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• The Oral Microbiome and Head and Neck Cancer

  Oral microbiota may influence head and neck squamous cell carcinoma (HNSCC) development, potentially related to carcinogen metabolism. The human oral cavity hosts a diverse microbiota, including bacteria and fungi. We performed shotgun sequencing and ITS1 sequencing on 236 HNSCC case participants who developed HNSCC during a mean follow-up of 5.1 years and 458 matched controls who remained HNSCC-free. Oral samples were obtained from a prospective nested case-control study within three epidemiological cohorts: the American Cancer Society Cancer Prevention Study II Nutrition Cohort (ACS CPS-II), the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), and the Southern Community Cohort Study (SCCS). Control participants were selected using 2:1 frequency matching based on cohort, age, sex, race and ethnicity, and time since oral sample collection.

  Study phs004018

• FEGA FAQs: a summary of the Q+A session from the FEGA workshop at ELIXIR AHM 2024

  The ELIXIR All Hands Meeting (AHM) was held in Uppsala, Sweden this June. We at EGA always look forward to this meeting as a chance to see many of our partners and colleagues face-to-face. The Federated EGA (FEGA) is one initiative that always benefits from the AHM, and this year FEGA was in the spotlight, with several questions related to the advances we've made recently. We held this year's FEGA workshop a little differently, with most time for discussions on various “hot topics”. Organised in different breakouts, over 2 rounds, participants could choose which session they wanted to attend. One breakout was a general Q+A about FEGA and the path to join. We had a diverse range of participants, including experts from Central EGA (CEGA) and FEGA inaugural nodes, people from up and coming nodes at various stages of readiness, as well as participants not directly a part of FEGA but curious to learn more. It made for a great discussion! In this blog post, we highlight some of the questions for those who didn’t have a chance to be there. What is the FEGA Collaboration Agreement? It is a legal agreement between the node and Central EGA (CEGA) where both parties agree to certain responsibilities, like what services will be provided, sharing of public metadata with CEGA, interoperable technologies and more. The agreement is for 4 years, with the expectation of long-term sustainability. If a node is made up of multiple institutes, one institute must be the signatory. This could require a legal agreement within the node. CEGA is composed of CRG and EMBL-EBI (EGA itself has its own legal agreement between these institutes) Check the FEGA Collaboration Agreement What about purely medical data? Is this accepted in FEGA? CEGA only accepts data approved for secondary research use. We do accept medical data collected in this context, as do some nodes. Nodes are able to accept any data they like, as long as it is sensitive, thus in need of controlled access. What about other data types other than genomics? Like proteomics or images? They can be accepted, although CEGA is currently not designed with those formats in mind, so they might not fit with precision in the data model. The FEGA nodes are welcome to accept any data they want. Proteomic studies generating sensitive data are increasing, and specific work will likely be developed in the near future to adress this need. Does CEGA require a certain amount or type of data to be shared by the node? No, we do not and it's up to each node to decide what specific data types they accept and in what format. Nonetheless, a FEGA node has the duty to be open to data submission from any institution of their country, and can't be limited by design to a single or limited data source. Does CEGA and FEGA require a certain amount or type of details and description on the data to be submitted to the node? Data description (technical and biological), usually called metadata in this field, is crucial for the findability of the submitted data. Thus, we highly recommend including as much information as available to maximise the discoverability of the data. Specifical minimal metadata is defined in the submission schema, and thresholds are specified by the nodes. We are currently working towards a unified FEGA metadata model. What are the geographical borders of FEGA? FEGA should make the E for Everyone, because any institute worldwide could join and we indeed do have countries and use-cases worldwide. Some of them are very close to officially joining the federation. What are the main differences between FEGA and GDI? The two networks have a lot in common and also some critical differences. You can read all about this in one of our latest blog post. If you have more questions, please consider having a look at the FEGA onboarding webpage and, of course, don't miss our workshop at the ELIXIR AHM next year!

  Blog fega-faqs-elixir-ahm-2024

• Integrative single-cell and cell-free plasma RNA transcriptomics elucidates placental cellular dynamics

  10 single-cell placental RNA libraries were generated using the Chromium Single Cell 3′ Reagent Kit (10X Genomics). All single-cell libraries were sequenced with a customized paired end with dual indexing (98/14/8/10-bp) format according to the recommendation by 10X Genomics. The data were aligned using the Cell Ranger Single-Cell Software Suite (version 1.0). Moreover, plasma RNA from 22 samples were extracted using the RNeasy Mini Kit (Qiagen). cDNA reverse transcription, second-strand synthesis, and RNA-sequencing (RNA-seq) library construction were performed using the Ovation RNA-seq System V2 (NuGEN) kit according to the manufacturer’s protocol. For alignment of the plasma RNA library, adaptor sequences and low-quality bases on the fragment ends (i.e., quality score < 5) were trimmed, and reads were aligned to the human reference genome (hg19) using the TopHat (v2.0.4) software. All aligned reads were deposited in bam file format.

  Dataset EGAD00001003705

• Mult-omics Palbociclib Resistance Study in HR+/HER2– Metastatic Breast Cancer

  This study is multi-omics study of a Asian longitudinal metastatic breast cancer (MBC) cohort treated with palbociclib plus endocrine therapy. It contains NGS of baseline (BL) and progressive disease (PD) from 70 patients, consisting of 79 tumor/normal matched whole exome sequencing (WES) from 62 patients and 90 tumor whole transcriptome sequecing samples (WTS) from 70 patients. There were 56 BL biopsies profiled by WES and 64 by WTS; 23 PD biopsies were profiled by WES and 26 by WTS. Twenty and 23 patients had paired BL and PD biopsies profiled by WES and WTS, respectively.

