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• Same-day genomic and epigenomic diagnosis of brain tumors using realtime nanopore sequencing

  Molecular classification of cancer has entered clinical routine to inform diagnosis, prognosis and treatment decisions. At the same time, new tumor entities have been identified that cannot be defined histologically. For central nervous systems tumors, the current World Health Organization classification explicitly demands molecular testing, e.g. for 1p/19q- codeletion or IDH mutations, to make an integrated histomolecular diagnosis. However, a plethora of sophisticated technologies is currently needed to assess different genomic and epigenomic alterations and turnaround times are in the range of weeks, which makes standardized and widespread implementation difficult and hinders timely decision making. Here, we explored the potential of a pocket-size nanopore sequencing device for multimodal and rapid molecular diagnostics of cancer. Low-pass whole genome sequencing was used to simultaneously generate copy number (CN) and methylation profiles from native tumor DNA in the same sequencing run. Single nucleotide variants in IDH1, IDH2, TP53, H3F3A and the TERT promoter region were identified using deep amplicon sequencing. Nanopore sequencing yielded ~0.1X genome coverage within six hours and resulting CN and epigenetic profiles correlated well with matched microarray data. Diagnostically relevant alterations, such as 1p/19q codeletion, and focal amplifications could be recapitulated. Using ad hoc random forests, we could perform supervised pan-cancer classification to distinguish gliomas, medulloblastomas and brain metastases of different primary sites. Single nucleotide variants in IDH1, IDH2 and H3F3A were identified using deep amplicon sequencing within minutes of sequencing. Detection of TP53 and TERT promoter mutations shows that sequencing of entire genes and GC-rich regions is feasible. Nanopore sequencing allows same-day detection of structural variants, point mutations and methylation profiling using a single device with negligible capital cost. It outperforms hybridization-based and current sequencing technologies with respect to time-to diagnosis and required laboratory equipment and expertise, aiming to make precision medicine possible for every cancer patient, even in resource restricted settings.

  Study EGAS00001002213

• Platelet_collagen_defect

  As part of the Bloodomics collaboration we have several categories of pedigrees with diseases/syndromes relevant to cardiovascular diseases (CVD). One such pedigree, is from families who have a platelet collagen defect. Exome sequencing has been performed as part of a discovery program to ascertain potential causative variants of the clinical phenotype.

  Study EGAS00001000105

• Progression to AML is predictable and distinct from age related clonal hematopoiesis

  To examine the occurrence of somatic mutations prior to the development of acute myeloid leukemia, we undertook deep ECS (estimated limit of detection 1 mutation in 2500 cells) of 261 AML associated genes in 96 pre-AML cases and 420 age and gender-matched healthy controls of an average of 3853 unique DNA molecules covering each of the 1.19M bases spanning the target gene panel. The findings suggest that the development of clonal hematopoiesis and accumulation of somatic mutations is distinct and accelerated in pre-AML cases compared to healthy individuals

  Study EGAS00001002570

• Persistent Mutation Burden Drives Sustained Anti-Tumor Immune Responses

  Tumor mutation burden is an imperfect proxy of tumor foreignness and has therefore failed to consistently demonstrate clinical utility in predicting responses in the context of immunotherapy. We evaluated mutations in regions of the genome that are unlikely to undergo loss and discovered that clonal mutations in single-copy regions and those present in multiple copies per cell constitute a persistent tumor mutation burden (pTMB) that is linked with therapeutic response to immune checkpoint blockade. Persistent mutations were retained in the context of tumor evolution under selective pressure of immunotherapy and tumors with a high pTMB content were characterized by a more inflamed tumor microenvironment. pTMB imposes an evolutionary bottleneck that cancer cells cannot overcome and may thus drive sustained immunologic tumor control in the context of immunotherapy.

  Study EGAS00001006660

• Hydroxyurea to Prevent Organ Damage in Children with Sickle Cell Anemia (BABY HUG) Phase III Clinical Trial and Follow-Up Observational Studies I and II

  Sickle cell anemia is associated with substantial morbidity from acute complications and organ dysfunction beginning in the first year of life. In 1995, the Multicenter Study of Hydroxyurea (MSH) (dbGaP phs002348) demonstrated that, in adults, hydroxyurea is effective in decreasing the frequency of painful crises, hospitalizations for crises, acute chest syndrome, and blood transfusions by 50%. The phase I/II study of hydroxyurea in children (HUG KIDS) demonstrated that children have a response to hydroxyurea similar to that seen in adults in terms of increasing fetal hemoglobin levels and total hemoglobin, and decreasing complications associated with sickle cell anemia. In addition, this study demonstrated that the drug does not adversely affect growth and development between the ages of 5 and 15. A pilot study of hydroxyurea (HUSOFT) given to children between the ages of 6 months and 24 months demonstrated that the drug was well tolerated and that the fetal hemoglobin levels rose and remained elevated compared to baseline with continued hydroxyurea administration. A Special Emphasis Panel (SEP) met on April 12, 1996 to review the results of the MSH trial and the progress to date of the HUG KIDS study. The SEP recommended that NHLBI undertake the BABY HUG trial. The BABY HUG Randomized Controlled Trial concluded that hydroxyurea treatment in very young children seemed to have an acceptable safety profile and to reduce complications of sickle cell anemia. However, more data were needed on the long-term safety of hydroxyurea use in very young children. As a result, follow-up studies were initiated. The Follow-Up Study II provided longer follow-up than Follow-Up Study I, and included more assessment types than Follow-Up Study I.The BABY HUG program consisted of three related studies, each of which has associated datasets and bio-specimens. A randomized controlled trial comparing hydroxyurea to placebo in very young children with sickle cell anemia (BABY HUG Randomized Controlled Trial) The first observational follow-up study of children from the randomized controlled trial (BABY HUG Follow-Up Study I). All children in Follow-Up Study I were offered the option of taking open-label hydroxyurea, with treatment decisions made by the family and the clinical team caring for the child. The second observational follow-up study of children from BABY HUG Follow-Up Study I. All children in Follow-Up Study II were offered the option of taking open-label hydroxyurea, with treatment decisions made by the family and the clinical team caring for the child.The purpose of the Randomized Controlled Trial was to determine if hydroxyurea can safely prevent early end organ damage in very young children with sickle cell anemia. The purpose of the BABY HUG Follow-up Study I was to provide structured follow-up of the children enrolled in the BABY HUG Randomized Controlled Trial, in order to characterize the long-term toxicities and unexpected risks (if any) associated with treatment with hydroxyurea at an early age. The objective of Follow-Up Study II was to obtain additional data about the long-term safety and efficacy of hydroxyurea use in children with Sickle Cell Anemia through at least the first decade of life.Instructions for requesting individual-level data are available on BioData Catalyst at https://biodatacatalyst.nhlbi.nih.gov/resources/data/. Apply for data access in dbGaP. Upon approval, users may begin accessing requested data in BioData Catalyst. For questions about availability, you may contact the BioData Catalyst team at https://biodatacatalyst.nhlbi.nih.gov/contact.

  Study phs002415

• Collaborative Cohort of Cohorts for COVID-19 Research (C4R): Mediators of Atherosclerosis in South Asians Living in America Study (MASALA)

  Cohort Description The Mediators of Atherosclerosis in South Asians Living in America (MASALA) study is a prospective cohort of South Asians that aims to identify risk factors for heart disease in a large, growing Asian American subgroup. MASALA enrolled 906 South Asians in 2010-2013 and then added a new wave of 258 South Asian participants from 2017-2018, for a full cohort size of 1,164. Data Being Submitted Wave 1 questionnaire data includes 3967 variables for up to 431 MASALA participants in C4R. Wave 2 questionnaire data includes 448 variables for up to 313 MASALA participants in C4R. Dried Blood Spot/Serosurvey data includes 7 variables for up to 248 MASALA participants in C4R. Derived data includes 43 variables for up to 528 MASALA participants in C4R. Phenotype data includes 113 variables for up to 429 MASALA participants in C4R.

  Study phs002980

• A single-cell atlas of the early COPD lung - Nanopore long-read

  Single cell atlas of the human airways from 10 patients suffering of early stage Chronic Obstructive Pulmonary Disease and 12 healthy age matched volunteers. This dataset was sequenced by 10X Genomics 3’ RNA-seq profiling. It is composed of more than 400 000 cells coming from 119 samples total. Sampling was performed by brushings and biopsies from the nose to the 6 th division of the airways. 14 samples were also sequenced using Nanopore long-read sequencing.

  Dataset EGAD50000001002

• Distinct immune cell infiltration patterns in pancreatic ductal adenocarcinoma (PDAC) exhibit divergent immune cell selection and immunosuppressive mechanisms

  Pancreatic ductal adenocarcinoma has a dismal prognosis. A comprehensive analysis of single-cell multi-omic data from matched tumour-infiltrated CD45+ cells and peripheral blood in 12 patients, and two published datasets, reveals a complex immune infiltrate. Patients have either a myeloid-enriched or adaptive-enriched tumour microenvironment. Lymphocyte enrichment is intrinsically linked with highly distinct B and T cell clonal selection, diversification, and differentiation. Using TCR data, we see the largest clonal expansions in CD8 effector memory, senescent cells, and highly activated regulatory T cells which are induced within the tumour from naïve cells. We identify pathways that potentially lead to a suppressive microenvironement, including targets of immunotherapy and checkpoints including TIGIT/PVR and SIRPA/CD47. PDAC patient tumors from the APACT clinical trial revealed that patients with myeloid enrichment had the shorter overall survival compared to those adaptive cell enrichment. We identify multiple therapeutic targets that should form the basis for rational design including boosting of B cell responses, targeting immunosuppressive macrophages, and specific Treg depletion approaches. The dataset is scRNA-seq data from PDAC patients.

  Dac EGAC50000000319

• Human CD4+ T cells regulate peripheral immune responses in rheumatoid arthritis via IGFL2

  To elucidate the role of the immunoregulatory mechanisms of human CD4+ T cells, we analyzed CD4+ T cells in PBMC, synovium and synovial fluid using single-cell RNA sequencing (scRNA-seq). We identified insulin-like growth factor (IGF) like family member 2 (IGFL2), an evolutionary novel paralogous inflammatory factor found exclusively in primates. ScRNA-seq of RA synovium showed that IGFL2 is specifically expressed by CD4+ T cells, predominantly within peripheral helper T (Tph) cells, with upregulation correlating to disease severity. IGFL2 promotes TGF-��-induced CXCL13 production in CD4+ T cells. In addition, IGFL2 activates NF-��B signaling and induces monocyte gene signatures associated with pathogenic macrophages from RA synovial tissue, including CXCL10 and CXCL9. Notably, blood IGFL2 protein levels significantly correlate with RA disease severity and effectively discriminate RA patients. These findings highlight the substantial involvement of IGFL2 in RA pathogenesis, emphasizing how human CD4+ T cells exert pleiotropic regulation of local immune responses via this novel primate-specific soluble factor.

  Study JGAS000727

• A novel subset of human CD33+ haematopoietic stem cells characterized at single-cell resolution

  Elucidation of the identity and diversity of mechanisms that sustain long-term human blood cell production remains an important challenge. Previous studies indicate that, in adult mice, this property is ultimately vested in cells uniquely identified by their ability to clonally regenerate detectable levels of mature blood cells in serially transplanted recipients. We now present a combined multi-parameter analysis of the molecular features of very primitive human cord blood cells that display different cell output activities in vitro and in vivo. These analyses identified a new, prospectively separable, but still functionally heterogeneous, subset of long-term human blood-forming cells. Single-cell measurements of their transcriptional, DNA methylation and 40-protein content and of closely related phenotypes revealed numerous subtle, but consistent differences both within and between each subset analyzed. These results suggest that multiple regulatory mechanisms underlie the functional heterogeneity exhibited by clonally tracked human blood cell precursors with long-term output abilities.

  Study EGAS00001002826

• Assessment of de novo copy number variations in Italian patients with schizophrenia.

  We investigated de novo CNVs in the whole genomic DNA of schizophrenia patients and their parents and, specifically, in putative enhancer motifs.Study participants were part of a wider multicenter study, involving an Italian cohort of schizophrenia patients recruited by members of INRP - Italian Network for Research on Psychoses.Whole genomic DNA obtained from 46 family trios of schizophrenia probands was analyzed using the Enhancer Chip, a customized array CGH developed using the Agilent SurePrint G3 8X60K format, which is able to investigate the whole genome with a 300Kb resolution, specific disease loci at a tenfold higher resolution, and that was highly enriched in probes in more than 1.250 enhancer elements selected from the Vista Enhancer Browser (PLoS One. 2012;7(12):e52264).

  Study EGAS00001002159

• Effect of 28-day administration of Urolithin A to sedentary elderly on muscle gene expression

  Urolithin A (UA) is a natural dietary, microflora derived, metabolite shown to stimulate mitophagy and improve muscle health in old animals and pre-clinical models of aging. UA was administered for 28-day in a first-in-human clinical trial to sedentary elderly subjects. Muscle biopsies were collected before the first dosing, and at the end of the 28-day period, under fasted conditions. Gene expression was measured by microarray. Gene-set enrichment analysis of the gene expression data showed that UA increased the transcription of mitochondrial related genesets. These observed effects on mitochondrial biomarkers show that UA induces a molecular signature of improved mitochondrial and cellular health following regular oral consumption in humans.

  Study EGAS00001003638

• Epigenome and transcriptome profiling of chronic lymphocytic leukemia patients

  Chronic lymphocytic leukemia (CLL) is characterized by substantial clinical heterogeneity, despite relatively few genetic alterations. To provide a basis for studying epigenome deregulation in CLL, we established genome-wide chromatin accessibility maps for 88 CLL samples from 55 patients using the ATAC-seq assay, and we also performed ChIPmentation and RNA-seq profiling for ten representative samples. Based on the resulting dataset, we devised and applied a bioinformatic method that links chromatin profiles to clinical annotations. Our analysis identified sample-specific variation on top of a shared core of CLL regulatory regions. IGHV mutation status – which distinguishes the two major subtypes of CLL – was accurately predicted by the chromatin profiles, and gene regulatory networks inferred for IGHV-mutated vs. IGHV-unmutated samples identified characteristic differences between these two disease subtypes. In summary, we discovered widespread heterogeneity in the chromatin landscape of CLL, established a community resource for studying epigenome deregulation in leukemia, and demonstrated the feasibility of chromatin accessibility mapping in cancer cohorts and clinical research.

