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• Spinocerebellar ataxia 15 (SCA15) derived iPSC WGS

  A collection of four induced pluripotent stem cell models (iPSC) derived from patients diagnosed with Spinocerebellar ataxia 15 (SCA15) . Spinocerebellar ataxia 15 (SCA15) is a neurological condition characterised by progressive gait and limb ataxia as well as abnormalities in eye movement and difficulties with balance, speech and swallowing (Synofzik et al., 2011). Whole Genome Sequencing was performed to confirm the presence of a heterozygous deletions in the inositol 1,4,5-triphosphate receptor gene (ITPR1), characteristic of the disease. Cell models names: HPSI0216i-vieg_5 or Vieg_5 (WTSIi472-A), HPSI0216i-vieg_3 or Vieg_3 (WTSIi472-B), HPSI0216i-dacv_6 or Dacv_6 (WTSIi554-A), HPSI0216i-boho_3 or Boho_3 (WTSIi502-A). All iPSC models are available via ECACC-Culture Collections.

  Dataset EGAD00001009851

• Genetic architecture of autism spectrum disorder in India

  The dataset consists of whole exome sequencing data (fastq format) of 100 non-syndromic autism spectrum disorder patients from India. Whole exome sequencing data is generated using Agilent SureSelect v6 capture kit and Illumina HiSeq sequencing platform. Paired end fastq files are available.

  Dataset EGAD00001008621

• Induction Failure in Childhood and Young Adult T-cell Acute Lymphoblastic Leukemia

  We carried out WGS and RNAseq on a cohort of 48 children and young adults with induction failure in T-cell Acute Lymphoblastic Leukemia (T-ALL) to identify genomic drivers of treatment resistance. The study includes WGS for 33 tumour/normal pairs and 15 tumour-only samples. In addition, there is RNAseq data for 37 cases.

  Dataset EGAD00001009058

• Summary Statistics GWAS SSNS

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

  Dataset EGAD00001008782

• DNA demethylation is associated with malignant progression of low-grade gliomas

  To elucidate the mechanisms of tumor progression is key to discovering strategies for treating patients with lower-grade glioma. Thus to characterize the changes in the molecular profile during malignant progression, we performed methylation array analysis (122 tumors), whole-exome sequencing (36 tumors and matched normal samples), and RNA sequencing (31 tumors). This cohort included 24 matched pairs of initial lower-grade gliomas and recurrent tumors, most of which showed malignant progression when they recurred. Nearly half of IDH-mutant glioblastomas that had progressed from lower-grade gliomas exhibited characteristic partial DNA demethylation in previously methylated genomic regions of their corresponding initial tumors, which had the glioma CpG island methylator phenotype (G-CIMP). In these glioblastomas, cell cycle-related genes were upregulated, RB and PI3K-AKT pathway genes were frequently altered. Notably, bioinformatics analysis revealed that late-replicating domain was significantly enriched in the demethylated regions that were mostly located in non-regulatory regions, suggesting that the loss of DNA methylation during malignant transformation may involve mainly passive demethylation due to a delay in maintenance of methylation during accelerated cell division. Nonetheless, a limited number of genes including IGF2BP3, which potentially drives cell proliferation, were presumed to be upregulated due to demethylation of their promoter. Thus, cell proliferation was further promoted by passive demethylation in the promoter region of these oncogenic genes. Our data indicated that demethylation of the G-CIMP profile found in a subset of recurrent gliomas reflects accelerated cell divisions accompanied by malignant transformation. Oncogenic genes activated by such epigenetic change represent potential therapeutic targets.

