12305 results for ""statistically+reactive"+taxa+in+microbial+community"

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• Impact of DIS3 Aso on BCR repertoir in human buffy coat purified B-Cells

  The aim is to identify difference in the BCR of Aso DIS3 treated cells compared to Control Aso. Using extracted DNA from human B-cells

  Study EGAS50000001107

• Circulating Tumor DNA analysis in Relapsed/Refractory Germ Cell Tumors Treated with Salvage High-Dose Chemotherapy - IGG-04 Study

  Shallow whole genome analysis of circulating tumor DNA detected in the plasma of Relapsed/Refractory germ cell tumors treated with high dose chemotherapy

  Study EGAS50000001510

• Dynamic N6-methyladenosine Epitranscriptomic Landscape in Lung Adenocarcinoma

  Systematically evaluate the global effect of dysregulated m6A regulators on the m6A epitranscriptome in patient tumors, and identify prognostic m6A markers by linking with patients' clinicopathological and outcome information.

  Study EGAS00001005524

• DNA repair knockouts

  We generated HPRT-only knockout lines as well as the combination of HPRT with MSH2, UNG and XPC. Whole genome sequencing was performed on generated clones and subclones. By subtracting variants present in the clones from those in the subclones, the somatic mutations, that accumulated in between the clonal steps, were determined.

  Dataset EGAD00001006777

• Oxford Nanopore Technologies (ONT) long-read sequencing in a paired diagnostic and post- therapy medulloblastoma

  Oxford Nanopore Technologies (ONT) long-read sequencing in a paired diagnostic and post- therapy medulloblastoma (2 samples). One sequencing was done on GridION, the other one on a P2 Solo. In both cases the SQK LSK-109 Kit was used for preparation.

  Dataset EGAD00001009490

• Single-cell short-read transcriptomes from CH, MDS and AML patients with splicing factor mutations

  Single-cell RNA sequencing from CH (n = 2), MDS (n = 6, MDS02 in 2 replicates) and AML (n = 1, in 2 replicates) samples with mutations in splicing factors (SF3B1 - n = 8, U2AF1 n = 1). cDNA from 10x Genomics 3' V3.

  Dataset EGAD00001011283

• Combined Metabolic Activators Reduces Liver Fat in Nonalcoholic Fatty Liver Disease Patients

  Metagenomics data for "Combined Metabolic Activators Reduces Liver Fat in Nonalcoholic Fatty Liver Disease Patients". Samples were sequenced on NovaSeq6000(NovaSeq Control Software 1.7.0/RTA v3.4.4) with a 151nt (Read1)-10nt(Index1)-10nt(Index2)-151nt(Read2) setup using ‘NovaSeqXp’ workflow in ‘S4’ mode flow cell.

  Dataset EGAD00001008142

• Chromosomally integrated HHV6 data of parent-infant pairs

  Raw data used in the analysis of chromosomally integrated HHV6 genomes in parent-infant pairs, generated by means of full viral genome sequencing by SureSelect target enrichment, in the context of a larger study investigating the relationship between HHV6 and adverse pregnancy outcome.

  Dataset EGAD00001004592

• Somatic pseudogenes acquired during cancer development – Whole Genome sequencing

  Insertion of processed pseudogenes is known to occur in the germline but has not previously been observed in somatic cells. Formation of pseudogenes could represent a new class of mutation in cancers and a new source of potential driver events.

  Dataset EGAD00001000638

• Somatic pseudogenes acquired during cancer development – Whole Exome sequencing

  Insertion of processed pseudogenes is known to occur in the germline but has not previously been observed in somatic cells. Formation of pseudogenes could represent a new class of mutation in cancers and a new source of potential driver events.

  Dataset EGAD00001000637

• RNA-seq data from DMD patients and healthy controls

  This dataset comprises RNA-seq expression profiles from 57 subjects, of which 39 are DMD patients and 18 healthy controls. The data are described in the following article: Signorelli, Ebrahimpoor et al. (in review). Peripheral blood transcriptome profiling enables monitoring disease progression in dystrophic mice and patients.

  Dataset EGAD00001006826

• scRNAseq data from ALI cultures of healthy donors and patients with asthma, infected with RSV

  This dataset contains the count matrices and corresponding metadata for our study on bronchial epithelial cells response to RSV in healthy and in asthma. This scRNAseq data is from primary cells, that have been differentiated in ALI cultures and infected with RSV.

  Dataset EGAD00001011264

• Whole Exome Sequencing of Congenital Diaphragmatic Hernia Patients and Trios

  Congenital diaphragmatic hernia (CDH) is a common and severe birth defect characterized by structural defects of the diaphragm and by pulmonary hypoplasia. Congenital diaphragmatic hernia patient may present either as an isolated phenotype or together with other congenital anomalies in a complex phenotype. Despite the clinical significance of CDH, the underlying genetic and developmental pathways are incompletely understood. In order to establish a catalog of human genetic variation for this condition, we performed whole exome sequencing (WES) on 275 carefully phenotyped individuals with CDH in the Pediatric Surgical Research Laboratories at the Massachusetts General Hospital (Boston, MA, USA) and Boston Children's Hospital (Boston, MA, USA). The exome data generated are valuable for comparison of candidate genes derived from WES of other CDH cohorts or affected kindreds, and to provide ideal candidates for further functional studies with the ultimate goal of enhancing our understanding of the heterogeneous and, possibly, oligogenic molecular etiology of CDH. While familial clustering has been reported in rare kindreds, the majority of probands with CDH have no family history of CDH leading to the hypothesis that de novo variants are an important and relatively frequent etiological mechanism. In the second version of the study, we performed WES analysis on 87 trios, to assess the contribution of de novo mutations in the etiology of diaphragmatic and pulmonary defects and to identify previously unknown candidate genes. This dbGaP submission includes WES data on: (a) 20 new probands, (b) 9 probands also reported in the previous version (dbGaP accession no. phs000783.v1.p1), (c) 174 unaffected parents, including the parents of 67 previously reported probands. Combined analysis with other available cohorts of congenital diaphragmatic hernia revealed a genome-wide enrichment of likely gene-disrupting de novo variants (i.e., nonsense, frameshift or splice site), and missense de novo variants predicted in silico to be damaging.

  Study phs000783

• Genetic Studies of Chronic Kidney Disease (CKD)

  The Genetic Studies of Chronic Kidney Disease (CKD) is an ongoing genetic research and biobanking protocol which aims to elucidate the genetic basis CKD. The study recruits patients seen at the Columbia University Medical Center (CUMC) Nephrology Division for the evaluation and care of CKD. All patients clinically diagnosed with CKD are eligible to participate; there are no inclusion or exclusion criteria related to age, sex/gender, and/or race/ethnicity. In addition to office visits, patients are recruited in contexts including perinatal care and nonprofit events for patients with various forms of CKD; recruitment tools include bilingual informational brochures, flyers, and consent forms. All individuals provide informed consent; for minors, signature of the parent/guardian is required. Consent includes: use of biosamples given for genetic studies, and the request to be re-contacted if medically actionable genetic findings are identified. In the case of the latter, such research-level findings are first validated in a clinically certified (CLIA) laboratory environment, using a second sample given by the individual at the time of re-contact; following CLIA validation, the individual is once again re-contacted, and, assuming he or she still desires return of these results, they can then be returned. Following the above consent process to participate in the study, individuals provide a single biosample (generally, a venous blood sample), from which DNA is extracted using standard protocols and used for genetic studies, such as exome sequencing. Basic clinical and demographic data, including sex/gender, age, and race/ethnicity are also collected. All data collected is stored in a secure computerized database, with patient samples anonymized using numerical identifiers; the relation of this identifier to patients' names is kept in a locked computer file in a centralized database. Electronic data complies with all HIPAA and other privacy and security regulations, and resides on a firewall server maintained by the CUMC IT department.

