3613 results for "*geneti*"

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• CSER: Exome Sequencing in Diverse Populations in Colorado and Oregon/CHARM Cancer Health Assessments Reaching Many

  The CHARM (Cancer Health Assessment Reaching Many) study, part of the Clinical Sequencing Evidence-Generating Research (CS.ER2) effort, aimed to assess the utility of clinical exome sequencing and how it affects care in diverse populations. The study population included adults at risk for hereditary cancer syndromes. The primary objective was the implementation of a hereditary cancer risk assessment program in healthy 18-49 year-olds in primary care settings within a vertically integrated health delivery system (Kaiser Permanente) and a federal qualified health center (Denver Health). The investigators aimed to assess clinical exome sequencing implementation and interpretation, as well as tailored interactions for low health literacy including a contextualized consent process, and a modified approach to results disclosure and genetic counseling. The investigators were also assessing the clinical utility (healthcare utilization and adherence to recommended care) and personal utility of primary and additional results from clinical exome sequencing, and evaluate the ethical and policy implications of considering personal utility of genomic information decisions for health care coverage.Sequencing and analysis for CHARM was conducted at the Northwest Clinical Genomics Laboratory, University of Washington, Seattle (https://nwgc.gs.washington.edu/).

  Study phs002111

• Acute Respiratory Distress Network (ARDSNet) Studies 06 and 08 Prospective, Randomized, Multicenter Trial of Aerosolized Albuterol Versus Placebo for the Treatment of Acute Lung Injury (ALTA) (ARDSNet-ALTA-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-ALTA include Plasma, DNA, Urine, and BAL. Please note that use of biospecimens in genetic research is subject to a tiered consent. Objectives This clinical trial was designed to test the hypothesis that an aerosolized beta-2-agonist, albuterol, would improve clinical outcomes in participants with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Background In participants with acute lung injury and acute respiratory distress syndrome (ALI/ARDS), inflammation of the pulmonary circulation increases vascular permeability. Fluid leaks from blood vessels into the pulmonary interstitium and alveoli. Recovery from this form of acute respiratory failure requires that the pulmonary edema resolve. The resolution of alveolar edema is driven by active transport of sodium and chloride ions from the luminal space across both type I and type II alveolar epithelial cells, creating an osmotic gradient for the reabsorption of water. In the ex vivo human lung, the rate of alveolar fluid clearance can be doubled by treatment with a cyclic AMP beta-2 adrenergic receptor agonist. On the basis of the preclinical observations that treatment with beta-2-agonists could reduce pulmonary edema and accelerate the rate of alveolar fluid clearance, the ALTA study was designed and undertaken with the hypothesis that treatment of participants with ALI/ARDS with beta-agonist therapy would accelerate the resolution of alveolar edema and improve clinical outcomes. Participants There were 282 participants. Design Study staff conducted a multicenter, randomized, placebo-controlled clinical trial in which participants were randomized to receive aerosolized albuterol (5 mg) or saline placebo every 4 hours for up to 10 days. The primary outcome variable for the trial was ventilator-free days. Conclusions Ventilator-free days were not significantly different between the albuterol and placebo groups. The results suggest that aerosolized albuterol does not improve clinical outcomes in participants with ALI. Routine use of beta-2 agonist therapy in mechanically ventilated participants with ALI cannot be recommended (Matthay, et al., 2011, PMID: 21562125).

  Study phs003743

• Blood and Marrow Clinical Trials Network Fludarabine-based Conditioning for Severe Aplastic Anemia (BMTCTN-0301-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.ObjectivesThe primary objective of this study was to determine the feasibility and toxicity of employing fludarabine-based conditioning to reduce transplant-related toxicity while maintaining (or ideally improving) engraftment in allogeneic donor marrow transplantation from matched (and mismatched) unrelated donors in patients with severe aplastic anemia (SAA). Additionally, the study examined the degree of cyclophosphamide (CY) dose reduction achievable with the introduction of fludarabine in the preparative regimen, with the goal of maintaining (or improving) engraftment, reducing major transplant-related toxicity and early deaths, and thereby ultimately improving long-term survival.BackgroundUnrelated donor bone marrow transplantation (BMT) is an option for the treatment of patients with severe acquired aplastic anemia who do not have HLA-matched siblings and sustained responses to immunosuppressive therapy. Outcomes after unrelated donor BMT have improved over the past decades, presumably because of closer donor–recipient HLA matching and improved supportive care.The optimum preparative regimen remains to be established. Ideally, the conditioning regimen should maximize engraftment while minimizing organ toxicity. However, with transplant conditioning at the time of the study, graft rejection and regimen-related toxicity continued to adversely affect patient outcome. Conditioning regimens for unrelated donor BMT in patients with aplastic anemia are typically combinations of cyclophosphamide, anti-thymocyte globulin, and total body irradiation (TBI). Although cyclophosphamide is a key part of the preparative regimen for patients with severe aplastic anemia, the optimum dose remained undefined. In view of the known toxicities linked to high-dose (i.e., 200 mg/kg) cyclophosphamide, a reduction of the cyclophosphamide dose would be desirable.The study investigated whether the combination of fludarabine, anti-thymocyte globulin, and TBI would enable reduction of the cyclophosphamide dose to less than 200 mg/kg while maintaining engraftment and having a survival similar to or better than that with standard regimens using a cyclophosphamide dose of 200 mg/kg (known to be associated with significant organ toxicity) for unrelated donor transplantation for severe aplastic anemia.ParticipantsBetween Feb 22, 2006, and Aug 1, 2007, 21 patients were accrued to phase 1 of the study. Phase 2 opened in Nov 5, 2007, and closed to accrual on Dec 2, 2013, with a final enrolment of 96 patients. One patient who withdrew consent prior to transplant was not included in the final analysis.Patients were eligible for inclusion in the study if they were 65 years old or younger, had adequate organ function, and had an unrelated adult donor HLA matched at the allele-level for HLA A, B, C, and DRB1 or mismatched at a single HLA locus.Exclusion criteria were Karnofsky performance status of less than 60, clonal cytogenetic abnormalities, Fanconi's anemia, or other marrow failure syndromes. Bone marrow was the only stem cell source allowed because of the poor outcome reported in patients with severe acquired aplastic anemia transplanted with peripheral blood cells.DesignThe study was a prospective phase I/II dose optimization study. All patients were given a fixed dose of anti-thymocyte globulin (either thymoglobulin: 3 mg/kg IV daily x 3 or ATGAM 30 mg/kg IV daily x 3, on Days –4 to –2), Fludarabine (30 mg/m2 IV daily x 4, on Days – 5 to –2), and TBI (200 cGy from a linear accelerator at ≤ 20 cGy/min on Day –1).The phase I portion of the trial tested each of four dose levels of cyclophosphamide (0 mg/kg, 50 mg/kg, 100 mg/kg, and 150 mg/kg) for adequate safety and graft retention. 6 patients were allocated to each of the doses, except for the 0 mg/kg dose which was closed after accrual of three patients due to secondary graft failure. The phase II portion of the trial refined the dose selection and allocated an additional 68 patients to the optimal dose, as assigned by the Bayesian approach. The starting cyclophosphamide dose was 150 mg/kg, and was de-escalated depending on engraftment and toxicity. Eight patients were accrued to the cyclophosphamide dose of 150 mg/kg, which was then closed because of excess toxicity. Patients were subsequently enrolled to the 100 mg/kg dose in cohorts of six. While enrollment at this dose paused until all patients in a cohort had their day 100 assessments, additional patients were assigned to cyclophosphamide 50 mg/kg. The last 20 patients were preferentially assigned to cyclophosphamide 50 mg/kg to balance accrual to the two doses.The primary endpoint was the selection of the optimum cyclophosphamide dose based on assessments of graft failure (primary or secondary), toxicity, and early death during 100 days of follow-up after the transplant.ConclusionsThe study identified cyclophosphamide 50 mg/kg as the most desirable dose in combination with TBI 2 Gy, fludarabine 120 mg/m², and anti-thymocyte globulin for engraftment and early survival for unrelated donor transplantation in patients with severe acquired aplastic anemia. A dose of 100 mg/kg, although slightly less desirable, also provided promising early results. These cyclophosphamide doses should be assessed further, ideally in the context of a randomized trial (Anderlini P, Wu J, Gersten I, et al., Lancet Haematol. 2015;2(9):e367–e375. doi:10.1016/S2352-3026(15)00147-7).