  Dataset EGAD00001008314

• The light chain IgLV3-21 defines a new poor prognostic subgroup in Chronic Lymphocytic Leukemia: results from a multicenter study

  Purpose: Unmutated (UM) immunoglobulin heavy chain region (IgHV) status or IgHV3-21 gene usage is associated with poor prognosis in chronic lymphocytic leukemia (CLL). Interestingly, IgHV3-21 is often co-expressed with light chain IgLV3-21 which is potentially able to trigger cell-autonomous BCR-mediated signaling. However this light chain has never been characterized independently of the heavy chain IgHV3-21.Experimental Design: we performed total RNA sequencing to characterize IgLV3-21 patients (n=32) and investigated IgLV3-21 prognostic impact in terms of treatment-free (TFS) and overall (OS) survival in 3 other independent cohorts for a total of 813 patients where IgLV3-21 presence was tested by real-time PCR and confirmed by Sanger sequencing.Results: Using total RNA sequencing to characterize 32 patients with high-risk CLL, we found a high frequency (28%) of IgLV3-21 rearrangements. Gene set enrichment analysis revealed that these patients present higher expression of genes responsible for ribosome biogenesis and translation initiation (P<0.0001) and MYC target genes (P=0.0003). Patients with IgLV3-21 rearrangements displayed a significantly shorter TFS and OS (P<0.05), in particular in IgHV mutated patients. In each of the 3 independent validation cohorts (n=813), we showed that IgLV3-21 rearrangements -similar to UM IgHV status- conferred poor prognosis compared to mutated IgHV (P<0.0001). Importantly, we confirmed in multivariate analysis that this was independent of IgHV mutational status or subset #2 stereotyped receptor (P<0.0001). Conclusions: We therefore demonstrate for the first time that a light chain can impact on CLL prognosis and that IgLV3-21 light chain usage defines a new poor prognostic subgroup in CLL.

  Study EGAS00001002894

• Histone chaperone CHAF1A promotes proliferation and tumorigenicity in gastric cancer and impacts prognosis via context-depedent regulation of gene expression

  The histone chaperone CHAF1A is associated with some tumors, but its mechanisms in tumor biology remain elusive. Gastric cancer (GC) has significant heterogeneity among patients, and novel prognostic markers and therapeutic targets may improve its outcomes. The role of CHAF1A in GC is unknown. In this study, we demonstrated that CHAF1A was overexpressed in GC tissues accompanied by low expression of wild-type P53 and high expression of the proliferation marker MKI67. In vitro, CHAF1A knockdown inhibited cell proliferation, induced cell cycle arrest and promoted apoptosis, while CHAF1A overexpression had contrary effects. In vivo, CHAF1A knockdown inhibited tumorigenicity of GC cells. A microarray assay with CHAF1A inhibition and a PathScan signaling antibody array with CHAF1A overexpression showed that CHAF1A inhibited the P53 pathway, activated stress response and induced glycolytic metabolism. In 665 patients, the expression level of CHAF1A protein was an independent predictor for overall survival and disease-free survival in non-cardia GC and also had survival associations in patients with small or perineural invasion-negative tumors. Tumor mRNA analyses based on next-generation sequencing in patients indicated that CHAF1A promoted the Warburg effect by depressing oxidative phosphorylation and increasing glycolysis. Furthermore, the heterogeneous clinical significance of CHAF1A among patient subgroups was associated with its differential regulation of gene expression involved with glycolysis and cell proliferation and survival, indicating that the role of CHAF1A is depended on patient characteristics. These results reveal critical roles and clinical values for CHAF1A in GC. CHAF1A may have context-dependent effects in GC, which increases understandings for GC heterogeneity.

  Study EGAS00001003064

• Survival Benefit and Genetic Profile of Pemetrexed as Initial Chemotherapy in Selected Chinese Patients with Advanced Lung Adenocarcinoma

  We retrospectively collected patients (n=1047) enrolled in the Chinese Patient Assistance Program from multiple centers who received pemetrexed alone or combined with platinum as initial chemotherapy and continued pemetrexed maintenance therapy for advanced lung adenocarcinoma from November 2014 to June 2017. The outcomes were duration of treatment (DOT) and overall survival (OS). Clinical features were analyzed for their influence on the treatment effect and prognosis. Next-generation sequencing (NGS) was performed to identify genetic biomarkers associated with the efficacy of pemetrexed. The median DOT was 9.1 months (95% CI: 8.5-9.8), and the median OS was 26.2 months (95% CI: 24.2-28.1). OS was positively correlated with DOT (r=0.403, P<0.001). Multivariable analysis showed that smoking status and Eastern Cooperative Oncology Group (ECOG) performance status (PS) were independently associated with DOT; smoking status, ECOG PS, targeted therapy, and EGFR/ALK/ROS1 status were independently associated with OS. NGS in 22 patients with available samples showed genes with high mutation rates were: TP53 (54.5%), EGFR (50.0%), MYC (18.2%), PIK3CA (13.6%). When grouped based on progression-free survival (PFS) reported in the PARAMOUNT study, the DOT >6.9 months set was associated with PIK3CA, ALK, BRINP3, CDKN2A, CSMD3, EPHA3, KRAS, and RB1 mutations, while ERBB2 mutation was observed only in the DOT ≤6.9 months set. This study shows that initial chemotherapy with pemetrexed is an effective regimen for advanced lung adenocarcinoma in selected Chinese patients. There is no specific genetic profile predicting the benefit of pemetrexed found by NGS. Biomarkers predicting the efficacy of pemetrexed need further exploration.

