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231.
Elizabethkingia spp. are common environmental pathogens responsible for infections in more vulnerable populations. Although the exposure routes of concern are not well understood, some hospital-associated outbreaks have indicated possible waterborne transmission. In order to facilitate quantitative microbial risk assessment (QMRA) for Elizabethkingia spp., this study fit dose–response models to frog and mice datasets that evaluated intramuscular and intraperitoneal exposure to Elizabethkingia spp. The frog datasets could be pooled, and the exact beta-Poisson model was the best fitting model with optimized parameters α = 0.52 and β = 86,351. Using the exact beta-Poisson model, the dose of Elizabethkingia miricola resulting in a 50% morbidity response (LD50) was estimated to be approximately 237,000 CFU. The model developed herein was used to estimate the probability of infection for a hospital patient under a modeled exposure scenario involving a contaminated medical device and reported Elizabethkingia spp. concentrations isolated from hospital sinks after an outbreak. The median exposure dose was approximately 3 CFU/insertion event, and the corresponding median risk of infection was 3.4E-05. The median risk estimated in this case study was lower than the 3% attack rate observed in a previous outbreak, however, there are noted gaps pertaining to the possible concentrations of Elizabethkingia spp. in tap water and the most likely exposure routes. This is the first dose–response model developed for Elizabethkingia spp. thus enabling future risk assessments to help determine levels of risk and potential effective risk management strategies. 相似文献
232.
Alicia A. Taylor Joyce S. Tsuji Margaret E. McArdle William J. Adams William L. Goodfellow Jr. 《Risk analysis》2023,43(2):211-218
The U.S. Environmental Protection Agency's (EPA) Integrated Risk Information System (IRIS) database, the authoritative source of U.S. risk assessment toxicity factors, currently lacks an oral reference dose (RfD) for copper. In the absence of such a value, various health-based reference values for copper are available for use in risk assessment. We summarize the scientific bases and differences in assumptions among key reference values for ingested copper to guide selection of appropriate values for risk assessment. A comprehensive review of the scientific literature best supports the oral RfD of 0.04 mg/kg body weight/day derived by EPA from their Drinking Water Action Level. This value is based on acute gastrointestinal effects but is further supported by broader analysis of copper deficiency and toxicity. 相似文献
233.
The primary objective of an oncology dose-finding trial for novel therapies, such as molecularly targeted agents and immune-oncology therapies, is to identify the optimal dose (OD) that is tolerable and therapeutically beneficial for subjects in subsequent clinical trials. Pharmacokinetic (PK) information is considered an appropriate indicator for evaluating the level of drug intervention in humans from a pharmacological perspective. Several novel anticancer agents have been shown to have significant exposure-efficacy relationships, and some PK information has been considered an important predictor of efficacy. This paper proposes a Bayesian optimal interval design for dose optimization with a randomization scheme based on PK outcomes in oncology. A simulation study shows that the proposed design has advantages compared to the other designs in the percentage of correct OD selection and the average number of patients allocated to OD in various realistic settings. 相似文献
234.
Estimating microbial dose–response is an important aspect of a food safety risk assessment. In recent years, there has been considerable interest to advance these models with potential incorporation of gene expression data. The aim of this study was to develop a novel machine learning model that considers the weights of expression of Salmonella genes that could be associated with illness, given exposure, in hosts. Here, an elastic net-based weighted Poisson regression method was proposed to identify Salmonella enterica genes that could be significantly associated with the illness response, irrespective of serovar. The best-fit elastic net model was obtained by 10-fold cross-validation. The best-fit elastic net model identified 33 gene expression–dose interaction terms that added to the predictability of the model. Of these, nine genes associated with Salmonella metabolism and virulence were found to be significant by the best-fit Poisson regression model (p < 0.05). This method could improve or redefine dose–response relationships for illness from relative proportions of significant genes from a microbial genetic dataset, which would help in refining endpoint and risk estimations. 相似文献
235.