  Study phs004813

• Uncovering Colorectal Cancer Etiology and Biology by Integrating Proteomics with Other Omics Data

  This study included the expression profiling of approximately 10,000 proteins generated in normal colon tissue samples collected from 323 participants of European descent, paired with genome-wide genotype data obtained from blood samples. Using these proteomics and genotype datasets, we developed genetically prediction models for protein expression and conducted a proteome-wide association study (PWAS) of colorectal cancer (CRC) in European populations to identify proteins associated with CRC risk.

  Study phs004089

• Re-Evaluation of Systemic Early Neuromuscular Blockade

  This study of the ROSE trial data explored two distinct molecular subtypes of ARDS (Acute Respiratory Distress Syndrome) to better understand the disease's complexity and potential for personalized treatment. Previous studies had identified different inflammatory profiles in ARDS patients, with this research addressing three key questions: Can these molecular subtypes be consistently identified in a more severe group of ARDS patients? Do these subtypes respond differently to neuromuscular blockade treatment? What specific biological processes differentiate these inflammatory profiles? Advanced transcriptomic and protein analyses examined blood samples from ARDS patients. Analysis of these data revealed two main molecular phenotypes: Hypoinflammatory phenotype (60.4% of patients) Hyperinflammatory phenotype (39.6% of patients) Key findings demonstrated that the hyperinflammatory subtype was associated with:Significantly higher mortality rates relative to hypoinflammatory (61.6% vs. 30.3%)Significantly higher mortality rates relative to hypoinflammatory (61.6% vs. 30.3%)Distinct gene expression patterns related to immune responseUnique changes in genes associated with tissue remodeling and cellular processes Notably, the neuromuscular blockade treatment showed no difference in effects across these subtypes. Complex relationships emerged between gene expression and protein levels, with some genes closely matching their protein counterparts and others displaying more variable connections. The study concludes that these molecular phenotypes possess distinct clinical, protein, and genetic characteristics, suggesting potential for more precise, personalized approaches to ARDS treatment in the future.

  Study phs003929

• Kids First: Genomics of Isolated Cleft Lip

  Isolated Cleft Lip (CL, Human Phenotype Ontology # HP0100335) is a subtype within Orofacial Clefts (OFC, HP0000202) birth defects. OFCs can involve gaps in the lip, alveolus and/or the hard or soft palate. Developmental origins of the affected structures, epidemiology, and familial patterns of CL versus other OFCs suggest some common risk factors, but emerging evidence emphasizes that these subtypes also have unique risk factors. Isolated CL has seldom been investigated separately in genetic studies. Early studies using microsatellite markers prior to the availability of SNP chips found differences in CL families versus other cleft subtypes, notably reporting increased association with certain IRF6 variants in CL families versus other cleft types. With the advent of SNP chips, some studies addressed CL, e.g. genome-wide association of CL was seen with TPM1 and NOG and 9q21.32. We have performed some of the only genome-wide association studies (GWAS) to compare and contrast CL and Cleft Lip with Cleft Palate (CLP). We find evidence that CL and CLP have some distinct genetic risk factors, differences in strength or direction of effects between CL and CLP, and modifying loci that predispose specifically for CL over CLP. Some loci are most-significant in families where all affected members had CL. Modifiers of cleft lip laterality and side of the cleft were more successful in CL than in CLP and the loci identified in CL had no detectable effect in CLP, reinforcing the idea that CL and CLP have distinct risk factors. An overall conclusion from these studies is that CL appears more genetically homogeneous than does CLP, thus highlighting the importance of subtype and family type inclusion in studies of OFCs. Importantly, the homogeneity of CL makes it more amenable to gene discovery in the moderate sample sizes available with whole genome sequencing (WGS). The current project builds upon the GWAS and WGS analyses by our group and others. The WGS data generated will be used to discover new loci for CL, to replicate/prioritize previously published loci, and to aid in determining CL-specific causal genes/alleles. Short Read WGS data available for 1903 individuals include 629 affected probands: 553 CL and 40 CLP (with CL relatives) complete trios, 29 CL and 1 CLP dyads, and 5 CL and 1 CLP singletons. Of the 1903 total individuals, 554 are of European descent, 381 Central/South American descent, 857 of Asian descent, 7 of African descent, and 104 are race other/unknown. With our phenotypic data plus the WGS, we will be able to find new loci, gain better understanding of how risk related to those loci differs across populations, create the knowledge needed to choose loci for follow-up functional studies, build the knowledge needed for accurate risk predictions, and ultimately set the stage for translation into clinical practice. Study Population: The individuals and families utilized in this project were recruited through the Pittsburgh Orofacial Cleft study (POFC) involved research collaborations world-wide coordinated by the Center for Craniofacial and Dental Genetics of the University of Pittsburgh (CCDG). Extensive information is available for many of these trios, including sex, self-reported race and ethnicity, birth date and age at enrollment, phenotypes for affected cases (i.e. extensive detail on the OFC defect in terms of type, laterality, completeness), phenotypes for all affected and unaffected family members (including facial measurements, lip morphology, dental characteristics and many more), vital status and age at last known vital status, clinical information (e.g. surgical and medical history for all affected cases, some limited systems review for unaffected family members), and family medical history (e.g., family history of cancer and birth defects).Molecular Technology: Short Read WGSData Available: Demographics (site, age, sex, race, ethnicity) Cleft details Family level cleft details (i.e. multiplex, clefting maternal side, clefting paternal side, or both) Height/Weight Pregnancy Exposures data (birth height, birth weight, smoking, vitamins, alcohol, epilepsy, gestational diabetes) for 3 months prior to first trimester and first trimester. Subject_IDs from other sequencing studies Data use limitations from the consents The remaining phenotypic/medical/image data for this study are available through FaceBase (facebase.org): DOI: 10.25550/5A-FJBJ and DOI: 10.25550/56-ES6P.

