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• Sequential Antigen-loss and Branching Evolution in Lymphoma after Anti-CD19 and Anti-CD20 Targeted T Cell Engaging Immunotherapy

  CD19 CAR T cells and CD20 targeting T cell engaging bispecific antibodies have been approved in B-cell Non-Hodgkin lymphoma lately, heralding a new clinical setting where patients are treated with both approaches, sequentially. The aim of our study was to investigate the selective pressure of CD19 and CD20 directed therapy on the clonal architecture in lymphoma. Using a broad analytical pipeline, we identified truncating mutations in the gene encoding CD20 conferring antigen loss in 80% of patients relapsing from CD20 bispecs. Pronounced T cell exhaustion was identified in cases with progressive disease and retained CD20 expression. We also confirmed CD19 loss after CAR T cell therapy and report the case of sequential CD19 and CD20 loss. We observed branching evolution with re-emergence of CD20 positive subclones at later time points and spatial heterogeneity for CD20 expression in response to targeted therapy. Our results highlight immunotherapy as an evolutionary bottleneck selecting for antigen-loss variants but also complex evolutionary pathways underlying disease progression from these novel therapies.

  Study EGAS00001007561

• GOSH_Childhood_Leukemia_Behjati_WellcomeCore_RNA

  Paediatric single-cell archival project This project is taking sequential samples of children with B-cell acute lymphoblastic leukaemia (B-ALL) treated at Great Ormond Street Hospital (GOSH) between 2011 and the present day. Patients selected, are those that have done badly (e.g. had to escalate treatment, relapsed or died) despite having apparently ""good"" or ""intermediate"" risk cytogenetics, and often also had immunotherapy (e.g., the bi-specific T-cell engager blinatumomab) because of this. Using samples from key treatment-points, we hope to better characterise their disease and treatment response, to re-define understandings of risk for patients who did unexpectedly poorly. Additionally, we hope to define the disease/immunological factors that determine response to increasingly used immunotherapies within the field of paediatric B-ALL. Each of the samples will be viably frozen bone marrow-derived mononuclear cells. They will come in Eppendorf's, frozen and de-anonymised, from GOSH. We plan to primarily do single cell analysis (GEX, BCR +/-TCR), and then tumour-only WGS and bulk-RNA expression on left-over

  Study EGAS00001007616

• Selective targeting of TBXT with DARPins identifies regulatory networks and therapeutic vulnerabilities in chordoma

  The embryonic transcription factor TBXT (brachyury) drives chordoma, a spinal neoplasm without effective drug therapies. TBXT’s regulatory network is poorly understood, and strategies to disrupt its activity for therapeutic purposes are lacking. We developed designed ankyrin repeat proteins that block TBXT-DNA binding (T-DARPins). In chordoma cells, T-DARPins reduced cell cycle progression, spheroid formation, and tumor growth in mice and induced signs of senescence and differentiation. Transcriptomic and proteomic analyses identified gene networks involved in cell cycle regulation, embryonic cell identity, and interferon response and revealed features of regulome components, such as druggability for future translational studies and the fine-tuning of TBXT downstream effectors through IGFBP3. Finally, we found high interferon signaling in chordoma cell lines and patient tumors, which was promoted by TBXT and associated with sensitivity to JAK2 inhibitors. These findings demonstrate the potential of DARPins for probing nuclear proteins to understand the regulatory networks of transcription factor-driven cancers, including entry points for therapies that warrant testing in patients.

  Study EGAS00001008140

• 10x Genomics raw data of intestinal plasma cells

  The dataset contains raw fastq files (fastq.gz) for Chromium Single Cell 5’ gene expression (GEX), human B cell VDJ and feature barcode (CSP) sequencing from transglutaminase 2-specific and other small intestinal plasma cells isolated from four untreated celiac disease patients. Single cell 5’ gene expression, V(D)J-enriched and cell surface protein libraries were generated using Chromium single cell kits, and barcoded cDNA from a total of 5,000-10,000 cells per sample was generated using the 10x Genomics Chromium Controller. The libraries were pooled prior to sequencing on a NovaSeq 6000 instrument (Illumina) using the following configuration: read 1: 26 cycles, read 2: 89 cycles, index read 1: 8 cycles.

  Dataset EGAD50000000342

• Single-nucleus RNA-sequencing data of kidney biopsies from patients with primary FSGS, maladaptive FSGS, proteinuric controls and healthy controls

  This dataset includes FASTQ files of single-nucleus RNA sequencing of cryopreserved kidney biopsy cores from adult patients with diagnosed primary FSGS (n = 9, all nephrotic), maladaptive FSGS (n = 9, not nephrotic), proteinuric controls (PLA2R-positive membranous nephropathy, n = 3), and healthy controls (n = 4). A total of 120,751 high-quality nuclei were identified, including 2,471 podocytes and 1,574 parietal epithelial cells (PECs). In addition to the raw FASTQ files, the dataset includes processed data files from all 25 samples, generated using Seurat in R: barcode files, features, count matrices, and associated metadata. Details regarding the bioinformatics pipeline can be found at https://github.com/lambrechtslab/FSGS_Deleersnijder_et_al

  Dataset EGAD50000001557

• ICR96 exon CNV validation series

  A resource for assessment of exon CNV calling methods in targeted NGS data, we here present the ICR96 exon CNV validation series. The dataset includes high-quality sequencing data from a targeted NGS assay (the TruSight Cancer Panel) together with Multiplex Ligation-dependent Probe Amplification (MLPA) results for 96 independent samples. 66 samples contain at least one validated exon CNV and 30 samples have validated negative results for exon CNVs in 26 genes. The dataset includes 46 exon CNVs in BRCA1, BRCA2, TP53, MLH1, MSH2, MSH6, PMS2, EPCAM and PTEN, giving excellent representation of the cancer predisposition genes most frequently tested in clinical practice. Moreover, the validated exon CNVs include 25 single exon CNVs the most difficult exon CNV to detect.

  Dataset EGAD00001003335

• Bulk RNA sequencing of human T and B cells before and after interleukin-2 immunotherapy

  Bulk RNA sequencing of flow cytometry sorted human CD4+ regulatory T (Treg), CD4+ conventional T (Tcon), CD8+ T, and CD19+ B cells from systemic lupus erythematosus patients collected at baseline (day 0, before interleukin-2 immunotherpay), day 5 (after 1 treatment cycle of interleukin-2 immunotherapy), and day 68 (after 4 treatment cycles of interleukin-2 immunotherapy). The dataset comprises files from the above-mentioned 4 immune cell subsets, collected at 3 time points (day 0, day 5, and day 68) of 12 systemic lupus erythematosus patients. Due to technical reasons, day 5 samples of patient SLE_012 could not be processed and are thus missing. The complete dataset totals in 140 raw sequencing files (fastq format).

  Dataset EGAD50000000661

• Variant calling analysis of cfDNA whole exome sequencing in neuroblastoma

  This dataset contains VCF files from a variant calling analysis of 19 neuroblastoma patients. WES or WGS data of the primary tumor were compared to WES cfDNA analysis at the time of diagnosis and at a 2nd timepoint (complete remission, partial remission, disease progression or relapse). For 4 patients, WGS of germline, tumor at diagnosis and tumor at relapse DNA was performed on Illumina HiSeq2500, with 100-bp paired-end reads. For the other patients, WES was performed using either an AgilentSureSelect Human All Exon v5 or a Roche Nimblegen SeqCap EZ Exome V3 kit on Illumina HiSeq2000, with 100-bp paired-end reads. SNVs observed in any of the primary tumors or cfDNA samples studied by WES were targeted using a capture sequencing panel at all intermediate time points.

  Dataset EGAD00001003803

• Copy-Number Analysis of Understudied Black Women Ovarian Cancers

  Two general types of genetic alterations drive cancer progression: mutations and copy number alterations (CNAs). With the exception of p53, single nucleotide variant mutations (here, simply "mutations") are not drivers of 80% of tumors within the most frequent and deadly histotype of ovarian cancer: serous ovarian cancer (SOC). Rather, CNAs are more prevalent in SOC than any other cancer type studied by phs000178 The Cancer Genome Atlas (TCGA). Fully two-thirds of genes are altered by CNAs in the average SOC. Bioinformatic methods have shown that these CNAs modulate specific molecular pathways, such as autophagy, and this finding enabled effective pathway-targeted therapies1. Unfortunately, TCGA ovarian cancer data lacks racial diversity. Only 6% of SOC tumors (n=32) studied are from African origin. Black women diagnosed with ovarian cancer are more likely to die from their disease than white women. Five-year survival after diagnosis is 31% among blacks versus 42% among whites, and this disparity is seen in every age group and tumor stage distribution. Dr. Kelemen examined data from 365 white and 95 black ovarian cancer patients from the Hollings Cancer Center (HCC) Cancer Registry between 2000 and 2015 and found that black women had an 81% higher risk of death after diagnosis compared to white women (HR 1.81, 95% CI 1.35-2.43), independent of diagnosis center (98% were treated at HCC but half were diagnosed elsewhere), tumor stage, histology, extent of residual tumor remaining following surgery, insurance status, smoking, type of treatment for ovarian cancer, and age-adjusted Charlson comorbidity index. This disparity remained even when restricted to women who received the standard of care, surgery-chemotherapy sequence (HR 1.79, 95% CI 1.10-2.89). Despite receiving the same treatment, black race was still associated with inferior survival. A similar disparity has been reported by others, indicating that the HCC experience is representative of national data. Here, an additional set of high-grade serous ovarian cancer primary tumors were acquired from biorepositories with a focus on expanding data originating from African American women. Data were analyzed for copy-number alterations using exome sequencing and control-FREEC software.

  Study phs002313

• German early-onset prostate cancer cohort of the Pan-Prostate Cancer Genome (PPCG) project

  Prostate cancer is the most frequent malignant tumor in males and the second most frequent cause of cancer-related death. Currently, in Germany, more than 60,000 prostate cancers are diagnosed every year. Although most of these patients are treated in a curative attempt, more than 10,000 German men die from prostate cancer annually. Owing to the demographic changes of our society, a further doubling of prostate cancer incidences during the next 20 years is expected. Prostate cancer is generally considered a tumor of elderly men. However, a fraction of prostate cancers are diagnosed at the age of 55 years or less. For several reasons, these “early onset prostate cancers” may represent a key entity for the understanding of prostate cancer biology. First, it is likely that early onset prostate cancers represent a distinct molecular subgroup of prostate cancer (PCa), potentially characterized by relatively small numbers of genetic changes, some of which may be particularly strong driver mutations for PCa development. Second, a fraction of prostate cancers in young individuals could represent classical prostate cancers that are detected at a very early stage and might therefore have accumulated molecular changes/mutations occurring that are most instrumental for prostate cancer early detection. Third, PCa with hereditary backgrounds are likely to accumulate in the age group below 55 years. A comparison with other sample sets (e.g. from other ICGC consortia), a systematic genomic analysis of young men with PCa could therefore lead to the detection of mechanisms for hereditary PCa. Fourth, a better understanding of these tumors is particularly relevant as finding optimal treatment regimens is most critical in young cancer patients. We are analyzing the entire genomic DNA sequences of at least 200 PCas (and matched non-tumorous DNA) of young men (≤ 55y), to at least 30 fold coverage, and integrate single-nucleotide variants and genomic structural variations with differential methylation, mRNA and miRNA expression data.Tissues were collected at the University Medical Center Hamburg-Eppendorf. Sequencing was performed at DKFZ and NCT (Heidelberg), EMBL (Heidelberg), and MPIMG (Berlin). Data management and bioinformatic data analyses is being conducted at DKFZ.

  Study EGAS00001003373

• Single cell RNAseq FASTQ files of three PDAC organoid lines (P28, P40, P47) using SORT-seq

  This dataset contains raw FASTQ files from single cell RNA sequencing of three patient-derived pancreatic ductal adenocarcinoma (PDAC) organoid lines (P28, P40, P47) cultured under standard conditions. For each line, single cells were FACS sorted into 384-well capture plates, with each well containing a 50nl droplet of barcoded primers. Plates were processed following an adapted SORT-seq protocol, and cDNA libraries were generated using CEL-Seq2 with TruSeq small RNA primers (Illumina). Sequencing was performed on an Illumina NextSeq500 platform using paired-end reads (read 1: 26 cycles, index read: 6 cycles, read 2: 60 cycles). Data are controlled-access and intended for single cell transcriptomic analysis of PDAC organoid heterogeneity and WNT pathway activity.

  Dataset EGAD50000002220

• PAGE: Global Reference Panel

  Stanford contributed samples to the PAGE study that can act as a population reference dataset across the globe. Therefore this dataset includes reference individuals, without phenotypes, chosen to help infer ancestry that will help us understand the diverse samples available in PAGE. The complete dataset comprises individuals of European, African, Asian, Oceanian, and Native American descent, from a total of over 50 populations. A subset of these individuals from Puno, Peru and Easter Island (Rapa Nui), Chile, are included in the PAGE samples that were whole genome sequenced in 2015. Additional details are available in the Study Acknowledgments. The Global Reference Panel comprises 6 sample sets: A population sample of Andean individuals primarily of Quechuan/Aymaran ancestry from Puno, Peru A population sample of Easter Island (Rapa Nui), Chile Individuals of indigenous origin from Oaxaca, Mexico Individuals of indigenous origin from Honduras Individuals of indigenous origin from Colombia Individuals of indigenous origin from the Nama and Khomani KhoeSan populations of the Northern Cape, South Africa In addition, we genotyped publicly available samples that will be hosted on the Bustamante lab website (https://bustamantelab.stanford.edu/). These comprise large public datasets to provide an open reference dataset for the world: The additional related individuals from the Americas in the Human Genome Diversity Panel (H952) plus all additional samples from the Americas A subset of the unrelated individuals from the Maasai in Kinyawa, Kenya (MKK) dataset from the International Hapmap Project hosted at Coriell Additional samples will be available for restricted use with a data access agreement with the Bustamante Lab. This study is part of the Population Architecture using Genomics and Epidemiology (PAGE) study (phs000356).

  Study phs001033

• Genotyping NIGMS CEPH Samples from the United States, Venezuela, and France

  The Human Genetic Cell Repository (HGCR) is sponsored by the National Institute of General Medical Sciences (NIGMS) with the mission of supplying scientists with the materials for accelerating disease gene discovery and functional studies. The resources available include highly-characterized, contaminant-free fibroblast cell lines, transformed lymphoblastoid cell lines (LCLs), and DNA samples derived from these cultures. While the Repository has a major emphasis on inherited diseases, it also contains large collections of cell lines gathered from populations around the world that are intended for use in facilitating the understanding of human variation. Prominent among these resources is the CEPH Reference Family collection contributed by the Centre d'Etude du Polymorphisme Humain (CEPH), Foundation Jean Dausset, Paris, France. The CEPH collection includes families collected by R. White (Utah), J. Dausset (French), J. Gusella (Venezuelan), and J. Egeland (Amish). There are a total of 809 individuals accounting for 832 pedigree positions in the reference families. Family relationships for the 61 reference families were verified at Coriell and approved by CEPH. In an effort to enhance the value of this cell culture resource available from the Repository, the Coriell Genotyping and Microarray Center used the Affymetrix Genome-Wide Human SNP Array 6.0 platform to genotype 181 samples from the NIGMS HGCR CEPH collection. Included are thirteen families from the United States (Amish Pedigree 884 and Utah Pedigrees 1331, 1356, 1400, 1416, 1424, 1427, 1477, and 1582), France (Pedigrees 35 and 66), and Venezuela (Pedigrees 102 and 104). Twelve of the families consist of 3 generations and one family consists of 2 generations. Pedigree charts and sample descriptions are available on the Repository catalog website (see below).

  Study phs000268

• Rapid Acceleration of Diagnostics - Digital Health Technologies (RADx-DHT): NIH Digital Health Solutions for COVID-19: Team SAE

  The goal of this project is to develop a smartphone-based platform to monitor and support individuals with COVID-19 symptoms (who may need testing) and those who have already tested positive. The app will integrate a Bluetooth-enabled thermometer and pulse oximeter into an approach uniquely designed for low-resource settings and underserved populations. This project will focus on the American Indian/Alaskan Native (AI/AN) underserved population and will determine the feasibility of the digital health solution to collect symptom survey data and vital data including temperature, pulse, and oxygen saturation level. The complete study will include 300 participants 100% medically underserved with at least 51% from the AI/AN community. A combination of hard and soft data will be collected consisting of vital data, medical history and questionnaire data, and participant COVID-19 viral and antibody testing results collected during the study.DOI: https://rapids.ll.mit.edu/10.57895/wv88-by98

  Study phs002534

• Rare Mendelian Disease in Old Order Amish and Mennonite Patients

  The Clinic for Special Children (CSC) has integrated biochemical and molecular methods into a rural pediatric practice serving Old Order Amish and Mennonite (Plain) children. Among the Plain people, we have used single nucleotide polymorphism (SNP) microarrays to genetically map recessive disorders to large autozygous haplotype blocks (mean = 4.4 Mb) that contain many genes (mean = 79). For some, uninformative mapping or large gene lists preclude disease-gene identification by Sanger sequencing. Seven such conditions were selected for exome sequencing at the Broad Institute; all had been previously mapped at the CSC using low density SNP microarrays coupled with autozygosity and linkage analyses. Using between 1 and 5 patient samples per disorder, we identified sequence variants in the known disease-causing genes SLC6A3 and FLVCR1, and present evidence to strongly support the pathogenicity of variants identified in TUBGCP6, BRAT1, SNIP1, CRADD, and HARS. Our results reveal the power of coupling new genotyping technologies to population-specific genetic knowledge and robust clinical data.