  Study EGAS00001004546

• Whole genome sequencing of tumor samples from advanced pre-treated NSCLC patients recruited in a phase I/II single-arm trial utilising CVA21, an oncolytic coxsackie virus, in combination with pembrolizumab.

  Acquired or de novo resistance to immune checkpoint inhibitors occurs in the majority of advanced non-small cell lung cancers (NSCLC). There is an unmet need to improve outcomes for patients with this condition. Oncolytic viruses represent an attractive treatment approach due to their dual activity in inducing tumor cell lysis directly and potentially augmenting anti-tumor immunity. Here, we present the safety, efficacy and translational findings from a phase I/II single-arm trial utilising CVA21, an oncolytic coxsackie virus, in combination with pembrolizumab in patients with advanced pre-treated NSCLC. We performed paired biopsies pre- and post-treatment in 10 patients who received intravenous CVA21 and pembrolizumab, 8 of whom had prior treatment with immune checkpoint inhibitor (ICI) therapy. Whole genome sequencing and spatial proteomics were performed to comprehensively characterise the response to CVA21. Combination CVA21/pembrolizumab (anti PD-1) therapy was well tolerated with no serious treatment-related adverse events. Partial responses were seen in two patients with prior acquired anti-PD-1 resistance and disease stabilisation in 6 patients, giving a clinical benefit rate of 80%. High baseline tumor mutational burden and PD-L1 expression were observed in patients with better response to treatment. Interestingly, an increase in antigen presentation and CD8+ T cell infiltration was observed on treatment compared with baseline in patients with better progression-free survival. This study demonstrates the potential of CVA21 to modulate the immunogenicity of tumor cells and remodelling the tumor microenvironment, providing novel insights for patient selection for trials involving novel immunotherapeutic approaches.

  Study EGAS00001008258

• ctDNA quantification in Ewing sarcoma patients

  Background. Treatment stratification and response assessment in pediatric sarcomas has relied on imaging studies and surgical/histopathological evidence of vital tumor cells. Such studies and evidence collection processes often involve radiation and/or general anesthesia in children. Cell-free circulating tumor DNA (ctDNA) detection in blood plasma is one available method of so-called liquid biopsies that has been shown to correlate qualitatively and quantitatively to some extent with the existence of vital tumor cells in the body. Our clinical observational study focused on the utility and feasibility of ctDNA detection in pediatric Ewing sarcoma (EWS) as a marker of minimal residual disease (MRD). Patients and Methods. We performed whole genome sequencing to identify the exact breakpoints in tumors known to carry the EWS-FLI1 fusion gene. Patient-specific fusion breakpoints were tracked in peripheral blood plasma using digital droplet PCR (ddPCR) before, during, and after therapy in six consecutive children and young adults with EWS. Presence and levels of fusion breakpoints were correlated with clinical disease courses. The genetic changes in the tumors were defined, and inter- and intra-individual changes in the tumor DNA copy loads were observed over time. Results. We show that the detection of ctDNA in the peripheral blood of EWS patients i) is feasible in the clinical routine and ii) allows for the longitudinal real-time monitoring of MRD activity in children and young adults. Although changing ctDNA levels correlated well with clinical outcome within patients, between patients, a high variability was observed (inter-individually) for the six patients described here. Conclusions. ctDNA detection by ddPCR is a highly sensitive, specific, feasible, and highly accurate method that can be applied in EWS for follow-up assessments as an additional surrogate parameter for clinical MRD monitoring and, potentially, also for treatment stratification in the near future.

  Study EGAS00001006433

• 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

• BAM file s of WGS data of Progressive supranuclear palsy patients

  BAM files of healthy controls (3) and Progressive supranuclear palsy (PSP) patients (4). Genomic DNA from donors was fragmented, end-polished, A-tailed, and ligated with Illumina adapters, followed by size selection. Libraries were PCR-amplified (unless PCR-free), purified with AMPure XP, assessed on the Agilent Fragment Analyzer, and quantified using Qubit and qPCR. Qualified libraries were pooled and sequenced on Illumina platforms, and low-quality reads or adapter-contaminated reads were removed. Clean data were then mapped to the hg38 reference genome using BWA.

  Dataset EGAD50000001758

• Single-cell TCR sequencing of DQ2.5-hor-3-specific T cells

  In order to characterize the T cell receptor (TCR) repertoire of DQ2.5-hor-3-specific T cells, we performed high-throughput DNA sequencing of rearranged TCR-α and TCR-β genes of the single HLA-DQ2.5:DQ2.5-hor-3- tetramer binding CD4+ T cells isolated from biopsies of celiac disease patients. We also sequenced the TCR of the T-cell clones (TCCs) that were generated by cloning by limited dilution and antigen-free expansion of HLA-DQ2.5:DQ2.5-hor-3-tetramer binding CD4+ T cells from biopsies of celiac disease patients.