  Study phs001828

• Transcriptomic Analysis of HIV-Infected Cells

  Defining the attributes of rare CD4 T cells that harbor latent HIV under therapy with anti-retroviral agents has been challenging due to difficulties in identifying and isolating these cells. These cells represent an important barrier to cure, and characterizing them would aid the design and development of novel HIV cure strategies. In this study, we addressed this challenge using a custom microfluidic technology named Focused Interrogation of cells by Nucleic acid Detection and Sequencing (FIND-seq) that isolates HIV-infected cell transcriptomes, based on HIV DNA detection. We applied this method to HIV DNA+ memory CD4 T cells isolated from blood from five persons with HIV who were receiving anti-retroviral agents. After curating samples based on data quality, we proceeded with bioinformatics analysis from three persons. This analysis identified six transcriptomic pathways that were inhibited in HIV DNA+ cells compared to HIV DNA- cells. These included death receptor signaling, necroptosis signaling, and anti-proliferative G-alpha12/13 signaling. Furthermore, we identified two gene clusters, including 60 and 85 genes, that were significantly associated with HIV DNA+ cells identified by co-expression network analysis. These genes included negative regulators of HIV transcription that were higher in HIV DNA+ cells, positive regulators of HIV transcription that were lower in HIV DNA+ cells, and other genes involved in the negative regulation of mRNA translation, additional RNA processing functions, and the regulation of cellular state and fate. We further examined these signatures in transcriptomic data from CD4 T cell subsets sorted by flow cytometry from nine persons with HIV. We found a partial similarity between the smaller cluster of genes and the signature of CCR6- peripheral TFH cells. Raw sequencing data from all eleven human participant samples included in the study are available. These include samples from two participants who were studied only by FIND-seq, three participants who were studied by both FIND-seq and flow cytometry and six participants who were studied only by flow cytometry.

  Study phs003095

• GATA2 Deficiency and the MonoMAC Syndrome

  The aim of this study was to identify the germline mutation(s) in an extended family with individuals having MonoMAC Syndrome/GATA2 deficiency but lacking a canonical GATA2 mutation. GATA2 deficiency patients develop bone marrow failure, severe immunodeficiency and may progress to myeloid malignancies, including myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and chronic myelomonocytic leukemia (CMML). The definitive treatment for GATA2 deficiency is a bone marrow transplant. Approximately 90% of GATA2 deficiency patients have a known de novo or inherited germline mutation in the GATA2 gene, but ~10% have no identified mutation. The study was initiated with the first patient and her second cousin, both of whom were treated for MonoMAC Syndrome and received bone marrow transplants at the NIH. Pedigree analysis and clinical evaluation identified the individuals in several generations of these patients' near and distant relatives who are/were presenting or carrying the disease manifestations of GATA2 deficiency. Whole Genome Sequencing (WGS) was employed on these patients' two related nuclear families to identify variants that segregated with the disease trait and carrier status of their families. Genotyping was confirmed with direct DNA sequencing of these and other family members within the extended family across generations. A single base adenine-to-thymidine change was identified in a highly conserved enhancer element ~117,000 bp upstream of the GATA2 gene. It creates a new Composite Element, a DNA motif known to be critical in the regulation of hematopoiesis. This variant is unique to this family and is not present in dbSNP or other variant databases. It segregates with the disease trait and obligate carriers throughout a large pedigree. In vitro studies show that this variant drives allele-specific overexpression of the GATA2 gene in cultured cells and luciferase assays. The WGS sequence from the nuclear families will be shared on dbGaP.

  Study phs003269

• Genomic and Immune Profiling of Breast Cancer Brain Metastases

  Previous work has shown that breast cancer brain metastases (BCBrM) can have unique molecular profiles compared to extracranial tumors (ECTs), resulting in some patients demonstrating subtype switching between primary/extracranial tumors and brain metastases. Description of the biology of BCBrM and associations between biological features and clinical outcomes, particularly between molecular intrinsic subtypes, will facilitate the design of rational therapies for patients with BCBrM. To better characterize the molecular profiles of BCBrM, we conducted whole exome sequencing (WES) and total RNA sequencing (RNA-Seq) on BCBrM tissues, regardless of clinical or molecular subtype, obtained from a cohort of 42 patients from Duke University Medical Center. This cohort adds valuable patient samples to the field and enables strengthened investigation of somatic mutations, copy number alterations, gene expression profiles, and immune populations within and between BCBrM patients and other similar cohorts. The Duke BCBrM cohort includes clinical and molecular annotation of the 42 patient specimens and their associated WES and RNA-Seq data. Clinical and molecular (PAM50) intrinsic subtypes in ECTs and brain metastases were largely concordant within patients. There were observed differences in intrinsic subtype calls between frozen and FFPE specimens of the same tissue, with discordance mostly observed with LumB calls. Copy number alterations in chromosomal regions included clinically relevant genes, and somatic alterations were largely conserved within patients across matched samples, with few genes, including TP53, being recurrently altered in the majority of patient specimens. In matched FFPE brain metastasis and ECT samples, we observed differentially expressed genes and pathways that had increased or decreased expression in brain metastasis, including in oxidative phosphorylation and DNA repair. Survival outcomes for patients differed by intrinsic molecular subtypes, with some association between expression of select gene pathways and survival. Data available through dbGaP will be the sequencing data and sample attributes from BCBrM tissues obtained from 42 patients from Duke University Medical Center.

  Study phs003673

• Emirati Genome Project subset of 43,608 WGS samples for population-scale variant discovery and allele frequency mapping.

  Here, we present a comprehensive genomic characterization of a cohort of 43,608 Emirati genomes sequenced as part of the Emirati Genome Program (EGP). This study identified more than 421 million single nucleotide variants and indels and more than 600 million copy number- and structural variants. Small variants had 756 million molecular effects annotated. Of the identified variants, 69.04% were observed with more than one allele. Of 7.7 million polymorphic variants having an allele frequency (AF) of more than 5% in EGP, 1,348 have a predicted deleterious effect on a protein. Characterization of global variation reveals that EGP represents a genetic continuum encompassing the range of African, Asian, and European populations. It is best described by two Arabian, an Eurasian, and an African component, with the predominant Arabian component linked to mitochondrial haplogroups J and T, which are commonly attributed to the Middle East. Various aneuploidies of sex chromosomes were detected in 93 individuals overall and of chromosome 21 in 41 individuals. The median inbreeding coefficient and cumulative runs of homozygosity (ROHs) lengths were increased due to extensive consanguinity, being largest in the groups with Arabian main ancestry components and higher than reported for Qatar. Families were identified based on genetic relatedness and classified into 264 families with unrelated parents and 247 families with third- and fourth-degree consanguineous parents. Representative consanguineous pedigrees of families in EGP were outlined. Cumulative ROHs were affected by the main ancestry component and significantly increased in offspring of consanguineous parents, with a pronounced difference between 3rd and 4th-degree relatedness. Investigation of cumulative AFs of variants causing Mendelian diseases highlighted genes related to alpha- and beta-thalassemia (HBB, HBA2). It showed a high burden of variants causing severe recessive diseases, metabolic and retinal disorders, and hearing loss. In summary, EGP represents a landmark effort in characterizing the genetic diversity of the Emirati population, leveraging the largest Middle Eastern cohort reported to date.

  Study EGAS50000001071

• Human Dorsal Root Ganglion RNA Landscape Profiling for Neuropathic and Chronic Pain

  Bulk and spatial RNA sequencing were performed on human Dorsal Root Ganglia (DRGs), peripheral sensory nerves and nodose ganglia and relative gene abundances were calculated. Various analyses were performed: Human DRG gene expression profiles were contrasted with a panel of gene expression profiles of relevant tissues in human and mouse (integrating, among other sources, datasets from ENCODE and GTex) in order to identify. DRG-enriched gene expression, co-expression modules of DRG-expressed genes, and key transcriptional regulators in humans. Contrasting the human and mouse DRG transcriptomes to identify DRG-enriched gene expression patterns that were conserved between human and mouse, identifying putative cell types of expression of these genes, and potential known drugs that might target the corresponding gene products. Characterization of non-coding RNA profile of human and mouse DRGs. Characterization of DRG-enriched alternative splicing and alternative transcription start site usage based transcript variants in humans and mouse, and the overlap between these two species. Contrasting of human DRG and GTex human tibial nerve samples to identify putative axonally transported mRNAs in sensory neurons. Human DRG and peripheral nerves transcriptomes from donors suffering from neuropathic and/or chronic pain were contrasted with controls to identify. Differentially expressed genes, pathways and regulators path play a potential role in neuronal plasticity, electrophysiological activity, immune signaling and response. Predictive models (Random Forests) were built to jointly predict the sex and pain state of samples based on information contained solely in autosomal gene expression profile. Gene co-expression modules were identified and gene set enrichment analysis performed.to identify sample - pathway associations, and to broadly characterize plasticity in human DRG cell types. Spatial transcriptomics was performed on human DRGs and nodose ganglia to obtain near single-neuron resolution. We identified distinct clusters of human DRG sensory neurons. We characterized the expression of different gene families (e.g., GPCRs, sodium channels, potassium channels, etc.). We investigated differences between male and female neurons.

