New approach methodologies predicting human cardiotoxicity are of interest to support or even replace in vivo-based drug safety testing. The present study presents an in vitro–in silico approach to predict the effect of inter-individual and inter-ethnic kinetic variations in the cardiotoxicity of R- and S-methadone in the Caucasian and the Chinese population. In vitro cardiotoxicity data, and metabolic data obtained from two approaches, using either individual human liver microsomes or recombinant cytochrome P450 enzymes (rCYPs), were integrated with physiologically based kinetic (PBK) models and Monte Carlo simulations to predict inter-individual and inter-ethnic variations in methadone-induced cardiotoxicity. Chemical specific adjustment factors were defined and used to derive dose–response curves for the sensitive individuals. Our simulations indicated that Chinese are more sensitive towards methadone-induced cardiotoxicity with Margin of Safety values being generally two-fold lower than those for Caucasians for both methadone enantiomers. Individual PBK models using microsomes and PBK models using rCYPs combined with Monte Carlo simulations predicted similar inter-individual and inter-ethnic variations in methadone-induced cardiotoxicity. The present study illustrates how inter-individual and inter-ethnic variations in cardiotoxicity can be predicted by combining in vitro toxicity and metabolic data, PBK modelling and Monte Carlo simulations. The novel methodology can be used to enhance cardiac safety evaluations and risk assessment of chemicals.
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The aim of the present study was to predict the effect of inter-individual and inter-ethnic human kinetic variation on the sensitivity towards acute liver toxicity of lasiocarpine in the Chinese and the Caucasian population, and to derive chemical specific adjustment factors (CSAFs) by integrating variation in the in vitro kinetic constants Vmax and Km, physiologically based kinetic (PBK) modelling and Monte Carlo simulation. CSAFs were derived covering the 90th and 99th percentile of the population distribution of pyrrole glutathione adduct (7-GS-DHP) formation, reflecting bioactivation. The results revealed that in the Chinese population, as compared to the Caucasian population, the predicted 7-GS-DHP formation at the geometric mean, the 90th and the 99th percentile were 2.1-, 3.3- and 4.3-fold lower respectively. The CSAFs obtained using the 99th percentile values were 8.3, 17.0 and 19.5 in the Chinese, the Caucasian population and the two populations combined, respectively, while the CSAFs were generally 3.0-fold lower at the 90th percentile. These results indicate that when considering the formation of 7-GS-DHP the Caucasian population may be more sensitive towards acute liver toxicity of lasiocarpine, and further point out that the default safety factor of 3.16 for inter-individual human kinetic differences may not be sufficiently protective. Altogether, the results obtained demonstrate that integrating PBK modelling with Monte Carlo simulations using human in vitro data is a powerful strategy to quantify inter-individual variations in kinetics, and can be used to refine the human risk assessment of pyrrolizidine alkaloids.
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Epidemiological miner cohort data used to estimate lung cancer risks related to occupational radon exposure often lack cohort-wide information on exposure to tobacco smoke, a potential confounder and important effect modifier. We have developed a method to project data on smoking habits from a case-control study onto an entire cohort by means of a Monte Carlo resampling technique. As a proof of principle, this method is tested on a subcohort of 35,084 former uranium miners employed at the WISMUT company (Germany), with 461 lung cancer deaths in the follow-up period 1955–1998. After applying the proposed imputation technique, a biologically-based carcinogenesis model is employed to analyze the cohort's lung cancer mortality data. A sensitivity analysis based on a set of 200 independent projections with subsequent model analyses yields narrow distributions of the free model parameters, indicating that parameter values are relatively stable and independent of individual projections. This technique thus offers a possibility to account for unknown smoking habits, enabling us to unravel risks related to radon, to smoking, and to the combination of both.
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The present study compares two approaches to evaluate the effects of inter-individual differences in the biotransformation of chlorpyrifos (CPF) on the sensitivity towards in vivo red blood cell (RBC) acetylcholinesterase (AChE) inhibition and to calculate a chemical-specific adjustment factor (CSAF) to account for inter-individual differences in kinetics (HKAF). These approaches included use of a Supersome™ cytochromes P450 (CYP)-based and a human liver microsome (HLM)-based physiologically based kinetic (PBK) model, both combined with Monte Carlo simulations. The results revealed that bioactivation of CPF exhibits biphasic kinetics caused by distinct differences in the Km of CYPs involved, which was elucidated by Supersome™ CYP rather than by HLM. Use of Supersome™ CYP-derived kinetic data was influenced by the accuracy of the intersystem extrapolation factors (ISEFs) required to scale CYP isoform activity of Supersome™ to HLMs. The predicted dose–response curves for average, 99th percentile and 1st percentile sensitive individuals were found to be similar in the two approaches when biphasic kinetics was included in the HLM-based approach, resulting in similar benchmark dose lower confidence limits for 10% inhibition (BMDL10) and HKAF values. The variation in metabolism-related kinetic parameters resulted in HKAF values at the 99th percentile that were slightly higher than the default uncertainty factor of 3.16. While HKAF values up to 6.9 were obtained when including also the variability in other influential PBK model parameters. It is concluded that the Supersome™ CYP-based approach appeared most adequate for identifying inter-individual variation in biotransformation of CPF and its resulting RBC AChE inhibition.