  Study phs003893

• Kids First: Project on Congenital Clubfoot

  Talipes equinovarus (clubfoot) is a common congenital structural birth defect. Clubfoot occurs in ~1 in 1,000 live births in the United States, though the incidence varies in other worldwide populations. Clubfoot affects the structural components of the foot (tarsals), muscular and connective tissues including the Achilles and tibial tendons, and ligaments of the ankle. Males are affected twice as frequently as females, and at least half of patients present with bilateral disease. Surgical correction in infants requires tendoachilles lengthening, where the Achilles tendon is severed and the foot is casted to allow healing with the foot in a proper position. Although short-term success following clubfoot treatment is positive, long-term outcomes following surgical clubfoot correction are poor; complications include arthritis, reduced range of motion, weakness, pain and persistent deformity. Importantly, the number of surgical procedures required to produce a corrected clubfoot was significantly associated with poorer long-term outcomes. The pathogenesis of clubfoot remains largely unknown, though ~12% of patients report a family history. Targeted gene sequencing studies have failed to identify genetic loci associated with clubfoot. We recently reported FSTL5 as the first GWAS-associated locus associated with clubfoot, and we showed this gene was associated with sexually-dimorphic phenotypes in mice. Together with the Gabriella Miller Kids First Initiative (GMKF), we are poised to continue advancing the field's understanding of the genetic causes of clubfoot. The GMKF provides comprehensive genome sequencing (GS) in individuals and families with congenital birth defects. However, no study of congenital limb malformations has yet been conducted as part of the GMKF; thus, our study will be the first GMKF study to investigate genetic causes of congenital limb defects. For the past several decades, we have collected DNA samples from families with multiple relatives affected with clubfoot. Similar to our previously-awarded GMKF studies (1X01HL132375 led by Dr. Rios and DE031445 co-led by Dr. Hecht), we will utilize the power of family-based inheritance mapping to discovery genetic causes of clubfoot. Using the comprehensive GS provided by the GMKF, we will discover sequence variants and copy number variants co-segregating with clubfoot in these families. We present a systematic approach to discover these clubfoot-causing variants, including an integrated approach to investigate variants impacting potential non-coding regulatory elements, which have previously been implicated in other limb malformations. At the completion of this study, we will provide the field with the most comprehensive genomic analysis of families with clubfoot, which will provide novel hypotheses regarding the genetic etiology of this complex congenital birth defect.

  Study phs003336

• Detroit Research on Cancer Survivors (ROCS) and Disparities and Cancer Epidemiology - Colorectal Cancer (DANCE)

  The goals for this study were as follows:1. Enroll a total of 5,060 African Americans newly diagnosed with cancer into the Detroit Research on Cancer Survivors (Detroit ROCS) Cohort. These population-based cases will be ascertained through the Detroit Metropolitan Detroit Cancer Surveillance System (MDCSS), a founding member of the NCI SEER Program. Participation at baseline will include a written, web-based, or telephone interview, saliva and/or blood collection, and tumor block retrieval, with detailed cancer-related information coming from the MDCSS registry and medical records.2. Enroll a subgroup of colorectal cancer patients identified through the Louisiana Tumor Registry (LTR). An additional 500 colorectal cancer patients, approximately half non-Hispanic white and half African American, will be identified through the LTR and enrolled into the ROCS protocol. The survey is the same survey administered to the ROCS cohort. The Louisiana (“DANCE-CRC”) cohort will not be followed beyond baseline, and blood will not be collected (tumor tissue, however, will be collected, deidentified, and sent for processing through Dr. Rozek's laboratory at Georgetown University).The proposed cohorts will provide for a broad research agenda evaluating cancer outcomes in African Americans across a variety of factors from individual, provider, health care system and community perspectives. These factors include tumor characteristics driving individualized treatment planning, quality of life after a diagnosis and recurrence. Utilizing the MDCSS registry, we will enroll a large population-based sample of African-American cases with lung, breast, colorectal, and prostate cancers and their caregivers resulting in a cohort that will provide substantial benefit to the cancer research community. KCI has a strong history of research in the African-American community and the faculty represents a breadth of experience that includes clinical oncology, genetic epidemiology, environmental exposures, quality of life, treatment decision making, racism/discrimination, and health behaviors. Drs. Schwartz and Beebe-Dimmer have been and will continue to be generous collaborators with other institutions to ensure that this resource will be extensively utilized. The proposed overall cohort will be the only one of its kind, to our knowledge, filling a substantial gap in our understanding of the determinants driving cancer outcomes in African Americans. In addition to registry data detailing cancer specifics, yearly surveys have collected information about individualized treatment experiences, heath histories, family histories, quality of life after a diagnosis, recurrence and caregiving. Population: Adult cancer survivors (see inclusion criteria in next section) Molecular Technologies: Genotyping: Infinium Expanded Multi-Ethnic Genotyping Array (MEGAEX) DNA Sequencing: Illumina NovaSeq X Plus using XLEAP-SBS (sequencing by synthesis) Whole genome sequencingPrincipal Findings: The preliminary data collected reinforces differences by race in factors affecting cancer outcomes. Variants in DNA damage repair genes and HOXB13 may be important cancer risk factors for Black men diagnosed with prostate cancer, and are more frequently observed in men with a family history of cancer. ROCS participants reported high rates of a family history of cancer. The high rate of eligibility for Cancer genetic counseling among ROCS participants supports the need for interventions to increase referrals and uptake of genetic counseling among African Americans 60% of ROCS participants reported participating in regular physical activity (PA), with 24% reporting ≥150 min/wk. There were no differences by sex, but prostate cancer survivors were the most likely to report participating in regular PA, whereas lung cancer survivors were the least likely. Survivors who reported participating in regular PA reported higher health-related quality of life and lower depression. More African American than White survivors reported financial hardship and limiting care. More White than African American survivors reported utilizing assets, while more African American survivors reported cancer-related debt. Data available in dbGaP: Individual phenotype data Individual genotype data Individual sequencing dataSample types: Germline DNA

