659 results for ""option,com_discussions"+y+19"

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• Integrative understanding of human immune system by functional genomics and development of intervention strategies for the prevention of autoimmune diseases

  To elucidate the regulation of gene expression in immune cell subsets and its contribution to autoimmune diseases, Whole blood and various immune cell subsets from 119 Systemic Lupus Erythematosus (SLE), 65 Dermatomyositis & Polymyositis, 67 Systemic Sclerosis, 19 Mixed Connective Tissue Disease, 18 Sjogren's syndrome, 24 Rheumatoid Arthritis, 23 Behcet's disease, 18 Adult Onset Still���s Disease, 25 ANCA-associated Vasculitis, 16 Takayasu���s Arteritis and 141 healthy controls (C) were collected (Naive_CD4, Mem_CD4, Fr._I_nTreg, Fr._II_eTreg, Fr._III_T, Th1, Th2, Th17, Tfh, NK, Naive_CD8, Mem_CD8, EM_CD8, CM_CD8, TEMRA_CD8, Naive_B, USM_B, SM_B, DN_B, Plasmablast, CL_Mono (or CD16n_Mono), CD16p_Mono, Int_Mono, NC_Mono, mDC, pDC, LDG, Neu). Whole genome sequencing was performed with whole blood samples. RNA-seq was performed with each immune cell subset samples. After filtering and normalization of the gene expression data, eQTL analysis was performed in each immune cell type. 15 immune cell subsets ATAC-seq was also performed in 8 SLE and HCs, each.

  Study JGAS000220

• Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer

  Tumour heterogeneity in primary prostate cancer is a well-established phenomenon. However, how the subclonal diversity of tumours changes during metastasis and progression to lethality is poorly understood. Here we reveal the precise direction of metastatic spread across four lethal prostate cancer patients using whole-genome and ultra-deep targeted sequencing of longitudinally collected primary and metastatic tumours. We find one case of metastatic spread to the surgical bed causing local recurrence, and another case of cross-metastatic site seeding combining with dynamic remoulding of subclonal mixtures in response to therapy. By ultra-deep sequencing end-stage blood, we detect both metastatic and primary tumour clones, even years after removal of the prostate. Analysis of mutations associated with metastasis reveals an enrichment of TP53 mutations, and additional sequencing of metastases from 19 patients demonstrates that acquisition of TP53 mutations is linked with the expansion of subclones with metastatic potential which we can detect in the blood.

  Study EGAS00001000942

• 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

• FBSeq: RNA sequencing of human fetal brain.

  RNA sequencing of 120 human fetal brains (aged 12-19 post-conception weeks) was performed as part of a Medical Research Council (U.K.) funded project (MR/L010674/2) to investigate genetic effects on gene expression in the developing human brain and their role in neuropsychiatric disorders. Human fetal brain tissue from elective terminations of pregnancy was provided by the Human Developmental Biology Resource (HDBR) (http://www.hdbr.org), with ethical approval (#08/H0712/34), and with consent for use of fetal material for medical research provided by female donors. Total RNA was extracted from half of the available brain tissue from each fetus using Tri-Reagent and treated with TURBO DNase. RNA-Seq libraries were prepared using 1µg of purified total RNA and the Illumina TruSeq Stranded Total RNA Library Prep kit, following ribosomal RNA depletion. Libraries were sequenced on the Illumina HiSeq 2500 or HiSeq 4000 systems, generating at least 50 million read pairs per sample.

  Study EGAS00001003214

• Genome analysis of oesophageal cancer and Barrett's oesophagus

  The median survival of oesophageal cancer this year is only 13 to 19 months after diagnosis and more than 90% will die from their disease. Therefore better treatment options are needed. The likelihood of cure for early screen-detected cancers is much higher. Barrett's oesophagus is a pre-cancerous lesion associated with a 30-40 fold increased risk of developing cancer. In an attempt to detect cancer early many patients with Barrett's are enrolled into surveillance programs involving regular endoscopies. A major problem with this approach is that the prevalence of BO in the population is estimated to be around 2%, but most patients with BO will never develop cancer. We are undertaking genomic and/or transcriptomic analysis of oesophageal tumours, Barrett's oesophagus and matched normal samples. The aim is to identify oesophageal-related genomic and transcriptomic alterations, which may reveal mutational process occurring, suggest biomarkers of tumour progression and treatment and identify novel treatment strategies.

  Study EGAS00001002864

• Gut metagenome associations with extensive digital health data in a volunteer-based EstMB cohort

  Microbiome research is starting to move beyond the exploratory phase towards interventional trials and therefore well-characterized cohorts will be instrumental for generating hypothesis and providing new knowledge. As part of the Estonian Biobank, we established the Estonian Microbiome Cohort which includes stool, oral and plasma samples from 2,509 participants and is supplemented with multi-omic measurements, questionnaires, and regular linkages to national electronic health records. In this study, we analyzed stool data from deep metagenomic sequencing together with rich phenotyping, including 71 diseases, 136 medications, 21 dietary questions, 5 procedures, and 19 other factors. The data revealed numerous relationships with different microbiome features. Additionally, the long-term antibiotic usage, independent from recent administration, has a significant impact on the microbiome composition, partly explaining the common associations between diseases. Overall, this study extends the understanding of microbiome–host interactions and facilitates the development of microbiome-related studies.

  Study EGAS00001005900

• H014: HES5 mediates NOTCH signaling by interaction with AKT to drive liver carcinogenesis

  Notch signaling plays a pivotal role in liver development and aberrant Notch signaling may lead to hepatocellular (HCC) or cholangiocellular carcinoma (CCA) development. Using whole exome sequencing of 54 human HCC samples, we discovered 19 somatic missense mutations in 15 different Notch pathway genes affecting 24.6% (14 of 57) of patients. Prediction of functional impact of these Notch pathway mutations revealed HES5-R31G to have high relevance. We found HES5 to be strongly activated by Notch signaling. In vitro, HES5 reduced cell migration and clonogenicity and in vivo, HES5 inhibited MYC-dependent liver tumor formation. But together with AKT, HES5 increased liver tumor formation in a mouse model. HES5 directly binds to AKT and AKT expression leads to increase HES5 protein levels. Furthermore, HES5 exhibits a negative feed-back loop by inhibiting NOTCH1 and HES1 gene expression. In contrast, HES5-R31G appears to be non-functional possibly by loss of nuclear translocation