  Study phs000623

• Immune Response to Life-Threatening Respiratory Infections in Children and Young Adults

  This is a cross sectional study describing age-related differences in the nasal mucosal immune response to SARS-CoV-2. We collected nasal mucosal samples from six groups: healthy children, children infected with SARS-CoV-2, children infected with respiratory syncytial virus, children infected with influenza virus, healthy adults, and adults infected with SARS-CoV-2. Samples were obtained by mucosal scrape biopsy of the inferior turbinate using a sterile plastic curette. We performed bulk RNA-sequencing to obtain gene expression data. Clinical data was extracted from the electronic health record including: demographics, medical history, clinical presentation, duration of symptoms, intensive care unit admission, hospital and intensive care unit length of stay, type and duration of respiratory support at sample collection and peak illness. Our analysis described the host response to SARS-CoV-2 in the nasal mucosa in children and adults and compared it to the host response to respiratory syncytial virus and influenza virus.

  Study phs002579

• Direct genetic transformation bypasses tumor-associated DNA methylation alterations

  Tumors represent dynamically evolving populations of mutant cells, and many advances have been made in understanding the biology of their progression. However, key unresolved questions remain about the conditions that support their initial transformation, which cannot be easily captured in patient populations but are instead modeled using transgenic cellular or animal systems. Here, we used extensive patient atlas data to define common features of the tumor DNA methylation landscape as they compare to healthy human cells and used this benchmark to screen 21 engineered human and mouse models for their ability to reproduce these patterns. Notably, we find that genetically induced cellular transformation can trigger global changes in DNA methylation levels that are consistent with extensive proliferation but rarely recapitulate the widespread de novo methylation of Polycomb targets as found in clinical samples. Our results raise pertinent questions about the relationship between genetic and epigenetic aspects of tumorigenesis and provide an important molecular reference for evaluating existing as well as newer tumor models.

  Study EGAS50000000902

• Dual inhibition of FLT3 and BCL-2 is effective in preclinical models of BCL11B-activated lineage ambiguous leukemia

  Aberrant activation of BCL11B (“BCL11B-a”) defines a subtype of lineage ambiguous leukemias with T-lymphoid and myeloid features, co-occurring activating FLT3 mutations, and a stem/progenitor immunophenotype and gene expression profile. As with other lineage ambiguous leukemias, optimal treatment is unclear and there are limited targeted therapeutic options. Here, we investigated the efficacy of BCL-2 and FLT3 inhibition with venetoclax and gilteritinib, respectively, in preclinical models of BCL11B-a leukemia. Despite variation in response to single agent therapies, the combination of venetoclax plus gilteritinib was highly effective in all models evaluated. BH3 profiling and single cell RNA-seq analysis suggests that resistance to venetoclax and/or gilteritinib monotherapies is due to the tumor-intrinsic activity of BCL-xL and/or MCL-1 prior to drug treatment. These data support clinical evaluation of venetoclax in combination with gilteritinib in BCL11B-a lineage ambiguous leukemias.

  Study EGAS50000000978

• Whole genome sequencing of six ethnic groups from Burkina Faso, Cameroon, and Tanzania

  We conducted low-coverage (~10x) sequencing of six ethnic groups from three malaria-endemic countries in sub-Saharan Africa, with the aim of characterising genetic diversity and improving imputation performance for genotyped samples in these populations. This data is part of a pre-publication release and is available under managed access. Please see https://www.malariagen.net/data/terms-use/human-gwas-data for more information on MalariaGEN data access policies. The purpose of the project was to support the discovery and understanding of genetic variants that influence human disease. Specifically defined goals were: a. the discovery of single nucleotide variants at frequencies of 1% or higher in diverse populations, b. even more comprehensive discovery (variants down to frequencies of 0.1 - 0.5%) in functional gene regions, and c. discovery of structural variants, such as copy number variants, other insertions and deletions, and inversions, including sequence-level understanding of breakpoints.

  Study EGAS00001003648

• Spatial genomic heterogeneity in multiple myeloma revealed by multi- region sequencing

  The bone-marrow (BM) containing skeletal system is the reservoir of Multiple Myeloma (MM), the malignant counterpart of antibody-secreting plasma cells. To gain insight into its spatial clonal architecture, we performed multi-region whole-exome sequencing of radiology-guided fine-needle aspirates from 51 MM patients. We found spatial genomic heterogeneity in a substantial proportion of cases including bi-allelic inactivation of tumor suppressors and mutations affecting cancer genes. The amount of heterogeneous mutations associated with the size of focal tumor lesions in whole body imaging consistent with focal outgrowth of highly advanced clones. In conclusion, our results support the regional initiation of transformation processes leading to high-risk disease as well as the pre-existence of key driver events in restricted areas. As such, our study does not only provide new insights in the underlying biology of MM progression but also has considerable implications for standard diagnostic approaches in the clinic.

  Study EGAS00001002111

• A Genomics-Based Classification of Human Lung Tumors

  We characterized genome alterations in 1255 clinically annotated lung tumors of all histological subgroups to identify genetically defined and clinically relevant subtypes. More than 55% of all cases had at least one oncogenic genome alteration potentially amenable to specific therapeutic intervention, including several personalized treatment approaches that are already in clinical evaluation. Marked differences in the pattern of genomic alterations existed between and within histological subtypes, thus challenging the original histomorphological diagnosis. Immunohistochemical studies confirmed many of these reassigned subtypes. The reassignment eliminated almost all cases of large cell carcinomas, some of which had therapeutically relevant alterations. Prospective testing of our genomics-based diagnostic algorithm in 5145 lung cancer patients enabled a genome-based diagnosis in 3863 (75%) patients, confirmed the feasibility of rational reassignments of large cell lung cancer, and led to improvement in overall survival in patients with EGFR-mutant or ALK-rearranged cancers. Thus, our findings provide support for broad implementation of genome-based diagnosis of lung cancer.

  Study EGAS00001000647

• Hi-C dataset for testicular germ cell tumour GWAS risk loci, as described in the Oncoarray Litchfield et al. 2016 paper.

  Genome-wide association studies (GWAS) have transformed our understanding of testicular germ cell tumour (TGCT) susceptibility but much of the heritability remains unexplained. Here we report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 7,319 TGCT cases and 23,082 controls. We identify 19 new TGCT risk loci, approximately doubling the number of known TGCT risk loci to 44. By performing in-situ Hi-C in TGCT cells, we establish a network of physical interactions between all 44 TGCT risk SNPs and candidate causal genes. Our findings reveal widespread disruption of developmental transcriptional regulators as a basis of disease susceptibility, consistent with failed primordial germ cell differentiation as an initiating step in TGCT oncogenesis1. Defective microtubule assembly and dysregulation of KIT-MAPK signalling also feature as recurrently disrupted pathways. Our findings support a polygenic model of disease risk and provide insight into the biological basis of TGCT.

  Study EGAS00001001930

• Circulating tumor cells for comprehensive and multiregional non-invasive genetic characterization of multiple myeloma (arrays set)

  Multiple myeloma (MM) patients undergo repetitive bone marrow (BM) aspirates for genetic characterization. Circulating tumor cells (CTCs) are detectable in peripheral blood of virtually all MM cases and are prognostic, but their applicability for non-invasive screening has been poorly investigated. Here, we used next-generation flow cytometry to isolate matched CTCs and BM tumor cells from 42 patients and compare their genetic profile. In 8 cases, tumor cells from extramedullary plasmacytomas were also sorted and whole-exome sequencing performed in the three spatially-distributed clones. Noteworthy, ≥84% mutations present in BM and extramedullary clones were detectable in CTCs. Concordance between BM tumor cells and CTCs was high for chromosome arm-level copy-number alterations (≥94%) though not for translocations (43%). All high-risk genetic abnormalities except one t(4;14) were detected in CTCs whenever present in BM tumor cells. Altogether, these results support CTCs for non-invasive risk-stratification of MM patients based on their numbers and genetic profile.

  Study EGAS00001004314

• Oncogenic cooperation in a human de novo T-ALL model

  We previously modelled T-cell acute lymphoblastic leukemia (T-ALL) by over-expressing four oncogenes (activated NOTCH1, LMO2, TAL1, and BMI1) in healthy human umbilical cord blood cells through lentiviral transduction (Kusakabe et al, Nat Commun 10, 2913 (2019). https://doi.org/10.1038/s41467-019-10510-8). We have now tested individual effects of the four oncogenes by transducing human cells with all possible combinations of one, two, three, and four oncogenes. We also tested the effects of additional known T-ALL oncogenes including HOXA9, LYL1, MEF2C, NXK2.1, TLX1, and TLX3. In addition to culture in vitro on OP9-DL1 feeders, we also injected transduced cells into immunodeficient NSG mice. We observed differing abilities of the various oncogene combinations to support growth in vitro and frank leukemia in vivo. This study includes RNA-seq data from samples of transduced cells cultured in vitro as well as cells harvested from clinically moribund mice after development of leukemia in vivo.

  Study EGAS00001006055

• Genome-wide Rare Variant Score Associates With Morphological Subtypes of Autism Spectrum Disorder

  Defining different genetic subtypes of Autism Spectrum Disorder (ASD) can help predict developmental outcomes. Based on minor physical and major congenital anomalies, we categorized 325 Canadian children with ASD into dysmorphic and non-dysmorphic subgroupings. We developed a method to calculate a genome-wide rare variant score (GRVS) from whole-genome sequencing (WGS) data for each ASD proband. GRVS is a sum of the number of variants in morphology-associated coding and non-coding regions, weighted by their effect sizes. Probands with dysmorphic ASD had a significantly higher GRVS compared to those with non-dysmorphic ASD (P= 0.027). Using the polygenic transmission disequilibrium test, we observed an over-transmission of ASD-associated common variants in non-dysmorphic ASD probands (P= 2.9×10-3). We replicated our findings using 442 ASD probands that had accompanying morphology data in the Simons Simplex Collection. Our findings provide support for an alternative genomic classification of ASD subgroups using morphology data, which may inform intervention protocols.

  Study EGAS00001005753

• Pediatric Patient-Derived-Xenograft development in MAPPYACTS – international pediatric cancer precision medicine trial in relapsed and refractory tumors

  Pediatric patients with recurrent and refractory cancers are in most need for new treatments. This study developed patient-derived-xenograft (PDX) models within the European MAPPYACTS cancer precision medicine trial (NCT02613962). To date, 131 PDX models were established following heterotopical and/or orthotopical implantation in immunocompromised mice: 76 sarcomas, 25 other solid tumors, 12 central nervous system tumors, 15 acute leukemias, and 3 lymphomas. PDX establishment rate was 43%. Histology, whole exome and RNA sequencing revealed a high concordance with the primary patient’s tumor profile, human leukocyte-antigen characteristics and specific metabolic pathway signatures. A detailed patient molecular characterization, including specific mutations prioritized in the clinical molecular tumor boards are provided. Ninety models were shared with the IMI2 ITCC Paediatric Preclinical Proof-of-concept Platform (IMI2 ITCC-P4) for further exploitation. This new PDX biobank of unique recurrent childhood cancers provides an essential support for basic and translational research and new treatments development in advanced pediatric malignancies.

  Study EGAS00001007327

• Genetics of Glucose Regulation in Gestation and Growth (Gen3G) Cohort - Placenta Transcriptomics RNA Sequencing

  The overarching goals of Genetics of Glucose regulation in Gestation and Growth (Gen3G) are to increase our understanding of biological, environmental, and genetic determinants of glucose regulation during pregnancy and their impact on fetal/child development. Gen3G is a prospective cohort study: we initially recruited 1,024 pregnant women between 2010-2013 at Blood Sampling in Pregnancy Clinic during the first trimester of pregnancy (median 9 weeks of gestation) in Sherbrooke, Québec, Canada. We assessed 898 pregnant women at second trimester (median 26 weeks of gestation), when participants completed a 75g oral glucose tolerance test (OGTT) as clinically indicated for screening of gestational diabetes mellitus (GDM). We collected data for 854 mother-child dyads at delivery (from medical records), in addition to placenta and/or cord blood samples in majority of newborns.The overall goal of the grant that supported data that is included in this dbGaP submission was to discover novel placental factors that regulate glucose metabolism in pregnancy and predict GDM by conducting genome-wide transcriptomics (RNA and miRNA) in carefully collected placenta samples from Gen3G.

  Study phs003151

• Blood-based monitoring of relapsed/refractory cHL patients predict responses to PD-1 blockade treatment

  Hodgkin lymphoma (cHL) patients are uniquely susceptible to treatment with programmed cell death-1 (PD-1) treatment. However, monitoring with FDG-PET/CT, the current response detection standard, is challenging. Here, we address the potential applicability of tissue biomarkers and blood-based biomarkers in PD-1 treated cHL patients. We evaluated 9p24.1/PD-L1/PD-L2 alterations, and expression of PD-L1 and antigen presentation molecules (HLA class I/II) in 9 tissue biopsies of 4 patients. In addition, we assessed circulating tumor DNA (ctDNA), extracellular vesicle associated miRNAs (EV-miRNAs), soluble PD-L1 and serum TARC (sTARC) in 26 longitudinal blood samples of these patients during PD-1 treatment. We found that the predictive power of tissue biomarkers is dependent on the timing of the biopsy . The dynamics of blood-based biomarkers: sTARC, EV-miRNAs and ctDNA corresponded well immunotherapy treatment response. Therefore, blood-based biomarkers are promising monitoring strategies in PD-1 treated cHL patients and should be further explored in clinical trials or observational studies.

  Study EGAS00001005894

• Molecular stratification of endometrioid ovarian carcinoma predicts clinical outcome

  Endometrioid ovarian carcinoma (EnOC) is an under-investigated type of ovarian carcinoma. Here, we report the largest genomic study of EnOCs to date, performing whole exome sequencing of 112 cases following rigorous pathological assessment. High frequencies of mutation were detected in CTNNB1(43%), PIK3CA(43%), ARID1A(36%), PTEN(29%), TP53(26%) and SOX8(19%), a novel target of recurrent mutation in EnOC. POLE and mismatch repair protein-encoding genes were mutated at lower frequency (6%, 18%) with significant co-occurrence. A molecular taxonomy was constructed using a novel algorithm (PRISTINE), identifying clinically distinct EnOC subtypes: TP53m cases demonstrated greater genomic complexity, were frequently FIGO stage III/IV at diagnosis (48%) and incompletely debulked (44%), and demonstrated inferior survival; conversely, CTNNB1m cases demonstrated low complexity and excellent clinical outcome, were predominantly stage I/II at diagnosis (89%) and completely resected (87%). Tumour complexity provides further resolution within the TP53wt/CTNNB1wt group. Moreover, we identify the WNT, MAPK/RAS and PI3K pathways as good candidate targets for molecular therapeutics in EnOC.

  Study EGAS00001004366

• Experimental PfSPZ Vaccine in Adults Without Malaria

  The study was performed to evaluate whole-blood transcriptomic profiles via RNA-seq before, during, and after immunization with the PfSPZ Vaccine in malaria-naïve, healthy adults enrolled in VRC 312 (NCT01441167). VRC 312 was the second study of the PfSPZ Vaccine and the first study to evaluate intravenous (IV) administration of this vaccine. The study was an open-label evaluation of the safety, tolerability, immunogenicity, and protective efficacy of the vaccine at successively higher administered by the IV route. The highest dosages were evaluated for protection against a malaria challenge after 4 to 6 vaccinations. The primary objectives of the study were related to the safety and tolerability of the vaccine at the 4 different dosage levels when administered IV; the secondary objectives were related to PfSPZ vaccine-mediated protection against Plasmodium falciparum (Pf) challenge at the 3 higher dosage levels, and the exploratory objectives were related to the immunogenicity of the PfSPZ Vaccine and defining an immune correlate of protection. To further determine potential molecular correlates of immunogenicity and/or protection, RNA-seq was performed on whole blood collected from subjects in all dose groups at time points before, during, and after immunization.

