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• FLG LoF Variants are Associated with Atopic Dermatitis in an Early-Life Prospective Cohort

  We performed targeted sequencing of the FLG gene in 438 children with physician-diagnosed Atopic Dermatitis (AD), identified Loss-of-Function (LoF) variants, and tested the association of having one or more of these variants (binary composite) variants with AD-associated outcomes. We found that having a LoF variant was associated with moderate-severe AD compared to mild AD, food allergy at the first visit, and higher transepidermal water loss (TEWL) in both lesional and non-lesional skin in these children.

  Study phs003489

• Women's Interagency HIV Study (WIHS)

  The Women's Interagency HIV Study (WIHS), a multicenter, prospective study, was established in August 1993 to carry out comprehensive investigations of the impact of HIV infection and its clinical, laboratory, and psychosocial effects in women. The purpose of this study is to collect and evaluate these data from HIV infected and at-risk women to better understand and provide support for women whom are currently HIV infected or who are at risk for HIV infection. Participants will have study visits every 6 months. Questionnaires regarding sexual behavior, health care utilization, medical and obstetric/gynecological history, psychosocial factors, and sociodemographics will be completed by participants. Physical, gynecological, and lipodystrophy examinations will also be conducted at each visit, and current medication regimen will be noted. Blood and other bodily fluid samples will be collected and registered in both local and national repositories of the WIHS in conjunction with NIAID.

  Study phs001503

• Heart Failure Network - Xanthine Oxidase Inhibition for Hyperuricemic Heart Failure Patients (HFN EXACT-BioLINCC)

  ObjectivesTo determine the effect of allopurinol after 24 weeks on a composite clinical endpoint that classifies subject's clinical status (improved, worsened, unchanged) in patients with heart failure and high uric acid levels.BackgroundMorbidity and mortality rates for patients with heart failure are high, despite guideline-recommended therapy. Heart failure is characterized by an imbalance between left ventricular (LV) performance and myocardial energy consumption. There is a growing body of evidence that suggests oxidative stress contributes to ventricular and vascular remodeling, and disease progression in heart failure. Targeting potential source(s) of oxidative stress, e.g. Xanthine oxidase (XO), was the focus of recent clinical trials and epidemiological studies. Increased XO activity has been shown to lead to production of superoxide and uric acid (UA). Serum uric acid levels are included in heart failure risk scores, and hyperuricemia is present in about 25% of patients with heart failure. Hyperuricemia is associated with exercise intolerance, reduced survival, and worsening symptoms. The EXACT-HF trial tested allopurinol, an inhibitor of XO, as a potential target therapy for hyperuricemic heart failure patients.Subjects253 subjects were enrolled in the EXACT-HF study. 128 participants were randomized to the allopurinol arm, and of those participants, 119 completed the trial and 9 did not. 125 participants were randomized to the placebo arm, and of those participants, 116 completed the trial and 9 did not.DesignEXACT-HF was a multi-center, double-blind, placebo controlled, 24-week trial of allopurinol. Eligible participants had to be receiving a stable regimen for at least two weeks (3 months for beta-blockers) prior to randomization. Participants were randomized by an automated system to either the allopurinol or placebo arm, and started treatment within 12 hours of completing the baseline visit. During the first week, participants in both treatment arms received 300mg daily of the respective medications. For the following 23 weeks, participants in both treatment arms received 600mg daily of the respective medications. Patients unable to tolerate 600 mg were maintained on 300 mg.The primary endpoint was a composite clinical endpoint (CCE) that classified a subject's clinical status as improved, worsened, or unchanged at 24 weeks. The CCE was determined based on the following: death; hospitalization, emergency room visit or emergent clinic visit for worsening HF; medication change for worsening HF; and Patient Global Assessment using a 7-point scale. Secondary endpoints at 12 and 24 weeks included changes in quality of life as assessed by the Kansas City Cardiomyopathy Questionnaire, and submaximal exercise capacity as assessed by a 6-minute walk test.ConclusionsParticipants who received allopurinol had significantly less serum uric acid laboratory levels after 24 weeks; however, no significant difference was observed in the primary and secondary endpoints between the allopurinol and placebo-treated patients. Therefore, in high-risk HF patients with reduced ejection fraction and elevated uric acid levels, xanthine oxidase inhibition with allopurinol failed to improve clinical status, exercise capacity, quality of life, or LVEF at 24 weeks (Circulation. 2015 May 19; 131(20):1763-71).

  Study phs003533

• Genome-wide cell-free DNA termini in patients with cancer

  The structure, fragmentation pattern, length and terminal sequence of cell-free DNA (cfDNA) is under the influence of nucleases present in the blood. We hypothesized that differences in the diversity of bases at the end of cfDNA fragments can be leveraged on a genome-wide scale to enhance the sensitivity for detecting the presence of tumor signals in plasma. We surveyed the cfDNA termini in 72 plasma samples from 319 patients with 18 different cancer types using low-coverage whole genome sequencing. The fragment-end sequence and diversity were altered in all cancer types in comparison to 76 healthy controls. We converted the fragment end sequences into a quantitative metric and observed that this correlates with circulating tumor DNA tumor fraction (R = 0.58, p < 0.001, Spearman). Using these metrics, we were able to classify cancer samples from control at a low tumor content (AUROC of 91% at 1% tumor fraction) and shallow sequencing coverage (mean AUROC = 0.99 at >1M fragments). Combining fragment-end sequences and diversity using machine learning, we classified cancer from healthy controls (mean AUROC = 0.99, SD = 0.01). Using unsupervised clustering we showed that early-stage lung cancer can be classified from control or later stages based on fragment-end sequences. We observed that fragment-end sequences can be used for prognostication (hazard ratio: 0.49) and residual disease detection inresectable esophageal adenocarcinoma patients, moving fragmentomics toward a greater clinical implementation.

