ROC-guided survival trees and ensembles

Tree-based methods are popular nonparametric tools in studying time-to-event outcomes. In this article, we introduce a novel framework for survival trees and ensembles, where the trees partition the dynamic survivor population and can handle time-dependent covariates. Using the idea of randomized tests, we develop generalized time-dependent receiver operating characteristic (ROC) curves for evaluating the performance of survival trees. The tree-building algorithm is guided by decision-theoretic criteria based on ROC, targeting specifically for prediction accuracy. To address the instability issue of a single tree, we propose a novel ensemble procedure based on averaging martingale estimating equations, which is different from existing methods that average the predicted survival or cumulative hazard functions from individual trees. Extensive simulation studies are conducted to examine the performance of the proposed methods. We apply the methods to a study on AIDS for illustration.     

A resurrection study reveals limited evolution of thermal performance in response to recent climate change across the geographic range of the scarlet monkeyflower

Evolutionary rescue can prevent populations from declining under climate change, and should be more likely at high-latitude, “leading” edges of species’ ranges due to greater temperature anomalies and gene flow from warm-adapted populations. Using a resurrection study with seeds collected before and after a 7-year period of record warming, we tested for thermal adaptation in the scarlet monkeyflower Mimulus cardinalis. We grew ancestors and descendants from northern-edge, central, and southern-edge populations across eight temperatures. Despite recent climate anomalies, populations showed limited evolution of thermal performance curves. However, one southern population evolved a narrower thermal performance breadth by 1.31°C, which matches the direction and magnitude of the average decrease in seasonality experienced. Consistent with the climate variability hypothesis, thermal performance breadth increased with temperature seasonality across the species’ geographic range. Inconsistent with performance trade-offs between low and high temperatures across populations, we did not detect a positive relationship between thermal optimum and mean temperature. These findings fail to support the hypothesis that evolutionary response to climate change is greatest at the leading edge, and suggest that the evolution of thermal performance is unlikely to rescue most populations from the detrimental effects of rapidly changing climate.     

A new method for post Genome-Wide Association Study (GWAS) analysis of colorectal cancer in Taiwan

Recently, single nucleotide polymorphisms (SNPs) located in specific loci or genes have been identified associated with susceptibility to colorectal cancer (CRC) in Genome-Wide Association Studies (GWAS). However, in different ethnicities and regions, the genetic variations and the environmental factors can widely vary. Therefore, here we propose a post-GWAS analysis method to investigate the CRC susceptibility SNPs in Taiwan by conducting a replication analysis and bioinformatics analysis. One hundred and forty-four significant SNPs from published GWAS results were collected by a literature survey, and two hundred and eighteen CRC samples and 385 normal samples were collected for post-GWAS analysis. Finally, twenty-six significant SNPs were identified and reported as associated with susceptibility to colorectal cancer, other cancers, obesity, and celiac disease in a previous GWAS study. Functional analysis results of 26 SNPs indicate that most biological processes identified are involved in regulating immune responses and apoptosis. In addition, an efficient prediction model was constructed by applying Jackknife feature selection and ANOVA testing. As compared to another risk prediction model of CRC for European Caucasians population, which performs 0.616 of AUC by using 54 SNPs, the proposed model shows good performance in predicting CRC risk within the Taiwanese population, i.e., 0.724 AUC by using 16 SNPs. We believe that the proposed risk prediction model is highly promising for predicting CRC risk within the Taiwanese population. In addition, the functional analysis results could be helpful to explore the potential associated regulatory mechanisms that may be involved in CRC development.     

Host genetic risk factors for community-acquired pneumonia

This study was conducted to establish the contribution of genetic host factors in the susceptibility to community acquired pneumonia (CAP) in the Russian population. Patients with CAP (n = 334), volunteers without a previous history of CAP, constantly exposed to infectious agents, control A group (n = 141) and a second control group B consisted of healthy persons (n = 314) were included in the study. All subjects were genotyped for 13 polymorphic variants in the genes of xenobiotics detoxification CYP1A1 (rs2606345, rs4646903, and rs1048943), GSTM1 (Ins/del), GSTT1 (Ins/del), ABCB1 rs1045642); immune and inflammation response IL-6 (rs1800795), TNF-a (rs1800629), MBL2 (rs7096206), CCR5 (rs333), NOS3 (rs1799983), angiotensin-converting enzyme ACE (rs4340), and occlusive vascular disease/hyperhomocysteinemia MTHFR (rs1801133). Seven polymorphic variants in genes CYP1A1, GSTM1, ABCB1, NOS3, IL6, CCR5 and ACE were associated with CAP. For two genes CYP1A1 and GSTM1 associations remained significant after correction for multiple comparisons. Multiple analysis by the number of all risk genotypes showed a highly significant association with CAP (P = 2.4 × 10^− 7, OR = 3.03, 95% CI 1.98–4.64) with the threshold for three risk genotypes. Using the ROC-analysis, the AUC value for multi-locus model was estimated as 68.38.     