  Study phs002422

• Gut microbiome dynamics unravelled with metagenomics sequencing

  It has been already several years since we discovered that microbial therapeutics like Faecal Microbiota Transplantation can be used to treat Clostridium difficile infection (CDI) and Inflammatory bowel disease (IBD) with great success. The concept has challenged us to test the limits of our knowledge with the perspective to improve health in the most diverse conditions like Parkinson disease, depression, autism and obesity, just to mention a few. Note: the figure belongs to the original paper and is owned by the authors. Allyson L.Bird and colleagues from Genentech Inc. (San Francisco) recently published an interesting study building up on the key concept that “As microbial therapeutics are increasingly being tested in diverse patient populations, it is essential to understand the host and environmental factors influencing the microbiome.” The authors of this work analysed 1359 gut microbiome samples using shotgun metagenomics sequencing.  The results of the comparison done between microbiota composition across the different groups showed that biological sex is the strongest driver of diversity, while aging (age range studied: 20–69) appears to be the second factor. As smartly outlined in the authors’ own graphical abstract (figure to the left), Bacteroidota species consistently increased with donors' age while Actinobacteriota species, including Bifidobacterium, decreased. This study also integrated data from oncological patients to draw cancer-related evidences. After correcting the biases for technical and geographic differences, they found that cancer patients show significantly altered gut bacterial communities compared with their healthy counterparts. Eg. E.coli was found to be increased in cancer patients together with Bacteroidota/Firmicutes ratios. By comparing sequential samples taken from the same donors (413) within short-distance time points, the authors found that in the short term, intra-individual differences were less than the inter-individual ones, indicating a certain community stability being the norm. One of the pivotal points from this interesting study is that the data proceeds from extremely well-defined and selected donors. Specifically, the data for 949 selected healthy donors came from the Milieu Intérieur (MI) Consortium and extensive metadata, including demographic variables, serological measures, dietary information, and systemic immune profiles, are available. This precise stratification allowed for the robust detection of smaller changes, compared to former works. All sequencing data has been deposited in the EGA archive under the accession number EGAS00001004437. Enjoy this amazing open access paper published in the Experimental Journal of Medicine on January 2021.

  Blog gut-microbiome-dynamics-unravelled

• Spatial multi-omic map of human myocardial infarction

  Myocardial infarction is a leading cause of mortality worldwide 1 . While advances have been made in acute treatment, an incomplete understanding of remodelling processes has limited the effectiveness of therapies to reduce late-stage mortality 2 . Here, we generate an integrative high- resolution map of human cardiac remodelling after myocardial infarction using single-cell gene expression, chromatin accessibility, and spatial transcriptomic profiling of multiple physiological zones at distinct time points in myocardium from myocardial infarction and control patients. Multimodal data integration allowed us to evaluate cardiac cell-type compositions at increased resolution, yielding insights into changes of the cardiac transcriptome and epigenome through the identification of distinct tissue structures of injury, repair and remodelling. We identified and validated disease-specific cardiac cell-states of major cell-types and analysed them in their spatial context, evaluating their dependency on other cell-types. Our data elucidates molecular principles of human myocardial tissue organisation, recapitulating a gradual cardiomyocyte and myeloid continuum following ischemic injury. In total, our study provides an integrative molecular map of human myocardial infarction and represents an essential reference for the field and paves the way for advanced mechanistic and therapeutic studies of cardiac disease.

  Study EGAS00001006330

• Treatment-mediated selection of lethal prostate cancer clones defined by copy number architectures

  Despite initial responses to hormone treatment, metastatic prostate cancer invariably evolves to a lethal state. To characterize the intra-patient relationships of metastases that evade treatment, we performed genome- wide copy number profiling and bespoke approaches targeting the androgen receptor (AR) on 142 metastatic regions from 10 organs harvested post-mortem from nine men who died from prostate cancer. We identified diverse and patient-unique alterations clustering around the AR in metastases from every patient with evidence of independent acquisition of related genomic changes within an individual and, in some patients, the co-existence of AR-neutral clones. Using the genomic boundaries of pan-autosome copy number change, we confirmed a common clone of origin across metastases and diagnostic biopsies; and identified in individual patients, clusters of metastases occupied by dominant clones with diverged autosomal copy number alterations. Autosome-defined clusters were characterized by cluster-specific AR gene architectures that in two index cases were topologically more congruent than by chance (p-values 0.03, 3.07x10-8). Integration with anatomical site suggested patterns of spread and points of genomic divergence. Copy number boundaries identified treatment-selected clones with putatively distinct lethal trajectories.

  Study EGAS00001006598

• IMCISION DNAseq

  Whole-exome sequencing of 32 primary head and neck squamous cell carcinoma samples prior to treatment with neoadjuvant anti-PD-1 (n=6) or anti-PD-1 + anti-CTLA-4 (n=26) immunotherapy. DNA quantity used: 50ng. Library Preparation Kit: Twist Human Core Exome Plus (Twist Bioscience). Sequencing parameters: NovaSeq 6000, 2x 100 bp. File type: fastQ.

  Dataset EGAD00001008139

• EOSC4Cancer Longitudinal Synthetic Colorectal Cancer Genomic data developed at BSC

  The synthetic genomes have been created trying to mimic real cancer data of 4 patients (Named 185,186,187 and 188). Mutations are based on real CRC patients from the PCAWG dataset. For each patient, two tumor samples at different time points and one healthy sample have been simulated. The cancer intra-tumor heterogeneity and evolution in the patients is depicted by simulating reads from tumor subclones separately and then mixing them according to their clonal proportions in each sample. For rapid use and transfer only selected chromosomes have been generated for each patient. Chromosomes per patient: -185: chr4, chr5, chr7, chr17 -186: chr1, chr7, chr12, chr17 -187: chr1, chr2, chr5, chr12, chr17 -188: chr2, chr5, chr12, chr13, chr17 Worflows used to create BAM/BAI, VCF and MAF files from FASTQ (Alignment with GRCh38): - https://usegalaxy.eu/published/workflow?id=2c3d05023c02113e - https://usegalaxy.eu/published/workflow?id=1da86d74f8535f4e

  Dataset EGAD50000000276

• Single-Cell and Bulk RNA Sequencing of Oncolytic Measles Virus Treatment in Pediatric Medulloblastoma and ATRT

  This dataset includes single-cell RNA sequencing profiles from five mice bearing Group 3 medulloblastoma (CSCG) treated with oncolytic measles virus (MV-NIS) and three mice treated with MV-NIS combined with anti-PD1 therapy. Additionally, bulk RNA sequencing data were generated from 12 samples across PBS control, heat-inactivated (HI) control, MV mid-treatment, and treatment resistance conditions. Pediatric patient data were collected from the PNOC005 trial, which enrolled patients into three strata: Stratum A (focal recurrence, local MV-NIS administration post-surgical resection), Stratum B (disseminated recurrence, single MV-NIS dose via lumbar puncture), and Stratum C (disseminated recurrence, two consecutive MV-NIS doses via lumbar puncture on Day 0 and Day 7). Whole blood and PBMC samples were collected from 17 patients across all strata, generating 72 bulk RNA-seq datasets at multiple time points. All datasets are provided as raw sequencing data in FASTQ format.

  Dataset EGAD50000001197

• Whole Exome Sequencing analysis of three tumor biopsies from a LUAD patient

  Whole Exome Sequencing (WES) analysis was performed on three distinct tumor biopsies collected at different time points, along with their matched germline non-tumor sample, from the same LUAD patient. DNA was extracted using the DNeasy Blood and Tissue Kit (Qiagen, Germantown, MD) according to the manufacturer’s instructions and quantified using the Qubit Fluorometer assay (Life Technologies, Carlsbad, CA). To minimize FFPE-related sequencing artifacts (e.g., C:G > T:A transitions), the extracted DNA was treated with the DNA repair enzyme Uracil-DNA-Glycosylase (UDG) following the manufacturer’s protocol (New England Biolabs, Ipswich, MA). Whole-exome capture was performed with the Twist Human Core Exome + RefSeq + Mito-Panel kit (Twist Bioscience), in accordance with the manufacturer’s guidelines. Sequencing generated paired-end 100-bp reads on the Illumina NovaSeq 6000 platform. The resulting reads were aligned to the reference human genome (GRCh38) using the Burrows-Wheeler Aligner (BWA, v0.7.12).

  Dataset EGAD50000001198

• Single cell RNA-seq of two rare cases of human glioblastoma at multiple sampling points

  Glioblastoma is characterized by large cellular diversity whose complexity and organizing principles are only starting to be uncovered. Both neurodevelopment-like and mesenchymal-like cell states have been described in glioblastoma but the nature of the mesenchymal-like cell states remains unresolved. Here, we performed deep single-cell RNA sequencing of two rare glioblastoma cases where tissue could be sampled from tumor core to macroscopically normal cortex with the aim of understanding these tumor cell states.

  Study EGAS50000001030

• Undifferentiated sarcomas develop through distinct evolutionary pathways

  Undifferentiated sarcomas (USARC) of adults are diverse, rare and aggressive soft tissue cancers. Recent efforts have confirmed that USARC exhibit one of the highest burdens of structural aberrations across human cancer. Here, we sought to unravel the genomic basis of this structural complexity by integrating whole genome sequencing, ploidy analysis and methylation profiling of 53 USARC. We identified whole genome doubling as a prevalent and pernicious force in USARC tumourigenesis. Deconvolution of the complex copy number and rearrangement landscapes show distinct signatures associated with chromothripsis, early-haploidy, and successive whole-genome-doubling events, suggesting four divergent models of sarcoma development. We show similar distinct evolutionary tumourigenic pathways in different sarcoma subtypes from the Cancer Genome Atlas. Thirteen percent of tumours exhibited a hypermutator phenotype, opening new avenues for clinical management such as immunotherapy, whilst the period prior to and between genome doubling events may represent clinically relevant interventional points in USARC.

  Dataset EGAD00001004162

• Action to Control Cardiovascular Risk in Diabetes (ACCORD - Imaging)

  Available DataAction to Control Cardiovascular Risk in Diabetes (ACCORD-Imaging), provides access to ECG signals data from the ACCORD clinical trial. The clinical phenotyping and outcomes data from the trial are associated with ACCORD-BioLINCC, phs003551.ObjectivesThe purpose of this study was to determine if intensive glycemic control, multiple lipid management and intensive blood pressure control could prevent major cardiovascular events (myocardial infarction, stroke or cardiovascular death) in adults with type 2 diabetes mellitus. Secondary hypotheses included treatment differences in other cardiovascular outcomes, total mortality, microvascular outcomes, health-related quality of life and cost-effectiveness.BackgroundGlycemia Trial:Patients with type 2 diabetes mellitus die of cardiovascular disease (CVD) at rates two to four times higher than non-diabetic populations of similar demographic characteristics. They also experience increased rates of nonfatal myocardial infarction and stroke. With the growing prevalence of obesity in the United States, CVD associated with type 2 diabetes is expected to become an even greater public health challenge in the coming decades than it is now. Expected increases in event rates will be associated with a concomitant rise in suffering and resource utilization.The ACCORD study investigated whether intensive therapy to target normal glycated hemoglobin (HbA1c) levels would reduce cardiovascular events in patients with type 2 diabetes who had either established cardiovascular disease or additional cardiovascular risk factors when compared to standard therapy (HbA1c between 7.0% and 7.9%). A separate analysis investigated whether reduction of blood glucose concentration decreases the rate of microvascular complications in these patients.Lipid Therapy Trial:Patients with type 2 diabetes mellitus have an increased incidence of atherosclerotic cardiovascular disease attributable, in part, to associated risk factors such as dyslipidemia. This is characterized by elevated plasma triglyceride levels, low levels of high-density lipoprotein (HDL) cholesterol and small, dense low-density lipoprotein (LDL) particles. The ACCORD Lipid Therapy trial was designed to test the effect of a therapeutic strategy that uses a fibrate to raise HDL-C and lower triglyceride levels and uses a statin for treatment of LDL-C reduce the rate of CVD events compared to a strategy that only uses a statin for treatment of LDL-C on cardiovascular outcomes in patients with type 2 diabetes that were at high risk for cardiovascular disease.Blood Pressure Trial:Diabetes mellitus increases the risk of cardiovascular disease at every level of systolic blood pressure. Because cardiovascular risk in patients with diabetes is graded and continuous across the entire range of levels of systolic blood pressure, even at prehypertensive levels, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommended beginning drug treatment in patients with diabetes who have systolic blood pressures of 130 mm Hg or higher, with a treatment goal of reducing systolic blood pressure to below 130 mm Hg. There is, however, a paucity of evidence from randomized clinical trials to support these recommendations. The ACCORD Blood Pressure trial tested the effect of a target systolic blood pressure below 120 mm Hg on major cardiovascular events among high-risk persons with type 2 diabetes compared to a strategy that targeted a SBP of EYE Substudy:Diabetic retinopathy, an important microvascular complication of diabetes, is a leading cause of blindness in the United States. Randomized, controlled clinical trials in cohorts of patients with type 1 diabetes and those with type 2 diabetes have shown the beneficial effects of intensive glycemic control and intensive treatment of elevated blood pressure on the progression of diabetic retinopathy. Elevated serum cholesterol and triglyceride levels have been implicated, in observational studies and small trials, as additional risk factors for the development of diabetic retinopathy and visual loss. The ACCORD EYE Substudy evaluated the effects of the ACCORD medical strategies on the progression of diabetic retinopathy in a subgroup of trial patients.MIND Substudy:Studies suggest that older persons with type 2 diabetes have at least twice the likelihood of developing late-life cognitive impairment or dementia compared to those without. The mechanisms underlying these cognitive disorders are increasingly thought to reflect a mixed pathology pattern with contributions from vascular, neurodegenerative and neurovascular processes. Pathophysiological mechanisms that have been described include inflammation, oxidative stress, energy imbalance, protein misfolding, glucocorticoid-mediated effects and differences in genetic susceptibilities. The ACCORD MIND substudy took as a premise that early intervention with the ACCORD therapeutic strategies to improve glycemic control could mitigate the adverse effects of type 2 diabetes on the brain.Subjects10,251 patients with type 2 diabetes and HbA1c concentrations of 7.5% or more participated in the trial. Of these patients, 5518 were assigned to the lipid therapy arm and 4733 to the blood pressure arm. EYE Substudy:A subgroup of 2856 patients was evaluated for the effects of the ACCORD interventions at 4 years on the progression of diabetic retinopathy. Patients who, at baseline, had a history of proliferative diabetic retinopathy that had been treated with laser photocoagulation or vitrectomy were excluded.MIND Substudy:A subgroup of 2977 patients was evaluated for cognitive function and brain volume. The ACCORD MIND substudy excluded patients aged DesignPatients were randomly assigned to undergo either intensive glycemic control (targeting a glycated hemoglobin level EYE Substudy:EYE Substudy patients were evaluated at two standardized and comprehensive eye examinations for the effects of the ACCORD interventions at 4 years on the progression of diabetic retinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study Severity Scale (as assessed from seven-field stereoscopic fundus photographs, with 17 possible steps and a higher number of steps indicating greater severity) or the development of diabetic retinopathy necessitating laser photocoagulation or vitrectomy.MIND Substudy:The cognitive primary outcome, the Digit Symbol Substitution Test (DSST) score, was assessed at baseline, 20 and 40 months. Total brain volume (TBV), the primary brain structure outcome, was assessed with MRI at baseline and 40 months in a sub-set of 632 patients. All patients with follow-up data were included in the primary analyses.ConclusionsGlycemia Trial:As compared with standard therapy, the use of intensive therapy to target normal glycated hemoglobin levels for 3.5 years increased mortality and did not significantly reduce major cardiovascular events. (NEJM. 2008; 358(24): 2545-59).Microvascular Outcomes of the Glycemia Trial:Intensive therapy did not reduce the risk of advanced measures of microvascular outcomes, but delayed the onset of albuminuria and some measures of eye complications and neuropathy. Microvascular benefits of intensive therapy should be weighed against the risk of increased total and cardiovascular disease-related mortality, increased weight gain, and higher risk for severe hypoglycemia. (Lancet. 2010; 376(9739): 419-30)Lipid Therapy Trial:The combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal myocardial infarction or nonfatal stroke, as compared with simvastatin alone. These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority of high-risk patients with type 2 diabetes (NEJM. 2010; 362(17): 1563–1574).Blood Pressure Trial:In patients with type 2 diabetes at high risk for cardiovascular events, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events (NEJM. 2010; 362: 1575-1585).EYE Substudy:Intensive glycemic control and intensive combination treatment of dyslipidemia, but not intensive blood-pressure control, reduced the rate of progression of diabetic retinopathy (NEJM. 2010; 363: 233-244).MIND Substudy:Although significant differences in TBV favored the intensive therapy, cognitive outcomes were not different. Combined with the unfavorable effects on other ACCORD outcomes, MIND findings do not support using intensive therapy to reduce the adverse effects of diabetes on the brain in patients similar to MIND patients (Lancet Neurol. 2011; 10(11): 969–977).