  Study EGAS00001005738

• Genome-wide cell-free DNA termini in patients with cancer

  The structure, fragmentation pattern, length and terminal sequence of cell-free DNA (cfDNA) is under the influence of nucleases present in the blood. We hypothesized that differences in the diversity of bases at the end of cfDNA fragments can be leveraged on a genome-wide scale to enhance the sensitivity for detecting the presence of tumor signals in plasma. We surveyed the cfDNA termini in 72 plasma samples from 319 patients with 18 different cancer types using low-coverage whole genome sequencing. The fragment-end sequence and diversity were altered in all cancer types in comparison to 76 healthy controls. We converted the fragment end sequences into a quantitative metric and observed that this correlates with circulating tumor DNA tumor fraction (R = 0.58, p < 0.001, Spearman). Using these metrics, we were able to classify cancer samples from control at a low tumor content (AUROC of 91% at 1% tumor fraction) and shallow sequencing coverage (mean AUROC = 0.99 at >1M fragments). Combining fragment-end sequences and diversity using machine learning, we classified cancer from healthy controls (mean AUROC = 0.99, SD = 0.01). Using unsupervised clustering we showed that early-stage lung cancer can be classified from control or later stages based on fragment-end sequences. We observed that fragment-end sequences can be used for prognostication (hazard ratio: 0.49) and residual disease detection inresectable esophageal adenocarcinoma patients, moving fragmentomics toward a greater clinical implementation.

  Study EGAS00001005747

• Idiopathic Pulmonary Fibrosis Network (IPFNet) Sildenafil Trial of Exercise Performance in Idiopathic Pulmonary Fibrosis (IPFNet-STEP-IPF-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 STEP-IPF study sought to evaluate whether treatment with sildenafil would improve walk distance, dyspnea, and quality of life in participants with advanced idiopathic pulmonary fibrosis (IPF).Background: IPF is a chronic, progressive lung disease of unknown cause that is characterized by the histopathologic pattern of usual interstitial pneumonia. Progression to end-stage respiratory insufficiency and death within 5 years after the onset of symptoms is characteristic. To date, no pharmacologic therapies have definitively been shown to improve survival or quality of life in participants with this disease.Participants with severe IPF have abnormalities of the pulmonary vasculature leading to decreased levels of resting and exercise-induced production of nitric oxide. Since nitric oxide is a potent pulmonary vasodilator, reduced levels are associated with pulmonary vasoconstriction and impaired gas exchange. Sildenafil (Revatio, Pfizer) is a phosphodiesterase-5 inhibitor that stabilizes the second messenger of nitric oxide, cyclic guanosine monophosphate, which leads to pulmonary vasodilatation. Such vasodilatation could improve ventilation–perfusion matching and thus gas exchange in with IPF.Design: STEP-IPF was a double-blind, randomized, placebo-controlled trial of oral sildenafil (20 mg three times daily). Participants meeting eligibility criteria were randomly assigned in a 1:1 ratio to receive sildenafil or matched placebo with the use of a permuted-block design, with stratification according to clinical center. The primary outcome was the presence or absence of an improvement of at least 20% in the 6-minute walk distance at 12 weeks, as compared with baseline. Key secondary outcomes included changes in the 6-minute walk distance, degree of dyspnea, and quality of life.Screening procedures included the taking of a detailed history, a physical examination, spirometry, echocardiography, CT imaging, and measurements of lung volume on plethysmography, carbon monoxide diffusion capacity, and arterial blood gases. Eligible participants returned for an enrollment visit within 6 weeks after screening. All participants received an initial dose of a study drug at this visit and were monitored for 60 minutes for adverse effects. Follow-up visits were scheduled at 1, 6, and 12 weeks. After completion of the 12-week visit, all participants were started on treatment with open-label sildenafil. Visits were scheduled at 13, 18, and 24 weeks; at 28 weeks, serious adverse events and vital status were documented. Testing of the 6-minute walk distance was performed with the use of a standardized protocol at the time of screening and enrollment and at study visits at 6, 12, 18, and 24 weeks. Participants with pulse oxygen saturation below 88% received supplemental oxygen. Conclusions: This study did not show a benefit for sildenafil for the primary outcome. The presence of some positive secondary outcomes creates clinical equipoise for further research. There were small but significant differences in arterial oxygenation, carbon monoxide diffusion capacity, degree of dyspnea, and quality of life favoring the sildenafil group.

