The RD-Connect Genome-Phenome Analysis Platform: Accelerating diagnosis, research, and gene discovery for rare diseases.

Rare disease patients are more likely to receive a rapid molecular diagnosis nowadays thanks to the wide adoption of next-generation sequencing. However, many cases remain undiagnosed even after exome or genome analysis, because the methods used missed the molecular cause in a known gene, or a novel causative gene could not be identified and/or confirmed. To address these challenges, the RD-Connect Genome-Phenome Analysis Platform (GPAP) facilitates the collation, discovery, sharing, and analysis of standardized genome-phenome data within a collaborative environment. Authorized clinicians and researchers submit pseudonymised phenotypic profiles encoded using the Human Phenotype Ontology, and raw genomic data which is processed through a standardized pipeline. After an optional embargo period, the data are shared with other platform users, with the objective that similar cases in the system and queries from peers may help diagnose the case. Additionally, the platform enables bidirectional discovery of similar cases in other databases from the Matchmaker Exchange network. To facilitate genome-phenome analysis and interpretation by clinical researchers, the RD-Connect GPAP provides a powerful user-friendly interface and leverages tens of information sources. As a result, the resource has already helped diagnose hundreds of rare disease patients and discover new disease causing genes

Systematic Collaborative Reanalysis of Genomic Data Improves Diagnostic Yield in Neurologic Rare Diseases

Altres ajuts: Generalitat de Catalunya, Departament de Salut; Generalitat de Catalunya, Departament d'Empresa i Coneixement i CERCA Program; Ministerio de Ciencia e Innovación; Instituto Nacional de Bioinformática; ELIXIR Implementation Studies (CNAG-CRG); Centro de Investigaciones Biomédicas en Red de Enfermedades Raras; Centro de Excelencia Severo Ochoa; European Regional Development Fund (FEDER).Many patients experiencing a rare disease remain undiagnosed even after genomic testing. Reanalysis of existing genomic data has shown to increase diagnostic yield, although there are few systematic and comprehensive reanalysis efforts that enable collaborative interpretation and future reinterpretation. The Undiagnosed Rare Disease Program of Catalonia project collated previously inconclusive good quality genomic data (panels, exomes, and genomes) and standardized phenotypic profiles from 323 families (543 individuals) with a neurologic rare disease. The data were reanalyzed systematically to identify relatedness, runs of homozygosity, consanguinity, single-nucleotide variants, insertions and deletions, and copy number variants. Data were shared and collaboratively interpreted within the consortium through a customized Genome-Phenome Analysis Platform, which also enables future data reinterpretation. Reanalysis of existing genomic data provided a diagnosis for 20.7% of the patients, including 1.8% diagnosed after the generation of additional genomic data to identify a second pathogenic heterozygous variant. Diagnostic rate was significantly higher for family-based exome/genome reanalysis compared with singleton panels. Most new diagnoses were attributable to recent gene-disease associations (50.8%), additional or improved bioinformatic analysis (19.7%), and standardized phenotyping data integrated within the Undiagnosed Rare Disease Program of Catalonia Genome-Phenome Analysis Platform functionalities (18%)

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Biblioteca de l'heurística constructiva Clarke and Wright combinada amb simulació Monte Carlo per resoldre el problema d'adreçament de vehicles

En aquesta recerca es presenta una biblioteca de programari lliure basada en l'heurística constructiva de Clarke & Wright combinada amb simulació Monte Carlo que permet, de manera simple, generar solucions al problema d'adreçament de vehicles. Aquesta metodologia construeix solucions competents en poc temps i sense necessitat d'ajustar o configurar paràmetres previs. La biblioteca pot integrar-se fàcilment en projectes que resolguin variants del VRP amb canvis mínims sobre el codi. Aquest es troba ben documentat i accessible de manera lliure a través de la xarxa. Els resultats computacionals indiquen que es resolen instàncies VRP en temps i costos significativament inferiors a altres propostes de la mateixa família.En esta investigación se presenta una biblioteca de software libre basada en la heurística constructiva de Clarke & Wright combinada con simulación Monte Carlo que permite, de manera simple, generar soluciones al problema de direccionamiento de vehículos. Esta metodología construye soluciones competentes en poco tiempo y sin necesidad de ajustar o configurar parámetros previos. La biblioteca puede integrarse fácilmente en proyectos que resuelvan variantes del VRP con cambios mínimos sobre el código. Éste se encuentra bien documentado y accesible de manera libre a través de la red. Los resultados computacionales indican que se resuelven instancias VRP en tiempo y costes significativamente inferiores a otras propuestas de la misma familia.Master thesis for the Free Software program