  Study phs003562

• MicroRNAs, Hypertension and End Organ Damage in Humans

  Study 1) Profiling of microRNAs in plasma of patients with hypertension complicated or not by metabolic syndrome or chronic kidney disease Hypertension (HTN) or high blood pressure is associated with subclinical target organ damage such as cardiac, vascular and kidney injury, which may lead to complications and death. In this study, we investigated circulating microRNAs as biomarkers of target organ damage in HTN patients. We profiled circulating microRNAs by RNA sequencing in platelet-poor plasma of normotensive subjects and patients with HTN complicated or not by metabolic syndrome (MetS) or chronic kidney disease (CKD) (n=15 each group). Differentially expressed microRNAs were identified with a threshold of false discovery rate <0.1. Differentially expressed microRNAs were identified uniquely to associate with HTN (8), MetS (1) or CKD (13), and 8 were similarly differentially expressed in different groups. This study identified the association of differentially expressed circulating microRNAs with target organ damage in HTN patients, which could have some pathophysiological and therapeutic implications. Study 2) Profiling of microRNAs in gluteal subcutaneous small arteries of patients with hypertension complicated or not by chronic kidney disease Hypertension (HTN) is associated with vascular damage characterized by endothelial dysfunction and vascular remodeling and stiffening, which contributes to kidney injury leading to chronic kidney disease (CKD). MicroRNAs are short non-coding RNAs which repress/degrade target mRNAs. The microRNA role in vascular injury in HTN remains unclear. In this study, we aimed to identify differentially expressed microRNAs in small arteries of patients with HTN associated or not with CKD, in order to shed light on the pathophysiological molecular mechanisms. Normotensive subjects and HTN patients associated or not with CKD grades 3-4 were studied (n=15-16). Small arteries were isolated from subcutaneous gluteal biopsies, RNAs were extracted, and small and total RNA sequencing was performed by Illumina HiSeq-2500. Differentially expressed genes were identified with a P<0.05 and fold change (FC) >1.3. Differentially expressed microRNAs and mRNAs were identified uniquely to associate with HTN (microRNAs: 10, mRNAs: 68), CKD (microRNAs: 68, mRNAs: 395), and both groups (microRNAs: 2, mRNAs: 32). This study identified differentially expressed microRNAs and mRNAs in small arteries with target organ damage in HTN, which could have some pathophysiological and therapeutic implications.

  Study phs002389

• Best Practices for DACs

  Best Practices Data access committees (DACs) are institutional safeguards responsible for ensuring a balance between data protection and accessibility. However, there are no procedural standards that apply across DACs, which can lead to inconsistencies in their reviews and compromise their quality and effectiveness. Standardising DAC processes can foster trust and mutual recognition, paving the way for greater coordination, collaboration, and delegation between DACs and other oversight bodies to improve the efficiency of data access without sacrificing protection. To provide guidance, the following are suggestions for actions a DAC might take upon receiving a data access request: Aim to respond to all initial requests in less than 2 weeks. Failure to do so may result in follow-up emails from the EGA, journals, and ultimately dataset withdrawal. First, check that the data/EGAD number is consistent with your data submission. In other words, ensure that the requester has contacted the correct DAC. Verify that the user will be using the data within the terms of consent by asking them to sign up to the terms within the DAA. Ensure that data users who are granted access to the data comply with the terms of a Data Access Agreement (DAA) and to use the data only in approved ways. Look for an institutional email address for the requester. Search for evidence that the requester is "appropriately qualified/bona fide" for using the data, for example on PubMed, Research Gate, LinkedIn, etc. Confirm that the affiliated organisation is real and that the requester still works there. Inquire with the requester about who should have accounts created at the EGA under the terms of the agreement. If a negative decision is made, promptly communicate it to the requester and support it with the terms of the Data Access Policy that the requester has not met or cannot meet. Keep the information in the DAC up to date. If you leave your institution and are unable to manage data access requests on their behalf, you should add your replacement as a new contact in the DAC. Assist with data access requests for any further questions related to your data. The EGA can only check information that has been deposited in the repository. If the user has a specific question that the EGA cannot answer, we will redirect the user to the DAC. All the EGA studies and datasets referenced in a publication under your DAC must be publicly searchable on the EGA website before the paper is released. If possible, describe the permitted purposes for subsequent research projects, including associated limits and conditions, for all resources hosted in a repository using a common ontology, such as the GA4GH Data Use Ontology (DUO). It is considered best practice to try and release data only to those with an institutional email address. This gives reassurance to the EGA, research participants, and the general public that an appropriate individual is accessing and using the data. To prevent potential data breaches and ensure adherence to GDPR regulations, it is essential that the European Genome-Phenome Archive (EGA) is informed via the Helpdesk team of any changes to the Data Access Committee (DAC). This should be done in addition to any changes being made on the DAC portal. Data Controllers (as per the definition in the DPA) are also responsible for notifying the previous DAC of any modifications. Without proper notification, changes might not be automatically updated in our system, leading to the risk of incorrect permissions being applied and potential data access issues. Therefore, it is imperative that all Data Controllers follow this protocol to maintain data integrity and security.

  Documentation access/data-access-committee/best-practices

• Exploring high-throughput drug sensitivity testing in neuroblastoma cell lines and patient-derived tumor organoids in the era of precision medicine

  Despite druggable events in 80% of neuroblastoma patients within the Princess Máxima Center precision medicine program 'iTHER', clinical uptake of treatment recommendations has been low, and the clinical impact for individual patients remains hard to predict. This stresses the need for a method integrating genomics and transcriptomics with functional approaches into therapeutic decision making. We aimed to launch an online repository integrating genomics and transcriptomics with high-throughput drug screening (HTS) of nineteen commonly used neuroblastoma cell lines and fourteen generated neuroblastoma patient-derived organoids (NBL-PDOs) to improve identification of molecularly matched therapies and support clinical uptake. Cell lines, NBL-PDOs and their parental tumors were characterized utilizing (lc)WGS, WES and RNAseq. Cells were exposed to a ~200 compound library, and viability was assessed using CellTiterGlo or MTT. Molecular and HTS results were transferred to the R2 platform (http://r2platform.com/pmc_nb_drugs/), in which a comprehensive suite of visualizations and analysis options were implemented. As a result, a powerful reference set of cell lines is available, reflecting distinct known pharmacologic vulnerabilities, including resistance of TP53-inactivated lines to MDM2 inhibitor idasanutlin; ALK-inhibitor sensitivity in ALK-activated lines, and sensitivity of an ATM-deleted cell line to PARP- and CHEK1-inhibitors. Novel established NBL-PDOs retained molecular features of their parental tumor and again reflected established drug sensitivities. However, HTS also identified additional therapeutic vulnerabilities in vitro, such as a striking correlation between a positive mesenchymal signature and sensitivity to BCL2-inhibitor venetoclax. Finally, we explored personalized drug sensitivities within iTHER, demonstrating HTS can support genomic and transcriptomic results, thereby strengthening the rationale for clinical uptake. Furthermore, in vitro insensitivity may avoid ineffective treatments. Lastly, novel treatment options may be identified, as indicated by sensitivity to ponatinib correlating with overexpression of RET or KIT. In conclusion, we established a dynamic publicly available dataset with detailed genomic, transcriptomic, and pharmacological annotation of classical neuroblastoma cell lines as well as NBL-PDOs, representing the heterogeneous landscape of neuroblastoma. We anticipate that in vitro drug screening will be complementary to genomic-guided precision medicine by supporting clinical decision making, thereby improving prognosis for all neuroblastoma patients in the future.

  Study EGAS00001007160

• HCA_Adrenal_Foetal_WSSS_RNA_SB

  The Human Cell Atlas initiative is an ambitious global research effort which aims to describe every cell in the human body across all developmental stages to generate a reference map to accelerate progress in science and medicine particularly relating to human development and disease. The initiative is led by investigators based at the Wellcome Sanger Institute and the Broad Institute of MIT and Harvard and funding support from the Wellcome and NIH. This specific project will assess human development. We aim to interrogate the cellular composition and molecular regulators underpinning development and maturation through single cell RNA-sequencing/spatial transcriptomics and computational algorithms to predict cellular developmental trajectories and cell-cell interactions. We will subsequent validate these findings in situ using allied imaging technologies e.g. immunohistochemistry and RNAscope and in vitro culture of human intestinal organoids (HIOs). This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001004089

• Circulating Tumor Cell Heterogeneity in Neuroendocrine Prostate Cancer by Single Cell Copy Number Analysis

  Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer that may arise de novo or develop from pre-existing prostate adenocarcinoma as a mechanism of treatment resistance. Combined loss of tumor suppressors RB1, TP53, PTEN are frequent in NEPC but also present in a subset of prostate adenocarcinomas. Most clinical and preclinical studies support a trans-differentiation process, whereby NEPC arises clonally from a prostate adenocarcinoma precursor during the course of treatment resistance. Here we highlight a case of NEPC with significant intra-patient heterogeneity observed across metastases. We further demonstrate how single-cell genomic analysis of circulating tumor cells combined with phenotypic evaluation of cellular diversity can be considered as a window into tumor heterogeneity in patients with advanced prostate cancer. We performed whole genome sequencing of circulating tumor cells (CTCs) from patients with castration resistant adenocarcinoma (n=4) and neuroendocrine prostate cancer (n=8). CTCs were collected via Epic Sciences platform and single CTC genomic data (n=215) generated via Illumina NextSeq500. 

  Study phs002462

• 99 Cases of Small Cell Lung Cancer Study

  Small cell lung cancer (SCLC) is an aggressive disease with poor survival. A few sequencing studies performed on limited number of samples have revealed potential disease-driving genes in SCLC, however, much still remains unknown, particularly in the Asian patient population. Here we conducted whole exome sequencing (WES) and transcriptomic sequencing of primary tumors from 99 Chinese SCLC patients. Dysregulation of tumor suppressor genes TP53 and RB1 was observed in 82% and 62% of SCLC patients, respectively, and more than half of the SCLC patients (62%) harbored TP53 and RB1 mutation and/or copy number loss. Additionally, Serine/Arginine Splicing Factor 1 (SRSF1) DNA copy number gain and mRNA over-expression was strongly associated with poor survival using both discovery and validation patient cohorts. Functional studies in vitro and in vivo demonstrate that SRSF1 is important for tumorigenicity of SCLC and may play a key role in DNA repair and chemo-sensitivity. These results strongly support SRSF1 as a prognostic biomarker in SCLC and provide a rationale for personalized therapy in SCLC. The manuscript has been accepted by Plos Genetics.

  Study phs001083

• Kids First: Genomics of Orofacial Clefts in the Philippines

  Orofacial clefts (OFCs) are the most common craniofacial structural birth defect in humans caused by incomplete formation of the upper lip and/or the palate. Over 4,000 children in the Philippines are born with an OFC every year, and the Filipino OFC birth prevalence rate of 1 in 500 live births is one of the highest in the world. Genome-wide association studies support a multifactorial etiology for OFCs, but common variants only account for up to ~25% of the heritable risk in any one population. Sequencing studies in diverse populations is essential to fully understand the genetic architecture of OFCs. The study goals of the Kids First project are to sequence a collection of case-parent trios from the Philippines, in order to identify de novo mutations and inherited rare variants, and understand the population differences in common variant signals in the Philippines versus other populations. Approximately 373 trios from the Philippines were selected for whole genome sequencing (WGS) as part of this Gabriella Miller Kids First project.

  Study phs002595

• PETAL Repository of Electronic Data COVID-19 Observational Study (RED CORAL)

  To describe characteristics, treatment, and outcomes among patients hospitalized with COVID-19 early in the pandemic, 1480 consecutive adult inpatients with laboratory-confirmed, symptomatic SARS-CoV-2 infection admitted to 57 US hospitals from March 1 to April 1, 2020 were studied.It was found that in a geographically diverse early-pandemic COVID-19 cohort with complete hospital folllow-up, hospital mortality was associated with older age, comorbidity burden, and male sex. Intensive care unit admissions occurred early and were associated with protracted hospital stays. Survivors often required new health care services or respiratory support at discharge.The PETAL Network central institutional review board at Vanderbilt University and the institutional review boards at each participating hospital approved the study or determined that the study was exempt from review. 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 phs002363

• Efficacy and safety of entrectinib in patients with ROS1-positive advanced/metastatic non-small cell lung cancer (NSCLC) from the Blood First Assay Screening Trial (BFAST)

  BFAST is a global, open-label, multicohort trial that evaluates the efficacy and safety of multiple therapies in patients with advanced/metastatic NSCLC and targetable alterations, identified by blood-based molecular testing. We present data from Cohort D (ROS1-positive). Patients ≥18 years old with stage IIIB/IV, ROS1-positive NSCLC detected by blood-based testing, received entrectinib 600 mg daily. At data cut-off (November 2021), 55 patients were enrolled and 54 had measurable disease. Cohort D met its primary endpoint; the confirmed objective response rate (ORR) by investigator was 81.5% which was consistent with the ORR from the integrated analysis of entrectinib (investigator-assessed ORR: 73.4%, data cut-off May 2019, ≥12 months follow-up). The safety profile of entrectinib was consistent with prior reports. These results demonstrate consistency with those from the integrated analysis of entrectinib in patients with ROS1-positive NSCLC identified by tissue-based testing and support the clinical value of blood-based testing to inform clinical decision-making.

  Study EGAS50000000105

• Acute Respiratory Distress Network (ARDSNet) Study 02 Late Steroid Rescue Study (LaSRS) (ARDSNet-LaSRS-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Biospecimens: Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from ARDSNet-LaSRS include BAL Slides, Bronchial Lavage, and Plasma. Please note that use of biospecimens in genetic research is subject to a tiered consent.Objectives: Since previous reports suggested that corticosteroids may improve survival, this project was developed as a multicenter, randomized controlled trial of corticosteroids in patients with persistent ARDS.Background: Persistent acute respiratory distress syndrome (ARDS) is characterized by excessive fibroproliferation, ongoing inflammation, prolonged mechanical ventilation, and a substantial risk of death.Participants: There were 180 participants.Conclusions: The results do not support the routine use of methylprednisolone for persistent ARDS despite the improvement in cardiopulmonary physiology. In addition, starting methylprednisolone therapy more than two weeks after the onset of ARDS may increase the risk of death. (NEJM April 20, 2006; Vol 354, No. 16, pp 1671-84).

  Study phs003769

• Fetal Genomics Consortium (FGC)

  Many of the congenital anomalies and associated genomic variants identified during prenatal care are rare, requiring aggregation and harmonization to assure their appropriate clinical interpretation and to support the expanding utility of genomics in perinatal medicine. The primary step in accomplishing this is the creation of interoperability allowing collection, collaborative storage, dissemination and use of harmonized and vetted genomic and phenotypic data. The overall goal of this project is to generate a prenatal repository for both clinical care and research ensuring data are Findable; Accessible; Interoperable; and Reusable. The specific goals are: (1) collect and organize data contributions from multiple sites using the cloud-based Terra platform; (2) establish a governance structure for data contributions across sites; (3) develop and implement a pipeline for phenotype driven analysis and implementation of fetal specific Phenopackets on Terra; (4) generate a searchable callset of genomic variants and phenotype features on Terra; and (5) explore methods for facilitating broad access and sharing of longitudinal phenotype and genomic data facilitating genomic analysis in the prenatal space.

  Study phs003193

• Plasma cell‐Free transcriptome profiling in chronic liver disease

  Chronic liver disease (CLD) encompasses a wide range of hepatic disorders that progressively compromise liver function. In order to support the development of non-invasive diagnostic tools and improve patient stratification, we generated a high-throughput extracellular RNA sequencing dataset from blood plasma samples collected from patients at various stages of liver disease. Samples were obtained from two independent cohorts of 112 (cohort 1) and 489 (cohort 2) patients using standardized collection and processing protocols, and profiled using total RNA sequencing (SMARTer Stranded Total RNA-Seq Kit v3 - Pico Input Mammalian), resulting in 112 and 820 extracellular transcriptomic profiles for cohort 1 and 2, respectively. This dataset is provided with full documentation of the preprocessing analysis pipeline and accompanying metadata, enabling its use as an independent validation cohort for biomarker discovery and as a complementary resource for integrative multi-omics studies, even in cases with incomplete data modalities. The publicly available resource is intended to facilitate reproducibility and foster further research in the field of liver disease diagnostics

  Study EGAS50000000545

• Chromatin remodeler CHD7 regulates the stem cell identity of human neural progenitors

  Multiple congenital disorders often present complex phenotypes, but how the mutation of individual genetic factors can lead to multiple defects remains poorly understood. In the present study, we used human neuroepithelial (NE) cells and CHARGE patient-derived cells as an in vitro model system to identify the function of chromodomain helicase DNA-binding 7 (CHD7) in NE?neural crest bifurcation, thus revealing an etiological link between the central nervous system (CNS) and craniofacial anomalies observed in CHARGE syndrome. We found that CHD7 is required for epigenetic activation of superenhancers and CNS-specific enhancers, which support the maintenance of the NE and CNS lineage identities. Furthermore, we found that BRN2 and SOX21 are downstream effectors of CHD7, which shapes cellular identities by enhancing a CNS-specific cellular program and indirectly repressing non- CNS-specific cellular programs. Based on our results, CHD7, through its interactions with superenhancer elements, acts as a regulatory hub in the orchestration of the spatiotemporal dynamics of transcription factors to regulate NE and CNS lineage identities.