  Study phs004085

• NHLBI TOPMed: The Genetic Epidemiology of Asthma in Costa Rica

  This administrative supplement to the project, "The Genetic Epidemiology of Asthma in Costa Rica" (R37 HL066289) is in response to NOT-HL-14-029 to perform whole genome sequencing (WGS) on existing NHLBI populations. We focus on asthma because of its public health significance. Asthma affects 26 million U.S. children and adults, remains a major cause of morbidity (one-half million hospitalizations a year) and is the most common cause of school and work days lost. Asthma-related costs are estimated to be over $12.7 billion annually. The Asthma Probands for both the extended pedigrees and the trios utilized in this study were selected on the basis of a physician diagnosis of asthma; a history of recurrent asthma attacks or at least 2 respiratory symptoms; and either airway hyperresponsiveness to methacholine or significant response to bronchodilator (Albuterol) administration. These criteria are identical to the criteria used in the Childhood Asthma Management Program (CAMP). The three primary goals of this project are to: (1) identify common and rare genetic variants that determine asthma and its associated phenotypes (height, weight, IgE level, lung function, bronchodilator response, steroid treatment response) through whole genome sequencing (WGS); (2) perform novel family based association analysis of our WGS data to identify novel genes for asthma; and (3) integrate epigenomic and transcriptomic data with our WGS data and determine the epistatic interactions present using systems genomics approaches. Identification of the molecular determinants of asthma remains an important priority in translational science. Genome-wide association studies (GWAS) have been successful in this regard, identifying at least 10 novel susceptibility genes for asthma. However, as with most complex traits, the variants identified by GWAS explain only a fraction of the estimated heritability of this disorder. Herein, we propose a novel family-based study design and state-of-the-art genome sequencing techniques to map a set of sequence variants for asthma and its associated phenotypes and assess the interrelationships of the identified genes and variants using systems genomics methods. We have assembled a team of investigators highly-skilled and expert in whole genome sequencing (Drs. Michael Cho and Benjamin Raby), genetic association analysis (Drs. Scott T. Weiss, Jessica Lasky-Su and Christoph Lange), integrative genomics (Drs. Raby, Kelan Tantisira, Augusto Litonjua and Dawn DeMeo), and systems genomics (Drs. Weiss, Amitabh Sharma, Lange and Raby) to address this important problem with both a novel study design and data set.

  Study phs000988

• CNS Embryonal tumors

  The dataset represents a total of 58 DNA samples from 16 male and 12 female pediatric patients affected with embryonal central nervous system tumors. The samples were subject to whole genome sequencing, WGS, [48 samples, (representing 12 male and 11 female individuals)] and whole exome sequencing, WES, [10 samples, (representing 4 male and 1 female individuals)]. One tumor tissue sample and one peripheral blood sample were analyzed from each of 26 patients, whereas two tumor tissue samples and one peripheral blood sample were analyzed from two patients. The WGS samples were sequenced 2x150 bp paired-end on an Illumina HiSeqX v2.5 instrument, and the WES samples were sequenced 2x100 bp paired-end on an Illumina HiSeq 2500 instrument. The FASTQ files generated were aligned to the human reference genome sequence GRCh38/hg38 using bwa-mem, with the ALT-aware option turned on. Sorting of reads and marking of PCR duplicates was performed with GATK. Base quality score recalibration and joint realignment of reads around insertions and deletions (indels) were conducted using GATK tools. The dataset consists of 58 files in the CRAM format (lossless compression) with a total file size of ~8,8 TB. All CRAM files but one, are derived from one sequence run and one sample. P4551_227N_P4552_112N is a CRAM file where 2 sequence runs (P4551_227N and P4552_112N) from peripheral blood samples from the same individual, P019, were aligned into one single CRAM file. Additional genomic and molecular data (FASTQ, BAM, IDAT, and VCF files) and limited clinical data can be requested by ethically approved projects conducting research in the field of pediatric cancer.

  Dataset EGAD50000000298

• Molecularly matched targeted therapies plus radiotherapy in patients with newly diagnosed glioblastoma without MGMT promoter hypermethylation (N2M2/NOA-20 phase I/IIa umbrella trial)

  Background: Patients with glioblastoma without MGMT promoter hypermethylation are unlikely to benefit from temozolomide (TMZ). Trials aiming at replacing TMZ with targeted agents in not molecularly selected patient populations have failed. Methods: This phase I/IIa umbrella trial aimed at showing safety, feasibility, and preliminary efficacy of targeted compounds in addition to standard radiotherapy initiated within 42 days postoperatively. Molecular diagnostics and bioinformatic evaluation are performed within 28 days after surgery. Stratification for treatment takes place in five subtrials, including alectinib, idasanutlin, palbociclib, vismogedib and temsirolimus, according to the best matching molecular alteration. Patients without matching alterations are randomized between subtrials without strong biomarkers using atezolizumab and asunercept and TMZ as standard of care. Primary objective of the phase I parts of the trial was dose finding or dose validation. In the phase IIa trials, centrally determined progression-free survival at six months (PFS-6) is used as endpoint for efficacy with interim analyses for futility (H0: p=0.231). Results: From May 2018 through July 2022, 301 patients were enrolled and 228 treated in 13 German NOA sites. The alectinib and vismodegib subtrials were closed since no molecularly matching patients were accrued; the idasanutlin subtrial was closed prior to the optimal dose at nine patients at discretion of the company providing the drug. The TMZ subtrial showed a PFS-6 of 18.52% (10/54 patients) (p=0.831) and a median overall survival (OS) of 12.1 months. Asunercept: PFS-6 of 15.4% (4/26) (p=0.8825) and OS of 12.8 months. Atezolizumab: PFS-6 of 21.4% (9/42) (p=0.660) and OS of 11.7 months. Palbociclib with patients demonstrating CDK4 amplification or CDKN2A/B codeletion: PFS-6 of 24.4% (10/41) (p=0.4823) and OS of 12.6 months. Temsirolimus with patients demonstrating mTOR activation: PFS-6 of 39.1% (18/46) (p=0.0109) and OS of 15.4 months. The regimen-limiting toxicity (RLT)-rate is 34.8%, which is insignificantly above the predefined unacceptable rate for RLTs of 30%. Most RLTs had severity grade 3, one RLT had severity grade 4. No RLTs resulted in death. Conclusions: N2M2 allows for elaborate molecular testing being integrated into the treatment decision and efficient determination of treatment activity for patients with newly diagnosed glioblastoma. There is clinical activity of temsirolimus in patients with tumors harboring an activated mTOR pathway although this is not positively prognostic without mTOR inhibition; there is no clinical activity for asunercept and atezolizumab in not molecularly selected patients and also palbociclib in molecularly selected patients.

