Search Results - EGA European Genome-Phenome Archive

National Sleep Research Resource (NSRR): Cleveland Family Study (CFS)

The Cleveland Family Study (CFS) is a family-based study of sleep apnea, consisting of 2,284 individuals (46% African American) from 361 families studied on up to 4 occasions over a period of 16 years. The study began in 1990 with the initial aims of quantifying the familial aggregation of sleep apnea. National Institutes of Health (NIH) renewals provided expansion of the original cohort, including increased minority recruitment, and longitudinal follow-up, with the last exam occurring in February 2006. The CFS was designed to provide fundamental epidemiological data on risk factors for sleep disordered breathing (SDB). The sample was selected by identifying affected probands who had laboratory diagnosed obstructive sleep apnea. All first-degree relatives, spouses and available second-degree relatives of affected probands were studied. In addition, during the first 5 study years, neighborhood control families were identified through a neighborhood proband, and his/her spouses and first-degree relatives. Each exam, occurring at approximately 4-year intervals, included new enrollment as well as follow up exams for previously enrolled subjects. For the first three visits, data, including an overnight sleep study, were collected in participants' homes while the last visit occurred in a general clinical research center (GCRC). Phenotypic characterization of the entire cohort included overnight sleep apnea studies, blood pressure, spirometry, anthropometry and questionnaires. Currently, data of 710 individuals are available for use through BioData Catalyst (with genotype data available through dbGaP).The National Sleep Research Resource (NSRR) is a NIH-supported sleep data repository that offers free access to large collections of de-identified physiological signals and related clinical data from a large range of cohort studies, clinical trials and other data sources from children and adults, including healthy individuals from the community and individuals with known sleep or other health disorders. The goals of NSRR are to facilitate rigorous research that requires access to large or more diverse data sets, including raw physiological signals, to promote a better understanding of risk factors for sleep and circadian disorders and/or the impact of sleep disturbances on health-related outcomes. Data from over 15 data sources and more than 40,000 individual sleep studies, many linked to dozens if not hundreds of clinical data elements, are available (as of Feb. 2022). Query tools are available to identify variables of interest, and their meta-data and provenance.

Study phs002715

Cystic Fibrosis Nasal Epithelium Gene Expression by RNAseq

Cystic fibrosis (CF) is a monogenic disorder leading to multi-organ system dysfunction, with the primary cause of morbidity and mortality being lung disease. Mutations in CFTR result in defective ion channel transport leading to hyperviscous mucus, airway infection, inflammation and lung function decline. While the Phe508del mutation is the most common CFTR mutation in North American people with CF, it is well known that there is a broad range of lung disease severity even amongst Phe508del homozygotes, including twins/siblings. Heritability analyses showing the relative contribution of non-CFTR modifier genes in such differences in phenotype, have led to our genomic and transcriptomic studies of gene modifiers in CF. Complementary to two international CF GWAS studies, this study was performed to a) determine differential expression of genes relative to a quantitative lung disease severity phenotype score (KNoRMA; as used in CF GWAS studies) and b) to assess expression quantitative trait loci. To better understand genetic modification of CF lung disease severity, we analyzed gene expression (transcriptomic) profiles by mRNA sequencing from nasal mucosal biopsy specimens of 134 people with CF. Each study participants was characterized for CF lung disease severity phenotype by averaging three years of lung function data (forced expiratory volume in 1 second; FEV1), normalized to a CF-specific reference population matching for age, sex, and height. Participants completed nasal lavage and nasal curettage mucosal sampling, with directed sampling to the inferior nasal turbinate, a well validated surrogate for cellular characteristics and CFTR function of the lower CF airways. Participants were further invited to complete a second set of these sampling procedures for validation analysis. Specimen and concurrent clinical data collection occurred across four North American study sites and nasal mucosal specimens were subjected to RNASeq analysis. These data were to be made available in the dbGaP. Our association analyses of gene expression relative to quantitative CF lung disease phenotype, taken together with previously identified GWAS signals, identified biological pathways correlated with CF lung disease pathogenesis. Our further association analyses of gene expression relative to single nucleotide polymorphism variation at significant CF GWAS loci further identified potential mechanisms of genetic variants associated with CF lung disease. This resource is intended to aid researchers in characterizing airway mucosal gene expression from the CF airways for the purpose of gene expression profiling in CF and in muco-obstructive airways disease.