  Study EGAS00001003329

• UK renal cancer samples genotyped on Illumina OmniExpress BeadChip

  Renal cell carcinoma (RCC) cases comprised adult patients with histologically proven RCC were collected through two sources within the UK. First, 856 cases from SORCE, a MRC collection of surgically treated RCC cases ascertained through UK clinical oncology centres. Second, 189 RCC cases collected through the ICR and Royal Marsden NHS Hospitals Trust. Cases included 590 clear cell carcinomas (CCCs), 42 papillary carcinomas (PCs), 33 chromophobe carcinomas (CCs) and 19 mixed or other histological subtypes. DNA was extracted from EDTA-venous blood samples using the conventional methods and quantified using PicoGreen (Invitrogen). Cases were genotyped using the Human OmniExpress-12 BeadChip according to the manufacturer's recommendations (Illumina Inc, San Diego, CA, USA). After strict QC, 944 cases were retained. Data provided in plink format. Controls used were data from the Wellcome Trust Case Control Consortium 2 (WTCCC2) 1958 birth cohort and the UK Blood Service Control Group (available as EGAS00000000028).

  Study EGAS00001002336

• Interethnic comparability in blood pressure GWAS

  We carried out a genome-wide association and replication study for blood pressure in a two-stage approach (max N = 289,038) with a discovery stage sample of 130,777 East Asian individuals, identifying 19 new genetic loci. We found a significant genetic heterogeneity between East Asian and European-descent populations at several blood pressure loci, conforming to “a common ancestry-specific variant association model”. At 6 unique loci, distinct non-rare (or common) ancestry-specific variants co-localized within the same linkage disequilibrium block despite the significantly discordant direction of effects for the proxy shared variants between the ethnic groups. The genome-wide transethnic correlation of causal-variant effect sizes is 0.898 and 0.851 for systolic and diastolic blood pressure, respectively. Some of the ancestry-specific association signals were also influenced by a selective sweep. Our results provide new evidence for the role of common ancestry-specific variants and natural selection in the occurrence of ethnic differences in complex traits such as blood pressure.

  Study EGAS00001002991

• CentralAfricanCMC_Pemberton

  The CentralAfricanCMC_Pemberton dataset encompasses 153,798 SNPs from the Illumina Cardio-MetaboChip (Voight et al. 2012) genotyped in 406 individuals from 19 Central African Populations from Gabon, Cameroon, Centralafrican Republic and Uganda). Individual phenotypic and cultural information at the individual level for this data set encompass gender, lifestyle (hunter-gatherer or farmer), and, when available, stature phenotype (standing height in cm, sitting-height in cm, and weight in kg). Other cultural, linguistic, and geographical location information about the sampled populations can be found in Pemberton et al. , Human Genetics, 2018 (https://doi.org/10.1007/s00439-018-1902-3).This dataset can only be accessed and used for non-commercial research purposes with a finality complying with the informed consent provided by Central African donors for the study of human evolutionary history only.

  Dataset EGAD00010001584

• Genomics characterization of BRAF-V600E colorectal cancer patients treated with anti-BRAF/EGFR

  WES files (fastQ) from 19 germline DNA, 22 tumor DNA, 5 patient-derived xenograft (PDX) DNA, and 9 plasma cfDNA) samples from 28 CRC-BRAF-mutated patients collected at baseline to anti-BRAF/EGFR therapies.

  Dataset EGAD00001008755

• Whole Genome Sequencing Consortium on Frontotemporal Dementia With Underlying TDP-43 Pathology

  Frontotemporal lobar degeneration (FTLD) is one of the leading causes of dementia in individuals younger than 65 years. The FTLD symptoms of most patients are not yet explained by mutations in the known FTLD genes (C9orf72, GRN, MAPT). Identifying genetic risk associated with the disease is key for developing disease models and new therapeutic avenues. We performed short-read whole-genome sequencing (WGS) on 19 neuropathologically normal individuals and 560 patients with FTLD, including 171 pathologically confirmed FTLD patients, 352 clinically diagnosed FTLD patients, and 37 autosomal dominant FTLD patients. Pathologically confirmed FTLD patients include FTLD with TDP43 inclusions (FTLD-TDP) and FTLD with FUS inclusions (FTLD-FUS), autosomal dominant FTLD patients include GRN (FTLD-TDP GRN) and C9ORF72 (FTLD-TDP C9ORF72) mutation carriers, clinically diagnosed patients include behavioral variant of frontotemporal dementia (bvFTD), frontotemporal dementia with amyotrophic lateral sclerosis (FTD-ALS), frontotemporal dementia with corticobasal syndrome (FTD-CBS), semantic variant of primary progressive aphasia (svPPA), and non-fluent variant of primary progressive aphasia (nfvPPA).

  Study phs003309

• Integrated genomic analyses identify ARID1A and ARID1B alterations in the childhood cancer neuroblastoma

  Neuroblastomas are tumors of peripheral sympathetic neurons and are the most common solid tumor in children. To determine the genetic basis for neuroblastoma we performed whole-genome sequencing (6 cases), exome sequencing (16 cases), genome-wide rearrangement analyses (32 cases), and targeted analyses of specific genomic loci (40 cases) using massively parallel sequencing. On average each tumor had 19 somatic alterations in coding genes (range, 3-70). Among genes not previously known to be involved in neuroblastoma, chromosomal deletions and sequence alterations of chromatin remodeling genes, ARID1A and ARID1B, were identified in 8 of 71 tumors (11%) and were associated with early treatment failure and decreased survival. Using tumor-specific structural alterations, we developed an approach to identify rearranged DNA fragments in sera, providing personalized biomarkers for minimal residual disease detection and monitoring. These results highlight dysregulation of chromatin remodeling in pediatric tumorigenesis and provide new approaches for the management of neuroblastoma patients.Data Provider: Johns Hopkins Sidney Kimmel Comprehensive Cancer Center (SKCCC)

  Study EGAS00001000369

• Serum proteomics of aortic diseases

  Aortic diseases are a rare but potentially life-threatening condition. We present a serum proteomic study for a spectrum of aortic diseases including thoracic aortic aneurysms (n = 11), chronic dissections (n = 9), acute aortic dissections (n = 11), and surgically treated dissections (n = 19) as well as healthy controls (n = 10) and patients of coronary heart disease (n = 10) to represent non-aortic cardiovascular disease. In total, we identified and quantified 425 proteins across all 70 samples. The different aortic diseases represented distinguishable proteome profiles. We identified protein clusters that positively or negatively correlate with disease severity, including increase of cytosolic tissue leakage proteins and decrease of components of the coagulation and complement system. Further, we identified a serum proteome fingerprint of acute aortic dissections, consisting, among others, of enriched inflammatory markers such as C-reactive protein and members of the S100 protein family. The study underlines the applicability of serum proteomics for the investigation of aortic diseases and highlights the possibility to establish disease-specific prognostic markers.