  Study phs003116

• Genome Sequencing and Variant Calling of HCM Patients with MYH7 Variants

  To investigate potential genetic causes of cardiomyopathy we recruited 48 patients harboring rare MYH7 variants identified from panel-based testing and with a clinical manifestation of cardiomyopathy. Genome sequencing was performed to identify other potential causative variants and genetic modifiers of the cardiomyopathy phenotype, which varied among patients.

  Study phs004024

• Host-Specific Effects on Bacterial Modulation of Respiratory Epithelial Gene Expression and Alternative Splicing

  Given the extensive variability inherent to humans and how variable microbiome composition is between individuals, we wanted to investigate inter-individual differences in host response to microbial colonization. Using primary normal human bronchial epithelial cells from six different adult donors (including both males and females and spanning in age from mid-20s to mid-50s), we cultivated air-liquid interface tissue cultures (ALI) from each donor. ALIs are pseudostratified cell cultures where the epithelial cells have differentiated into the appropriate subtypes (goblet cells, ciliated cells, club cells, etc). We colonized the ALI with one of three phylogenetically diverse microbes (Staphylococcus epidermidis, Rothia aeria, and Klebsiella aerogenes) for 12, 24, and 48 hours. At each time point, we sequenced the total RNA from the eukaryotic respiratory epithelial cells with the goal of identifying patterns of the gene expression change that were consistent or variable across the donors and evaluate if these patterns were dependent on the colonizing microbe.

  Study phs004345

• Wnt Activity Reveals Context-Dependent Genetic Effects on Gene Regulation in Neural Progenitors

  In this study we aimed to identify context-dependent regulatory functions of common genetic variation after stimulation of the canonical Wnt pathway. Fetal cortical tissue between 14 and 21 gestation weeks was subjected to RNA-Sequencing (242 samples) and ATAC-Sequencing (222 samples) to profile expression and chromatin accessibility, respectively. Considering donor genotypes, we were able to identify eQTLs, caQTLs, as well as response QTLs of both categories. The dataset provided here includes 242 RNA-sequencing files in bam format and 222 ATAC-sequencing files in bam format. We also provide 83 donor genotypes in VCF format (hg38).

  Study phs003642

• Interdisciplinary Approaches for Understanding how Arsenic and Micronutrients Affect the Epigenome to Influence Spina Bifida Risk

  This hospital-based case-control study was conducted in Bangladesh between December 2016 and December 2022 to investigate the association between environmental arsenic exposure and the risk of spina bifida. The study enrolled children with spina bifida (cases) and unaffected children (controls), along with their biological parents. Cases included infants under one year of age with clinically confirmed diagnoses of myelomeningocele or meningocele at the National Institute of Neurosciences & Hospital (NINS). Controls were frequency-matched on age and recruited from the same catchment area through NINS and Dhaka Shishu Hospital. Children with conditions potentially related to arsenic exposure, such as keratosis or cancer, were excluded from the control group. A small subset of case families were reclassified as controls following surgical reevaluation and a revised diagnosis of lipomeningocele, then later removed from the control group. They are no longer assigned to either the case or control category in the datasets. Saliva samples were collected from children and parents using Oragene® kits and stored at room temperature before shipment to Boston, MA, USA. DNA extraction was carried out with the Maxwell® RSC Buccal Swab DNA kit. A total of 749 saliva DNA samples, representing 713 unique individuals and 36 replicates, were shipped to the Broad Institute for analysis. Samples were randomized across Illumina Global Screening Array (GSA) chips to minimize batch effects. The primary molecular technology employed in this study was the Illumina Global Screening Array (GSAMD-24v1-0), which includes approximately 688,000 genetic markers. Data generated include raw and processed genotype files as well as a comprehensive quality control report. The genotyping dataset available through dbGaP will consist of genotype calls from spina bifida cases, controls, and their parents, along with associated demographic, clinical, and exposure metadata, enabling future analyses of gene-environment interactions in the context of neural tube defect risk.

  Study phs003733

• Identifying the Genetic Basis of Variably Protease-Sensitive Prionopathy (VPSPr)

  Design: Sequencing of cases onlyMolecular technologies: Exome sequencing and custom targeted sequencing of PRNPAims: Identify modestly penetrant, high odds ratio variants conferring risk of variably protease-sensitive prionopathy (VPSPr)Population: n=67 autopsy-confirmed VPSPr cases, United States, 1997-2021Principal findings: Association to PRNP M129V replicated, no other causal variants identifiedData available: Raw sequencing data and metadata

