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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: Physiologically-based pharmacokinetic (PBPK) modeling in predicting metabolic drug-drug interactions (mDDIs) is routinely used in drug development. Currently, the US FDA endorses the use of PBPK to potentially support dosing recommendations for investigational drugs as enzyme substrates of mDDIs, and to inform a lack of mDDIs for investigational drugs as enzyme modulators.Methods: We systematically evaluated the performance of PBPK modeling in predicting mDDIs published in the literature. Models developed to assess both investigational drugs as enzyme substrates (Groups 1 and 2, as being inhibited and induced, respectively) or enzyme modulators (Groups 3 and 4, as inhibitors and inducers, respectively) were evaluated. Predicted ratios of the area under the curve (AUCRs) and/or maximum plasma concentration (CmaxRs) with and without comedication were compared with the observed ratios.Results: For Groups 1, 2, 3, and 4, 62, 50, 44, and 43% of model-predicted AUCRs, respectively, were within a predefined threshold of 1.25-fold of observed values (0.8-1.25x). When the threshold was widened to twofold, the values increased to 100, 80, 81, and 86% (0.5-2.0x). For Groups 3 and 4, prediction for mDDI liability (the existence or lack of mDDIs) using PBPK appears to be satisfactory.Conclusion: Our analysis supports the FDA's current recommendations on the use of PBPK to predict mDDIs. [ABSTRACT FROM AUTHOR]

A web-based Roof Savings Calculator (RSC) has been deployed for the United States Department of Energy as an industry-consensus tool to help building owners, manufacturers, distributors, contractors and researchers easily run complex roof and attic simulations. RSC simulates multiple roof and attic technologies for side-by-side comparison including reflective roofs, different roof slopes, above sheathing ventilation, radiant barriers, low-emittance roof surfaces, duct location, duct leakage rates, multiple substrate types, and insulation levels. Annual simulations of hour-by-hour, whole-building performance are used to provide estimated annual energy and cost savings from reduced HVAC use. While RSC reported similar cooling savings to other simulation engines, heating penalty varied significantly. RSC results show reduced cool roofing cost-effectiveness, thus mitigating expected economic incentives for this countermeasure to the urban heat island effect. This paper consolidates comparison of RSC's projected energy savings to other simulation engines including DOE-2.1E, AtticSim, Micropas, and EnergyPlus. Also included are comparisons to previous simulation-based studies, analysis of RSC cooling savings and heating penalties, the role of radiative heat exchange in an attic assembly, and changes made for increased accuracy of the duct model. Radiant heat transfer and duct interaction not previously modeled is considered a major contributor to heating penalties. [ABSTRACT FROM AUTHOR]

The joinpoint regression model (JRM) is used to describe trend changes in many applications and relies on the detection of joinpoints (changepoints). However, the existing joinpoint detection methods, namely, the grid search (GS)-based methods, are computationally demanding, and hence, the maximum number of computable joinpoints is limited. Herein, we developed a genetic algorithm-based joinpoint (GAJP) model in which an explicitly decoupled computing procedure for optimization and regression is used to embed a binary genetic algorithm into the JRM for optimal joinpoint detection. The combinations of joinpoints were represented as binary chromosomes, and genetic operations were performed to determine the optimum solution by minimizing the fitness function, the Bayesian information criterion (BIC) and BIC3 . The accuracy and computational performance of the GAJP model were evaluated via intensive simulation studies and compared with those of the GS-based methods using BIC, BIC3 , and permutation test. The proposed method showed an outstanding computational efficiency in detecting multiple joinpoints. Finally, the suitability of the GAJP model for the analysis of cancer incidence trends was demonstrated by applying this model to data on the incidence of colorectal cancer in the United States from 1975 to 2016 from the National Cancer Institute's Surveillance, Epidemiology, and End Results program. Thus, the GAJP model was concluded to be practically feasible to detect multiple joinpoints up to the number of grids without requirement to preassign the number of joinpoints and be easily extendable to cancer trend analysis utilizing large datasets. [ABSTRACT FROM AUTHOR]