  Study EGAS00001006201

• 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

• An Isogenic Cell Line Panel for Sequence-based Screening of Targeted Anti-cancer Drugs

  We describe the creation and characterization of an isogenic cell line panel representing common cancer pathways, with multiple features optimized for high-throughput screening. More than 1,800 cell lines from three normal human cells were generated using CRISPR-technologies. Surprisingly, we discovered most of these lines did not result in complete gene inactivation, despite integration of sgRNA at the desired genomic site. However, a subset of the lines harbored true, biallelic disruptions of the targeted tumor suppressor gene, yielding a final panel of 100 well-characterize lines covering 19 pathways frequently subject to loss of function in cancers. This panel included genetic markers optimized for sequence-based ratiometric assays for drug-based screening assays. To illustrate the potential utility of this panel, we developed a multiplexed high-throughput screen that identified Wee1 inhibitor MK-1775 as a selective growth inhibitor of cells with inactivation of TP53. These cell lines and screening approach should prove useful for researchers studying a variety of cellular and biochemical phenomena

  Study EGAS00001005974

• The cellular immune and airway epithelial profile throughout childhood and in response to COVID-19 at multi-omic single cell level.

  Single-cell data gene expression data set (5’Chromium 10X) of healthy paediatric volunteers, and paediatric and adult COVID-19 patients. Gene expression was determined from samples of nasal, tracheal and bronchial brushings and blood (PBMCs). In addition to gene expression, PBMC’s were assayed by CITE-seq. A subset of samples have VDJ sequencing data for T cell receptors (TCR) and B cell receptors (BCR).

  Dataset EGAD00001007718

• UK_RCC_GWAS

  Renal cell carcinoma (RCC) cases comprised adult patients with histologically proven RCC were collected through two sources within the UK. First, 856 cases from SORCE, a MRC collection of surgically treated RCC cases ascertained through UK clinical oncology centres. Second, 189 RCC cases collected through the ICR and Royal Marsden NHS Hospitals Trust. Cases included 590 clear cell carcinomas (CCCs), 42 papillary carcinomas (PCs), 33 chromophobe carcinomas (CCs) and 19 mixed or other histological subtypes. DNA was extracted from EDTA-venous blood samples using the conventional methods and quantified using PicoGreen (Invitrogen). Cases were genotyped using the Human OmniExpress-12 BeadChip according to the manufacturer's recommendations (Illumina Inc, San Diego, CA, USA). After strict QC, 944 cases were retained. Data provided in plink format. Controls used were data from the Wellcome Trust Case Control Consortium 2 (WTCCC2) 1958 birth cohort and the UK Blood Service Control Group (available as EGAS00000000028). 

  Dataset EGAD00010002310

• Elucidation of the association between viruses and autoimmune diseases and COVID-19

  We determined the presence or absence of endogenous herpesvirus 6 (eHHV-6) and calculated annelovirus levels from whole genome sequencing of 2,238 patients with autoimmune diseases and 2,919 controls. We performed genome-wide association analysis using WGS of 22 eHHV-6B-positive cases and -negative cases. Single-cell RNA sequencing was performed using human peripheral blood mononuclear cells from 3 eHHV-6B-positive SLE patients and 5 -negative SLE patients.

  Study JGAS000741

• Policy Documentation

  Policy Documentation The following policy documentation is required to be prepared and submitted to the EGA, together with your data files and associated metadata. Data Access Agreement (DAA) The Data Access Agreement is a contract made between Data User and Data Access Committee. The agreement should be drafted by the DAC and includes, but is not limited to, details of data use, publication embargoes and storage. Completion of a DAA by the applicant/s should form part of the application process to the DAC. NOTICE The data access agreement template below is provided for guidance only and should be adapted as you see fit to suit your own purpose. In the interest of promoting data sharing, we suggest that if an agreement cannot be met around clause 19 in this example that both parties should agree to remain silent, and that the clause should be removed from the agreement. Example DAA template Alternate (harmonised) DAA template

  Documentation access/data-access-committee/policy-documentation

• Induction of trained immunity by influenza vaccine: impact on COVID-19

  Cryopreserved PBMCs from 10 individuals before and after vaccination were used to perform single cell RNA sequencing. Equal number of cells per individual were pooled together (5 individuals per pool) and single-cell RNA sequencing was performed in paired-end mode on NovaSeq 6000 (Illumina) with a depth of 50,000 reads per cell. DNA was isolated from PBMCs and then used for genotyping by Illumina GSA Beadchip. This dataset contains the fastq sequence files, genotypes of the donors used for demultiplexing the pools and files indicating the linkages between individuals, pools and fastq files. The number of samples listed by EGA does not match the actual number of samples due to limitations on the upload scheme used.

  Dataset EGAD00001007827

• 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

• Timing chromosomal amplification events using patterns of somatic mutations in high hyperdiploid acute lymphoblastic leukemia

  This dataset included 19 paired diagnostic and remission samples with high hyperdiploid acute lymphoblastic leukemia (ALL) that were collected from four different cohorts: the Division of Clinical Genetics, Lund University, Sweden. All samples were subjected to whole genome sequencing using the Illumina HiSeqX platform. Paired-end sequencing (2x150bp) was done to ~60x coverage for diagnostic samples and ~30x coverage for remission samples. The paired-end reads were aligned to the human reference genome GRCh37 (ftp://ftp.ncbi.nlm.nih.gov/genomes/refseq/vertebrate_mammalian/Homo_sapiens/all_assembly_versions/GCF_000001405.25_GRCh37.p13/GCF_000001405.25_GRCh37.p13_genomic.fna.gz) by the Burrows-Wheeler Aligner tool (version 0.7.17). Duplicate reads marking and local realignment were performed by GATK (version 4.0.11.0).

  Dataset EGAD00001010103

• Whole exome sequencing of SarBC-01- and UroBC-01-related samples.