  Study EGAS00001001821

• National Institute on Alcohol Abuse and Alcoholism (NIAAA) Postmortem Prefrontal Cortex eQTL and mQTL Study

  Mapping expression and methylation quantitative trait loci (eQTLs and mQTLs) using genome-wide genotype, transcriptome, and DNA methylome data can provide an unbiased approach to identify novel functional variants. One critical issue of the eQTL/mQTL analysis is that the role of genetic variants in regulating gene expression (or DNA methylation) can be tissue- or cell-specific. To unravel causal variants from disease-associated loci, it would be necessary to map eQTLs and mQTLs in both patients and controls. Those eQTLs and mQTLs in patients are more likely to be causal variants for the disease. Identification of disease- and tissue-specific eQTLs and mQTLs will help disentangle the role of the specific tissue in disease development as well. In the present study, we mapped eQTLs and mQTLs in postmortem prefrontal cortex of patients with alcoholism or alcohol use disorder (AUD) and matched control subjects by integrative analyses of genome-wide SNP genotype, mRNA transcriptome, and DNA methylome data. As AUD is comorbid with schizophrenia (SCZ), bipolar disorder (BIP), major depressive disorder (MDD), and attention deficit/hyperactivity disorder (ADHD), we further examined the co-localization of PFC eQTLs/mQTLs and GWAS-identified SNPs (mainly noncoding SNPs) that were associated with AUD as well as comorbid SCZ, BIP, MDD, and ADHD. Our study demonstrated the enrichment of PFC eQTLs/mQTLs in the above psychiatric disorder-associated genetic variants identified by genome-wide association studies (GWAS).

  Study phs001981

• Genomic Characterization of Metastatic Castration Resistant Prostate Cancer

  Biopsies of castration resistant prostate cancer metastases were subjected to whole genome sequencing (WGS), along with RNA-sequencing (RNA-Seq). The overarching goal of the study is to illuminate molecular mechanisms of acquired resistance to therapeutic agents, and particularly androgen signaling inhibitors, in the treatment of metastatic castration resistant prostate cancer (mCRPC).

  Study phs001648

• Screening_for_abnormal_CGI_methylation_in_primary_colorectal_tumours

  A common hallmark of neoplastic cells is abnormal acquisition of CpG island (CGI) methylation and the silencing of associated gene promoters. To determine the extent and distribution of CGI methylation in colorectal cancer, we solexa sequenced MBD affinity purified DNA prepared from five colorectal tumours and matched colon mucosa from the same individuals.

  Study EGAS00001000076

• The_life_history_of_colorectal_cancer_metastases_study_WGS_X10

  Whole genome sequencing of a series of metastasis collected from 2 patients at autopsy will be used to construct a life history of the cancer, including phylogenetic relationship between the different metastases an also whether there is evidence of convergence towards common biological processes that underpin the metastatic process but though different mutational events

  Study EGAS00001000864

• Targeted_sequencing_of_candidate_genes_in_calcific_aortic_valve_stenosis

  The objective is to identify new disease genes involved in calcific aortic valve stenosis (CAVS) by screening newly identified candidate genes. The recruitment of patients with CAVS has been achieved by l’institut du thorax (Nantes, France). DNA from the selected patients has been analysed by targeted capture (Agilent SureSelect) and massively parallel sequencing (Illumina).

  Study EGAS00001000308

• Collaborative Cohort of Cohorts for COVID-19 Research (C4R): Hispanic Community Health Study/Study of Latinos (HCHS/SOL)

  Cohort DescriptionHispanic Community Health Study/Study of Latinos (HCHS/SOL) is an ongoing population-based prospective cohort study of 16,415 community dwelling Hispanic/Latino adults aged 18-74 years at baseline, recruited from four urban field centers with large populations of Hispanics/ Latinos (Bronx, NY; Chicago, IL; Miami, FL; and San Diego, CA). The primary goals of the HCHS/SOL are to describe: (1) the prevalence and incidence of cardiovascular, pulmonary, and other major chronic conditions (2) the risk and/or protective factors associated with these conditions; and (3) the relationships between the initial sociodemographic and health profiles and future health events in the target population. Data Being Submitted Wave 1 questionnaire data includes 397 variables for up to 9817 HCHS/SOL participants in C4R. Wave 2 questionnaire data includes 448 variables for up to 7536 HCHS/SOL participants in C4R. Derived data includes 43 variables for up to 11182 HCHS/SOL participants in C4R. Phenotype data includes 113 variables for up to 11182 HCHS/SOL participants in C4R.

  Study phs002908

• RA-Map, A multi-omic survey of whole blood and subsets in early rheumatoid arthritis and vaccine study controls

  Rheumatoid arthritis (RA) is a chronic inflammatory disorder of unknown aetiology characterised by synovial inflammation with variable disease severity and drug responsiveness. To investigate the molecular heterogeneity and pathogenesis of RA, we performed a comprehensive clinical and molecular profile of 267 RA patients for up to 18 months to establish a high quality biobank of barcoded samples that included plasma, serum, peripheral blood cells, whole blood RNA, RNA from lymphocyte and monocyte subsets, genomic DNA and urine. We have performed extensive multi-omic immune phenotyping, including genomic, metabolomic, proteomic, transcriptomic and auto-antibody profiling. We anticipate that these detailed clinical and molecular data will serve as a fundamental resource for the development and application of targeted therapies for RA and reveal further insights into disease pathogenesis and therapeutic response.

  Study EGAS00001004424

• Spatiotemporal Charting of Human Esophageal Development for Epidermolysis Bullosa Cell Therapy

  Human fetal esophageal development is not well understood. We present a spatio-temporal single-cell multi-omics atlas to close such a long-standing knowledge gap. With such an atlas, we describe the cellular heterogeneity and lineage transitions of esophageal epithelium and stroma. We delineate the cellular dynamics of both epithelial and stromal populations during the establishment of esophageal tissue architecture. We identify niche paracrine signals that drive the development of the epithelium. We develop an in silico perturbation deep learning algorithm to further enlighten the in vitro derivation of esophageal basal cells (eBCs) and we use the algorithm to screen for effective and efficient signaling pathway perturbations that could guide in vitro eBC differentiation. We observe that chemically perturbing prioritized pathways yields functional eBCs. Such success sheds light on cell replacement therapy of eBC dysfunction, such as Epidermolysis Bullosa.

  Study phs003281

• Somatic mutation and selection at epidemiological scale - Sanger_NanoSeq_RandD

  Bottleneck sequencing of human tissue including neurons, cord blood, sperm 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/. As we age, many tissues become colonised by microscopic clones carrying somatic driver mutations. Some of these clones represent a first step towards cancer whereas others may contribute to ageing and other diseases. However, our understanding of the clonal landscapes of human tissues, and their impact on cancer risk, ageing and disease, remains limited due to the challenge of detecting somatic mutations present in small numbers of cells. Here, we introduce a new version of nanorate sequencing (NanoSeq), a duplex sequencing method with error rates of less than 5 per billion base pairs, which is compatible with whole-exome and targeted gene sequencing. Deep sequencing of polyclonal samples with single-molecule sensitivity enables the simultaneous detection of mutations in large numbers of clones, yielding accurate somatic mutation rates, mutational signatures and driver mutation frequencies in any tissue. Applying targeted NanoSeq to 1,042 non-invasive samples of oral epithelium and 371 samples of blood from a twin cohort, we found an unprecedentedly rich landscape of selection, with 46 genes under positive selection driving clonal expansions in the oral epithelium, over 62,000 driver mutations, and evidence of negative selection in some genes. The high number of positively selected mutations in multiple genes provides high-resolution maps of selection across coding and non-coding sites, a form of in vivo saturation mutagenesis. Multivariate regression models enable mutational epidemiology studies on how carcinogenic exposures and cancer risk factors, such as age, tobacco or alcohol, alter the acquisition and selection of somatic mutations. Accurate single-molecule sequencing has the potential to unveil the polyclonal landscape of any tissue, providing a powerful tool to study early carcinogenesis, cancer prevention and the role of somatic mutations in ageing and disease.

  Dataset EGAD00001015624

• National Cancer Institute (NCI) Study of Lung Cancer and Smoking Phenotypes in African-American Cases and Controls

  This is a two-stage case-control study designed to evaluate the association between common genetic variants and the risk of lung cancer. The stage 1 studies included 1737 cases and 3602 controls from the following studies: MD Anderson Lung Cancer Epidemiology Study, The Multiethnic Cohort Study (MEC), NCI-MD Lung Cancer-Case Control Study, Northern California Lung Cancer Study, Project CHURCH (Creating a Higher Understanding of Cancer Research δ Community Health), Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), Southern Community Cohort Study (SCCS), and the Karmanos Cancer Institute at Wayne State University (KCI/WSU). The stage 2 studies included an independent set of 866 cases and 796 controls from the following studies: The Black Women's Health Study (BWHS), The Harvard-MGH Lung Cancer Susceptibility Study (HLCS), MD Anderson Lung Cancer Epidemiology Study, MD Anderson/LBJ Hospital Biorepository, NCI-MD Lung Cancer Case-Control Study, Northern California Lung Cancer Study, Philadelphia Lung Cancer Study on Gene Environment Interactions (Plus-Gene), Southern Community Cohort Study (SCCS), and KCI/WSU.

  Study phs001210

• Metagenomics-Guided Pathogen Discovery in Travelers' Diarrhea

  Traveler's diarrhea (TD) is caused by enterotoxigenic Escherichia coli (ETEC), other pathogenic gram-negative pathogens, norovirus and some parasites. Nevertheless, standard diagnostic methods fail to identify pathogens in more than 30% of TD patients, so it is predicted that new pathogens or groups of pathogens may be causative agents of disease. A comprehensive metagenomic study of the fecal microbiomes from 23 TD patients and seven healthy travelers was performed, all of which tested negative for the known etiologic agents of TD in standard tests. Metagenomic reads were assembled and the resulting contigs were subjected to semi-manual binning to assemble independent genomes from metagenomic pools. Taxonomic and functional annotations were conducted to assist identification of putative pathogens. We extracted 560 draft genomes, 320 of which were complete enough to be enough characterized as cellular genomes and 160 of which were bacteriophage genomes. We made predictions of the etiology of disease in individual subjects based on the properties and features of the recovered cellular genomes. Three subtypes of samples were observed. First were four patients with low diversity metagenomes that were predominated by one or more pathogenic E. coli strains. Annotation allowed prediction of pathogenic type in most cases. Second, five patients were co-infected with E. coli and other members of the Enterobacteriaceae, including antibiotic resistant Enterobacter, Klebsiella, and Citrobacter. Finally, several samples contained genomes that represented dark matter. In one of these samples we identified a TM7 genome that phylogenetically clustered with a strain isolated from wastewater and carries genes encoding potential virulence factors. We also observed a very high proportion of bacteriophage reads in some samples. The relative abundance of phage was significantly higher in healthy travelers when compared to TD patients. Our results highlight that assembly-based analysis revealed that diarrhea is often polymicrobial and includes members of the Enterobacteriaceae not normally associated with TD and have implicated a new member of the TM7 phylum as a potential player in diarrheal disease.

  Study phs001352

• Age related Macular Degeneration (AMD) - Michigan, Mayo, AREDS, Pennsylvania (MMAP) Cohort Study: Association and Sequencing Studies

  Age-related Macular Degeneration (AMD) is a leading cause of incurable blindness in people over the age of 65. AMD is a late-onset multi-factorial neurodegenerative disease and its pathogenesis involves interaction of genetic and environmental factors. Several chromosomal regions have been associated with AMD susceptibility through linkage analysis (Swaroop et al., 2009). More recent studies provide strong evidence that variants within the CFH gene cluster on chromosome 1 and at/near LOC387715/ARMS2 on chromosome 10 are strongly associated with the disease. Variants at other genes including C2/BF, C3, CFI and APOE4, also contribute to AMD susceptibility. Our primary goals are to identify genetic variants and haplotypes that are associated with AMD. The underlying hypothesis is that DNA variation(s) in multiple genetic susceptibility loci will predispose individuals to AMD pathogenesis, and comparison of DNA of cases and controls should identify these susceptibility variants. Our studies are focused on the genetic analysis of advanced AMD and should provide novel insights into disease diagnosis, progression and pathology. We have assembled a collaborative group of researchers from the University of Michigan, Mayo Clinic, University of Pennsylvania, and the AREDS group including National Eye Institute intramural investigators, who collected clinical data and DNA from a large number of patients affected with AMD and from unaffected controls. The primary source of funding was National Eye Institute. Study 1: To identify genetic variants and haplotypes that are associated with AMD, we submitted and obtained usable genotyping data on 2185 patients and 1155 controls from the Center for Inherited Disease Research (CIDR). Study 2: To identify rare coding variants associated with a large increase in risk of AMD, 10 candidate loci spanning 57 genes were sequenced in 2,335 cases and 789 controls. Probes were designed to capture 96.5% of the coding sequence and 35% of total locus sequence, generating an average 123Mb of on-target sequence per individual at 127x average depth. Substudies: phs000182 AMD-MMAP Cohort Study: A Joint Genome-Wide Asscociation Study phs000246 Fuchs' Corneal Dystrophy GWAS phs000457 MMAP Methylation in AMD phs000685 Age-Related Macular Degeneration Targeted Sequencing Study

  Study phs000684

• bulk ATACseq: A Cultured Leukemia Stem Cell Model Enables Validation of CDK6 as a Stemness Target Against Acute Myeloid Leukemia

  Acute myeloid leukemia (AML) represents a group of aggressive hematological malignancies, the clinical management of which is made challenging due to the persistence of rare and therapy resistant leukemia stem cells (LSCs) which serve as a source of disease relapse and poor outcomes. There are currently a paucity of methods to reliably enrich and study LSCs, hindering the development of therapies that specifically target LSCs. In this study, we deeply characterize the OCI-AML8227 culture model, which maintains a functional stemness hierarchy originating from its highly primitive CD34⁺CD38⁻ cells, to elucidate LSC biology and uncover LSC-specific therapeutic vulnerabilities. We analyzed both bulk and single-cell proteomics, transcriptomics, and epigenomics to generate a LSC protein-protein interaction network, which was then integrated with an LSC-focused small molecule screen using this model. From these findings, CDK6 was discovered as a therapeutic vulnerability specific to LSCs, which was validated in findings from the BEAT-AML cohort and a patient-derived xenograft (PDX) panel of AML samples through palbociclib treatment. Taken together, our studies validate CDK6 as a druggable vulnerability in LSCs, and authenticate OCI-AML8227 cells as a LSC target discovery engine.

  Study EGAS50000000787

• scATAC: A Cultured Leukemia Stem Cell Model Enables Validation of CDK6 as a Stemness Target Against Acute Myeloid Leukemia

  Acute myeloid leukemia (AML) represents a group of aggressive hematological malignancies, the clinical management of which is made challenging due to the persistence of rare and therapy resistant leukemia stem cells (LSCs) which serve as a source of disease relapse and poor outcomes. There are currently a paucity of methods to reliably enrich and study LSCs, hindering the development of therapies that specifically target LSCs. In this study, we deeply characterize the OCI-AML8227 culture model, which maintains a functional stemness hierarchy originating from its highly primitive CD34⁺CD38⁻ cells, to elucidate LSC biology and uncover LSC-specific therapeutic vulnerabilities. We analyzed both bulk and single-cell proteomics, transcriptomics, and epigenomics to generate a LSC protein-protein interaction network, which was then integrated with an LSC-focused small molecule screen using this model. From these findings, CDK6 was discovered as a therapeutic vulnerability specific to LSCs, which was validated in findings from the BEAT-AML cohort and a patient-derived xenograft (PDX) panel of AML samples through palbociclib treatment. Taken together, our studies validate CDK6 as a druggable vulnerability in LSCs, and authenticate OCI-AML8227 cells as a LSC target discovery engine.