  Study phs001158

• Molecular analysis of diffuse cerebellar gliomas

  Among diffuse gliomas, oligodendrogliomas show relatively better prognosis, respond well to radiotherapy and chemotherapy, and seldom progress to very aggressive tumors. To elucidate the genetic and epigenetic background for such behavior and tumor evolution during tumor relapse, we comparatively analyzed 12 pairs of primary and recurrent oligodendrogliomas with 1p/19q-codeletion. Initial treatment for these patients was mostly chemotherapy alone. Temozolomide was used for 3, and procarbazine, nimustine and vincristine (PAV chemotherapy) were used for 7 patients. World Health Organization histological grade at recurrence was mostly stable; it was increased in 2, the same in 9, and decreased in 1 cases. Whole-exome sequencing demonstrated that the rate of shared mutation between the primary and recurrent tumors was relatively low, ranging from 3.2-57.9% (average, 33.3%), indicating a branched evolutionary pattern. The trunk alterations that existed throughout the course were restricted to IDH1 mutation, 1p/19q-codeletion, and TERT promoter mutation, and mutation of the known candidate tumor suppressor genes CIC and FUBP1 were not consistently observed between primary and recurrent tumors. Multiple sampling from different regions within a tumor showed marked intratumoral heterogeneity. Notably, in general, the number of mutations was not significantly different after recurrence, remaining under 100, and no hypermutator phenotype was observed. FUBP1 mutation, loss of chr. 9p21, and TCF12 mutation were among a few recurrent de novo alterations that were found at recurrence, indicating that these events were clonally selected at recurrence but were not enough to enhance malignancy. Genome-wide methylation status, measured by Illumina 450 K arrays, was stable between recurrence and the primary tumor. In summary, although oligodendroglioma displays marked mutational heterogeneity, histological malignant transformation accompanying events such as considerable increase in mutation number and epigenetic profile change were not observed at recurrence, indicating that noticeable temporal and spatial genetic heterogeneity in oligodendrogliomas does not result in rapid tumor progression.

  Study JGAS000106

• Genetic_Heterogeneity_of_the_familial_gastric_neuroendocrine_tumors

  Gastric neuroendocrine tumors (gNETs) occur with an estimated frequency of 2 per 100,000 in the general population. Type I gastric neuroendocrine tumors (NETs) represent the 75% of gNTEs and arise from gastric enterochromaffin-like (ECL) cells. They have late age of onset and usually benigh course. Classically, hypergastrinemia in patients who have autoimmune atrophic gastritis, causes hyperplasia of gastric ECL cells that progresses into type I gastric NETs and parietal cell (PC) destruction. The genetic bases in families with this disease are unknown. We performed an exome sequencing study of an atypical aggressive familial gNETs case (with early age onset, nodal infiltrations and gastric adenocarcinomas) that followed a recessive model. We identified a deleterious mutation in homozygosis in the ATP4A gene, which encodes the proton pump responsible for acid secretion by gastric parietal cells. This mutation lead to achlorhydria first, and hypergastrinemia and gNET developing as consequence (Calvete et al. 2014). Recently, two more families with gNETs, classical clinical traits and recessive model have been studies by WES but we didn't find any mutation in the ATP4a gene. However, putative mutations affecting genes that contribute to the development and the integrity of PC have been found suggesting that genetic alterations associated to this disorder target to a unique cell type (parietal cells). In order to cinfirm this hypothesis, it is necessary the search for new genes implicated in the gNETs, more familial cases are needed to be studied. We have identified four more new familial gNETs cases. Here, we propose their study by WES. The first family is formed by thress siblings with gNETs. The other families include two siblings with gNETs. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001002273

• Next-Generation Sequencing of RNA and DNA Isolated from Paired Fresh-Frozen and Formalin-Fixed Paraffin-Embedded Samples of Human Cancer and Normal Tissue

  Formalin-fixed, paraffin-embedded (FFPE) tissues are an invaluable resource for clinical research. However, nucleic acids extracted from FFPE tissues are fragmented and chemically modified making them challenging to use in molecular studies. We analysed 23 fresh-frozen (FF), 35 FFPE and 38 paired FF/FFPE specimens, representing six different human tissue types (bladder, prostate and colon carcinoma; liver and colon normal tissue; reactive tonsil) in order to examine the potential use of FFPE samples in next-generation sequencing (NGS) based retrospective and prospective clinical studies. Two methods for DNA and three methods for RNA extraction from FFPE tissues were compared and were found to affect nucleic acid quantity and quality. DNA and RNA from selected FFPE and paired FF/FFPE specimens were used for exome and transcriptome analysis. Preparations of DNA Exome-Seq libraries was more challenging (29.5 % success) than that of RNA-Seq libraries, presumably because of modifications to FFPE tissue-derived DNA. Libraries could still be prepared from RNA isolated from two-decade old FFPE tissues. Data were analysed using the CLC Bio Genomics Workbench and revealed systematic differences between FF and FFPE tissue-derived nucleic acid libraries. In spite of this, pairwise analysis of DNA Exome-Seq data showed concordance for 70-80 % of variants in FF and FFPE samples stored for fewer than three years. RNA-Seq data showed high correlation of expression profiles in FF/FFPE pairs (Pearson Correlations of 0.90 +/- 0.05), irrespective of storage time (up to 244 months) and tissue type. A common set of 1,494 genes was identified with expression profiles that were significantly different between paired FF and FFPE samples irrespective of tissue type. Our results are promising and suggest that NGS can be used to study FFPE specimens in both prospective and retrospective archive-based studies in which FF specimens are not available.

  Study EGAS00001000737

• Deep single-cell RNA sequencing data for 11138 T cells from tumour, adjacent normal tissue and peripheral blood of treatment-naive CRC patients. The DATA ACCESS AGREEMENT is provided at https://github.com/zhangyybio/single-T-cell-data-access. Applicants can request access to the data by directly downloading it or by sending an email to cancerpku@pku.edu.cn. The process that is used to approve an application includes verifying the institution, participants and research purposes of the application. In general this process will take about two weeks. In principal, any scientific research program complying with the laws and bioethic regulation policies of China will be approved.

  T cells are central players in cancer immunotherapy1, yet some of their fundamental properties such as development and migration within tumours remain elusive. The enormous T cell receptor (TCR) repertoire, required for recognising foreign and self-antigens2,3, could serve as lineage tags to track these T cells in tumours4. Here, we obtained transcriptomes of 11,138 single T cells from 12 colorectal cancer (CRC) patients and developed STARTRAC (Single T-cell Analysis by Rna-seq and Tcr TRACking) indices to quantitatively analyse dynamic relationships among 20 identified T cell subsets with distinct functions and clonalities. While both CD8+ effector and “exhausted” T cells exhibited high clonal expansion, they were independently connected with tumour-resident CD8+ effector memory cells, implicating a TCR-based fate decision. Of the CD4+ T cells, the majority of tumour-infiltrating Tregs showed clonal exclusivity, whereas certain Treg clones were developmentally linked to multiple TH clones. Notably, we identified two IFNG+ TH1-like clusters in tumours, the GZMK+ TEM and CXCL13+ TH1-like clusters, which were associated with distinct IFN-γ-regulating transcription factors, EOMES/RUNX3 and BHLHE40, respectively. Only CXCL13+BHLHE40+ TH1-like cells were preferentially enriched in tumours of microsatellite-instable (MSI) patients, which might explain their favourable response rates to immune-checkpoint blockade. Furthermore, we found IGFLR1 to be highly expressed in both CXCL13+BHLHE40+ TH1-like and CD8+ exhausted T cells and possessed co-stimulatory functions. Our integrated STARTRAC analyses provides a powerful avenue to comprehensively dissect the T cell properties in CRC, which could shed new insights into the dynamic relationships of T cells in other cancers

  Study EGAS00001002791

• Prediction of Resistance and Sensitivity to HER2 Targeted Therapy in the Neoadjuvant Setting