Study phs002254

Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE-BioLINCC)

Data Access NOTE Please refer to the "Authorized Access" section below for information about how access to the data from this accession differs from many other dbGaP accessions. Objectives The primary aim of the RESTORE clinical trial was to determine whether critically ill children managed with a nurse-implemented, goal-directed sedation protocol would experience fewer days of mechanical ventilation than participants receiving usual care. Background Ensuring the safety and comfort of critically ill infants and children supported by mechanical ventilation is integral to the practice of pediatric critical care. Although sedation therapy benefits young participants who cannot understand the imperative nature of invasive life-sustaining therapies, sedative use is also associated with untoward adverse effects. Specifically, opioids and benzodiazepines commonly used for pediatric sedation may impair bedside neurological assessment, depress spontaneous ventilation, and prolong mechanical ventilation. Over time, drug tolerance develops, which may precipitate iatrogenic withdrawal syndrome when sedation therapy is no longer necessary.Numerous studies in adult critical care support a minimal yet effective approach to sedation management. Sedation goals for mechanically ventilated adults have shifted from an unresponsive state to a calm, easily aroused, readily evaluated participant. Studies in adult participants evaluating targeted sedation, daily interruption and/or titration of sedation, pairing of spontaneous awakening with breathing, and no sedation have reported improved clinical outcomes, including decreased length of mechanical ventilation when compared with usual care. In contrast, few data inform sedation practices in pediatric critical care, and international studies describe significant practice variation. Given unique biobehavioral differences, knowledge generated in adult critical care may not translate to the care of critically ill children. The RESTORE study was conducted to test the effect of a nurse-implemented, goal-directed sedation protocol on clinical outcomes in pediatric participants with acute respiratory failure. Participants There was a total of 2,449 participants (mean age: 4.7 years; range: 2 weeks to 17 years). Design The RESTORE study was a cluster randomized clinical trial conducted in 31 US PICUs. Intervention PICUs (17 sites; 1,225 participants) used a protocol that included targeted sedation, arousal assessments, extubation readiness testing, sedation adjustment every 8 hours, and sedation weaning. Control PICUs (14 sites; 1,224 participants) managed sedation per usual care. The primary outcome variable was duration of mechanical ventilation. Conclusions Among children undergoing mechanical ventilation for acute respiratory failure, the use of a sedation protocol compared with usual care did not reduce the duration of mechanical ventilation. Exploratory analyses of secondary outcomes suggest a complex relationship among wakefulness, pain, and agitation (JAMA 2015; 313(4):379-89).

Study phs003783

Neoadjuvant immunotherapy leads to pathological responses in MMR proficient and MMR deficient early stage colon cancers

PD-1 plus CTLA-4 blockade is highly effective in advanced-stage, mismatch repair (MMR)-deficient (dMMR) colorectal cancers, yet not in MMR-proficient (pMMR) tumors. We postulated a higher efficacy of neoadjuvant immunotherapy in early-stage colon cancers. In the exploratory NICHE study (ClinicalTrials.gov: NCT03026140), patients with dMMR or pMMR tumors received a single dose of ipilimumab and two doses of nivolumab before surgery, the pMMR group with or without celecoxib. The primary objective was safety and feasibility; 40 patients with 21 dMMR and 20 pMMR tumors were treated, and 3 patients received nivolumab monotherapy in the safety run-in. Treatment was well tolerated and all patients underwent radical resections without delays, meeting the primary endpoint. Of the patients who received ipilimumab + nivolumab (20 dMMR and 15 pMMR tumors), 35 were evaluable for efficacy and translational endpoints. Pathological response was observed in 20/20 (100%; 95% exact confidence interval (CI): 86–100%) dMMR tumors, with 19 major pathological responses (MPRs, ≤10% residual viable tumor) and 12 pathological complete responses. In pMMR tumors, 4/15 (27%; 95% exact CI: 8–55%) showed pathological responses, with 3 MPRs and 1 partial response. CD8+PD-1+ T cell infiltration was predictive of response in pMMR tumors. These data indicate that neoadjuvant immunotherapy may have the potential to become the standard of care for a defined group of colon cancer patients when validated in larger studies with at least 3 years of disease-free survival data.