  Study EGAS50000000788

• bulk RNA-seq: A Cultured Leukemia Stem Cell Model Enables Validation of CDK6 as a Stemness Target Against Acute Myeloid Leukemia

  Acute myeloid leukemia (AML) represents a group of aggressive hematological malignancies, the clinical management of which is made challenging due to the persistence of rare and therapy resistant leukemia stem cells (LSCs) which serve as a source of disease relapse and poor outcomes. There are currently a paucity of methods to reliably enrich and study LSCs, hindering the development of therapies that specifically target LSCs. In this study, we deeply characterize the OCI-AML8227 culture model, which maintains a functional stemness hierarchy originating from its highly primitive CD34⁺CD38⁻ cells, to elucidate LSC biology and uncover LSC-specific therapeutic vulnerabilities. We analyzed both bulk and single-cell proteomics, transcriptomics, and epigenomics to generate a LSC protein-protein interaction network, which was then integrated with an LSC-focused small molecule screen using this model. From these findings, CDK6 was discovered as a therapeutic vulnerability specific to LSCs, which was validated in findings from the BEAT-AML cohort and a patient-derived xenograft (PDX) panel of AML samples through palbociclib treatment. Taken together, our studies validate CDK6 as a druggable vulnerability in LSCs, and authenticate OCI-AML8227 cells as a LSC target discovery engine.

  Study EGAS50000000789

• snRNA: A Cultured Leukemia Stem Cell Model Enables Validation of CDK6 as a Stemness Target Against Acute Myeloid Leukemia

  Acute myeloid leukemia (AML) represents a group of aggressive hematological malignancies, the clinical management of which is made challenging due to the persistence of rare and therapy resistant leukemia stem cells (LSCs) which serve as a source of disease relapse and poor outcomes. There are currently a paucity of methods to reliably enrich and study LSCs, hindering the development of therapies that specifically target LSCs. In this study, we deeply characterize the OCI-AML8227 culture model, which maintains a functional stemness hierarchy originating from its highly primitive CD34⁺CD38⁻ cells, to elucidate LSC biology and uncover LSC-specific therapeutic vulnerabilities. We analyzed both bulk and single-cell proteomics, transcriptomics, and epigenomics to generate a LSC protein-protein interaction network, which was then integrated with an LSC-focused small molecule screen using this model. From these findings, CDK6 was discovered as a therapeutic vulnerability specific to LSCs, which was validated in findings from the BEAT-AML cohort and a patient-derived xenograft (PDX) panel of AML samples through palbociclib treatment. Taken together, our studies validate CDK6 as a druggable vulnerability in LSCs, and authenticate OCI-AML8227 cells as a LSC target discovery engine.

  Study EGAS50000000786

• Collaborative Cohort of Cohorts for COVID-19 Research (C4R): REasons for Geographic and Racial Differences in Stroke (REGARDS)

  Cohort DescriptionThe REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort is one of the nation's largest, most comprehensive population-based cohorts, and it uses innovative home- and telephone-based data collection. REGARDS centrally recruited and initially examined 30,239 Black and White men and women aged ≥45 years in 2003-7 to understand why Southerners and Black Americans have a higher incidence of stroke and related diseases that affect brain health.Data Being Submitted Wave 1 questionnaire data includes 397 variables for 8109 REGARDS participants in C4R. Wave 2 questionnaire data includes 448 variables for 6421 REGARDS participants in C4R. Dried Blood Spot/Serosurvey data includes 7 variables for 4058 REGARDS participants in C4R. Derived data includes 43 variables for 8606 REGARDS participants in C4R. Phenotype data includes 113 variables for 7880 REGARDS participants in C4R.

  Study phs002919

• DAC for Combined MEK and BCL-2/XL inhibition is effective in high-grade serous ovarian cancer patient-derived xenograft models and BIM levels are predictive of responsiveness

  Dac EGAC00001001250

• The Ultrasound Study of Tamoxifen

  The Ultrasound Study of Tamoxifen is a 12-month longitudinal study to describe volumetric breast density change over time among women with and without tamoxifen exposure. Women were enrolled at the Karmanos Cancer Institute and Henry Ford Health Systems in Detroit, Michigan between 2011-2014. Enrollment included women prescribed tamoxifen for clinical indication (n=82) and a comparison group of women frequency matched on age, race, and menopausal status (n=165). Whole breast ultrasound tomography (UST) scans were used to measure volume averaged sound speed (m/s) as a surrogate of volumetric breast density. Ultrasound tomography (UST) scans were completed at baseline prior to tamoxifen initiation and were repeated at 1-3 months, 4-6 months, and 12 months after tamoxifen initiation. For the comparison group, UST scans were completed at baseline and 12 months. Questionnaires were completed at each scan.

  Study phs003183

• Batches 4-6 prostatectomy analysis

  Whole Genome Sequencing Illumina HiSeq data from 111 men with prostate cancer. Samples were taken from primary tissue obtained at prostatectomy (target sequencing depth 50X) with matched blood control (target sequencing depth 30X). This data is from batches 4 to 6.

  Dataset EGAD00001003225

• Single Cell Targeted Sequence Capture

  This study is to ascertain whether it is feasible to extract single cell from a tumour, perform amplification, generate a library and sequence a targeted pulldown.

  Dataset EGAD00001001450

• Whole exome sequencing of non-small cell lung cancer patient-derived xenografts

  Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths worldwide. Only a fraction of NSCLC harbour actionable driver mutations and there is an urgent need for patient-derived model systems that will enable the development of new targeted therapies. We generated NSCLC patient-derived xenografts (PDXs) that recapitulate the histology and molecular features of primary NSCLC. Here, we completed whole exome sequencing on 122 NSCLC PDXs.

  Dataset EGAD00001008601

• Identification of rare variants associated with cardiovascular traits in Cilento isolates

  The aim of this project is to identify rare genetic variants of large effect implicated in complex diseases by focusing on the study of cardiovascular diseases and related quantitative traits in a well characterized isolated population in Cilento area, Italy. The reference panel has been selected carefully in order to maximize the imputation coverage and quality on the all population samples. The selected individuals should meet three criteria: selected individuals should be chip-genotyped and closely related to the maximum number of chip-genotyped individuals so as to maximize imputation coverage; relatedness between selected individuals should be minimal, so as to minimize redundancy in genetic information of the reference panel. We perform exome sequencing on samples from 250 individuals from the Campora and Gioi-Cardile populations.

  Dataset EGAD00001002195

• Summary Statistics GWAS SSNS

  Column 1 rsid: SNP identifier;Column 2 chromosome: name of chromosome on which the SNP is located;Column 3: position: base pair position on the chromosome;Column 4 minor_test_allele: the base that constitutes the minor allele;Column 5 major_allele: the base that constitutes the major allele;Column 6 maf: the frequency of the minor allele, indicated as a fraction of 1;Column 7 allele_freq_cases: the minor allele frequency in cases;Column 8 allele_freq_controls: the minor allele frequency in controls;Column 9 regression_pvalue: the p-value for the difference in allele frequency between cases and controls;Column 10 odds_ratio: the odds ratio, as calculated using logistic regression under an additive model with adjustment for the first ten principal components of ancestry

  Dataset EGAD00010002316

• Summary Statistics GWAS SSNS

  Column 1 “rsid”: SNP identifier Column 2 “chromosome”: name of chromosome on which the SNP is located Column 3: “position”: base pair position on the chromosome Column 4 “minor_test_allele”: the base that constitutes the minor allele Column 5 “major_allele”: the base that constitutes the major allele Column 6 “maf”: the frequency of the minor allele, indicated as a fraction of 1 Column 7 “allele_freq_cases”: the minor allele frequency in cases Column 8 “allele_freq_controls”: the minor allele frequency in controls Column 9 “regression_pvalue”: the p-value for the difference in allele frequency between cases and controls Column 10 “odds_ratio”: the odds ratio, as calculated using logistic regression under an additive model with adjustment for the first ten principal components of ancestry

  Dataset EGAD00001008782

• Whole exome sequencing from early stage non-small cell lung cancer patients at MDACC

  The purpose of the study is to evaluate the mutational landscape and tumor mutational burden in tumor from patients with early stage non-small cell lung cancer. Mutational landscape was compared to the T cell repertoire to determine the relationship between somatic mutations and T cell response in early-stage NSCLC.

  Study EGAS00001004026

• Detection of ctDNA in Plasma of Patients with Clinically Localised Prostate Cancer is Associated with Rapid Disease Progression

  Purpose: DNA originating from degenerate tumour cells can be detected in the circulation in many tumour types, where it can be used as a marker of disease burden as well as to monitor treatment response. Although circulating tumour DNA (ctDNA) measurement has prognostic/predictive value in metastatic prostate cancer, its utility in localised disease is unknown. Patients and Methods: We performed whole genome sequencing of tumour-normal pairs in eight patients with clinically localised disease undergoing prostatectomy, identifying high confidence genomic aberrations. A bespoke DNA capture and amplification panel against the highest prevalence, highest confidence aberrations for each individual was designed and used to interrogate ctDNA isolated from plasma prospectively obtained pre- and post- (24 hours and 6 weeks) surgery. In a separate cohort (n=189) we identified the presence of ctDNA TP53 mutations in pre-operative plasma in a retrospective cohort, and determined its association with biochemical- and metastasis-free survival. Results: Tumour variants in ctDNA were positively identified pre-treatment in two of eight patients, which in both cases remained detectable postoperatively. Patients with tumour variants in ctDNA had extremely rapid disease recurrence and progression compared to those where variants could not be detected. In terms of aberrations targeted, single nucleotide and structural variants outperformed indels and copy number aberrations. Detection of ctDNA TP53 mutations was associated with a significantly shorter metastasis-free survival (6.2 vs. 9.5 years (HR 2.4; 95% CIs 1.2-4.8, p = 0.014)). Conclusions: CtDNA is uncommonly detected in localised prostate cancer but its presence portends more rapidly progressive disease.

  Study EGAS00001004636

• Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma.

  follicular lymphoma (FL), the most common indolent non-Hodgkin’s lymphoma, remains incurable. A well-recognized complication of FL is its transformation to a diffuse large B-cell lymphoma (DLBCL)-morphology in a subset of patients, for which the clinical outcomes are poor. Recent genetic profiling and single case studies of donor-derived FL following stem cell transplantation had alluded to the putative existence of a ‘long lived’ tumor-initiating progenitor cell compartment from which successive disease events occurred. To chronicle the genetic changes associated with progression to transformation, we conducted whole-genome sequencing (WGS) of FL-tFL pairs and matched germline (GL) samples from six patients, a total of 20 genomes.

  Study EGAS00001000399

• The 3D evolution of glioma cell populations

  Study description: A detailed understanding of heterogeneity in solid tumors has been limited due to insufficient sampling and a lack of knowledge from where within the tumor the sample was taken from. We present here a novel resource - the 3D Glioma Atlas - in which we record the precise, three-dimensional (3D) coordinate for each of 8-20 spatially-distinct samples obtained from each patient tumor.By revealing how genetic alterations and tumor cell states are patterned in glioma in 3D space, our Atlas shows that genetic diversity is more regionally confined in indolent as compared to aggressive tumors, that recurrent tumors have a greater density of genetic diversity, and that more aggressive tumors have greater tumor-wide transcriptomic heterogeneity.

  Study EGAS00001003710

• Exome Sequencing of Statin-Induced Myopathy Cases

  Severe myopathic events occur in 0.1-0.5% of patients taking statins. Although genetic association studies have identified some possibly associated gene loci, these have not been reproducible in additional studies with independent patient cohorts. A more reasonable explanation for susceptibility to statin-induced myopathy is the presence of rare pathogenic variants in genes important for skeletal muscle structure and function. In support of this, we have previously reported an increased incidence of pathogenic variants in genes causing metabolic myopathies in patients with statin-induced myopathy (Vladutiu et al.,2006). We also reported a patient with statin myopathy who had an RYR1 variant known to be causative of malignant hyperthermia susceptibility (MHS) (Vladutiu et al., 2011). There are a number of genes associated with metabolic myopathies triggered by various factors such as extreme exercise, fasting, extremes in temperature, viral infection and exposure to volatile anesthetics. In addition, many of the genes causing congenital myopathies, myofibrillar myopathies and muscular dystrophies have overlapping phenotypes with these genes. We propose that statins act as an additional trigger inducing myopathic symptoms and many patients with severe statin-induced myopathy have causative genetic variants within similar genes associated with MHS and congenital myopathy. We have analyzed the resultant data using a disease model in which rare pathogenic variants, possibly within multiple genes, are causative of statin-induced myopathy. In this study, we have identified potentially causative genetic variants in greater than 50% of the statin-induced myopathy cases and in particular, rare and possibly pathogenic in the RYR1 and CACNA1S genes were present in 25% of the patient samples studied. Vladutiu, G. D., Simmons, Z., Isackson, P.J., Tarnopolsky, M., Peltier, W.L., Barboi, A.C., Sripathi, N., Wortmann, R.L., Phillips, P.S., (2006). "Genetic risk factors associated with lipid-lowering drug-induced myopathies." Muscle Nerve 34: 153-162. Vladutiu, G. D., Isackson, P.J., Kaufman, K., Harley, J.B., Cobb, B., Christopher-Stine, L., Wortmann, R.L, (2011). "Genetic risk for malignant hyperthermia in non-anesthesia-induced myopathies." Mol Genet Metab 104: 167-173.

  Study phs001342

• Genome-wide prediction of human embryos

  BACKGROUND: Preimplantation genetic diagnosis (PGD) enables profiling of embryos for genetic disorders prior to implantation. The majority of PGD testing is restricted in the scope of variants assayed or by the availability of extended family members. While recent advances in single cell sequencing show promise, they remain limited by bias in DNA amplification and the rapid turnaround time (<36 h) required for fresh embryo transfer. Here, we describe and validate a method for inferring the inherited whole genome sequence of an embryo for preimplantation genetic diagnosis (PGD). METHODS: We combine haplotype-resolved, parental genome sequencing with rapid embryo genotyping to predict the whole genome sequence of a day-5 human embryo in a couple at risk of transmitting alpha-thalassemia. RESULTS: Inheritance was predicted at approximately 3 million paternally and/or maternally heterozygous sites with greater than 99% accuracy. Furthermore, we successfully phase and predict the transmission of an HBA1/HBA2 deletion from each parent. CONCLUSIONS: Our results suggest that preimplantation whole genome prediction may facilitate the comprehensive diagnosis of diseases with a known genetic basis in embryos.

  Study EGAS00001001020

• Epigenome maps of time-resolved monocyte to macrophage differentiation and innate immune memory

  Innate immune memory is the phenomenon whereby innate immune cells such as monocytes or macrophages undergo functional reprogramming after exposure to microbial components such as LPS. We apply an integrated epigenomic approach to characterize the molecular events involved in LPS-induced tolerance in a time dependent manner. ChIP-seq, RNA-seq, WGBS and ATAC-seq data were generated. This analysis identified epigenetic programs in tolerance and trained macrophages, and the potential transcription factors involved. Experimental set-up Time-course in vitro culture of human monocytes. Two innate immune memory states can be induced in culture through an initial exposure of primary human monocytes to either LPS or BG for 24 hours, followed by removal of stimulus and differentiation to macrophages for an additional 5 days. Cells were collected at baseline (day 0), 1 hour, 4 hour, 24 hour and 6 days.