  Women with breast cancers that overexpress HER2 are at greater risk for disease progression and death than women whose tumors do not overexpress HER2. Trastuzumab, a recombinant humanized monoclonal antibody against the extracellular domain of the HER2 protein blocks downstream signaling of HER2 and substantially improves the efficacy of chemotherapy in women with metastatic and early-stage HER2-positive breast cancers. Because resistance to trastuzumab eventually results in progressive disease in the metastatic setting and contributes to recurrence following adjuvant trastuzumab-based therapy, it is important to develop agents other than trastuzumab that target HER2 signaling through different mechanisms of action. Lapatinib is an oral, small molecule, dual tyrosine kinase inhibitor of HER2 and EGFR. Lapatinib has shown a lack of cross-resistance with trastuzumab in preclinical studies and activity in women with HER2-positive, metastatic breast cancer that has progressed during trastuzumab treatment. Trastuzumab blocks the downstream signaling of HER2 by binding to the extracellular domain of the receptor. Lapatinib binds to the intracellular domains of HER2 and EGFR and prevents activation of downstream signaling pathways. Because of this different mechanism of action, lapatinib may be effective in trastuzumab-resistant disease. The study will also provide important safety information on trastuzumab and lapatinib combinations immediately following anthracycline exposure, and also provide an initial direct comparison of cardiac effects of trastuzumab and lapatinib when incorporated into a standard sequential adriamycin and cyclophosphamide (AC) followed by weekly paclitaxel neoadjuvant regimen. Availability of a second agent that can interrupt HER2-signaling pathways through completely different mechanisms than those of trastuzumab offers the potential for further improvement in the management of patients with HER2-overexpressing breast cancer in both the adjuvant and metastatic setting. Co-administration of both trastuzumab and lapatinib with chemotherapy may be important in improving outcomes in subsets of HER2-positive breast cancers. However, use of two inhibitors of the HER2 pathway will increase costs and may increase toxicity, so it will be important to identify the subsets of patients who would benefit from the dual therapy. Inhibition of HER2 with a single agent clearly is sufficient for many patients as evidenced by the results of the trastuzumab trials. Therefore, co-administration to unselected populations of women with HER2-positive breast cancers would not represent an optimal approach. Given the activity of lapatinib, it is likely that it will also be sufficiently active in inhibiting HER2-pathway activation in some patients to allow for its use as the sole inhibitor of the HER2 pathway. Different populations may also derive greater benefit from one of the HER2-blocking agents relative to the other. Identification of potential predictive factors for pathologic complete response to the combination or to either agent administered alone in neoadjuvant trials would provide important information for adjuvant trials designed to definitively address these important issues. This study will compare 3 combined chemotherapy regimens: AC followed by paclitaxel plus trastuzumab and lapatinib, AC followed by paclitaxel plus lapatinib, and AC followed by paclitaxel plus trastuzumab given before surgery to patients with HER2-positive breast cancer.Tumor samples were collected prior to and post-treatment, and RNA sequencing was performed with this version.

  Study phs003275

• Recurrent DNMT3B gene rearrangements are associated with unfavorable outcome in dicentric (9;20)-positive pediatric BCP-ALL

  The dicentric chromosome dic(9;20)(p11∼13;q11), occurs in 2% of pediatric acute lymphoblastic leukemia (ALL) cases. However, the prognostic significance of the dic(9;20) alterations and the mechanism in which these alterations drive leukemogenesis remains elusive. Our study describes the demographic, clinical, prognostic, and molecular characteristics of the dic(9;20)-positive ALL in a cohort of 57 pediatric BCP-ALL patients. Targeted RNA-seq and Array CGH analysis unraveled heterogeneous breakpoints on chromosomes 9 and 20 and frequent deletions of the IKZF1 gene. Together with the intrinsic susceptibility for deletions in CDKN2A, CDKN2B, and PAX5 genes in the dic(9;20)-positive ALL, these patients are eligible for treatment escalation in the AIEOP-BFM ALL 2017 clinical study. Survival analysis revealed poor 5-year event-free survival (pEFS) of 69% in dic(9;20)-positive ALL cases, compared to BCP-ALL patients enrolled in modern treatment studies. Strikingly, we identified six dic(9;20)-positive cases with rearrangements involving the DNMT3B gene, and poor 5-year pEFS of 25% (SE = 20%), compared to 79% (SE = 9%) for the remaining cohort (P = 0.011). Despite the loss of the methyltransferase domain of the DNMT3B gene in most cases with DNMT3B rearrangements, we did not observe major changes in the global methylation patterns. Differential gene expression analysis of DNMT3B-rearranged ALL unraveled a dysregulation of genes involved in hematopoiesis, lymphocyte maturation, and the PI3K/AKT signaling pathway. After confirmation in an independent cohort, DNMT3B-rearranged ALL cases should be considered high-risk for relapse and treated accordingly. We provide clinical data sets of Array CGH, targeted RNA-seq, total RNA-seq, whole genome bisulfite (WGBS) and whole genome DNA sequencing (WGS) obtained from bone marrow (BM) or peripheral blood (PB) mononuclear cells of 57 pediatric patients with dicentric chromosome dic(9;20) positive Acute lymphocytic leukemia (ALL), from which in 6 cases DNMT3B gene rearrangement was identified. This data is complemented by total RNA-seq and WGBS of samples from 4 additional ALL patients with a t(12;21) translocation and ETV6-RUNX1 gene fusion. DNA was isolated from BM or PB lymphocytes using Qiagen QIAamp DNA Blood Midi Kit to perform i) Array CGH of 58 dic(9;20) positive samples by hybridizing 500ng DNA using a Agilent 400K SurePrint G3 Custom CGH Human Genome Microarray (e-Array design 84704) ii) WGBS of 6 DNMT3B rearrangement positive samples and 4 ETV6-RUNX1 positive samples using Tecan TrueMethyl oxBS-Seq module for library preparation and Illumina NovaSeq 6000 platform to run 2x151 cycles iii) WGS of DNMT3B rearrangement positive samples using Illumina Lotus DNA Library Prep Kit followed by sequencing running 2x160 cycles on an Illumina NovaSeq 6000 platform. RNA was isolated from PB lymphocytes using the PerkinElmer Chemagic 360 instrument, followed by i) targeted RNA-seq of 56 dic(9;20) positive samples prepared using Illumina TruSight RNA Pan-Cancer Panel and sequenced on an Illumina MiSeq platform running 2x75 cycles ii) total RNA-seq of 6 DNMT3B rearrangement positive samples and 4 ETV6-RUNX1 positive samples utilizing TruSeq Stranded Total RNA Library Prep Gold kit and running 2x100 cycles on an Illumina NovaSeq 6000 platform.

  Study EGAS00001007383

• DAC-2020-03-26-Lemola (DAC-039))

  DAC-2020-03-26-Lemola (DAC-039)), raw data in EGA, metadata in Harvard Dataverse

  Dataset EGAD50000000897

• DAC Clonal Evolution of PPM1D Mutations in the Spectrum of Myeloid Disorders

  Data access committee for Clonal Evolution of PPM1D Mutations in the Spectrum of Myeloid Disorders

  Dac EGAC50000000527

• Somatic_mutation_in_edited_cholangiocyte_organoids__Targeted_NanoSeq_

  Characterisation of mutation rates and patterns in edited human cholangiocyte organoids (Targeted NanoSeq)

  Study EGAS00001007266

• Somatic_mutation_in_edited_cholangiocyte_organoids_NanoSeq

  Characterisation of mutation rates and patterns in edited human cholangiocyte organoids (NanoSeq)

  Study EGAS00001006405

• Children's Hospital of Philadelphia (CHOP) Control Copy Number Variation (CNV) Study

  We present a database of copy number variations (CNVs) detected in 2,026 disease-free individuals, using high-density, SNP-based oligonucleotide microarrays. This large cohort analyzed for CNVs in a single study using a uniform array platform and computational tools, comprises mainly of Caucasians (65.2%) and African-Americans (34.2%), We have catalogued and characterized 54,462 individual CNVs, 77.8% of which were identified in multiple unrelated individuals. These non-unique CNVs mapped to 3,272 distinct regions of genomic variation spanning 5.9% of the genome; 51.5% of these were previously unreported, and >85% are rare. Our annotation and analysis confirmed and extended previously reported correlations between CNVs and several genomic features such as repetitive DNA elements, segmental duplications and genes. We demonstrate the utility of this data set in distinguishing CNVs with pathologic significance from normal variants. Together, this analysis and annotation provides a useful resource to assist with the assessment of CNVs in the contexts of human variation, disease susceptibility, and clinical molecular diagnostics. The CNV resource is available at: http://cnv.chop.edu. Reprinted from Shaikh T., et al., High-Resolution Mapping and Analysis of Copy Number Variations in the Human Genome: A Data Resource for Clinical and Research Applications Genome Research. 2009, with permission from Genome Research. CHOP CNVs from 2,026 disease-free individuals are available through dbVar at http://www.ncbi.nlm.nih.gov/dbvar/studies/nstd21.

  Study phs000199

• NHLBI TOPMed: Best ADd-on Therapy Giving Effective Response (BADGER)

  BADGER is a 56-week randomized, double-blind, three-treatment, three-period cross-over trial that will evaluate the differential improvement in control that is achieved following three separate treatment interventions in children whose asthma is not acceptably controlled on a low dose of ICS (per NAEPP guidelines). All participants will enter an 8-week run-in period during which time they will receive a dose of 1x ICS (fluticasone 200 μg/day). During this 8-week time period, running 2-week averages to establish the lack of acceptable asthma control will be calculated. Thus, a child could qualify for randomization at any time during this 8-week run-in period. This approach should maximize both patient safety and successful enrollment. Children will continue to receive 1x ICS during the entire treatment phase. During each period of the treatment phase, they also will receive one add-on therapy in the form of LABA, LTRA or additional 1x ICS. The order of the add-on therapy assignment will be determined by randomization into one of six treatment sequences (order determined randomly). Each treatment period will be 16 weeks in length; the initial 4 weeks of each period will be considered to be the washout period for the previous treatment. The primary outcome measures will be frequency of asthma exacerbations, asthma control days, and FEV1.

