A genome-wide tree- and forest-based association analysis of comorbidity of alcoholism and smoking

Genetic mechanisms underlying alcoholism are complex. Understanding the etiology of alcohol dependence and its comorbid conditions such as smoking is important because of the significant health concerns. In this report, we describe a method based on classification trees and deterministic forests for association studies to perform a genome-wide joint association analysis of alcoholism and smoking. This approach is used to analyze the single-nucleotide polymorphism data from the Collaborative Study on the Genetics of Alcoholism in the Genetic Analysis Workshop 14. Our analysis reaffirmed the importance of sex difference in alcoholism. Our analysis also identified genes that were reported in other studies of alcoholism and identified new genes or single-nucleotide polymorphisms that can be useful candidates for future studies

Multivariate linkage analysis using the electrophysiological phenotypes in the COGA alcoholism data

Multivariate linkage analysis using several correlated traits may provide greater statistical power to detect susceptibility genes in loci whose effects are too small to be detected in univariate analysis. In this analysis, we apply a new approach and perform a linkage analysis of several electrophysiological phenotypes of the Collaborative Study on the Genetics of Alcoholism data of the Genetic Analysis Workshop 14. Our approach is based on a variance-component model to map candidate genes using repeated or longitudinal measurements. It can take into account covariate effects and time-dependent genetic effects in general pedigree data. We compare our results with the ones obtained by SOLAR using single measurement data. Our multivariate linkage analysis found linkage evidence on two regions on chromosome 4: around marker GABRB1 at 51.4 cM and marker FABP2 at 116.8 cM (unadjusted p-value = 0.00006)

Association of Prenatal Urinary Concentrations of Phthalates and Bisphenol A and Pubertal Timing in Boys and Girls.

BackgroundAnimal studies suggest that phthalates and bisphenol A (BPA), endocrine-disrupting chemicals found in many consumer products, may impact the timing of puberty.ObjectivesWe aimed to determine the association of prenatal exposure to high-molecular-weight phthalates and BPA with pubertal timing in boys and girls participating in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) longitudinal cohort study.MethodsWe quantified urinary concentrations of eight phthalate metabolites and BPA at two time points during pregnancy among participating mothers ([Formula: see text]) and conducted clinical Tanner staging of puberty on their children every 9 months between 9 and 13 y of age. We conducted accelerated failure time models and examined the role of child overweight/obese status in this association.ResultsThe sum of urinary metabolites of di(2-ethylhexyl) phthalate [Formula: see text], monobenzyl phthalate (MBzP), and BPA were associated with later onset of at least one of the three outcomes assessed in girls (thelarche, pubarche, or menarche) and with earlier onset of at least one of the two outcomes assessed in boys (gondarche and pubarche). We found that monocarboxynonyl phthalate, monocarboxyoctyl phthalate, mono(3-carboxypropyl) phthalate, and BPA were associated with later pubarche and menarche mostly among normal-weight girls but not overweight/obese girls. MBzP was associated with later thelarche in all girls, and [Formula: see text] was associated with later thelarche and menarche in all girls. BPA and all phthalate biomarkers were associated with earlier gonadarche and pubarche in all boys as well as in overweight/obese boys when stratified by weight. Among normal-weight boys, associations with BPA were also inverse, whereas associations with phthalate metabolites were close to the null or positive.ConclusionsSeveral high-molecular-weight phthalates and BPA were associated with later puberty in girls and earlier puberty in boys included in the CHAMACOS cohort study. Childhood overweight/obesity may modify these associations. https://doi.org/10.1289/EHP3424

Variability of Urinary Concentrations of Bisphenol A in Spot Samples, First Morning Voids, and 24-Hour Collections

Background: Human exposure to bisphenol A (BPA) is widespread. After exposure, BPA is rapidly metabolized and eliminated in urine. Therefore, there is considerable within-person and between-person variability of BPA concentrations in spot urine samples. However, no information exists on the within-day variability of urinary BPA concentrations

A Robust and Fast System for CTC Computer-Aided Detection of Colorectal Lesions

We present a complete, end-to-end computer-aided detection (CAD) system for identifying lesions in the colon, imaged with computed tomography (CT). This system includes facilities for colon segmentation, candidate generation, feature analysis, and classification. The algorithms have been designed to offer robust performance to variation in image data and patient preparation. By utilizing efficient 2D and 3D processing, software optimizations, multi-threading, feature selection, and an optimized cascade classifier, the CAD system quickly determines a set of detection marks. The colon CAD system has been validated on the largest set of data to date, and demonstrates excellent performance, in terms of its high sensitivity, low false positive rate, and computational efficiency