  Study JGAS000146

• Women's Health Initiative Clinical Trial and Observational Study - Imaging

  Objectives: The clinical trial assessed the safety and efficacy of three interventions. Specifically, it evaluated (1) the major health benefits and risks of estrogen plus progestin and estrogen alone, (2) the effects of a low-fat eating pattern on risk of colorectal cancer, and (3) the efficacy of calcium with vitamin D supplementation for preventing hip and other fractures. The objective of the memory study was to determine whether estrogen plus progestin therapy protects global cognitive function, and evaluate the therapy's effect on the incidence of dementia and mild cognitive impairment.The observational study is examining the relationship between lifestyle, socioeconomic, health, and other risk factors with cardiovascular, breast cancer, colorectal cancer and osteoporotic fracture outcomes. Secondary objectives include providing more reliable estimates of the extent to which known risk factors predict disease, more precise estimates of new occurrences of disease, and to provide a future resource for the identification of new or novel risk factors especially factors found in blood. Background: The Women's Health Initiative (WHI) is a long-term national health study that has focused on strategies for preventing the major causes of death, disability, and frailty in postmenopausal women, specifically heart disease, cancer, and osteoporotic fractures. The WHI is primarily composed of an observational study (OS), as well a clinical trial (CT) with three components: Hormone Replacement Therapy (HT), Dietary Modification, (DM) and Calcium/Vitamin D supplementation (CaD).Prior to the WHI, observational studies suggested that postmenopausal hormone therapy was associated with a decreased risk of coronary heart disease (CHD). Potential cardioprotection was based on generally supportive data on lipid levels in intermediate outcome clinical trials, trials in nonhuman primates, and a large body of observational studies suggesting a 40% to 50% reduction in risk among users of either estrogen alone or, less frequently, combined estrogen and progestin. Observational studies primarily examining unopposed estrogen preparations have suggested a 30% to 50% reduction in coronary events, and an 8% to 30% increase in breast cancer with extended use. Other research findings indicated that hormone therapy was also associated with a decreased risk of osteoporosis and increased bone density. The WHI HT trials were designed to test the effects of postmenopausal hormone therapy on risk for coronary heart disease and assess overall risks and benefits in predominantly healthy women. The Women's Health Initiative Memory Program (WHIMS) consists of a suite of studies which include cohorts of women who participated in the WHI HT trials. Postmenopausal women have a greater risk than men of developing Alzheimer's disease, but studies of the effects of estrogen therapy on Alzheimer's disease have been inconsistent. Additionally, observational studies have suggested that postmenopausal hormone treatment may improve cognitive function, but data from randomized clinical trials have been sparse and inconclusive. International comparisons and migration studies have suggested that countries with 50% lower fat intake than the US population had approximately one third the risk of colorectal cancer. Additionally, fairly consistent evidence existed for an effect of dietary fat, vegetables and fruits, and grains on colorectal cancer risk from within-country observational studies, although the protective effect of lower fat intake was no longer clear after adjusting for energy intake. The WHI DM trial was the first randomized trial to directly address the health effects of a low-fat eating pattern in predominantly healthy postmenopausal women from diverse racial/ethnic, geographic, and socioeconomic backgrounds. Osteoporosis is a major cause of injury, loss of independence, and death, and contributes to hip fractures. Observational evidence and data from previous randomized clinical trials suggest that calcium and/or vitamin D supplements may slow bone loss and reduce the risk of falls in postmenopausal and elderly women. However, evidence from trials, observational studies, and meta-analyses of calcium and vitamin D supplementation with respect to hip and other fractures was limited at the time the WHI was initiated. In two prior randomized trials, calcium plus vitamin D supplements did not reduce the risk of nonvertebral fractures among older women. When the WHI CaD trial was designed, guidelines recommended daily intakes of 800 to 1200 mg of calcium with 400 IU of vitamin D for the prevention of osteoporosis, which was not met by many American women. Therefore, the WHI CaD trial was designed to test the primary hypothesis that postmenopausal women randomly assigned to calcium plus vitamin D supplementation would have a lower risk of hip fracture and, secondarily, of all fractures than women assigned to placebo. Subjects: Postmenopausal women ages 50 to 79 were eligible to participate. A woman was considered postmenopausal if she had experienced no vaginal bleeding for 6 months (12 months for women under 55 years of age), had had a hysterectomy, or had ever used postmenopausal hormones. Recruitment was carried out in 40 US clinical centers in 1993-1998. The clinical trial components had additional specific inclusion or exclusion criteria.A total of 68,132 women were randomized into at least one component of the clinical trial. 27,347 women were enrolled in the hormone therapy component with 16,608 in the estrogen plus progestin trial and 10,739 in the unopposed estrogen trial, 48,835 women were enrolled in the diet modification component, and 36,282 women were enrolled in the calcium/vitamin D component. 7,479 women 65 years of age and older at baseline and that participated in the HT trial component were enrolled in the ancillary memory study. Women who were either ineligible or unwilling to participate in the clinical trial component were enrolled in the observational study. For example, many potential participants to the clinical trial component of the study were already undertaking a low fat diet or were using hormone replacement therapy. The effect of the selection process was that women enrolled in the observational study tended to have healthier lifestyles compared to those enrolled in the clinical trial. In total, 93,676 subjects were enrolled in WHI OS, with over 16% being members of a racial/ethnic minority group. The first WHI Extension Study enrolled 115,407 consenting participants from all components of the original WHI study for an additional five years of follow-up, from 2005 to 2010. In 2010, 93,567 women consented to continued follow-up. Design: The clinical trial component of the WHI included three randomized comparisons: hormone therapy, dietary modification, and calcium/vitamin D supplementation. Women could have been randomized into one, two or all three trials.The hormone therapy trial enrolled women to one of two double-blinded trials: estrogen (0.625 mg of conjugated equine estrogens daily) plus progestin (2.5 mg of medroxyprogesterone acetate daily) or estrogen alone. Women with a prior hysterectomy were eligible for the trial of unopposed estrogen. Women with an intact uterus at screening were initially also eligible for unopposed estrogen, but were reassigned to the trial of combined postmenopausal hormones beginning in 1995. Both trials randomized participants 1:1 to either hormone therapy or placebo. A 3-month washout period was required before baseline evaluation of women using postmenopausal hormones at initial screening. Study participants were contacted by telephone 6 weeks after randomization to assess symptoms and reinforce adherence. Follow-up contacts by telephone or clinic visit occurred every 6 months, with clinic visits required annually. The estrogen plus progestin trial was halted in July 2002 after a mean 5.2 years of follow-up because health risks, including increased risk of breast cancer and cardiovascular disease, exceeded benefits. The estrogen alone trial was stopped early in March 2004, because an increased risk of stroke was found with no benefit for coronary heart disease. The primary outcome was coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome. The dietary modification trial evaluated the effect of a low-fat, high fruit, vegetable, and grain diet on preventing cardiovascular disease and cancer. Participants were randomly assigned to an intervention or a comparison group in the ratio of 2:3 for cost-efficiency. The intervention was an intensive behavioral modification program, using 18 group sessions in the first year and quarterly sessions thereafter, led by specially trained and certified nutritionists. The program was designed to promote dietary change with the goals of reducing total fat to 20% of energy intake, increasing vegetables and fruits to at least 5 servings daily and grains to at least 6 servings daily. The intervention did not include total energy reduction or weight loss goals. Comparison group participants received a copy of the US Department of Health and Human Services' Dietary Guidelines for Americans and other health-related materials but were not asked to make dietary changes. Dietary intake was monitored using the WHI food frequency questionnaire at 1 year and in a rotating one-third subsample every year thereafter. Women completed a medical update questionnaire every 6 months, and medical records were sought for all women reporting colorectal cancer. The primary outcome was invasive colorectal cancer incidence. Participants in the calcium/vitamin D trial were randomized 1:1 to either supplements or placebo. Active tablets contained 500 mg of elemental calcium (as calcium carbonate) and 200 IU of vitamin D3, to be taken twice daily with meals. The presence and severity of symptoms, safety concerns, and outcomes were ascertained at annual clinic visits and telephone or clinic visits at intervening six-month intervals. Risk factors for fracture were assessed by questionnaire, interview, and clinical examination. The primary outcome was incidence of hip fracture. Participants in the observational study attended a baseline examination and were re-examined three years later. Participants completed annual updates of exposures and clinical outcomes by mail. Final data were collected by mail during the close-out period in April 2004 to March 2005. The major clinical outcomes of interest were coronary heart disease, stroke, breast cancer, colorectal cancer, endometrial cancer, ovarian cancer, osteoporotic fractures, diabetes, and total mortality. Most outcomes were initially ascertained by self-report on an annual questionnaire and documented by hospital and related records. Charts with potential cardiovascular, cancer, and fracture outcomes were sent to the local physician adjudicator for evaluation and classification. Staff at the Clinical Coordinating Center coded and adjudicated all cancers of major interest in the study using standardized SEER guidelines. In 2005, WHI participants were invited to join the Extension Study for an additional five years of follow-up in order to collect long-term outcomes. Participants completed annual data collection forms primarily by mail, similar to the OS follow-up. Women reporting study outcomes were contacted by WHI field center staff to obtain additional details and medical records, which were evaluated by physician adjudicators. In 2010, the woman remaining were invited to join the next Extension Study. In the second extension, women were divided into two groups, one of which would have outcomes documented with medical records (the Medical Records Cohort, MRC), and the other would just be followed by self-report (the Self-Report Cohort, SRC). The MRC consists of women who were in the hormone therapy trials, and all African-American and Hispanic women. In 2012-2013, a subset of the MRC was identified for a potential in-home visit to collect blood and several objective measures of physical functioning. Conclusions: Overall health risks exceeded benefits from use of combined estrogen plus progestin after an average 5.2 year follow-up among healthy postmenopausal US women (Rossouw et al., 2002, PMID:12117397). Among postmenopausal women aged 65 years or older, estrogen plus progestin did not improve cognitive function when compared with placebo (Rapp et al., 2003, PMID: 12771113), increased the risk for probable dementia, and did not prevent mild cognitive impairment (Shumaker, et al., 2003, PMID: 12771112). The use of conjugated equine estrogen increased the risk of stroke, decreased the risk of hip fracture, and did not affect CHD incidence in postmenopausal women with prior hysterectomy after an average of 6.8 years of follow-up (Anderson et al., 2004, PMID: 15082697). Over approximately 8 years of follow-up, a low-fat dietary pattern did not reduce the risk of colorectal cancer (Beresford, et al., PMID: 16467233). Calcium with vitamin D supplementation resulted in a small but significant improvement in hip bone density; however, no significant difference was observed in hip fractures (Jackson, et al., 2006, PMID: 16481635). A recent review summarizes the conclusions from the WHI clinical trials with a focus on clinical practice (Manson, et al., 2024, PMID: 38691368).Description of ECG Imaging Data: Electric cardiograms (ECGs) were given to all clinical trial participants at baseline and in years 3, 6, and 9 of the original WHI study.EKG data consist of 12 lead 10 seconds ECGS sampled at 500Hz via GE ECG machines and process via GE MUSE system. The ECG waveform were directly exported from GE MUSE using MUSE export function in XML format, which include EKG waveform data as well as other ECG characteristics. Waveform data is in base64 encoded format, when it is decoded, it is a binary data that can be used to draw waveform graph. Many programming languages and data tools have built in functions to decode base64 strings. All the other necessary information is included in the LeadData section, total byte size, total sample size etc. (usually 1 sample is 2 bytes). See example below: encoded-data (base64 encoded string) JwAoAC0AKAAiACIAJAAkACQAIwAiACIAHgAcABwAGwAZABgAGAAYABcAEwAQABAAEAAL^/AAsADAAM... decoded-binary-data (1 sample is 2 bytes) 270028002D002800220022002400240024002300220022001E001C001C001B00 1900180018001800170013001000100010000B000B000C000C000D000D000D00 0A000A000A0009000600040004000700070005000500020... These binary values are integers (Y axis data of the graph), hence it is a straightforward process to draw the waveform graph. Acquisition dates have been redacted from this ECG data to comply with WHI policy. All acquisition dates within files and in file names have been set to January 1, 1900 (19000101) to comply with this policy.

  Study phs003824

• Low T cell diversity is associated with poor outcome in bladder cancer - Total RNAseq data

  T cells are crucial effector cells in the endogenous defense against cancer, yet the clinical impact of their quantity, diversity, and dynamics remains underexplored. In this study we performed total RNAseq on blood samples from 8 patients with muscle invasive bladder cancer. The goal was to compare blood T cell subtype composition between patients with low and high TCR diversity.

  Study EGAS50000000939

• Synergy study: "Tissue resident CD8+ T cell clonal expansion in advanced triple negative breast cancer is associated with response to chemoimmunotherapy"

  Dataset of 10x Genomics 5'prime single-cell RNA sequencing of 40 tumor biopsy samples or triple negative breast cancer. Samples are taken before and after immuno checkpoint blockade treatment. Processed according the 10X genomics protocol, sequenced on Immumina NovaSeq6000. Raw sequencing reads are further processed with Cellranger 3.0 to get gene-expression matrices.

  Study EGAS50000000527

• Transcriptomic profiling of T cells following ABHD11 inhibition

  This dataset contains paired-end RNA sequencing data from human T cells treated with ML226, a selective ABHD11 inhibitor, and matched vehicle controls. The experiment was designed to investigate the role of ABHD11 in sterol metabolism and its impact on T cell effector function and autoimmunity. Samples were collected across biological replicates following 24-hour treatment, and RNA was extracted for high-throughput sequencing. Sequencing was performed using an Illumina platform. The dataset supports analysis of differentially expressed genes, alternative transcript usage, and pathway-level effects of ABHD11 inhibition. This dataset is part of the study titled "ABHD11 inhibition drives sterol metabolism to modulate T cell effector function and alleviate autoimmunity".

  Dataset EGAD50000001845

• SCANDARE TNBC shallow WGS data

  SCANDARE (NCT03017573) is a multicentric biobanking study, enrolling adult patients with newly diagnosed head and neck squamous cell carcinoma (HNSCC), triple negative breast cancer (TNBC), ovarian and cervical cancer. Tumor tissue and blood samples are collected at several time points during patient's journey, including at diagnosis, post-neoadjuvant chemotherapy in case of neoadjuvant treatment, at surgery, at recurrence and at disease progression following treatment initiated at recurrence. Since its launch in 2017 at Institut Curie, SCANDARE has enabled the longitudinal collection and preservation of samples for in-depth analyses. Here, we describe molecular alterations in 251 frozen samples at baseline from 143 TNBC patients using shallow WGS technology, with FASTQ files deposited in the dataset.