  Dataset EGAD00001002693

• Multiple migrations to the Philippines during the last 50,000 years

  A key link to understand human history in Island Southeast Asia is the Philippine archipelago and its poorly investigated genetic diversity. We collected and analyzed the most comprehensive set of population-genomic data for the Philippines, 1028 individuals covering 115 indigenous communities. We demonstrate that the Philippines were populated by at least five waves of human migration. The Cordillerans migrated into the Philippines prior to the arrival of rice agriculture, where some remain to be the least admixed East Asians carrying an ancestry shared by all Austronesian-speaking populations; thereby challenging an exclusive Out-of-Taiwan model of joint farming-language-people dispersal. Altogether, our findings portray Philippines as a crucial gateway, with a multilayered history, that ultimately changed the genetic landscape of the Asia-Pacific region.

  Study EGAS00001005083

• A Heterozygous Missense Mutation in the Coiled-Coil Domain of STAT5B is Associated with Leukocytosis, Lymphadenopathy, Splenomegaly, Necrotizing Granulomas, Hyper-IgM and Thrombocytopenia

  We describe one patient with a heterozygous missense mutation in the coiled-coil domain of STAT5B. This patient presented with leukocytosis, lymphadenopathy, splenomegaly, necrotizing granulomas, hyper-IgM and autoimmune thrombocytopenia. Mutant STAT5B protein was shown to dominantly-interfere with IL2-induced transcriptional activity resulting in global downregulation of STAT5-regulated genes in patient T cells. The patient exhibited an increase in CD4+ T effector memory cells in the peripheral blood and these cells were resistant to restimulation-induced cell death in vitro.

  Study phs001479

• Heart Failure Network Oral Iron Repletion Effects on Oxygen Uptake in Heart Failure (HFN IRONOUT-BioLINCC)

  ObjectivesTo test the hypothesis that, compared to placebo, oral iron repletion in heart failure patients with iron deficiency improves exercise capacity after 16 weeks of therapy.Background Iron deficiency affects approximately one half of patients with symptomatic heart failure. The presence of iron deficiency in patients with heart failure is associated with reduced functional capacity, poorer quality of life, and increased mortality. Despite growing recognition of the significance of iron deficiency, randomized multicenter trials exploring the utility of oral iron supplementation, a therapy that is inexpensive, readily available, and safe, have not been performed in patients with heart failure. Moreover, patient characteristics and biochemical profiles that may influence responsiveness to oral iron in patients with heart failure have not been defined. Results of intravenous iron repletion trials have been favorable, but regularly treating patients with intravenous iron products is expensive and poses logistical challenges for outpatients. Therefore, the HFN-IRONOUT study was initiated to investigate the efficacy of oral iron in patients with heart failure with reduced ejection fraction (HFrEF). ParticipantsA total of 225 participants were enrolled, 111 randomized to receive oral iron and 114 randomized to receive the placebo. Design The HFN-IRONOUT study was a phase 2, double-blind, placebo-controlled randomized clinical trial that enrolled participants at 23 sites in the United States. Participants were randomly assigned, in a 1:1 ratio, to receive either oral iron polysaccharide or placebo with the use of an automated web-based system. A permuted block randomization method (with 4 participants per block) was stratified by enrolling site and anemia status (defined as hemoglobin At baseline, 8 weeks, and 16 weeks participants underwent studies including history and physical examination, cardiopulmonary exercise testing (CPET), Kansas City Cardiomyopathy Questionnaire (KCCQ), and 6-minute walk test. CPETs were performed using a 10 Watt/minute incremental ramp protocol and breath-by-breath measures of oxygen uptake were uniformly analyzed by the CPET Core Lab. Participants also underwent phlebotomy for biomarkers. Iron studies, including iron, total iron binding capacity, and ferritin, were measured at baseline and after 16 weeks to determine the extent to which oral iron led to iron repletion. The primary end point was the change in peak oxygen uptake (peak VO2) after 16 weeks of therapy. Conclusions Among participants with HFrEF with iron deficiency, high-dose oral iron did not improve exercise capacity over 16 weeks.

  Study phs003557

• Single-cell Transcriptome Profiling of Treatment-naïve and Post-treatment Colorectal Cancer: Insights into Putative Mechanisms of Chemoresistance

  Drug resistance remains a major clinical challenge in the treatment of colorectal cancer (CRC) with conventional chemotherapy. Investigation of cancer cells and tumor microenvironment (TME) following chemotherapy is critical for unraveling the mechanisms of resistance. In this study, we analyzed scRNA-Seq data from 56 CRCs including treatment-naïve tumors (25 microsatellite stable (MSS) tumors and 7 tumors with microsatellite instability (MSI)); and tumors treated with standard chemotherapy with the known response status (18 responders and 6 progressors). We observed in treatment-naïve MSS CRC that right-sided tumors are more immunogenic with higher numbers of B cells and CD8+ T memory effector cells than left-sided tumors. MSI CRC were even more immunogenic then MSS CRC and were characterized by elevated Tregs in their TME. In the post-treatment CRC there was a high prevalence of dendritic cells (DC) in the TME in the response group. The DC-derived signature was associated with better survival in a large CRC cohort from the TCGA. We also observed two fibroblast subtypes in CRC, one of which was enriched in progressors and was associated with poor survival in a CRC-TCGA cohort. Progressors also showed elevated exhausted CD8+ T memory cells and monocytes suggesting a pro-inflammatory TME. In tumor cells in progressor group we identified specific expression of chemo-protective markers MTRNR2L1 and CDX1; and their co-expression with stemness-related marker CD24. In summary, scRNA-Seq provides a valuable information for the discovery of prognostic markers, and reveals distinct features of CRC based on location, metastasis status, MSI status and treatment response status.

  Study EGAS50000000830

• BAMSE (Swedish abbreviation for Children, Allergy, Milieu, Stockholm, Epidemiology)

  The BAMSE (Swedish abbreviation for Children, Allergy, Milieu, Stockholm, Epidemiology) study is an ongoing longitudinal, population-based prospective birth cohort including 4,089 children born between 1994 and 1996 in Stockholm, Sweden. The cohort was initially designed to study risk factors for asthma, allergic diseases and lung function in childhood, and to study factors of importance for prognosis at already established disease.Questionnaires on respiratory symptoms and medication were answered at age of 1, 2, 4, 8 and 16 years. Response rates ranged from 96-82% at each occasion with very minor selection bias over the years. Exposure to air pollutants and other environmental factors has been mapped since birth.At the 8 and 16 year follow-up, spirometry and FeNO measurements were performed and at the latter, impulse oscillometry was measured. Blood samples (including plasma) from around 2,500 children were taken at 4, 8 and 16 years and have been analyzed for different IgE-ab and biomarkers. Genome-wide genetic, global methylation and transcriptomic data exist on a subset of the children.

  Study EGAS00001002746

• WGS data from LCNEC patient derived tumor organoids (PDTOs) and matched parental tumors - SA

  The dataset includes cram files from WGS of 2 LCNEC tumors and matched PDTOs. For all tumors, cram files from WGS of matched normal tissue derived organoids from the corresponding patients is included. Analysis VCF files are also included in the dataset. The sequencing was done with a NovaSeq 6000 instrument.

  Dataset EGAD00001009990

• MYC Drives Progression of Small Cell Lung Cancer to a Variant Neuroendocrine Subtype with Vulnerability to Aurora Kinase Inhibition

  Loss of the tumor suppressors RB1 and TP53 and MYC amplification are frequent oncogenic events in small cell lung cancer (SCLC). We show that Myc expression cooperates with Rb1 and Trp53 loss in the mouse lung to promote aggressive, highly metastatic tumors, that are initially sensitive to chemotherapy followed by relapse, similar to human SCLC. Importantly, MYC drives a neuroendocrine-low “variant” subset of SCLC with high NEUROD1 expression corresponding to transcriptional profiles of human SCLC. Targeted drug screening reveals that SCLC with high MYC expression is vulnerable to Aurora kinase inhibition, which combined with chemotherapy strongly suppresses tumor progression and increases survival. These data identify molecular features for patient stratification and uncover a novel targeted treatment approach for MYC-driven SCLC.

  Study EGAS00001002115

• Molecular sub-classification of hormone receptor-positive breast cancer

  Patients with estrogen and/or progesterone receptor-positive breast cancer benefit from hormonal treatment, yet high global death burdens due to high prevalence and long-term recurrence risk call for biomarkers to guide additional treatment approaches. From a prospective, observational study of postmenopausal early breast cancer patients treated with tamoxifen or aromatase inhibitors gene expression analyses of 612 tumors was performed using the NanoString® Breast Cancer 360 panel. We identified novel gene expression signatures, i.e. BRCAness and Tumor Inflammation Signature (associated with high tumor lymphocyte infiltration), that may aid to select high-risk patients in order to improve adjuvant treatment by targeting DNA repair deficiency or immune-checkpoints in addition to standard chemo-endocrine treatment. The overall goal is to foster novel concepts for a stratified early breast cancer management.

  Study EGAS00001004594

• The genomic landscape of primary cutaneous anaplastic large cell lymphoma (pcALCL)

  Primary cutaneous anaplastic large cell lymphoma (pcALCL) is the second most common variant of cutaneous T-cell lymphoma. We subjected tumor biopsies from patients with pcALCL to whole-genome sequencing, whole-exome sequencing and RNA-sequencing to investigate genomic alterations and deregulated gene expression in the disease.

  Study EGAS00001004429

• Targeting the p53 pathway to treat Malignant Rhabdoid and High-Risk Atypical Teratoid Rhabdoid Tumors

  Rhabdoid tumors (RTs) predominantly affect young children and are among the deadliest pediatric solid tumors. Despite multimodal therapy consisting of surgery, radiation, and chemotherapy, children with these tumors have median survival of less than one year. RTs can arise throughout the body, including the central nervous system (CNS) where they are called atypical teratoid rhabdoid tumors (AT/RTs), and in extra-CNS locations such as the kidneys and other soft tissues where they are designated malignant RTs (MRTs). We previously identified MDM2 and MDM4 as therapeutic vulnerabilities in RTs and showed that treatment with the MDM2 inhibitor idasanutlin increased survival in mice bearing MRT xenografts. However, the therapeutic potential of idasanutlin in CNS RT tumors is unknown. Single agent therapies are prone to resistance and show limited clinical benefit on their own. Therefore, we sought to identify combination strategies incorporating idasanutlin that would be effective in both CNS and extra-CNS RTs. Here, we show that the XPO1 inhibitor selinexor increased nuclear retention of p53 and potentiated idasanutlin-induced p53 pathway activation and cytotoxicity in AT/RT and MRT cell lines in vitro. Importantly, combination therapy limited acquired resistance through TP53 mutation. In vivo, combination therapy was well-tolerated, reduced tumor burden, and increased survival in orthotopic models of both AT/RT and MRT. Our results demonstrate that combining idasanutlin with selinexor is a promising therapeutic strategy for children with rhabdoid tumors.

  Study EGAS00001007680

• Atypical B cells and impaired SARS-CoV-2 neutralisation following heterologous vaccination in the elderly

  Age is a major risk factor for hospitalization and death after SARS-CoV-2 infection, even in vaccinees. Suboptimal responses to a primary vaccination course have been reported in the elderly, but there is little information regarding the impact of age on responses to booster third doses. Here we show that individuals 70 or older who received a primary two dose schedule with AZD1222 and booster third dose with mRNA vaccine achieved significantly lower neutralizing antibody responses against SARS-CoV-2 spike pseudotyped virus compared to those below 70 at one month post booster. Neither the concentration of serum binding anti spike IgG antibody, nor the frequency of spike- specific B cells showed differences by age grouping. Impaired neutralization potency and breadth post-third dose in the elderly was associated with enrichment of circulating “atypical” spike-specific B cells expressing CD11c and FCRL5. Presence of these atypical B cells was confirmed by scRNA seq. However, when considering individuals who received three doses of mRNA vaccine, we did not observe statistically significant differences in neutralization or enrichment in atypical B cells by age grouping following dose 3. Together, our data reveal impaired neutralising antibody responses in the elderly after heterologous vaccination with AdV followed by mRNA booster dose, but not in homologous three dose mRNA vaccination highlighting that different vaccine formats differentially instruct the memory B cell response.

  Study EGAS00001007385

• Detection of Clinically Relevant Genetic Variantsin Autism Spectrum Disorderby Whole-Genome Sequencing

  Autism Spectrum Disorder (ASD) demonstrates high heritability and familial clustering, yet the genetic causes remain only partially understood as a result of extensive clinical and genomic heterogeneity. Whole-genome sequencing (WGS) shows promise as a tool for identifying ASD risk genes as well as unreported mutations in known loci, but an assessment of its full utility in an ASD group has not been performed. We used WGS to examine 32 families with ASD to detect de novo or rare inherited genetic variants predicted to be deleterious (loss-of-function and damaging missense mutations). Among ASD probands, we identified deleterious de novo muta- tions in six of 32 (19%) families and X-linked or autosomal inherited alterations in ten of 32 (31%) families (some had combinations of mutations). The proportion of families identified with such putative mutations was larger than has been previously reported; this yield was in part due to the comprehensive and uniform coverage afforded by WGS. Deleterious variants were found in four unrecognized, nine known, and eight candidate ASD risk genes. Examples include CAPRIN1 and AFF2 (both linked to FMR1, which is involved in fragile X syndrome), VIP (involved in social-cognitive deficits), and other genes such as SCN2A and KCNQ2 (linked to epilepsy), NRXN1, and CHD7, which causes ASD-associated CHARGE syndrome. Taken together, these results suggest that WGS and thorough bioinformatic analyses for de novo and rare inherited mutations will improve the detection of genetic variants likely to be associated with ASD or its accompanying clinical symptoms.

  Study EGAS00001000850

• The Mood and Methylation Study (MMS)

  The Mood Methylation Study (MMS) is an observational study designed to understand epigenetic mechanisms underlying major depression symptoms (MDD) using a co-twin control design. Twins enrolled in the MMS were monozygotic (MZ) twin pairs discordant on lifetime history of MDD. All twins were members of the Washington State Twin Registry (WSTR), a community-based twin registry consisting of over 10,000 twin pairs. Lifetime and current MDD diagnoses were determined using the Structured Clinical Interview for DSM-IV Research Version (SCID-4-RV). DNA methylation in blood monocytes was measured using the Infinium HumanMethylationEPIC BeadChip. Monocyte gene expression was quantified by paired end RNA-seq (50 PE). Zygosity of the twin pairs included in the MMS was self-reported and confirmed using the polymorphic SNPs included in the DNA methylation array.

