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With advancement of medicine, alternative exposures or interventions are emerging with respect to a common outcome, and there are needs to formally test the difference in the associations of multiple exposures. We propose a duplication method-based multivariate Wald test in the Cox proportional hazard regression analyses to test the difference in the associations of multiple exposures with a same outcome. The proposed method applies to linear or categorical exposures. To illustrate our method, we applied our method to compare the associations between alignment to two different dietary patterns, either as continuous or quartile exposures, and incident chronic diseases, defined as a composite of CVD, cancer, and diabetes, in the Health Professional Follow-up Study. Relevant sample codes in R that implement the proposed approach are provided. The proposed duplication-method-based approach offers a flexible, formal statistical test of multiple exposures for the common outcome with minimal assumptions.

In environmental health research, it is of interest to understand the effect of the neighborhood environment on health. Researchers have shown a protective association between green space around a person's residential address and depression outcomes. In measuring exposure to green space, distance buffers are often used. However, buffer distances differ across studies. Typically, the buffer distance is determined by researchers a priori. It is unclear how to identify an appropriate buffer distance for exposure assessment. To address geographic uncertainty problem for exposure assessment, we present a domain selection algorithm based on the penalized functional linear Cox regression model. The theoretical properties of our proposed method are studied and simulation studies are conducted to evaluate finite sample performances of our method. The proposed method is illustrated in a study of associations of green space exposure with depression and/or antidepressant use in the Nurses' Health Study., Comment: 27 pages, 5 figures

In this paper, we identify the criteria for the selection of the minimal and most efficient covariate adjustment sets for the regression calibration method developed by Carroll, Rupert and Stefanski (CRS, 1992), used to correct bias due to continuous exposure measurement error. We utilize directed acyclic graphs to illustrate how subject matter knowledge can aid in the selection of such adjustment sets. Valid measurement error correction requires the collection of data on any (1) common causes of true exposure and outcome and (2) common causes of measurement error and outcome, in both the main study and validation study. For the CRS regression calibration method to be valid, researchers need to minimally adjust for covariate set (1) in both the measurement error model (MEM) and the outcome model and adjust for covariate set (2) at least in the MEM. In practice, we recommend including the minimal covariate adjustment set in both the MEM and the outcome model. In contrast with the regression calibration method developed by Rosner, Spiegelman and Willet, it is valid and more efficient to adjust for correlates of the true exposure or of measurement error that are not risk factors in the MEM only under CRS method. We applied the proposed covariate selection approach to the Health Professional Follow-up Study, examining the effect of fiber intake on cardiovascular incidence. In this study, we demonstrated potential issues with a data-driven approach to building the MEM that is agnostic to the structural assumptions. We extend the originally proposed estimators to settings where effect modification by a covariate is allowed. Finally, we caution against the use of the regression calibration method to calibrate the true nutrition intake using biomarkers., Comment: 11 pages, 4 tables, 3 figures. arXiv admin note: text overlap with arXiv:2212.00795

Due to the nature of pure-tone audiometry test, hearing loss data often has a complicated correlation structure. Generalized estimating equation (GEE) is commonly used to investigate the association between exposures and hearing loss, because it is robust to misspecification of the correlation matrix. However, this robustness typically entails a moderate loss of estimation efficiency in finite samples. This paper proposes to model the correlation coefficients and use second-order generalized estimating equations to estimate the correlation parameters. In simulation studies, we assessed the finite sample performance of our proposed method and compared it with other methods, such as GEE with independent, exchangeable and unstructured correlation structures. Our method achieves an efficiency gain which is larger for the coefficients of the covariates corresponding to the within-cluster variation (e.g., ear-level covariates) than the coefficients of cluster-level covariates. The efficiency gain is also more pronounced when the within-cluster correlations are moderate to strong, or when comparing to GEE with an unstructured correlation structure. As a real-world example, we applied the proposed method to data from the Audiology Assessment Arm of the Conservation of Hearing Study, and studied the association between a dietary adherence score and hearing loss., Comment: 14 pages, 5 tables, 4 supplementary tables; submitted to Biometrical Journal

In epidemiological studies, participants' disease status is often collected through self-reported outcomes in place of formal medical tests due to budget constraints. However, self-reported outcomes are often subject to measurement errors, and may lead to biased estimates if used in statistical analyses. In this paper, we propose statistical methods to correct for outcome measurement errors in survival analyses with multiple failure types through a reweighting strategy. We also discuss asymptotic properties of the proposed estimators and derive their asymptotic variances. The work is motivated by Conservation of Hearing Study (CHEARS) which aims to evaluate risk factors for hearing loss in the Nurses' Health Studies II (NHS II). We apply the proposed method to adjust for the measurement errors in self-reported hearing outcomes; the analysis results suggest that tinnitus is positively associated with moderate hearing loss at both low or mid and high sound frequencies, while the effects between different frequencies are similar.