  This dataset contains raw FASTQ files from DNA of SarBC-01-related samples (SarBC-01 patient Germline, SarBC-01 patient Urothelial tumor, SarBC-01 patient Sarcomatoid tumor, SarBC-01 Passage 6 organoids, SarBC-01 Passage 20 organoids) and UroBC-01 related samples (UroBC-01 patient Germline, UroBC-01 patient Urothelial tumor, UroBC-01 Passage 19 organoids, UroBC-01 Passage 6 organoids). DNA was extracted from FFPE tissue, using RecoverAll RNA/DNA extraction kit (Invitrogen, Carlsbad, CA, USA, AM1975) followed by incubation with Uracil-DNA Glycosylase, and fresh or flash frozen tissue, using Quick-DNA/RNA Miniprep kit (Zymo Research, Irvine, CA, USA, D7001). Twist Human Core Exome + RefSeq + Mito-Panel kit (Twist Bioscience, 102031) was used for the whole exome capturing. Sequencing was performed on Illumina NovaSeq 6000 using paired-end 100-bp reads.

  Dataset EGAD00001011157

• Human and rat skeletal muscle multiomic profiling sequencing data

  Illumina sequencing data (fastq files) representing single-nucleus (sn) ATAC-seq, snRNA-seq, bulk ATAC-seq, and snATACseq+snRNAseq multiomics data from human and rat skeletal muscle samples (19 libraries total). Includes a README file that describes the relationship between libraries, samples, and files.

  Dataset EGAD00001008323

• Pediatric Papillary Thyroid Carcinoma RNA-Seq

  Papillary thyroid carcinoma (PTC) is the most common malignancy amongst adolescent and young adult women. Clinical and genomic features of PTC in children differ from those in adults. Historically, a substantial proportion (~50%) of pediatric PTC (PPTC) lack any of the common driver mutations typical of adult PTC. Thus, molecular diagnostics developed for adults may not be valid in children. We applied novel bioinformatic pipelines to RNASeq analysis of pediatric thyroid tumors to identify known and novel fusion oncogenes as drivers of tumorigenesis and to define gene expression patterns among tumors. Analysis of 38 samples resulted in identification of 16 previously reported oncogenic fusions and three novel candidate fusions. In conducting these analyses, we reduced the proportion of cancers with unknown drivers from approximately 50% to 6%. Gene expression analysis identified three distinct categories of tumors. These studies represent the first unbiased genomic approach to childhood PTC. Novel bioinformatic pipeline. GEC Identified 3 distinct classes. DICER1, PTEN segregated with benign tumors. >90% of PPTC carry identifiable ongognic driver variants, however, the landscape differs from that in adults and existing tools for tumor genotyping in adults may not be applicable to pediatric tumors. BACKGROUND: Papillary thyroid carcinoma demonstrates clinically distinct behaviour in pediatric patients when compared to adults, with increased regional and distal metastases, more frequent recurrence, yet overall highly favourable prognosis. Recent tumor genotyping has demonstrated that in pediatric tumors, ***-*** do not carry the most common genomic variants found in adult PTC, leaving a substantial proportion of driver-unknown or “dark matter” tumors. METHODS: We established a cohort of 52 pediatric PTC and performed quantitative-PCR genotyping followed in a subset by whole exome and whole transcriptome (RNASeq) sequencing using a novel, robust bioinformatic pipeline to identify oncogenic fusion transcripts. Gene expression analysis was used to derive distinct clusters. RESULTS: In 52 pediatric PTC, genotyping identified BRAFV600E(21%), NRASQ61R(2%), RET/PTC1 (21%), RET/PTC3 (17%) or PAX8-PPAR in 33 (63%) of tumors. Among the remaining 19 tumors, oncogenic variants were identified in /19 (%). The variants included SNVs in DICER1, ETV6-NTRK3, PTEN and 9 additional oncogenic fusions including two previously-undescribed fusion transcripts, *** and ***. CONCLUSIONS: The genomic landscape of PTC differs between children and adults. In children, there is a substantial fraction of tumors that are unexplained by variants typical of adult PTC. This discrepancy is explained largely by uncommon oncogenic fusions which can be identified by whole-transcriptome analysis.

  Study EGAS00001005182

• Epigenetic Biomarkers of Aging

  The aim of the study was to discover new epigenetic biomarkers of aging. We used a genome-wide screen for genetic loci showing consistent changes of DNA methylation with progressive aging. Blood DNA samples from 19 apparently healthy individuals aged 22-80 years obtained from the NINDS repositories were analyzed for DNA methylation using Reduced Representation Bisulfite Sequencing. We followed the New England Biolabs (NEB) protocol for methylated adaptors as described previously. Briefly, 1 microgram of genomic DNA was spiked with 100 picograms of lambda phage DNA as the unmethylated standard and digested with MspI endonuclease at C’CGG sites. Ends of restriction fragments were filled in, 3’-dA tailed and methylated adaptors were ligated to the ends of restriction fragments. Bisulfite treatment using the Epitect kit (Qiagen) followed. Bisulfite-converted libraries were amplified using EpiMark Taq DNA polymerase (NEB) and primers with dual barcode indices. The libraries were pooled and sequenced on Illumina HiSeqX instrument using paired end reads of 150 bases. We used Bismark v0.23.1 to align the sequences to hg19 human genome assembly. We used methylKit v1.22.0 to analyze differential methylation in individuals of different ages.

  Study phs003046

• Integrated Analysis of Multimodal Single-Cell Data

  The simultaneous measurement of multiple modalities, known as multimodal analysis, represents an exciting frontier for single cell genomics and necessitates new computational methods that can define cellular states based on multiple data types. Here, we introduce 'weighted nearest neighbor' analysis, an unsupervised framework to learn the relative utility of each data type in each cell, enabling an integrative analysis of multiple modalities. We apply our procedure to a CITE-seq dataset of hundreds of thousands of human white blood cells alongside a panel of 228 antibodies to construct a multimodal reference atlas of the circulating immune system. We demonstrate that integrative analysis substantially improves our ability to resolve cell states and validate the presence of previously unreported lymphoid subpopulations. Moreover, we demonstrate how to leverage this reference to rapidly map new datasets, and to interpret immune responses to vaccination and COVID-19. Our approach represents a broadly applicable strategy to analyze single-cell multimodal datasets, including paired measurements of RNA and chromatin state, and to look beyond the transcriptome towards a unified and multimodal definition of cellular identity. All CITE-seq and ECCITE-seq raw matrices are available in GEO database under the accession number GEO: GSE164378.