  Dataset EGAD50000001849

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

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

  Dataset EGAD50000001002

• RNA-Seq of human longitudinal whole blood samples from PCR-positive and PCR-negative adults following controlled inoculation with Influenza A H3N2 virus.

  Understanding of the transcriptomic profile of individuals in early influenza infection is limited. To investigate this, longitudinal whole-blood samples (n=178) were taken from adult participants following controlled inoculation with Influenza A H3N2 virus (sampling at baseline (0) and days 1, 2, 3, 7, 10 and 14 post-challenge). Most participants became influenza PCR-positive; a minority remained PCR-negative. Total RNA was extracted from PAXgene tubes before undergoing globin and rRNA depletion. DNA libraries were constructed using the NEBNext® Ultra™ II Directional RNA Library Prep Kit for Illumina. All samples were then sequenced using Illumina NovaSeq 6000.

  Dataset EGAD50000000956

• Illumina GSA-MD v3 genotyping arrays for 183 samples

  Genotyping arrays for 183 samples from patients with a neuroendocrine tumor of the small intestine. All samples have been hybridized on Illumina GSA-MD v3 arrays with standard automated protocols. Reading of the chips was performed on Illumina iScan+ scanners and this file is the result of primary analysis done using Illumina GenomeStudio software. It contains data for 147 tumors, 2 adenomas, 1 lymph node, 19 mesenteric nodules, 6 liver metastasis and 8 normal ileum samples.

  Dataset EGAD50000000905

• Lipomatous tumors with 12q amplification

  The project concerns whole genome sequencing (short-read and long-read) and RNA-sequencing of lipomatous tumors with 12q-amplification. A subset of lipomatous tumors is driven by amplification of genes mapping to chromosome arm 12q, including the MDM2 gene. The goals of the study were to compare expression levels of genes mapping to 12q in tumors with amplification in rod-shaped or circularized chromosomes as well as to assess and compare the structural variants in those tumors. In total, 20 samples were analyzed, and the data were correlated with genomic data on bulk and single cell DNA from the same tumors. The fastq files from the tumors were uploaded to EGA.

  Dataset EGAD50000000087

• FASTQ Files from Breast Tumor Biopsies Collected Across Five Timepoints in the PROMETEO Phase II Trial

  The dataset contains RNA sequencing raw data from tumor biopsies collected at five time points during the SOLTI-1503 PROMETEO trial: baseline (pre-NAC), post-NAC screening, Cycle 2 Day 1, Cycle 3 Day 1, and surgery. The study intervention consisted of intratumoral injections of T-VEC followed by intravenous administrations of atezolizumab prior to surgery. The data is obtained from tumor samples of patients included in the study: female breast cancer patients with residual disease after neoadjuvant chemotherapy, including both triple-negative and Luminal B-like subtypes. Each sample includes raw paired-end RNAseq reads (~110 million reads per library) aligned to the GRCh38/hg38 reference genome

  Dataset EGAD50000002165

• WGS and WES of 78 pairs Chinese gastric cancer

  Gastric Cancer (GC) is a highly heterogeneous disease. To identify potential clinically actionable therapeutic targets that may inform individualized treatment strategies, we performed whole-exome sequencing on 78 GCs of differing histologies and anatomic locations, as well as whole-genome sequencing on two GC cases, each with 3 primary tumours and 2 matching lymph node metastases. The data showed two distinct GC subtypes with either high-clonality (HiC) or low-clonality (LoC).

  Dataset EGAD00001001118

• DPY30 ChIP-seq

  H9 human embryonic stem cells (hESCs) were cultured in feeder-free chemically-defined conditions in medium containing 10ng/ml Activin A and 12ng/ml FGF2 (Vallier L. 2011, Methods in Molecular Biology, 690: 57-66). Chromatin immunoprecipitation was performed as described in Brown S. et al. 2011. Stem Cells 29: 1176-85 by using 5ug of anti-DPY30 antibody (Sigma, cat. number HPA043761). This protocol was performed in control hESCs (expressing a scrambled shRNA) and in hESCs stably expressing an shRNA against DPY30 (Sigma, clone n. TRCN0000131112).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/

  Dataset EGAD00001001268

• Melanoma-Til Study RNAseq

  In this study, mutations present in a series of human melanomas (stage IV disease) will be determined, using autologous blood cells to obtain a reference genome. From each of the samples that are analyzed, tumour-infiltrating T lymphocytes have also been isolated. This offers a unique opportunity to determine which (fraction of) mutations in human cancer leads to epitopes that are recognized by T cells. The resulting information is likely to be of value to understand how T cell activating drugs exert their action.

  Dataset EGAD00001000325

• DNA repair in BLM deficient hiPSCs

  We are aiming to investigate repair of a double strand break (DSB) within the genome in the presence and absence of the BLOOM protein. Zinc Finger Nucleases introduce DSBs at specified loci within the genome. Using sequencing we will assess the size of the deletion following repair. Protocol 1. Transfect normal and BLOOM deficient human iPS cells with ZFNs, using AMXA 2. Harvest cells after 5 days 3. Perform column extraction of DNA 4. PCR-amplify the ZFN region 5. Sequence and analyse repair of the DSB 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/

  Dataset EGAD00001000819

• Tumor-derived cell lines as pharmacogenomic models to predict therapeutic vulnerabilities in hepatocellular carcinoma

  Hepatocellular carcinoma (HCC) is a heterogeneous aggressive malignancy with low efficacy of current therapies at advanced stages. We integrated molecular and pharmacological profiling of a large panel of liver cancer cell lines (LCCL) to assess their clinical relevance as HCC preclinical models and identify new effective therapies and biomarkers of response. Here, we performed multi-omic analysis including whole-exome, RNA and microRNA sequencing in a series 34 LCCL. Molecular profiles of LCCL and primary HCC were compared and we searched for molecular features associated with drug response. Our panel of LCCL faithfully recapitulated the most aggressive molecular “proliferation class” of HCC.

  Dataset EGAD00001004938

• Understand Paratyphoid Disease - host responses to human challenge with S. Paratyphi A (2019-08-28)

  This project aims to evaluate the transcriptional response to disease measured in whole blood of participants who developed enteric fever after challenge and, importantly, those who were challenged but stayed well throughout the challenge period. This data will provide unique coverage of the transcriptome and will yield invaluable insight after integration with a wealth of clinical data collected during this trial. 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/ . This dataset contains all the data available for this study on 2019-08-28.

  Dataset EGAD00001005298

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

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

  Dataset EGAD00001006341

• sWGS on cfDNA and matching tumor DNA in pediatric cancer

  This dataset contains shallow whole genome sequencing data from paired cfDNA - tumor DNA samples of various pediatric cancer entities (total 215 samples). Files are provided in fastq format. Samples were sequenced on an Ion Proton sequencer (Thermo Fisher Scientific) or a Hiseq3000 (Illumina). Data analysis is available at https://github.com/rmvpaeme/sWGS_pediatric_cancer.

  Dataset EGAD00001007508

• Pathogenic Neurofibromatosis type 1 (NF1) RNA splicing resolved by targeted RNAseq

  Neurofibromatosis type 1 (NF1) is caused by loss-of-function variants in the NF1 gene. Approximately 10% of these variants affect RNA splicing and are either missed by conventional DNA diagnostics or are misinterpreted by in silico splicing predictions. Therefore, a targeted RNAseq-based approach was designed to detect pathogenic RNA splicing and associated pathogenic DNA variants. an in-house developed tool (QURNAS) was used to calculate the enrichment score (ERS) for each splicing event. RNA enrichment of NF1 and SPRED1 was done using SPET (NUGEN - NF1 only) and using SureSelect (Agilent - NF1 and SPRED1).