  Study JGAS000131

• Human lymphoid-neutrophil/monocyte restriction co-ordinately activates increased proliferation despite parallel heterogeneity in transcriptional changes

  Recent studies indicate the human lympho-myeloid restriction process to be a different and more heterogeneous one than historically inferred. Here we describe the development of bulk and clonal culture systems that efficiently support early B-lymphoid differentiation and their use to identify biological and molecular changes that accompany their initial restriction from subsets of CD34+ human cord blood cells with lympho-myeloid-limited potential. Analyses of the changes observed revealed the acquisition of B-lymphoid- and neutrophil/monocyte (NM)-restricted properties are accompanied by a concomitantly accelerated and lineage-shared cell cycling activity and loss of self-renewal properties. Parallel, single-cell transcriptome analysis identified reduced expression of multiple self-renewal-associated genes and an accompanying heterogeneous activation of lineage-regulatory modules during the production of B, NM and dendritic cell precursors. These results uncover a connected regulation of lineage-shared proliferation control with persistent heterogeneity in the biological and transcriptional changes in the same cells undergoing B and NM lineage restriction.

  Study EGAS50000000278

• Fragmentomics Uncover Non-Mutational HRD Features

  Homologous recombination deficiency (HRD) is a key biomarker in prostate cancer (PCa), predicting response to PARP inhibitors and platinum-based therapies. However, current diagnostics often rely solely on BRCA1/2 mutations or genomic scars, missing cases driven by other mechanisms. Tissue-based testing is further limited by tumor heterogeneity and biopsy challenges in metastatic bone disease. Here, we applied a comprehensive multimodal approach to assess HRD in 106 advanced PCa patients using circulating tumor DNA (ctDNA). This included targeted sequencing of homologous recombination repair (HRR) genes, low-pass WGS for genomic instability (sHRD), WES for mutational signatures, and cfDNA fragmentomics and chromatin accessibility profiling. BRCA2 was the most frequently altered gene, often co-occurring with PTEN loss. High sHRD scores correlated with BRCA2/RB1 loss, somatic copy number alterations, and poor survival. HRD tumors showed enrichment of SBS3/ID6 signatures, altered fragment lengths, and reduced accessibility at zinc finger transcription factor sites. These results support ctDNA-based multimodal profiling as a non-invasive strategy for HRD detection and stratification.

  Study EGAS00001008190

• HCA_Female_Reporductive_Adult_WSSS_RNA

  Cell atlas of the human placenta The Human Cell Atlas initiative is an ambitious global research effort which aims to describe every cell in the human body across all developmental stages to generate a reference map to accelerate progress in science and medicine particularly relating to human development and disease. The initiative is led by investigators based at the Wellcome Sanger Institute and the Broad Institute of MIT and Harvard and funding support from the Wellcome and NIH. This specific project will assess human development. We aim to interrogate the cellular composition and molecular regulators underpinning development and maturation through single cell RNA-sequencing/spatial transcriptomics and computational algorithms to predict cellular developmental trajectories and cell-cell interactions. We will subsequent validate these findings in situ using allied imaging technologies e.g. immunohistochemistry and RNAscope and in vitro culture of human intestinal organoids (HIOs). This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001004210

• HCA_Placenta_Adult_Vento_RNA

  The Human Cell Atlas initiative is an ambitious global research effort which aims to describe every cell in the human body across all developmental stages to generate a reference map to accelerate progress in science and medicine particularly relating to human development and disease. The initiative is led by investigators based at the Wellcome Sanger Institute and the Broad Institute of MIT and Harvard and funding support from the Wellcome and NIH. This specific project will assess human development. We aim to interrogate the cellular composition and molecular regulators underpinning development and maturation through single cell RNA-sequencing/spatial transcriptomics and computational algorithms to predict cellular developmental trajectories and cell-cell interactions. We will subsequent validate these findings in situ using allied imaging technologies e.g. immunohistochemistry and RNAscope and in vitro culture of human intestinal organoids (HIOs). This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001004069

• DLBCL NGS Genomic Datasets of non-China cohort from Phoenix Clinical Trial

  Study biopsies (n=773; 189 cases as China cohort and 584 cases as non-China cohort) underwent whole exome sequencing or targeted gene panel DNA sequencing and RNA sequencing, allowing the identification of somatic mutations. Tumors were assigned to DLBCL genetic subtypes as the MCD (n=110), BN2 (n=47) or N1 (n=28) using the LymphGen algorithm based on their somatically mutated genes. In younger patients (age≤60), ibrutinib plus R-CHOP was associated with a 100% event free survival (EFS) at 3-years in the MCD and N1 groups, whereas R-CHOP alone was associated with a 3-year EFS of 42.9% (p=0.01) and 50% (p=0.016) in the MCD and N1 groups, respectively. This analysis showed a benefit of ibrutinib with R-CHOP chemotherapy in particular genetic subtypes, providing mechanistic support for its survival benefit in younger patients with non-GCB DLBCL. The EGA collects RNA-Seq and NuGene targeted sequencing datasets of 584 cases for non-China cohort.

  Study EGAS00001005554

• Circulating Tumor DNA Analysis Profiles of Repotrectinib in NTRK fusion–positive advanced solid tumors: a phase 1/2 trial

  The dataset contains circulating tumor DNA (ctDNA) profiles from frozen plasma samples of 593 patients from the TRIDENT-1 clinical trial. Plasma was processed with centrifugation and automated liquid handling systems, and cell-free DNA was extracted using the Qiagen QIAsymphony platform. ctDNA libraries were constructed with the Guardant360 2.11 assay, which used targeted, hybridization-based capture and barcoding of cfDNA fragments for digital analysis, followed by high-throughput sequencing on the Illumina NextSeq 550 instrument. Sequencing data were processed and interpreted using the Bioinformatics Pipeline (BIP v3.5.2 or later) for variant calling and quantification and managed within LabVantage LIMS (v3.7 or later) to support sample tracking and workflow integration. Aligned read files are provided in bam and bai formats.

  Dataset EGAD50000002249

• VCRC Imaging Protocol for Magnetic Resonance and Positron Emission Tomography in Large-Vessel Vasculitis (Takayasu's Arteritis): Development as Clinical Trial Outcome Measures Vasculitis Clinical Research Consortium

  Takayasu's arteritis is a rare disease that affects the blood vessels. Takayasu's arteritis can cause swelling of large and medium-sized blood vessels. The blood vessels that are commonly affected are the branches of the aorta (the main blood vessel that leaves the heart). The purpose of this study is to help doctors learn more about this disease by using x-ray like tests to see if they are helpful in taking care of patients with Takayasu's arteritis. This is an imaging study that compares x-ray-like tests that would not be a part of your regular care (PET/CT) with x-ray-like tests that are a part of your regular care (MRI). At two visits, three months apart, patients will have a PET/CT scan performed at the same time as their MRI scan; some patients will also have a third PET/CT scan. A total of 36 people with Takayasu's arteritis at several hospitals will take part in this study. Doctors will use images from the different time points, along with information from exams and symptoms, to learn more about the disease.

  Study phs001715

• Genomics and Epigenomics of the Elderly Response to Pneumococcal Vaccines

  Pneumococcal Vaccine Study: This is a study designed to develop a detailed transcriptional and cellular profile of the immune response to pneumococcal vaccination with conjugated and non-conjugated polysaccharide vaccines in the senescent immune system of older adults. In this study, 39 healthy adults ages 60 and older that have never received pneumococcal vaccination, have been randomized to receive Prevnar 13 (Pfizer), a conjugated 13-valent vaccine or Pneumovax 23 (Merck), a non-conjugated 23-valent vaccine. Four (4) study visits occurred over 70 days at Day -7 (baseline), day 1, day 10 and day 60 (± 5d) post vaccination.Bulk RNA-sequencing data are available on the 4 time points for 31 of the participants and 1 replicate. ATAC-Doublet Detector Study: We generated single nucleus ATAC-seq (snATAC-seq) data from PBMCs of 2 baseline blood samples from the pneumococcal study. Generated data was then used to benchmark a novel computational method for detecting multiplets in snATAC-seq data, namely, AMULET (https://github.com/UcarLab/AMULET). Multiplets confound downstream analyses by introducing combined epigenomic profiles from 2 or more cells/nuclei. AMULET detects multiplets by using unique snATAC-seq data features that allow it to reliably use read counts to detect multiplets for their removal from data analyses.

  Study phs002361

• A system-wide approach to monitor responses to synergistic BRAF and EGFR inhibition in colorectal cancer cells

  Molecular heterogeneity of tumors, epigenetic changes and a diverse range of molecular mechanisms are main contributors to drug resistance, which represents one of the great challenges in cancer treatment. A deeper understanding of the molecular biology of cancer has resulted in better targeted therapies, where one or multiple drugs are adopted in novel therapies to tackle resistance. This beneficial effect of using combination treatments has to some extent also been observed in colorectal cancer (CRC) patients harboring the BRAF(V600E) mutation, whereby dual inhibition of BRAF(V600E) and EGFR increases antitumor activity. Notwithstanding this success, it is not clear whether this combination treatment is the only or most effective treatment to block resistance. Here, we investigate molecular responses upon single and multi-target treatments, over time, using BRAF(V600E) mutant CRC cells as a well-define model system. Through integration of transcriptomic, proteomic and phosphoproteomics data we obtain a comprehensive overview, revealing both well-known and novel responses. We primarily observe widespread upregulation of tyrosine kinases (RTKs) and and metabolic pathways. This points to by which the treated cells switch energy sources as a defensive response entering a quiescent like state, while activating signalling to re-activate the MAPK pathway.

  Study EGAS00001002654

• Defining Cutaneous Gene Expression Signatures in Juvenile Dermatomyositis

  Skin inflammation in juvenile dermatomyositis (JDM) can signal disease onset or flare up and prevent complete disease remission. Our objective was to evaluate JDM cutaneous expression signatures through tape stripping in both lesional and non-lesional skin and as compared to paired blood. A total of 28 JDM and 20 control (CTL) patients participated in the study. All patients had tape strip sampling of non-lesional (NL) skin at enrollment visit. Within our JDM cohort, paired lesional (L) skin was additionally sampled if rash was present. 16/28 of JDM patients had at least one additional skin sample associated with a follow-up (FU) visit (total number of follow-up samples included = 26 NL and 4 L). We identified a common innate immune signature in both lesional and non-lesional JDM skin. Using unsupervised hierarchical clustering of skin expression data, we distinguished a JDM molecular subgroup characterized by a mitochondrial dysfunction signature. In comparison to blood expression data, we determined that skin may more effectively highlight the JDM subgroup characterized by a mitochondrial dysfunction expression signature. Data available include bulk RNA-sequencing data from tape strips and blood of the JDM and control patients from this study.

  Study phs003884

• Pediatric Whole Genome Sequencing Diagnostic Utility

  The standard of care for first-tier clinical investigation of the etiology of congenital malformations and neurodevelopmental disorders is chromosome microarray analysis (CMA) for copy number variations (CNVs), often followed by gene(s)-specific sequencing searching for smaller insertion-deletions (indels) and single nucleotide variant (SNV) mutations. We compared diagnostic rate of WGS to CMA and targeted gene testing of 100 patients referred to The Hospital for Sick Children Genetics clinic in 2014. WGS identified genetic variants meeting clinical diagnostic criteria in 34% of cases, representing a 4-fold increase in diagnostic rate over CMA (8%) (p-value = 1.42e-05) alone and >2-fold increase in CMA plus targeted gene sequencing (13%) (p-value = 0.0009). WGS identified all rare clinically significant CNVs that were detected by CMA. In an additional 26 patients, WGS revealed indel and missense mutations presenting in a dominant (63%) or a recessive (37%) manner. We found four subjects with mutations in at least two genes associated with distinct genetic disorders, including two cases harboring a pathogenic CNV and SNV. When considering medically actionable secondary findings in addition to primary WGS findings, 38% of patients would benefit from genetic counselling.

  Study EGAS00001001623

• PATL2 is a key actor of oocyte maturation whose invalidation causes infertility in women and mice

  The genetic causes of oocyte meiotic deficiency (OMD), a form of primary infertility characterised by the production of immature oocytes, remain largely unexplored. Using whole exome sequencing, we found that 26% of a cohort of 23 subjects with OMD harboured the same homozygous nonsense pathogenic mutation in PATL2, a gene encoding a putative RNA-binding protein. Using Patl2 knockout mice, we confirmed that PATL2 deficiency disturbs oocyte maturation, since oocytes and zygotes exhibit morphological and developmental defects respectively. PATL2's amphibian orthologue is involved in the regulation of oocyte mRNA as a partner of CPEB. However, Patl2's expression profile throughout oocyte development in mice, alongside colocalisation experiments with Cpeb1, Msy2 and Ddx6 (three oocyte RNA-regulators) suggest an original role for Patl2 in Mammals. Accordingly, transcriptomic analysis of oocytes from WT and Patl2-/- animals demonstrated that in the absence of Patl2, expression levels of a select number of highly relevant genes involved in oocyte maturation and early embryonic development are deregulated. In conclusion, PATL2 is a novel actor of mammalian oocyte maturation whose invalidation causes OMD in humans.

  Study EGAS00001002903

• The scRNA dataset for TIGIT in MCL with CART

  We collected longitudinal samples from 15 patients with MCL at various clinical time points before and after CAT-T therapy brexucabtagene autoleucel (BA) infusion. The patients were grouped into three categories based on their clinical responses after BA treatment: 1) responsive (n = 9), 2) relapsed (n = 5), and 3) refractory (n = 1). All patients in category #1 and #2 had initially attained a complete response (CR) after BA therapy. The responsive group maintained CR with no relapse at the time of last follow up, while the relapsed group achieved initial CR but eventually relapsed. The 10x Chromium™ Single-Cell 5′ Reagent Kit v2 (PN-1000190, 10x GENOMICS) and Chromium Single-Cell Human TCR amplification Kit (PN-1000252, 10x GENOMICS) were used to perform single-cell separation, cDNA amplification, and library construction for gene expression and TCR repertoire following the manufacturer’s guidelines. Thirty-nine samples passed quality control and underwent single-cell transcriptome profiling with simultaneous single-cell T-cell receptor (TCR) repertoire analysis.

  Dataset EGAD00001010180

• Single cell targeted DNA-sequencing (and antibody sequencing) of high hyperdiploid B-ALL

  This dataset contains all sequencing data of the publication "Single-cell DNA and Surface Protein Characterization of High Hyperdiploid Acute Lymphoblastic Leukemia at Diagnosis and During Treatment". We provide both the raw fastq-files as well as the processed data in the form of .h5 files. There are 13 patients: XJ176, XH135, XJ180, XI145, XI148, XI167, XI150, XJ175, XJ178, XI162, XF98, XG111 and XG115. Of 9 patients, also follow-up samples during/after treatment were sequenced: XJ180, XI145, XI148, XI167, XI150, XJ175, XJ178, XI162 and XG111. To identify the cell types and distinguish between normal and leukemic cells, cell surface proteins were also captured for 6 samples: XF98, XG111 (at diagnosis and during treatment), XG115, XI162 (after treatment) and XJ175 (after treatment). All samples were processed on the MissionBio platform with a custom amplicon panel, and DaB-seq for the combined targeted DNA and protein sequencing.

  Dataset EGAD50000000829

• fragmentomic features of individuals with different cfDNA concentrations

  The uploaded data includes sequencing data of 862 individuals from the nasopharyngeal carcinoma (NPC) screening study. Samples from this cohort were sequenced using targeted sequencing methods for the Epstein Barr Virus (EBV) and selected autosomal DNA, but only ‘off-target’ reads were used for fragmentomic analyses. We have also performed genome-wide (non-targeted sequencing) for 1) Individuals with the highest and lowest cell-free DNA concentration (40 individuals); 2) A subsequent collection of the subjects with the highest and lowest DNA concentrations after six years (26 individuals); 3) 30 cases of pregnancy and 4) 20 patients with hepatocellular carcinoma. All sequencing data are of extracted plasma cfDNA from human subjects. The targeted sequencing samples from 862 individuals were sequenced on the NextSeq500 System (Illumina) and aligned to the EBV genome (AJ507799.2) and the human genome (hg19). The alignments were provided in bam format. The original fastq files of the remaining non-target sequencing samples were provided.