Daily Behavioral Rhythmicity and Organization of the Suprachiasmatic Nuclei in the Diurnal Rodent,Lemniscomys barbarus

Wheel‐running activity was recorded in Lemniscomys barbarus exposed to different lighting conditions. This rodent shows rhythmic locomotor activity under natural twilight‐light/dark (LD) as well as squared‐LD cycles. A mean of 77% of the activity occurred during the light phase. Under different controlled photoperiods, the quantity of daily locomotor activity was relatively stable except for a lower level in the shortest photoperiod tested (LD 06∶18). The duration of the active phase tended to increase with the duration of the light phase, especially in the longer photoperiods. Whatever the lighting conditions, Lemniscomys barbarus started running before lights‐on and stopped after lights‐off. The phase angle of activity offset relative to lights‐off was stable in each squared‐photoperiod, whereas the phase angle of activity onset relative to lights‐on was significantly the highest under the shortest photoperiods. Recording of activity under constant lighting conditions showed that the daily rhythm of locomotor activity is fundamentally circadian. The endogenous period was slightly<24 h (mean=23.8 h) in permanent darkness and>24 h (mean=24.5 h) in continuous light. Re‐entrainment of the locomotor activity rhythm after a 6 h phase advance or delay requires only four days on average. Moreover, the phase‐responses curve to a 30 min light pulse (200 lux) in Lemniscomys barbarus kept in constant dark reveals large phase shifts according to circadian times (CT). With CT0 being defined as the onset of daily activity, maximum phase delay and advance shifts were observed at CT11 (Δ Ψ=‐5.7 h±2.3 h) and CT21 (Δ Ψ =4.9±1.2 h), respectively. Interestingly, the phase‐response curve to light did not show any dead zone. Immunohistochemical staining of the suprachiasmatic nuclei indicates that arginine vasopressin‐immunoreactive cell bodies and fibers delimited a dorsal subregion that extends laterally and medially. The ventral subregion is rich in vasoactive intestinal peptide‐immunoreactive neurones overlapping a smaller area containing gastrin‐releasing peptide‐expressing cells and receives numerous fibers labeled with neuropeptide Y antibody. The results of this study clearly demonstrate that Lemniscomys barbarus is a diurnal species highly sensitive to the shifting effects of light. Overall, this rodent can be considered a new and interesting model for circadian rhythm neurobiology.     

Low,but not high,doses of melatonin entrained a free-running blind person with a long circadian period

In a previous report, we were unable to entrain one out of seven totally blind people with free-running endogenous melatonin rhythms to 10 mg of exogenous melatonin. This person had the longest circadian period (24.9 h) of the group. We now find that this person can be entrained to 0.5 mg of melatonin, but not to 20 mg. These results are consistent with the idea that too much melatonin may spill over onto the wrong zone of the melatonin phase–response curve.     

CIRCADIAN PHASE AND PERIOD RESPONSES TO LIGHT STIMULI IN TWO NOCTURNAL RODENTS

We report period response curves (τRC) for two nocturnal Murid species from India, Mus booduga and Mus platythrix. We further discuss the method of phase shift estimation in the presence of τ-changes, because such changes pose a serious methodological problem in the estimation of phase shifts. Although the τRC indicates that most of the phase shifts are associated with small changes in τ, the period changes across all the phases showed a significant positive correlation with the phase shifts. We conclude that τRCs are a reality even in nocturnal mammals, although their amplitude is less than what is usually found in diurnal mammals, and requires a larger data set to be distinguished from noise.     

Melatonin Entrains Free‐running Blind People According to a Physiological Dose‐response Curve

The specific circadian role proposed for endogenous melatonin production was based on a study of sighted people who took low pharmacological doses (500 µg) of this chemical signal for the “biological night”: the magnitude and direction of the induced phase shifts were dependent on what time of day exogenous melatonin was administered and were described by a phase‐response curve that turned out to be the opposite of that for light. We now report that lower (physiological) doses of up to 300 µg can entrain (synchronize) free‐running circadian rhythms of 10 totally blind subjects that would otherwise drift later each day. The resulting log‐linear dose‐response curve in the physiological range adds support for a circadian function of endogenous melatonin in humans. Efficacy of exogenous doses in the physiological range are of clinical significance for totally blind people who will need to take melatonin daily over their entire lifetimes in order to remain entrained to the 24 h day. Left untreated, their free‐running endocrine, metabolic, behavioral, and sleep/wake cycles can be almost as burdensome as not having vision.     

Farm‐scale dispersal of Bactericera cockerelli in potato crops measured using Bt mark‐capture techniques

Natural populations of Bactericera cockerelli (Sulc) (Hemiptera: Triozidae), also known as tomato/potato psyllid, were marked in potato [Solanum tuberosum L. (Solanaceae)] crops using Bacillus thuringiensis Berliner (Bt) to investigate the impact of dispersal on crop infestation and management of potential insecticide resistance in New Zealand. The technique was adapted from previous studies that used conventional spray applications of Bt to mark Phthorimaea operculella (Zeller) (Lepidoptera: Gelechiidae), and identified marked individuals with selective microbiological assays and identification of characteristic crystal inclusions. Initially, marking rates of B. cockerelli were improved by using ultra‐low volume applications of undiluted Bt, but this result was not consistent. Several other pests and natural enemies were also marked. In mark‐capture studies, marked B. cockerelli were captured over 3 days on yellow sticky traps in small trap plots of potatoes at 60, 120, 180, 250, and 350 m from the sprayed crop. Bactericera cockerelli flight activity occurred throughout daylight hours with evidence of bimodal diurnal peaks. Significantly greater numbers of B. cockerelli were captured in downwind traps. The combined dispersal curve derived from two mark‐capture experiments estimated a mean dispersal distance for B. cockerelli of 100 m in 3 days and indicated that 10% of the population dispersed further than ca. 250 m. Over the period of a growing season, this level of dispersal suggests that B. cockerelli can disperse throughout a vegetable‐growing region, with implications for crop infestation and management of potential insecticide resistance.