Biosurveillance for rapid detection of epidemics of diseases is a challenging area of endeavor in many respects. Hence, this area is in need of development of methodology and opens to novel methods of detection. In this study, a new simple statistical early outbreak detection approach is proposed to detect outbreaks of diseases in real time. The new approach is called LWMAT since it is based on linearly weighted moving average. Furthermore, it does not require a long baseline and partly takes into account of likely features of biosurveillance data such as nonstationary and overdispersion to some extent. Moreover, this newly proposed method is easily adapted to automated use in public health surveillance systems to monitor simultaneously large number time series of indicators associated with the relevant diseases. To compare the performance of the new method with those of some well-known outbreak detection methods, semisynthetic data with outbreaks of various magnitudes and durations are simulated by considering the weekly number of outpatient visits for influenza-like illness for the influenza seasons 2014-2015 through 2017-2018 at Centers for Disease Control and Prevention (CDC) in the United States. Under the conditions of the simulation studies, Serfling regression and Farrington flexible seem to be preferable methods for monitoring the weekly influenza data at CDC in terms of early identification of influenza outbreaks with a high probability. In addition, the newly proposed LWMAT-type methods appear to be promising and useful methods in the case of small magnitude outbreaks with a short duration. [ABSTRACT FROM AUTHOR]

Objective: The objective of this research study was to estimate the number of left turn across path/opposite direction (LTAP/OD) crashes and injuries that could be prevented in the United States if vehicles were equipped with an intersection advanced driver assistance system (I-ADAS). Methods: This study reconstructed 501 vehicle-to-vehicle LTAP/OD crashes in the United States that were investigated in the NHTSA National Motor Vehicle Crash Causation Survey (NMVCCS). The performance of 30 different I-ADAS system variations was evaluated for each crash. These variations were the combinations of 5 time-to-collision (TTC) activation thresholds, 3 latency times, and 2 different response types (automated braking and driver warning). In addition, 2 sightline assumptions were modeled for each crash: One where the turning vehicle was visible long before the intersection and one where the turning vehicle was only visible within the intersection. For resimulated crashes that were not avoided by I-ADAS, a new crash delta-V was computed for each vehicle. The probability of Abbreviated Injury Scale 2 or higher injury in any body region (Maximum Abbreviated Injury Scale [MAIS] 2+F) to each front-row occupant was computed. Results: Depending on the system design, sightline assumption, I-ADAS variation, and fleet penetration, an I-ADAS system that automatically applies emergency braking could avoid 18-84% of all LTAP/OD crashes. Only 0-32% of all LTAP/OD crashes could have been avoided using an I-ADAS system that only warns the driver. An I-ADAS system that applies emergency braking could prevent 47-93% of front-row occupants from receiving MAIS 2 + F injuries. A system that warns the driver in LTAP/OD crashes was able to prevent 0-37% of front-row occupants from receiving MAIS 2 + F injuries. The effectiveness of I-ADAS in reducing crashes and number of injured persons was higher when both vehicles were equipped with I-ADAS. Conclusions: This study presents the simulated effectiveness of a hypothetical intersection active safety system on real crashes that occurred in the United States. This work shows that there is a strong potential to reduce crashes and injuries in the United States. [ABSTRACT FROM AUTHOR]

Objective: Analyses of crash data have shown that older, obese, and/or female occupants have a higher risk of injury in frontal crashes compared to the rest of the population. The objective of this study was to use parametric finite element (FE) human models to assess the increased injury risks and identify safety concerns for these vulnerable populations. Methods: We sampled 100 occupants based on age, sex, stature, and body mass index (BMI) to span a wide range of the U.S. adult population. The target anatomical geometry for each of the 100 models was predicted by the statistical geometry models for the rib cage, pelvis, femur, tibia, and external body surface developed previously. A regional landmark-based mesh morphing method was used to morph the Global Human Body Models Consortium (GHBMC) M50-OS model into the target geometries. The morphed human models were then positioned in a validated generic vehicle driver compartment model using a statistical driving posture model. Frontal crash simulations based on U.S. New Car Assessment Program (U.S. NCAP) were conducted. Body region injury risks were calculated based on the risk curves used in the US NCAP, except that scaling was used for the neck, chest, and knee-thigh-hip injury risk curves based on the sizes of the bony structures in the corresponding body regions. Age effects were also considered for predicting chest injury risk. Results: The simulations demonstrated that driver stature and body shape affect occupant interactions with the restraints and consequently affect occupant kinematics and injury risks in severe frontal crashes. U-shaped relations between occupant stature/weight and head injury risk were observed. Chest injury risk was strongly affected by age and sex, with older female occupants having the highest risk. A strong correlation was also observed between BMI and knee-thigh-hip injury risk, whereas none of the occupant parameters meaningfully affected neck injury risks. Conclusions: This study is the first to use a large set of diverse FE human models to investigate the combined effects of age, sex, stature, and BMI on injury risks in frontal crashes. The study demonstrated that parametric human models can effectively predict the injury trends for the population and may now be used to optimize restraint systems for people who are not similar in size and shape to the available anthropomorphic test devices (ATDs). New restraints that adapt to occupant age, sex, stature, and body shape may improve crash safety for all occupants. [ABSTRACT FROM AUTHOR]

