Benchmark dose risk analysis with mixed-factor quantal data in environmental risk assessment.

Benchmark analysis is a general risk estimation strategy for identifying the benchmark dose (BMD) past which the risk of exhibiting an adverse environmental response exceeds a fixed, target value of benchmark response (BMR). Estimation of BMD and of its lower confidence limit (BMDL) is well understood for the case of an adverse response to a single stimulus. In many environmental settings, however, one or more additional, secondary, qualitative factor(s) may collude to affect the adverse outcome, such that the risk changes with differential levels of the secondary factor. This paper extends the single-dose BMD paradigm to a mixed-factor setting with a secondary qualitative factor possessing two levels. With focus on quantal-response data and using a generalized linear model with a complementary-log link function, we derive expressions for BMD and BMDL. We study the operating characteristics of six different multiplicity-adjusted approaches to calculate the BMDL, using Monte Carlo evaluations. We illustrate the calculations via an example data set from environmental carcinogenicity testing.

Computing Accurate Probabilistic Estimates of One-D Entropy from Equiprobable Random Samples.

We develop a simple Quantile Spacing (QS) method for accurate probabilistic estimation of one-dimensional entropy from equiprobable random samples, and compare it with the popular Bin-Counting (BC) and Kernel Density (KD) methods. In contrast to BC, which uses equal-width bins with varying probability mass, the QS method uses estimates of the quantiles that divide the support of the data generating probability density function (pdf) into equal-probability-mass intervals. And, whereas BC and KD each require optimal tuning of a hyper-parameter whose value varies with sample size and shape of the pdf, QS only requires specification of the number of quantiles to be used. Results indicate, for the class of distributions tested, that the optimal number of quantiles is a fixed fraction of the sample size (empirically determined to be ~0.25-0.35), and that this value is relatively insensitive to distributional form or sample size. This provides a clear advantage over BC and KD since hyper-parameter tuning is not required. Further, unlike KD, there is no need to select an appropriate kernel-type, and so QS is applicable to pdfs of arbitrary shape, including those with discontinuous slope and/or magnitude. Bootstrapping is used to approximate the sampling variability distribution of the resulting entropy estimate, and is shown to accurately reflect the true uncertainty. For the four distributional forms studied (Gaussian, Log-Normal, Exponential and Bimodal Gaussian Mixture), expected estimation bias is less than 1% and uncertainty is low even for samples of as few as 100 data points; in contrast, for KD the small sample bias can be as large as -10% and for BC as large as -50%. We speculate that estimating quantile locations, rather than bin-probabilities, results in more efficient use of the information in the data to approximate the underlying shape of an unknown data generating pdf.

Delayed Sleep Time in African Americans and Depression in a Community-Based Population.

STUDY OBJECTIVES: Studies have shown racial differences in circadian rhythm in African Americans when compared to non-Hispanic whites, and an association between circadian dyssynchrony and depression. We hypothesized that the prevalence of delayed sleep time is greater in African Americans when compared to whites and that delayed sleep time is associated with depression. METHODS: We analyzed data from the Sleep Heart Health Study (SHHS), a large community-based sample. Delayed sleep time was defined as self-reported weeknight bedtime after midnight. Depression was defined based on participant's response to the question, "In the past 4 weeks have you felt downhearted and blue?" or reported antidepressant use. We performed multivariate linear and logistic regression, adjusting for age, sex, race, body mass index, smoking, apnea-hypopnea index, alcohol use, and caffeine consumption. RESULTS: Adjusted weekday bedtime was 15 ± 7 minutes later in African Americans compared to whites (P < .001). Similarly, weekend bedtime was 18 ± 7 minutes later in African Americans compared to whites (P = .025). The prevalence of delayed sleep time was greater in African Americans (33.3%) compared to whites (18.7%; P < .001). After adjusting for confounders, when compared to whites, a greater proportion of African Americans had delayed sleep time (adjusted odds ratio [aOR] 2.03; 95% confidence interval [95% CI] 1.5, 2.4; P < .0001). Depression was independently associated with delayed sleep time after adjustment (aOR 1.4; 95% CI 1.1, 1.7; P = .007). CONCLUSIONS: African Americans are more likely to have a delayed sleep time compared to whites, and delayed sleep time was independently associated with depression.

Common distribution patterns of marsupials related to physiographical diversity in Venezuela.

The aim of this study is to identify significant biotic regions (groups of areas with similar biotas) and biotic elements (groups of taxa with similar distributions) for the marsupial fauna in a part of northern South America using physiographical areas as Operational Geographical Units (OGUs). We considered Venezuela a good model to elucidate this issue because of its high diversity in landscapes and the relatively vast amount of information available on the geographical distribution of marsupial species. Based on the presence-absence of 33 species in 15 physiographical sub-regions (OGUs) we identified Operational Biogeographical Units (OBUs) and chorotypes using a quantitative analysis that tested statistical significance of the resulting groups. Altitudinal and/or climatic trends in the OBUs and chorotypes were studied using a redundancy analysis. The classification method revealed four OBUs. Strong biotic boundaries separated: i) the xerophytic zone of the Continental coast (OBU I); ii) the sub-regions north of the Orinoco River (OBU III and IV); and those south to the river (OBU II). Eleven chorotypes were identified, four of which included a single species with a restricted geographic distribution. As for the other chorotypes, three main common distribution patterns have been inferred: i) species from the Llanos and/or distributed south of the Orinoco River; ii) species exclusively from the Andes; and iii) species that either occur exclusively north of the Orinoco River or that show a wide distribution throughout Venezuela. Mean altitude, evapotranspiration and precipitation of the driest month, and temperature range allowed us to characterize environmentally most of the OBUs and chorotypes obtained.