  Study phs002858

• Rare coding variants in lupus risk genes

  Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease. It is thought that many common variant gene loci of weak effect act additively to predispose to common autoimmune diseases, while the contribution of rare variants remains unclear. Here we describe that rare coding variants in lupus-risk genes are present in most SLE patients and healthy controls. We demonstrate the functional consequences of rare and low frequency missense variants in the interacting proteins BLK and BANK1, which are present alone, or in combination, in a substantial proportion of lupus patients. The rare variants found in patients, but not those found exclusively in controls, impair suppression of IRF5 and type-I IFN in human B cell lines and increase pathogenic lymphocytes in lupus-prone mice. Thus, rare gene variants are common in SLE and likely contribute to genetic risk.

  Study EGAS00001003548

• Transcriptomics-driven classification of ALAL

  Acute leukemia of ambiguous lineage (ALAL) is a rare, poor-prognosis subtype of acute leukemia that cannot be assigned to a single hematopoietic lineage. Although ALAL patients are typically treated with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) regimens, optimal treatment choice is hindered by their lineage ambiguity. Therefore, we investigated the added value of transcriptomics for improving lineage assignment, currently based mainly on surface markers. First, we used an in-house pipeline to comprehensively detect genetic lesions in RNA-sequencing data (n=23) with a sensitivity >90%, as confirmed by targeted DNA sequencing. Second, we compared ALAL gene expression profiles (GEPs) with representative AML (n=145), B-ALL (n=223) and T-ALL (n=85) cases. In a principal component analysis, ALALs did not form a separate group, but clustered with AML, B-ALL or T-ALL. Accordingly, a machine learning classifier trained with GEPs of acute leukemias segregated 20/23 ALALs into myeloid-, B- or T-lymphoid leukemia. These 20 cases harbored genetic abnormalities consistent with the classifier-assigned leukemia. Furthermore, ALAL GEPs were deconvoluted with single-cell transcriptional profiles of normal hematopoietic cells using CIBERSORTx, revealing enrichment for signatures of lineages corresponding to the leukemic type predicted by our algorithm. The classifier was validated on an external ALAL cohort (n=24), assigning 75% of the patients to a lineage matching their immunophenotypic and methylation profiles. In conclusion, integrative analysis of RNA-sequencing data can accurately classify most ALAL cases. The pipeline and classifier developed in our study are valuable tools to improve ALAL diagnosis and guide therapeutic decisions.

  Study EGAS00001007967

• 3/7 Psychiatric Genomics Consortium: Finding Actionable Variation

  The goal of this study was to generate new therapeutic hypotheses by targeted sequencing of 161 genes most likely to harbor schizophrenia (SCZ) causal variants in multi-ancestry schizophrenia case-control cohorts. The gene panel was intended to contain putative SCZ risk genes, from within which, the majority of new discoveries from additional WES/WGS would come. To this end, we integrated current knowledge of the genetic architecture of SCZ (results from The Schizophrenia Exome Sequencing Meta-Analysis Consortium, or SCHEMA) and gene membership in gene sets that have been implicated in SCZ using a Bayesian framework. A total of 23,352 individuals selected to be non-overlapping with SCHEMA, as well as other previous and ongoing sequencing efforts in the field, were identified from over 20 individual study sites. Sequencing of the exonic regions of 161 prioritized genes was performed on the Ion Torrent platform in between June 2018 and April 2019. Sequencing plates were matched with respect to ancestry and case/control composition whenever possible. The average sequencing depth across all samples was 224x. Single sample calling was performed using Torrent Variant Caller v5.8.0, which is specially optimized to exploit the underlying flow signal information generated by the Ion Torrent sequencing. The schizophrenia case-control status was obtained from each original study site.

  Study phs003138

• Heart Failure Network - Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure (HFN RELAX-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. Related StudyEcho images are available through HFN RELAX-ImagingObjectivesThe RELAX trial tested the hypothesis that chronic phosphodiesterase type-5 inhibitor therapy with sildenafil would improve exercise capacity and clinical status in heart failure patients with normal ejection fraction, as compared to placebo. Background Heart failure (HF) with preserved ejection fraction (HFpEF) is a common and highly morbid condition that is characterized by chronic exercise intolerance, progressive functional decline and a high rate of readmission. At the time of the RELAX trial, clinical trials of renin-angiotensin system antagonists had not demonstrated improvement in outcomes or clinical status in HFpEF, and effective therapies were needed. Phosphodiesterase type-5 (PDE-5) metabolizes the nitric oxide (NO) and natriuretic peptide (NP) systems' second messenger cyclic guanosine monophosphate (cGMP), and thus may limit beneficial NO and NP actions in the heart, vasculature and kidney. Pre-clinical studies suggest that inhibition of PDE-5 reverses adverse cardiac structural and functional remodeling and enhances vascular, neuroendocrine and renal function. In clinical studies, PDE-5 inhibitor therapy improved exercise tolerance and clinical status in patients with idiopathic pulmonary arterial hypertension and in patients with HF and reduced ejection fraction (HFrEF). A small, single-center study in HFpEF observed improved hemodynamics, left ventricular (LV) diastolic function, right ventricular (RV) systolic function, LV hypertrophy and lung function with chronic PDE-5 inhibition as compared to placebo. In aggregate, these studies suggested the potential for PDE-5 inhibition to ameliorate several key pathophysiological perturbations in HFpEF, and thus improve exercise capacity and clinical status. ParticipantsA total of 216 participants were enrolled in the trial with 113 in the Sildenafil group and 103 in the placebo group. Design Participants who met screening criteria underwent baseline studies including a history and physical examination, cardiopulmonary exercise test (CPXT), six-minute walk distance, Minnesota Living with Heart Failure Questionnaire (MLWHFQ), echocardiography, cardiac magnetic resonance imaging, and phlebotomy for biomarkers. Subjects were then randomly assigned, in a 1:1 ratio, to either the sildenafil or placebo intervention group. The study drug was administered orally at 20 mg three times daily (TID) for 12 weeks. If the dose was well tolerated at 12 weeks, it was increased to 60 mg TID for another 12 weeks. If side effects developed, study staff could recommend discontinuation or return to a lower or previously tolerated dose of study drug. Sildenafil levels 2 hours after a scheduled dose of study drug were obtained at 12 and 24 weeks. The primary endpoint was exercise capacity determined by change in peak oxygen consumption during the CPXT after 24 weeks of therapy. Secondary endpoints included change in six-minute walk distance at 12 and 24 weeks, change in peak oxygen consumption at 12 weeks, and a three tier score reflective of clinical status where patients were ranked based on time to death (lowest tier), time to cardiovascular or cardiorenal hospitalization (middle tier), and change in the MLWHFQ for patients alive without cardiovascular or cardiorenal hospitalization after 24 weeks (highest tier). Conclusions Chronic phosphodiesterase type-5 inhibitor therapy with sildenafil for 24 weeks did not alter exercise capacity or clinical status compared to placebo in patients with heart failure and preserved ejection fraction.

  Study phs003565

• Coronary Artery Risk Development in Young Adults (CARDIA-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.Related Studies: Other CARDIA data available include:phs000236.v2.p2 PAGE: CALiCo: Coronary Artery Risk Development in Young Adults(CARDIA) phs000309.v3.p2 The CARDIA-GENEVA Study phs000399.v1.p2 NHLBI GO-ESP: Heart Cohorts Exome Sequencing Project (CARDIA) phs000613.v1.p2 NHLBI CARDIA Candidate Gene Association Resource (CARe) phs003675.v1.p1 CARDIA Multi-omics Obesity & CVD Substudy – Year 20 Untargeted Metabolomics Data phs001612.v3.p2 NHLBI TOPMed: CARDIA (Coronary Artery Risk Development in Young Adults) phs003045.v1.p1 Collaborative Cohort of Cohorts for COVID-19 Research (C4R): Coronary Artery Risk Development in Young Adults Study (CARDIA) phs000285.v4.p3 CARDIA_Cohort Available Data: Available data for request include exam data through Year 30 and outcomes and death data through 2022. Additionally, data from 28 ancillary studies are available for request.Objectives: The original objectives of CARDIA were to document levels of risk factors for coronary artery disease and potential determinants of these risk factors in young adults; to study the interrelationships of risk factors and lifestyles and to document behavioral and environmental changes during the transition from young adulthood to middle age; to compare cross-sectional and longitudinal data on age-related trends in cardiovascular disease risk factors; and to compare levels and evolution of risk factors between men and women, blacks and whites, and in groups of differing socioeconomic status. Goals of the study have evolved to emphasize understanding determinants of left ventricular mass, emerging obesity and hypertension, and sequelae of hypertension in pregnancy.Background: CARDIA is designed to increase understanding of contributors to changes in cardiovascular disease (CVD) risk factors during the critical years of transition from young adulthood to middle age. CARDIA was funded initially in 1983 for a five-year cycle that included two rounds of examinations. Contract renewals have allowed for subsequent re-examinations.Participants: Black and white men and women; ages 18-30 years at entry with a range of attained education; original sample size: 5,115.Design: CARDIA is a population-based observational study of 5,115 participants aged 18-30 years recruited in 1985-1986. The sample was designed to achieve approximately balanced subgroups of race, gender, education (high school or less and more than high school) and age (18-24 and 25-30). Forty percent of the cohort had no more than a high school education. A total of nine examinations have been completed in the cohort with examination cycles at year 2 of the project and years 5, 7, 10 , 15, 20, 25, and 30.In addition to standard measurements of blood pressure, anthropometry, blood lipids, smoking behavior, physical activity, diet, pulmonary function, and many psychological factors, CARDIA has other included measurements (in subsets or in the full cohort) to obtain unique information on other aspects of risk factor development and early morbidity. These have included: graded exercise treadmill testing; echocardiography, particularly for measurement of left ventricular mass; cardiovascular reactivity; serum cotinine; Lp(a), apoE phenotype, apolipoprotein A1 and B; homocysteine; skin reflectance; body composition by dual X-ray absorptiometry; glucose tolerance testing; vascular resistance and compliance; and plasma renin activity and sympathetic nervous system activity.

  Study phs003739

• Lipid Research Clinics - Prevalence Study (LRC-PS-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Objectives: The LRC Program began in 1971 under the sponsorship of the National Heart, Lung, and Blood Institute, National Institutes of Health. Part of this program was the Lipid Research Clinics Prevalence Study, a standardized series of cross-sectional surveys of various North American populations designed to determine the prevalence of dyslipidemias and to describe the distributions of lipids and lipoproteins in major ethnic and social groups. In addition to contributing to the aggregate analysis, each independent population-based study was designed with capabilities for separate analyses of lipid and lipoprotein distributions. The participating populations were not selected to be a probability sample representative of the North American population per se, but by virtue of their size and economic and geographical diversity, they provide a useful cross-sectional group. The Family Study was the third phase of the Lipids Research Clinics North American Population Studies. The Family Study was designed to obtain knowledge of the distribution of lipids and lipoproteins among family members and of the association of familial and genetic attributes to dyslipoproteinemias. Background: An association between serum cholesterol and coronary heart disease is well established. A system was developed for classifying hyperlipoproteinemias into six types of patterns, as a basis for characterizing lipoprotein disorders. The Lipid Research Clinics was thus created to improve the detection of and clinical management of hyperlipoproteinemias. The three primary objectives were: 1) to acquire data on the prevalence of different types of hyperlipoproteinemia in various age and ethnic groups, with special emphasis on the nature and frequency of genetic forms; 2) to collect reliable data on the prevalence and incidence of atherosclerosis in different types of hyperlipoproteinemia; and 3) to conduct an intervention trial to determine if lowering plasma lipid levels would reduce the risk of CHD. Participants: There were 60,495 participants. Conclusions: Data from this study confirm findings from earlier studies in developed countries, showing age-related differences in plasma lipid levels. However, for overall distributions, the LRC data showed slightly lower cholesterol and markedly higher trigylceride values than those previously reported for North America. Some variation in plasma lipid values was evident among the clinic populations. The large number of participants within most subgroups permitted a variety of analytic and comparative studies. For example, data from the large pediatric population revealed a drop in plasma cholesterol levels in adolescent males and females. Males aged 20-50 years had higher cholesterol levels than females in the same age group, and higher trigylceride levels between ages 20-70 years. Numbers were also significient for meaningful comparisons between lipid distributions of females who were taking sex hormones and those who were not; in females taking sex hormones, cholesterol and triglyceride levels were higher for subjects younger than 45 years, but slightly lower after age 45, than lipid levels in females not taking hormones (Circulation 1979; 60(2):427-439).

  Study phs003995

• Exome_sequencing_of_thyroid_disease_in_Val_Borbera

  The Val Borbera is a region characterized by low iodine and high prevalence of thyroid disorders, the commonest endocrine disorders in the general population. About 30% of the participants of the Val Borbera Project were affected by such disorders and were characterized by several parameters, TSH level, anti TPO antibodies, echography, family origin. Individuals with extreme phenotypes were identified and could be clustered based on family origin and genotype. We propose to exome sequence 6 of them, affected with true goiter, at high dept (40-60x) to obtain information on exonic rare variants. Due to the family structure and to the availability of whole genome sequence information on 110 individuals from the isolated population we expect to be able to identify putative causative variants for thyroid disorders that may be studied in the remaining affected individuals.

  Study EGAS00001000344

• National Cancer Institute (NCI) TARGET: Therapeutically Applicable Research to Generate Effective Treatments

  The Therapeutically Applicable Research to Generate Effective Treatments (TARGET) Initiative seeks to accelerate research in novel marker and drug development, along with understanding the molecular basis of pediatric malignancy, through identification of genomic changes associated with the following childhood cancers: Acute Lymphoblastic Leukemia (ALL) - A fast-growing type of blood cancer in which too many immature white blood cells are found in the blood and bone marrow. Acute Myeloid Leukemia (AML), including AML Induction Failure cases (AML-IF) - Another type of blood cancer marked by too many myeloblasts, an alternate type of immature white blood cell, are found in the blood and bone marrow. Upon diagnosis, AML patients without high-risk genetic markers undergo standard chemotherapy regimen, called the primary induction phase, to eliminate most cancer cells and induce a remission state. Clear Cell Sarcoma of the Kidney (CCSK) - A rare type of kidney cancer, in which the inside of the cells looks clear when viewed under a microscope. Clear cell sarcoma can spread from the kidney to other organs, most commonly the bone, but also including the lungs, brain, and soft tissues of the body. Neuroblastoma (NBL) - Cancer of cells of the sympathetic nervous system. Cancer Model Systems (MDLS), including PPTP - MDLS includes acute leukemia cell lines and xenografts with matched primary and/or relapsed tumor information, NBL cell lines and xenografts with matched controls, kidney tumor cell lines, normal brain tissues, and embryonic stem cell lines that were sequenced for some TARGET disease projects. Osteosarcoma (OS) - A cancer of the bone that primarily affects children and adolescents. Rhabdoid Tumor (RT) - A rare, fast-growing cancer that usually forms in the kidney or central nervous system (the brain and spinal cord) but can also form in soft tissues in other areas of the body. Rhabdoid tumors tend to spread quickly, are hard to treat, and have a poor prognosis. Wilms' Tumor (WT) - A cancer of cells in the kidney that can spread to the liver, lung and lymph nodes. More information can be found about each TARGET subproject by following the links on the top of this page. Together these cancers account for the majority of the more than 10,000 childhood cancer cases diagnosed in the United States each year. TARGET has employed a set of advanced and complementary genome analysis technologies, including large scale 2nd and 3rd generation genome sequencing, to strategically characterize alterations in both gene expression and in genomic structure (such as deletions and amplification) that are involved in childhood cancers. The goal of this coordinated effort has been to create a comprehensive genomic and transcriptomic profile of each cancer. Integrated analysis of the TARGET data has identified those genes that are either altered in their expression level or mapped to the chromosome regions of deletion/amplification/translocation, as these genes represent strong candidates for therapeutic targeting. To learn more about the TARGET project, which is now completed, visit the website at https://www.cancer.gov/ccg/research/genome-sequencing/target. TARGET data is accessible at the NCI's Genomic Data Commons (GDC) via the GDC's Data Portal and from each of the TARGET Publication Pages at the GDC (Please see the "Supplemental Links" section of any TARGET publication's "Publication Information and Associated Data Files page" at the GDC.). Available datasets include raw sequencing data, datasets generated by the original TARGET research teams (fully annotated clinical information and higher-level/analyzed molecular characterization data - gene expression, copy number variation, epigenetics, targeted sequencing), as well as higher level data generated by the GDC. Please see the TARGET Use and Publication Guidelines for updated details on the sharing of any TARGET substudy data, including how to cite TARGET.