  Study phs004012

• Prevention and Early Treatment of Acute Lung Injury (PETAL) Acetaminophen in Sepsis: Targeted Therapy to Enhance Recovery (ASTER) (PETAL ASTER-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from PETAL ASTER include plasma, urine and whole blood. Please note that use of biospecimens in genetic research is subject to a tiered consent. Objectives: To determine whether acetaminophen increases days alive and free of organ dysfunction in sepsis participants compared with placebo.Background: Acetaminophen (paracetamol) has many effects that can be beneficial in sepsis treatment, including analgesia, antipyresis, cyclooxygenase-2 inhibition, as well as a potent and specific hemoprotein reduction that can block hemoglobin-induced oxidation of lipids and other substrates. The majority of sepsis participants experience elevated circulating cell-free hemoglobin levels, which is associated with development of organ dysfunction including acute respiratory distress syndrome (ARDS) and death.Acetaminophen has been found in observational studies to be associated with improved survival in critically ill sepsis participants with elevated plasma cell-free hemoglobin, and small clinical trials have had positive sepsis participant outcomes such as reduced plasma biomarkers of lipid peroxidation and improved kidney function. However, a large, randomized trial of acetaminophen administration for treatment of fever in participants with suspected infection did not show a mortality benefit. The NHLBI PETAL Network initiated ASTER as a larger phase trial to examine the utility of plasma cell-free hemoglobin level as a biomarker for future sepsis trials and whether acetaminophen would increase the number of days alive and free of organ support for participants with sepsis and respiratory or circulatory organ dysfunction. Participants: A total of 447 participants were enrolled and randomized, 227 to the acetaminophen arm and 220 to the placebo arm. Data from 40 participants who were randomized to the Vitamin C arm, which was stopped early (see Design section below), is also included.Design: ASTER was a phase 2b multicenter, randomized, double-blind trial. The study originally had a 3-arm platform trial in which participants were randomized 1:1:1 to treatment with intravenous acetaminophen, vitamin C, or a common placebo. The vitamin C arm of the trial was stopped after enrolling 79 participants due to external clinical trial data for vitamin C.Participants randomized to the acetaminophen arm received acetaminophen at the dose of 1 g in 100 mL diluent (or 15 mg/kg if actual body weight was Conclusions: Intravenous acetaminophen was considered to be safe but did not significantly improve days alive and free of organ support in critically ill sepsis participants. There was no significant interaction between cell-free hemoglobin levels and acetaminophen.

  Study phs003900

• AsthmaNet Best African American Response to Asthma Drugs (BARD-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Objectives: To assess whether patients of African American heritage with inadequately controlled asthma benefit from the addition of a long-acting beta-agonist and/or increased glucocorticoids dosage, and whether the response varies for children vs. adolescents and adults.Background: Epidemiologic studies have demonstrated that African American patients with asthma experience more complications including exacerbations, asthma-related urgent-care visits, hospitalizations, and deaths, as compared to Caucasian patients with asthma. Ethnicity can also influence medication response, and studies have shown that African Americans patients have more glucocorticoid resistance, less cellular sensitivity to glucocorticoids, and more eosinophilic inflammation during inhaled glucocorticoid treatment than Caucasian patients. This may be due to the effect of genetic variants on response to pharmacotherapy for asthma.Asthma symptoms are primarily controlled with inhaled glucocorticoids, but a long-acting β2-adrenergic receptor agonist (LABA) may be used as an additional treatment when glucocorticoids alone do not sufficiently suppress symptoms. However, prior to the BARD study, this recommendation was based on studies with limited numbers of African American patients and without evaluation of differences in genetic ancestry. In particular, additional analysis has indicated that adding a LABA was not superior to increasing the dose of an inhaled glucocorticoid in African American patients. Therefore, the BARD trials were initiated to address this gap in scientific understanding and determine a preferred pharmacotherapy strategy in African American children, adolescents, and adults.Participants: Eligible participants were recruited from nine AsthmaNet sites and consisted of asthma patients at least five years of age that had at least one African American grandparent. Participants were required to have a baseline forced expiratory volume in 1 second (FEV1) of at least 40% of the predicted value after bronchodilator use (four 90 μg puffs of albuterol) and a diagnosis of asthma, as confirmed by beta-agonist reversibility, a methacholine provocation concentration causing a 20% decrease in the FEV1 of 16 mg per milliliter or less, or an absolute difference in the percentage of the predicted FEV1 of at least 12 percentage points over two measurements documented within the previous year. The asthma must also be inadequately controlled (CT/c-ACT score A total of 280 children and 294 adolescents and adults were enrolled and underwent randomization.Design: BARD consisted of two prospective, randomized, double-blind trials. One trial involved children 5 to 11 years of age with four treatment groups: doubling the dose of an inhaled glucocorticoid (fluticasone propionate) to 100 μg twice daily; doubling the dose of fluticasone to 100 μg and adding a LABA (salmeterol) at a dose of 50 μg; quintupling the dose of fluticasone to 250 μg; or quintupling the dose of fluticasone to 250 μg and adding 50 μg of salmeterol. The other trial involved adolescents and adults 12 years of age or older with four treatment groups: adding twice-daily salmeterol at a dose of 50 μg to baseline twice-daily administration of fluticasone propionate at a dose of 100 μg; increasing the dose of fluticasone by a factor of 2.5 to 250 μg; quintupling the dose of fluticasone to 500 μg; or increasing the dose of fluticasone by a factor of 2.5 to 250 μg and adding 50 μg of salmeterol. The first step-up regimen differed between trials due to the lack of a low-dose inhaled glucocorticoid-LABA medication for children. The trials were otherwise identical in design and step-up dosing strategies.The run-in period consisted of treatment up to 10 weeks with an open-label low-dose inhaled glucocorticoid (50 μg of fluticasone propionate twice daily in children and 100 μg twice daily in adolescents and adults) in order to assess whether patients had inadequately controlled asthma prior to randomization. Eligible patients were then randomly assigned to the step-up treatment sequences, each lasting 14 weeks, in a four-way crossover design with add-on LABA, different strengths of increased doses of inhaled glucocorticoid, or an increased dose of inhaled glucocorticoid with LABA in dry-powder. The initial 2 weeks of each period were considered to be a washout period for the previous treatment and a wash-in period for the new regimen. The primary clinical outcome of each trial was a hierarchical composite measure that sequentially evaluated asthma exacerbations, asthma-control days, and lung function (percentage of the predicted FEV1) at the end of the 14-week treatment regimens to determine a differential response. Conclusions: In African American adolescents and adults with poorly controlled asthma, the addition of a LABA to inhaled glucocorticoid was more likely to produce superior responses than increasing the dose of an inhaled glucocorticoid. In contrast, almost half of the African American children with poorly controlled asthma had a superior response to an increase in the dose of an inhaled glucocorticoid and almost half had a superior response to the addition of a LABA.

  Study phs004585

• BIRC5 Upregulation Enhances DNMT3A-Mutant T-ALL Cell Survival and Pathogenesis

  The goal of this study was to determine how patients with T-ALL who have DNA methyltransferase 3 alpha (DNMT3A) mutations develop resistance to therapy. Since DNMT3A is a methyltransferase, we examined the effect of those mutations on epigenetic regulation using whole genome bisulfite sequencing (WGBS). We also assessed any changes in gene expression using RNA-sequencing. We found that T-ALL patients with DNMT3A mutations are resistant to apoptosis and some chemotherapies. WGBS showed that DNMT3A mutated patients clustered together by their epigenetic profile, which was associated with hypomethylation at TERT and HOX genes. RNA sequencing identified differences in JAK/STAT signaling.