  Dataset EGAD00001005048

• untargeted whole genome sequencing - Evaluation and correction of GC biases in cell-free DNA at the fragment level

  These are aligned paired-end reads from Illumina NovaSeq 6000 whole-genome sequencing of 4 cfDNA samples extracted from blood plasma (plasma-Seq). Three samples from patients with breast cancer, prostate cancer, or colorectal cancer and one sample from a healthy individual were aligned to GRCh38 (GCA_000001405.15_GRCh38_no_alt_plus_hs38d1_analysis_set). The observed GC bias is different in each of these cfDNA samples which leads to different average GC content per sample. This bias is corrected using the GCparagon commandline tool.

  Dataset EGAD00001010100

• Whole-genome sequencing of high-grade serous ovarian cancer (HGSC) tumours and matched normals from long-term survivors.

  Whole-genome sequencing of high-grade serous ovarian cancer (HGSC) tumours and matched normals from long-term survivors performed as part of the Multidisciplinary Ovarian Cancer Outcomes Group (MOCOG) study. The dataset includes fastq files from 58 HGSC tumours (53 primary tumours and 5 recurrent tumours) and 53 matched normals from 53 long-term survivor patients. Sequence libraries were generated from tumour and matched normal genomic DNA using the KAPA HyperPrep PCR-free library preparation kit (Roche) according to manufacturer’s instructions. Sequencing was carried out by the Kinghorn Centre for Clinical Genomics Sequencing Laboratory (Sydney, Australia) on the HiSeq X Ten System (Illumina) to a minimum base coverage of 30-fold for normal DNA and 60-fold for tumour DNA samples.

  Dataset EGAD00001009398

• Systolic Blood Pressure Intervention Trial (SPRINT-BioLINCC)

  Available DataThe available data include all elements of the previously released SPRINT Primary Outcome Paper (SPRINT-POP) data, the full SPRINT clinical data including the MRI and MIND data, and select ancillary study data (Ambulatory Blood Pressure Monitoring, APOL1, Acute Kidney Injury, ASK, Heart, FAST, PWV, Renal Resistance, Biomarkers, Plasma AD).ObjectiveThe Systolic Blood Pressure Trial (SPRINT) was conducted to test the hypothesis that treating systolic blood pressure to a target of less than 120 mm Hg, as compared to a target of less than 140 mm Hg, would reduce the incidence of cardiovascular disease.BackgroundHypertension is a highly prevalent condition among adults and is a leading risk factor for myocardial infarction and stroke. Further, isolated systolic hypertension is the most common form of hypertension in adults over 50 years of age. Observational studies have shown a monotonic increase in cardiovascular risk with systolic blood pressures above 115 mm Hg; however, general population clinical trials have only documented the benefits of lowering systolic blood pressure to a target of 150 mm Hg. A 2007 expert panel sponsored by the National Heart, Lung, and Blood Institute designated the hypothesis that lowering the systolic blood pressure goal to a level SubjectsA total of 9361 participants were enrolled, with 4,678 randomized to the intensive-treatment group and 4,683 randomized to the standard-treatment group.DesignSPRINT was a randomized, single blinded (outcome adjudicators were blinded to treatment assignment) treatment trial with participants randomized to a systolic blood-pressure target of either less than 140 mm Hg (the standard-treatment group) or less than 120 mm Hg (the intensive-treatment group). Following randomization, baseline hypertensive regimens were adjusted in accordance with study treatment algorithms established for each group. The study formulary included all major classes of antihypertensive agents. Investigators could prescribe other antihypertensive medications, but the use of drug classes with the strongest evidence for reduction in cardiovascular outcomes was encouraged. This included thiazide-type diuretics as the first-line agent, loop diuretics for participants with advanced chronic kidney disease, and beta-adrenergic blockers for participants with coronary artery disease. Medications for participants in the intensive-treatment group were adjusted on a monthly basis to target a systolic blood pressure of less than 120 mm Hg. Medications for participants in the standard-treatment group were adjusted to target a systolic blood pressure of 135 to 139 mm Hg, and the dose was reduced if systolic blood pressure was less than 130 mm Hg on a single visit or less than 135 mm Hg on two consecutive visits. Lifestyle modification was encouraged as part of the management strategy.Participants were seen monthly for the first 3 months and every 3 months thereafter. Demographic data were collected at baseline. Clinical and laboratory data were obtained at baseline and every 3 months thereafter. A structured interview was used in both groups every 3 months to obtain self-reported cardiovascular disease outcomes. Medical records and electrocardiograms were obtained for documentation of events. Incidences of hypotension, syncope, injurious falls, electrolyte abnormalities, and bradycardia that were evaluated in an emergency department were included in adverse event reporting. Occurrences of acute kidney injury or acute renal failure requiring hospitalization were also monitored. The primary outcome was a composite outcome of myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes.ConclusionsThe blood pressure intervention was stopped in August of 2015 (median follow-up of 3.26 years) after the cardiovascular outcome results exceeded the boundary for efficacy at two consecutive time points. Compared with a systolic blood pressure target of less than 140 mm Hg, an intensive systolic blood pressure target of 120 mm Hg resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause. Significantly higher rates of some adverse events were observed in the intensive-treatment group.