  Study phs000218

• RNA-seq of iPSC-derived oligodendrocytes of individuals with and without t(1;11) translocation

  This dataset contains high-throughput RNA-sequencing of 14 samples, each sample comprising oligodendrocytes derived from human induced pluripotent stem cells, from individuals with and without a balanced t(1;11) translocation which substantially increases risk of major mental illness. 5 samples derive from 2 control individuals, and 9 samples from 3 individuals carrying the translocation. Libraries were prepared from each total-RNA sample using the TruSeq Stranded Total RNA with Ribo-Zero kit. Libraries were then sequenced using the NextSeq 500/550 High-Output v2 (150 cycle) Kit on the NextSeq 550 platform. Raw paired-end sequencing data is stored in two FASTQ files per sample.

  Dataset EGAD00001006341

• Functionally-defined Therapeutic Targets in Diffuse Intrinsic Pontine Glioma (DIPG)

  Diffuse Intrinsic Pontine Glioma (DIPG) is a universally fatal childhood cancer. Here, we performed a chemical screen in patient-derived DIPG cell cultures along with RNAseq expression analysis and integrated computational modeling to identify potentially effective therapeutic strategies. Panobinostat, among the more promising agents identified, demonstrated efficacy in pontine orthotopic xenograft models of both H3K27M and histone WT DIPG. These data suggest the potential utility of specific drug combinations and provides evidence of in vivo treatment efficacy of the multi-histone deacetylase inhibitor panobinostat. We are depositing to dbGaP deep sequencing whole exome data for 22 patient tumor samples and 13 matched normals, along with RNAseq data for 12 patient tumor samples and 6 normal pediatric brain tissue samples. In addition, we are depositing 22 RNAseq samples from DIPG cell lines before and after panobinostat treatment.

  Study phs000900

• Epigenetic profiling of colorectal cancer initiating cells (CC-ICs) to identify bivalently marked genes (H3K4me3 and H3K27me3 ChIP-seq), and investigation of changes in transcriptome following EZH2 inhibition using RNA-seq.

  Epigenetic regulation of transcription plays a crucial role in lineage commitment of embryonic stem cells. Promoters of key lineage-specific differentiation genes are found in a repressed bivalent state, having both activating H3K4me3 and repressive H3K27me3 histone marks, making them poised for transcription upon loss of H3K27me3 in response to environmental cues. Whether the tumour-initiating, self-renewing, cancer-initiating cells (C-ICs) have similar epigenetic regulatory mechanism that prevent lineage commitment is unknown. In order to investigate bivalently marked and repressed promoters, we used a patient-derived CC-IC enriched model to identify the changes in transcriptome following inhibition of EZH2, the H3K27 methyltransferase. We also performed ChIP-seq for H3K27me3 and H3K4me3 at baseline in order to identify repressed and bivalently marked promoters.

  Study EGAS00001003003

• Resuscitation Outcomes Consortium (ROC) Amiodarone, Lidocaine or Neither for Out-Of-Hospital Cardiac Arrest Due to Ventricular Fibrillation or Ventricular Tachycardia (ALPS)(ROC-ALPS-BioLINCC)

  Accessing Data Please refer to “Authorized Access” below regarding accessing data through the BioData Catalyst ecosystem. The data from this accession is not available for download through dbGaP. Objective To compare the effects of amiodarone, lidocaine, and placebo on survival to hospital discharge after out-of-hospital cardiac arrest due to shock-refractory ventricular fibrillation or pulseless ventricular tachycardia. Background Ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT) are common causes of out-of-hospital cardiac arrest, but are considered the most responsive to shock and therefore the most treatable. Nonetheless, most defibrillation attempts do not result in sustained return of spontaneous circulation, and VF or VT may persist or recur after shock. There is also evidence that longer durations of VF or VT are associated with decreases in the likelihood of resuscitation. Amiodarone and lidocaine are commonly used to promote successful defibrillation of shock-refractory VF or VT and prevent recurrences. Previous trials have shown amiodarone to be more effective than placebo or lidocaine for return of spontaneous circulation and survival at hospital admittance. This study sought to further extend the research and examine whether amiodarone would improve survival to hospital discharge and neurologic outcomes, as compared to placebo or lidocaine. Participants 3,026 eligible participants were enrolled, with 974 assigned to amiodarone, 993 assigned to lidocaine, and 1,059 assigned to placebo. An additional 1,627 participants that received a study intervention, but did not meet eligibility criteria, were included in analysis of the intention-to-treat population. Design The study interventions (amiodarone, lidocaine, and saline) were packaged in indistinguishable sealed kits and randomly distributed in to Emergency Medical Services (EMS) providers in a 1:1:1 ratio, stratified by participating site and agency. Each kit contained three syringes, and each syringe held 3 ml of colorless fluid containing 150 mg of amiodarone, 60 mg of lidocaine, or normal saline. Participants with out-of-hospital cardiac arrest were treated in accordance with local EMS protocols, in compliance with American Heart Association (AHA) guidelines. If VF or VT persisted or recurred after one or more shocks, eligible participants received a vasopressor and the masked kit containing amiodarone, lidocaine, or placebo. Approximating current clinical practice, the initial dose consisted of two syringes administered by rapid bolus. If the estimated body weight of the patient was less than 100 lbs., then one syringe was used. If VF or VT persisted, standard resuscitation measures, additional shocks, and an additional syringe of the study drug were administered. At that point the trial interventions were completed and standard interventions for advanced life support were employed. Upon arrival at the hospital, providers were notified of the patient's enrollment in the trial and encouraged to provide usual care in accordance with AHA guidelines, including open-label amiodarone or lidocaine if necessary. Components of hospital care were monitored but not standardized by the trial protocol. Participants, providers, and trial personnel were blinded to the trial drug assignments, with the exception of treating physicians if emergency un-blinding was required for care. Data from pre-hospital patient care records, CPR process measures, and hospital medical records were collected. The primary outcome of the trial was survival to hospital discharge, and the secondary outcome was survival with favorable neurologic status at discharge, defined as a score on the modified Rankin scale of 3 or less. Conclusions Neither amiodarone nor lidocaine resulted in a significantly higher rate of survival to hospital discharge or favorable neurologic outcome, as compared to placebo, among participants with out-of-hospital cardiac arrest due to initial shock-refractory ventricular fibrillation or pulseless ventricular tachycardia.

  Study phs003784

• Single-Nuclei Paired Multiomic Analysis of Young, Aged, and Parkinson's Disease Human Midbrain Reveals Age-Associated Glial Changes and Their Contribution to Parkinson's Disease

  Age is the primary risk factor for Parkinson's disease (PD), but how aging to change the expression and regulatory landscape of the brain remains unclear. Here, we present a single-nuclei multiomic study profiling shared gene expression and chromatin accessibility of young, aged and PD post-mortem midbrain samples. Combined multiomic analysis of midbrain nuclei along a pseudo-pathogenesis trajectory reveals that all glial cell types are affected by age, but microglia and oligodendrocytes are further altered in PD. We present evidence for a novel disease-associated oligodendrocyte subtype and identify genes lost over the aging and disease process, including CARNS1, that may predispose healthy cells to develop a disease-associated phenotype. Peak-gene association analysis from paired data identifies 89 PD-associated SNP loci, including five in MAPT, that only correlate with gene expression in disease-associated oligodendrocytes. Our study suggests a previously undescribed role for oligodendrocytes in aging and PD pathogenesis.

  Study phs002819

• Tocilizumab treatment leads to early resolution of myeloid dysfunction and lymphopenia in patients hospitalized with COVID-19

  Tocilizumab, an anti-interleukin-6 receptor inhibitor, is recommended in global treatment guidelines for patients hospitalized with severe COVID-19. Using proteomic and transcriptomic analysis, we characterized the immune profile and identified cellular and molecular pathways directly modified by tocilizumab in peripheral blood samples collected from patients enrolled in the COVACTA study, a phase 3, randomized, double-blind, placebo-controlled trial, to assess the efficacy and safety of tocilizumab in hospitalized patients with severe COVID-19 pneumonia. We identified factors predicting disease severity and clinical outcomes, including markers of inflammation, lymphopenia, myeloid dysfunction, and organ injury. Proteomic analysis confirmed a pharmacodynamic effect for tocilizumab. Transcriptomic analysis revealed that tocilizumab treatment leads to faster resolution of lymphopenia and myeloid dysfunction associated with severe COVID-19 thus supporting an underlying anti-inflammatory mechanism of action for the beneficial effects of tocilizumab in patients hospitalized with COVID-19.

  Study EGAS00001006688

• A clinically applicable connectivity signature for glioblastoma includes the tumor network driver CHI3L1

  Tumor microtubes (TMs) connect glioma cells to a network with considerable relevance for tumor progression and therapy resistance. The determination of TM-interconnectivity in individual tumors has been challenging and the impact on patient survival unresolved. Here, a connectivity signature from single-cell RNA-sequenced (scRNA-Seq) xenografted primary glioblastoma (GB) cells has been established using a dye uptake methodology, confirmed with recording of cellular calcium epochs and validated with clinical correlations. Astrocyte-like and mesenchymal-like GB cells have the highest connectivity signature scores in scRNA-sequenced patient-derived xenografts and patient samples. In large GB cohorts, network connectivity correlated with the mesenchymal subtype and dismal patient survival. CHI3L1 has been identified and validated as a robust molecular marker of connectivity with functional relevance. The connectivity signature allows novel insights into brain tumor biology, provides a proof-of-principle that tumor cell TM-connectivity is relevant for patients’ prognosis, and serves as a robust prognostic biomarker.

  Study EGAS00001007611

• WTCCC2 Visceral Leishmaniasis (VL) samples

  A WTCCC2 project genome-wide association study for visceral leishmaniasis (VL) in individuals from India, Brazil and Sudan, genotyped on the custom Illumina 670k array. The WTCCC2 analysis of the Brazilian and Indian samples is described in Fakiola et al. [Nat Genet. 2013 Feb;45(2):208-13].It should be noted that due to expected family structure in the data, normal analyses of these data should include an estimation of the relatedness between the samples. For more details about sample collection for the project please refer to the Methods section of the paper above. The samples from India were all collected from Bihar state in northeastern India. The Brazilian samples were collected from a wide area of northern Brazil, and managed at two laboratories in Natal and Belem. For more details on the geographic distribution of the Brazil samples please see Jamieson et al. [Genes Immun. 2007 Jan;8(1):84-90]. We have not generated qc_passed or info files for the Sudanese data, a preliminary scan of the data indicated that there may be DNA quality issues with these samples.

  Study EGAS00001000773

• Novel compound heterozygous mutations in UHRF1 are associated with atypical immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome with distinctive genome-wide DNA hypomethylation

  Our study goal is to reveal underlying molecular pathogenesis of Immunodeficiency, Centromeric instability, and Facial anomalies (ICF) syndrome, which is characterized by hypomethylation of centromeric/pericentromeric repeats.

  Study JGAS000559

• Cancer Research UK Manchester Institute/ Cancer Research UK National Biomarker Centre Data Access Committee

  Cancer Research UK Manchester Institute/Cancer Research UK National Biomarker Centre Data Access Committee is created to • Review and approve data access requests. • Ensure data security and compliance with institutional and legal obligations. • Maintain accurate records of access decisions For questions or further information, please contact: Chair of the Data Access Committee: Caroline Wilkinson Email: dac@cruk.manchester.ac.uk

  Dac EGAC50000000795

• Methylation Array data for: Three-dimensional patient-derived models of glioblastoma retain intra-tumoral heterogeneity

  3 sets of matched patient-derived-organoids (PDOs),  -neurospheres (PDNs), and parent glioblastoma tissue (9 samples total) underwent methylation array analysis. 200ng of each sample DNA extracted via a commercial kit (Qiagen) and loaded onto the Illumina EPIC v2.0 array. Data is provided as raw red and green .idat files.

  Dataset EGAD00010002745

• single-cell RNA-Seq samples of CRC patients

  The dataset contains samples of 11 CRC patients (2 samples for each patient, tumor and normal adjacent tissue site, 22 samples in total). Dataset is composed by fastq file (paired end) type from 10x single-cell RNA-Seq.

  Dataset EGAD00001009634

• RNA-Seq Dataset of Organoid drug profiling identifies methotrexate as a therapy for SCCOHT, a rare pediatric cancer

  We generated and characterized tumoroids from small cell carcinoma of the ovary, hypercalcemic type. Furthermore, we identified a drug that is selective and effective against SCCOHT tumoroids.

  Dataset EGAD00001015441

• Assessment of genetic and epigenetic variation in human IPS cells

  In order to progress human induced pluripotent stem cells (hiPSCs) towards the clinic, several outstanding questions must be addressed. It is possible to reprogram different somatic cell types into hiPSCs but it is unlcear whether some cell types carry through fewer mutations through reprogramming (either due to mutations present in the primary cells, or mutations accumulated during reprogramming). Through in depth analysis of hiPSCs generated from different somatic cells, it will be possible to assess the variation in genetic stability of different cell types.

  Dataset EGAD00001000384

• cfDNA dataset from extracelular vesicles and paired non-fractionated samples

  Liquid biopsies contain multiple analytes that can be mined to improve the detection and management of cancer. Beyond cell-free DNA (cfDNA), mutations have been detected in DNA associated with extracellular vesicles (EV-DNA). The genome-wide composition and structure of EV-DNA remains poorly characterized, and whether circulating EVs are enriched in tumor signal compared to unfractionated cfDNA is still unclear. Here, using whole genome sequencing from selected lung cancer patients with a relatively high cfDNA tumor content >5%, we determined that the tumor fraction and heterogeneity are comparable between DNA associated with small (<200 nm) EVs and matched plasma cfDNA. DNA in EV fractions, obtained with standardized size-exclusion chromatography, are comprised of short ~150-180 bp fragments and long >1000 bp fragments that are poor in tumor signal. Other fractions only exhibit short fragments with similar tumor DNA content. The composition in bases at the end of EV-DNA fragments, as well as their fragmentation patterns are similar to total plasma cfDNA. Mitochondrial DNA however is relatively enriched in EV fractions. Our results suggests that cfDNA in plasma may be of dual nature, either bound to proteins (including the nucleosome) but also associated to EVs. cfDNA associated to small EV (including exosomes) is however not preferentially enriched in tumor signal.