  Study EGAS00001008033

• Heart Failure Network: Diuretic Optimization Strategies Evaluation in Acute Heart Failure (HFN DOSE-BioLINCC)

  ObjectivesThe DOSE study sought to evaluate the most effective dosing (high vs. low) and administration (continuous infusion vs. intermittent boluses) combination of the diuretic Furosemide in the treatment of patients with acute decompensated heart failure.BackgroundAcute decompensated heart failure is the most common cause of hospital admissions among patients older than 65 years of age and is responsible for more than 1 million hospitalizations annually in the United States. Intravenous loop diuretics are an essential component of current treatment and are administered to approximately 90% of patients who are hospitalized with heart failure. Despite decades of clinical experience with these agents, prospective data to guide the use of loop diuretics are sparse, and current guidelines are based primarily on expert opinion. As a result, clinical practice varies widely with regard to both the mode of administration and the dosing.SubjectsA total of 308 patients were enrolled between March 2008 and November 2009 at 26 clinical sites in the United States and Canada. DesignThe DOSE study was a prospective, randomized, double-blind, controlled trial with a 2-by-2 factorial design. Patients were randomly assigned to either a low-dose strategy (total intravenous furosemide dose equal to their total daily oral loop diuretic dose in furosemide equivalents) or a high-dose strategy (total daily intravenous furosemide dose 2.5 times their total daily oral loop diuretic dose in furosemide equivalents) and to administration of furosemide either by intravenous bolus every 12 hours or by continuous intravenous infusion.The study treatment, with group assignments concealed, was continued for up to 72 hours. At 48 hours, the treating physician had the option of adjusting the diuretic strategy on the basis of the clinical response. An assessment of biomarkers, including creatinine, cystatin C, and N-terminal pro-brain natriuretic peptide, was performed at a central core laboratory at baseline, 72 hours, and 60 days. Patients were followed for clinical events to day 60. The coprimary end points were patients' global assessment of symptoms, quantified as the area under the curve (AUC) of the score on a visual-analogue scale over the course of 72 hours, and the change in the serum creatinine level from baseline to 72 hours.ConclusionsAmong patients with acute decompensated heart failure, there were no significant differences in patients' global assessment of symptoms or in the change in renal function when diuretic therapy was administered by bolus as compared with continuous infusion or at a high dose as compared with a low dose. (Felker et. al., 2011, PMID: 21366472)

  Study phs003524

• Nanopore sequencing from liquid biopsy: analysis of copy number variations from cell-free DNA of lung cancer patients

  Molecular cancer paper (https://doi.org/10.1186/s12943-021-01327-5): This dataset contain shallow whole-genome sequencing (sWGS) of plasma cell-free DNA from cancer patients and healthy subjects, obtained with both Nanopore and Illumina technology. A total of 6 cancer patients and 5 healthy subjects have been sequenced with Nanopore; 4 of the cancer patients have been also sequenced with Illumina. In addition, genomic DNA from white blood cells of one healthy subjects, genomic and 160bp DNA from HEK cells have been sequenced with Nanopore. Genome Biology paper: 3 additional healthy samples have been sequenced (HU), two different bioinformatic pipeline were applied. 2019: Fastqs from the molecular cancer paper were re-demultiplexed and adapter-trimmed (using guppy for multiplex samples, and porechop for singleplex) preserving 5' ends to allow fragmentomics analysis. HAC: All the samples were basecalled with the same updated High Accuracy model (the latest at the time of the analysis) and post-processed as the 2019 dataset. Raw FAST5 are currently available upon request, but will be uploaded soon.

  Dataset EGAD00001006888

• Longitudinal Study of Vaginal Flora

  This prospective observational study aims to advance our knowledge of the natural history and abnormal alteration in vaginal microbial flora, and to identify risk factors that are associated with these changes. A total of 5500 healthy, non-pregnant women of reproductive age will be enrolled and followed up in Birmingham, Alabama, for one year (baseline visit plus once every three months afterwards, totaling 5 visits). Detailed information on sociodemographic status, medical history, hygiene practice, sexual behavior and psychosocial stress will be collected through in-person interviews. Routine gynecological and dental examinations will be carried out during the study visits. Samples of vaginal secretion and blood will be collected. Laboratory tests to quantify vaginal microbial flora and to identify infection of bacterial vaginosis as well as common sexually transmitted diseases will be conducted. Future submissions may contain metadata or molecular data from additional subjects.