  Dataset EGAD00001007978

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

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

  Study phs000285

• Sleep Abnormalities in Rare Genetic Disorders: Angelman Syndrome, Rett Syndrome, and Prader-Willi Syndrome

  This research study will investigate sleep behavior in the rare neurological disorders Angelman Syndrome (AS), Rett Syndrome (RTT), Prader-Willi Syndrome (PWS) and Early-onset Morbid Obesity (EMO). Sleep is very important to proper health and plays a critical role in learning, memory, brain development and brain function. Sleep disturbances can have negative effects on health and the quality of life of children and their families. Sleep disorders are common in individuals with AS, RTT, PWS and EMO. As a result, individuals with AS, RTT, PWS and EMO are at risk for sleep-related health problems that can worsen existing daytime behaviors and lead to additional problems with learning and memory. The principal objectives of the study are to: Characterize sleep behavior in individuals with Angelman Syndrome, Rett Syndrome, Prader-Willi Syndrome and Early-onset Morbid Obesity. Compare sleep behavior in these individuals with sleep behavior in normal controls Assess the natural history of sleep behavior in individuals with Angelman Syndrome, Rett Syndrome, Prader-Willi Syndrome and Early-onset Morbid Obesity About this Study This is a questionnaire study that will evaluate the sleep behavior of individuals with AS, RTT or PWS (participants), or unaffected siblings of individuals with AS, RTT or PWS (controls). Those participating in the study will already be registered with the Rare Disease Clinical Research Network (RDCRN) and have a confirmed diagnosis of AS, RTT or PWS or be an unaffected sibling. We will look at the medical records on file with the RDCRN to confirm diagnosis of AS, RTT or PWS. Study participants will participate in the study at their regularly scheduled RDCRN clinic visits. Participants will be asked to complete questionnaires at the study visits that will document their sleep behaviors. The questionnaires are not difficult and participants should be able to complete them in approximately 15-30 minutes. Parents and legal guardians are allowed to assist participants or answer on their behalf. Questionnaires will be administered at the initial study visit and at a 12 month follow-up visit to document any changes in sleep behavior. We hope to enroll approximately 1400 individuals with either AS, RTT or PWS or their unaffected siblings.

  Study phs001292

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

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

  Study phs000649

• Kids First: Congenital Heart Defects and Laterality Birth Defects

  Laterality defects occur in approximately 1:10,000 newborns and are associated with a range of structural birth defects and abnormalities of organ positioning. Gut malrotation, biliary atresia, asplenia or polysplenia, complex cardiovascular malformations, and midline defects such as neural tube defects, vertebral anomalies and rib fusions are found in various combinations in patients with laterality defects. In addition, a subset of laterality defects caused by abnormalities of cilia position or function are associated with additional medical problems such as chronic sinusitis and bronchiectasis that require specific preventive care; however these patients frequently are undiagnosed until late in disease course. The goal of this project is to elucidate the genetic architecture of laterality disorders in order to inform medical management and risk stratification and to prevent complications. Laterality disorders are genetically heterogeneous and we and others have previously identified single nucleotide variants inherited in an X-linked or autosomal recessive manner as explanations for a minority of cases. In addition, we have demonstrated copy number variants (CNVs) as a mechanism of disease that requires additional investigation. We hypothesize that the majority of cases result from complex genetic inheritance. We propose to investigate this hypothesis using a multifaceted analysis approach in our extremely well phenotyped cohort of 538 probands with laterality disorders. Nested within this cohort are 105 trios who have not had previous sequencing, probands who have had exome sequencing and are excellent candidates for gene discovery via whole genome sequencing (WGS), and families with multiple affected family members for family-based analysis. All trios will be analyzed by transmission disequilibrium test (TDT) including rare variant TDT. De novo mutations will also be identified from trios for potential gene discovery. Using all probands, we will identify the prevalence of pathogenic CNVs. In addition, we will perform burden analyses to identify genes, gene interactions, and pathways important for susceptibility to laterality disorders. Finally, our rare families with multiple affected members will be studied using family based segregation analysis. This comprehensive genetic analysis in patients with laterality disorders is necessary to identify the appropriate clinical diagnostic testing for risk stratification, to elucidate underlying genetic architecture and facilitate novel gene discovery, and to provide essential knowledge about genes and pathways impacting the development of laterality disorders.

  Study phs002589

• The Effect of the Menstrual Cycle on DNA Expression in the Normal Human Breast Epithelium

  The Susan G. Komen for the Cure® Tissue Bank at the IU Simon Cancer Center [www.komentissuebank.iu.edu] (KTB) was established expressly for the prospective collection of normal, healthy breast tissue from volunteer donors. Blood is also obtained from donors at the time of donation and is processed for serum, plasma and peripheral blood leukocyte DNA. Specimens are annotated and data includes age, race, ethnicity, personal health history, family cancer history, medication usage at the time of donation, and breast cancer risk factors. Premenopausal donors to the KTB were identified by a query of the Bank's database. Hematoxylin and eosin stained sections of the formalin-fixed paraffin-embedded tissue of the identified donors were reviewed and tissue was graded on the basis of the abundance of epithelium within the section. Only tissue containing abundant epithelium was considered for this study. Based on dates, the specimens of nine women in the follicular phase of the menstrual cycle and five in the luteal phase were chosen. Six donors using hormonal contraception at the time of donation were also included. Whole blood obtained from 19 of the 20 donors at the time of tissue donation was available and it was processed for serum. Estradiol, estriol, luteinizing hormone and progesterone concentrations were determined by the Indiana University Health Pathology Laboratory using a Beckman Unicel DxI 800 Immunoassay System. The phase of the menstrual cycle was verified by serum progesterone concentration. The epithelium of these 20 specimens was microdissected from multiple 8 micron frozen tissue sections. Total RNA extracted from the tissue was subsequently depleted of rRNA via locked nucleic acid probes. This enabled profiling of both poly-A and non-poly-A RNA species. Barcoded cDNA libraries from the 20 normal breast epithelia were prepared and sequenced on an Applied Biosystems (AB) SOLiD3 or SOLiD 4 platform. RNA-seq reads for each sample were then mapped to the human genome (hg19) using the LifeScope software version 2.5.1 (Life Technologies, Foster City, CA) and BAM (Binary Alignment/Map) files generated. Read counts for each gene were derived from the output BAM files using the RefSeq database (UCSC Genome Brower) as the gene model.

  Study phs000644

• Prematurity and Respiratory Outcome Program: Clinical Research Center Study of Functional and Lymphocytic Markers of Respiratory Morbidity in Hyperoxic Preemies

  Approximately 550,000 babies born prematurely each year in the United States suffer from birth at a time in development when the respiratory tract and immune system would normally be protected and maintained in a naïve state. This project is a component of the NIH Prematurity and Respiratory Outcomes Program (PROP) whose goals are the identification of disease mechanisms and biomarkers to stratify premature infants, at the time of discharge, for their risk of subsequent pulmonary morbidity. This Clinical Research Center (CRC) project will investigate prematurity-dependent alterations in cellular innate and adaptive immune systems resulting in increased susceptibility to respiratory infections and environmental irritants, and leading to respiratory morbidity in the first year of life. Prior studies have established developmental (maturity) and disease-related changes in circulating and pulmonary lymphocyte populations, but a comprehensive assessment of their relationship to disease risk/outcome has not been undertaken. We hypothesize that cellular and molecular immuno-maturity is altered due to intrinsic and extrinsic factors presented by premature birth in such a way as to reduce resistance to viral infections and to promote cytotoxic damage to the lung. We will evaluate immunologic maturity by comprehensively phenotyping lymphocyte populations in peripheral blood sampled at premature delivery, at the time of discharge from the hospital and at twelve months corrected age. The lymphocytic phenotype will be analyzed particularly in the context of gestational age and maternal-fetal stressors capable of modulating oxidative stress (oxygen exposure, infection and environmental tobacco smoke exposure). Additionally, we will assess changes in the molecular phenotype of isolated CD8 lymphocytes, a cell type preferentially recruited to the lungs of premature infants and capable of contributing to disease pathogenesis, by genome-wide expression profiling, in order to uncover novel disease pathways and define a gene expression signature associated with disease risk. We propose to build a statistical model, using cellular and molecular phenotypes and additional clinical variables, for stratifying risk of lung morbidity within the first year of life. Finally, we will assess the development of the gut microbiome in the preterm subjects to correlate with the observation of development of the adaptive immune system.

  Study phs001297

• International Consortium to Identify Genes and Interactions Controlling Oral Clefts

  Oral clefts represent the most common group of craniofacial birth defects in humans, and include cleft lip with or without cleft palate (CL/P) and cleft palate (CP). Oral clefts have a complex and heterogeneous etiology, with strong evidence for both genetic and environmental causal factors. Candidate gene studies and genome wide linkage studies have yielded compelling but inconsistent evidence that multiple genes control risk, and several studies have shown evidence for interaction between genes and environmental exposures, especially maternal smoking and nutrient intake. This consortium pulls together a very large collection of cases and their parents from multiple populations, and offers a unique opportunity to expand the search for genes controlling risk to the genome wide level. The specific aims are: To conduct a genome wide analysis on 2000+ case-parent trios ascertained through a case with isolated, non-syndromic CL/P or CP to test for linkage and disequilibrium. Initial analysis will consist of individual tests for gene effects while simultaneously testing for GxE interaction with common maternal exposures including vitamin supplementation, cigarette smoking and alcohol consumption (which have all been implicated as environmental risk factors for oral clefts). To use haplotypes in tests for GxE interaction incorporating population specific estimates. Since haplotype frequencies vary among populations, trios will be assigned haplotypes in a stratified estimation and then a pooled test statistic will be constructed. To test for interaction between SNPs in different genes showing evidence of influencing risk in a test for GxG interaction. To test for interaction between genes and maternal biomarkers using trios from Utah where measures of plasma folate, vitamin B-6, homocysteine and zinc in mothers are available. This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org), which was developed through the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to oral clefts through large-scale genome-wide association studies of well-characterized cases and their parents from multiple populations. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). The study was supported by the National Institute of Dental and Craniofacial Research (NIDCR). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington.

