LIMIX: genetic analysis of multiple traits

Multi-trait mixed models have emerged as a promising approach for joint analyses of multiple traits. In principle, the mixed model framework is remarkably general. However, current methods implement only a very specific range of tasks to optimize the necessary computations. Here, we present a multi-trait modeling framework that is versatile and fast: LIMIX enables to exibly adapt mixed models for a broad range of applications with different observed and hidden covariates, and variable study designs. To highlight the novel modeling aspects of LIMIX we performed three vastly different genetic studies: joint GWAS of correlated blood lipid phenotypes, joint analysis of the expression levels of the multiple transcript-isoforms of a gene, and pathway-based modeling of molecular traits across environments. In these applications we show that LIMIX increases GWAS power and phenotype prediction accuracy, in particular when integrating stepwise multi-locus regression into multi-trait models, and when analyzing large numbers of traits. An open source implementation of LIMIX is freely available at: https://github.com/PMBio/limix

An integrated map of structural variation in 2,504 human genomes

Structural variants are implicated in numerous diseases and make up the majority of varying nucleotides among human genomes. Here we describe an integrated set of eight structural variant classes comprising both balanced and unbalanced variants, which we constructed using short-read DNA sequencing data and statistically phased onto haplotype blocks in 26 human populations. Analysing this set, we identify numerous gene-intersecting structural variants exhibiting population stratification and describe naturally occurring homozygous gene knockouts that suggest the dispensability of a variety of human genes. We demonstrate that structural variants are enriched on haplotypes identified by genome-wide association studies and exhibit enrichment for expression quantitative trait loci. Additionally, we uncover appreciable levels of structural variant complexity at different scales, including genic loci subject to clusters of repeated rearrangement and complex structural variants with multiple breakpoints likely to have formed through individual mutational events. Our catalogue will enhance future studies into structural variant demography, functional impact and disease association. © 2015 Macmillan Publishers Limited. All rights reserved

Computational analysis of cell-to-cell heterogeneity in single-cell RNA-sequencing data reveals hidden subpopulations of cells.

Recent technical developments have enabled the transcriptomes of hundreds of cells to be assayed in an unbiased manner, opening up the possibility that new subpopulations of cells can be found. However, the effects of potential confounding factors, such as the cell cycle, on the heterogeneity of gene expression and therefore on the ability to robustly identify subpopulations remain unclear. We present and validate a computational approach that uses latent variable models to account for such hidden factors. We show that our single-cell latent variable model (scLVM) allows the identification of otherwise undetectable subpopulations of cells that correspond to different stages during the differentiation of naive T cells into T helper 2 cells. Our approach can be used not only to identify cellular subpopulations but also to tease apart different sources of gene expression heterogeneity in single-cell transcriptomes

Costo sociale annuo della dispepsia funzionale dopo l'eradicazione dell'Helicobacter pylori : risultati di un'indagine in centri di endoscopia digestiva

Objective: The aim of this study was to evaluate socio-demographic and clinical characteristics of dyspeptic patients in Italy after the eradication of Helicobacter pylori infection and to evaluate the impact of this syndrome on daily activities, on loss of production, and, finally, to estimate its cost for both National Health Service and society. Design: An observational, prospective, one-year, multicenter study was conducted from April 1999 to April 2002 under the aegis of the Italian study group of digestive tract motility (GISMAD). The study was based on 577 consecutive functional dyspeptic patients after eradication of H. pylori. Data were collected by a Case Report Form (CRF). Setting: 91 Centres of Digestive Endoscopy (CED), all located in Italy. Results: The mean age of the 577 dyspeptic patients enrolled in the study was 52 yrs.\ub114 (13.3% was younger than 40 yrs old; mostly females: 56.7%). Sixty point seven percent of patients met expenses related with the treatment of dyspepsia. Patients were stratified into four groups according to their prevalent symptoms: ulcer-like (UL), dismotility-like (DL), reflux-like (RL) and 'other'. Annual mean cost estimated for each patient was \u20ac 145.54, with differences between females and males ( \u20ac 168.95 vs \u20ac 114.91 respectively). "RL" patients resulted at the highest cost (\u20ac 204.32). Total costs were divided into health related costs (\u20ac 60.87) and loss of productivity (\u20ac 84.67), the latter being mostly related absences (21%). Conclusions: During a follow-up period of 12 months, in each group there was a clear evidence of both a reduction of negative influence of dyspeptic symptoms on the patients' activities and a decrease of the mean cost for the treatment of dyspepsia. "RL" group presents cost 30% higher when compared with "UL" and "DL" groups, and 90% higher when compared with "other"

Adherence to treatment in allergic rhinitis using mobile technology. The MASK Study

Background: Mobile technology may help to better understand the adherence to treatment. MASK-rhinitis (Mobile Airways Sentinel NetworK for allergic rhinitis) is a patient-centred ICT system. A mobile phone app (the Allergy Diary) central to MASK is available in 22 countries. Objectives: To assess the adherence to treatment in allergic rhinitis patients using the Allergy Diary App. Methods: An observational cross-sectional study was carried out on all users who filled in the Allergy Diary from 1 January 2016 to 1 August 2017. Secondary adherence was assessed by using the modified Medication Possession Ratio (MPR) and the Proportion of days covered (PDC) approach. Results: A total of 12 143 users were registered. A total of 6 949 users reported at least one VAS data recording. Among them, 1 887 users reported ≥7 VAS data. About 1 195 subjects were included in the analysis of adherence. One hundred and thirty-six (11.28%) users were adherent (MPR ≥70% and PDC ≤1.25), 51 (4.23%) were partly adherent (MPR ≥70% and PDC = 1.50) and 176 (14.60%) were switchers. On the other hand, 832 (69.05%) users were non-adherent to medications (MPR <70%). Of those, the largest group was non-adherent to medications and the time interval was increased in 442 (36.68%) users. Conclusion and clinical relevance: Adherence to treatment is low. The relative efficacy of continuous vs on-demand treatment for allergic rhinitis symptoms is still a matter of debate. This study shows an approach for measuring retrospective adherence based on a mobile app. This also represents a novel approach for analysing medication-taking behaviour in a real-world setting