  Study phs001728

• A comprehensive DNA methylation landscape of human and mouse cell lines derived from hematological malignancies

  Human cancer cell lines constitute useful models to study the primary disease and many relevant findings in tumor biology have been originated from them since the first immortalized cell line (HeLa) was obtained. The easy experimental intervention, the purity of the transformed cells and their versatility to undergo high-throughput screenings represent advantageous features of the established cancer cell lines. In recent years, major efforts have characterized in detail the multiomics make-up of hundreds of cancer cell lines and studied their association with sensitivity to anticancer drugs. Most of these studies have been genetic-centric and have not characterized in detail the epigenetic profiles underlying the characteristics of these cells or their impact on the efficacy of antitumoral compounds. In this regard, a past version of a DNA methylation microarray or a less accessible and more time-consuming such as reduced representation bisulfite sequencing have been used in those attempts to interrogate the epigenetic setting. Herein, we have obtained the DNA methylation profiles of 210 cell lines derived from hematological malignancies utilizing comprehensive DNA methylation microarrays that interrogates more than 850,000 and 285,000 CpG sites from human and mouse genomes, respectively. Importantly, we also provide a pharmacoepigenetic example of the potential use of this resource by showing how DNA methylation can predict response to nucleoside analogues.

  Study EGAS50000000627

• NIH RECOVER: A Multi-Site Pathology Study of Post-Acute Sequelae of SARS-CoV-2 Infection

  The RECOVER tissue pathology study is a cross-sectional study designed to define and characterize the epidemiology, natural history, clinical spectrum, and underlying mechanisms of post-acute effects of SARS-CoV-2 infection in a diverse population representative of the general COVID-19 population in the US. The autopsy study will characterize the pathology of PASC in decedents who die more than 60 days after initial onset or after hospital discharge, whether in-hospital or out-of-hospital at time of death, and who meet the working definition of PASC as defined by the recent World Health Organization publication given in Section 5.4. The autopsy study will also explore the pathology of acute SARS-CoV-2 infection in a smaller subset of decedents who died between15-60 days from symptom onset. This protocol defines the common set of clinical data elements, autopsy procedures for tissue collection, core measures, pathology protocols, shared pathology tissues, data elements, and methodology. Each investigator site is expected to perform autopsies on the decedents to address the pathophysiology of the potential long-term effects of SARS-CoV-2 infection on human health. The Consortium analysis plan aims to address research questions by incorporating: 1) tissue obtained from autopsies performed at each Phase II participant's site; and 2) tissue available from other pathology investigators/autopsy sites within the Consortium.

  Study phs003768

• Illumina HumanOmniExpress genotyping data from the TEENAGE (TEENs of Attica: Genes and Environment) study.

  The TEENAGE study is a cross-sectional study comprising healthy Greek adolescents. The study was conducted according to the guidelines specified in the Declaration of Helsinki and all procedures involving human subjects were approved by the Institutional Review Board of Harokopio University and the Greek Ministry of Education, Lifelong Learning and Religious Affairs. The TEENAGE study target population comprised adolescent students aged 13 to 15 years attending the first three classes of public secondary schools located in the wider Athens area of Attica. The regions across Attica from which students were recruited were physically similar and all urban in nature. Sampling of regions and schools selected to participate was random. Students were enrolled from the wider urban region to ensure that they were coming from families with varying educational background and socio-economic status. Moreover, in order to exclude any vast economic disparities, all participating schools were exclusively public schools, which are free of charge. A total of twenty-four schools participated in the study out of 285 junior secondary public schools in Attica. Anthropometric, medical and dietary information was obtained. DNA samples were genotyped using Illumina HumanOmniExpress BeadChips (Illumina, San Diego, CA, USA) at the Wellcome Trust Sanger Institute, Hinxton, UK. Genotype calling algorithm used was Illuminus (Teo et al., 2007).

  Study EGAS00001000996

• Insular Celtic population structure and genomic footprints of migration

  Previous studies of the genetic landscape of Ireland have suggested homogeneity, with population substructure undetectable using single-marker methods. Here we have harnessed the haplotype-based method fineSTRUCTURE in an Irish genome-wide SNP dataset, identifying 23 discrete genetic clusters which segregate with geographical provenance. Cluster diversity is pronounced in the west of Ireland but reduced in the east where older structure has been eroded by historical migrations. Accordingly, when populations from the neighbouring island of Britain are included, a west-east cline of Celtic-British ancestry is revealed along with a particularly striking correlation between haplotypes and geography across both islands. A strong relationship is revealed between subsets of Northern Irish and Scottish populations, where discordant genetic and geographic affinities reflect major migrations in recent centuries. Additionally, Irish genetic proximity of all Scottish samples likely reflects older strata of communication across the narrowest inter-island crossing. Using GLOBETROTTER we detected Irish admixture signals from Britain and Europe and estimated dates for events consistent with the historical migrations of the Norse-Vikings, the Anglo-Normans and the British Plantations. The influence of the former is greater than previously estimated from Y chromosome haplotypes. In all, we paint a new picture of the genetic landscape of Ireland, revealing structure which should be considered in the design of studies examining rare genetic variation and its association with traits.

  Study EGAS00001002769

• Transcriptomic analysis of Acute Myeloid Leukemia stem cells

  Acute Myeloid Leukemia (AML) is characterized by the accumulation of clonal myeloid blast cells unable to differentiate into mature leukocytes. Chemotherapy induces remission in the majority of patients, but relapse rates are high and lead to poor clinical outcomes. Since this is primarily caused by chemotherapy-resistant leukemic stem cells (LSCs), it is essential to eradicate LSCs to improve patient survival. LSCs have predominantly been studied at the transcript level, thus lacking information about post-transcriptionally regulated genes and associated networks. Here we extend our previous report on LSC proteomes to healthy age-matched hematopoietic stem and progenitor cells (HSPCs) and correlate the proteomes to the corresponding transcriptomes. By comparing LSCs to leukemic blasts and healthy HSPCs, we validate candidate LSC markers and highlight novel and potentially targetable proteins that are absent or only lowly expressed in HSPCs. In addition, our data provides strong evidence that LSCs harbor a characteristic energy metabolism, adhesion molecule composition, as well as RNA processing properties. Furthermore, correlating proteome and transcript data of the same individual samples highlights the strength of proteome analyses, which are particularly potent in detecting alterations in metabolic pathways. In summary, our study provides a comprehensive proteomic and transcriptomic characterization of functionally validated LSCs, blasts and healthy HSPCs, representing a valuable resource helping to design LSC-directed therapies.

  Study EGAS00001004402

• scRNA-seq of HGSC tumor and ascites

  Immune regulatory metabolites are key features of the tumor microenvironment (TME), yet with a few notable exceptions, their identities remain largely unknown. We uncovered the immune regulatory metabolic states and metabolomes of sorted tumor and stromal, CD4+, and CD8+ cells from the tumor and ascites of patients with high-grade serous ovarian cancer (HGSC) using high-dimensional flow cytometry and metabolomics supplemented with single cell RNA sequencing. Flow cytometry revealed that tumor cells show a consistently greater uptake of glucose than T cells, but similar mitochondrial activity. Cells within the ascites and tumor had pervasive metabolite differences, with a striking enrichment in 1-methylnicotinamide (MNA) in T cells infiltrating the tumor compared to ascites. Despite the elevated levels of MNA in T cells, the expression of nicotinamide N-methyltransferase, the gene encoding the enzyme that catalyses the transfer of a methyl group from S-adenosylmethionine to nicotinamide, was restricted to fibroblasts and tumor cells. Treatment of T cells with MNA resulted in an increase in T cell-mediated secretion of the tumor promoting cytokine tumor necrosis factor alpha. Thus, the TME-derived metabolite MNA contributes to an alternative and non-cell autonomous mechanism of immune modulation of T cells in HGSC. Collectively, uncovering the tumor-T cell metabolome may reveal metabolic vulnerabilities that can be exploited using T cell-based immunotherapies to treat human cancer.

  Study EGAS00001004829

• Bulk-tissue RNA-sequencing paired nuclear and cytoplasmic fractions of anterior prefrontal cortex, cerebellar cortex and putamen tissues from post-mortem neuropathologically-confirmed control individuals.