  Study phs003623

• NHLBI TOPMed: Pulmonary Vascular Disease Phenomics Program (PVDOMICS)

  Pulmonary Vascular Diseases (PVD) are classified into 5 World Health Organization (WHO) groups using clinical presentation and hemodynamics. WHO 1 Pulmonary Arterial Hypertension (PAH) is rare with heritable [HPAH] known deleterious genetic variants associated with severe, progressive lethal disease, and disproportionately affects women. Little is known of the more common WHO 2-5, which have PVD related to heart, lung, blood and sleep (HLBS) diseases. Current classification and guidelines offer no PVD-specific therapy for WHO 2-5. They receive standard of care for their HLBS disease, although they suffer much higher mortality than their nonPVD HLBS counterparts. The NHLBI Pulmonary Vascular Disease OMICS (PVDOMICS) network was created to establish a deeply-characterized cohort of all PVD patients linked to biospecimens to develop new classifications by characteristics (phenomes) associated with mechanisms of pathogenesis using multi-omic studies. PVDOMICS is the most thoroughly phenotyped PAH cohort, and the only cohort to include all 5 WHO and nonPVD comparators [patients with HLBS diseases without PVD, and healthy controls)].All PVD and nonPVD comparator participants and healthy controls with blood samples were selected for sequencing in TOPMed.

  Study phs002451

• Pediatric Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV Infection (P2C2-BioLINCC)

  Data Access NOTE: Please refer to the "Authorized Access" section below for information about how access to the data from this accession differs from many other dbGaP accessions. Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from P2C2 include Serum. Please note that use of biospecimens in genetic research is subject to a tiered consent. Objectives: The objective of this study was to determine the prevalence and natural history of pulmonary and cardiac complications associated with HIV infection in utero, in infancy, and during early childhood.Background: In 1982, a year after the discovery of AIDS in adults, cases were described in children. Subsequent cross-sectional and short term longitudinal studies indicated that pulmonary and cardiac diseases contributed significantly to morbidity and mortality in children infected with the human immunodeficiency virus. This study aimed to investigate this hypothesis in a long-term cohort study.Participants: Children were enrolled at 5 geographically separated centers in Houston, TX, USA; Boston, MA; New York, NY; and Los Angeles, CA. The cohort of participants included two groups. Group I was composed of infants and children with vertically transmitted HIV-infection over 28 days of age. Children in Group I must have been born after April 1, 1985 except where vertical transmission of HIV infection could be documented with reasonable medical certainty and be more than 28 days old. Group II was composed of fetuses and infants of mothers infected with HIV.Participants in group I included children who were likely to develop extensive disease during the course of the study and therefore provide the opportunity to study the full range of cardiovascular and pulmonary complications associated with vertically-transmitted HIV-infection in children. Group II provided the opportunity to determine the earliest features of infection in the fetus and longitudinally to follow these effects in the child. Since a proportion of infants in this group were not infected, they represented a control group for the infected infants. Children in group I (n=205) were a median of 22.9 months of age at enrollment (1.7-166 months) of which 11.7% had asymptomatic infection and 88.3% presented with symptomatic infection. Among 600 infants born to HIV-1–infected women, 432 (72.0 %) were enrolled while their mothers were pregnant and 168 (28.0 %) before 28 days post partum. Among 93 HIV-1–infected infants, 29 (31.2 %) were enrolled postnatally (median, 12 days; range, 1 to 28). Design: In this prospective natural history study, research was conducted on the response of the immature lung to Pneumocystis carinii and other opportunistic lung infections, as well as on the etiology and pathogenesis of lymphocytic pulmonary disorders. The types, incidence, course, outcome, and origin of cardiac disorders were also determined. In addition to the pulmonary and cardiovascular measurements, data on the effects of co-infection with other viruses, CMV and EBV, were obtained.Enrollment of participants began in May 1990 and continued through April 1993 in Group I and through January 1994 for Group II. The cohort was followed at specified intervals for an additional three years beyond the end of recruitment for clinical examination, cardiac, pulmonary, immunologic, and infectious studies and for intercurrent illnesses. Follow-up ranged from 2.5 to 6.6 years. Conclusions: Vertically-transmitted HIV-1 infection is associated with persistent cardiovascular abnormalities identifiable shortly after birth. Irrespective of their HIV-1 status, infants born to women infected with HIV-1 have significantly worse cardiac function than other infants, suggesting that the uterine environment has an important role in postnatal cardiovascular abnormalities.

  Study phs004322

• Leukemia Relapse via Genetic Immune Escape after Allogeneic Hematopoietic Cell Transplantation

  Graft-versus-leukemia (GvL) reactions are responsible for the effectiveness of allogeneic hematopoietic cell transplantation as a treatment modality for myeloid neoplasia, whereby donor T- effector cells recognize leukemia neoantigens. However, a substantial fraction of patients experience relapses because of the failure of the immunological responses to control leukemic outgrowth. Here we demonstrate, through a broad immunogenetic study, that germline and somatic reduction of human leucocyte antigen (HLA) heterogeneity enhances the risk of leukemic recurrence. We show that preexistent germline-encoded low evolutionary divergence of class II HLA genotypes constitutes an independent factor associated with disease relapse and that acquisition of clonal somatic defects in HLA alleles may lead to escape from GvL control. Both class I and II HLA genes are targeted by somatic mutations as clonal selection factors potentially impairing cellular immune responses and responses to immunomodulatory strategies. These findings define new molecular modes of post-transplant leukemia escape contributing to relapse.The present dataset provides HLA peripheral blood and bone marrow samples supporting the genotyping studies performed for this research. This sample set originates from patients with acute myeloid leukemia or myelodysplastic syndromes receiving allogeneic hematopoietic cell transplantation and relapsing after transplant.

