8 research outputs found
Standardized analysis and sharing of genome-phenome data for neuromuscular and rare disease research through the RD-Connect platform
<b>Abstract:Â </b><div>RD-Connect (rd-connect.eu) is an EU-funded project building an integrated platform to narrow the gaps in rare disease research, where patient populations, clinical expertise and research communities are small in number and highly fragmented. Guided by the needs of rare disease researchers and with neuromuscular and neurodegenerative researchers as its original collaborators, the RD-Connect platform securely integrates multiple types of omics data (genomics, proteomics and transcriptomics) with biosample and clinical information â at the level of an individual patient, a family or a whole cohort, providing not only a centralized data repository but also a sophisticated and user-friendly online analysis system. Whole-genome, exome or gene panel NGS datasets from individuals with rare diseases and family members are deposited at the European Genome-phenome Archive, a longstanding archiving system designed for long-term storage of these large datasets. The raw data is then processed by RD-Connect's standardised analysis and annotation pipeline to make data from different sequencing providers more comparable. The corresponding clinical information from each individual is recorded in a connected PhenoTips instance, a software solution that simplifies the capture of clinical data using the Human Phenotype Ontology, OMIM and Orpha codes. The results are made available to authorised users through the highly configurable online platform (platform.rd-connect.eu), which runs on a Hadoop cluster and uses ElasticSearch â technologies designed to handle big data at high speeds. The user-friendly interface enables filtering and prioritization of variants using the most common quality, genomic location, effect, pathogenicity and population frequency annotations, enabling users from clinical labs without extensive bioinformatics support to do their primary genomic analysis of their own patients online and compare them with other submitted cohorts. Additional tools, such as Exomiser, DiseaseCard, Alamut Functional Annotation (ALFA) and UMD Predictor (umd-predictor.eu) are integrated at several levels. The RD-Connect platform is designed to enable data sharing at various levels depending on user permissions. At the most basic level (âdoes this specific variant exist in any individual in this cohort?â) it has lit a Beacon within the Global Alliance for Genomics and Healthâs Beacon Network (www.beacon-network.org). At the next stage of sharing â finding similarities between patients in different databases with a matching phenotype and a candidate variant in the same gene â it is actively involved in the development of Matchmaker Exchange (www.matchmakerexchange.org), allowing users of different systems to securely exchange information to find confirmatory cases. And finally, since all patients within the system have been consented for data sharing, users of the system, after validation and authorization, are able to access datasets from other centres, providing an instant means of gathering cohorts for cross-validation and further study. Although open to any rare disease, the platform is currently enriched for neuromuscular and neurodegenerative phenotypes and includes almost 1000 genomic datasets from the NeurOmics project (www.rd-neuromics.eu) with several other contributions in the pipeline, including 1000 limb-girdle muscular dystrophy index cases from the Myo-Seq project (www.myo-seq.org) and more. The platform is free of charge to use and is open for contributions of NGS and phenotypic data from research labs worldwide via [email protected]Â <p></p></div
Description of <i>DPYD</i> variations along with <i>in silico</i> / <i>in vitro</i> functionality.
<p>Description of <i>DPYD</i> variations along with <i>in silico</i> / <i>in vitro</i> functionality.</p
Association of variant combinations and/or DPD phenotype with capecitabine-related toxicity (maximum toxicity grade considering hematotoxicity, digestive and neurotoxicity).
<p>Association of variant combinations and/or DPD phenotype with capecitabine-related toxicity (maximum toxicity grade considering hematotoxicity, digestive and neurotoxicity).</p
Location of F100L variant within the N-terminal Fe-S cluster containing the alpha helical domain I of the DPD protein.
<p>Protein modeling was performed using UCSF Chimera version 1.8. The pig crystal structure (PDB ID 1gTH) was used as a template. The F100L variant could impair enzyme function by disrupting a conserved residue F100 important for electron transfer via the [4Fe-4S] cluster.</p
New advances in <i>DPYD</i> genotype and risk of severe toxicity under capecitabine - Fig 3
<p>Distribution of pre-treatment plasma UH2/U ratio (A) and Uracil concentrations (B) for the 205 patients with validated phenotypic data, according to <i>DPYD</i> variants of interest: variant *2A (3 heterozygous patients), D949V (3 heterozygous patients), R592W (1 heterozygous patient), D342G (1 heterozygous patient), HapB3 (4 heterozygous patients), 166VV (3 homozygous patients) <i>vs</i> any other variations (185 patients) <i>vs</i> no variation (5 patients). DPD deficiency is reflected by plasma UH2/U decrease or plasma uracil increase. All indicated genotypes were mutually exclusive. Horizontal solid lines indicate median values (10.6 for UH2/U and 9.6 ng/ml for Uracil concentration). Horizontal dotted line on Uracil plot indicates the 91st percentile (16 ng/ml) associated with enhanced grade 3â4 toxicity. Open diamonds indicate patients with toxicity grade 0-1-2 and solid bow ties indicate patients with grade 3â4 toxicity. For variants carried by at least 3 patients, distribution of phenotype was compared between carriers and non-carriers using the non-parametric Mann-Whitney test (* indicates 0.01â€p<0.05 and ** indicates p<0.01).</p
Patient and treatment characteristics (N = 243).
<p>Patient and treatment characteristics (N = 243).</p
Profile of patients with grade 4â5 toxicity.
<p>Profile of patients with grade 4â5 toxicity.</p