Objective: To provide an alternative to propensity scoring (PS) for the common situation where there are interacting covariates.Setting: We used 1.3 million assessments of residents of the United States Veterans Affairs nursing homes, collected from January 1, 2000, through October 9, 2012.Design: In stratified covariate balancing (SCB), data are divided into naturally occurring strata, where each stratum is an observed combination of the covariates. Within each stratum, cases with, and controls without, the target event are counted; controls are weighted to be as frequent as cases. This weighting procedure guarantees that covariates, or combination of covariates, are balanced, meaning they occur at the same rate among cases and controls. Finally, impact of the target event is calculated in the weighted data. We compare the performance of SCB, logistic regression (LR), and propensity scoring (PS) in simulated and real data. We examined the calibration of SCB and PS in predicting 6-month mortality from inability to eat, controlling for age, gender, and nine other disabilities for 296,051 residents in Veterans Affairs nursing homes. We also performed a simulation study, where outcomes were randomly generated from treatment, 10 covariates, and increasing number of covariate interactions. The accuracy of SCB, PS, and LR in recovering the simulated treatment effect was reported.Findings: In simulated environment, as the number of interactions among the covariates increased, SCB and properly specified LR remained accurate but pairwise LR and pairwise PS, the most common applications of these tools, performed poorly. In real data, application of SCB was practical. SCB was better calibrated than linear PS, the most common method of PS.Conclusions: In environments where covariates interact, SCB is practical and more accurate than common methods of applying LR and PS. [ABSTRACT FROM AUTHOR]

Objective: (1) To evaluate the operational efficiency of various sampling methods for patient exit interviews; (2) to discuss under what circumstances each method yields an unbiased sample; and (3) to propose a new, operationally efficient, and unbiased sampling method.Study Design: Literature review, mathematical derivation, and Monte Carlo simulations.Principal Findings: Our simulations show that in patient exit interviews it is most operationally efficient if the interviewer, after completing an interview, selects the next patient exiting the clinical consultation. We demonstrate mathematically that this method yields a biased sample: patients who spend a longer time with the clinician are overrepresented. This bias can be removed by selecting the next patient who enters, rather than exits, the consultation room. We show that this sampling method is operationally more efficient than alternative methods (systematic and simple random sampling) in most primary health care settings.Conclusion: Under the assumption that the order in which patients enter the consultation room is unrelated to the length of time spent with the clinician and the interviewer, selecting the next patient entering the consultation room tends to be the operationally most efficient unbiased sampling method for patient exit interviews. [ABSTRACT FROM AUTHOR]

Objective: The conflicts among motorists entering a signalized intersection with the red light indication have become a national safety issue. Because of its sensitivity, efforts have been made to investigate the possible causes and effectiveness of countermeasures using comparison sites and/or before-and-after studies. Nevertheless, these approaches are ineffective when comparison sites cannot be found, or crash data sets are not readily available or not reliable for statistical analysis. Considering the random nature of red light running (RLR) crashes, an inventive approach regardless of data availability is necessary to evaluate the effectiveness of each countermeasure face to face.Method: The aims of this research are to (1) review erstwhile literature related to red light running and traffic safety models; (2) propose a practical methodology for evaluation of RLR countermeasures with a microscopic traffic simulation model and surrogate safety assessment model (SSAM); (3) apply the proposed methodology to actual signalized intersection in Virginia, with the most prevalent scenarios-increasing the yellow signal interval duration, installing an advance warning sign, and an RLR camera; and (4) analyze the relative effectiveness by RLR frequency and the number of conflicts (rear-end and crossing).Results: All scenarios show a reduction in RLR frequency (-7.8, -45.5, and -52.4%, respectively), but only increasing the yellow signal interval duration results in a reduced total number of conflicts (-11.3%; a surrogate safety measure of possible RLR-related crashes). An RLR camera makes the greatest reduction (-60.9%) in crossing conflicts (a surrogate safety measure of possible angle crashes), whereas increasing the yellow signal interval duration results in only a 12.8% reduction of rear-end conflicts (a surrogate safety measure of possible rear-end crash).Conclusions: Although increasing the yellow signal interval duration is advantageous because this reduces the total conflicts (a possibility of total RLR-related crashes), each countermeasure shows different effects by RLR-related conflict types that can be referred to when making a decision. Given that each intersection has different RLR crash issues, evaluated countermeasures are directly applicable to enhance the cost and time effectiveness, according to the situation of the target intersection. In addition, the proposed methodology is replicable at any site that has a dearth of crash data and/or comparison sites in order to test any other countermeasures (both engineering and enforcement countermeasures) for RLR crashes. [ABSTRACT FROM AUTHOR]