  Study phs003483

• Systolic Blood Pressure Intervention Trial (SPRINT-Imaging)

  Available DataSystolic Blood Pressure Intervention Trial, SPRINT-Imaging, provides access to ECG signals data from the SPRINT clinical trial. The clinical phenotyping and outcomes data from the trial are associated with SPRINT-BioLINCC, phs003483.ObjectiveThe Systolic Blood Pressure Trial (SPRINT) was conducted to test the hypothesis that treating systolic blood pressure to a target of less than 120 mm Hg, as compared to a target of less than 140 mm Hg, would reduce the incidence of cardiovascular disease. BackgroundHypertension is a highly prevalent condition among adults and is a leading risk factor for myocardial infarction and stroke. Further, isolated systolic hypertension is the most common form of hypertension in adults over 50 years of age. Observational studies have shown a monotonic increase in cardiovascular risk with systolic blood pressures above 115 mm Hg; however, general population clinical trials have only documented the benefits of lowering systolic blood pressure to a target of 150 mm Hg. A 2007 expert panel sponsored by the National Heart, Lung, and Blood Institute designated the hypothesis that lowering the systolic blood pressure goal to a level SubjectsA total of 9361 participants were enrolled, with 4,678 randomized to the intensive-treatment group and 4,683 randomized to the standard-treatment group. DesignSPRINT was a randomized, single blinded (outcome adjudicators were blinded to treatment assignment) treatment trial with participants randomized to a systolic blood-pressure target of either less than 140 mm Hg (the standard-treatment group) or less than 120 mm Hg (the intensive-treatment group). Following randomization, baseline hypertensive regimens were adjusted in accordance with study treatment algorithms established for each group. The study formulary included all major classes of antihypertensive agents. Investigators could prescribe other antihypertensive medications, but the use of drug classes with the strongest evidence for reduction in cardiovascular outcomes was encouraged. This included thiazide-type diuretics as the first-line agent, loop diuretics for participants with advanced chronic kidney disease, and beta-adrenergic blockers for participants with coronary artery disease. Medications for participants in the intensive-treatment group were adjusted on a monthly basis to target a systolic blood pressure of less than 120 mm Hg. Medications for participants in the standard-treatment group were adjusted to target a systolic blood pressure of 135 to 139 mm Hg, and the dose was reduced if systolic blood pressure was less than 130 mm Hg on a single visit or less than 135 mm Hg on two consecutive visits. Lifestyle modification was encouraged as part of the management strategy. Participants were seen monthly for the first 3 months and every 3 months thereafter. Demographic data were collected at baseline. Clinical and laboratory data were obtained at baseline and every 3 months thereafter. A structured interview was used in both groups every 3 months to obtain self-reported cardiovascular disease outcomes. Medical records and electrocardiograms were obtained for documentation of events. Incidences of hypotension, syncope, injurious falls, electrolyte abnormalities, and bradycardia that were evaluated in an emergency department were included in adverse event reporting. Occurrences of acute kidney injury or acute renal failure requiring hospitalization were also monitored. The primary outcome was a composite outcome of myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes. ConclusionsThe blood pressure intervention was stopped in August of 2015 (median follow-up of 3.26 years) after the cardiovascular outcome results exceeded the boundary for efficacy at two consecutive time points. Compared with a systolic blood pressure target of less than 140 mm Hg, an intensive systolic blood pressure target of 120 mm Hg resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause. Significantly higher rates of some adverse events were observed in the intensive-treatment group.

  Study phs003566

• The Environmental Determinants of Diabetes in the Young Study (TEDDY)

  The Environmental Determinants of Diabetes in the Young (TEDDY) Study investigates genetic and genetic-environmental interactions, including gestational infection or other gestational events, childhood infections and other environmental factors after birth, in relation to the development of pre-diabetic islet autoimmunity and type 1 diabetes (T1D). Beginning in 2002, a consortium of six centers assembled to participate in the development and implementation of studies to identify environmental factors that trigger the development of islet autoimmunity and T1D in genetically susceptible individuals. The TEDDY study screened around 400,000 newborns and recruited 7,749 neonates from the general population with a pre-determined T1D risk of 3% and 919 neonates with first degree relatives who have T1D and who have a pre-determined T1D risk of 10%. Thus, TEDDY proposes to follow over 8,000 participants across six clinical centers worldwide (Finland, Germany, Sweden and three in the United States) until the age of 15. Participants are followed every three months for islet autoantibody measurements with blood sampling until four years of age and then at least every six months until the age of 15. After the age of four, autoantibody positive subjects continue to be followed at 3 month intervals and autoantibody negative subjects are followed at six month intervals. In addition to the analysis of autoantibodies, additional data and sample collection is performed at each visit. The parents collect monthly stool samples in early childhood. The parents also fill out questionnaires at regular intervals in connection with study visits and record information about diet and health status in the child's TEDDY Book between visits. Continued long-term follow-up of the currently active TEDDY participants will provide important scientific information on early childhood diet, reported and measured infections, vaccinations, and psychosocial stressors that may contribute to the development of type 1 diabetes and islet autoimmunity. DNA extracted from the 9-month TEDDY blood sample was used for SNP genotyping. Samples were available for 7,082 participants. SNPs were genotyped by the Center for Public Health Genomics at the University of Virginia, using the Illumina ImmunoChip SNP microarray of around 196,000 SNPs selected from 186 regions associated with 12 autoimmune diseases (including T1D) (Hadley et al., 2015). "Data quality control (QC) steps included eliminating subjects with a low call rate (> 5% SNPs missing) and discrepancies between reported gender and prior genotyping at the HLA laboratory. Secondly, SNPs were removed from analysis due to low call rate, Hardy-Weinberg equilibrium P value < 10-6, except for chromosome 6 due to HLA eligibility requirements)" (Törn et al., 2015). QC resulted in a total of 7,023 subjects with data on 176,586 SNPs. Additional information on the TEDDY study are available in the following articles: The Environmental Determinants of Diabetes in the Young (TEDDY) Study. TEDDY Study Group. Annals of the New York Academy of Science, 2008 and TEDDY - The Environmental Determinants of Diabetes in the Young - An Observational Clinical Trial. Annals of the New York Academy of Science, 2006 Details of the TEDDY protocol can be found in The Environmental Determinants of Diabetes in the Young (TEDDY): Genetic Criteria and International Diabetes Risk Screening of 421,000 infants. Pediatric Diabetes, 2011