  Study phs002367

• Stress and Treatment Response in Puerto Rican and African American Children with Asthma (STAR)

  The Stress and Treatment Response in Puerto Rican and African American Children with Asthma Study (STAR) was a 6-week study of response to inhaled corticosteroids (ICS) in youth aged 8-20 years recruited at the University of Puerto Rico Medical Center and UPMC Children's Hospital of Pittsburgh from June 5, 2018 to May 16, 2022. At a baseline visit, participants completed questionnaires and underwent collection of nasal specimens. After nasal sampling, participants were treated with daily medium-dose inhaled Mometasone for 6 weeks, with adherence measured using a dose-counter. Spirometry and fractional exhaled nitric oxide (FeNO) measurements were conducted at baseline and after 6 weeks of ICS. STAR was approved by the institutional review boards (IRBs) of the University of Puerto Rico and the University of Pittsburgh. Written parental consent and assent were obtained from participants

  Study phs004052

• UK10K NEURO IMGSAC

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches.The IMGSAC cohort is an international collection of families containing children ascertained for ASDs (autism spectrum disorders). The affected individuals are have been phenotyped, including using the ADI-R and ADOS instruments. Individuals with a past or current medical disorder of probable etiological significance or TSC have been excluded. Where possible, karyotyping has been performed on one affected individual per family to exclude Fragile X syndrome. Many of the samples have been genotyped, using the Affymetrix 10k and Illumina 1M platforms. All samples to be included in the current study are of UK origin.For further information on this cohort please contact Jeremy Parr (jeremy.parr@newcastle.ac.uk).

  Study EGAS00001000120

• Title: Divergent levels of CD112 and INKA1 define a distinct subset of human long-term hematopoietic stem cells

  The data provided here was critical in establishing that human long-term hematopoietic stem cells (LT-HSC), previously described as the most primitive HSC population, is actually composed of distinct subsets that can be prospectively isolated. Via mechanistic studies centering around the Rho-GTPase effector kinase PAK4 and its inhibitor INKA1, we identified the immune checkpoint ligand CD112 as a marker for hematopoietic stem and progenitor cells, that is highest expressed on LT-HSC. More importantly, CD112 can be used to stratify functionally distinct subsets within LT-HSC: In response to regeneration-mediated stress, the CD112low subset exhibits a transient restraint (termed latency) before contributing to hematopoietic reconstitution, while the CD112high subset is primed to respond rapidly. High resolution RNA-seq of the CD112 surface expression spectrum within rare LT-HSC subsets (human umbilical cord blood) demonstrated that more genes are differentially upregulated in the deeper quiescent and less metabolic active subset. Genes enriched in this subset centre around cell adhesion and Rho-GTPase signaling. This is in agreement with the scRNAseq data from human G-CSF mobilized peripheral blood (mPB) generated here that was used as an model of in vivo activation/priming revealing via RNA-velocity and pseudo-time analysis that INKA1high versus PAK4high, CDK6high and CD112high enrichment are either detected early or late in diffusion pseudotime indicative of quiescent versus primed cell status, respectively. RNAseq following INKA1 overexpression in LT-HSC and ST-HSC revealed by GSEA an overall stemness preserving phenotype and particularly in LT-HSC, but not in short-term HSC (ST-HSC), suppression of transcriptional programs linked to activation. Collectively, our data decipher the molecular intricacies underlying HSC heterogeneity and self-renewal regulation and point to latency as an orchestrated physiological response that integrates quiescence control with HSC fate choices to preserve a stem cell reservoir.

  Dataset EGAD00001006541

• Integration of T Cell Repertoire, CyTOF, genotyping and symptomatology data reveals subphenotypic variability in COVID-19 Patients

  A total of 61 patients (33 mild and 28 severe) with a median age of 51 years who recovered from COVID-19 were included in this study (Table 1). All collected samples were confirmed in diagnosis of COVID-19 by RT-PCR and positive IgG serolog. For the 61 patients, TCR-seq, CyTOF, and genotyping data were generated and analyzed in separate studies, as part of larger cohorts. In total, there are 143 variables, with 129 being quantitative (TCRseq and CyTOF metrics) and 13 being qualitative (symptomatology and genotyping). For more information about cohort characteristics, data adquisition an pre-processing, please visit PMID: 39227859, 36969980 and 37287057.

  Dataset EGAD50000000840

• Colorectal adenomas, carcinomas and adjacent normal NKI-AvL TGO series NGS-ProToCol

  Cancer is caused by changes in the genome of cells, resulting in aberrant transcripts and proteins. In order to understand why normal cells become cancer cells and how we can identify and destroy them, the CTMM-NGS-ProToCol project aimed to understand prostate and colorectal cancer through DNA and RNA molecular profiling, to further improve diagnosis, prognosis and treatment.The state-of-the-art within the field of genome sequencing makes it possible to identify all the modifications in our genome that encode for RNA and of the transcripts themselves. The latest development in RNA sequencing is that if one does not select for polyA RNA, but first removes rRNA from the total RNA and then performs ‘random’ RNA sequencing, 30-60% of the reads are intronic. Since about 40% of the genome consists of genes (and only 1.6% is exonic), deep RNA sequencing will cover not only the exons, but also a large portion of the introns and therefore much of the genome. The power of the combined sequencing of genome and transcriptome is the full view of copy number aberrations (CNA), exon mutations and the consequence and relevance of the mutations at the RNA level in the form of differential gene expression, alternative splicing, alternative promoter usage, novel transcripts, fusion transcripts, read-through transcripts and mutations. For the colorectal (tumor) tissue dataset, we applied molecular profiling to 30 colorectal adenomas, 30 colorectal carcinomas and 18 normal adjacent colon tissues.

