Abstract
Identification of genetic variants affecting splicing in RNA sequencing population studies is still in its infancy. Splicing phenotype is more complex than gene expression and ought to be treated as a multivariate phenotype to be recapitulated completely. Here we represent the splicing pattern of a gene as the distribution of the relative abundances of a geneâ(tm) s alternative transcript isoforms. We develop a statistical framework that uses a distance-based approach to compute the variability of splicing ratios across observations, and a non-parametric analogue to multivariate analysis of variance. We implement this approach in the R package sQTLseekeR and use it to analyze RNA-Seq data from the Geuvadis project in 465 individuals. We identify hundreds of single nucleotide polymorphisms (SNPs) as splicing QTLs (sQTLs), including some falling in genome-wide association study SNPs. By developing the appropriate metrics, we show that sQTLseekeR compares favorably with existing methods that rely on univariate approaches, predicting variants that behave as expected from mutations affecting splicing. © 2014 Macmillan Publishers Limited.

Abstract
Chronic lymphocytic leukemia (CLL) has heterogeneous clinical and biological behavior. Whole-genome and -exome sequencing has contributed to the characterization of the mutational spectrum of the disease, but the underlying transcriptional profile is still poorly understood. We have performed deep RNA sequencing in different subpopulations of normal B-lymphocytes and CLL cells from a cohort of 98 patients, and characterized the CLL transcriptional landscape with unprecedented resolution. We detected thousands of transcriptional elements differentially expressed between the CLL and normal B cells, including protein-coding genes, noncoding RNAs, and pseudogenes. Transposable elements are globally derepressed in CLL cells. In addition, two thousand genes-most of which are not differentially expressed-exhibit CLL-specific splicing patterns. Genes involved in metabolic pathways showed higher expression in CLL, while genes related to spliceosome, proteasome, and ribosome were among the most down-regulated in CLL. Clustering of the CLL samples according to RNA-seq derived gene expression levels unveiled two robust molecular subgroups, C1 and C2. C1/C2 subgroups and the mutational status of the immunoglobulin heavy variable (IGHV ) region were the only independent variables in predicting time to treatment in a multivariate analysis with main clinico-biological features. This subdivision was validated in an independent cohort of patients monitored through DNA microarrays. Further analysis shows that B-cell receptor (BCR) activation in the microenvironment of the lymph node may be at the origin of the C1/C2 differences. © 2014 Hansen et al.

Abstract
In a lung nodule detection task, parenchyma segmentation is crucial to obtain the region of interest containing all the nodules. Thus, the challenge is to devise a methodology that includes all the lung nodules, particularly those close to the walls, as the juxtapleural nodules. In this paper, different region growing approaches are proposed for the automatic segmentation of the lung parenchyma. The methodology is organized in five different steps: first, the image intensity is corrected to improve the contrast of the lungs. With that, the fat area is obtained, automatically deriving the interior of the lung region. Then, the traquea is extracted by a 3D region growing, being subtracted from the lung region results. The next step is the division of the two lungs to guarantee that both are separated. And finally, the lung contours are refined to provide appropriate final results. The methodology was tested in 50 images taken from the LIDC image database, with a large variability and, specially, including different types of lung nodules. In particular, this dataset contains 158 nodules, from which 40 are juxtapleural nodules. Experimental results demonstrate that the method provides accurate lung regions, specially including the centers of 36 of the juxtapleural nodules. For the other 4, although the centers are not included, parts of their areas are retained in the segmentation, which is useful for lung nodule detection.

Abstract
The purpose of this study was the development of a clustering methodology to deal with arterial pressure waveform (APW) parameters to be used in the cardiovascular risk assessment. One hundred sixteen subjects were monitored and divided into two groups. The first one (23 hypertensive subjects) was analyzed using APW and biochemical parameters, while the remaining 93 healthy subjects were only evaluated through APW parameters. The expectation maximization (EM) and k-means algorithms were used in the cluster analysis, and the risk scores (the Framingham Risk Score (FRS), the Systematic COronary Risk Evaluation (SCORE) project, the Assessing cardiovascular risk using Scottish Intercollegiate Guidelines Network (ASSIGN) and the PROspective Cardiovascular munster (PROCAM)), commonly used in clinical practice were selected to the cluster risk validation. The result from the clustering risk analysis showed a very significant correlation with ASSIGN (r = 0.582, p < 0.01) and a significant correlation with FRS (r = 0.458, p < 0.05). The results from the comparison of both groups also allowed to identify the cluster with higher cardiovascular risk in the healthy group. These results give new insights to explore this methodology in future scoring trials.

Abstract
A new approach is introduced for the automatic detection of the lumen axis of the common carotid artery in B-mode ultrasound images. The image is smoothed using a Gaussian filter and then a dynamic programming scheme extracts the dominant paths of local minima of the intensity and the dominant paths of local maxima of the gradient magnitude with the gradient pointing downwards. Since these paths are possible estimates of the lumen axis and the far wall of a blood vessel, respectively, they are grouped together into pairs. Then, a pattern of two features is computed from each pair of paths and used as input to a linear discriminant classifier in order to select the pair of paths that correspond to the common carotid artery. The estimated lumen axis is the path of local minima of the intensity that belongs to the selected pair of paths. The proposed method is suited to real time processing, no user interaction is required and the number of parameters is minimal and easy to determine. The validation was performed using two datasets, with a total of 199 images, and has shown a success rate of 99.5% (100% if only the carotid regions for which a ground truth is available are considered). The datasets have a large diversity of images, including cases of arteries with plaque and images with heavy noise, text or other graphical markings inside the artery region.

Abstract
A critical question in tapping behavior is to understand whether the temporal control is exerted on the duration and trajectory of the downward-upward hand movement or on the pause between hand movements. In the present study, we determined the duration of both the movement execution and pauses of monkeys performing a synchronization-continuation task (SCT), using the speed profile of their tapping behavior. We found a linear increase in the variance of pause-duration as a function of interval, while the variance of the motor implementation was relatively constant across intervals. In fact, 96% of the variability of the duration of a complete tapping cycle (pause + movement) was due to the variability of the pause duration. In addition, we performed a Bayesian model selection to determine the effect of interval duration (450 -1,000 ms), serial-order (1-6 produced intervals), task phase (sensory cued or internally driven), and marker modality (auditory or visual) on the duration of the movement-pause and tapping movement. The results showed that the most important parameter used to successfully perform the SCT was the control of the pause duration. We also found that the kinematics of the tapping movements was concordant with a stereotyped ballistic control of the hand pressing the push-button. The present findings support the idea that monkeys used an explicit timing strategy to perform the SCT, where a dedicated timing mechanism controlled the duration of the pauses of movement, while also triggered the execution of fixed movements across each interval of the rhythmic sequence.