Study EGAS00001004160

Quantification of chromosomal copy number aberrations by shallow whole-genome sequencing

Detection of DNA copy number aberrations by shallow whole-genome sequencing (WGS) faces many challenges including lack of completion and errors in the human reference genome, repetitive sequences, polymorphisms, variable sample quality, and biases in the sequencing procedures.Formalin-fixed paraffin-embedded (FFPE) archival material, the analysis of which is important for studies of cancer, presents particular analytical difficulties due to degradation of the DNA and frequent lack of matched reference samples. We present a robust, cost-effective WGS method for DNA copy number analysis that addresses these challenges more successfully than currently available procedures. In practice very useful profiles can be obtained with 0.1 fold genome coverage. We improve on previous methods by; first, implementing a combined correction for sequence mappability and GC content, and second, applying this procedure to sequence data from the 1000 Genomes Project in order to develop a blacklist of problematic genome regions. A small subset of these blacklisted regions were previously identified by ENCODE, but the vast majority are novel unappreciated problematic regions. Our procedures are implemented in a pipeline called QDNAseq. We have analyzed over 1,000 samples, most of which were obtained from the fixed tissue archives of over 25 institutions.We demonstrate that for most samples our sequencing and analysis procedures yield genome profiles with noise levels near the statistical limit imposed by read counting. The described procedures also provide better correction of artifacts introduced by low DNA quality than prior approaches, and better copy number data than high-resolution microarrays at substantially lower cost.

Study EGAS00001000642

Raw bulk TCRseq data fromTIL and non-TIL expanded TRACERx samples in the manuscript Bulk TCRseq from TRACERx samples from 'Subclonal immune evasion in non-small cell lung cancer'

Immune checkpoint blockade in non-small cell lung cancer (NSCLC) rarely leads to complete tumour remission, suggesting that tumours harbour subpopulations of cancer cells that can escape immune predation. However, while tumours consist of multiple genetically distinct clones, the extent to which separate tumour subclones differ intrinsically in their functional capacity for immune evasion remains largely unexplored. This has been challenging to address due to an inability to isolate and propagate individual tumour subclones from human cancers. Here, we leverage the multi-region TRACERx lung cancer evolution study to generate a patient-derived platform that allows the functional analysis of immune escape at single clone resolution. We generated libraries of >20 separate NSCLC organoid lines per patient by isolating individual (clonal) organoids established from multiple spatially separated tumour regions. Each organoid subline was co-cultured with autologous tumour infiltrating lymphocytes (TIL) to evaluate their capacity to elicit a T cell response. Organoid lines derived from separate tumour regions, or from single clones within individual regions, differ vastly in their capacity to elicit a T cell response, showing the coexistence of intrinsically immune evading (‘cold) and non-evading (‘hot) clones in the same primary tumour. Organoid lines escaping T cell recognition represent genetically and transcriptionally unique subclones with a distinct evolutionary history, showing that evolutionary sculpting of subclonal diversity can have functional consequences for anti-tumour immunity. Notably, the identification of immune-evasive subclones would not have been possible using computational approaches alone, highlighting the unique value of functional co-culture platforms. This patient-derived functional co-culture platform reveals that tumour evolution can give rise to distinct cancer clones with intrinsic differences in immune evasion capacity and provides an approach to prospectively identify, isolate and characterise immune evading subclones from patients with cancer.

Study EGAS00001008118

Single cell TCRseq data fromTIL and non-TIL expanded TRACERx samples in the manuscript Bulk TCRseq from TRACERx samples from 'Subclonal immune evasion in non-small cell lung cancer'