Purpose: In this paper we consider the estimation of intracluster correlation for ordinal data. We focus on pure-tone audiometry hearing threshold data, where thresholds are measured in 5 decibel increments. We estimate the intracluster correlation for tests from iPhone-based hearing assessment application as a measure of test/retest reliability. Methods: We present a method to estimate the intracluster correlation using mixed effects cumulative logistic and probit models, which assume the outcome data are ordinal. This contrasts with using a mixed effects linear model which assumes that the outcome data are continuous. Results: In simulation studies we show that using a mixed effects linear model to estimate the intracluster correlation for ordinal data results in a negative finite sample bias, while using mixed effects cumulative logistic or probit models reduces this bias. The estimated intracluster correlation for the iPhone-based hearing assessment application is higher when using the mixed effects cumulative logistic and probit models compared to using a mixed effects linear model. Conclusion: When data are ordinal, using mixed effects cumulative logistic or probit models reduces the bias of intracluster correlation estimates relative to using a mixed effects linear model., Comment: 11 pages, 3 tables

Epidemiologic and medical studies often rely on evaluators to obtain measurements of exposures or outcomes for study participants, and valid estimates of associations depends on the quality of data. Even though statistical methods have been proposed to adjust for measurement errors, they often rely on unverifiable assumptions and could lead to biased estimates if those assumptions are violated. Therefore, methods for detecting potential `outlier' evaluators are needed to improve data quality during data collection stage. In this paper, we propose a two-stage algorithm to detect `outlier' evaluators whose evaluation results tend to be higher or lower than their counterparts. In the first stage, evaluators' effects are obtained by fitting a regression model. In the second stage, hypothesis tests are performed to detect `outlier' evaluators, where we consider both the power of each hypothesis test and the false discovery rate (FDR) among all tests. We conduct an extensive simulation study to evaluate the proposed method, and illustrate the method by detecting potential `outlier' audiologists in the data collection stage for the Audiology Assessment Arm of the Conservation of Hearing Study, an epidemiologic study for examining risk factors of hearing loss in the Nurses' Health Study II. Our simulation study shows that our method not only can detect true `outlier' evaluators, but also is less likely to falsely reject true `normal' evaluators. Our two-stage `outlier' detection algorithm is a flexible approach that can effectively detect `outlier' evaluators, and thus data quality can be improved during data collection stage.

Regression calibration as developed by Rosner, Spiegelman and Willet is used to correct the bias in effect estimates due to measurement error in continuous exposures. The method involves two models: a measurement error model (MEM) relating the mismeasured exposure to the true exposure and an outcome model relating the mismeasured exposure to outcome. However, no comprehensive guidance exists for determining which covariates should be included in each model. In this paper, we investigate the selection of the minimal and most efficient covariate adjustment sets under a causal inference framework. We show that in order to correct for the measurement error, researchers must adjust for, in both MEM and outcome model, any common causes (1) of true exposure and the outcome and (2) of measurement error and the outcome. When such variable(s) are only available in the main study, researchers should still adjust for them in the outcome model to reduce bias, provided that these covariates are at most weakly associated with measurement error. We also show that adjusting for so called prognostic variables that are independent of true exposure and measurement error in outcome model, may increase efficiency, while adjusting for any covariates that are associated only with true exposure generally results in efficiency loss in realistic settings. We apply the proposed covariate selection approach to the Health Professional Follow-up Study dataset to study the effect of fiber intake on cardiovascular disease. Finally, we extend the originally proposed estimators to a non-parametric setting where effect modification by covariates is allowed., Comment: 11 pages, 3 figures

In epidemiological studies, very often, evaluators obtain measurements of disease outcomes for study participants. In this paper, we propose a two-stage procedure for detecting outlier evaluators. In the first stage, a regression model is fitted to obtain the evaluators' effects. The outlier evaluators are considered as those with different effects compared with the normal evaluators. In the second stage, stepwise hypothesis testings are performed to detect outlier evaluators. The true positive rate and true negative rate of the proposed procedure are assessed in a simulation study. We apply the proposed method to detect potential outlier audiologists among the audiologists who measured hearing threshold levels of the participants in the Audiology Assessment Arm of the Conservation of Hearing Study, which is an epidemiological study for examining risk factors of hearing loss.