  Study phs000094

• Transcriptomic Profile of Whole Blood Cells from Elderly Subjects fed Probiotic Bacteria Lactobacillus rhamnosus GG ATCC 53103 (LGG) in a Phase I Open Label Study

  Open label study to evaluate the safety of Lactobacillus rhamnosus GG ATCC 53103 (LGG) in elderly subjects. Fifteen healthy elderly volunteers, ages 65-80 were enrolled in a study in which they received LGG capsules containing 1 x 1010 CFU, twice daily for 28 days and were followed through day 56. The study subjects completed a daily diary, a telephone call on study days 3, 7 and 14 and study visits at the Massachusetts General Hospital Clinical Research Center at baseline, day 28 and day 56. During each visit, the subject diary, interim history, potential adverse effects and concomitant medications were reviewed and vital signs and a physical examination were performed. Routine blood tests were obtained to monitor for safety during visits and nasopharyngeal and stool samples were collected for microbiome analysis. Volunteers interested in participating in the effect of LGG probiotic on the Human whole Blood Transcriptome substudy also had blood drawn for DNA and RNA extraction, after signing the substudy consent form. The main objective of the study was to assess the safety and tolerability of 2 x 1010 CFU LGG administered orally to elderly subjects for 28 days. Secondary objectives were to evaluate the richness and microbial diversity in nasopharyngeal and stool specimens using pyrosequencing, and to compare cytokine production in response to bacterial stimulation by following the kinetics of mRNA expression of pro and anti-inflammatory genes and different signaling pathways, in relation to changes in stool Bifidobacterium and Lactobacillus spp. The study was reviewed and approved by the Partners Human Research Committee (IRB # 2010P001695) and was registered at ClinicalTrials.gov (NCT01274598). The main results regarding the clinical signs and safety of intervention is published in PLoS One. 2014 Dec 1;9(12):e113456. doi: 10.1371/journal.pone.0113456. eCollection 2014. PMID: 25438151. RNA sequencing for transcriptome analysis was only done in 11 of the 15 subjects as RNA integrity and quantity had to be optimal for the three times where blood was collected in order for a subject to be included in the study. The information regarding the microbiome data associated with this study is presented in a separate paper, which can be found at dbGaP study accession, phs000896, and PMID: 25873374.

  Study phs000928

• Potential Modulatory Role of Osteoprotegerin in Bone Metabolism of Patients with 21-Hydroxylase Deficiency

  21-hydroxylase deficiency (21-OHD) is an inherited disorder that results from a mutation on the CYP21A2 gene. It affects the adrenal glands and is the most common cause of congenital adrenal hyperplasia (CAH). 21-OHD CAH causes the body to produce an insufficient amount of cortisol and an excess of androgen, the type of hormone that produces male characteristics. The primary treatment for 21-OHD CAH, glucocorticoid replacement therapy, has been shown to cause bone loss. However, the elevated hormone levels caused by 21-OHD CAH may increase production of the protein osteoprotegerin (OPG), which in turn may protect against bone loss. This study will compare bone density and OPG levels in women who have 21-OHD CAH and have undergone a lifetime of glucocorticoid replacement therapy to that in women who have neither of these criteria. In doing so, the study will aim to determine the relationship between OPG and bone loss. Because of the excess of androgen caused by 21-OHD CAH, women with CAH may exhibit some male-like characteristics. Glucocorticoids are a member of a class of drugs called corticosteroids, which are used in hormone replacement therapy. In order to counteract the effects of 21-OHD CAH, women with the disease are given hormone replacement therapy with glucocorticoids beginning at infancy. Glucocorticoids are known to cause bone loss. Despite many years of treatment with glucocorticoids, however, young women with 21-OHD CAH seem to be protected against bone loss. Researchers believe that the increased androgen levels in these women lead to increased estrogen levels, which in turn increase OPG production. The increase in OPG levels may protect women against bone loss. This study will evaluate bone density and OPG levels in women with and without 21-OHD CAH to determine the relationship between OPG and bone loss. Participants in this observational study will attend only one study visit. At this visit, they will undergo a blood draw; a scan of their lower spine, hip, and forearm; height and weight measurements; and a body fat analysis test. This last test will entail a weak and painless electrical signal being sent from foot to foot. Participants will not attend any follow-up visits for this study.

  Study phs001314

• Acute Respiratory Distress Network (ARDSNet) Studies 10 and 12 Statins for Acutely Injured Lungs from Sepsis (SAILS) (ARDSNet-SAILS-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-SAILS include Plasma, DNA, and Urine. Please note that use of biospecimens in genetic research is subject to a tiered consent. Objectives The SAILS trial was intended to assess the efficacy and safety of oral rosuvastatin in participants with sepsis-induced Acute Lung Injury (ALI) and test the hypothesis that rosuvastatin therapy would improve the clinical outcomes of critically ill participants with sepsis-associated acute respiratory distress syndrome (ARDS). Background In ARDS, inflammation in the lungs and other organs can cause life-threatening organ failure. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) can modulate inflammatory responses. Previous observational studies suggested that statins improved clinical outcomes in participants with sepsis. Participants There were 745 participants. Design Participants were randomly assigned in permuted blocks to receive either enteral rosuvastatin or placebo. A 40 mg loading dose of the study drug was administered within four hours after randomization. Subsequently, maintenance doses of 20 mg were administered daily until the third day after discharge from the intensive care unit, study day 28, hospital discharge, or death, whichever came first. The primary outcome measure was mortality before hospital discharge home or until study day 60 if the participant was still in a health care facility. Secondary outcome measures included the number of ventilator-free days to day 28, organ-failure-free days to day 14, and ICU-free days to day 28. Conclusions The study was stopped because of futility after 745 of an estimated 1000 participants had been enrolled. There was no significant difference between study groups in 60 day in-hospital mortality or in mean ventilator-free days. The rosuvastatin group had fewer days free of hepatic or renal failure. Thus, rosuvastatin therapy did not improve clinical outcomes in participants with sepsis-associated ARDS and may have contributed to hepatic and renal organ dysfunction.

  Study phs003736

• Whole Blood Transcriptomics of Patients With Melioidosis

  Melioidosis is a neglected tropical infection caused by the Gram negative bacterium Burkholderia pseudomallei that is associated with high mortality rates in southeast Asia. The goal of this study was to a) identify human blood leukocyte transcriptomic features and pathways specific to melioidosis (vs other etiologies of infection), b) identify transcriptomic features and pathways specific to fatal melioidosis, and c) identify transcriptomic predictors of death in patients with melioidosis. This study used clinical data and whole blood leukocyte samples from a subset of participants in the Ubon Sepsis Study, a prospective single-center cohort study conducted at Sunpasitthiprasong Hospital, Ubon Ratchathani, Thailand between 2013 and 2017. Participants in the Ubon Sepsis Study had suspected or documented infection with accompanying systemic manifestations of infection and were enrolled, with blood sampling, within 24 hours of admission to the study hospital. Enrolled patients were followed over time and vital status was determined at 28 days after enrollment. The subset of participants from the parent Ubon Sepsis Study cohort selected for this study was comprised of 164 patients with melioidosis (defined as having a culture of clinical sample positive for B. pseudomallei), 35 patients with Gram negative bacteremia due to either Escherichia coli or Klebsiella pneumoniae, 16 patients with Gram positive bacteremia due to Staphylococcus aureus, and 19 patients who had negative blood cultures and no clinical sample culture-positive for B. pseudomallei. Fifty uninfected control patients with or without diabetes were recruited from the outpatient department and blood donation center at Udon Thani hospital, Udon Thani, Thailand from 2018 to 2019. Blood was collected at the time of enrollment in Tempus Blood RNA tubes. RNA was extracted using the Tempus Spin RNA Isolation kit. RNA sequencing (RNA-Seq) was performed at the University of Washington Northwest Genomics Center. Analysis was performed using a variety of statistical methods. The main finding of the study was that the transcriptomes of melioidosis patients, compared to patients with other infections, were characterized by upregulation of interferon signaling. The transcriptomes of patients with fatal melioidosis were notable for upregulation of inflammatory and type 2 immune responses and downregulation of genes related to T-cell function. A five-gene (EPHB1, SYCP2L, MERTK, IL5RA, and SPOCK1) predictive signature for death in melioidosis was developed.