  Dataset EGAD50000000970

• Metabolic reprogramming towards OXPHOS identifies a novel therapeutic target for mantle cell lymphoma

  Metabolic reprogramming is linked to cancer cell growth and proliferation, metastasis, and therapeutic resistance in a multitude of cancers. Targeting dysregulated metabolic pathways to overcome resistance, an urgent clinical need in all relapsed/refractory cancers, remains difficult. Through genomics analysis of clinical specimens, we show that metabolic reprogramming towards oxidative phosphorylation (OXPHOS) and glutaminolysis is associated with therapeutic resistance to the Bruton’s tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma (MCL), an incurable B-cell lymphoma with poor clinical outcomes. Inhibition of OXPHOS with a novel, clinically applicable small molecule, IACS-010759, which targets complex I of the mitochondrial electron transport chain, results in significant growth inhibition in vitro and in vivo in ibrutinib-resistant patient-derived cancer models. This work suggests that targeting metabolic pathways to subvert therapeutic resistance is a clinically viable approach to treat highly refractory malignancies.

  Dataset EGAD00001004577

• IMCISION RNAseq

  RNA sequencing of 32 primary head and neck squamous cell carcinoma (HNSCC) samples prior to treatment with neoadjuvant anti-PD-1 (n=6) or anti-PD-1 + anti-CTLA-4 (n=26) immunotherapy, and 30 paired on-treatment HNSCC samples (i.e. after neoadjuvant immunotherapy). RNA quantity used: 10ng. Library Preparation Kit: SMART Stranded Total RNA Seq Kit (Takara). Sequencing parameters: NovaSeq 6000, 2x 100 bp. File type: fastQ

  Dataset EGAD00001008127

• single cell RNA-seq of peripheral blood from analysis in infants with MLL-rearranged Acute Lymphoblastic Leukemia

  This dataset contains two experiments. 1) Single cell RNA-seq of peripheral blood diagnostic samples from patients with MLL-rearranged infant ALL that underwent relapse or not (samples ending in R relapsed, samples ending in N did not), sequenced with SORT-seq (see cell systems, 2016, doi:10.1016/j.cels.2016.09.002). For some of the patients, multiple indipendent plates were produced (each plate is a sample). Barcode-well correspondence can be found here: https://bitbucket.org/princessmaximacenter/sharq/src/master/data/celseq2_bc384-v4.csv . 2) Single cell RNA-seq of peripheral blood diagnostic samples from patients with MLL-rearranged infant ALL that underwent relapse or not (samples ending in R relapsed, samples ending in N did not), sequenced with10x Genomics Version 2.

  Dataset EGAD00001007752

• Germline RUNX1 Variation and Predisposition to Childhood Acute Lymphoblastic

  Somatic mutations of RUNX1, which encodes the myeloid and lymphoid transcriptional factor RUNX1, are common in both B- and T- acute lymphoid leukemia (ALL) and are associated with poor prognosis of T-ALL. However, there has been no comprehensive investigation of the pattern or prevalence of RUNX1 germline mutation in both B- and T-ALL. Here we report germline RUNX1 variants in 1.23% of B-ALL and 2.11% of T-ALL, identifying 31 unique variants in 62 B-ALL and 18 unique variants in 26 T-ALL children. The majority of frameshift and nonsense variants affected RUNX1 function in transcriptional regulation, hematopoiesis, and cellular proliferation. We identified JAK3 as the most frequent somatic mutation in T-ALL with RUNX1 variants. These results not only identify RUNX1 as a leukemia predisposition gene but also further underline the importance of germline genetic variants to the development of ALL

  Dataset EGAD00001007793

• Beacon v2 and Federated EGA, part of the GDI project Starter Kit to enable access to genomic and phenotypic data across borders

  The European Genomic Data Infrastructure project has released a ‘Starter Kit’ based on the rare disease and cancer proof-of-concepts from the Beyond 1 Million Genomes (B1MG) project. The Starter Kit, freely available to any interested parties, contains a set of software applications and components co-developed by the 20 GDI nodes and based on open community standards from the Global Alliance for Genomics and Health (GA4GH). Products in the Starter Kit give all countries the technical capability to access synthetic genomic and phenotypic data across borders. The image above shows the full workflow of the GDI Starter Kit user journey. The dotted circles are not included in the Starter Kit yet The EGA’s work is represented in the Starter Kit with Beacon v2 and Federated EGA among the software applications and components. About Beacon v2 Beacon is a protocol for data discovery. This API allows the search of genomic variants and associated information without breaching the datasets privacy. The European Genome-phenome Archive (EGA) is a key contributor to the Beacon v2 Protocol, the Beacon v2 Reference Implementation (B2RI) and the EGA Beacon(s). About Federated EGA The Federated EGA network offers a tool for data storage and sharing. Officially launched in 2022, this network of connected resources enables transnational discovery of and access to human omics data for research, while also respecting jurisdictional data protection regulations. The Federated EGA Onboarding Website contains all the information related to the establishment of a Federated Node.

  Blog beacon-v2-and-federated-ega-part-of-the-gdi-project-starter-kit

• Security Overview

  Security Overview The European Genome-phenome Archive (EGA) houses consented human data under controlled access. Access decisions are handled by the relevant Data Access Committee (DAC), which autonomously manages requests through the DAC Portal. This document provides an overview of EGA’s practices in ensuring the security of data stored at EGA. As security is a prime concern of the EGA, the EGA is a member of the Global Alliance for Genomics and Health (GA4GH) Data Security work stream. The EGA contributes and helps develop the recommendations outlined the GA4GH Security Technology Infrastructure document, which defines guidelines, best practices, and standards for building and operating an infrastructure that promotes responsible data sharing in accordance with the GA4GH Privacy and Security Policy. Explore the EGA dataflow to gain deeper insights! Accessing data in the EGA involves several steps. First, users need to create an EGA account. Once logged in, they can request access to data controlled by a DAC through the EGA website (see documentation). The DAC oversees these requests through the DAC Portal, and if approved, grants the necessary permissions to the user's EGA account, allowing them to access and download all relevant data and metadata for the requested dataset(s). The key points of EGA security strategy are: 1 Regular Risk Assessment The EGA regularly identifies and assesses risk related to the following: Breach of confidentiality,Breach of privacy or autonomy,Malicious or accidental corruption or destruction of data archived at EGA,Disruption of services provided by the EGA. 2 Risk mitigation The EGA implements and maintains safeguards to minimise the risks identified above in accordance with the 6 control objectives listed in Appendix 1 and outlined in the GA4GH Security and Infrastructure document.If a breach is discovered, the EGA applies a defined protocol to minimise damage. 3 Identity and authorisation management The EGA authenticates the identity of individuals or software accessing controlled access data held at the EGA.The EGA ensures an appropriate level of assurance (LoA) is applied to the identity consistent with the risk associated with that individual, such as multi-factor authentication for DACs.The EGA provides the minimum access rights and privileges consistent with the user’s identity, allowing access consistent with the GA4GH Privacy and Security Policy, as determined by the appropriate DAC. 4 Audit Logs The EGA maintains a set of logs recording: Changes to user access rights,Data access requests,Resource usage. 5 Cryptography, communication security, and data integrity The EGA ensures data transmission integrity using a hash function.All data transmitted to or from the EGA is end-to-end encrypted.All data at EGA is stored using strong encryption.Encryption keys are not stored in the same system as the encrypted data.All data archived at EGA must be accompanied by a signed submission statement ensuring appropriate consent or ethical approval has been obtained, and is in accordance with all applicable laws and regulations. The EGA has a defined protocol defining the response in the event of a security breach, and is continuing to work with the GA4GH Data Security Work Stream to help define best practice and associated standards for breach responses. Appendix 1 GA4GH Control Objectives Control Objective 1: Implement technology safeguards to minimise the risk of unauthorised access, use, or disclosure of confidential and private data.Control Objective 2: Implement technology safeguards to minimise the risk of discovery, access, and use of individuals’ clinical and genomic data, and individual identities, other than as authorised by applicable jurisdictional law, institutional policy, and individual consents.Control Objective 3: Implement technology safeguards to minimise the risk of accidental or malicious corruption or destruction of data.Control Objective 4: Implement technology safeguards to minimise the risk of disruption, degradation, and interruption of services enabling access to data.Control Objective 5: Implement technology safeguards to minimise the risk of potential security attacks and misuse of authorised accesses and privileges.Control Objective 6: Implement technology safeguards to promptly detect the failure to attain the above control objectives and to respond with proper countermeasures.Appendix 2Refer to the document below to learn more about EGA long-term data preservation policy and procedures at EMBL-EBI.Long-term data preservation

  Documentation about/security

• RNA-seq of high grade serous ovarian tumours

  Somatic RNA for 40 samples matched to the WGS was extracted using the Qiagen Qiasymphony RNA protcol (cat no 931636). The tissue was initially homogenised using a Qiagen Bioruptor, followed by the manufacturers recommended protocol (including DNase digestion). The resulting RNA the underwent quality control as follows: firstly, A260 and A280nm were measured on a Denovix DS-11 Fx to qualitatively illustrate A260/280nm and A260/230nm ratios as measures of RNA purity. A260/280 had to be 2.0 and A260/230 had to be 2.0-2.2. Then RNA was quantified using LifeTechnologies Qubit RNA BR kit (cat no Q10210). RNAseq was carried out by the Edinburgh Clinical Research Facility on an Illumina NExtSeq500. Total RNA samples were assessed on the Agilent Bioanalyser (Agilent Technologies, #G2939AA) with the RNA 6000 Nano Kit (#5067-1512) for quality and integrity of total RNA, and then quantified using the Qubit 2.0 Fluorometer (Thermo Fisher Scientific Inc, #Q32866) and the Qubit RNA HS assay kit (#Q32855). Libraries were prepared from total-RNA sample using the NEBNext Ultra 2 Directional RNA library prep kit for Illumina (#E7760S) with the NEBNext rRNA Depletion kit (#E6310) according to the provided protocol. 400ng of totalRNA was then added to the ribosomal RNA (rRNA) depletion reaction using the NEBNext rRNA depletion kit (Human/mouse/rat) (#E6310). This step uses specific probes that bind to the rRNA in order to cleave it. rRNA-depleted RNA was then DNase treated and purified using Agencourt RNAClean XP beads (Beckman Coulter Inc, #66514). RNA was then fragmented using random primers before undergoing first strand and second strand synthesis to create cDNA. cDNA was end repaired before ligation of sequencing adapters, and libraries were enriched by PCR using the NEBNext Multiplex oligos for Illumina set 1 and 2 (#E7500). Final libraries had an average peak size of 271bp. Libraries were quantified by fluorometry using the Qubit dsDNA HS assay and assessed for quality and fragment size using the Agilent Bioanalyser with the DNA HS Kit (#5067-4626). Sequencing was performed using the NextSeq 500/550 High-Output v2 (150 cycle) Kit (# FC- 404-2002) on the NextSeq 550 platform (Illumina Inc, #SY-415-1002). Libraries were combined in an equimolar pool based on the library quantification results and run across 5 High-Output Flow Cell v2.5.

  Dataset EGAD00001009048

• RNA-seq of high grade serous ovarian tumours

  Somatic RNA for 37 samples was extracted using the Qiagen Qiasymphony RNA protcol (cat no 931636). The tissue was initially homogenised using a Qiagen Bioruptor, followed by the manufacturers recommended protocol (including DNase digestion). The resulting RNA the underwent quality control as follows: firstly, A260 and A280nm were measured on a Denovix DS-11 Fx to qualitatively illustrate A260/280nm and A260/230nm ratios as measures of RNA purity. A260/280 had to be 2.0 and A260/230 had to be 2.0-2.2. Then RNA was quantified using LifeTechnologies Qubit RNA BR kit (cat no Q10210). RNAseq was carried out by the Edinburgh Clinical Research Facility on an Illumina NExtSeq500. Total RNA samples were assessed on the Agilent Bioanalyser (Agilent Technologies, #G2939AA) with the RNA 6000 Nano Kit (#5067-1512) for quality and integrity of total RNA, and then quantified using the Qubit 2.0 Fluorometer (Thermo Fisher Scientific Inc, #Q32866) and the Qubit RNA HS assay kit (#Q32855). Libraries were prepared from total-RNA sample using the NEBNext Ultra 2 Directional RNA library prep kit for Illumina (#E7760S) with the NEBNext rRNA Depletion kit (#E6310) according to the provided protocol. 400ng of totalRNA was then added to the ribosomal RNA (rRNA) depletion reaction using the NEBNext rRNA depletion kit (Human/mouse/rat) (#E6310). This step uses specific probes that bind to the rRNA in order to cleave it. rRNA-depleted RNA was then DNase treated and purified using Agencourt RNAClean XP beads (Beckman Coulter Inc, #66514). RNA was then fragmented using random primers before undergoing first strand and second strand synthesis to create cDNA. cDNA was end repaired before ligation of sequencing adapters, and libraries were enriched by PCR using the NEBNext Multiplex oligos for Illumina set 1 and 2 (#E7500). Final libraries had an average peak size of 271bp. Libraries were quantified by fluorometry using the Qubit dsDNA HS assay and assessed for quality and fragment size using the Agilent Bioanalyser with the DNA HS Kit (#5067-4626). Sequencing was performed using the NextSeq 500/550 High-Output v2 (150 cycle) Kit (# FC- 404-2002) on the NextSeq 550 platform (Illumina Inc, #SY-415-1002). Libraries were combined in an equimolar pool based on the library quantification results and run across 5 High-Output Flow Cell v2.5.

  Dataset EGAD00001010139

• Center for Oral Health Research in Appalachia (COHRA) Genomic Studies of Oral Health and Disease

  The purpose of this project is to identify the genetic factors contributing to dental caries in children and adults. The datasets come from the Center for Oral Health Research in Appalachia (COHRA), which has the long-term goal of determining the sources of oral health disparities in a high risk, Northern Appalachian population so that effective preventive interventions can be designed and targeted. The Specific Aims of this project are to perform genome-wide association scans of dental caries of the (1) primary dentition in children, and (2) permanent dentition in adults, to identify novel risk variants and to replicate previously nominated risk variants. This project brings together samples from three cohorts: COHRA1 is a cross-sectional cohort comprising members of 862 northern Appalachian families; approximately 80% of the cohort has been previously genotyped by the Center for Inherited Disease Research with support from NIDCR using the Illumina Quad W array (see dbGaP Study Accession: phs000095.v3.p1). Dental SCORE is a cross-sectional cohort comprising approximately 550 unrelated individuals who underwent the same data collection protocol as COHRA1. COHRA2 is an ongoing longitudinal cohort that recruited approximately 1100 northern Appalachian women during pregnancy, and followed them and their children through their children's early childhood; the current project period will continue data collect though age 6 of the child. Phenotypes for this project were derived from intra-oral examinations performed by trained and calibrated research hygienists. In brief, each tooth was recorded as present or absent, and each surface of each present tooth was scored for evidence of decay. From these data, dental caries indices were generated. This project contains two phases of genotyping: (1) collection of exome SNP Chip data for the previously genotyped COHRA1 samples, and (2) collection of whole-genome SNP Chip data for the remaining COHRA1 samples and all Dental SCORE and COHRA2 samples. These data will support efforts to test hypotheses regarding the causal relationships of risk factors contributing to the unusually high rates of caries formation in the Appalachian population. Ultimately, these data may inform the development of an integrated model of caries risk, in which the effects of genetics, oral ecology, diet, and other environmental/psychosocial factors and behaviors are modeled in concert to explain the disparities, including the high rate of caries onset before age 6. The gene-mapping Aims of this project, which seek to identify the genetic factors that contribute to caries risk, are a requisite step in realizing this integrated model.