Laboratorio virtual de sistemas digitales

El projecte "Laboratori virtual de sistemes digitals" és un simulador de l'aula de pràctiques de l'assignatura de sistemes digitals, desenvolupat en Java. Integra tots els components que es troben els estudiants de la matèria quan han de realitzar les pràctiques: placa, xips, cables, generador d'ones, oscil·loscopi.... I es permetrà així la implementació i prova de circuits digitals. També pretén ser una eina útil pel funcionament de la part pràctica de l'assignatura, sent un recurs gratuït i accessible gràcies a Internet.El proyecto "Laboratorio virtual de sistemas digitales" es un simulador del aula de prácticas de la asignatura de sistemas digitales, desarrollado en Java. Integra todos los componentes que se encuentran los estudiantes de la materia cuando tienen que realizar las prácticas: placa, chips, cables, generador de ondas, osciloscopio,…. Permitiendo así la implementación y prueba de circuitos digitales. También pretende ser una herramienta útil para el funcionamiento de la parte práctica de la asignatura, siendo un recurso gratuito y accesible gracias a Internet.The project "Digital systems virtual laboratory" is a simulator of the practical classroom of digital system’s subject, developed in Java. Compiles all components that students can find when they are doing the practical part of the subject: breadboard, chips, cables, function generator, oscilloscope… It allows digital circuit’s implementation and testing. Also, tries to be an useful tool to the behaviour of the practical subject’s part, being a free software and accesible by Internet.O proxecto “Laboratorio virtual de sistemas dixitais” é un simulador da aula de prácticas da materia de sistemas dixitais, desenvolvido en Java. Integra todos os compoñentes que se atopan os estudantes cando teñen que facer as prácticas: placa, chips, cables, xerador de ondas, osciloscopio,... Permitindo deste xeito a implementación e proba de circuítos dixitais. Tamén, pretende ser unha ferramenta útil para o funcionamento da parte práctica da materia, sendo un recursos gratuíto e accesible grazas a Internet.Nota: Aquest document conté originàriament altre material i/o programari només consultable a la Biblioteca de Ciència i Tecnologia

Laboratorio virtual de sistemas digitales

El projecte "Laboratori virtual de sistemes digitals" és un simulador de l'aula de pràctiques de l'assignatura de sistemes digitals, desenvolupat en Java. Integra tots els components que es troben els estudiants de la matèria quan han de realitzar les pràctiques: placa, xips, cables, generador d'ones, oscil·loscopi.... I es permetrà així la implementació i prova de circuits digitals. També pretén ser una eina útil pel funcionament de la part pràctica de l'assignatura, sent un recurs gratuït i accessible gràcies a Internet.El proyecto "Laboratorio virtual de sistemas digitales" es un simulador del aula de prácticas de la asignatura de sistemas digitales, desarrollado en Java. Integra todos los componentes que se encuentran los estudiantes de la materia cuando tienen que realizar las prácticas: placa, chips, cables, generador de ondas, osciloscopio,…. Permitiendo así la implementación y prueba de circuitos digitales. También pretende ser una herramienta útil para el funcionamiento de la parte práctica de la asignatura, siendo un recurso gratuito y accesible gracias a Internet.The project "Digital systems virtual laboratory" is a simulator of the practical classroom of digital system's subject, developed in Java. Compiles all components that students can find when they are doing the practical part of the subject: breadboard, chips, cables, function generator, oscilloscope… It allows digital circuit's implementation and testing. Also, tries to be an useful tool to the behaviour of the practical subject's part, being a free software and accesible by Internet.O proxecto "Laboratorio virtual de sistemas dixitais" é un simulador da aula de prácticas da materia de sistemas dixitais, desenvolvido en Java. Integra todos os compoñentes que se atopan os estudantes cando teñen que facer as prácticas: placa, chips, cables, xerador de ondas, osciloscopio,... Permitindo deste xeito a implementación e proba de circuítos dixitais. Tamén, pretende ser unha ferramenta útil para o funcionamento da parte práctica da materia, sendo un recursos gratuíto e accesible grazas a Internet.Nota: Aquest document conté originàriament altre material i/o programari només consultable a la Biblioteca de Ciència i Tecnologia

gemBS: high throughput processing for DNA methylation data from bisulfite sequencing