Immune checkpoint blockade in non-small cell lung cancer (NSCLC) rarely leads to complete tumour remission, suggesting that tumours harbour subpopulations of cancer cells that can escape immune predation. However, while tumours consist of multiple genetically distinct clones, the extent to which separate tumour subclones differ intrinsically in their functional capacity for immune evasion remains largely unexplored. This has been challenging to address due to an inability to isolate and propagate individual tumour subclones from human cancers. Here, we leverage the multi-region TRACERx lung cancer evolution study to generate a patient-derived platform that allows the functional analysis of immune escape at single clone resolution. We generated libraries of >20 separate NSCLC organoid lines per patient by isolating individual (clonal) organoids established from multiple spatially separated tumour regions. Each organoid subline was co-cultured with autologous tumour infiltrating lymphocytes (TIL) to evaluate their capacity to elicit a T cell response. Organoid lines derived from separate tumour regions, or from single clones within individual regions, differ vastly in their capacity to elicit a T cell response, showing the coexistence of intrinsically immune evading (‘cold) and non-evading (‘hot) clones in the same primary tumour. Organoid lines escaping T cell recognition represent genetically and transcriptionally unique subclones with a distinct evolutionary history, showing that evolutionary sculpting of subclonal diversity can have functional consequences for anti-tumour immunity. Notably, the identification of immune-evasive subclones would not have been possible using computational approaches alone, highlighting the unique value of functional co-culture platforms. This patient-derived functional co-culture platform reveals that tumour evolution can give rise to distinct cancer clones with intrinsic differences in immune evasion capacity and provides an approach to prospectively identify, isolate and characterise immune evading subclones from patients with cancer.

Study EGAS00001008161

Versatile workflow for cell-type resolved transcriptional and epigenetic profiles from cryopreserved human lung

The complexity of the lung microenvironment and changes in cellular composition during disease progression make it exceptionally hard to understand molecular mechanisms leading to the development of chronic lung diseases. Although recent advances in cell-type resolved and single-cell sequencing approaches hold great promise for studying complex diseases, their implementation relies on local access to fresh tissue, as traditional tissue storage methods do not allow viable cell isolation. To overcome these hurdles, we developed a novel, versatile workflow that allows long-term storage of human lung tissue with high cell viability, permits thorough sample quality check before cell isolation, and is compatible with sequencing-based profiling, including single-cell approaches. We demonstrate that cryopreservation is suitable for the isolation of multiple cell types from human lung and is applicable to both healthy and diseased tissue, including COPD and tumour samples. Basal cells isolated from cryopreserved airways retain the ability to differentiate, indicating that cellular identity is not altered by cryopreservation. Importantly, using RNA sequencing and EPIC Array, we show that genome-wide gene expression and DNA methylation signatures are preserved upon cryopreservation, emphasizing the suitability of our workflow for -omics profiling of human lung cells. In addition, we obtained high-quality single-cell RNA sequencing data of cells isolated from the cryopreserved human lung, demonstrating that cryopreservation empowers single-cell approaches. Overall, thanks to its simplicity, our cryopreservation workflow is well-suited for prospective tissue collection by academic collaborators and biobanks, opening worldwide access to human tissue.

Study EGAS00001004477

NHLBI GO-ESP: Family Studies (Familial Interstitial Pneumonia)

The NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), a signature project of the NHLBI Recovery Act investment, was designed to identify genetic variants in coding regions (exons) of the human genome (the "exome") that are associated with heart, lung and blood diseases. These and related diseases that are of high impact to public health and individuals from diverse racial and ethnic groups will be studied. These data may help researchers understand the causes of disease, contributing to better ways to prevent, diagnose, and treat diseases, as well as determine whether to tailor prevention and treatments to specific populations. This could lead to more effective treatments and reduce the likelihood of side effects. GO-ESP is comprised of five collaborative components: 3 cohort consortia - HeartGO, LungGO, and WHISP - and 2 sequencing centers - BroadGO and SeattleGO. The Familial Interstitial Pneumonia (FIP) project seeks to identify genetic variants in coding regions of the human genome that are linked to FIP by examining the coding regions among relatives with FIP. These data will be used in conjunction with our other genetic studies to help us better understand how and why some individuals develop pulmonary fibrosis.

Study phs000582

Pharmacogenomic Analysis Reveals New Therapeutic Options for Pleural Mesothelioma