  Study phs002315

• Methotrexate Clearance GWAS in Acute Lymphoblastic Leukemia (ALL) Patients

  We estimated the plasma clearance of methotrexate from 1279 acute lymphoblastic leukemia (ALL) patients treated on the Children Oncology Group 9904 and 9905 trials (http://clinicaltrials.gov/show/NCT00005585 and http://clinicaltrials.gov/show/NCT00005596). Patients received either a 24-hour infusion of a 1 g/m2 dose or 4-hour infusion of a 2 g/m2 dose). Methotrexate clearance was lower in older children (p=7 x 10-7), females (p=2.7 x 10-4), and patients who received a delayed intensification phase (p=0.0022). In a genome-wide analysis, methotrexate clearance was associated with polymorphisms in the SLCO1B1 gene (p=2.1 x 10-11), which encodes for an organic anion transporter. This replicates findings using different schedules of high-dose methotrexate in ALL patients treated on St. Jude protocols. A combined meta-analysis yields a p-value of 5.7 x 10-19 for the association of methotrexate clearance with SLCO1B1 SNP rs4149056 (Trevino et al, PMID 19901119 and Ramsey et al, PMID 23233662). This data set includes the dependent variable of methotrexate clearance and all of the SNP data available from arrays.

  Study phs000637

• Genomic Analysis of Prostate Tumor Heterogeneity in Metastasis

  To investigate the molecular changes, mutations, and signaling pathways that characterize the initial steps of prostate cancer metastasis to the lymph nodes, we analyzed 19 discrete lymph node (LN) metastases, 97 primary tumor foci, 39 benign lymph nodes, and 10 normal adjacent prostate tissue samples from 43 patients enrolled in a clinical trial (NCT01808222) of extended lymphadenectomy and metastasis excision guided by [18F]-fluciclovine PET imaging for high risk, newly diagnosed prostate cancer conducted at Emory University. These patients fell within high or very high-risk groups (T3a, Gleason score 8-10, or PSA greater than 20 ng/ml). Of these patients, 16 had LN metastases at least 4 mm in diameter, and 20 patients had no metastases. For metastatic patients, we performed RNA and Whole Exome Sequencing (WES) on three primary tumor foci, one benign LN, and all LN metastases greater than 4mm in diameter. For non-metastatic patients, we sequenced two primary tumor foci and one benign LN. In total, RNAseq was performed on 165 tissue samples from 43 patients, and WES was performed on 137 samples from 35 patients.

  Study phs003404

• The Somatic Mutational Landscape of Thyroid Cancer in Patients with Germline PTEN Mutations

  PTEN hamartoma tumor syndrome (PHTS) is associated with a high rate of thyroid cancer and benign thyroid disease, yet nothing is known of the genomic landscape of PHTS-associated thyroid tumors. In this study, exome sequencing was performed on 58 thyroid tumors (28 cancers, 30 benign nodules) from 19 patients with PHTS, sequenced in tumor-normal pairs. Somatic variant calling was utilized to determine the somatic mutational landscape of thyroid tumors in this population. This was then compared to the known mutational landscape of sporadic thyroid cancer in the general population using sequencing data from The Cancer Genome Atlas. The primary finding of the study was that PHTS-associated thyroid tumors had a unique genomic landscape, including a high frequency of second-hit somatic PTEN alterations compared to the sporadic thyroid tumors. Additionally, PHTS-associated thyroid cancers were found to have somatic alterations in BRAF, RAS family members, and genes associated with DNA double stranded break repair. Data available through dbGAP will include tumor BAM files for each tumor, normal BAM files for each patient, and MAF files for PHTS-associated thyroid cancer and PHTS associated benign thyroid nodules.

  Study phs003640

• Mind Body Study: A Sub-Study on Psychosocial Factors and Microbiomes of Nurses in the Nurse's Health Study II

  The Mind-Body Study is a sub-study of the Nurses' Health Study II (NHSII) which investigated associations between biomarkers and psychosocial factors. The prevalences of clinically meaningful depressive symptoms, mild-to-severe anxiety symptoms, experiencing major-life discrimination, and food addiction were 19%, 21%, 30%, and 5% respectively. These participants were more likely to have experienced childhood abuse and take psychotropic medications but less likely to have chronic conditions such as diabetes and hypertension than participants in the larger NHSII cohort. Participants (n = 213, mean age = 60.6) provided one or two separate stool samples for microbiome profiling between 2013 and 2014, and completed two online psychosocial assessments 10 months apart. The participants also completed two 30-day FFQs around the two microbiome collections. There was excellent reproducibility of psychosocial factors over 1 year. Moderate-to-strong positive correlations were observed between markers of distress and between positive psychosocial factors such as mindfulness and optimism. Here, the subjects' metadata including phenotypic and diet covariates have been provided. Microbial DNA sequence data from the stool microbiome collections is provided via Sequence Read Archive (SRA).

  Study phs003786

• Whole-genome methylation profiling of menstrual stem cells identifies novel biomarkers for endometriosis

  Endometriosis is a highly prevalent condition that remains underdiagnosed and poorly managed due to the lack of clinically validated biomarkers and limited understanding of its underlying pathophysiology. Although menstrual blood–derived stem cells (MenSCs) have been implicated in disease pathogenesis, their potential as a diagnostic source has not been systematically explored. We conducted a clinical study including 42 women (19 with endometriosis and 23 controls) to evaluate whether DNA methylation profiles from freshly isolated MenSCs could identify disease-specific biomarkers. Whole-genome DNA methylation sequencing identified differentially methylated regions (DMRs) enriched in genes associated with key features of endometriosis, including inflammation, tissue remodelling, and developmental processes. These DMRs robustly discriminated cases from controls, independently of technical and clinical confounders. Machine learning models trained and validated on these regions demonstrated strong diagnostic performance (specificity 83%, sensitivity 79%). Integration with an independent single-cell RNA sequencing dataset suggested that the identified DMRs may influence gene expression, supporting their biological relevance. Collectively, these findings highlight MenSC DNA methylation profiling as a promising, non-invasive strategy for early diagnosis and personalised management of endometriosis. (PubMed IDs will be provided once the manuscript is published.)