  Gaining insight into the genetic regulation of gene expression in human brain is key to the interpretation of genome-wide association studies for major neurological and neuropsychiatric diseases. Expression quantitative trait loci (eQTL) analyses have largely been used to achieve this, providing valuable insights into the genetic regulation of steady-state RNA in human brain, but not distinguishing between molecular processes regulating transcription and stability. RNA quantification within cellular fractions can disentangle these processes in cell types and tissues which are challenging to model in vitro. We investigated the underlying molecular processes driving the genetic regulation of gene expression specific to a cellular fraction using allele-specific expression (ASE). Applying ASE analysis to genomic and transcriptomic data from paired nuclear and cytoplasmic fractions of anterior prefrontal cortex, cerebellar cortex and putamen tissues from 4 post-mortem neuropathologically-confirmed control human brains, we demonstrate that a significant proportion of genetic regulation of gene expression occurs post-transcriptionally in the cytoplasm, with genes undergoing this form of regulation more likely to be synaptic. These findings have implications for understanding the structure of gene expression regulation in human brain, and importantly the interpretation of rapidly growing single-nucleus brain RNA-sequencing and eQTL datasets, where cytoplasm-specific regulatory events could be missed.

  Study EGAS00001006380

• Type 2 Diabetes Genetic Exploration by Next-Generation Sequencing in Multi-Ethnic Samples (T2D-GENES) Project 1: KARE

  T2D-GENES (Type 2 Diabetes Genetic Exploration by Next-Generation Sequencing in Multi-Ethnic Samples) is a NIDDK-funded international research consortium which seeks to identify genetic variants for type 2 diabetes (T2D) through multiethnic sequencing studies. T2D-GENES Project 1 is a multi-ethnic sequencing study designed to assess whether less common variants play a role in T2D risk and to assess similarities and differences in the distribution of T2D risk variants across ancestry groups. The individuals were obtained from 14 cohorts that are listed in Table 1. The strategy was to perform deep exome sequencing of 12,940 individuals, 6,504 with T2D and 6,436 controls, divided among five ancestry groups: Europeans, East Asians, South Asians, American Hispanics, and African Americans. Sequencing was performed at the Broad Institute using the Agilent v2 capture reagent on Illumina HiSeq machines. Please note that while we summarize the full sample list in publications and below, the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) study does not have a sub study, as it is not consented to be deposited in dbGAP. Table 1. T2D-GENES Whole Exome Sequencing Studies Ancestry Study Countries of Origin # Cases # Controls African American Jackson Heart Study US 502 527 African American Wake Forest School of Medicine Study US 518 532 East Asian Korea Association Research Project Korea 526 561 East Asian Singapore Diabetes Cohort Study; Singapore Prospective Study Program Singapore (Chinese) 486 592 European Ashkenazi US, Israel 506 352 European Metabolic Syndrome in Men Study (METSIM) Finland 484 498 European Finland-United States Investigation of NIDDM Genetics (FUSION) Study Finland 472 476 European Kooperative Gesundheitsforschung in der Region Augsburg (KORA) Germany 97 90 European UK Type 2 Diabetes Genetics Consortium (UKT2D) UK 322 320 European Malmö-Botnia Study Finland, Sweden 478 443 Hispanic San Antonio Family Heart Study, San Antonio Family Diabetes/ Gallbladder Study, Veterans Administration Genetic Epidemiology Study, and the Investigation of Nephropathy and Diabetes Study Family Component US 272 219 Hispanic Starr County, Texas US 749 704 South Asian London Life Sciences Population Study (LOLIPOP) UK (Indian Asian) 530 538 South Asian Singapore Indian Eye Study Singapore (Indian Asian) 563 585 The Korea Association Research Project (KARE) studies contributed 526 cases and 561 controls to T2D-GENES Project 1.

  Study phs001096

• Genomics of Opioid Pharmacogenomics and Acute/Chronic Postsurgical Pain after Major Surgery in Children

  Pain management after surgery is not optimal, partly due to great interindividual variability in pain perception and coping. This can lead to persistent pain beyond the healing period and disability. Up to two-thirds of the inter-individual variability results from genetic variations in pain perception as well as response to the pain medicine. The investigators aim to identify genomic (genetic/epigenetic), psychological and drug profiles contributing to this variability. Opioids are the mainstay for treatment of postoperative pain in children. Experience dictates that opioids have narrow therapeutic indices and large inter-patient variability in response. This leads to serious side effects like respiratory depression in up to 50% of children undergoing invasive surgery, which can be fatal. It is evident that there are particular children who are more susceptible to suffering side effects and having inadequate pain relief from opioids.It is hypothesized that much of the genetic variability can be explained by gene function which is modulated by a) Single Nucleotide Polymorphisms (SNPs) in genes that encode proteins involved in pain perception, opioid transport/metabolism (pharmacokinetics), and opioid receptor signaling (pharmacodynamics); b) epigenetics which modify gene expression without structural changes to the DNA, and c) genes that influence psychological factors.The purpose of this research study is to identify factors and genes that may be associated with acute and chronic post-surgical pain, and to develop pharmacometric models for response to opioids, like morphine and hydromorphone. While children undergoing different surgeries will be recruited for acute outcomes, children undergoing spine fusion will be followed for 10-12 months for evaluation of psychological and genomic factors affecting chronic post-surgical pain, with a goal of identifying genetic and epigenetic risk models for prediction of acute and chronic post-surgical pain. Although opioids are used every day, some children have bad reactions from their use, like breathing problems, sedation, etc. The investigators want to study factors that may be associated with pain sensitivity, opioid requirements after surgery, their metabolism, efficacy and their side-effects. The investigators expect that the information obtained in this research study will help to develop effective, safer, and tailored treatment options in the future.

  Study phs002105

• Type 2 Diabetes Genetic Exploration by Next-Generation Sequencing in Multi-Ethnic Samples (T2D-GENES) Project 1: Ashkenazi

  T2D-GENES (Type 2 Diabetes Genetic Exploration by Next-Generation Sequencing in Multi-Ethnic Samples) is a NIDDK-funded international research consortium which seeks to identify genetic variants for type 2 diabetes (T2D) through multiethnic sequencing studies. T2D-GENES Project 1 is a multi-ethnic sequencing study designed to assess whether less common variants play a role in T2D risk and to assess similarities and differences in the distribution of T2D risk variants across ancestry groups. The individuals were obtained from 14 cohorts that are listed in Table 1. The strategy was to perform deep exome sequencing of 12,940 individuals, 6,504 with T2D and 6,436 controls, divided among five ancestry groups: Europeans, East Asians, South Asians, American Hispanics, and African Americans. Sequencing was performed at the Broad Institute using the Agilent v2 capture reagent on Illumina HiSeq machines. Please note that while we summarize the full sample list in publications and below, the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) study does not have a sub study, as it is not consented to be deposited in dbGAP. Table 1. T2D-GENES Whole Exome Sequencing Studies Ancestry Study Countries of Origin # Cases # Controls African American Jackson Heart Study US 502 527 African American Wake Forest School of Medicine Study US 518 532 East Asian Korea Association Research Project Korea 526 561 East Asian Singapore Diabetes Cohort Study; Singapore Prospective Study Program Singapore (Chinese) 486 592 European Ashkenazi US, Israel 506 352 European Metabolic Syndrome in Men Study (METSIM) Finland 484 498 European Finland-United States Investigation of NIDDM Genetics (FUSION) Study Finland 472 476 European Kooperative Gesundheitsforschung in der Region Augsburg (KORA) Germany 97 90 European UK Type 2 Diabetes Genetics Consortium (UKT2D) UK 322 320 European Malmö-Botnia Study Finland, Sweden 478 443 Hispanic San Antonio Family Heart Study, San Antonio Family Diabetes/ Gallbladder Study, Veterans Administration Genetic Epidemiology Study, and the Investigation of Nephropathy and Diabetes Study Family Component US 272 219 Hispanic Starr County, Texas US 749 704 South Asian London Life Sciences Population Study (LOLIPOP) UK (Indian Asian) 530 538 South Asian Singapore Indian Eye Study Singapore (Indian Asian) 563 585 The Ashkenazi study contributed 506 cases and 352 controls to T2D-GENES Project 1.