  Study phs003235

• Acute Respiratory Distress Network (ARDSNet) Studies 01 and 03 Lower Versus Higher Tidal Volume, Ketoconazole Treatment and Lisofylline Treatment (ARMA/KARMA/LARMA) (ARDSNet-ARMA/KARMA/LARMA-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-ARMA/KARMA/LARMA include plasma, serum and urine. Please note that use of biospecimens in genetic research is subject to a tiered consent. Objectives The ARDS Network is a consortium of clinical centers and a coordinating center to design and test novel therapies for the treatment of Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS). The primary objective of the KARMA trial was to investigate the efficacy and safety of Ketoconazole and Respiratory Management in the treatment of ALI and ARDS. The Ketoconazole arm of the study was later stopped due to an inability to show efficacy. Participants continued to be randomized to the respiratory management arms of the study (ARMA), which compared two ventilator strategies: a tidal volume of 6 mL/kg versus 12 mL/kg. The LARMA phase of the study investigated the efficacy of Lisofylline and Respiratory Management. Background Participants suffering from ARDS are extremely ill, require mechanical ventilation and, despite improvements in medical care and technology, had a mortality rate as high as 50 percent. An excessive inflammatory response is characteristic of ALI of which ARDS represents the most severe end of the pathophysiologic spectrum. The inflammatory response includes increased numbers of neutrophils activated to produce cytokines, proteases, and reactive oxygen intermediates. Pulmonary injury may also be enhanced by alveolar and tissue macrophages as a producer of vasoactive substances, neutrophil chemoattractants, and procoagulant substances. Ketoconazole, a synthetic antifungal imidazole, also has anti-inflammatory activities and may inhibit neutrophil recruitment via several different pathways known to be involved in the development of ALI and ARDS. Lisofylline causes a marked decrease in the circulating levels of the major oxidizable species of free fatty acids and also inhibits proinflammatory intracellular signaling. Mechanical ventilation in participants with ALI and ARDS have traditionally used tidal volumes of 10 to 15 ml per kilogram of body weight. These large tidal volumes are often necessary to achieve normal partial pressure of arterial carbon dioxide and pH, but may induce inflammatory responses through disruption of pulmonary epithelium and endothelium. Mechanical ventilation at lower tidal volumes may reduce injurious lung stretch and decrease the inflammatory response. Participants The Ketoconazole and Lisofylline trials were designed as 2 x 2 factorials and included 220 participants in each trial. A total of 860 participants were randomized into the ventilator management trial. Participants enrolled in the Lisofylline or Ketoconozole studies had to be concurrently enrolled in the ventilator management study and were first randomized into a ventilator strategy and then to drug or placebo. Conclusions Ketoconazole was found to be safe but did not reduce mortality, duration of mechanical ventilation, or improve lung function. Lisofylline was also found to be safe and to have no beneficial effect for participants with ALI or ARDS. Ventilation at lower tidal volumes resulted in reduced mortality and an increase in the number of days without ventilator support. (PMIDs: 10789668, 11902249, 10793162).

  Study phs003734

• Epigenomics of Prostate Cancer from Cell Free Plasma

  We sought to perform epigenomic characterization of prostate cancers by profiling circulating nucleosomes isolated from patient plasma using cell free chromatin immunoprecipitation followed by sequencing (cfChIP-seq). Our major findings include identification of prostate-cancer specific regulatory elements using a novel statistical method accounting for variable tumor DNA fraction in plasma, inferring transcription factor activity based on binding motif enrichment within regulatory elements, and epigenetically phenotyping patients based on clinical and genomic features. Data available in dbGaP will include cfChIP-seq and targeted sequencing from approximately 50 patients with a known diagnosis of cancer and healthy patient controls.

  Study phs003482

• PGE2-Driven Inhibition of T Cell Activation

  We aim to elucidate the functional effects of PGE2 and non-coding, inflammatory bowel disease (IBD)-associated genetic variants on T cells exposed to activation stimuli and other inflammatory mediators that are known to be overexpressed in IBD tissues and to influence the development, function, and plasticity of T cells, particularly Th17 cells. Using DOGMA-seq, a single-cell multi-omics approach, we profiled 171,829 T cells isolated from the peripheral blood of 25 healthy adult study subjects with ages 18-35 years at the time of recruitment. All participants were enrolled with informed consent under a research protocol approved by the University of Pittsburgh Institutional Review Board. Study subject phenotype data include self-reported age, gender, ancestry, and healthy status with no personal history of IBD or other chronic immune-mediated diseases, no known first-degree relatives with IBD, and no use of immunomodulatory or biologic medications. T cells were exposed to activation stimuli, IL-1β and IL-23 alone or in combination with PGE2, TGF-β, or both PGE2 and TGF-β. Sample-level metadata include T cell donor identifiers and cell culture treatment conditions.

  Study phs004468

• Jackson Heart Study (JHS-BioLINCC)

  Accessing Data: Please refer to “Authorized Access” below regarding accessing data through the BioData Catalyst ecosystem. The data from this accession is not available for download through dbGaP.Related Studies: Other Jackson Heart Study data available include: Imaging studies (JHS-Imaging), Genetics and genomics (The Jackson Heart Study, phs000286.v7.p2), and Collaborative Cohort of Cohorts for COVID-19 Research (C4R-JHS, phs002907.v1.p1): Jackson Heart Study (phs002907.v1.p1).Available Data: Data available for request include Jackson Heart Study visit 1-3 examination cycles, collated annual follow-up communication data through 2016, and follow-up for mortality, heart disease, and stroke events through 2014.Objectives: The objectives of the Jackson Heart Study are to: 1) investigate the associations of biological, psychosocial, and behavioral factors with the incidence atherosclerotic events and health outcomes in an African American cohort; and 2) increase access to and the participation of African American populations and scientists in biomedical research and professions.Background: It has long been recognized that African Americans share a disproportionate burden of deleterious health outcomes including diabetes, hypertension, kidney disease and early onset of cardiovascular disease. The Jackson Heart Study was initiated in 2000 to explore potential mechanisms and mediators of health outcomes in a large African American cohort. In addition, the JHS conducts a variety of community education and outreach activities to promote healthy lifestyles to reduce disease risk burden and student training programs to promote and support public health research.Participants: African American men and women, age 35-84 at entry. Of the 5306 cohort members enrolled in the study, the data repository contains data from 3,883 that provided informed consent to share their data with investigators not affiliated with the study.Design: Participants were enrolled in the study from 2000-2004 from urban and rural areas of three counties (Hinds, Madison and Rankin) in the Jackson, MS metropolitan statistical area. Participants were enrolled from each of 4 recruitment pools: a random sample component (17%), volunteer component (30%), currently enrolled in the Atherosclerosis Risk in Communities (ARIC) Study (31%), and secondary family members (22%). Recruitment was limited to non-institutionalized adult African Americans age 35-84 years, except in the family cohort where those age ≥21 years were eligible. The final cohort of 5,306 participants includes 6.59% of all African American residents aged 35-84 (N=76,426, US Census 2000). Data collection at the baseline exam included a medical history, physical examination, blood/urine analytes and interview questions on areas such as: physical activity; stress, coping and spirituality; racism and discrimination; socioeconomic status; and health care access.The current release of the Jackson Heart Study includes data collected at baseline, exam 2 (2005-2008), and exam 3 (2009-2013). Annual follow-up and surveillance of clinical cardiovascular events is ongoing.