  Study phs001591

• Genomics of Kidney Transplantation

  We have an established consortium consisting of 5 clinical centers which do a total of >800 kidney transplants/year. We have developed a quality-controlled multicenter database with high quality data, and obtained DNA samples and clinical data on 962 recipients and 442 donors. Using our developed infrastructure, we propose to study whether genetic variants are, in part, responsible for the differing outcomes of transplant recipients treated with contemporary immunosuppressive protocols. Our central hypotheses are that the genetic variation is associated with a) kidney transplant outcome, and b) immunosuppressive drug disposition and toxicity. Our long-term goals are to determine whether it is possible to individualize immunosuppressive therapy, based on genetics. At the same time, our studies may elicit new information on pathways important in the immune response or in immunosuppressive drug efficacy, disposition, and toxicity.Our application consists of 3 cores (Genetics Core, Clinical Core, and Administrative Core). We will do a genome wide association study (GWAS). Significant single nucleotide polymorphisms (SNPs) will be identified using the GWAS.Project 1 has 2 specific aims.Aim 1: To identify recipient SNPs that are associated with kidney allograft outcomes, including acute rejection, chronic graft dysfunction, and graft failure. Aim 2: To identify living donor SNPs that are associated with kidney allograft outcomes. Project 2 has 4 specific aims. Aim 1: To identify SNPs that are associated with tacrolimus blood levels.Aim 2: To identify SNPs that are associated with early tacrolimus-related nephrotoxicity and immune suppressant-related new onset diabetes.Aim 3: To identify SNPs that are associated with mycophenolate-related toxicity. Aim 4: To establish the relationships between candidate recipient SNPs, enzyme activity and mRNA expression of the pharmacologic targets of mycophenolate and calcineurin inhibitors. The projects use the genotyping data, which were provided by the Genetics Core, and clinical information, which were collected and entered into the multicenter database by the Clinical Core. Further, biostatistical support (Clinical Core) and administrative oversight and support (Administrative Core) will facilitate data collection, data entry, and data analyses for both projects. The Administrative Core will also facilitate interaction between Sites, Cores, and Projects.Technical note: Regarding to the study design, all transplant recipients should be unrelated. Given the nature of transplantation, some donors may be related to recipients. The donor-recipient relationships are reported in the demographic file under the "related" column. As we did not collect full pedigree information for the related donor-recipient pairs, we have included a IBD file (calculated using PLINK) with the genotype data.

  Study phs001667

• NHLBI Recipient Epidemiology Donor Evaluation Study (REDS)-III - Brazil Sickle Cell Disease Cohort (REDS-BSCDC)

  The Recipient Epidemiology and Donor Evaluation Study (REDS)-III program established a Brazilian Sickle Cell Disease (SCD) Cohort to identify molecular determinants of response to transfusions, alloimmunization and risk factors associated with HIV infection. The Brazil population presents a complex admixture of African, European, Asian and Indigenous heritage and will provide insights into genetic, demographic, social, and healthcare system determinates of SCD outcomes. The REDS-III Brazil SCD cohort began in the Fall of 2013 and aimed to: Establish a cohort of SCD patients with a comprehensive centralized electronic database of detailed clinical, laboratory and transfusion information, as well as establish a repository of blood samples to support biological studies relevant to SCD pathogenesis and transfusion complications; Characterize changes in markers of inflammation in response to transfusion by analyzing chemokine/cytokine panels in serial post transfusion specimens; Identify single nucleotide polymorphisms (SNPs) that contribute to the risk of red blood cell alloimmunization in SCD by performing a genome-wide association (GWA) study in transfused SCD patients; Characterize risk of HIV and HIV outcomes in the Brazilian SCD population and compare SCD outcomes among HIV sero-positive and sero-negative SCD patients.

  Study phs001972

• Functional single-cell characterization of immune aplastic anemia shows convergence of NK and NK-like CD8+ T cells with disease-associated TCR signature

  Immune aplastic anemia (AA) is a life-threatening bone marrow (BM) failure disorder driven by an autoimmune T cell attack against the hematopoietic stem and progenitor cells (HSPCs). However, the autoantigen targets and the role of other immune cells are unknown. Here, by analyzing an international cohort of 156 AA patients with scRNA+TCRαβ-seq, TCRβ-seq, flow cytometry, and plasma cytokine profiling with comparisons to healthy controls and patients with other hematological disorders, we identify NK cells and CD8+ TEMRA cells expressing NK receptors with AA-associated TCRβ-seq motifs as the most dysregulated immune cell populations in AA BM. Functional co-culture experiments with scRNA-TCRαβ-seq readout utilizing primary HSPCs and immune cells provide evidence that NK cellscannot kill HSPCs alone, but sensitize them to CD8+ T cell-mediated killing. Furthermore, HSPCs induce strong activation of T cell clones with CD8+ TEMRA NK-like phenotype and AA-associated TCR motifs. Our results reveal the convergent evolution of innate and adaptive immune cells in AA, where NK cells support CD8+ T cell-mediated autoimmunity.

  Study EGAS00001007602

• Spatial_transcriptome_analysis_of_Paediatric_Thymus

  Cell atlas of Paediatric Thymus Cell atlas of Paediatric Thymus - The Human Cell Atlas initiative is an ambitious global research effort which aims to describe every cell in the human body across all developmental stages to generate a reference map to accelerate progress in science and medicine particularly relating to human development and disease. The initiative is led by investigators based at the Wellcome Sanger Institute and the Broad Institute of MIT and Harvard and funding support from the Wellcome and NIH. We aim to interrogate the cellular composition and molecular regulators underpinning a cells identity through; genetic and genomic analysis, expression analysis, non-identifiable video imaging and cell line and organoid production, as well as, computational algorithms to predict cellular developmental trajectories and cell-cell interactions. We will subsequently validate these findings in situ using spatial genomic and imaging technologies e.g. immunohistochemistry, RNAscope, in situ sequencing and spatial transcriptomic analyses. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001004281

• Functional single-cell characterization of immune aplastic anemia shows convergence of NK and NK-like CD8+ T cells with disease-associated TCR signature

  Immune aplastic anemia (AA) is a life-threatening bone marrow (BM) failure disorder driven by an autoimmune T cell attack against the hematopoietic stem and progenitor cells (HSPCs). However, the autoantigen targets and the role of other immune cells are unknown. Here, by analyzing an international cohort of 156 AA patients with scRNA+TCRαβ-seq, TCRβ-seq, flow cytometry, and plasma cytokine profiling with comparisons to healthy controls and patients with other hematological disorders, we identify NK cells and CD8+ TEMRA cells expressing NK receptors with AA-associated TCRβ-seq motifs as the most dysregulated immune cell populations in AA BM. Functional co-culture experiments with scRNA-TCRαβ-seq readout utilizing primary HSPCs and immune cells provide evidence that NK cellscannot kill HSPCs alone, but sensitize them to CD8+ T cell-mediated killing. Furthermore, HSPCs induce strong activation of T cell clones with CD8+ TEMRA NK-like phenotype and AA-associated TCR motifs. Our results reveal the convergent evolution of innate and adaptive immune cells in AA, where NK cells support CD8+ T cell-mediated autoimmunity.

  Study EGAS00001007604

• The Egyptian Collaborative Cardiac Genomics (ECCO-GEN) Project: Defining a Healthy Volunteer Cohort

  The integration of comprehensive genomic and phenotypic data from diverse ethnic populations offers unprecedented opportunities towards advancements in precision medicine and novel diagnostic technologies. Current reference genomic databases are not representative of the global human population, making variant interpretation challenging, especially in underrepresented populations such as the North African population. To address this, the Egyptian Collaborative Cardiac Genomics (ECCO-GEN) Project launched a study comprising 1000 individuals free of cardiovascular disease (CVD). Here, we present the first 391 Egyptian healthy volunteers (EHVols) recruited to establish a pilot phenotyped control cohort. All individuals underwent detailed clinical investigation, including cardiac MRI, and were sequenced using a targeted panel of 174 genes with reported roles in inherited cardiac conditions (ICC). We identified 1,262 variants in 27 cardiomyopathy genes of which 15.1% were not captured in current global and regional genetic reference databases (here: gnomAD and Great Middle Eastern (GME) Variome). The ECCO-GEN project aims at defining the genetic landscape of an understudied population and providing individual-level genetic and phenotypic data to support future studies in CVD and population genetics.

  Study EGAS00001004434

• Patient-derived neuroblastoma model system OHC-NB1

  Accurate disease modeling presents a bottleneck against effective translation of novel neuroblastoma therapies into the clinic. Recently, considerable intra-tumor genetic heterogeneity has been observed in neuroblastoma, which calls for preclinical models that reflect this feature. Flexibility in a testing platform is also desirable to support assessment of different endpoints and tumor cell characteristics. We present the novel neuroblastoma model OHC-NB1, propagated from a bone marrow metastasis from a patient with INRG stage M, MYCN-amplified neuroblastoma at first diagnosis. To model different aspects of the disease, several preclinical models were developed from the bone marrow aspirate: a tissue plastic-adherent cell line, a 3-dimensional (3D) spheroid culture, and cell line-derived xenografts that were subcutaneously passaged in mice. Typical aspects of MYCN-amplified neuroblastoma, such as MYCN amplification in double minutes, 1p deletion, 17q gain, and a diploid karyotype, are present in OHC-NB1 and persist in all culture types. Whole exome sequencing revealed intra-tumor heterogeneity in the bone marrow metastasis reflected in the culture models. The set of OHC-NB1 cultures with a genetically heterogeneous MYCN-amplified neuroblastoma background provide a flexible preclinical testing system that recapitulates important features of metastatic neuroblastoma.

  Study EGAS00001003031

• Accurate detection of tumor-specific fusion genes reveals strongly immunogenic personal neo-antigens

  Fusion genes arising from cancer-associated somatic mutations are a potential rich source for highly immunogenic neo-antigens. However, their exploitation as targets for personalized cancer immunotherapy is currently limited by the lack of computational tools allowing transcriptome-wide identification of unique fusion genes in an accurate and sensitive manner. Here, we present EasyFuse, a computational pipeline, to detect individual and cancer-specific fusion genes in next-generation-sequencing transcriptome data obtained from human cancer samples. Using machine learning, EasyFuse predicts personal fusion genes with high precision and sensitivity and outperforms previously described approaches as qualified by an unprecedented ground-truth dataset of >1500 verification experiments in relevant patient samples. By testing immunogenicity with autologous blood lymphocytes from cancer patients we detected pre-established CD4+ and CD8+ T cell responses for 10 of 21 (48%), and for 1 of 30 (3%) of identified fusion genes, respectively. In conclusion, we demonstrate accurate detection of cancer-specific fusion genes. The high frequency of T cell responses detected in cancer patients support the relevance of private fusion genes as neo-antigens for personalized immunotherapies, especially for tumors with low point mutation burdens.

  Study EGAS00001004877

• RNA-sequencing of tumors from 45 patients with recurrent or metastatic gastric cancer treated with immune checkpoint inhibitors

  Genomic profiling can provide prognostic and predictive information to guide clinical care. Biomarkers that reliably predict patient response to chemotherapy and immune checkpoint inhibition in gastric cancer are lacking. In this work, we used our machine learning algorithm NTriPath to identify a gastric-cancer specific 32-gene signature. Using unsupervised clustering on expression levels of these 32 genes in tumors from 567 patients, we identified four molecular subtypes that were prognostic for survival. We then built a support vector machine with linear kernel and the binary classifier to generate a risk score that is prognostic for 5-year overall survival and validated the risk score using three independent datasets. We also found that the molecular subtypes predicted response to adjuvant 5-fluorouracil and platinum after gastrectomy and immune checkpoint inhibitors in patients with metastatic or recurrent disease. The 32-gene signature is a promising prognostic and predictive biomarker to guide the clinical care of gastric cancer patients and should be validated in a prospective manner. This EGA archive includes both St.Mary hospital cohort samples (n=28) and Yonsei immunotherapy patient samples (n=17).

  Study EGAS00001005588

• Human CD4 Memory T Cell Activation Time Course

  We performed a high-resolution time course RNA-seq experiment on CD4+ memory T cells during activation with anti-CD3/CD28 beads. We performed this in 24 adult individuals of European ancestry with no autoimmune diseases. We used 1 million cells as starting material, per time point (up to 8 time points per individual from 0 to 72 hours). We identified widespread dynamic allele-specific expression (dynASE) across the genome, i.e. ASE that changes with time after activation, which reflects cell state-dependent genetic regulatory effects. DynASE events were enriched in risk loci for multiple autoimmune diseases. This highlights the importance of studying multiple cellular states in order to elucidate the mechanisms of autoimmune disease. It also provides a successful framework to do it in other cellular systems relevant for other traits. We also showed an unprecedented amount of regulatory variation for HLA genes. HLA-DQB1 has 3 distinct regulatory haplotypes with expression profiles that could come from 3 different genes. We performed ATAC-seq in replicate for CD4+ memory T cells stimulated for 72 hours from another healthy individual. These data, together with genetic fine-mapping, CRISPR editing, EMSA and luciferase assays, helped us find a SNP in the promoter of HLA-DQB1 that causes at least part of the large cell state-dependent change in expression, at the RNA and protein levels.

  Study phs002259

• INSIGHT (Intervention Nurses Start Infants Growing on Healthy Trajectories) Cohort

  This is a study of the biological risk factors for children enrolled in the INSIGHT (Intervention Nurses Start Infants Growing on Healthy Trajectories) study. INSIGHT is a randomized, controlled trial testing a responsive parenting intervention designed for the primary prevention of childhood obesity against a safety control. These first-born children were deeply studied in this time period with data collected on a wide variety of variables including mode of delivery, gender, weight and height (collected at 7 time points), medication usage, diet information, and maternal health information (gestational weight gain, gestational diabetes, smoking during pregnancy). This study includes a survey of the oral and gut microbiota from 226 mother-child dyads. It was designed to investigate the relationship between a cross-sectional view of the child's microbiome (at two years of age) and the patterns of growth between birth and 2 years. Microbiome samples from children (buccal swab and stool sample) and their mothers (buccal swab) are collected at the children's 2-year clinical research visit. Stool metabolites have also been assayed for a subset of the 226 children using 1H-NMR. Additionally, we genotyped the same individuals for SNPs across the genome. For a subset of 48 individuals we have added second-born siblings. For these additional 48 children, we characterized the methylation pattern across the genome using cord blood and placenta samples.

  Study phs001498

• Analysis_of_genomic_integrity_of_disease_corrected_human_induced_pluripotent_stem_cells_by_exome_sequencing

  Induced pluripotent stem (iPS) cells hold great promise for autologous cell transplantation. In order to apply this therapy to monogenic disorder, disease-causing mutations must be corrected prior to transplantation. We generated iPS cells from patients with alpha-1 antitrypsin deficiency, which is caused by homozygous non-synonymous mutation in the SERPINA1 gene. In vitro differentiation of patient-derived iPS cells to hepatocytes showed recapitulation of the disease phenotype. We corrected the mutations by gene targeting using zinc finger nuclease (ZFN) and piggyBac transposon technologies. Our mutation correction is highly accurate. There is no exogenous sequence left behind at the targeted site. The corrected iPS cell-derived hepatocytes were indistinguishable from healthy hepatocyte, suggesting that the corrected gene was fully functional. The genomic integrity was also analyzed by CGH and SNP array, showing no genomic alterations. These are important points to ensure clinical safety as well as functional restoration of the corrected gene. One remaining question is if these corrected iPS cells are clinically safe at the single base-pair level. Recent publications suggested that cancer-related mutations are significantly accumulated during iPS cell propagation. We aim to assess the clinical safety of the corrected iPS cells by using exome sequencing. Outcome from this project would bring iPS cell technology one step closer to clinical applications.

  Study EGAS00001000055

• Drug-perturbation-based stratification of blood cancer

  As new generations of targeted therapies emerge and tumor genome sequencing discovers increasingly comprehensive mutation repertoires, the functional relationships of mutations to tumor phenotypes remain largely unknown. Here, we measured ex vivo sensitivity of 246 blood cancers to 63 drugs alongside genome, transcriptome, and DNA methylome analysis to understand determinants of drug response. We assembled a primary blood cancer cell encyclopedia data set that revealed disease-specific sensitivities for each cancer. Within chronic lymphocytic leukemia (CLL), responses to 62% of drugs were associated with 2 or more mutations, and linked the B cell receptor (BCR) pathway to trisomy 12, an important driver of CLL. Based on drug responses, the disease could be organized into phenotypic subgroups characterized by exploitable dependencies on BCR, mTOR, or MEK signaling and associated with mutations, gene expression, and DNA methylation. Fourteen percent of CLLs were driven by mTOR signaling in a non–BCR-dependent manner. Multivariate modeling revealed immunoglobulin heavy chain variable gene (IGHV) mutation status and trisomy 12 as the most important modulators of response to kinase inhibitors in CLL. Ex vivo drug responses were associated with outcome. This study overcomes the perception that most mutations do not influence drug response of cancer, and points to an updated approach to understanding tumor biology, with implications for biomarker discovery and cancer care.

  Study EGAS00001001746

• Platinum Genomes

  Improvement of variant calling in next-generation sequence data requires a comprehensive, genome-wide catalogue of high-confidence variants called in a set of genomes for use as a benchmark. We generated deep, whole-genome sequence data of seventeen individuals in a three-generation pedigree and called variants in each genome using a range of currently available algorithms. We used haplotype transmission information to create a phased "platinum" variant catalogue of 4.7 million single nucleotide variants (SNVs) plus 0.7 million small (1-50bp) insertions and deletions (indels) that are consistent with the pattern of inheritance in the parents and eleven children of this pedigree. Platinum genotypes are highly concordant with the current catalogue of the National Institute of Standards and Technology for both SNVs (>99.99%) and indels (99.92%), and add a validated truth catalogue that has 26% more SNVs and 45% more indels. Analysis of 334,652 SNVs that were consistent between informatics pipelines yet inconsistent with haplotype transmission ("non-platinum") revealed that the majority of these variants are de novo and cell-line mutations or reside within previously unidentified duplications and deletions. The reference materials from this study are a resource for objective assessment of the accuracy of variant calls throughout genomes.