  Study phs001037

• STAMPEED: Northern Finland Birth Cohort 1966 (NFBC1966)

  The Northern Finland Birth Cohorts program (NFBC) was initiated in the 1960s in the two northernmost provinces of Finland to study risk factors involved in pre-term birth and intrauterine growth retardation, and the consequences of these early adverse events on subsequent morbidity and mortality. The uniqueness of NBFCs is that the data of the cohorts were obtained from early fetal life (including maternal health during pregnancy) to adulthood. The NFBC1966 includes 12,058 live births to mothers in the two northern-most provinces of Finland. Two decades later, a second cohort of 9432 births was obtained (NFBC1986). In NFBC1966 pregnancies were followed prospectively from the first antenatal contact (10-16th week). After birth, the offspring were examined and then again underwent clinical evaluation at ages 1y, 7y, 14-16y and 31y. At each visit, a wide range of phenotypic, lifestyle and demographic data were gathered by questionnaires and clinical examinations. For the most part, NFBC1986 has undergone similar evaluations to NFBC1966. Linkage to national registries includes hospitalization, deaths, education, medication, pensions, and provides up-to-date demographic and clinical information for members of both cohorts. DNA samples were obtained from 5,923 subjects from NFBC1966 and 6688 subjects from NFBC1986. Data coverage, 96% of all births in 1966 and 99% in 1986, is highly representative for the whole population. The NFBC program comprises more than 20 different projects coordinated by the Center of Lifecourse Disease studies in Northern Finland (COLD) at Oulu University. The prospective data collected from the NFBCs form a unique resource, allowing the study of disease emergence, and of the importance of genetic, biological, social and behavioral risk factors. The genome-wide association (GWA) study sponsored through the STAMPEED program of NHLBI employed genomic DNA samples previously collected by the NFBC1966 study and stored in the DNA repository of the National Institute for Health and Welfare, Finland. This NHLBI sponsored RO1 project aimed to identify genetic variants contributing to metabolic and cardiovascular diseases (CVD). In addition to de-identified genome wide genotypic data, a selected list of phenotypic data related to CVD including weight, height, BMI, HDL, LDL, total cholesterol, triglyceride, glucose, insulin and fasting status, are also available in dbGaP. A summary of the GWAS for the NFBC1966 cardiovascular risk traits can be found in Sabatti et al., Nature Genetics 41: 35-46, 2009, PMID: 19060910. The version 2 release of this study contains sequence data from seventeen loci associated with levels of triglyceride, HDL-C, LDL-C, total cholesterol, fasting plasma glucose, and fasting plasma insulin (Kathiresan et al. 2008, Willer et al. 2008, Sabatti et al. 2009, Dupuis et al. 2010, Teslovich et al. 2010). At each locus, protein-coding regions and 5' and 3' untranslated regions of genes nearest to single nucleotide polymorphisms showing genome-wide significant association with metabolic syndrome-related traits, were sequenced. Targeted Illumina sequencing of 78 genes (~270kb) using 150bp probes was performed on 4943 subjects of the Northern Finland Birth Cohort 1966 (NFBC1966). Whole exome sequencing on the Illumina platform was carried out on 586 of those participants. The sequencing study is part of a larger project that is funded by the National Human Genome Research Institute's Allelic Spectrum in Common Disease Initiative, and comprises sequence data from more than 7000 individuals in two Finnish cohorts: NFBC1966 and the Finland-United States Investigation of NIDDM Genetics (FUSION) study.