Light responses of the circadian system in leptin deficient mice.

Some evidences postulate a link between obesity and disturbances in circadian behavior. Here, we studied the manifestation of the circadian rhythm of motor activity and its response to light in the leptin deficiency model of obesity ob/ob mice. Motor activity in both ob/ob and wild type mice was first recorded in a small cage by activity meters with crossed infrared beams (IR) and later in a larger cage with a running wheel, where the number of wheel revolutions (WR) was also determined. Animals were maintained under light-dark (LD) or constant-dark (DD) conditions. We studied the free-running period and the rhythm profile, with special emphasis on the amount of activity in the dark and light phases of the LD cycle, and the phase and period responses to a light pulse. The results showed that ob/ob mice have a strong ultradian, rather than a circadian pattern, whose period range between 3 and 4.8h. Also, these animals showed a percentage of activity during light higher than controls. We did not find differences in the endogenous period of the circadian rhythm between mice groups in DD. However, ob/ob mice showed stronger phase delays after a light pulse at ZT15 than controls, and less masking effects in the transition from LD to DD compared with controls. This suggests a weaker circadian pacemaker of the ob/ob mice compared with controls.

Staggered chromosomal hybrid zones in the house mouse: relevance to reticulate evolution and speciation.

In the house mouse there are numerous chromosomal races distinguished by different combinations of metacentric chromosomes. These may come into contact with each other and with the ancestral all-acrocentric race, and form hybrid zones. The chromosomal clines that make up these hybrid zones may be coincident or separated from each other (staggered). Such staggered hybrid zones are interesting because they may include populations of individuals homozygous for a mix of features of the hybridising races. We review the characteristics of four staggered hybrid zones in the house mouse and discuss whether they are examples of primary or secondary contact and whether they represent reticulate evolution or not. However, the most important aspect of staggered hybrid zones is that the homozygous populations within the zones have the potential to expand their distributions and become new races (a process termed 'zonal raciation'). In this way they can add to the total 'stock' of chromosomal races in the species concerned. Speciation is an infrequent phenomenon that may involve an unusual set of circumstances. Each one of the products of zonal raciation has the potential to become a new species and by having more races increases the chance of a speciation event.

Genome-wide patterns of gene flow across a house mouse hybrid zone.

Hybrid zones between closely related species or subspecies provide useful settings for studying the genetic architecture of speciation. Using markers distributed throughout the mouse genome, we use a hybrid zone between two recently diverged species of house mice (Mus musculus and Mus domesticus) as a natural mapping experiment to identify genomic regions that may be involved in reproductive isolation. Using cline analysis we document a nearly 50-fold variation in level of introgression among markers. Some markers have extremely narrow cline widths; these genomic regions may contribute to reproductive isolation. Biological processes associated with these narrow clines include physiological and immune responses to the environment as well as physiological and behavioral aspects of reproduction. Other autosomal markers exhibit asymmetrically broad clines, usually with high frequencies of M. domesticus alleles on the M. musculus side of the hybrid zone. These markers identify genome regions likely housing genes with alleles that are spreading from one species to the other. Biological processes associated with these wide clines include cell signaling, olfaction, and pheromone response. These processes play important roles in survival and reproduction, and associated genes are likely targets of selection. Patterns of linkage disequilibrium in the center of the hybrid zone suggest that isolation may be caused by multiple epistatic interactions between sets of genes. These data highlight the complex genetic architecture underlying speciation even at early stages of divergence and point to some of the biological processes that may govern this architecture.

Rb(7.17), a rare Robertsonian fusion in wild populations of the house mouse.

Robertsonian (Rb) translocation is the largest source of chromosomal diversity in the western European house mouse (Mus musculus domesticus). Recently, the fusion Rb(7.17) was found in the chromosomal polymorphic zone of this subspecies in the north-east of the Iberian Peninsula. This fusion has not been reported in any other European population. Here we give data on the distribution and frequency of this mutation in this region. Results revealed that Rb(7.17) is restricted to a small geographic area, and that, in comparison with other fusions in this polymorphic zone, it occurs at low frequencies. We suggest some possible explanations for the distribution of this translocation.

Effect of Robertsonian translocations on the motor activity rhythm in the house mouse.

Here we studied the circadian rhythm of motor activity in two groups of wild house mice from the chromosomal polymorphic zone of Barcelona, which differed in diploid number (2n): standard (2n = 40), with all acrocentric chromosomes, and Robertsonian (2n = 29-32), with several Robertsonian translocations. Motor activity under three lighting conditions, light-dark cycle, constant darkness, and constant light, was recorded for each mouse. The motor activity rhythm was examined by Fourier analysis and the daily power spectra were obtained. On the basis of the mean power spectrum of each animal and under each lighting condition, stepwise discriminant analyses were performed to classify the two chromosomal groups. This method allowed the correct classification of a large number of animals, the rhythms of about 2-2.6 hour periods being the most significant, with higher values in Robertsonian than in standard mice. Our results indicate that the daily motor activity pattern differs between the two chromosomal groups and its analysis may have a valuable interest for behavioral investigations on Robertsonian polymorphic zones of this species.