Objectives: The U.S. New Car Assessment Program (NCAP) now tests for forward collision warning (FCW) and lane departure warning (LDW). The design of these warnings differs greatly between vehicles and can result in different real-world field performance in preventing or mitigating the effects of collisions. The objective of this study was to compare the expected number of crashes and injured drivers that could be prevented if all vehicles in the fleet were equipped with the FCW and LDW systems tested under the U.S. NCAP.Methods: To predict the potential crashes and serious injury that could be prevented, our approach was to computationally model the U.S. crash population. The models simulated all rear-end and single-vehicle road departure collisions that occurred in a nationally representative crash database (NASS-CDS). A sample of 478 single-vehicle crashes from NASS-CDS 2012 was the basis for 24,822 simulations for LDW. A sample of 1,042 rear-end collisions from NASS-CDS years 1997-2013 was the basis for 7,616 simulations for FCW. For each crash, 2 simulations were performed: (1) without the system present and (2) with the system present. Models of each production safety system were based on 54 model year 2010-2014 vehicles that were evaluated under the NCAP confirmation procedure for LDW and/or FCW. NCAP performed 40 LDW and 45 FCW tests of these vehicles.Results: The design of the FCW systems had a dramatic impact on their potential to prevent crashes and injuries. Between 0 and 67% of crashes and 2 and 69% of moderately to fatally injured drivers in rear-end impacts could have been prevented if all vehicles were equipped with the FCW systems. Earlier warning times resulted in increased benefits. The largest effect on benefits, however, was the lower operating speed threshold of the systems. Systems that only operated at speeds above 20 mph were less than half as effective as those that operated above 5 mph with similar warning times. The production LDW systems could have prevented between 11 and 23% of drift-out-of-lane crashes and 13 and 22% of seriously to fatally injured drivers. A majority of the tested LDW systems delivered warnings near the point when the vehicle first touched the lane line, leading to similar benefits. Minimum operating speed also greatly affected LDW effectiveness.Conclusions: The results of this study show that the expected field performance of FCW and LDW systems are highly dependent on the design and system limitations. Systems that delivered warnings earlier and operated at lower speeds may prevent far more crashes and injuries than systems that warn late and operate only at high speeds. These results suggest that future FCW and LDW evaluation should prioritize early warnings and full-speed range operation. A limitation of this study is that additional crash avoidance features that may also mitigate collisions-for example, brake assist, automated braking, or lane-keeping assistance-were not evaluated during the NCAP tests or in our benefits models. The potential additional mitigating effects of these systems were not quantified in this study. [ABSTRACT FROM AUTHOR]

Recent studies found that infection-related hospitalization was associated with increased risk of cardiovascular (CV) events, such as myocardial infarction and stroke in the dialysis population. In this work, we develop time-varying effects modeling tools in order to examine the CV outcome risk trajectories during the time periods before and after an initial infection-related hospitalization. For this, we propose partly conditional and fully conditional partially linear generalized varying coefficient models (PL-GVCMs) for modeling time-varying effects in longitudinal data with substantial follow-up truncation by death. Unconditional models that implicitly target an immortal population is not a relevant target of inference in applications involving a population with high mortality, like the dialysis population. A partly conditional model characterizes the outcome trajectory for the dynamic cohort of survivors, where each point in the longitudinal trajectory represents a snapshot of the population relationships among subjects who are alive at that time point. In contrast, a fully conditional approach models the time-varying effects of the population stratified by the actual time of death, where the mean response characterizes individual trends in each cohort stratum. We compare and contrast partly and fully conditional PL-GVCMs in our aforementioned application using hospitalization data from the United States Renal Data System. For inference, we develop generalized likelihood ratio tests. Simulation studies examine the efficacy of estimation and inference procedures. [ABSTRACT FROM AUTHOR]