  Study phs003724

• Single Cell and Spatial Transcriptomics Studies of Fibrosis in Prospective Registry in IBD Study at MGH and GI Disease and Endoscopy Registry

  Stricturing disease or fibrosis is a common complication of inflammatory bowel disease (IBD), often requiring surgical intervention. This process is caused by the abnormal deposition of extracellular matrix in the context of inflammation, and thus involves crosstalk between multiple cell types including fibroblasts and immune cells. To understand the cellular interactions involved in fibrosis, we performed single cell and spatial transcriptomic analyses of biopsy or resection samples from IBD patients, diverticulitis patients or controls.For single cell analyses, intestinal samples were processed within three hours of collection by first stripping the epithelial layer with EDTA and then enzymatically digesting the underlying tissue. Cells from both the epithelial and tissue fractions were separately loaded in two channels on a 10x Chromium controller and libraries were generated with the 3'v3 Chemistry pipeline before sequencing on an Illumina sequencer. The resulting sequence data was demultiplexed and analyzed with the CellRanger pipeline to generate raw fastq files and processed gene-count matrices for each sample.For spatial transcriptomic analyses, intestinal resection samples were snap frozen in OCT (optimal cutting temperature embedding medium). Blocks were cut into 10μm sections in a cryostat and transferred to a 10x Genomics Visium slide v1. Spatially barcoded libraries were prepared according to manufacturer's instructions and sequencing on an Illumina sequencer. The resulting sequence data was processed with the SpaceRanger pipeline to generate fastq files and processed barcode-count matrices. Using the samples deposited here, we defined 68 fine-grained cell types across the ileum and colon of control and fibrotic intestinal tissues. We show that intestinal strictures were characterized by increased immune cells - including IgG+ plasma cells and CCR7hiCD4+ T cells - and inflammatory fibroblasts. We also define the transcriptional differences associated with fibrosis, with inflammatory fibroblasts in particular showing broad changes in gene expression. Spatial transcriptomics showed that key subsets colocalize within diseased tissues and identified additional populations such as interstitial cells of Cajal and enteric neurons. Further, we mapped gene expression onto intestinal biogeography, finding that known genetic risk loci are enriched within discrete spatial modules, defined by the presence of inflammatory fibroblasts and lymphoid follicles. Altogether, our datasets chart the key transcriptomic and cellular networks in stricturing CD and highlight the spatial organization of multicellular genetic risk factors.

  Study phs003943

• Kids First: Genetics of Pediatric Germ Cell Tumors

  The Gabriella Miller Kids First Pediatric Research Program (Kids First) is a trans-NIH effort initiated in response to the 2014 Gabriella Miller Kids First Research Act and supported by the NIH Common Fund. This program focuses on gene discovery in pediatric cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource). All of the genomic and phenotypic data from this study are accessible through dbGaP. The data is also available at the Kids First Portal, where other Kids First datasets can also be accessed in the cloud for data analysis, data visualization, collaboration and interoperability, open to all researchers and developers.Pediatric malignant germ cell tumors (GCTs) represent approximately 6% of childhood cancers, including 3% of tumors in children aged 0-14 years and 15% of tumors in adolescents. GCTs are heterogeneous and grouped together due to the presumed common cell of origin, the primordial germ cell (PGC). GCTs typically occur in the testes or ovaries; however, extragonadal GCTs can occur and are likely a result of abnormal germ cell migration during development. Evidence suggests that GCTs, including those diagnosed in adults, are initiated in utero. Thus, alterations in normal embryonic development are likely to be especially relevant to GCT etiology. Germline susceptibility has not been evaluated in an agnostic fashion in pediatric GCT, mainly due to a lack of an adequate number of samples; however, emerging evidence supports a genetic etiology.In the two Kids First GCT projects, we will evaluate genetic susceptibility to intracranial and extracranial GCT by sequencing probands and their unaffected parents. The goals of the project are to: 1) evaluate the contribution of rare genetic variants in GCT through the use of aggregate burden tests, focusing on genes and established regulatory regions; 2) identify de novo SNVs and CNVs in pediatric GCT using a case-parent triad design; and 3) identify molecular signatures in GCT tumor specimens, overall and by age group and tumor characteristics. Whole Genome Sequencing (WGS) data generated through the Gabriella Miller Kids First Pediatric Research Program will provide an opportunity to investigate the genetic origins of GCT in a diverse set of samples. Given the limited knowledge of GCT etiology and biology, the results of the proposed analyses are likely to have a big impact on the field.

  Study phs002322

• Exome Sequencing of Alcohol-Associated Hepatitis

  Alcoholic hepatitis (AH) is a clinically severe, acute disease that only afflicts a fraction of patients with alcohol use disorder (AUD). Although recent genomic studies of alcoholic cirrhosis (AC) and steatosis have revealed that several genes of large effect are shared between these disorders, the genetic and environmental sources of variation that lead to AH, AC or alcohol fatty liver disease (AFLD) in some AUD patients remain largely unknown. In order to investigate the genetic determinants of AH, we sequenced a 58 Mb exome target to high genotype accuracy (0.996) and completeness (0.941) in 1,735 patients with AH (N=784) and heavy drinking controls without alcohol-associated liver disease (ALD) (N=951), detecting 1,085,982 unique single nucleotide variants (SNVs). Analysis of common SNPs that comprised 17.5% of those SNVs, we observed exome-wide significant association of PNPLA3 (rs738409-G allele: odds ratio [OR]=1.73, 95% confidence interval [CI]: 1.44-2.08, p =3.75e-9), as had previously been seen for AH in candidate gene contexts, and as previously observed for PNPLA3 to AC and nonalcohol steatohepatitis in GWAS. Other genes previously implicated in AC did not strongly contribute to AH, and the only prominently implicated (but not exome wide significant) gene overlapping with AUD was ADH1B, also a known liver disease gene. However, SNPs at ICOSLG (Chr 21) and TOX4/RAB2B (Chr 14), were also exome-wide significant and of large effect-size (ICOSLG rs13052840-C allele: OR=1.67, 95% CI: 1.39-2.02, p = 4.59e-8; TOX4/RAB2B rs17516362-C allele: OR = 0.61, 95% CI: 0.50-0.74, p=1.25e-7). ICOSLG encodes a co-stimulatory signal for T-cell proliferation and cytokine secretion and induces B-cell proliferation and differentiation, and thus could be tied to the inflammatory component of AH. TOX4 was previously implicated in diabetes and immune system and its linked SNP is a cis eQTL for TOX4 and RAB2B. A polygenic signal was visible on the exome-wide quantile-quantile graph, where there was modest p value inflation (lambda = 1.040). Ranking p values of all 18,705 genes evaluated versus a list of 227 genes objectively precompiled for relationship to liver diseases (via GWAS), we observed a strong (pThe data generated here also represents a resource that can be used cumulatively or meta-analytically with future datasets.

  Study phs003659

• The Haemgen RBC study

  Anaemia is a major determinant of global ill-health. To refine our understanding of the genetic factors influencing red blood cell formation and function, we carried out a meta-analysis of genome-wide association studies (GWAS) for six red blood cell traits: haemoglobin (HB), mean cell haemoglobin (MCH), mean cell haemoglobin concentration (MCHC), mean cell volume (MCV), packed cell volume (PCV) and red blood cell count (RBC). We provide genome-wide association results for 62,553 people of European ancestry using up to 2,644,161 autosomal SNPs. Participants with extreme measurements (>+/-3SD from mean) were excluded on a per phenotype basis. Imputation was done using haplotypes from HapMap Phase 2. SNP associations with each phenotype were tested by linear regression using an additive genetic model. Associations were tested separately in each cohort, with principal components and other study specific factors as covariates to account of population substructure. We then carried out meta-analysis of results from the individual cohorts using z-scores weighted by square root of sample size. SNPs with MAF<1% (weighted average across cohorts) were removed, as were SNPs with weight <50% of phenotype sample size. Anaemia is a major determinant of global ill-health. To refine our understanding of the genetic factors influencing red blood cell formation and function, we carried out a meta-analysis of genome-wide association studies (GWAS) for six red blood cell traits: haemoglobin (HB), mean cell haemoglobin (MCH), mean cell haemoglobin concentration (MCHC), mean cell volume (MCV), packed cell volume (PCV) and red blood cell count (RBC). We provide genome-wide association results for 62,553 people of European ancestry using up to 2,644,161 autosomal SNPs. Participants with extreme measurements (>+/-3SD from mean) were excluded on a per phenotype basis. Imputation was done using haplotypes from HapMap Phase 2. SNP associations with each phenotype were tested by linear regression using an additive genetic model. Associations were tested separately in each cohort, with principal components and other study specific factors as covariates to account of population substructure. We then carried out meta-analysis of results from the individual cohorts using z-scores weighted by square root of sample size. SNPs with MAF<1% (weighted average across cohorts) were removed, as were SNPs with weight <50% of phenotype sample size.