  Study EGAS00001002854

• All you need to know about our new DAC Portal v2

  An updated version to boost the management of DACs (Data Access Committees), policies, and data access requests. In September of 2023, we launched new services for all EGA users, including a DAC Portal. Since then, our team has been working to refine it and improve the user experience. The version 2 of our DAC Portal is now ready, with a range of new features aimed at streamlining your workflow and boosting productivity. If you are interested in learning more about the latest version of our DAC Portal, then you are in the right place! In this post, you will find information about the implemented features and more. The full documentation is available on our website. Moreover, we highly recommend exploring the DAC Portal through the Take the Tour. This said, let's get cracking! Customise your data access requests table This table offers the possibility to tailor information about the data access requests by making visible or hiding different columns regarding the Dataset Persistent Identifier, the Organisation or the requestor's name s, among others. You can choose which columns to see, depending on your needs and interests. Additionally, we have implemented two new features columns with two new functionalities, DAC Comment and Expiration Date. You can find more details in the following sections! In this table, all data access requests are displayed by default. With the latest version of the Portal, you can now apply filters, combine them, and save them for future use. Leave internal comments on pending requests and visible to all the DAC Members We understand that many Data Access Committees (DACs) cannot instantly approve or deny data access requests. Often, there's an intermediary phase where discussions and the signing of legal documents are necessary. To facilitate this process, we've introduced the DAC comment feature! When you navigate to the DAC column, you'll find two tabs: "User" and "DAC". Under "User", you'll see the message provided by the requester at the time of requesting access to the data. As a DAC member/admin, you can then add an internal comment in the "DAC" tab. These comments are visible only to DAC members/admins, ensuring confidentiality. Requesters won't have access to DAC comments. By adding a DAC comment to a pending request, we'll know that you've begun reviewing it. This allows you to filter pending requests without DAC comments to focus on genuinely new requests, and it prevents you from receiving email notifications about ongoing data requests. Set expiration dates for permissions and revoke them automatically The latest update to the DAC Portal introduces a new feature allowing you to set expiration dates for new access requests. For instance, if you anticipate approving a data access request but only wish to grant access for a limited time, you can now specify an expiration date for the granted permissions. Once this date is reached, the permissions will automatically be revoked. By default, permissions are granted indefinitely without an expiration date. However, if you ever need to revoke permissions, you can easily do so from the History page. Audit your metadata objects Managing and auditing your metadata objects will be easier from now on as the new DAC Portal enhances and facilitates your role as a Data Controller. This is possible thanks to the tables available in each of the primary tabs visible on the homepage: DACs, Policies and Datasets. Starting with DACs, this section allows to check the policies linked to a specific DAC. In Policies, you can obtain a list of the datasets connected to a particular policy. In the Dataset tab, it is possible to group datasets by either DAC or Policy, as well as the release status. Now you have the option of deprecating metadata objects that you don’t want to use anymore, or that were created by mistake. You will find the deprecate button on the EDIT page of the DAC, as well as for registered policies. You can find more information here. What's neat about this feature is that once a DAC or policy is deprecated, it becomes hidden within the DAC Portal. This ensures that you only see information that is consistently up to date! Define your preferences regarding email notifications For pending requests, you will be able to decide how often you want to get the notifications: daily, weekly or fortnightly. Remember, you will not receive email notifications for pending requests with a DAC comment! Furthermore, you have the flexibility to decide which notifications you wish to receive, such as invitations to join a new DAC or notifications regarding DAC acceptance by the Helpdesk, among other options. Check the User preference to see the complete list of available notification settings! What’s next: incoming DAC Portal API In addition to the new DAC Portal, we are excited to announce the release of the DAC API! This enables users to programmatically manage permissions. If you are interested in learning more about the technical specifications, you can consult the DAC API specification. This post was written by Aina Jené and Ana T. Alonso.

  Blog new-dac-portal-v2

• Single cell RNAseq of stenotic, inflamed and non-inflamed transmural lesions from patients with Crohn's disease