Studies have shown that the effect an exposure may have on a disease can vary for different subtypes of the same disease. However, existing approaches to estimate and compare these effects largely overlook causality. In this paper, we study the effect smoking may have on having colorectal cancer subtypes defined by a trait known as microsatellite instability (MSI). We use principal stratification to propose an alternative causal estimand, the Subtype-Free Average Causal Effect (SF-ACE). The SF-ACE is the causal effect of the exposure among those who would be free from other disease subtypes under any exposure level. We study non-parametric identification of the SF-ACE, and discuss different monotonicity assumptions, which are more nuanced than in the standard setting. As is often the case with principal stratum effects, the assumptions underlying the identification of the SF-ACE from the data are untestable and can be too strong. Therefore, we also develop sensitivity analysis methods that relax these assumptions. We present three different estimators, including a doubly-robust estimator, for the SF-ACE. We implement our methodology for data from two large cohorts to study the heterogeneity in the causal effect of smoking on colorectal cancer with respect to MSI subtypes.

Participant level meta-analysis across multiple studies increases the sample size for pooled analyses, thereby improving precision in effect estimates and enabling subgroup analyses. For analyses involving biomarker measurements as an exposure of interest, investigators must first calibrate the data to address measurement variability arising from usage of different laboratories and/or assays. In practice, the calibration process involves reassaying a random subset of biospecimens from each study at a central laboratory and fitting models that relate the study-specific "local" and central laboratory measurements. Previous work in this area treats the calibration process from the perspective of measurement error techniques and imputes the estimated central laboratory value among individuals with only a local laboratory measurement. In this work, we propose a repeated measures method to calibrate biomarker measurements pooled from multiple studies with study-specific calibration subsets. We account for correlation between measurements made on the same person and between measurements made at the same laboratory. We demonstrate that the repeated measures approach provides valid inference, and compare it to existing calibration approaches grounded in measurement error techniques in an example describing the association between circulating vitamin D and stroke., Comment: 25 pages, 2 figures, 3 tables

Pooling biomarker data across multiple studies enables researchers to get more precise estimates of the association between biomarker exposure measurements and disease risks due to increased sample sizes. However, biomarker measurements vary significantly across different assays and laboratories, and therefore calibration of the local laboratory measurements to a reference laboratory is necessary before pooling data. We propose two methods that can estimate a nonlinear relationship between biomarker exposure measurements and disease risks using spline functions with a nested case-control study design: full calibration and internalized calibration. The full calibration method calibrates all observations using a study-specific calibration model while the internalized calibration method only calibrates observations that do not have reference laboratory measurements available. We compare the two methods with a naive method whereby data are pooled without calibration. We find that: (1) Internalized and full calibration methods have substantially better performance than the naive method in terms of average relative bias and coverage rate. (2) Full calibration is more robust than internalized calibration when the size of calibration subsets varies. We apply our methods to a pooling project with nested case-control study design to estimate the association of circulating Vitamin D levels with the risk of colorectal cancer.

Pooling biomarker data across multiple studies allows for examination of a wider exposure range than generally possible in individual studies, evaluation of population subgroups and disease subtypes with more statistical power, and more precise estimation of biomarker-disease associations. However, biomarker measurements often require calibration to a reference assay prior to pooling due to assay and laboratory variability across studies. We propose several methods for calibrating and combining biomarker data from nested case-control studies when reference assay data are obtained from a subset of controls in each contributing study. Specifically, we describe a two-stage method and two aggregated methods, named the internalized and full calibration methods, to evaluate the main effect of the biomarker exposure on disease risk and whether that association is modified by a potential covariate. The internalized method uses the reference laboratory measurement in the analysis when available and otherwise uses the calibrated measurement. The full calibration method uses calibrated biomarker measurements for all subjects, even those with reference laboratory measurements. Our results demonstrate that the full calibration method is the preferred aggregated approach to minimize bias in point estimates regardless of the inclusion of an interaction term in the model. We also observe that the two-stage and full calibration methods provide similar effect and variance estimates, but that the variance estimates for these two methods are slightly larger than those from the internalized approach. As an illustrative example, we apply the methods in a pooling project of nested case-control studies to evaluate (i) the association between circulating vitamin D levels and risk of stroke, and (ii) how BMI modifies the association between circulating vitamin D levels and cardiovascular disease., Comment: 2 figures, 5 tables

In epidemiology, identifying the effect of exposure variables in relation to a time-to-event outcome is a classical research area of practical importance. Incorporating propensity score in the Cox regression model, as a measure to control for confounding, has certain advantages when outcome is rare. However, in situations involving exposure measured with moderate to substantial error, identifying the exposure effect using propensity score in Cox models remains a challenging yet unresolved problem. In this paper, we propose an estimating equation method to correct for the exposure misclassification-caused bias in the estimation of exposure-outcome associations. We also discuss the asymptotic properties and derive the asymptotic variances of the proposed estimators. We conduct a simulation study to evaluate the performance of the proposed estimators in various settings. As an illustration, we apply our method to correct for the misclassification-caused bias in estimating the association of PM2.5 level with lung cancer mortality using a nationwide prospective cohort, the Nurses' Health Study (NHS). The proposed methodology can be applied using our user-friendly R function published online., Comment: Withdrawn due to grant related requirements