  Study phs000276

• Prevention and Early Treatment of Acute Lung Injury (PETAL) Network - Functional, Imaging, and Respiratory Evaluation in CORAL (PETAL FIRE CORAL-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.Biospecimens: Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from PETAL FIRE CORAL include plasma and whole blood. Please note that use of biospecimens in genetic research is subject to a tiered consent and biospecimens may not be used to produce commercial products.Objectives: To examine the recovery from COVID-19 disease following acute hospitalization with an emphasis on functional, imaging, and respiratory evaluation, and assess the feasibility of conducting a larger study to evaluate variables associated with differential recovery.Background: The BLUE CORAL study, dbGaP phs003419, was intended to address the knowledge gaps and provide critical data to help guide clinical care, public health, and scientific efforts regarding SARS-CoV-2 (COVID-19) recovery. The understanding and treatment of long-term sequelae of COVID-19, referred to variously as post-acute sequelae of COVID-19 (PASC), post-acute COVID, long COVID, or long-haul COVID, is fundamental to patient recovery. These long-term consequences are common and increasingly recognized, although heterogeneous in manifestation, and can result in a failure to return to baseline level of health. At the time of the FIRE CORAL study, there were limited studies that collected objective assessments following hospital discharge for a wide spectrum of patients surviving COVID-19.Participants: FIRE CORAL enrolled adult participants as a subset of those enrolled in the BLUE CORAL study with a recent COVID-19 hospitalization and that completed the 1- or 3-month post-hospital telephone long-term outcomes assessment. The target enrollment for this pilot study cohort was 80 participants.Design: FIRE CORAL was a multicenter prospective cohort study of participants recovering from COVID-19 disease with in-person follow-up, as an extension of the BLUE CORAL study. The study consisted of a battery of assessments objectively measuring pulmonary function, abnormalities on lung imaging, and functional status. Participants were to attend and perform initial in-person testing at 3 to 9 months after hospital discharge. Participants with abnormal findings on pulmonary function testing or chest imaging during their initial assessment or those with persistent respiratory symptoms were eligible to repeat study procedures 3 months later with a subsequent visit at 12 months. All participants were invited to return for in-person follow up at 12 months after hospital discharge. Assessments included high-resolution chest CT scan without contrast, spirometry, lung volume assessment, diffusing capacity measured by single breath measurement, Six Minute Walk Test, Short Physical Performance Battery, St. George's Respiratory Questionnaire, and Functional Assessment of Chronic Illness Therapy-Fatigue scale. Demographic and hospitalization data are available as part of the BLUE CORAL study.The primary aim of the FIRE CORAL study was to examine the feasibility of conducting rigorous in-person follow-up testing of participants discharged from the hospital following COVID-19 illness to assist with planning for a larger study to evaluate variables associated with differential recovery. The secondary aim was to describe the pulmonary, imaging, and functional recovery following COVID-19 hospitalization in a diverse population of patients.

  Study phs004130

• Single Chromatin Fiber Profiling in the Human Brain

  We developed a human postmortem brain-applicable ‘Fiber-seq' protocol for genome-scale, PCR-free single molecule sequencing of on average 8-10kb long chromatin fibers, to map nucleosome positioning and nucleosome-depleted regions which include, for example, active promoters and enhancers. We generated two Fiber-seq reference sets, one from sorted non-neuronal NeuN- prefrontal cortex (PFC) nuclei from a 32 year old female donor, with total of 11,143,795 reads/fibers, and median of 30-fold genomic coverage. The other reference set was generated on sorted prefrontal NeuN+ neurons, from two 24 year old brain donors (1 female/1 male), with a combined total read/fiber count of 4,749,556 and median of 20-fold genomic coverage. Each of the peaks in the Fiber-seq libraries seq signal correlated with the ATAC peak levels in the neuronal and non-neuronal ATAC-seq libraries, respectively (promoters, clusters 1, 3; NeuN+, r = 0.574; NeuN-, r=0.683, PHowever, Fiber-seq detected 19,978 highly significant peaks which, while showing some non-significant/near-background ATAC-Seq alignments, lacked a corresponding site-specific enrichment in conventional short-read ATAC- and ChIP-seq datasets. However, 60% of these peaks were in repetitive DNA elements. Therefore, long read single chromatin fiber sequencing, which exceed the base pair length of conventional short-read libraries by two orders of magnitude, could capture many actively regulated repeat elements at the site of specific gene loci, that otherwise would remain unmappable by conventional ATAC-, and histone- ChiP-seq.

  Study phs003771

• Circulating Tumor DNA Analysis in ERBB2-Amplified Colorectal Cancer: Biomarker Analysis of the MyPathway Trial

  Combination of two HER2-directed antibodies, pertuzumab and trastuzumab (P+T), has antitumor activity in HER2-positive colorectal cancer (CRC). Although liquid biopsies are increasingly being used in clinical oncology, the association between tumor and circulating tumor DNA (ctDNA) ERBB2 status and ctDNA monitoring for early response and resistance are unknown. Eighty-five patients with ERBB2-amplified and/or overexpressed CRC were treated with P+T in the MyPathway trial; 42 had ctDNA testing at Cycle 1 Day 1 (C1D1), and 38 had longitudinal plasma tested for ctDNA. We analyzed the ctDNA vs tissue ERBB2 concordance, genomic co-alterations, and ctDNA dynamics and association with response. Forty-one (98%) of 42 patients had genomic alterations detected in ctDNA at C1D1, and 29 (69%) had ERBB2 amplification in ctDNA. There was a strong correlation between ERBB2 copy number on next-generation sequencing in tissue and C1D1 ERBB2 ctDNA copy number. Thirty-seven percent achieved a molecular response by C3D1 on P+T, which was associated with prolonged progression-free survival and overall survival (OS). CDKN2A and KRAS mutations were associated with shorter OS, and a trend was seen with PIK3CA mutations. Several emerging co-alterations were identified in ctDNA at progression, including in the MAPK and PI3K pathways and other tyrosine receptor kinases. ctDNA can detect ERBB2 amplification in many, but not all, patients with ERBB2 amplification detected in tumor samples. ctDNA molecular response was associated with better survival, and ctDNA co-alterations may offer insights into mechanisms of intrinsic and acquired resistance.

