixture, and interaction effects on a survival outcome. We illustrate the selected methods in a real-world data application. We estimated the effects of arsenic, cadmium, molybdenum, selenium, tungsten, and zinc on incidence of cardiovascular disease in American Indians using data from the Strong Heart Study (SHS). In the simulation study, there was a consistent bias-variance trade off. The more flexible models (BART, GPR and MARS) were found to be most advantageous in the presence of nonproportional hazards, where the Cox models often did not capture the true effects due to their higher bias and lower variance. In the SHS, estimates of the effect of selenium and the overall mixture indicated negative effects, but the magnitudes of the estimated effects varied across methods. In practice, we recommend evaluating if findings are consistent across methods.

The US Census Bureau will implement a new privacy-preserving disclosure avoidance system (DAS), which includes application of differential privacy, on the public-release 2020 census data. There are concerns that the DAS may bias small-area and demographically-stratified population counts, which play a critical role in public health research and policy, serving as denominators in estimation of disease/mortality rates. Employing three DAS demonstration products, we quantify errors attributable to reliance on DAS-protected denominators in standard small-area disease mapping models for characterizing health inequities. We conduct simulation studies and real data analyses of inequities in premature mortality at the census tract level in Massachusetts. Results show that overall patterns of inequity by racialized group and economic deprivation level are not compromised by the DAS. While early versions of DAS induce errors in mortality rate estimation that are larger for Black than for non-Hispanic white populations, this issue is ameliorated in newer DAS versions.

We develop a simple and unified framework for nonlinear variable selection that incorporates uncertainty in the prediction function and is compatible with a wide range of machine learning models (e.g., tree ensembles, kernel methods, neural networks, etc). In particular, for a learned nonlinear model $f(\mathbf{x})$, we consider quantifying the importance of an input variable $\mathbf{x}^j$ using the integrated partial derivative $\Psi_j = \Vert \frac{\partial}{\partial \mathbf{x}^j} f(\mathbf{x})\Vert^2_{P_\mathcal{X}}$. We then (1) provide a principled approach for quantifying variable selection uncertainty by deriving its posterior distribution, and (2) show that the approach is generalizable even to non-differentiable models such as tree ensembles. Rigorous Bayesian nonparametric theorems are derived to guarantee the posterior consistency and asymptotic uncertainty of the proposed approach. Extensive simulations and experiments on healthcare benchmark datasets confirm that the proposed algorithm outperforms existing classic and recent variable selection methods., Comment: 50 pages, 16 figures, 11 tables

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.

Clusters of similar or dissimilar objects are encountered in many fields. Frequently used approaches treat the central object of each cluster as latent. Yet, often objects of one or more types cluster around objects of another type. Such arrangements are common in biomedical images of cells, in which nearby cell types likely interact. Quantifying spatial relationships may elucidate biological mechanisms. Parent-offspring statistical frameworks can be usefully applied even when central objects (parents) differ from peripheral ones (offspring). We propose the novel multivariate cluster point process (MCPP) to quantify multi-object (e.g., multi-cellular) arrangements. Unlike commonly used approaches, the MCPP exploits locations of the central parent object in clusters. It accounts for possibly multilayered, multivariate clustering. The model formulation requires specification of which object types function as cluster centers and which reside peripherally. If such information is unknown, the relative roles of object types may be explored by comparing fit of different models via the deviance information criterion (DIC). In simulated data, we compared DIC of a series of models; the MCPP correctly identified simulated relationships. It also produced more accurate and precise parameter estimates than the classical univariate Neyman-Scott process model. We also used the MCPP to quantify proposed configurations and explore new ones in human dental plaque biofilm image data. MCPP models quantified simultaneous clustering of Streptococcus and Porphyromonas around Corynebacterium and of Pasteurellaceae around Streptococcus and successfully captured hypothesized structures for all taxa. Further exploration suggested the presence of clustering between Fusobacterium and Leptotrichia, a previously unreported relationship.

Small area estimates of population are necessary for many epidemiological studies, yet their quality and accuracy are often not assessed. In the United States, small area estimates of population counts are published by the United States Census Bureau (USCB) in the form of the Decennial census counts, Intercensal population projections (PEP), and American Community Survey (ACS) estimates. Although there are significant relationships between these data sources, there are important contrasts in data collection and processing methodologies, such that each set of estimates may be subject to different sources and magnitudes of error. Additionally, these data sources do not report identical small area population counts due to post-survey adjustments specific to each data source. Resulting small area disease/mortality rates may differ depending on which data source is used for population counts (denominator data). To accurately capture annual small area population counts, and associated uncertainties, we present a Bayesian population model (B-Pop), which fuses information from all three USCB sources, accounting for data source specific methodologies and associated errors. The main features of our framework are: 1) a single model integrating multiple data sources, 2) accounting for data source specific data generating mechanisms, and specifically accounting for data source specific errors, and 3) prediction of estimates for years without USCB reported data. We focus our study on the 159 counties of Georgia, and produce estimates for years 2005-2021.

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

We consider asymptotically exact inference on the leading canonical correlation directions and strengths between two high dimensional vectors under sparsity restrictions. In this regard, our main contribution is the development of a loss function, based on which, one can operationalize a one-step bias-correction on reasonable initial estimators. Our analytic results in this regard are adaptive over suitable structural restrictions of the high dimensional nuisance parameters, which, in this set-up, correspond to the covariance matrices of the variables of interest. We further supplement the theoretical guarantees behind our procedures with extensive numerical studies.

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.

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.

Statistical learning (SL) includes methods that extract knowledge from complex data. SL methods beyond generalized linear models are being increasingly implemented in public health research and epidemiology because they can perform better in instances with complex or high-dimensional data---settings when traditional statistical methods fail. These novel methods, however, often include random sampling which may induce variability in results. Best practices in data science can help to ensure robustness. As a case study, we included four SL models that have been applied previously to analyze the relationship between environmental mixtures and health outcomes. We ran each model across 100 initializing values for random number generation, or "seeds," and assessed variability in resulting estimation and inference. All methods exhibited some seed-dependent variability in results. The degree of variability differed across methods and exposure of interest. Any SL method reliant on a random seed will exhibit some degree of seed sensitivity. We recommend that researchers repeat their analysis with various seeds as a sensitivity analysis when implementing these methods to enhance interpretability and robustness of results., Comment: 19 pages, 5 figures, 1 table. For associated code, visit https://github.com/yanellinunez/Commentary-to-mixture-methods-paper