  Study phs001095

• Coronary Artery Risk Development in Young Adults (CARDIA) Study - Cohort

  CARDIA is a study examining the etiology and natural history of cardiovascular disease beginning in young adulthood. In 1985-1986, a cohort of 5115 healthy black and white men and women aged 18-30 years were selected to have approximately the same number of people in subgroups of age (18-24 and 25-30), sex, race, and education (high school or less and more than high school) within each of four US Field Centers. These same participants were asked to participate in follow-up examinations during 1987-1988 (Year 2), 1990-1991 (Year 5), 1992-1993 (Year 7), 1995-1996 (Year 10), 2000-2001 (Year 15), 2005-2006 (Year 20), and 2010-2011 (Year 25); the proportions of the surviving cohort that have returned for the seven follow-up examinations were 90%, 86%, 81%, 79%, 74%, 72%, and 72%, respectively. In addition to the follow-up examinations, participants are contacted regularly for the ascertainment of information on out-patient procedures and hospitalizations experienced between contacts. Within the past five years, 95% of the original surviving cohort has been contacted. While the specifics of each examination has differed somewhat, data have been collected on a variety of factors believed to be related to heart disease. These include conditions with clear links to heart disease such as blood pressure, cholesterol and other lipids. Data have also been collected on physical measurements such as weight and skinfold fat as well as lifestyle factors such as substance use (tobacco and alcohol), dietary and exercise patterns, behavioral and psychological variables, medical and family history, and other chemistries (e.g., insulin and glucose). In addition, subclinical atherosclerosis was measured via echocardiography during Years 5, 10, and 25, computed tomography during Years 15 and 20, and carotid ultrasound during Year 20. The CARDIA Cohort is utilized in the following dbGaP sub-studies. To view genotypes, other molecular data, and derived variables collected in these sub-studies, please click on the following sub-studies below or in the "Sub-studies" box located on the right hand side of this top-level study page phs000285 CARDIA Cohort. phs000236 PAGE_CALiCo_CARDIA phs000309 GENEVA_CARDIA phs000399 GO-ESP HeartGO_CARDIA phs000613 CARDIA_CARe

  Study phs000285

• Type 2 Diabetes Genetic Exploration by Next-Generation Sequencing in Multi-Ethnic Samples (T2D-GENES) Project 1: Singapore

  T2D-GENES (Type 2 Diabetes Genetic Exploration by Next-Generation Sequencing in Multi-Ethnic Samples) is a NIDDK-funded international research consortium which seeks to identify genetic variants for type 2 diabetes (T2D) through multiethnic sequencing studies. T2D-GENES Project 1 is a multi-ethnic sequencing study designed to assess whether less common variants play a role in T2D risk and to assess similarities and differences in the distribution of T2D risk variants across ancestry groups. The individuals were obtained from 14 cohorts that are listed in Table 1. The strategy was to perform deep exome sequencing of 12,940 individuals, 6,504 with T2D and 6,436 controls, divided among five ancestry groups: Europeans, East Asians, South Asians, American Hispanics, and African Americans. Sequencing was performed at the Broad Institute using the Agilent v2 capture reagent on Illumina HiSeq machines. Please note that while we summarize the full sample list in publications and below, the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) study does not have a sub study, as it is not consented to be deposited in dbGAP. Table 1. T2D-GENES Whole Exome Sequencing Studies Ancestry Study Countries of Origin # Cases # Controls African American Jackson Heart Study US 502 527 African American Wake Forest School of Medicine Study US 518 532 East Asian Korea Association Research Project Korea 526 561 East Asian Singapore Diabetes Cohort Study; Singapore Prospective Study Program Singapore (Chinese) 486 592 European Ashkenazi US, Israel 506 352 European Metabolic Syndrome in Men Study (METSIM) Finland 484 498 European Finland-United States Investigation of NIDDM Genetics (FUSION) Study Finland 472 476 European Kooperative Gesundheitsforschung in der Region Augsburg (KORA) Germany 97 90 European UK Type 2 Diabetes Genetics Consortium (UKT2D) UK 322 320 European Malmö-Botnia Study Finland, Sweden 478 443 Hispanic San Antonio Family Heart Study, San Antonio Family Diabetes/ Gallbladder Study, Veterans Administration Genetic Epidemiology Study, and the Investigation of Nephropathy and Diabetes Study Family Component US 272 219 Hispanic Starr County, Texas US 749 704 South Asian London Life Sciences Population Study (LOLIPOP) UK (Indian Asian) 530 538 South Asian Singapore Indian Eye Study Singapore (Indian Asian) 563 585 The Singapore studies contributed 1049 cases and 1177 controls to T2D-GENES Project 1.

  Study phs001097

• Type 2 Diabetes Genetic Exploration by Next-generation Sequencing in Multi-Ethnic Samples (T2D-GENES) Project 1: London Life Sciences Population Study (LOLIPOP) UK South Asian

  T2D-GENES (Type 2 Diabetes Genetic Exploration by Next-Generation Sequencing in Multi-Ethnic Samples) is a NIDDK-funded international research consortium which seeks to identify genetic variants for type 2 diabetes (T2D) through multiethnic sequencing studies. T2D-GENES Project 1 is a multi-ethnic sequencing study designed to assess whether less common variants play a role in T2D risk and to assess similarities and differences in the distribution of T2D risk variants across ancestry groups. The individuals were obtained from 14 cohorts that are listed in Table 1. The strategy was to perform deep exome sequencing of 12,940 individuals, 6,504 with T2D and 6,436 controls, divided among five ancestry groups: Europeans, East Asians, South Asians, American Hispanics, and African Americans. Sequencing was performed at the Broad Institute using the Agilent v2 capture reagent on Illumina HiSeq machines. Please note that while we summarize the full sample list in publications and below, the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) study does not have a sub study, as it is not consented to be deposited in dbGAP. Table 1. T2D-GENES Whole Exome Sequencing Studies Ancestry Study Countries of Origin # Cases # Controls African American Jackson Heart Study US 502 527 African American Wake Forest School of Medicine Study US 518 532 East Asian Korea Association Research Project Korea 526 561 East Asian Singapore Diabetes Cohort Study; Singapore Prospective Study Program Singapore (Chinese) 486 592 European Ashkenazi US, Israel 506 352 European Metabolic Syndrome in Men Study (METSIM) Finland 484 498 European Finland-United States Investigation of NIDDM Genetics (FUSION) Study Finland 472 476 European Kooperative Gesundheitsforschung in der Region Augsburg (KORA) Germany 97 90 European UK Type 2 Diabetes Genetics Consortium (UKT2D) UK 322 320 European Malmö-Botnia Study Finland, Sweden 478 443 Hispanic San Antonio Family Heart Study, San Antonio Family Diabetes/ Gallbladder Study, Veterans Administration Genetic Epidemiology Study, and the Investigation of Nephropathy and Diabetes Study Family Component US 272 219 Hispanic Starr County, Texas US 749 704 South Asian London Life Sciences Population Study (LOLIPOP) UK (Indian Asian) 530 538 South Asian Singapore Indian Eye Study Singapore (Indian Asian) 563 585 The London Life Sciences Population Study (LOLIPOP) contributed 530 cases and 538 controls to T2D-GENES Project 1.

  Study phs001093

• Discrepancies in Tumour Mutation Burden (TMB) reporting from sequential Endobronchial ultrasound trans bronchial needle aspiration (EBUS TBNA) samples within single lymph node stations

  Introduction: Tumour Mutation Burden (TMB) is a potential biomarker for immune therapies. Identifying factors that may affect TMB prediction is key to its utility as biomarker for treatment options. Here we investigated parameters that might affect TMB using cytology smears obtained from endobronchial ultrasound transbronchial needle aspiration (EBUS TBNA)-sampled malignant lymph nodes, which are often the only diagnostic samples collected in patients with advanced lung cancer. Methods: Individual Diff-Quik cytology smears were prepared for each needle pass from the same enlarged malignant mediastinal lymph nodes. DNA extracted from smears of each pass underwent sequencing using a large gene panel sequencing (TSO500, Illumina). TMB was estimated for each individual needle pass using the TSO500 Local App v. 2.0 (Illumina). Results: Twenty patients had two or more Diff-Quik smears (total 45 smears) which passed sequencing quality control. Average TMB for all smears was 8.7 ± 5.0 mutations per megabase (Mb). Sixteen of the 20 patients had paired samples with minimal differences in TMB score (average difference 1.3 ± 0.85). Paired samples from 13 patients had concordant TMB in terms of scores being below or above a threshold of 10 mutations/Mb. Samples from seven patients had discrepant TMB, with four cases in particular exhibiting an average difference of 11.3 ± 2.7 mutations/Mb. Factors affecting TMB calling involved tumour content of the samples, the amount of DNA used in sequencing as well as bone fide intra tumour heterogeneity between paired samples. Conclusions: TMB assessment is feasible from EBUS-TBNA derived Diff-Quik slides from a single needle pass. Repeated samples of one or more lymph nodes have minimal variation in TMB in most cases (80%), suggesting accuracy of the test overall. To enhance accuracy of the result, care should be taken in relation to the tumour content of the cytology smear. Further, clinicians should be aware that even slight differences in lymph node site selection could give rise to variable genomics and discrepant TMB due to tumour heterogeneity. Therefore, it would be reasonable for multi-lymph node site analysis of TMB to be performed using EBUS TBNA aspirates from different easily accessible lymph nodes. Further investigations need to determine whether these samples should be combined as one sample or tested separately.