  Study phs001224

• A Chromatin Accessibility Atlas of the Developing Human Telencephalon

  Gene expression differs between cell types and regions within complex tissues such as the developing brain. To discover regulatory elements underlying this specificity, we generated genome-wide maps of chromatin accessibility in nine anatomically-defined regions of the developing human telencephalon. Additionally, we defined the histone modification landscape of the prefrontal cortex and generated chromatin accessibility maps of its upper and deep layers. We predicted a subset of open chromatin regions (18%) that are most likely to be active enhancers, many of which are dynamic with 26% differing between early and late mid-gestation and 28% present in only one brain region. These predicted regulatory elements (pREs) are enriched proximal to genes with expression differences across developmental stages, regions, and cortical laminae; they harbor distinct sequence motifs that suggest potential upstream regulators. We leveraged this atlas to predict and validate novel regulatory elements of genes that control cortex laminar identity and genes associated with autism spectrum disorder (ASD). These include enhancers proximal to FEZF2 and BCL11A that were validated in mouse, and an enhancer of ASD gene SLC6A1 containing two functional de novo mutations in individuals with ASD whose enhancer function we validated via CRISPRa. We also include data for transcription factor binding in mid-fetal cortex tissues, using CUT&RUN methods.

  Study phs002033

• Pancreatic, Small-intestinal and Pulmonary Neuroendocrine Tumors

  Purpose: The primary origin of neuroendocrine tumor metastases can be difficult to determine by histopathology alone, but is critical for therapeutic decision making. DNA methylation-based profiling is now routinely used in the diagnostic workup of brain tumors. This has been enabled by the availability of cost-efficient array-based platforms. We have extended these efforts to augment histopathological diagnosis in neuroendocrine tumors. Experimental Design and Results: We compiled data of 69 small-intestinal, pulmonary, and pancreatic neuroendocrine tumors. These data were used to build a ridge regression calibrated random forest classification algorithm (NEN-ID) that predicts the origin of tumor samples with high accuracy (> 95%). The model was validated during 3x3 nested cross validation and tested in a local (n=26) and external (n=172) cohort. In addition, we show that our diagnostic approach is robust across a range of possible confounding experimental parameters such as tumor purity and array quality. A software infrastructure and online user interface was built to make the model available to the scientific community. Conclusions: This DNA methylation-based prediction model can be used in the workup for patients with neuroendocrine tumors of unknown primary. To facilitate validation and clinical implementation, we provide a user-friendly, publicly available web-based version of NEN-ID.

  Study EGAS00001004878

• Single_Cell_Sequencing_of_Sperm__scSperm_

  The aim of this project is to genotype and sequence single spermatozoa from two men, one in his twenties and the other in his seventies. The resulting data is used to quantify the mutations that have arisen in the gametes of both individuals in order to better understand the effect of aging on mutation rates and modes.Project Outline. In order to quantify mutations, semen from two individuals are sequenced. 48 single sperm cells are isolated from each individual, and their DNA is extracted. The resulting genomes are amplified using PicoPlex, GenomiPhi MDA, Repli-G MDA, and MALBAC. QC step is applied to check the quality of WGA DNA using standard Sequenom plex (26 SNPs). A subset of 32 amplification products which pass the intiall QC, are genotyped using Affymetrix SNP6 chips. 12 of the genotyped amplification products are also sequenced. In addition, one multi-cell sample per individual is sequenced as a reference and for validation purposes.Altogether, 12 single cell sperm genomes and two multi-cell genomes are sequenced, coming to a total of 14 genomes. Of the single cell sperm genomes, 2 are sequenced to 50x coverage, and the other 10 to 25x coverage. Both multi-cell genomes are sequenced to 25x coverage.

  Study EGAS00001000935

• Spatiotemporal Genomic Profiling of Intestinal Metaplasia Reveals Clonal Dynamics of Gastric Cancer Progression

  Intestinal metaplasia (IM) is a pre-malignant condition of the gastric mucosa associated with increased gastric cancer (GC) risk. We analyzed 1256 gastric samples (1152 IMs) from 692 subjects from a 10-year prospective study. We identified 26 IM driver genes in diverse pathways including chromatin regulation (ARID1A) and intestinal homeostasis (SOX9), largely occurring as subclonal events. Analysis of clonal dynamics between and within subjects, and also longitudinally across time, revealed that IM clones are likely transient but increase in size upon progression to dysplasia, with eventual transmission of genetic events to paired GCs. Single-cell and spatial profiling highlighted changes in tissue ecology and lineage heterogeneity in IM, including an intestinal stem-cell dominant cellular compartment linked to early malignancy. Expanded transcriptome profiling revealed expression-based molecular subtypes of IM, including a body-resident “pseudoantralized” subtype associated with incomplete histology, antral/intestinal cell types, ARID1A mutations, inflammation, and microbial communities normally associated with the healthy oral tract. We demonstrate that combined clinical-genomic models outperform clinical-only models in predicting IMs likely to progress. Our results raise opportunities for GC precision prevention and interception by highlighting strategies for accurately identifying IM patients at high GC risk and a role for microbial dysbiosis in IM progression.

  Study EGAS00001007067

• Action to Control Cardiovascular Risk in Diabetes (ACCORD-BioLINCC)

  Related StudiesWhole genome and whole exome data is available on a subset of participants with phs001411. ECG signal data is available with phs003562.ObjectivesThe purpose of this study was to determine if intensive glycemic control, multiple lipid management and intensive blood pressure control could prevent major cardiovascular events (myocardial infarction, stroke or cardiovascular death) in adults with type 2 diabetes mellitus. Secondary hypotheses included treatment differences in other cardiovascular outcomes, total mortality, microvascular outcomes, health-related quality of life and cost-effectiveness. BackgroundGlycemia Trial:Patients with type 2 diabetes mellitus die of cardiovascular disease (CVD) at rates two to four times higher than non-diabetic populations of similar demographic characteristics. They also experience increased rates of nonfatal myocardial infarction and stroke. With the growing prevalence of obesity in the United States, CVD associated with type 2 diabetes is expected to become an even greater public health challenge in the coming decades than it is now. Expected increases in event rates will be associated with a concomitant rise in suffering and resource utilization.The ACCORD study investigated whether intensive therapy to target normal glycated hemoglobin (HbA1c) levels would reduce cardiovascular events in patients with type 2 diabetes who had either established cardiovascular disease or additional cardiovascular risk factors when compared to standard therapy (HbA1c between 7.0% and 7.9%). A separate analysis investigated whether reduction of blood glucose concentration decreases the rate of microvascular complications in these patients. Lipid Therapy Trial: Patients with type 2 diabetes mellitus have an increased incidence of atherosclerotic cardiovascular disease attributable, in part, to associated risk factors such as dyslipidemia. This is characterized by elevated plasma triglyceride levels, low levels of high-density lipoprotein (HDL) cholesterol and small, dense low-density lipoprotein (LDL) particles. The ACCORD Lipid Therapy trial was designed to test the effect of a therapeutic strategy that uses a fibrate to raise HDL-C and lower triglyceride levels and uses a statin for treatment of LDL-C reduce the rate of CVD events compared to a strategy that only uses a statin for treatment of LDL-C on cardiovascular outcomes in patients with type 2 diabetes that were at high risk for cardiovascular disease. Blood Pressure Trial: Diabetes mellitus increases the risk of cardiovascular disease at every level of systolic blood pressure. Because cardiovascular risk in patients with diabetes is graded and continuous across the entire range of levels of systolic blood pressure, even at prehypertensive levels, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommended beginning drug treatment in patients with diabetes who have systolic blood pressures of 130 mm Hg or higher, with a treatment goal of reducing systolic blood pressure to below 130 mm Hg. There is, however, a paucity of evidence from randomized clinical trials to support these recommendations. The ACCORD Blood Pressure trial tested the effect of a target systolic blood pressure below 120 mm Hg on major cardiovascular events among high-risk persons with type 2 diabetes compared to a strategy that targeted a SBP of EYE Substudy: Diabetic retinopathy, an important microvascular complication of diabetes, is a leading cause of blindness in the United States. Randomized, controlled clinical trials in cohorts of patients with type 1 diabetes and those with type 2 diabetes have shown the beneficial effects of intensive glycemic control and intensive treatment of elevated blood pressure on the progression of diabetic retinopathy. Elevated serum cholesterol and triglyceride levels have been implicated, in observational studies and small trials, as additional risk factors for the development of diabetic retinopathy and visual loss. The ACCORD EYE Substudy evaluated the effects of the ACCORD medical strategies on the progression of diabetic retinopathy in a subgroup of trial patients. MIND Substudy: Studies suggest that older persons with type 2 diabetes have at least twice the likelihood of developing late-life cognitive impairment or dementia compared to those without. The mechanisms underlying these cognitive disorders are increasingly thought to reflect a mixed pathology pattern with contributions from vascular, neurodegenerative and neurovascular processes. Pathophysiological mechanisms that have been described include inflammation, oxidative stress, energy imbalance, protein misfolding, glucocorticoid-mediated effects and differences in genetic susceptibilities. The ACCORD MIND substudy took as a premise that early intervention with the ACCORD therapeutic strategies to improve glycemic control could mitigate the adverse effects of type 2 diabetes on the brain. Participants10,251 participants with type 2 diabetes and HbA1c concentrations of 7.5% or more participated in the trial. Of these patients, 5518 were assigned to the lipid therapy arm and 4733 to the blood pressure arm. EYE Substudy: A subgroup of 2856 participants was evaluated for the effects of the ACCORD interventions at 4 years on the progression of diabetic retinopathy. Participants who, at baseline, had a history of proliferative diabetic retinopathy that had been treated with laser photocoagulation or vitrectomy were excluded. MIND Substudy: A subgroup of 2977 participants was evaluated for cognitive function and brain volume. The ACCORD MIND substudy excluded participants aged Design Participants were randomly assigned to undergo either intensive glycemic control (targeting a glycated hemoglobin level EYE Substudy: EYE Substudy participants were evaluated at two standardized and comprehensive eye examinations for the effects of the ACCORD interventions at 4 years on the progression of diabetic retinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study Severity Scale (as assessed from seven-field stereoscopic fundus photographs, with 17 possible steps and a higher number of steps indicating greater severity) or the development of diabetic retinopathy necessitating laser photocoagulation or vitrectomy. MIND Substudy: The cognitive primary outcome, the Digit Symbol Substitution Test (DSST) score, was assessed at baseline, 20 and 40 months. Total brain volume (TBV), the primary brain structure outcome, was assessed with MRI at baseline and 40 months in a sub-set of 632 patients. All patients with follow-up data were included in the primary analyses. Conclusions Glycemia Trial: As compared with standard therapy, the use of intensive therapy to target normal glycated hemoglobin levels for 3.5 years increased mortality and did not significantly reduce major cardiovascular events. (Action to Control Cardiovascular Risk in Diabetes Study Group, et al.,2008, PMID:18539917). Microvascular Outcomes of the Glycemia Trial: Intensive therapy did not reduce the risk of advanced measures of microvascular outcomes, but delayed the onset of albuminuria and some measures of eye complications and neuropathy. Microvascular benefits of intensive therapy should be weighed against the risk of increased total and cardiovascular disease-related mortality, increased weight gain, and higher risk for severe hypoglycemia. (Ismail-Beigi et al., 2010, PMID: 20594588) Lipid Therapy Trial: The combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal myocardial infarction or nonfatal stroke, as compared with simvastatin alone. These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority of high-risk patients with type 2 diabetes (ACCORD Study Group, et al., 2010, PMID: 20228404). Blood Pressure Trial: In patients with type 2 diabetes at high risk for cardiovascular events, targeting a systolic blood pressure of less than 120 mm Hg, as compared with less than 140 mm Hg, did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events (ACCORD Study Group, et al., 2010, PMID: 20228401). EYE Substudy: Intensive glycemic control and intensive combination treatment of dyslipidemia, but not intensive blood-pressure control, reduced the rate of progression of diabetic retinopathy (ACCORD Study Group, et al., 2010, PMID: 20587587). MIND Substudy: Although significant differences in TBV favored the intensive therapy, cognitive outcomes were not different. Combined with the unfavorable effects on other ACCORD outcomes, MIND findings do not support using intensive therapy to reduce the adverse effects of diabetes on the brain in patients similar to MIND patients (Launer et al., 2011, PMID: 21958949).

  Study phs003551

• Single nuclei ATAC-Seq data from the human ganglionic eminences

  Data generated through single nuclei ATAC sequencing on whole ganglionic eminences from 3 human fetuses (two of 16 and one of 17 gestational weeks). Tissue was acquired from the MRC-Wellcome Trust Human Developmental Biology Resource with ethical approval. snATAC-Seq libraries were prepared from ~8,000 nuclei per sample using Chromium Next GEM Single Cell ATAC (v1.1) reagents (10X Genomics). Quality control of libraries was performed using the Agilent 5200 Fragment Analyzer before sequencing on an Illumina NovaSeq 6000 to a depth of at least 617 million read pairs per library. Raw sequencing data were converted into FASTQ files. For a full description of data generation, please see Cameron et al, Schizophrenia Bulletin 2024, https://doi.org/10.1093/schbul/sbae083. Please note that 10X generated BAM files, rather than FASTQ files, have been uploded. FASTQ files can be regenerated using the 10X Genomics bamtofastq tool. https://support.10xgenomics.com/docs/bamtofastq

  Dataset EGAD50000000601

• Single-cell RNA-sequencing of rhabdomyosarcoma tumour tissue (2025-09-30)

  This study investigates high-risk rhabdomyosarcoma (RMS) using multiple single-cell and spatial genomic technologies. We generated and analysed single-cell and single-nucleus RNA-sequencing, chromatin accessibility, and spatial transcriptomics data from primary tumours and validation samples. These datasets characterise cellular diversity within rhabdomyosarcoma and identify cell states associated with aggressive disease. The data support research into tumour biology, risk stratification, and therapeutic target discovery. This repository houses the single-cell RNA sequencing of RMS tumours data. . This dataset contains all the data available for this study on 2025-09-30.

  Dataset EGAD00001015713

• CcRCC_metabolic_heterogeneity

  Heterogeneity is a hallmark of clear cell renal cell carcinoma (ccRCC). In this study, hyperpolarized [1-13C]pyruvate MRI (HP-13C-MRI) was used to probe metabolic heterogeneity non-invasively in 6 ccRCC patients from which 58 tumor and healthy tissues biopsies were acquired postoperatively. MRI parameters were correlated with 146 metabolite concentrations and the expression of 2523 metabolic genes across 34 metabolic pathways. Using metabologram projections and pathway consensus scoring, several metabolic pathways were correlated with the metabolic MRI, including glycolysis, pentose phosphate pathway, and the TCA cycle. A simple thresholding approach applied to the imaging metrics was sufficient to provide meaningful metabolic pathway information. We also show that tissue metabolic heterogeneity increases in regions with higher pyruvate-to-lactate conversion on imaging. These results provide validation of the biological relevance of HP-13C-MRI and support the possibility of its clinical use to improve disease characterization, stratification, targeting of biopsies, and providing novel methods to monitor treatment response.

  Dataset EGAD00001015780

• Effects of Metformin on Transcriptomic and Metabolomic Profiles in Breast Cancer Survivors Enrolled in the Randomized Placebo-Controlled MetBreCS Trial

  RNA from snap-frozen breast tissue biopsies were purified after lysing by tissuelyser (Qiagen) and using RNA Purification Plus Kit (Norgen biotek CORP, 47700) with additional on-column DNase-I treatment (Qiagen, 79254) at 27 °C. RNA purity and integrity (RIN) were quantified using RNA 6000 Nano kit (Agilent Technologies, 5067-1511) on the 4200 TapeStation (Agilent, Santa Clara, USA). Library preparation and 2x75bp paired-end of 160 ng total RNA input was performed using Illumina Stranded Total RNA Prep Ligation kit and Illumina HiSeq4000 system (Illumina, Sand Diego, CA, USA). RNA sequencing data from HiSeq4000 were quality checked and aligned to GRCh38 (GCA_000001405.15) reference genome using HISAT2 2.0.5 and submitted to subread v.1.5.2 for feature counts calculation. Finally, 36 paired biopsies samples (metformin n=26 and placebo n=12) were sequenced and included in the final analyses.

  Dataset EGAD50000001274