  Study EGAS00001006848

• International Genetics of Parkinson Disease Progression (IGPP) Consortium: EPIPARK and HBS2 Cohorts

  EPIPARK and HBS2 cohorts were analyzed as part of the International Genetics of Parkinson Disease Progression (IGPP) Consortium. EPIPARK is a population-based cohort to study non-motor symptoms in parkinsonism in the city of Lübeck, Germany led by Drs. Meike Kasten and Christine Klein. HBS2 is a recently enrolled subset of participants in the Harvard Biomarkers Study led by Dr. Clemens Scherzer (www.bwhparkinsoncenter.org/biobank) of 89 participants with a diagnosis of Parkinson Disease (PD). Genotyping with Illumina Infinium Multi-Ethnic Genotyping Arrays (MEGA chip) was performed by Dr. Scherzer, Harvard Medical School and Brigham and Women’s Hospital. 179 participants with a diagnosis of PD from EPIPARK and 89 participants with a diagnosis of PD from HBS2 met Q/C criteria were analyzed.

  Study phs002328

• mutational landscape of normal human breast

  The accumulation of somatic mutations in the healthy breast throughout life and pregnancy is poorly understood. Here we describe whole genome sequencing analysis of epithelial and stromal compartments from the normal breast. We aimed to study how pregnancy and age affect both the mutational burden and the clonality of the healthy breast, and the subsequent implications on breast cancer risk.

  Study EGAS00001004672

• TIRE-seq_PDN

  TIRE-seq is a novel RNA sequencing method that integrates mRNA purification directly into library preparation, eliminating separate RNA extraction. The technique demonstrated utility across three biological applications, including capturing transcriptional changes in human T cells, identifying genes driving murine dendritic cell differentiation, and analyzing the dose-response effects of temozolomide on patient-derived neurospheres. With its simplified approach and high sequencing efficiency, TIRE-seq offers a cost-effective solution for large-scale gene expression studies.

  Dataset EGAD50000001261

• Anaplastic Thyroid Cancer aligned sequence data

  Sequence data in fastq format was aligned to the GRCH38 reference genome. Aligned sequence was preprocessed with GATK for Indel Realignment and Base Quality Score Recalibration. Duplicates were marked with Picard Mark Duplicates. Aligned sequence is in bam format. Details of the alignment can be found int he bam header. In total, data generated from 174 tumour samples 102 matched blood normal controls was aligned. Tumour samples were classified as Anaplastic Thyroid, Poorly-differentiated or well-differentiated cancers.

  Dataset EGAD00001004126

• Single cell RNA sequencing of colorectal cancer

  To understand intrinsic cancer cell signatures and the surrounding microenvironemt and their interactions, we performed single-cell RNA sequencing on 63,689 cells from 23 patients with 23 primary colorectal cancer and 10 matched normal mucosa samples. Analyzing of primary colorectal cancer and normal mucosa samples show a comprehensive cellular landscape of colon cancer, which is a valuable resource for the development of therapeutic strategies.

  Dataset EGAD00001005198

• WGS of off-target analysis of base editing in organoids

  Seven clonal organoid lines and one bulk wild-type control sample were paired-end whole-genome sequenced using the Illumina Novaseq 6000 system. We sequenced four clonal intestinal organoid lines harbouring engineered TP53 and FBXW7 mutations as well as three lines targeted for oncogenic APC/TP53/PIK3CA/SMAD4 mutations. The reads were mapped to hg38 genome assembly and data is provided as BAM files.

  Dataset EGAD00001009827

• DAC Portal documentation

  DAC Portal Welcome to the DAC Portal documentation! If you are involved in governance or legal aspects, technical or operational aspects, or serving as a data steward, this page will be helpful for you. By exploring these materials, you can define your own Data Access Committee (DAC) and policies, understand the minimal requirements for a DAC and a policy object, and comprehend how the EGA data access requests are managed. DAC Portal Index Setting up your account DACs and Policies Pending Request table Manage Data Requests History page Audit your DACs, policies, and datasets Deprecation User Preferences DAC API - A programmatic approach Setting up your account Register yourself as an EGA user. The Helpdesk team will validate your account (this could take up to 48 hours). After validation, you will receive an email with a link to verify your email - Make sure you click on the link to verify your account! If you don’t receive the email, please check your spam folder. Once your account is active you can login to the DAC Portal. We recommend you to check out the Take The Tour! DACs and Policies Create a DAC Click on Create a DAC Add the title and description to your DAC. Once ready, click on the ‘Create’ button. You will have to wait until the Helpdesk Team validates the creation of your DAC. Once approved by Helpdesk, your DAC will be assigned with a persistent identifier (EGAC). Edit a DAC Once your DAC is registered and approved, you can edit it and add contacts. Remember, you can add as many contacts as needed. And, you can also remove/add contacts anytime. To add a contact, you must write the username or email of a registered EGA user in the Members field. Once you have typed the whole username or email, a drop-down menu will appear where you can select the contact. Select a contact from the drop-down menu. Make sure you write the full username or email of the contact so it appears as an option. Make sure that you select one main contact. Set up the role you want to grant to the new contact of the DAC. We recommend you to check out the FAQ to learn more about the different roles! After adding all the necessary contacts and assigning roles, click on Update. This will send an email notification to the new DAC member, letting them know about the invitation to managing the DAC. Once they log into the DAC Portal, they will be able to either accept or turn down the invitation. Create a policy First, please note that all information registered in a policy metadata object will be publicly available on the EGA website. For each released dataset, all users will be able to read the policy under the “Data Access” tab. Select Create a Policy from the Policies tab. Select the DAC that you want your policy to depend on. Add the title and terms and conditions for accessing and using your data. If you already have an external website for data access requests, you can add the URL directly here (see example here). You can find a template of a Data Access Agreement (DAA) document in our Policy documentation page. The DAA template is provided for guidance only and should be adapted to suit your own purpose depending on the security policies, terms for publication or embargoes, and restrictions on data use or sharing. You can also add Data Use Ontologies (DUO) to your policy. These DUO codes are used to semantically tag the terms and conditions of using the data linked to the policy (example). For more information, you can refer to the Data Uso Ontology documentation. Once completed, make sure to click the Create button in order to register your policy. A persistent identifier (EGAP) will be assigned automatically. Edit a policy Please, note that you will not be able to edit the policy if it shows in orange. Meaning that you are a member of the DAC linked to that policy. Members don’t have edit rights. Only admins can edit objects. You can check your registered policies on My policies, available at the menu in the top-right corner. Select your policy. It will then display the information of that policy, allowing you to edit the information. Once you are done with the modifications, click Update. Pending Requests Table Table Settings Upon selecting a specific DAC, you will be presented with a customisable table showcasing all pending data access requests. This table allows you to tailor the displayed information according to your preferences by selecting desired columns. Available Columns (Displayed with the Eye Icon): Date: The date when the data access request was submitted. Full Name: Name and surname of the user submitting the request. Email: Email address associated with the user's request. Username: The username linked to the EGA account of the user submitting the request. Organisation: Affiliated organisation of the user submitting the request. Dataset: EGA accession ID for the requested EGA dataset. Dataset Title: Title of the requested dataset. DAC Comment: Space provided for internal comments related to the request. Expiration: Option to specify an expiration date for granted permissions. Check more information on the pending request table here! Table Filters By default, all data access requests are displayed. However, you have the option to apply filters to refine your view. Follow these steps to apply filters: Click on the More button. This action will reveal the different columns available for applying filters. As you select columns, the checked fields will be displayed at the top of the request table. Choose the specific values within the selected columns that you want to filter for. Click the Search button to apply the selected filters. Do you find yourself frequently applying the same filters? You can save multiple combinations of filters for easy access at any time! Here's how: Click the Save button. Provide a descriptive name for the filter combination. Click Save to confirm. To load saved filters, simply select the saved filter from the dropdown menu to apply it automatically. Check more information on filters here! Advanced Search For users requiring more granular control over their data access requests, the DAC Portal offers an Advanced Search feature using JIRA Query Language (JQL). With JQL, you can craft precise and complex queries to filter and retrieve specific data access requests based on various criteria such as date, user details, dataset attributes, and more. Using JQL's flexibility, you can create custom queries to meet your specific needs, allowing for advanced filtering options beyond the standard filters provided. You can find the Advanced Search feature following these steps: Click the … button Select Advanced To view the allowed fields for filtering and explore all available options, simply click on the info icon. Once you have written the filtering values, click the Search button to apply. Check more information on filters here! Manage Data Requests Upon logging into the DAC Portal, you'll notice a sand clock icon next to the DAC ID, indicating the number of pending requests. Click on the DAC to review these requests. Accept requests Click on the right side of the toggle button to grant access to the user. You can manage other requests before proceeding to the next step. After managing the requests, click on the Apply button. A confirmation box will appear summarising the options to be applied. Click on Yes, Confirm to proceed with granting permissions. Deny requests Click on the left side of the toggle button to deny access to the user. Provide a reason for the denial. Note that the user will receive an email with this reason. Click on the Done button. You can manage other requests before proceeding to the next step. After managing the requests, click on the Apply button. A confirmation box will appear summarising the options to be applied. Click on Yes, Confirm to proceed with denying permissions. Tips! Apply a filter to view all requests to be managed at once. Use the toggle in the row with column names to grant or deny permissions for multiple requests simultaneously. You can grant and deny permissions in the same action, simplifying the process. The confirmation box will provide a summary of all actions, including grants, denials, DAC comments, and expiration dates. History Page The History page serves as a dedicated space to view information regarding all requests managed by all DAC members. Here, you can review active permissions and revoke them as needed. Go to the History page by clicking on the "HISTORY" button from a DAC page in the DAC Portal. Here are the different row types you may find: Current permissions: row in green with a toggle button to revoke permissions on the right. Approved requests: row in green, with no toggle button. Request denied: row in red with “request denied” on the right. Permission revoked: row in red with “permission revoked” on the right. Distinctions to Note! Between Request Denied and Permission Revoked: Request Denied: Refers to requests that were rejected from the outset, indicating that access to the dataset was never granted. Permission Revoked: Indicates that permissions were previously granted but have since been revoked. Users with permissions revoked have previously accessed the dataset. Between Approved Request and Current Permissions: Approved Request: Represents an entry when a data access request has been approved in the past. Current Permissions: Denotes ongoing permissions where a user has present access to the dataset. An approved request may now appear as Permission Revoked in the present. By observing these different rows, users can gain insight into the complete history of a user's interactions and permissions regarding a dataset over time. To revoke access to a specific user for a dataset, follow these steps: Go to History page Look for the row with the specific permissions. You can use the filters! Click on the toggle button to revoke access. Add a denial reason. Bear in mind that the requester will receive the denial reason! Click on the Apply button. Check more information on the Hisotry page here! Audit your metadata objects In the DAC Portal, you can efficiently manage and audit various metadata objects pertinent to your role as a Data Controller. Upon accessing the DAC Portal, you will encounter three primary tabs on the homepage: DAC: Contains information about Data Access Committees (DACs). Policies: Provides insights into linked policies. Datasets: Displays datasets and relevant details. Within each tab, you'll find a comprehensive list of the objects you manage, these being grouped by type (DAC, Policies, Datasets), as well as by your role (member/admin). Whilst the lists give you a quick look, to check how things are connected, we've added a table at the bottom DACs and policies. DACs Let’s check which policies are linked to a specific DAC: Go to "My DACs." Select a DAC. Click on "EDIT" to see more details. You are now on this page: Scroll down to see the linked policies. Click on “List of linked policies of this DAC” and you will see a list of all policies linked to your selected DAC. Policies Do you want to view a list of datasets connected to a particular policy? Follow the same steps mentioned earlier, but head to the policy tab this time. In the policy tab, you'll find a list of all your policies. Here, you may notice two different icons next to the policy ID (EGAP): DAC Icon (): This represents the DAC. Hover your mouse over the icon to see the DAC ID. Dataset icon (): This indicates datasets falling under that policy. The number next to the icon tells you how many datasets are linked to the policy. For example, if you see "2" next to the icon, it means there are two datasets linked to that policy. If you want to check the linked datasets and their relevant information, simply click on a specific policy. You'll then find the "List of linked datasets of this policy" at the bottom of the page. Datasets Finally, in the dataset tab, by default you will see a list of all the datasets you can manage with all your DACs and policies. Yet, we've included two handy ways to organise them: DAC vs. policy: You can group by datasets, either by DAC or policy. Released vs. unreleased: You can sort out datasets based on their release status. Feel free to experiment with both options! For instance, if you want to see which DACs have unreleased datasets, simply select DAC and unreleased, and you'll get the details you need! Deprecation Do you have a bunch of metadata objects like DACs and policies that you don’t need anymore? This section shows you how to get rid of them! But what does "deprecation" mean for EGA? It's basically changing the status of a metadata object to "deprecated," which means we won't be using it in the future. In simple terms, it's like saying these objects are no longer useful. However, because we believe in making metadata FAIR, once an object has a persistent identifier, we can't just delete it. So, instead of deleting, we deprecate it. Here's a helpful tip! If you want to make a metadata object disappear from the DAC Portal, deprecate it. You won’t see it in the portal anymore! Let’s say you want to deprecate a DAC. Let’s do it! Go to "My DACs." Select a DAC. Click "EDIT" to see more details. You are now in this page: Click on the Deprecate button It will then appear a message. There are two options here: Your DAC is not linked to any policy, hence it’s ready to be deprecated. Click on “Yes. Confirm” to deprecate your DAC object! Your DAC is linked to at least one policy, and you need to either: Deprecate the linked policy first, or Link the policy to a different DAC Now, let’s say you don’t want to get rid of the policy altogether, but you want to change the DAC it’s linked to. Here's how: Go to the policy tab. Find the policy you want to change (for example, EGAP50000000019). Choose a new DAC to link it to. Click on Update. See the Edit Policy section for more details. After ensuring that the DAC we want to deprecate isn’t linked to any policy, return to the "My DACs" section and follow the steps outlined previously. This will lead you to a confirmation message. You can only deprecate DACs and Policies. To deprecate a dataset, please contact our Helpdesk team. Check more information on how deprecation works here! User Preferences We have implemented email notifications in the DAC Portal. Here’s the complete list: DACs: Pending requests Approved by Helpdesk Rejected by Helpdesk DAC Invitation Requesters: Data access request approved Data access request denied Permissions revoked Upcoming expiration date As a DAC member, you will be able to decide whether you want to receive the DAC notifications or not. For that, go to the top-right corner menu, select User Preference. You will be able to decide whether you want to receive notifications for: Approved by Helpdesk Rejected by Helpdesk DAC Invitation For pending requests, you will be able to select how often do you want to receive the notification: Daily Weekly Fortnightly As a DAC member, you are responsible for managing data access requests. Consequently, you will receive notifications for pending requests. If you prefer not to manage these requests, please arrange to be removed as a contact for your DAC. Here's a tip! Do you have a pending request that you don’t want to receive a notification? Add a DAC comment! The EGA understands that a request resolution can take some time, for this reason, if you add a comment (make sure you save it by clicking the APPLY button!) we will filter those requests at the time of sending the notification! DAC API - A programmatic approach In addition to the new DAC Portal, we are excited to announce the release of the DAC API. This enables users to programmatically manage permissions. If you are interested in learning more about the technical specifications, you can click the button below. Check out the DAC API specification!