Background: Pleural mesothelioma (PM) urgently requires novel effective treatments. Drug repurposing is a relevant strategy to discover new therapeutic options among well-known drugs used in clinical practice. This study aimed to identify new therapies in the context of molecular heterogeneity of PM. Methods: We performed a multi-omics study of the largest cohort of patient-derived primary PM cell lines (n=58) to date, using whole exome sequencing, RNA sequencing and methylome analysis. We also conducted a large-scale drug screening of over 1300 compounds on a subset of cell lines (n=11), as well as an extension screen (n=48) for selected drugs of interest. The best candidates were validated using 3D culture and mouse models. Results: We demonstrated that the molecular landscape of the cell lines cohort recapitulates the main findings in tumours and revealed new specific features of PM. The large-scale drug screening and subsequent validations highlighted notably strong sensitivity to entinostat and fluvastatin. Importantly, both compounds displayed same efficacy in 2D and 3D culture models and single treatment prolonged survival in vivo similarly or even better than standard chemotherapy. Strikingly, combining entinostat treatment with anti-PD1 led to cures in some mice and immunized them against tumour cells. Conclusions: Among several candidates, we identified entinostat, notably in combination with immune checkpoint inhibitor, and to a lesser extent fluvastatin, as promising therapeutic options for patients. We believe our study provides a valuable resource that could contribute to advances in the field and warrants further clinical investigation.

Study EGAS00001007866

Single-cell targeted DNA-sequencing and protein sequencing

We performed single-cell targeted DNA sequencing (MissionBio) on 13 high hyperdiploid B-ALL patients at diagnosis to study the genetic heterogeneity. For a number of patients single-cell surface protein antibody sequencing was added (DAB-seq) to better characterize the different cell types. Furthermore, additional samples during treatment were collected and analysed for some patients. In this way we want to study the clonal heterogeneity of these B-ALL samples, based both on mutations and CNVs, and identify resistant clones that could be targeted after relapse.

Study EGAS50000000580

DEPArray-based sorting of pure carcinoma and stromal populations from formalin-fixed paraffin-embedded (FFPE) tissues followed by targeted sequencing

To overcome the challenges of low DNA yields, degraded DNA by formalin fixation and diluted signal of genomic aberrations by non-carcinoma components in the heterogeneous FFPE samples, we isolated pure carcinoma and stromal cells using the DEPArray™ NxT system, a microchip-based digital sorter that allows isolation of pure, homogeneous subpopulations of cells from FFPE samples. We isolated pure carcinoma and stromal cell populations from 12 FFPE tissues, including tissues from 9 primary and metastatic breast cancer and 3 primary ovarian high-grade serous carcinomas. This was followed by a targeted panel for somatic mutation and sCNA analysis (7 samples), subject to cell availability. Mutation analysis was performed successfully in 6/7 samples and somatic mutations were detected in all of them.

Study EGAS50000001327

Whole-genome sequencing of bladder cancers of various stages and grades to search for driver mutations, chromosome-scale somatic changes, mutation signatures and clonal structures.

This discovery set of tumours cancers with whole-genome sequence data comprised 14 bladder cancers, paired with peripheral blood, that had been collected from unrelated individuals presenting to the Urology Department, Royal Hallamshire Hospital, Sheffield between June 2008 and September 2011. Four cancers were of low-grade papillary morphology (pTaG1-2), five were high grade invading the lamina propria (pT1G3, with two subsequently becoming muscle-invasive); and five were muscle-invasive (pT2-pT3). All tumours were sampled at transurethral resection or cystectomy and had not previously received any other therapy. The presence of a majority of cancer cells in the tumour specimens was confirmed by routine histological assessment. Genomic DNA was extracted from each tumour and paired blood sample using standard methods.

Study EGAS00001000738

RNA sequencing of lung fibroblasts

Study EGAS00001007857

Raw molecular data for "Subclonal immune evasion in non-small cell lung cancer"

Whole exome, RNA sequencing and TCR sequencing of organoid samples derived from TRACERx patients. The dataset also includes whole exome sequencing from the tumour samples from which the organoids were generated, as well as whole exome sequencing from PDX derived from said tumours.

Dataset EGAD00001015537

Single cell RNA sequencing of normal endometrial derived organoids uncovers novel cell type markers for prognostication

Endometrial carcinoma, the most common gynecologic cancer, develops from endometrial epithelium which is composed of secretory and ciliated cells. Pathologic classification is unreliable and there is a need for prognostic tools. We used single cell sequencing to study organoid model systems derived from normal endometrial endometrium to discover novel markers specific for endometrial ciliated or secretory cells. We performed single cell sequencing on endometrial and ovarian tumors and found both secretory-like and ciliated-like tumor cells.

Study EGAS00001004466

15020 results for "cancer studies using rna-seq"

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