  Study EGAS00000000132

• Identification of improved IL28B SNPs and haplotypes for prediction of drug response in treatment of hepatitis C using massively parallel sequencing in a cross-sectional European cohort

  The hepatitis C virus infects nearly 3% of the World’s population, causing severe liver disease in many. Standard of care therapy is currently pegylated interferon alpha and ribavirin (PegIFN/R), which is effective in less than half of those infected with the most common viral genotype. Two IL28B SNPs, rs8099917 and rs12979860, predict response to (PegIFN/R) therapy in treatment of hepatitis C virus infection. These SNPs were identified in genome wide analyses using Illumina genotyping chips. In people of European ancestry, there are 6 common (>1%) haplotypes for IL28B, one tagged by rs8099917 minor allele, four tagged by rs12979860. We used massive parallel sequencing of the IL28B and IL28A gene regions generated by PCR from pooled DNA samples from 100 responders and 99 non-responders to therapy, to identify common variants. Variants that had high odds ratios and were validated were then genotyped in a cohort of 905 responders and non-responders. Their predictive power was assessed, alone and in combination with HLA-C. Only SNPs in the IL28B linkage disequilibrium block predicted drug response. Eighteen SNPs were identified with evidence for association with drug response, and with a high degree of confidence in the sequence call. We found that two SNPs, rs4803221 (homozygote minor allele positive predictive value (PPV) of 77%) and rs7248668 (PPV 78%), predicted failure to respond better than the current best, rs8099917 (PPV 73%) and rs12979860 (PPV 68%) in this cross-sectional cohort. The best SNPs tagged a single common haplotype, haplotype 2. Genotypes predicted lack of response better than alleles. However, combination of IL28B haplotype 2 carrier status with the HLA-C C2C2 genotype, which has previousl y been reported to improve prediction in combination with IL28B, provides the highest PPV (80%). The haplotypes present alternative putative transcription factor binding and methylation sites. Massive parallel sequencing allowed identification and comparison of the best common SNPs for identifying treatment failure in therapy for HCV SNPs tagging a single haplotype have the highest PPV, especially in combination with HLA-C. The functional basis for the association may be due to altered regulation of the gene. These approaches have utility in improving diagnostic testing and identifying causal haplotypes or SNPs.

  Study EGAS00001000096

• UK10K_OBESITY_SCOOP

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches.The SCOOP samples are part of the Obesity group and will undergo exome sequencing. Severe Childhood Onset Obesity Project (SCOOP) is a sub-cohort of the Genetics Of Obesity Study (GOOS) cohort established by Sadaf Farooqi and Steve O’Rahilly at the University of Cambridge over the last 12 years. The GOOS cohort contains &gt;4,000 patients of diverse geographic origin, many of whom have monogenic and syndromic forms of obesity, and includes patients that are offspring of consanguineous union. SCOOP is a subset of &gt;1500 UK Caucasian patients with severe, early onset obesity (all patients have a BMI Standard Deviation Score (SDS) &gt; 3 and obesity onset before the age of 10 years), in whom all known monogenic causes of obesity have been excluded. GWAS data on the SCOOP cohort will be available (WTCCC2 independent study) at the time of the start of this study. Data from this cohort has demonstrated that the prevalence of the common obesity risk alleles in FTO, MC4R and NEGR1 are amongst the highest within SCOOP, demonstrating its value also in the study of genetic variants with an impact on more common obesity. For further information with regard to this cohort please contact Sadaf Farooqi (isf20@medschl.cam.ac.uk).

  Study EGAS00001000124

• The EGA at the International Congress of Human Genetics

  Today is the start of the International Congress of Human Genetics (ICHG). This event, hosted by the African Society of Human Genetics (AfSHG) and the Southern African Society for Human Genetics (SASHG), will reunite international experts to highlight how genomic technologies are being managed to address challenges generated by the current status of Human Health and Genomics. The European Genome-phenome Archive (EGA) will be at the Congress participating in workshops, meetings and talks where topics such as data access and discovery as well as the Federated EGA will be present. Data access and discovery In the context of the “Federated data analysis workshop“ that will be held the 26ᵗʰ, managed in the context of the CINECA project, a hands-on-session on Beacon v2 Discovery will be led by Mauricio Moldes. Another session on authorisation and data access will be presented by Mallory Freeberg and Coline Thomas, with and introduction by Thomas Keane. During the workshop, an end-to-end federated data analysis use case will be presented. Data access and discovery In the context of the “ Federated data analysis workshop“ that will be held the 26ᵗʰ, managed in the context of the CINECA project, a hands-on-session on Beacon v2 Discovery will be led by Mauricio Moldes. Another session on authorisation and data access will be presented by Mallory Freeberg and Coline Thomas, with and introduction by Thomas Keane. During the workshop, an end-to-end federated data analysis use case will be presented. During the last four years, CINECA has been identifying gaps in data sharing between Africa, Canada and Europe in order to build a federated solution for data access. Thomas Keane will present the project within the sessions happening the 24ᵗʰ. The Federated EGA at the ICHG A Federated EGA poster will be shown during the Poster Session 1 that will take place the 23ʳᵈ. The objective is to bring awareness of the European Genome-phenome Archive as a resource for permanent archive and secure data sharing. In this context, the network generated by the Federated EGA is key for cases where research data cannot be shared outside local jurisdictions. The Federated EGA was officially launched on 2022 with research institutes from five countries becoming the first nodes of this network. Nowadays, with more than 20 nodes preparing to join, it aims to become the largest human omics data sharing initiative towards understanding human health and disease. The H3Africa Initiative and the African research represented in the EGA 1.1% of the EGA studies include samples from African populations. Countries such as South Africa, Kenya, Uganda or Egypt, among others, are present in the 72.577 samples from African individuals archived at the EGA. 23 EGA datasets are managed by the Human Heredity and Health in Africa Initiative (H3Africa). This Initiative will celebrate its Consortium Meeting the 27ᵗʰ and 28ᵗʰ, back-to-back with the ICHG. H3ABioNet, the Pan African Bioinformatics Network for the H3Africa consortium, will also take this context to celebrate its 10-Year Symposium during the Congress. Members of the EGA team will attend both of them, as the H3ABioNet works in conjunction with H3Africa projects, to submit data to the European Genome-Phenome Archive.

  Blog the-ega-at-the-international-congress-of-human-genetics

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

  Most patients with late stage high-grade serous ovarian cancer (HGSOC) initially respond to chemotherapy but inevitably relapse and develop resistance, highlighting the need for novel therapies to improve patient outcomes. The MEK/ERK pathway is activated in a large subset of HGSOC, thus making it an attractive therapeutic target. Here, we systematically evaluated the extent of MEK/ERK pathway activation and efficacy of pathway inhibition in a large panel of well-annotated HGSOC patient-derived xenograft (PDX) models. The vast majority of models were nonresponsive to the MEK inhibitor cobimetinib (GDC-0973) despite effective pathway inhibition. Proteomic analyses of adaptive responses to GDC-0973 revealed that GDC-0973 upregulated the pro-apoptotic protein BIM, thus priming the cells for apoptosis regulated by BCL2-family proteins. Indeed, combination of both MEK inhibitor and dual BCL-2/XL inhibitor (ABT-263) significantly reduced cell number, increased cell death and displayed synergy in vitro in most models. In vivo, the GDC-0973 and ABT-263 combination was well tolerated and resulted in greater tumor growth inhibition than single agents. Detailed proteomic and correlation analyses identified two subsets of responsive models – those with high BIM at baseline that was increased with MEK inhibition and those with low basal Bim and high pERK levels. Models with low BIM and low pERK were non-responsive. Our findings demonstrate that combined MEK and BCL-2/XL inhibition has therapeutic activity in HGSOC models and provide a mechanistic rationale for clinical evaluation of this drug combination as well as the assessment of the extent to which BIM and/or pERK levels predict drug combination effectiveness in chemoresistant HGSOC.

  Study EGAS00001003427

• 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&#8211;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&#8211;977).

