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Mediation analysis allows the examination of effects of a third variable in the pathway between an exposure and an outcome. The general multiple mediation analysis method, proposed by Yu et al, improves traditional methods (eg, estimation of natural and controlled direct effects) to enable consideration of multiple mediators/confounders simultaneously and the use of linear and nonlinear predictive models for estimating mediation/confounding effects. In this paper, we extend the method for time-to-event outcomes and apply the method to explore the racial disparity in breast cancer survivals. Breast cancer is the most common cancer and the second leading cause of cancer death among women of all races. Despite improvement of survival rates of breast cancer in the US, a significant difference between white and black women remains. Previous studies have found that more advanced and aggressive tumors and less than optimal treatment may explain the lower survival rates for black women as compared to white women. Due to limitations of current analytic methods and the lack of comprehensive data sets, researchers have not been able to differentiate the relative effect each factor contributes to the overall racial disparity. We use the CDC-funded Patterns of Care study to examine the determinants of racial disparities in breast cancer survival using a novel multiple mediation analysis. Using the proposed method, we applied the Cox hazard model and multiple additive regression trees as predictive models and found that all racial disparity in survival among Louisiana breast cancer patients were explained by factors included in the study. [ABSTRACT FROM AUTHOR]

Drug-drug interactions (DDIs) are a common cause of adverse drug events (ADEs). The electronic medical record (EMR) database and the FDA's adverse event reporting system (FAERS) database are the major data sources for mining and testing the ADE associated DDI signals. Most DDI data mining methods focus on pair-wise drug interactions, and methods to detect high-dimensional DDIs in medical databases are lacking. In this paper, we propose 2 novel mixture drug-count response models for detecting high-dimensional drug combinations that induce myopathy. The "count" indicates the number of drugs in a combination. One model is called fixed probability mixture drug-count response model with a maximum risk threshold (FMDRM-MRT). The other model is called count-dependent probability mixture drug-count response model with a maximum risk threshold (CMDRM-MRT), in which the mixture probability is count dependent. Compared with the previous mixture drug-count response model (MDRM) developed by our group, these 2 new models show a better likelihood in detecting high-dimensional drug combinatory effects on myopathy. CMDRM-MRT identified and validated (54; 374; 637; 442; 131) 2-way to 6-way drug interactions, respectively, which induce myopathy in both EMR and FAERS databases. We further demonstrate FAERS data capture much higher maximum myopathy risk than EMR data do. The consistency of 2 mixture models' parameters and local false discovery rate estimates are evaluated through statistical simulation studies. [ABSTRACT FROM AUTHOR]

Background: Tier 1 exposure tools recommended for use under REACH are designed to easily identify situations that may pose a risk to health through conservative exposure predictions. However, no comprehensive evaluation of the performance of the lower tier tools has previously been carried out. The ETEAM project aimed to evaluate several lower tier exposure tools (ECETOC TRA, MEASE, and EMKG-EXPO-TOOL) as well as one higher tier tool (STOFFENMANAGER®). This paper describes the results of the external validation of tool estimates using measurement data. Methods: Measurement data were collected from a range of providers, both in Europe and United States, together with contextual information. Individual measurement and aggregated measurement data were obtained. The contextual information was coded into the tools to obtain exposure estimates. Results were expressed as percentage of measurements exceeding the tool estimates and presented by exposure category (non-volatile liquid, volatile liquid, metal abrasion, metal processing, and powder handling). We also explored tool performance for different process activities as well as different scenario conditions and exposure levels. Results: In total, results from nearly 4000 measurements were obtained, with the majority for the use of volatile liquids and powder handling. The comparisons of measurement results with tool estimates suggest that the tools are generally conservative. However, the tools were more conservative when estimating exposure from powder handling compared to volatile liquids and other exposure categories. In addition, results suggested that tool performance varies between process activities and scenario conditions. For example, tools were less conservative when estimating exposure during activities involving tabletting, compression, extrusion, pelletisation, granulation (common process activity PROC14) and transfer of substance or mixture (charging and discharging) at nondedicated facilities (PROC8a; powder handling only). With the exception of STOFFENMANAGER® (for estimating exposure during powder handling), the tools were less conservative for scenarios with lower estimated exposure levels. Conclusions: This is the most comprehensive evaluation of the performance of REACH exposure tools carried out to date. The results show that, although generally conservative, the tools may not always achieve the performance specified in the REACH guidance, i.e. using the 75th or 90th percentile of the exposure distribution for the risk characterisation. Ongoing development, adjustment, and recalibration of the tools with new measurement data are essential to ensure adequate characterisation and control of worker exposure to hazardous substances. [ABSTRACT FROM AUTHOR]