  Study EGAS50000000916

• Durable clinical impacts and mechanisms of action and resistance in histone K27 methylation-targeting epigenetic therapy

  Epigenomes allow the rectification of disordered cancer gene expressions, thereby providing new targets for pharmacological interventions in cancer therapy. The clinical utility of targeting histone H3 lysine tri-methylation (H3K27me3) as an epigenetic hallmark has been demonstrated. However, in actual therapeutic settings, the mechanism by which H3K27me3-targeting therapies exert their effects and the response of tumor cells remain unclear. Here we show the potency and mechanisms of action and resistance of a newly developed EZH1/2 dual inhibitor, valemetostat, in the clinical trials of patients with adult T-cell leukemia/lymphoma (ATL). Valemetostat administration reduced the tumor size and demonstrated durable clinical benefits. Integrative single-cell analyses of patients before and after the administration of valemetostat showed that valemetostat abolishes the highly condensed chromatin structure formed by the plastic H3K27me3 and neutralizes multiple gene loci, such as tumor suppressor genes. Nevertheless, subsequent long-term treatment encounters the emergence of resistant clones with reconstructed aggregate chromatin that closely resemble the pre-dose state. The acquired mutations at the EZH2???compound interface result in the propagation of the clones with re-increased H3K27me3. In patients free of this mutation, TET2 mutation or elevated DNMT3A expression causes similar chromatin recondensation through de novo DNA methylation at the H3K27me3-associated regions. We identified subpopulations with distinct metabolic and gene translation characteristics implicated in primary susceptibility until the acquisition of the heritable (epi)mutations. Targeting chromatin homeostasis might provide opportunities for further sustained epigenetic cancer therapies.

  Study JGAS000553

• 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

• HGSC WGS for the study Genomic consequences of aberrant DNA repair mechanisms stratify ovarian cancer histotypes

  HGSC cases in the OvCaRe and CRCHUM Tumour Banks were selected according to the following criteria: (i) were administered platinum taxane based therapy; (ii) relapsed within 12 months (365 days) or had at least longer than 4.5 years (1642.5 days) follow-up data; (iii) had at least 50% tumour content by H&E staining and expert pathology review. All cases were re-reviewed by expert pathologists to confirm the diagnosis of HGSC. Germline BRCA1 and BRCA2 was determined for all patients through hereditary cancer screening programs. The design of cases selection as a discovery cohort was engineered to amplify biological differences by selecting cases from the extremes of the outcome distribution. All HGSC tumours are primary tumour samples. Library construction and sequencing Frozen specimens with >50% tumour cellularity (based on initial slide review) were used for cryosectioning and subsequent nucleic acid extraction. Patient tumour and normal blood samples derived from primary, untreated fresh frozen tumour specimens harvested at diagnosis during standard of care debulking surgery. Germline DNA was provided from peripheral blood buffy coat on all specimens except 13 from Tokyo, where non-cancer frozen tissue was used as a germline source. DNA extraction from both matched normal (blood) and tumour samples (frozen tissue) were performed using the QIAamp Blood and Tissue DNA kit (Qiagen) and quantified using a Qbit fluorometer and reagents (high-sensitivity assay). Three lanes of Illumina HiSeq 2500 v4 chemistry for normal samples and five lanes for tumour samples were obtained. The PCR-free protocol was adopted to eliminate the PCR-induced bias and improve coverage across the genome.

  Dataset EGAD00001003268

• CaBagE: a Cas9-Based Background Elimination Strategy for Targeted, Long-Read DNA Sequencing

  While repeat-expansion polymorphisms are known to underlie several developmental and neurological disorders, technological limitations have inhibited the ability to resolve accurate genotypes for these variants. A pertinent example is the (CCCCGG)n repeat expansion in C9orf72 that segregates with up to 40% of familial amyotrophic lateral sclerosis (ALS) cases. There is a clear relationship between this repeat expansion and neurodegeneration. However, widely-used short-read sequencing is ill-suited to characterize the C9orf72 repeat expansion due to polymerase slippage over low complexity sequences and the inherently limited mapping/haplotype resolution of redundant short sequences. Consequently, researchers and physicians must rely on crude variant characterization methods (e.g. Southern blots), which limit direct genotype-phenotype associations and create challenges for the diagnosis of disease in patients with atypical clinical presentation. In contrast, ultra-long (e.g., 10-150kb) sequencing reads generated by Oxford Nanopore Technologies (ONT) enable direct measurement of loci containing complex structures without being subject to amplification or alignment bias. We are therefore developed a molecular and computational framework for targeted sequencing and quantification of pathogenic repeat expansions by combining Cas9 and amplification-free sequence capture methods with Nanopore long-read sequencing technology. First, extracted high molecular weight DNA is bound by Cas9 on either side of a DNA target. Bound Cas9 protects the target DNA from challenge by processive exonucleases. Unprotected (off-target) DNA is degraded with exonucleases and the remaining sample is sequenced using the ONT MinION sequencer. Then, base-called reads are aligned to the target locus and repeat copy number genotypes are estimated using a Gaussian Mixture Model. We applied this molecular and computational framework to 2 ALS patients with C9orf72 repeat expansions with biospecimens available from the NINDS collection from Coriell. Genotype estimates produced with CaBagE were commensurate with genotypes derived from repeat-primed PCR for each individual.

  Study phs002368