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PURPOSE: Advanced radiotherapy treatments require appropriate quality assurance (QA) to verify 3D dose distributions. Moreover, increase in patient numbers demand efficient QA-methods. In this study, a time efficient method that combines model-based QA and measurement-based QA was developed; i.e., the hybrid-QA. The purpose of this study was to determine the reliability of the model-based QA and to evaluate time efficiency of the hybrid-QA method.METHODS: Accuracy of the model-based QA was determined by comparison of COMPASS calculated dose with Monte Carlo calculations for heterogeneous media. In total, 330 intensity modulated radiation therapy (IMRT) treatment plans were evaluated based on the mean gamma index (GI) with criteria of 3%∕3mm and classification of PASS (GI ≤ 0.4), EVAL (0.4 < GI > 0.6), and FAIL (GI ≥ 0.6). Agreement between model-based QA and measurement-based QA was determined for 48 treatment plans, and linac stability was verified for 15 months. Finally, time efficiency improvement of the hybrid-QA was quantified for four representative treatment plans.RESULTS: COMPASS calculated dose was in agreement with Monte Carlo dose, with a maximum error of 3.2% in heterogeneous media with high density (2.4 g∕cm(3)). Hybrid-QA results for IMRT treatment plans showed an excellent PASS rate of 98% for all cases. Model-based QA was in agreement with measurement-based QA, as shown by a minimal difference in GI of 0.03 ± 0.08. Linac stability was high with an average GI of 0.28 ± 0.04. The hybrid-QA method resulted in a time efficiency improvement of 15 min per treatment plan QA compared to measurement-based QA.CONCLUSIONS: The hybrid-QA method is adequate for efficient and accurate 3D dose verification. It combines time efficiency of model-based QA with reliability of measurement-based QA and is suitable for implementation within any radiotherapy department.
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The two-dimensional vehicle routing problem (2L-VRP) is a realistic extension of the classical vehicle routing problem where customers’ demands are composed by sets of non-stackable items. Examples of such problems can be found in many real-life applications, e.g. furniture or industrial machinery transportation. Often, these real-life instances have to deal with uncertainty in many aspects of the problem, such as variable traveling times due to traffic conditions or customers availability. We present a hybrid simheuristic algorithm that combines biased-randomized routing and packing heuristics within a multi-start framework. Monte Carlo simulation is used to deal with uncertainty at different stages of the search process. With the goal of minimizing total expected cost, we use this methodology to solve a set of stochastic instances of the 2L-VRP with unrestricted oriented loading. Our results show that accounting for systems variability during the algorithm search yields more robust solutions with lower expected costs.
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We propose a novel deception detection system based on Rapid Serial Visual Presentation (RSVP). One motivation for the new method is to present stimuli on the fringe of awareness, such that it is more difficult for deceivers to confound the deception test using countermeasures. The proposed system is able to detect identity deception (by using the first names of participants) with a 100% hit rate (at an alpha level of 0.05). To achieve this, we extended the classic Event-Related Potential (ERP) techniques (such as peak-to-peak) by applying Randomisation, a form of Monte Carlo resampling, which we used to detect deception at an individual level. In order to make the deployment of the system simple and rapid, we utilised data from three electrodes only: Fz, Cz and Pz. We then combined data from the three electrodes using Fisher's method so that each participant was assigned a single p-value, which represents the combined probability that a specific participant was being deceptive. We also present subliminal salience search as a general method to determine what participants find salient by detecting breakthrough into conscious awareness using EEG.
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ObjectiveTo compare estimates of effect and variability resulting from standard linear regression analysis and hierarchical multilevel analysis with cross-classified multilevel analysis under various scenarios.Study design and settingWe performed a simulation study based on a data structure from an observational study in clinical mental health care. We used a Markov chain Monte Carlo approach to simulate 18 scenarios, varying sample sizes, cluster sizes, effect sizes and between group variances. For each scenario, we performed standard linear regression, multilevel regression with random intercept on patient level, multilevel regression with random intercept on nursing team level and cross-classified multilevel analysis.ResultsApplying cross-classified multilevel analyses had negligible influence on the effect estimates. However, ignoring cross-classification led to underestimation of the standard errors of the covariates at the two cross-classified levels and to invalidly narrow confidence intervals. This may lead to incorrect statistical inference. Varying sample size, cluster size, effect size and variance had no meaningful influence on these findings.ConclusionIn case of cross-classified data structures, the use of a cross-classified multilevel model helps estimating valid precision of effects, and thereby, support correct inferences.
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Spontaneous speech is an important source of information for aphasia research. It is essential to collect the right amount of data: enough for distinctions in the data to become meaningful, but not so much that the data collection becomes too expensive or places an undue burden on participants. The latter issue is an ethical consideration when working with participants that find speaking difficult, such as speakers with aphasia. So, how much speech data is enough to draw meaningful conclusions? How does the uncertainty around the estimation of model parameters in a predictive model vary as a function of the length of texts used for training?
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