  This dataset contains a gene-cell matrix derived from single-cell RNA sequencing (scRNA-seq) data of ileal tissue from Crohn's disease (CD) patients and colorectal cancer (CRC) patients. It includes: Crohn's Disease Patients: A trio of transmural lesions (stenotic, inflamed, and non-inflamed) from each patient. Colorectal Cancer Patients: Unaffected ileal tissue used as external non-inflamed control. Cell Level Metadata: The dataset includes relevant cell-level metadata such as cell type annotations used in the study. Experimental Details: Platform: 10x Genomics Chromium Single Cell 3' GEX Sequencing: Illumina NovaSeq Processing: Data processed with Cell Ranger software. Resulting count matrices were merged for downstream analysis, including integration and dimensionality reduction. Dataset Composition: Crohn's Disease Patients: 10 patients with 3 samples each (non-inflamed, inflamed, stenotic), totaling 30 samples. Colorectal Cancer Patients: 5 patients with 1 sample each of unaffected tissue, totaling 5 samples. Data Provided: Merged Raw Count Matrix: The final merged raw count matrix used for downstream analysis. Cell Metadata File: Contains details of sample, tissue, and patient for each cell in the count matrix. Barcodes File: Indicate each cell barcode which also encodes the sample, tissue, and patient details for each cell. CD.S_Inf: Stenotic Corhn's disease inflamed samples CD.S_Sten: Stenotic CD patient stenosis sample CD.S_Prox: Stenotic CD Patient - proximal non-inflamed sample CC.C_Prox: CRC Patient proximal unaffected sample eg: A barcode 'CC.C_1_Prox_AAGTCGTAGACCCTTA' indicates CRC Patient unaffected proximal sampe from CRC Patient no.1 and the nucleic acid sequence indicate a unique cell from this sample. Total Samples: Crohn's Disease (CD) Patients: 30 samples Colorectal Cancer (CRC) Patients: 5 samples Patient_no Sample Sample_type 1 CC.C_1 CC.C_1_Prox CC.C_Prox 2 CD.S_1 CD.S_1_Prox CD.S_Prox 3 CD.S_1 CD.S_1_Infl CD.S_Infl 4 CD.S_1 CD.S_1_Sten CD.S_Sten 5 CC.C_2 CC.C_2_Prox CC.C_Prox 6 CD.S_2 CD.S_2_Prox CD.S_Prox 7 CD.S_2 CD.S_2_Infl CD.S_Infl 8 CD.S_2 CD.S_2_Sten CD.S_Sten 9 CC.C_3 CC.C_3_Prox CC.C_Prox 10 CC.C_4 CC.C_4_Prox CC.C_Prox 11 CD.S_3 CD.S_3_Prox CD.S_Prox 12 CD.S_3 CD.S_3_Infl CD.S_Infl 13 CD.S_3 CD.S_3_Sten CD.S_Sten 14 CD.S_4 CD.S_4_Prox CD.S_Prox 15 CD.S_4 CD.S_4_Infl CD.S_Infl 16 CD.S_4 CD.S_4_Sten CD.S_Sten 17 CC.C_5 CC.C_5_Prox CC.C_Prox 18 CD.S_5 CD.S_5_Prox CD.S_Prox 19 CD.S_5 CD.S_5_Infl CD.S_Infl 20 CD.S_5 CD.S_5_Sten CD.S_Sten 21 CD.S_6 CD.S_6_Prox CD.S_Prox 22 CD.S_6 CD.S_6_Infl CD.S_Infl 23 CD.S_6 CD.S_6_Sten CD.S_Sten 24 CD.S_7 CD.S_7_Prox CD.S_Prox 25 CD.S_7 CD.S_7_Infl CD.S_Infl 26 CD.S_7 CD.S_7_Sten CD.S_Sten 27 CD.S_8 CD.S_8_Prox CD.S_Prox 28 CD.S_8 CD.S_8_Infl CD.S_Infl 29 CD.S_8 CD.S_8_Sten CD.S_Sten 30 CD.S_9 CD.S_9_Prox CD.S_Prox 31 CD.S_9 CD.S_9_Infl CD.S_Infl 32 CD.S_9 CD.S_9_Sten CD.S_Sten 33 CD.S_10 CD.S_10_Prox CD.S_Prox 34 CD.S_10 CD.S_10_Infl CD.S_Infl 35 CD.S_10 CD.S_10_Sten CD.S_Sten

  Dataset EGAD50000000559

• Cell-free DNA sequencing data of healthy control, atrophic gastritis, and gastric cancer patients’ blood

  Sample cohort (n=48) is consisted of healthy, atrophic gastritis and gastric cancer patients. Some of the gastric cancer patients samples are collected at the separate time points: -1 before the operation; -2 after the operation; -3 during the control visit. For the hybridisation capture of the genes unique 15 gastric cancer-related gene panel was developed and very deep sequencing using TruSight Oncology Unique Molecular Identifier (UMI) Reagents (Illumina) was used.

  Dataset EGAD00001011153

• Ribosomal Depleted Total RNA-Seq of PBMCs and Skin from Controls and Systemic Sclerosis Patients

  This study involved prospective collection of skin biopsies and peripheral blood mononuclear cell (PBMC) samples from controls with no self-reported history of autoimmune or inflammatory disease and cases with Rheumatologist-confirmed systemic sclerosis: limited cutaneous systemic sclerosis (lcSSc), diffuse cutaneous systemic sclerosis (dcSSc), very early diagnosis of systemic sclerosis (VEDOSS), and systemic sclerosis sine scleroderma (SSS). Some SSc cases were sampled at a 6 month routine follow-up visit. PBMCs were collected and lysed immediately. Skin punches were stabilized in RNAlater until extraction. All RNA-Seq libraries were created using Takara/Clontech ribosomal depletion kits, and sequenced on either a HiSeq2500 or HiSeq3000.

  Study phs002902

• Ethiopia_Genome_Project__high_coverage_

  The Ethiopian area stands among the most ancient ones ever occupied by human populations and their ancestors. Particularly, according to archaeological evidences, it is possible to trace back the presence of Hominids up to at least 3 million years ago. Furthermore, the present day human populations show a great cultural, linguistic and historic diversity which makes them essential candidate to investigate a considerable part of the African variability. Following the typing of 300 Ethiopian samples on Illumina Omni 1M (see Human Variability in Ethiopia project, previously approved by the Genotyping committee) we now have a clearer idea on which populations living in the area include the most of the diversity.This project therefore aims to sequence the whole genome of 300 individuals at low (4-8x) depth belonging to the six most representative populations of the Ethiopian area to produce a unique catalogue of variants peculiar of the North East Africa. Furthermore 6 samples (one from each population) will also be sequenced at high (30x) depth to ensure full coverage of the diversity spectrum.The retrieved variants will be of great help in evaluating the demographic dynamics of those populations as well as shedding light on the migrations out of Africa.