Considerations for Master Protocols Using External Controls

There has been an increasing use of master protocols in oncology clinical trials because of its efficiency and flexibility to accelerate cancer drug development. Depending on the study objective and design, a master protocol trial can be a basket trial, an umbrella trial, a platform trial, or any other form of trials in which multiple drugs and/or multiple subpopulations are studied in parallel under a single protocol. External data and evidence (EDE) can be used in the design and analysis of master protocols such as external controls for treatment effect estimation, which can further improve efficiency of the master protocol trial. This paper provides an overview of different types of external controls and their unique features when used in master protocols. Some key considerations in master protocols with external controls are discussed including construction of estimands and assessment of fit-for-use real-world data. A targeted learning-based causal roadmap is presented which constitutes three key steps: (1) define a target statistical estimand that aligns with the causal estimand for the study objective, (2) use an efficient estimator to estimate the target statistical estimand and its uncertainty, and (3) evaluate the impact of causal assumptions on the study conclusion by performing a sensitivity analysis. Two illustrative examples are provided for master protocols using external controls

Involvement of an alternatively spliced mitochondrial oxodicarboxylate carrier in adipogenesis in 3T3-L1 cells

<p>Abstract</p> <p>Background</p> <p>Adipogenesis is a complex process that involves many genes/proteins at different stages of differentiation. In order to identify genes critical for adipogeneis, we took a novel approach based on phenotype change of individual cell, to search for genes with regulatory roles in adipogenesis genome-wide in 3T3-L1 cells.</p> <p>Methods</p> <p>Lentivirus-based inducible random homologous knockdown was used for the screening of functional gene that altered lipid formation in the adipocyte during differentiation.</p> <p>Results</p> <p>In the present study, we reported the identification of an alternatively spliced mitochondrial oxodicarboxylate carrier (ODC), so named ODC-AS. ODC-AS is different from ODC by replacing 22 amino acids with 29 amino acids at the N-terminal. ODC was widely expressed in most tissues in mouse as determined by multi-tissue cDNA panel polymerase chain reaction. However, ODC-AS was only detected in adipose tissue and in iris and sclera-choroid complex of the eye. The expression of ODC-AS in 3T3-L1 was detected after the induction of differentiation, and reached a peak at day 4 and then reduced thereafter, whereas no ODC transcript detected in the cells neither before nor after differentiation. Knocking down of ODC-AS expression by RNA interference led to significant reduction in lipid accumulation as determined by triglyceride measurement and Nile Red staining, as well as adipogenic marker CEBPα, PPARγ, aP2 and CD36. Although both ODC and ODC-AS are expressed in white and brown adipose tissues, only the expression of ODC-AS was down-regulated in brown adipose tissue by cold exposure.</p> <p>Conclusion</p> <p>These results implicate that ODC-AS may promote lipid accumulation during adipocyte differentiation and play an important role in the regulation of lipid metabolism in adipose tissues.</p

Exposure to Bisphenol A and Other Phenols in Neonatal Intensive Care Unit Premature Infants

Objective: We previously demonstrated that exposure to polyvinyl chloride plastic medical devices containing di(2-ethylhexyl) phthalate (DEHP) was associated with higher urinary concentrations of several DEHP metabolites in 54 premature infants in two neonatal intensive care units than in the general population. For 42 of these infants, we evaluated urinary concentrations of several phenols, including bisphenol A (BPA), in association with the use of the same medical devices. Measurements: We measured the urinary concentrations of free and total (free plus conjugated) species of BPA, triclosan, benzophenone-3, methyl paraben, and propyl paraben. Results: The percentage of BPA present as its conjugated species was > 90% in more than three-quarters of the premature infants. Intensity of use of products containing DEHP was strongly associated with BPA total concentrations but not with any other phenol. Adjusting for institution and sex, BPA total concentrations among infants in the group of high use of DEHP-containing products were 8.75 times as high as among infants in the low use group (p < 0.0001). Similarly, after adjusting for sex and DEHP-containing product use category, BPA total concentrations among infants in Institution A were 16.6 times as high as those among infants in Institution B (p < 0.0001). Conclusion: BPA geometric mean urinary concentration (30.3 μg/L) among premature infants undergoing intensive therapeutic medical interventions was one order of magnitude higher than that among the general population. Conjugated species were the primary urinary metabolites of BPA, suggesting that premature infants have some capacity to metabolize BPA. The differences in exposure to BPA by intensity of use of DEHP-containing medical products highlight the need for further studies to determine the specific source(s) of exposure to BPA