  Documentation access/data-access-committee/dac-portal

• A compendium of mutational signatures due to environmental exposures

  Whole-genome-sequencing (WGS) of human tumours has revealed distinct mutation patterns that hint at the causative origins of cancer. We examined mutational-signatures in 324 WGS of human induced pluripotent stem cells (iPSCs) following exposure to known or suspected environmental carcinogens. 79 agents were tested with or without metabolic activation at concentrations that produced measurable cytotoxicity; 41 yielded characteristic substitution mutational signatures. Some exhibit similarity with signatures found in human tumours. Additionally, 6 agents produced double-substitution signatures and 8 produced indel signatures. Investigating mutation asymmetries across genome topography reveals fully functional mismatch and transcription-coupled repair pathways in iPSCs. Primary adducts induced by environmental carcinogens can be resolved by disparate repair/replicative pathways, resulting in an assortment of signature outcomes even for a single mutagen. This compendium of experimentally-induced mutational-signatures permits further exploration of roles of environmental agents in cancer aetiology, and underscores how human stem cell DNA is directly vulnerable to environmental agents.

  Dataset EGAD00001004583

• ucfDNA workflows for molecular profiling of malignant disease

  Urinary cell-free DNA (ucfDNA) is a promising liquid biopsy analyte obtained by a non-invasive sampling method, particularly valuable in urological cancers due to the proximity of biofluids to the tumor site. However, extremely high fragmentation and low abundance of ucfDNA pose significant analytical challenges. Improper handling and storage can severely affect ucfDNA quality, necessitating optimized pre-analytical workflows for clinical applications. We evaluated multiple pre-analytical workflows, including urine stabilization approaches against unstabilized urine samples. Our results demonstrated that without stabilization, ucfDNA degraded rapidly and minimal quantities remaining after 72 hours. In contrast, urine stabilization preserved ucfDNA integrity, enabling successful downstream analyses, including digital PCR and next-generation sequencing, for mutation detection in cancer-related genes and genome wide copy number profiling. These findings underscore the critical role of stabilization for a reliable ucfDNA analysis and highlight its potential in molecular diagnostics as a complementary tool to plasma-based liquid biopsies.

  Study EGAS50000001093

• Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR and PEAR-2)

  The primary aim of the Pharmacogenomic Evaluation of Antihypertensive Responses grant (funded by NIH Pharmacogenomic Research Network grant U01 GM074492) was to identify genetic determinants of blood pressure response and adverse events after antihypertensive treatments. Two different clinical trials with genomic information available were included: PEAR-1 and PEAR-2 studies. The PEAR-1 study (clinicaltrials.gov identifier NCT00246519) was a randomized controlled clinical trial evaluating genetic determinants of BP responses and adverse metabolic responses to atenolol and hydrochlorothiazide (HCTZ) monotherapy and in combination (PMID: 19249413). Briefly, PEAR-1 recruited 768 hypertension individuals with uncomplicated hypertension who were randomized to either monotherapy of atenolol 50 mg daily or HCTZ 12.5 mg daily for 3 weeks, followed by dose titration to 100 mg and 25 mg daily, then the combination therapy. BP and metabolic responses to monotherapy and combination therapy were assessed after an average of 9 weeks of antihypertensive treatment. BP was measured using three different methods: home, office and ambulatory. For the BP analysis, a composite weighted average of the office, home, ambulatory daytime and nighttime BP responses was calculated based on the row sums of the inverse of the inter-method covariance matrices. Genomic DNA from PEAR-1 participants was genotyped using the Illumina Human Omni1MQuad BeadChip (Illumina, San Diego, CA, USA). The PEAR-2 study was a multicenter sequential monotherapy clinical trial (clinicaltrials.gov identifier NCT01203852) evaluating genetic determinants of BP response to metoprolol monotherapy and chlorthalidone monotherapy. After a washout period (if necessary), eligible hypertensive patients with uncomplicated hypertension received metoprolol tartrate 50 mg twice daily for 3 weeks and the dose was increased to 100 mg twice daily for an additional six weeks if an inadequate response was observed (>120/70 mm Hg and heart rate >55 beats/min). After second washout period, patients received chlorthalidone monotherapy. Home and office BP measurements were collected in PEAR-2 study. We have previously demonstrated that home BP is the more informative single BP measurement compared to the office BP measurement. Therefore, home BP is the phenotype used for the genome-wide association analysis for PEAR-2. PEAR-2 samples were genotyped using the Illumina Human Omni2.5S Beadchip (Illumina, San Diego, CA, USA).

  Study phs000649

• Multi-omics analysis of pediatric high-risk neuroblastoma

  Neuroblastoma is the most common extracranial solid malignancy among children originating from undifferentiated neural crest cells. Despite recent intensified treatment, high-risk patients still show a high mortality rate. To explore a new therapeutic strategy, we performed integrated analysis in 30 neuroblastoma cases.

  Study JGAS000246

• Whole-Transcriptomic Profiling of Sorted Human Renal Cell Carcinoma Immune Populations

  It is poorly understood how the tumor immune micro-environment influences disease progression in renal cell carcinoma (RCC). Here we performed whole-transcriptomic profiling of immune cell populations which were derived from RCC patients representing distinct flow-sorted immune lineages.

  Study EGAS00001006593

• Mucosal Melanoma Targeted Exome Sequencing Study (UCSF)

  Mucosal melanoma is a deadly disease that carries the worst prognosis amongst subtypes of melanoma. Like all melanomas, mucosal melanomas are frequently driven by activating mutations in the MAPK and/or PI3K pathways; however, unlike melanomas that arise on sun-exposed skin, mucosal melanomas harbor few point mutations. Instead, most somatic alterations involve structural alterations, which appear early during tumor progression. Molecular studies in mucosal melanoma generally only profile point mutations without interrogating copy number alterations, and pathogenic mutations are only found in 30% of cases. We sequenced 38 mucosal melanomas, and in addition to profiling point mutations, we looked for copy number alterations that amplify oncogenes or delete tumor suppressors.

  Study phs001594

• Amplicon sequencing of various tumors

  In our previous studies on advanced esophageal, gastric, and colorectal carcinomas, measurement of circulating tumor DNA (ctDNA) in terms of variant allele frequency (VAF) in blood suggested: (1) patients with high VAF have a high chance of relapse; (2) VAF changes in response to treatment; and (3) ctDNA VAF elevation precedes imaging diagnosis of relapse. It is thus necessary to investigate whether these findings can be generalized in a wide cancer spectrum, types of treatment, and relapse phenotypes across cancer types. In the present study, we conduct a non-interventional observational study in a wide cancer spectrum on the basis of technical establishment for ctDNA using our unique digital PCR probe library.

  Study JGAS000366

• RNA sequencing of pretreatment, on-treatment and posttreatment gastric and gastroesophageal junction tumors treated with neoadjuvant anti-PD-L1 plus chemotherapy

  This set contains a total of 78 files cram files with RNA sequencing data from 20 patients included in the PANDA study treated with 1 cycle of monotherapy atezolizumab and 4 cycles atezolizumab plus chemotherapy (docetaxel, oxaliplatin and capecitabine). RNA was isolated from fresh frozen material and sequenced at 4 timepoints baseline, after monotherapy atezolizumab, after combination atezolizumab plus chemotherapy and at resection (due to 2 missing samples, there is a total of 78 samples).

  Dataset EGAD50000000241

• 16S sequencing data of mucosal biopsies

  This is the dataset of 16S data from mucosal biopsies.

  Dataset EGAD00001008215

• Rituximab-treated lymphoma patients show correlated deficiency in serological and T cell Spike-specific response after SARS-CoV-2 vaccination: insights from the CORSA Study.

  This study is part of the CORSA trial (NCT04345315), a prospective multicentric research project conducted by the Istituto Romagnolo per lo Studio dei Tumori “Dino Amadori” to investigate the immunologic response to mRNA SARS-CoV-2 vaccines in patients with hematologic malignancies (HM) and healthy individuals as controls (HC). The data in this repository refer to two subcohorts: 7 healthy controls and 10 lymphoma patients, randomly selected. Whole blood samples were collected to characterize T cell receptor (TCR) repertoire specificity against SARS-CoV-2 proteins before and after two BNT162b2 vaccination cycles, at baseline (before vaccination), 50 days after the first dose (V1), and 6 months after the first dose (V3). All participants were vaccinated under the Italian national campaign and provided informed consent following the Declaration of Helsinki. We investigated SARS-CoV-2-specific T cell responses through TCR repertoire profiling and examined correlations between serological and cellular responses in both patient and control groups. Using Next-Generation Sequencing (NGS) to characterize the CDR3 sequences of TCR β-chains from peripheral blood, we assessed clonal expansion (depth) and diversification (breadth) of SARS-CoV-2-specific T cell clonotypes over time, aiming to understand how cancer and its treatment influence vaccine-induced immunity in immunocompromised individuals.

  Study EGAS50000001205

• Cardiovascular Cell Therapy Research Network (CCTRN): A Phase II, RCT of Mesenchymal Stem Cells & Cardiac Stem Cells in Subjects With Ischemic HF (CONCERT HF-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. ObjectivesTo assess the feasibility, safety, and efficacy of autologous mesenchymal stromal cells (MSCs) and c-kit positive cardiac cells (CPCs), alone or in combination, in participants with ischemic heart failure.Background The prognosis of heart failure (HF) caused by chronic ischemic cardiomyopathy (coronary artery disease and prior myocardial infarction), hereby referred to as “ischemic HF”, remains poor. Many studies have explored the use of various types of stem or progenitor cells in participants with chronic ischemic HF, with encouraging results. Several clinical trials have suggested that MSCs and CPCs are both safe and beneficial in participants with ischemic HF. At the time of this study, no information was available on the efficacy of MSCs and CPCs in humans, however, both cell types have been shown to attenuate left ventricle (LV) dysfunction in animal models. Preclinical models indicate that combining MSCs and CPCs increases the therapeutic effects, but this had not yet been tested in humans. The CONCERT-HF study was initiated to assess whether autologous MSCs and CPCs, alone or in combination, can be manufactured and delivered to participants with ischemic HF; are well-tolerated; and improve LV function, quality of life, and functional capacity, and/or reduce scar size. Participants A total of 125 participants were randomized with 33 participants randomized to the MSCs and CPCs group, 29 participants to the MSCs alone group, 31 participants to the CPCs alone group, and 32 participants to the placebo group. Design The CONCERT-HF study was a multi-center Phase II, double-blind, randomized, placebo-controlled trial designed to evaluate the feasibility, safety, and efficacy of MSCs alone, CPCs alone, and their combination compared with placebo as well as each other in patients with ischemic HF. In Stage 1 (open label, lead-in study) participants were randomized 1:1 to either a standard-of-care control group (i.e., they did not undergo harvest, mapping, or injection procedures) or combination therapy (MSCs + CPCs, as described for Stage 2) to complete safety assessments. Once approval was granted for Stage 2, participants were randomized (1:1:1:1) to one of four treatments: placebo, autologous MSCs (target dose, 150 × 106 cells), autologous CPCs (target dose, 5 × 106 cells), or a combination of autologous MSCs and CPCs. At the harvest visit, right ventricular endocardial biopsy (EMB) was performed in participants randomized to receive CPCs alone or a combination of MSCs and CPCs. Participants randomized to receive MSCs alone or placebo had a sham procedure (right heart catheterization without EMB). All participants underwent a bone marrow aspiration and approximately 14 weeks later had transendocardial, electromechanically-guided injections of study product. Visits occurred at 1 day, 1 week, and 1, 3, 6, and 12 months after study product injection. A telephone contact took place at 24 months to assess the participant's current medications, as well as morbidity and mortality. Study endpoints included measures of safety, feasibility, and efficacy. Safety outcomes included all adverse events grade 2 and higher, including major adverse cardiac events (MACE) related to HF (death, hospitalization for worsening HF, and HF exacerbation not requiring hospitalization). Efficacy endpoints included quality of life, MRI measures of LV function and structure, functional capacity, and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. Conclusions In patients with ischemic HF, autologous MSCs and CPCs, alone or in combination, are safe and feasible; CPCs were associated with a reduction in the incidence of MACE related to HF compared to placebo; MSCs, either alone or in combination with CPCs, were associated with improved quality of life; these seemingly beneficial effects of CPCs and MSCs on clinical outcome were not associated with changes in LV function or structure; and combination therapy with MSCs and CPCs was associated with the best clinical outcomes with respect to both MACE related to HF and quality of life.

  Study phs004055

• Shanghai Breast Cancer Genetics Study (SBCGS)

  The Shanghai Breast Cancer Genetics Study (SBCGS) includes data from four population-based studies conducted among Chinese women in urban Shanghai: the Shanghai Breast Cancer Study (SBCS), the Shanghai Breast Cancer Survival Study (SBCSS), the Shanghai Women's Health Study (SWHS), and the Shanghai Endometrial Cancer Study (SECS, contributing controls only). Shanghai Breast Cancer Study (SBCS): The SBCS is a population-based, case-control study conducted in urban Shanghai. Subject recruitment in the initial phase of the SBCS (SBCS-I) was conducted between August 1996 and March 1998. The second phase (SBCS-II) of recruitment occurred between April 2002 and February 2005. Breast cancer cases were identified through the population-based Shanghai Cancer Registry and supplemented by a rapid case-ascertainment system. Controls were randomly selected using the Shanghai Resident Registry. Approximately 3500 cases and 3500 controls were recruited in the study. Shanghai Breast Cancer Survival Study (SBCSS) and Shanghai Endometrial Cancer Study (SECS): The SBCSS also used the population-based Shanghai Cancer Registry to identify newly diagnosed breast cancer cases. A total of 5,046 breast cancer patients were recruited. In-person interviews were conducted to collect information on known breast cancer risk factors and anthropometrics by using protocols and questionnaires similar to those used in the SBCS. For genetic studies, controls for the SBCSS cases came from the SECS, which recruited healthy women between January 1997 and December 2003. With the exception of a few questions related specifically to breast or endometrial cancer risk, the questionnaires used in the SECS and the SBCS were very similar. Shanghai Women's Health Study (SWHS): The SWHS is a population-based prospective cohort study of approximately 75,000 adult women who were recruited between 1997 and 2000. The cohort has been followed by a combination of record linkage and active follow-ups. Breast cancer patients identified in the SWHS and non-cases were included in the current study.

  Study phs001088