  Study EGAS00001000237

• Ethiopia_Genome_Project__low_coverage_

  The Ethiopian area stands among the most ancient ones ever occupied by human populations and their ancestors. Particularly, according to archaeological evidences, it is possible to trace back the presence of Hominids up to at least 3 million years ago. Furthermore, the present day human populations show a great cultural, linguistic and historic diversity which makes them essential candidate to investigate a considerable part of the African variability. Following the typing of 300 Ethiopian samples on Illumina Omni 1M (see Human Variability in Ethiopia project, previously approved by the Genotyping committee) we now have a clearer idea on which populations living in the area include the most of the diversity.This project therefore aims to sequence the whole genome of 300 individuals at low (4-8x) depth belonging to the six most representative populations of the Ethiopian area to produce a unique catalogue of variants peculiar of the North East Africa. Furthermore 6 samples (one from each population) will also be sequenced at high (30x) depth to ensure full coverage of the diversity spectrum.The retrieved variants will be of great help in evaluating the demographic dynamics of those populations as well as shedding light on the migrations out of Africa.

  Study EGAS00001000238

• Somatic Mutations in 3,929 HPV-Positive Exfoliated Cervical Cell Samples

  We investigated the detection, timing, and HPV type specificity of cervical somatic hotspot mutations (i.e., previously reported cancer driver mutations) in 3,929 HPV-positive exfoliated cervical cell samples from individuals undergoing routine cervical screening in the U.S. using deep-targeted sequencing of 20 candidate genes. Our study included samples from 3,351 women with the following infection outcomes: 1,478 HPV16-, HPV18- and/or HPV45-positive controls (i.e., HPV infections that did not progress to precancer and/or subsequently cleared), 1,712 cervical precancers, and 161 invasive cervical cancers. We utilized residual exfoliated cervical cell samples from women routinely screened for cervical cancer precursors at Kaiser Permanente Northern California (KPNC) as part of the prospective KPNC-NCI HPV Persistence and Progression (PaP) cohort. We included 3,929 samples collected from these 3,351 women, including 974 serial sample from 396 women collected prior to their most recent screening visit to evaluate somatic hotspot mutation detection prior to diagnosis.

  Study phs003691

• Heart Failure Network: Entresto(TM) in Advanced Heart Failure (HFN-LIFE-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: To compare treatment with sacubitril/valsartan versus valsartan alone in patients with advanced heart failure with a reduced ejection fraction and recent New York Heart Association class IV symptoms.Background: Treatment with evidence-based medical therapies improves survival, reduces heart failure hospitalizations, and improves quality of life in patients with chronic heart failure with a reduced ejection fraction. However, evidence supporting the use of medical therapies among patients with advanced heart failure is limited. Patients with New York Heart Association (NYHA) class IV heart failure are not often enrolled in clinical trials.A previous trial reported that, compared with the angiotensin-converting enzyme inhibitor enalapril, sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor, reduced the relative risk of cardiovascular mortality and heart failure hospitalizations by 20% in ambulatory patients with heart failure with a reduced ejection fraction. Although patients with NYHA class IV heart failure were eligible to enroll, this population was underrepresented. The HFN-LIFE trial was initiated to provide additional information about the tolerability, safety, and potential efficacy of sacubitril/valsartan in patients with advanced heart failure.Participants: Of the eligible patients that enrolled, a total of 335 patients tolerated the run-in phase and were randomized to a treatment group. 167 patients were randomly assigned to receive sacubitril/valsartan and 168 patients were randomly assigned to receive valsartan alone.Design: The HFN-LIFE trial was a prospective, multicenter, randomized, double-blind phase 4 clinical trial. Trial enrollment was suspended early, due to the high risk for adverse outcomes associated with COVID-19 infection.Eligible patients were enrolled and began an unblinded run-in period of 3 to 7 days with sacubitril/valsartan, 24/26 mg (50-mg fixed dose), administered orally twice daily. Participants tolerating the run-in phase were randomized in a 1:1 fashion to receive sacubitril/valsartan (target dose, 200 mg twice daily) or valsartan (target dose, 160 mg twice daily). The initial doses were selected based on guidelines with dose adjustments being made every 2 weeks.The primary efficacy outcome was the area under the curve of NT-proBNP levels at 2, 4, 8, 12, and 24 weeks compared with the level of NT-proBNP at randomization. The secondary efficacy end point was the number of days the patient was alive, out of the hospital, and free from any of the following outcomes: listing for cardiac transplant, cardiac transplant, implantation of a left ventricular assist device, receipt of continuous inotropic therapy for 7 or more days, or hospitalization for heart failure on 2 or more occasions other than the index admission.Conclusions: In patients with chronic advanced heart failure with a reduced ejection fraction, there was no statistically significant difference between sacubitril/valsartan and valsartan alone with respect to reducing NT-proBNP levels.

  Study phs004171