Approximating Cross-validatory Predictive P-values with Integrated IS for Disease Mapping Models

An important statistical task in disease mapping problems is to identify out- lier/divergent regions with unusually high or low residual risk of disease. Leave-one-out cross-validatory (LOOCV) model assessment is a gold standard for computing predictive p-value that can flag such outliers. However, actual LOOCV is time-consuming because one needs to re-simulate a Markov chain for each posterior distribution in which an observation is held out as a test case. This paper introduces a new method, called iIS, for approximating LOOCV with only Markov chain samples simulated from a posterior based on a full data set. iIS is based on importance sampling (IS). iIS integrates the p-value and the likelihood of the test observation with respect to the distribution of the latent variable without reference to the actual observation. The predictive p-values computed with iIS can be proved to be equivalent to the LOOCV predictive p-values, following the general theory for IS. We com- pare iIS and other three existing methods in the literature with a lip cancer dataset collected in Scotland. Our empirical results show that iIS provides predictive p-values that are al- most identical to the actual LOOCV predictive p-values and outperforms the existing three methods, including the recently proposed ghosting method by Marshall and Spiegelhalter (2007).Comment: 21 page

A Comparison of Parameter Estimation Methods for Shared Frailty Models

This paper compares six different parameter estimation methods for shared frailty models via a series of simulation studies. A shared frailty model is a survival model that incorporates a random effect term, where the frailties are common or shared among individuals within specific groups. Several parameter estimation methods are available for fitting shared frailty models, such as penalized partial likelihood (PPL), expectation-maximization (EM), pseudo full likelihood (PFL), hierarchical likelihood (HL), maximum marginal likelihood (MML), and maximization penalized likelihood (MPL) algorithms. These estimation methods are implemented in various R packages, providing researchers with various options for analyzing clustered survival data using shared frailty models. However, there is a limited amount of research comparing the performance of these parameter estimation methods for fitting shared frailty models. Consequently, it can be challenging for users to determine the most appropriate method for analyzing clustered survival data. To address this gap, this paper aims to conduct a series of simulation studies to compare the performance of different parameter estimation methods implemented in R packages. We will evaluate several key aspects, including parameter estimation, bias and variance of the parameter estimates, rate of convergence, and computational time required by each package. Through this systematic evaluation, our goal is to provide a comprehensive understanding of the advantages and limitations associated with each estimation method

Beyond Nigiri and Anisakiasis, The Tale of Sushi: History and Regulation

This paper is an exploration of the history of sushi consumption in the United States and how the ingredients of sushi are regulated. The paper delineates the course of sushi’s culinary history in Japan, and will attempt to present an overview on the incremental process by which sushi as a cuisine evolved from a humble street food with scarce recognition to an immensely sophisticated popular cuisine in Japan and America. After describing and analyzing the historical background of sushi, the paper will present the underpinnings of the confounding set of etiquettes that center the art of consuming sushi. This paper will also examine sushi as an exemplary form of successful, multi-directional product of globalization. It is intriguing to observe sushi as a circulating global commodity that internalizes and promotes regional dietary preferences and cultural practices. The second half of the paper will discuss both the health benefits and health hazards associated with the sushi cuisine. While the seafood, seaweed, and seasoning involved with eating sushi have high nutritional value, sushi consumers need to be aware of the perilous nature of mercury poisoning and the biological contaminants that are embedded in improperly processed sushi fish. The FDA’s current consumer advisory scheme on mercury poisoning is incomprehensive, conflicts with the guidelines that EPA delineates, and its inspection and surveillance guidelines are in practice difficult to enforce. The last section of the paper will trace the development of the Seafood Hazard Analysis and Critical Control Point Plan (HACCP) and compare its prospective policy visions and practical guidelines with the Hong Kong Food and Environmental Hygiene Department’s (FEHD) Sushi Surveillance Guidelines

An Opposite Effect of the CDK Inhibitor, p18^INK4c on Embryonic Stem Cells Compared with Tumor and Adult Stem Cells

Self-renewal is a feature common to both adult and embryonic stem (ES) cells, as well as tumor stem cells (TSCs). The cyclin-dependent kinase inhibitor, p18INK4c, is a known tumor suppressor that can inhibit self-renewal of tumor cells or adult stem cells. Here, we demonstrate an opposite effect of p18 on ES cells in comparison with teratoma cells. Our results unexpectedly showed that overexpression of p18 accelerated the growth of mouse ES cells and embryonic bodies (EB); on the contrary, inhibited the growth of late stage teratoma. Up-regulation of ES cell markers (i.e., Oct4, Nanog, Sox2, and Rex1) were detected in both ES and EB cells, while concomitant down-regulation of various differentiation markers was observed in EB cells. These results demonstrate that p18 has an opposite effect on ES cells as compared with tumor cells and adult stem cells. Mechanistically, expression of CDK4 was significantly increased with overexpression of p18 in ES cells, likely leading to a release of CDK2 from the inhibition by p21 and p27. As a result, self-renewal of ES cells was enhanced. Our current study suggests that targeting p18 in different cell types may yield different outcomes, thereby having implications for therapeutic manipulations of cell cycle machinery in stem cells. © 2012 Li et al

Functional analysis of BARD1 missense variants in homology-directed repair and damage sensitivity