In modern oncology drug development, adaptive designs have been proposed to identify the recommended phase 2 dose. The conventional dose finding designs focus on the identification of maximum tolerated dose (MTD). However, designs ignoring efficacy could put patients under risk by pushing to the MTD. Especially in immuno-oncology and cell therapy, the complex dose-toxicity and dose-efficacy relationships make such MTD driven designs more questionable. Additionally, it is not uncommon to have data available from other studies that target on similar mechanism of action and patient population. Due to the high variability from phase I trial, it is beneficial to borrow historical study information into the design when available. This will help to increase the model efficiency and accuracy and provide dose specific recommendation rules to avoid toxic dose level and increase the chance of patient allocation at potential efficacious dose levels. In this paper, we propose iBOIN-ET design that uses prior distribution extracted from historical studies to minimize the probability of decision error. The proposed design utilizes the concept of skeleton from both toxicity and efficacy data, coupled with prior effective sample size to control the amount of historical information to be incorporated. Extensive simulation studies across a variety of realistic settings are reported including a comparison of iBOIN-ET design to other model based and assisted approaches. The proposed novel design demonstrates the superior performances in percentage of selecting the correct optimal dose (OD), average number of patients allocated to the correct OD, and overdosing control during dose escalation process. 相似文献
236.
Yanhong Zhou Yujie Zhao Greg Cicconetti Yunming Mu Ying Yuan Li Wang Sudhir Penugonda Zeena Salman 《Pharmaceutical statistics》2023,22(2):300-311
Designing Phase I clinical trials is challenging when accrual is slow or sample size is limited. The corresponding key question is: how to efficiently and reliably identify the maximum tolerated dose (MTD) using a sample size as small as possible? We propose model-assisted and model-based designs with adaptive intrapatient dose escalation (AIDE) to address this challenge. AIDE is adaptive in that the decision of conducting intrapatient dose escalation depends on both the patient's individual safety data, as well as other enrolled patient's safety data. When both data indicate reasonable safety, a patient may perform intrapatient dose escalation, generating toxicity data at more than one dose. This strategy not only provides patients the opportunity to receive higher potentially more effective doses, but also enables efficient statistical learning of the dose-toxicity profile of the treatment, which dramatically reduces the required sample size. Simulation studies show that the proposed designs are safe, robust, and efficient to identify the MTD with a sample size that is substantially smaller than conventional interpatient dose escalation designs. Practical considerations are provided and R code for implementing AIDE is available upon request. 相似文献
237.
Recently, the US Food and Drug Administration Oncology Center of Excellence initiated Project Optimus to reform the dose optimization and dose selection paradigm in oncology drug development. The agency pointed out that the current paradigm for dose selection—based on the maximum tolerated dose (MTD)—is not sufficient for molecularly targeted therapies and immunotherapies, for which efficacy may not increase after the dose reaches a certain level. In these cases, it is more appropriate to identify the optimal biological dose (OBD) that optimizes the risk–benefit tradeoff of the drug. Project Optimus has spurred tremendous interest and urgent need for guidance on designing dose optimization trials. In this article, we review several representative dose optimization designs, including model-based and model-assisted designs, and compare their operating characteristics based on 10,000 randomly generated scenarios with various dose-toxicity and dose-efficacy curves and some fixed representative scenarios. The results show that, compared with model-based designs, model-assisted methods have advantages of easy-to-implement, robustness, and high accuracy to identify OBD. Some guidance is provided to help biostatisticians and clinicians to choose appropriate dose optimization methods in practice. 相似文献
238.
农村信贷与农业保险互动是金融支农的优化模式,在此模式下,农户、信贷机构和保险公司的合作博弈不仅能提高整体收益,并且根据Shapley值分配原则,农户、信贷机构与保险公司各自的收益也能得到提高。但小规模分散经营的农户因缺乏谈判力而面临利益被瓜分的风险,进而可能会退出参与或抵制合作;为了促进合作联盟的形成与稳固,一个可行的解决思路是政府制定贷款利率优惠政策,实施保费补贴,引导发展农村经济合作组织以保证农户的收益;同时,保险公司与信贷机构通过委托代理形成合作关系,并使用Shapley值分配原则来确定代理费率并签订合约。 相似文献