  Study EGAS50000001640

• Novel regional age-associated DNA methylation changes within human common disease-associated loci

  Background: Advancing age progressively impacts on risk and severity of chronic disease. It also modifies the epigenome, with changes in DNA methylation, due to both random drift and variation within specific functional loci. Results: In a discovery set of 2,238 peripheral-blood genome-wide DNA methylomes (MeDIP-seq) aged 19-82 years, we identified 71 age-associated Differentially Methylated Regions (a-DMRs, p < 1.85 x 10-8) within the Linkage Disequilibrium (LD) blocks of the NIH Catalogue of published GWAS SNPs. This included 52 novel regions, 29 within loci not covered by 450k or 27k Illumina array, and with marked enrichment for Poised Promoters and Enhancers across multiple cell types. In a replication set of 2,084 DNA methylomes, 95.7% of the a-DMRs showed the same direction of ageing effect, with 80.3% and 53.3% replicated to p < 0.05 and p < 1.85 x 10-8, respectively. Conclusion: By analysing the functionally enriched disease and trait-associated regions of the human genome, we identified novel epigenetic ageing changes, which could be useful biomarkers or provide mechanistic insights into age-related common diseases.

  Study EGAS00001001910

• An_evaluation_of_different_strategies_for_large_scale_pooled_sequencing_study_design_

  Second generation sequencing technology has enabled the design of large-scale sequencing experiments in targeted disease-related regions in thousands of cases and controls. Cost implications dictate a pooled DNA sequencing design, evaluation of allele frequency differences based on the resequenced samples and large-scale targeted follow-up in further samples. To evaluate the feasibility of this approach and to assess different study design strategies, we have carried out a pilot study which tests the feasibility of PCR-based and pull-down DNA pooling for (a) SNP discovery and (b) allele frequency comparison purposes. All samples are from the HapMap or 1958 BC. The sample composition of the pool is listed below: Pool 5: 31 HapMap Individuals (NA12249, NA12156, NA12004, NA11831, NA12716, NA11832, NA11993, NA12057, NA11995, NA12006, NA12144, NA12802, NA12146, NA12005, NA12003, NA07000, NA12043, NA12044, NA11992, NA11881, NA11994, NA07345, NA12154, NA06994, NA06985, NA12239, NA07022, NA07034, NA12155, NA07056, NA06993); 19 1958 BC Individuals (WTCCC88214, WTCCC88215, WTCCC88216, WTCCC88217, WTCCC88222, WTCCC88233, WTCCC88240, WTCCC88241, WTCCC88242, WTCCC88247, WTCCC88249, WTCCC88262, WTCCC88264, WTCCC88278, WTCCC88294, WTCCC88298, WTCCC88302, WTCCC88305, WTCCC88321) Some pools were carried out in duplicate to assess reproducibility. We focused on 10 (PD), 7(PCR) chromosomal regions, ~2(PD), ~1.6 (PCR) Mb in total.

  Study EGAS00001000134

• Pre-activated anti-viral innate immunity in the upper airways controls early SARS-CoV-2 infection in children

  Children have reduced SARS-CoV-2 infection rates and a substantially lower risk for developing severe COVID-19 than adults. However, the molecular mechanisms underlying protection in younger age groups remain unknown. Here, we characterize the single-cell transcriptional landscape in the upper airways of SARS-CoV-2-negative (n=18) and age-matched SARS-CoV-2–positive children (n=24) and corresponding samples from adults (n=44), covering an age range of four weeks to 77 years. Children displayed higher basal expression of the relevant pattern recognition receptors (PRR) such as MDA5 (IFIH1) and RIG-I (DDX58) in upper airway epithelial cells, macrophages, and dendritic cells, resulting in stronger innate antiviral responses upon SARS-CoV-2 infection than adults. We further detected distinct immune cell subpopulations including KLRC1 (NKG2A)+ cytotoxic T cells and a CD8+ T cell population with a memory phenotype occurring predominantly in children. Our study provides evidence that the airway immune cells of children are primed for virus sensing, resulting in a stronger early innate antiviral responses to SARS-CoV-2 infection than adults.

  Study EGAS00001005461

• Longitudinal Study of Fluoride and Other Factors Related to Dental Fluorosis, Dental Caries, and Bone Health

  This project is a combination of the Iowa Fluoride Study and the Iowa Bone Development Study from 1992 - 2019. The Iowa Fluoride Study (IFS) began in 1992 with recruitment of 1,882 mothers of newborns from eight Iowa hospital post-partum wards from March 1992 to February 1995. The focus of the IFS was to collect detailed fluoride, general dietary intake, and other data several times per year from age 6 weeks on and relate them to dental fluorosis and dental caries (cavities). Data collection occurred 3-5 times per year initially, and then twice per year after ~ age 4. Dental exams of the primary (baby) teeth were initiated at ~ age 5.The Iowa Bone Development Study (IBDS) grew out of the IFS in 1998 when we added a "normal bone development" focus, and soon after the age 5 dental exams, we began to collect genetic samples and accelerometry (motion sensor) data. All then-active parents of IFS-participating children were invited to have their child join the IBDS, and the majority agreed to do so. The majority of participating children received both ~ age 5 dental exams and bone densitometry assessments. The bone densitometry at age 5 was determined by dual-energy X-ray absorptiometry (DXA) of the hip, lumbar spine, and whole body.Dental exams for caries and fluorosis were performed again at age 8-9, along with DXA bone scans and accelerometry. DXA scans and accelerometry were performed again at ages 11 and 15 years, along with peripheral quantitative computed tomography (pQCT) scans of the distal tibia and radius, but no dental exams were performed.At ages 13 and 17, dental exams, DXA and pQCT scans, as well as accelerometry, were obtained.At age 19, no dental exams were conducted, but repeat DXA and pQCT scans and accelerometry were obtained, along with multi-slice detector CT (MDCT) of the distal tibia.At age 23, we conducted the final wave of exams, which included dental, DXA, pQCT, MDCT, and accelerometry assessments.In addition, parents were invited to participate once with DXA bone scans and to also provide limited questionnaire data about their own fluoride and dietary exposures and physical activity.Note: Please refer to the document Iowa Fluoride Study/Iowa Bone Development Study (IFS/IBDS) - dbGaP Data Tables: A User's Guide - Version 2.0 for a detailed reference manual on all of the clinical data submitted for this project.Note: No genetic data or specimens were submitted with this study. However, many of the child/parent participants in the study were genotyped. These genotyping data are linked to dbGaP Study Accession: phs000095 under Dr. Mary Marazita: "Dental Caries: Whole Genome Association and Gene X Environment Studies".<img style="width: 1155px;" 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

  Study phs002203

• Whole genome analyses of the childhood cancer neuroblastoma

  Neuroblastomas are tumors of peripheral sympathetic neurons and are the most common solid tumor in children. To determine the genetic basis for neuroblastoma we performed whole-genome sequencing (6 cases), exome sequencing (16 cases), genome-wide rearrangement analyses (32 cases), and targeted analyses of specific genomic loci (40 cases) using massively parallel sequencing. On average each tumor had 19 somatic alterations in coding genes (range, 3-70). Among genes not previously known to be involved in neuroblastoma, chromosomal deletions and sequence alterations of chromatin remodeling genes, ARID1A and ARID1B, were identified in 8 of 71 tumors (11%) and were associated with early treatment failure and decreased survival. Using tumor-specific structural alterations, we developed an approach to identify rearranged DNA fragments in sera, providing personalized biomarkers for minimal residual disease detection and monitoring. These results highlight dysregulation of chromatin remodeling in pediatric tumorigenesis and provide new approaches for the management of neuroblastoma patients.