Motivation: DNA methylation is essential for normal embryogenesis and development in mammals and can be captured at single base pair resolution by whole genome bisulfite sequencing (WGBS). Current available analysis tools are becoming rapidly outdated as they lack sensible functionality and efficiency to handle large amounts of data now commonly created. Results: We developed gemBS, a fast high-throughput bioinformatics pipeline specifically designed for large scale BS-Seq analysis that combines a high performance BS-mapper (GEM3) and a variant caller specifically for BS-Seq data (BScall). gemBS provides genotype information and methylation estimates for all genomic cytosines in different contexts (CpG and non-CpG) and a set of quality reports for comprehensive and reproducible analysis. gemBS is highly modular and can be easily automated, while producing robust and accurate results. Availability and implementation gemBS is released under the GNU GPLv3+ license. Source code and documentation are freely available from www.statgen.cat/gemBS. Supplementary information: Supplementary data are available at Bioinformatics online

Remote visualization of large-scale genomic alignments for collaborative clinical research and diagnosis of rare diseases

The Solve-RD project objectives include solving undiagnosed rare diseases (RD) through collaborative research on shared genome-phenome datasets. The RD-Connect Genome-Phenome Analysis Platform (GPAP), for data collation and analysis, and the European Genome-Phenome Archive (EGA), for file storage, are two key components of the Solve-RD infrastructure. Clinical researchers can identify candidate genetic variants within the RD-Connect GPAP and, thanks to the developments presented here as part of joint ELIXIR activities, are able to remotely visualize the corresponding alignments stored at the EGA. The Global Alliance for Genomics and Health (GA4GH) htsget streaming application programming interface (API) is used to retrieve alignment slices, which are rendered by an integrated genome viewer (IGV) instance embedded in the GPAP. As a result, it is no longer necessary for over 11,000 datasets to download large alignment files to visualize them locally. This work highlights the advantages, from both the user and infrastructure perspectives, of implementing interoperability standards for establishing federated genomics data networks.This study was partially funded by ELIXIR Implementation Studies “Remote real-time visualization of human RDs genomics data (RD-Connect) stored at the EGA ELIXIR” (2017–2018), “Integration of ELIXIR-IIB in ELIXIR Rare Disease activities (2017–2018),” and “Rare Disease Infrastructure ELIXIR (2019–2020)” and the Solve-RD project, which received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement no. 779257. Data were analyzed using the RD-Connect Genome-Phenome Analysis Platform, which has received funding from EU projects RD-Connect, Solve-RD, and EJP-RD (grant nos. FP7 305444, H2020 779257, and H2020 825575), Instituto de Salud Carlos III (grant nos. PT13/0001/0044 and PT17/0009/0019; Instituto Nacional de Bioinformática, INB), and ELIXIR Implementation Studies. We acknowledge the support of the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) to the EMBL partnership, the Centro de Excelencia Severo Ochoa, and the CERCA Programme/Generalitat de Catalunya

The interplay between DNA methylation and sequence divergence in recent human evolution

Despite the increasing knowledge about DNA methylation, the understanding of human epigenome evolution is in its infancy. Using whole genome bisulfite sequencing we identified hundreds of differentially methylated regions (DMRs) in humans compared to non-human primates and estimated that ∼25% of these regions were detectable throughout several human tissues. Human DMRs were enriched for specific histone modifications and the majority were located distal to transcription start sites, highlighting the importance of regions outside the direct regulatory context. We also found a significant excess of endogenous retrovirus elements in human-specific hypomethylated.We reported for the first time a close interplay between inter-species genetic and epigenetic variation in regions of incomplete lineage sorting, transcription factor binding sites and human differentially hypermethylated regions. Specifically, we observed an excess of human-specific substitutions in transcription factor binding sites located within human DMRs, suggesting that alteration of regulatory motifs underlies some human-specific methylation patterns. We also found that the acquisition of DNA hypermethylation in the human lineage is frequently coupled with a rapid evolution at nucleotide level in the neighborhood of these CpG sites. Taken together, our results reveal new insights into the mechanistic basis of human-specific DNA methylation patterns and the interpretation of inter-species non-coding variation.We acknowledge support from AGAUR (Generalitat de Catlunya, Spain) and the Barcelona Zoo (Ajuntament de Barcelona) for an award to I.H.H. H.H. is a Miguel Servet (CP14/00229) researcher funded by the Spanish Institute of Health Carlos III (ISCIII).T.M.B. and M.E. are ICREA Research Professors. Funding for open access charge: European Research Council (ERC), grant EPINORC, under agreement No. 268626; MICINN Projects—SAF2011-22803 and BFU2011-28549; Cellex Foundation; European Community's Seventh Framework Programme (FP7/2007-2013), grant HEALTH-F5-2011-282510—BLUEPRINT, and the Health and Science Departments of the Generalitat de Catalunya