  Study phs003562

• Framingham Cohort

  Startup of Framingham Heart Study. Cardiovascular disease (CVD) is the leading cause of death and serious illness in the United States. In 1948, the Framingham Heart Study (FHS) -- under the direction of the National Heart Institute (now known as the National Heart, Lung, and Blood Institute, NHLBI) -- embarked on a novel and ambitious project in health research. At the time, little was known about the general causes of heart disease and stroke, but the death rates for CVD had been increasing steadily since the beginning of the century and had become an American epidemic. The objective of the FHS was to identify the common factors or characteristics that contribute to CVD by following its development over a long period of time in a large group of participants who had not yet developed overt symptoms of CVD or suffered a heart attack or stroke. Design of Framingham Heart Study. In 1948, the researchers recruited 5,209 men and women between the ages of 30 and 62 from the town of Framingham, Massachusetts, and began the first round of extensive physical examinations and lifestyle interviews that they would later analyze for common patterns related to CVD development. Since 1948, the subjects have returned to the study every two years for an examination consisting of a detailed medical history, physical examination, and laboratory tests, and in 1971, the study enrolled a second-generation cohort -- 5,124 of the original participants' adult children and their spouses -- to participate in similar examinations. The second examination of the Offspring cohort occurred eight years after the first examination, and subsequent examinations have occurred approximately every four years thereafter. In April 2002 the Study entered a new phase: the enrollment of a third generation of participants, the grandchildren of the original cohort. The first examination of the Third Generation Study was completed in July 2005 and involved 4,095 participants. Thus, the FHS has evolved into a prospective, community-based, three generation family study. The FHS is a joint project of the National Heart, Lung and Blood Institute and Boston University. Research Areas in the Framingham Heart Study. Over the years, careful monitoring of the FHS population has led to the identification of the major CVD risk factors -- high blood pressure, high blood cholesterol, smoking, obesity, diabetes, and physical inactivity -- as well as a great deal of valuable information on the effects of related factors such as blood triglyceride and HDL cholesterol levels, age, gender, and psychosocial issues. Risk factors have been identified for the major components of CVD, including coronary heart disease, stroke, intermittent claudication, and heart failure. It is also clear from research in the FHS and other studies that substantial subclinical vascular disease occurs in the blood vessels, heart and brain that precedes clinical CVD. With recent advances in technology, the FHS has enhanced its research capabilities and capitalized on its inherent resources by the conduct of high resolution imaging to detect and quantify subclinical vascular disease in the major blood vessels, heart and brain. These studies have included ultrasound studies of the heart (echocardiography) and carotid arteries, computed tomography studies of the heart and aorta, and magnetic resonance imaging studies of the brain, heart, and aorta. Although the Framingham cohort is primarily white, the importance of the major CVD risk factors identified in this group have been shown in other studies to apply almost universally among racial and ethnic groups, even though the patterns of distribution may vary from group to group. In the past half century, the Study has produced approximately 1,200 articles in leading medical journals. The concept of CVD risk factors has become an integral part of the modern medical curriculum and has led to the development of effective treatment and preventive strategies in clinical practice. In addition to research studies focused on risk factors, subclinical CVD and clinically apparent CVD, Framingham investigators have also collaborated with leading researchers from around the country and throughout the world on projects involving some of the major chronic illnesses in men and women, including dementia, osteoporosis and arthritis, nutritional deficiencies, eye diseases, hearing disorders, and chronic obstructive lung diseases. Genetic Research in the Framingham Heart Study. While pursuing the Study's established research goals, the NHLBI and the Framingham investigators has expanded its research mission into the study of genetic factors underlying CVD and other disorders. Over the past two decades, DNA has been collected from blood samples and from immortalized cell lines obtained from Original Cohort participants, members of the Offspring Cohort and the Third Generation Cohort. Several large-scale genotyping projects have been conducted in the past decade. Genome-wide linkage analysis has been conducted using genotypes of approximately 400 microsatellite markers that have been completed in over 9,300 subjects in all three generations. Analyses using microsatellite markers completed in the original cohort and offspring cohorts have resulted in over 100 publications, including many publications from the Genetics Analysis Workshop 13. Several other recent collaborative projects have completed thousands of SNP genotypes for candidate gene regions in subsets of FHS subjects with available DNA. These projects include the Cardiogenomics Program of the NHLBI's Programs for Genomics Applications, the genotyping of ~3000 SNPs in inflammation genes, and the completion of a genome-wide scan of 100,000 SNPs using the Affymetrix 100K Genechip. Framingham Cohort Phenotype Data. The phenotype database contains a vast array of phenotype information available in all three generations. These will include the quantitative measures of the major risk factors such as systolic blood pressure, total and HDL cholesterol, fasting glucose, and cigarette use, as well as anthropomorphic measures such as body mass index, biomarkers such as fibrinogen and CRP, and electrocardiography measures such as the QT interval. Many of these measures have been collected repeatedly in the original and offspring cohorts. Also included in the SHARe database will be an array of recently collected biomarkers, subclinical disease imaging measures, clinical CVD outcomes as well as an array of ancillary studies. The phenotype data is located here in the top-level study phs000007 Framingham Cohort. To view the phenotype variables collected from the Framingham Cohort, please click on the "Variables" tab above. The Framingham Cohort is utilized in the following dbGaP substudies. To view genotypes, analysis, expression data, other molecular data, and derived variables collected in these substudies, please click on the following substudies below or in the "Substudies" section of this top-level study page phs000007 Framingham Cohort. phs000342 Framingham SHARe phs000282 Framingham CARe phs000363 Framingham SABRe phs000307 Framingham Medical Resequencing phs000401 Framingham ESP Heart-GO phs000651 Framingham CHARGE-S phs000724 Framingham DNA Methylation phs001610 Framingham T2D-GENES phs002558 Framingham ADSP phs002559 Framingham BRIDGET phs002560 Framingham Cholesterol phs002611 Framingham Post-Mortem Brain Tissue phs002938 Framingham Molecular QTL The unflagging commitment of the research participants in the NHLBI FHS has made more than a half century of research success possible. For decades, the FHS has made its data and DNA widely available to qualified investigators throughout the world through the Limited Access Datasets and the FHS DNA Committee, and the SHARe database will continue that tradition by allowing access to qualified investigators who agree to the requirements of data access. With the SHARe database, we continue with an ambitious research agenda and look forward to new discoveries in the decades to come.

  Study phs000007

• Whole Exome Sequencing of Pancreatic Neuroendocrine Tumors at The Human Genome Sequencing Center, Baylor College of Medicine (HGSC-BCM)

  Pancreatic neuroendocrine tumors (PNETs), often referred to as "islet cell tumors", are neuroendocrine neoplasms that arise from cells of the endocrine and nervous system within the pancreas. These rare tumors which originate from the pancreatic islet are divided into many categories and are often classified by the hormone most strongly secreted. With the collaboration of the Elkins Pancreatic Center, the Human Genome Sequencing Center (HGSC) at Baylor College of Medicine had access to approximately 30 untreated tumor specimens and matched normal blood samples. Since the onset and progression of cancer is driven by extensive mutation of the genome, we are combining enrichment of exonic DNA with next generation sequencing to detect and characterize the somatic mutation profile of patients with pancreatic neuroendocrine cancer. This work was done at the Human Genome Sequencing Center (HGSC) in collaboration with the Elkins Pancreatic Center at Baylor College of Medicine in Houston, TX and was supported by grant number 5U54HG003273 from National Human Genome Research Institute (NHGRI).

  Study phs000871

• 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.&nbsp;

  Study phs002462

• International Cancer Proteogenomics Consortium (ICPC): Proteogenomics of East-Asian Breast Cancer

  The incidence of invasive breast cancer is rapidly increasing in East Asia, enriching in younger patients and luminal disease. We presented a deep proteogenomic landscape of a prospectively enrolled early-stage cohort in Taiwan to uncover the etiology, age-related subtype and oncogenic vulnerabilities underlying the heterogeneous disease. Multilayer proteogenomic architecture revealed distinct endogenous and environmental carcinogen-associated mutagenesis, linking APOBEC (apolipoprotein-B mRNA editing enzyme, catalytic polypeptide-like) cytidine deaminase and DBAC (dibenz[a,j] acridine) signatures to significantly elevated hormone biosynthesis and chemical carcinogenesis in younger patients, and identifying a novel subset of high mutation burden and immune escape potentially beneficial from combined epigenetic therapy and immunotherapy. A proteomics-informed classification resolves luminal heterogeneity, defines high-risk recurrent luminal disease and nominates biomarkers and actionable druggable pathways. Furthermore, proteogenomics profile distinguished a young luminal population susceptible to exogenous carcinogen and having DNA repair deficiency. This study illuminates the age-related molecular subtypes and oncogenic vulnerabilities, providing a proteogenomics-transformative guide for patient stratification and precision therapeutics beyond clinical staging.

  Study phs003150

• Gut microbiome profiles according to sex, body mass index and dietary fiber intake

  Findings from recent studies suggest that the community of microbes residing in the human body is important in disease etiology; however, it remains unclear whether personal factors modulate human microbial composition. Studies based on animal models indicate that differences in composition might be attributed to sex-mediated effects. We analyzed the relationship of sex, adiposity, and dietary fiber intake with gut microbial composition using fecal samples from human subjects. We explored the associations of these factors with metrics of community composition and specific taxon abundances. We found that men and women had significantly different microbial community composition and that women had reduced abundance of a major phylum. Adiposity was associated with gut microbiome composition and specifically in women but not in men. Fiber from fruits and vegetables and fiber from beans were each associated with increased abundance of specific bacterial taxa. These findings provide initial indications that sex, adiposity, and dietary fiber might play important roles in influencing the human gut microbiome. Better understanding of these factors may have significant implications for gastrointestinal health and disease prevention.

  Study phs000884

• Role of the Cervico-Vaginal Microbiome in Spontaneous Preterm Birth

  Preterm birth is the leading cause of neonatal morbidity and mortality. A failure to predict and understand the causes of preterm birth have limited effective interventions and therapeutics. From a cohort of 2,000 pregnant women, we performed a nested case control study on 107 well-phenotyped cases of spontaneous preterm birth (sPTB) and 432 women delivering at term. Modern and innovative Bayesian modeling of vaginal microbiota identified features of these communities associated with PTB. Seven bacterial taxa were shown to have relative abundances significantly associated with an increased risk of sPTB, with a stronger effect in African American women. However, higher vaginal levels of &#946;-defensins significantly decreased the risk of sPTB associated with the vaginal microbiota in an ethnicity-dependent manner. These findings hold promise for the development of novel diagnostics that could more accurately identify women at risk for sPTB early in pregnancy and offer new therapeutic strategies that would include immune modulators and microbiome-based therapeutics to reduce this significant health burden.

  Study phs001739