Abstract
Exome and whole-genome sequencing are becoming increasingly routine approaches in Mendelian disease diagnosis. Despite their success, the current diagnostic rate for genomic analyses across a variety of rare diseases is approximately 25 to 50%. We explore the utility of transcriptome sequencing [RNA sequencing (RNA-seq)] as a complementary diagnostic tool in a cohort of 50 patients with genetically undiagnosed rare muscle disorders. We describe an integrated approach to analyze patient muscle RNA-seq, leveraging an analysis framework focused on the detection of transcript-level changes that are unique to the patient compared to more than 180 control skeletal muscle samples. We demonstrate the power of RNA-seq to validate candidate splice-disrupting mutations and to identify splice-altering variants in both exonic and deep intronic regions, yielding an overall diagnosis rate of 35%. We also report the discovery of a highly recurrent de novo intronic mutation in COL6A1 that results in a dominantly acting splice-gain event, disrupting the critical glycine repeat motif of the triple helical domain. We identify this pathogenic variant in a total of 27 genetically unsolved patients in an external collagen VI-like dystrophy cohort, thus explaining approximately 25% of patients clinically suggestive of having collagen VI dystrophy in whom prior genetic analysis is negative. Overall, this study represents a large systematic application of transcriptome sequencing to rare disease diagnosis and highlights its utility for the detection and interpretation of variants missed by current standard diagnostic approaches. 2017 © The Authors.

Abstract
Gene expression is dependent on genetic and environmental factors. In the last decade, a large body of research has significantly improved our understanding of the genetic architecture of gene expression. However, it remains unclear whether genetic effects on gene expression remain stable over time. Here, we show, using longitudinal whole-blood gene expression data from a twin cohort, that the genetic architecture of a subset of genes is unstable over time. In addition, we identified 2213 genes differentially expressed across time points that we linked with aging within and across studies. Interestingly, we discovered that most differentially expressed genes were affected by a subset of 77 putative causal genes. Finally, we observed that putative causal genes and down-regulated genes were affected by a loss of genetic control between time points. Taken together, our data suggest that instability in the genetic architecture of a subset of genes could lead to widespread effects on the transcriptome with an aging signature. ©2017 Bryois et al.

Abstract

Abstract
In the last decade, several HRV based novel methodologies for describing and assessing heart rate dynamics have been proposed in the literature with the aim of risk assessment. Such methodologies attempt to describe the non-linear and complex characteristics of HRV, and hereby the focus is in two of these characteristics, namely long memory and heteroscedasticity with variance clustering. The ARFIMA-GARCH modeling considered here allows the quantification of long range correlations and time-varying volatility. ARFIMA-GARCH HRV analysis is integrated with multimodal brain monitoring in several acute cerebral phenomena such as intracranial hypertension, decompressive craniectomy and brain death. The results indicate that ARFIMA-GARCH modeling appears to reflect changes in Heart Rate Variability (HRV) dynamics related both with the Acute Brain Injury (ABI) and the medical treatments effects. © 2017, Springer International Publishing AG.

Abstract
This study aims at characterizing the spatial and temporal dynamics of spatio-temporal data sets, characterized by high resolution in the temporal dimension which are becoming the norm rather than the exception in many application areas, namely environmental modelling. In particular, air pollution data, such as NO2 concentration levels, often incorporate also multiple recurring patterns in time imposed by social habits, anthropogenic activities and meteorological conditions. A two-stage modelling approach is proposed which combined with a block bootstrap procedure correctly assesses uncertainty in parameters estimates and produces reliable confidence regions for the space-time phenomenon under study. The methodology provides a model that is satisfactory in terms of goodness of fit, interpretability, parsimony, prediction and forecasting capability and computational costs. The proposed framework is potentially useful for scenario drawing in many areas, including assessment of environmental impact and environmental policies, and in a myriad applications to other research fields.

Abstract
Analysis of automatically-generated alignments shows that ambiguous situations are quite common, preventing their application in scenarios demanding high quality and completeness, such ontology mediation (e.g. data transformation and information/knowledge integration). Even the best-performing alignment needs to be manually corrected, completed and verified before application. In this paper, we propose a decision support system (DSS) based in a general-purpose rule engine that assists the expert on improving and completing the automatically-generated alignments into fully-fledged alignments, balancing the precision and recall of the system with the user participation in the process. For that, the rules capture the preconditions (existing facts) and the actions to solve each (ambiguous) alignment scenario, in which the expert decision will be adopted in further automatic decisions. The evaluation of the proposed DSS shows the gain in reducing the need for expert's decisions while increasing the accuracy of the alignments. © 2017 Copyright is held by the owner/author(s).