  Dataset EGAD00001000282

• Rapid Acceleration of Diagnostics - Digital Health Technologies (RADx-DHT): NIH Digital Health Solutions for COVID-19: SAFER-COVID - Integration of Testing and Digital Health

  SAFER-COVID provides a set of self-management tools to consumers to track symptoms, test results, vaccine record, and environmental factors, such as exposure to others. Consumers may choose to integrate data from wearables and electronic health records (EHR) for self management. These data are used to enable multiple use cases such as return-to-work, activity risk assessment and self-management within SAFER-COVID.DOI: https://rapids.ll.mit.edu/10.57895/cmt5-gh78

  Study phs002540

• Longitudinal Transcriptomic Profiling of Endothelial Progenitor Cells in Post-COVID-19 Patients: Insights at 3 and 6-Months Post-SARS-CoV-2 Infection

  Bulk RNA-sequencing analysis of endothelial cells isolated from post-COVID patients at 3 and 6 months post-infection, alongside healthy controls. This study aims to identify differentially expressed genes in endothelial cells from post-COVID patients—at both 3- and 6-month time points—compared to those from healthy individuals. The objective is to uncover upregulated and downregulated pathways potentially associated with long-term consequences of SARS-CoV-2 infection.

  Study EGAS50000000993

• Bulk-tissue paired-end RNA-sequencing of anterior cingulate cortex samples derived from Lewy body disease patients

  Profiling of 24 human anterior cingulate cortex samples by bulk-tissue RNA-sequencing. Samples were derived from 5 non-neurological control individuals and 19 individuals with Lewy body disease (Parkinson’s disease = 7 individuals; Parkinson’s disease with dementia = 6 individuals; dementia with Lewy bodies = 6 individuals). Paired-end FASTQ files for each of the human samples are provided and are denoted by the suffixes R1 (read 1) and R3 (read 2). Fastp (v 0.20.0), a fast all-in-one FASTQ pre-processor, was used for adapter trimming, read filtering and base correction. Fastp default settings were used for quality filtering and base correction. Further details on parameters used are available here: https://github.com/RHReynolds/RNAseqProcessing/blob/master/QC/prealignmentQC_fastp_PEadapters.R.

  Dataset EGAD00001007698

• Single-cell RNA sequencing data of human lymph node samples generated with BD Rhapsody

  The single cell data were generated based on four cartridges. The samples are multiplexed: 0. Sample Run Id Hash Gender Age 1. FL-6 Run1_C1 4 f 71 2. rLN-3 Run1_C1 6 f 72 3. DLBCL-4 Run1_C1 7 f 68 4. DLBCL-1 Run1_C1 8 m 66 5. FL-4 Run1_C1 9 m 41 6. DLBCL-3 Run1_C2 10 f 60 7. rLN-4 Run1_C2 11 f 58 8. rLN-5 Run1_C2 12 m 61 9. FL-1 Run2_C1 1 f 81 10. DLBCL-2 Run2_C1 2 m 80 11. rLN-2 Run2_C1 3 f 42 12. FL-5 Run2_C1 4 m 66 13. DLBCL-8 Run2_C1 5 m 64 14. DLBCL-6 Run2_C2 6 m 76 15. rLN-1 Run2_C2 7 m 39 16. FL-3 Run2_C2 8 f 76 17. DLBCL-5 Run2_C2 9 m 66 18. FL-2 Run2_C2 10 f 58 19. DLBCL-7 Run2_C2 11 f 71

  Dataset EGAD00001010044

• DNA whole-exome sequencing data from patients with metastatic basal cell carcinoma

  Whole-exome sequencing data in fastq format of matched tumour and germline DNA from 8 patients with metastatic basal cell carcinoma. Samples are labeled as Primary, Local or Metastasis: Primary: Sample was obtained from primary tumour. Local: Sample was obtained from local recurrence of primary tumour. Metastasis: Sample was obtained from a metastatic site. Germline: Sample was obtained from normal adjacent tissue. DNA was isolated from FFPE tissue sections of the tumor biopsies using the AllPrep DNA/RNA FFPE Kit (Qiagen) and quality controls conducted using the Qubit fluorometer (Thermo Fisher Scientific). Library preparation was performed using the Agilent SureSelect Human All Exon v7 XTHS2 probes and sequenced on a NovaSeq 6000 S2 2x100bp

  Dataset EGAD00001008675

• Postmortem Single Nuclei and Bulk RNA-seq data of the Motor Cortex and Spinal Cord for Healthy, C9ALS and sALS Patients

  This dataset contains both snRNA-seq and bulk RNA-seq data from 19 different patients, comprising of 9 healthy controls (4 Spinal Cord, 5 Motor Cortex) as well as 5 C9ALS patients and 5 sporadic ALS patients, each with paired data from the spinal cord and motor cortex. For the snRNA-seq data, fastq files containing the raw reads are provided, many of these samples were pooled for sequencing and subsequently require demultiplexing using SNPs using a tool such as freemuxlet. The paired bulk RNA-seq data (raw fastq files) can be used to acquire the ground truth per patient - a list of pooled samples can be found in map.txt. snRNA-seq data was produced using the 10X Genomics 3' v3 kit and bulk RNA-seq was produced using the Illumina TruSeq v2 kit.