The BARD1 protein, which heterodimerizes with BRCA1, is encoded by a known breast cancer susceptibility gene. While several BARD1 variants have been identified as pathogenic, many more missense variants exist that do not occur frequently enough to assign a clinical risk. In this paper, whole exome sequencing of over 10,000 cancer samples from 33 cancer types identified from somatic mutations and loss of heterozygosity in tumors 76 potentially cancer-associated BARD1 missense and truncation variants. These variants were tested in a functional assay for homology-directed repair (HDR), as HDR deficiencies have been shown to correlate with clinical pathogenicity for BRCA1 variants. From these 76 variants, 4 in the ankyrin repeat domain and 5 in the BRCT domain were found to be non-functional in HDR. Two known benign variants were found to be functional in HDR, and three known pathogenic variants were non-functional, supporting the notion that the HDR assay can be used to predict the clinical risk of BARD1 variants. The identification of HDR-deficient variants in the ankyrin repeat domain indicates there are DNA repair functions associated with this domain that have not been closely examined. In order to examine whether BARD1-associated loss of HDR function results in DNA damage sensitivity, cells expressing non-functional BARD1 variants were treated with ionizing radiation or cisplatin. These cells were found to be more sensitive to DNA damage, and variations in the residual HDR function of non-functional variants did not correlate with variations in sensitivity. These findings improve the understanding of BARD1 functional domains in DNA repair and support that this functional assay is useful for predicting the cancer association of BARD1 variants.</div

Prescription opioid injection and risk of hepatitis C in relation to traditional drugs of misuse in a prospective cohort of street youth

Objective: Despite dramatic increases in the misuse of prescription opioids, the extent to which their intravenous injection places drug users at risk of acquiring hepatitis C virus (HCV) remains unclear. We sought to compare risk of HCV acquisition from injection of prescription opioids to that from other street drugs among high-risk street youth. Design: Prospective cohort study. Setting: Vancouver, British Columbia, Canada from September 2005 to November 2011. Participants: The At-Risk Youth Study (ARYS) is a prospective cohort of drug-using adolescents and young adults aged 14–26 years. Participants were recruited through street-based outreach and snowball sampling. Primary outcome measure HCV antibody seroconversion, measured every 6 months during follow-up. Risk for seroconversion from injection of prescription opioids was compared with injection of other street drugs of misuse, including heroin, cocaine or crystal methamphetamine, using Cox proportional hazards regression controlling for age, gender and syringe sharing. Results: Baseline HCV seropositivity was 10.6%. Among 512 HCV-seronegative youth contributing 860.2 person-years of follow-up, 56 (10.9%) seroconverted, resulting in an incidence density of 6.5/100 person-years. In bivariate analyses, prescription opioid injection (HR=3.48; 95% CI 1.57 to 7.70) predicted HCV seroconversion. However, in multivariate modelling, only injection of heroin (adjusted HR=4.56; 95% CI 2.39 to 8.70), cocaine (adjusted HR=1.88; 95% CI 1.00 to 3.54) and crystal methamphetamine (adjusted HR=2.91; 95% CI 1.57 to 5.38) remained independently associated with HCV seroconversion, whereas injection of prescription opioids did not (adjusted HR=0.94; 95% CI 0.40 to 2.21). Conclusions: Although misuse of prescription opioids is on the rise, traditional street drugs still posed the greatest threat of HCV transmission in this setting. Nonetheless, the high prevalence and incidence of HCV among Canadian street youth underscore the need for evidence-based drug prevention, treatment and harm reduction interventions targeting this vulnerable population

Potential complementary therapy for adverse drug reactions to sulfonamides: Chemoprotection against oxidative and nitrosative stress by TCM constituents and defined mixtures

PURPOSE: Our working hypothesis is that bioactive phytochemicals that are important constituents of Traditional Chinese Medicine and their defined mixtures have potential as complementary therapy for chemoprotection against adverse drug reactions whose toxicity is not related to the pharmacological action of the drug but where oxidative and nitrosative stress are causative factors. METHODS: In this investigation we measured cytotoxicity, lipid peroxidation, protein carbonylation and ROS/NOS-mediated changes in the disulfide proteome of Jurkat E6.1 cells resulting from exposure to sulfamethoxazole N-hydroxylamine with or without pretreatment with low µM concentrations of baicalein, crocetin, resveratrol and schisanhenol alone and in defined mixtures to compare the ability of these treatment regimens to protect against ROS/RNS toxicity to Jurkat E6.1 cells in culture. RESULTS: Each of the Traditional Chinese Medicine constituents and defined mixtures tested had significant chemoprotective effects against the toxicity of ROS/RNS formed by exposure of Jurkat E6.1 cells to reactive metabolites of sulfamethoxazole implicated as the causative factors in adverse drug reactions to sulfa drugs used for therapy. At equimolar concentrations, the defined mixtures tended to be more effective chemoprotectants overall than any of the single constituents against ROS/RNs toxicity in this context. CONCLUSIONS: At low µM concentrations, defined mixtures of TCM constituents that contain ingredients with varied structures and multiple mechanisms for chemoprotection have excellent potential for complementary therapy with sulfa drugs to attenuate adverse effects caused by oxidative/nitrosative stress. Typically, such mixtures will have a combination of immediate activity due to short in vivo half-lives of some ingredients cleared rapidly following metabolism by phase 2 conjugation enzymes; and some ingredients with more prolonged halflives and activity reliant on phase 1 oxidation enzymes for their metabolic clearance