  Study EGAS00001007484

• Prevention and Early Treatment of Acute Lung Injury (PETAL) Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) (PETAL CLOVERS-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. Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from PETAL CLOVERS include plasma, and whole blood. Please note that use of biospecimens in genetic research is subject to a tiered consent. Available Data: The data available for request now include Long Term Outcome data.Objectives: To compare the effects of a restrictive fluid strategy (with early use of vasopressors) to a liberal fluid strategy in participants with sepsis-induced hypotension.Background: Intravenous fluid resuscitation is a common therapy used in the initial treatment of participants with septic shock and sepsis-induced hypotension. The goal of initial fluid therapy is to increase depleted or functionally reduced intravascular volume that occurs in sepsis due to a vasodilated vascular network. However, intravenous fluid resuscitation can create dilutional coagulopathy, fluid overload, and pathogenic edema in the lungs and other organs. Vasopressor agents are also commonly used to treat hypoperfusion by inducing constriction of arterioles and venules and increasing cardiac contractility. Vasopressor therapy also comes with risks that include vasoconstriction resulting in tissue ischemia, increased cardiac workload, and arrhythmias. Clinicians have used these strategies, typically in combination, to provide supportive care for participants with sepsis-induced hypoperfusion. However, at the time of the CLOVERS study, there was limited data to guide specific use of these therapies, including fluid volumes, in the early care of participants with sepsis-induced hypotension. The CLOVERS study hypothesized that a restrictive fluid strategy used during the first 24-hours of resuscitation for sepsis-induced hypotension would lead to lower mortality before discharge home by day 90 than a liberal fluid strategy.Participants: A total of 1,563 participants, from 60 medical centers, of the planned 2,230 participants were enrolled, with 782 assigned to the restrictive fluid group and 781 to the liberal fluid group. Enrollment in the trial was ended after the second interim analysis due to a lack of significant difference observed between the two 24-hour strategies.Design: This study was a multi-center, prospective, phase 3 randomized non-blinded interventional trial of fluid treatment strategies in the first 24 hours for participants with sepsis-induced hypotension. Participants were randomly assigned in a 1:1 ratio to either a restrictive fluid strategy (with early vasopressor use) or a liberal fluid strategy. In each group, the assigned protocol was followed for a period of 24 hours. The restrictive fluid protocol prioritized vasopressors as the primary treatment for sepsis-induced hypotension, with 'rescue fluids' being permitted for prespecified indications that suggested severe intravascular volume depletion. The liberal fluid protocol consisted of a recommended initial 2000-ml intravenous infusion of isotonic crystalloid, followed by fluid boluses administered on the basis of clinical triggers (e.g., tachycardia) with 'rescue vasopressors' permitted for prespecified indications. A protocol amendment implemented in October, 2019, allowed for limiting the initial infusion to 1,000 ml if the participant's blood pressure and heart rate had stabilized and the clinical assessment was that the participant was unlikely to benefit from additional intravenous fluid administration. The clinical team could override the protocol-specified care instructions at any time if it was judged to be in the best interest of the participant.The primary outcome was death from any cause before discharge home by day 90. Secondary outcomes included 28-day measures of the number of days free from ventilator use, days free from renal-replacement therapy, days free from vasopressor use, days out of the ICU, and days out of the hospital. Conclusions: Among participants with sepsis-induced hypotension, the restrictive fluid strategy that was used in this trial did not result in significantly lower (or higher) mortality, or other measures of recovery such as length of hospital stay, before discharge home by day 90 than the liberal fluid strategy.

  Study phs004080

• Studies of Left Ventricular Dysfunction (SOLVD-BioLINCC)

  Data Access NOTE:Please refer to the "Authorized Access" section below for information about how access to the data from this accession. Access differs from many other dbGaP accessions. ObjectivesThis study was initiated in 1986, primarily to evaluate the effects of enalapril, an ACE inhibitor, on long-term mortality and major morbidity in a group of participants with left ventricular dysfunction. Two large separate trials were run concurrently as part of SOLVD: 1) a prevention trial of participants with low ejection fraction but no overt symptoms of CHF and, 2) a treatment trial of participants with low ejection fraction and symptoms of CHF. In addition, participants at selected sites were entered into substudies to evaluate the effect of enalapril on a number of intermediate outcomes such as right and left ventricular function and hemodynamics, LV mass and wall stress, hormones, arrhythmias, exercise capacity, and quality of life in subsets of participants. Lastly, a registry of 6,336 participants with congestive heart failure of LV dysfunction was designed to describe the clinical course of an unselected group of participants. Background Congestive Heart Failure (CHF) is a major and increasingly recognized public health problem. The recognition that participants with CHF often have elevated peripheral vascular resistance has led to the introduction of vasodilator therapy, which has emerged as an important component of its treatment. Of the vasodilators, the angiotensin-converting enzyme (ACE) inhibitors appeared to be the most promising. In 1985, little was known about the impact of any long-term drug treatment on survival. SOLVD Registry: The SOLVD Registry is a hospital-based observational study, conducted at selected SOLVD hospitals, of participants with at least moderate left-ventricular dysfunction (EF ≤ 45%) and/or radiologically confirmed heart failure. It consists of a main study (n=6,273) and a substudy (n=898). Although there is overlap between the Registry and the SOLVD trials, the Registry sample is not a subset of SOLVD nor is it the pool of participants eligible for both trials. Participants A total of 2,569 participants were enrolled into the treatment study and 4,228 participants were enrolled in the prevention study. The dataset available through the NHLBI contains the prevention and treatment study data as well as the registry data. Conclusions In the prevention trial, a significant reduction in the incidence of heart failure and the rate of related hospitalizations was observed for participants in the enalapril arm. A statistically significant reduction in mortality was not observed in the enalapril treatment arm; however, there was a trend toward fewer total deaths and deaths due to cardiovascular causes among the enalapril participants (SOLVD Investigators, et al., 1992, PMID: 1463530).

  Study phs003668

• Clonally heritable gene expression imparts a layer of diversity within cell types

  Cell types can be classified according to shared patterns of transcription. Non-genetic variability among individual cells of the same type has been ascribed to stochastic transcriptional bursting and transient cell states. Using high coverage single cell RNA profiling, we asked whether long-term, heritable differences in gene expression can impart diversity within cells of the same type. Studying clonal human lymphocytes and mouse brain cells, we uncovered a vast diversity of heritable gene expression patterns among different clones of cells of the same type in vivo. We combined chromatin accessibility and RNA profiling on different lymphocyte clones to reveal thousands of regulatory regions exhibiting interclonal variation which could be directly linked to interclonal variation in gene expression. Our findings identify a source of cellular diversity, which may have important implications for how cellular populations are shaped by selective processes in development, aging and disease.

  Study EGAS50000000161

• ARST17B2-Q Germline and Somatic Genetic Landscape of Pediatric Rhabdomyosarcoma

  Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. While these malignancies display aberrant myogenic differentiation, relatively little is known about genetic susceptibility to RMS, or how genetic variants influence subsequent somatic events and may be used in risk stratification strategies. A small percentage of cases are associated with mutations in TP53 (Li-Fraumeni syndrome), HRAS (Costello syndrome), and PTCH1 (nevoid basal cell carcinoma syndrome/Gorlin syndrome), suggesting the genetic origins of childhood RMS. In spite of this, little work has been done to characterize genetic susceptibility to this malignancy. We plan to leverage samples collected as part of D9902 to conduct one of the largest germline genomic studies of RMS. We anticipate that once genetic associations are identified, researchers can use the information to develop better strategies to detect, treat, and prevent childhood RMS.

  Study phs003192

• Genotyping NIGMS Chromosomal Aberration and Inherited Disorder Samples

  As part of an effort to correlate molecular copy number variation determinations with state of the art karyotype analyses, 716 samples derived from 697 individuals from the Chromosomal Aberrations and Inherited Disorders collections of the NIGMS Human Genetic Cell Repository were genotyped and analyzed for CNV determination by the Microarray Center at the Coriell Institute for Medical Research. Karyotyping is performed on all cell cultures in the Repository with reported chromosome abnormalities. The samples chosen for genotyping in this study are intended to represent a diverse set of copy number variants, but the selection was also weighted to over-sample commonly manifested types of aberrations. When available, the ISCN description of the sample based on G-banding and FISH analysis is included in the phenotypic data. Karyotypes for these cells can be viewed in the online Repository catalog (http://ccr.coriell.org/Sections/Collections/NIGMS/?SsId=8).

  Study phs000269