  Dataset EGAD00001009686

• Somatic L1 retrotransposition in normal colorectal epthelium

  Throughout an individual’s lifetime, genomic alterations accumulate in somatic cells. However, the mutational landscape induced by retrotransposition of long interspersed nuclear element-1 (L1), a widespread mobile element in the human genome, is poorly understood in normal cells. Here, we explored the whole-genome sequences of 406 normal colorectal clones, 12 MUTYH-associated adenomatous clones, and 19 matched colorectal cancer tissues. In addition, we analyzed promoter DNA methylation status of retrotransposition-competent L1 (in 139 clones) and read-through RNA expression profiles (in 116 clones) to investigate the epigenetic regulation of L1 activity.

  Dataset EGAD00001010183

• A neoadjuvant, phase II trial demonstrates efficacy and tolerability of Talimogene laherparepvec in cutaneous basal cell carcinoma (NeoBCC trial)

  We present a single arm, phase II neoadjuvant trial with the oncolytic virus Talimogene laherparepvec (T-VEC) in 18 patients with difficult-to-resect basal cell carcinomas. Six cycles of T-VEC were applied intralesionally. The primary endpoint of the study, defined as the proportion of the patients, who after six cycles of T-VEC (13 weeks) at the time point of surgery, become resectable with primary wound closure without the need for plastic reconstructive surgery like skin flaps or skin grafts, was achieved (9/18 patients; 50.0%). Secondary endpoints also included the relapse free survival rate (100%), overall survival (100%) and biological read outs in the tumor samples. T-VEC led to a significant increase of cytotoxic T cells, B cells and myeloid cells, and a decrease of Tregs within the tumor microenvironment. We observed a potent induction of antitumoral and antiviral T cell clones, as well as a strong humoral immune response. The objective response rate was 55.6% and the complete pathological response rate was 33.3%. Only mild adverse events occurred. Together, neoadjuvant T-VEC represents a viable treatment option for patients with difficult-to-resect BCCs (EudraCT Number 2018-002165-19).

  Study EGAS50000000252

• Whole-exome and targeted sequencing of pediatric hyperdiploid B-cell precursor acute lymphoblastic leukemia

  High hyperdiploidy defines the largest genetic entity of childhood acute lymphoblastic leukemia (ALL). Despite its relatively low recurrence risk, this subgroup generates a high proportion of relapses. The cause and origin of these relapses remains obscure. We therefore explored the mutational landscape in high hyperdiploid (HD) ALL with whole-exome (n=19) and subsequent targeted deep sequencing of 60 genes in 100 relapsing and 51 non-relapsing cases. We identified multiple clones at diagnosis that were primarily defined by a variety of mutations in receptor tyrosine kinase (RTK)/Ras pathway and chromatin-modifying genes. The relapse clones consisted of reappearing as well as new mutations, and overall contained more mutations. Although RTK/Ras pathway mutations were similarly frequent between diagnosis and relapse, both intergenic and intragenic heterogeneity was essentially lost at relapse. CREBBP mutations, however, increased from initially 18-30% at relapse, then commonly co-occurred with KRAS mutations (P&lt;0.001) and these relapses appeared primarily early (P=0.012). Our results confirm the exceptional susceptibility of HD ALL to RTK/Ras pathway and CREBBP mutations, but, more importantly, suggest that mutant KRAS and CREBBP might cooperate and equip cells with the necessary capacity to evolve into a relapse-generating clone.

  Study EGAS00001001113

• Swarm Learning to identify COVID-19, tuberculosis and leukemia patients based on blood transcriptomes

  Identification of patients with life-threatening diseases including leukemias or infections such as tuberculosis or COVID-19 is an important goal of modern precision medicine. However, there is an increasing divide between what is technically possible and what is allowed because of privacy legislation. We have recently illustrated that classical machine learning can identify leukemia patients based on their blood transcriptomes. To facilitate integration of any omics data from any data owner world-wide without violating privacy laws, we here introduce Swarm Learning (SL), a decentralized machine learning approach uniting edge computing, artificial intelligence (AI), blockchain and privacy protection without the need for a central coordinator thereby going beyond federated learning. To illustrate its feasibility, using more than 12,000 transcriptomes from peripheral blood mononuclear cells and more than 2,000 peripheral blood transcriptomes we demonstrate that SL of omics data distributed across different individual sites leads to disease classifiers that outperform those developed at individual sites. Yet, SL completely protects local privacy regulations by design. We propose this approach to noticeably accelerate the introduction of precision medicine.

  Dataset EGAD00001006231

• Mapping_gene_environment_interactions_in_macrophages

  Immune cells sense and respond to external stimuli such as pathogens and initiate an inflammatory response. Genetic variants altering the behaviour and responses of immune cells may inform the results of disease association studies and provide an insight into the regulation of immune response. Studies mapping quantitative trait loci (QTL) are usually performed in quiescent or naïve cells and therefore any variants with a condition-specific manner (e.g. those with an effect only detectable in a specific time-point after cell stimulation) are likely to remain undiscovered. So far, only a handful of studies have attempted to study QTL in multiple states and even on those studies the number of states has remained relatively low (&lt;5). Only very recently Horst and colleagues published the largest study to date investigating the effect of host variable (e.g. age, sex, contraceptive use etc.) on protein levels in macrophages stimulated with 19 different conditions (Horst et al, 2016). This project aims to develop a high-throughput experimental platform to detect QTL in a large number of states using iPSC derived macrophages. 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 EGAS00001002268

• RNA-Seq of vocal fold fibroblasts in Reinke’s edema and control subjects

  The voice disorder Reinke’s edema (RE) is a smoking- and voice-abuse associated benign lesion of the vocal folds, defined by an edema of the Reinke space, accompanied with pathological microvasculature changes and immune cell infiltration. Vocal fold fibroblasts (VFF) are the main cell type of the lamina propria and play a key role in the disease progression. Current therapy is restricted to symptomatic treatment. Hence, there is an urgent need for a better understanding of the molecular causes of the disease. In the present study, we investigated differential expression profiles of RE and control VFF by means of RNA sequencing. In addition, fast gene set enrichment analysis (FGSEA) was performed in order to obtain involved biological processes, mRNA and protein levels of targets of interest were further evaluated. We identified 74 differentially regulated genes in total, 19 of which were upregulated and 55 downregulated. Differential expression analysis and FGSEA revealed upregulated genes and pathways involved in extracellular matrix (ECM) remodeling, inflammation and fibrosis. Downregulated genes and pathways were involved in ECM degradation, cell cycle control and proliferation. The current study addressed for the first time a direct comparison of VFF from RE to control and evaluated immediate functional consequences.

  Study EGAS00001005130