  Study phs003740

• dbGaP Collection: Open Translational Science in Schizophrenia (OPTICS)

  Schizophrenia is a chronic, severe, disabling brain disorder that affects approximately 1% of the population worldwide. Epidemiologic studies have clearly demonstrated that genetics play a strong role in etiology, but the inheritance is very complex. Innovative analytic approaches and creative ways of combining disparate data sets will be necessary for making breakthroughs in identifying causal pathways and ultimately new drug targets. This dbGaP Collection consists of all genetic studies of schizophrenia available in dbGaP that have been consented for general research use. The goal is to facilitate identification of datasets with related scientific content in order to expedite the application process and ascertainment of datasets of interest for increased scientific discovery. The Open Translational Science in Schizophrenia (OPTICS) Project, was launched by Janssen Research & Development, LLC, part of the Janssen Pharmaceutical Companies of Johnson & Johnson, with a group of leading research organizations including the National Institutes of Health, Yale University School of Medicine, Rutgers University and the Harvard T.H. Chan School of Public Health, to create a new forum for collaborative analysis of Janssen's schizophrenia clinical trial data and other publicly available data about schizophrenia with the goal of creating new models for conducting research. The OPTICS project is one part of a larger effort at Janssen and other Johnson & Johnson research companies to share clinical trials data to enhance public health and advance science and medicine. Qualified investigators and physicians may apply for access to anonymized clinical trials data from Janssen, for more information please visit https://sites.google.com/site/opticsschizophrenia/.

  Study phs000887

• Childhood Cancer Data Initiative (CCDI): NCI-COG Pediatric MATCH Precision Medicine Clinical Trial

  The National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric Molecular Analysis for Therapy Choice (MATCH) trial provides a framework for biomarker-driven early phase trials of targeted therapies in pediatric and young adult cancer patients across the United States. Pediatric MATCH enrolled more than 1,300 patients with treatment-refractory cancers, offering access to molecular screening and investigational targeted therapies. To further advance this, matched diagnostic, refractory tumor, and normal samples from Pediatric MATCH cases were molecularly characterized, creating one of the largest comprehensive data sets available for childhood cancers. This analysis has the potential to provide novel insights into the genetics of refractory pediatric, adolescent, and young adult cancers, as well as inform potential therapeutic strategies. The following molecular characterization assays were performed: Tumor whole exome sequencing (WES) Tumor whole genome sequencing (WGS) Tumor RNA sequencing (RNA-seq) Blood whole exome sequencing (WES) Blood whole genome sequencing (WGS)

  Study phs002883

• Childhood Cancer Data Initiative (CCDI): CCDI Pediatric In Vivo Testing Program - Leukemia

  The goal of this study is to molecularly characterize a large panel of pediatric acute lymphoblastic leukemia (ALL) patient-derived xenografts (PDXs) previously established in immune-deficient mice. These PDXs are utilized as part of the NCI-funded Pediatric Preclinical In vivo Testing (PIVOT) program to identify novel agents and combinations. Biospecimen data include next-generation sequencing (RNAseq, whole exome sequencing, DNA copy number variation), whole-genome analysis of cytogenetic abnormalities, and DNA fingerprint for quality control.

  Study phs003164

• Reduction of Lethal Prostate Cancer Disparities in Underserved Hispanic/Latino Populations

  This pilot study investigated the genomic underpinnings of prostate cancer in Puerto Rican Hispanic/Latino men, a group disproportionately affected by this disease, in terms of incidence, mortality and aggressiveness. By examining tumors from 35 patients for specific genetic mutations and gene expression patterns using cutting-edge genomic sequencing, we aimed to identify distinct genetic profiles that could influence the course of the disease and its treatment. Our initial findings suggest the presence of unique genomic characteristics in this population, offering a promising avenue for developing personalized treatments that could reduce the health disparities observed in these men. This study underscores the importance of including diverse ethnic groups in genomic studies to ensure that the published data required for personalized cancer care are available.

  Study phs004487

• Global Endometrial DNA Methylation Analysis Reveals Insights into mQTL Regulation and Associated Endometriosis Disease Risk and Endometrial Function

  Endometriosis is a common gynecological disorder affecting 11% of reproductive aged women and is a leading cause of pain and infertility. We investigated global DNA methylation (DNAm) profiles in endometrium associated with endometriosis, menstruation, and genetic variation. Endometrial samples were collected from 984 patients with confirmed endometriosis (n=637) and women without endometriosis (n=347). Patients were recruited through the University of California San Francisco, USA, University of Melbourne, Australia, Endometriosis CaRe Centre in Oxford, UK, and EXPPECT Centre, The University of Edinburgh, UK, using the World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project (WERF EPHect) standardized protocols for tissue collection and processing, and participant characteristics and clinical annotation. DNA was extracted from samples and was use to generate DNAm data using the Illumina Infinium MethylationEPIC Beadchip and genotype data using the Axiom Precision Medicine Research array. Estimates from this study suggest that 15.4% of the variation in endometriosis is captured by DNAm. DNAm analysis identified significant differences in DNAm profiles and DNAm networks, associated with endometriosis, endometriosis sub-phenotypes, and menstrual cycle phases. Integration of DNAm and genetic data in a DNAm quantitative trait locus (mQTL) analysis identified 118,185 independent cis-mQTLs including 51 associated with risk of endometriosis highlighting target genes contributing to disease risk. This study identified novel factors affecting epigenetic regulation in endometrium associated with endometriosis risk and disease heterogeneity and provides an important data resource for reproductive medicine. Genotype data generated as part of this study are available on dbGaP and methylation data are available on GEO.

  Study phs003307

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

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

  Study phs003309

• The Genetic Evolution of Acral Melanoma

  Acral melanoma is a rare melanoma subtype arising on the sole, palm, or nail apparatus. We performed whole-exome sequencing (WES) for a cohort of 35 acral melanoma patients. For each patient, we sequenced multiple tumor areas representing different tumor stages, including the in situ and invasive portions of the primary tumor and available regional or distant metastases. Normal areas were included for all except one patient. We identified distinct evolutional trajectory compared to melanomas arising on the sun-exposed skin. Whole-genome sequencing and targeted sequencing were additionally performed for a subset of the samples. Particularly, in acral melanomas, complex genomic aberrations, characterized by clustered copy number transitions and focal amplifications, and telomerase reverse transcriptase (TERT) activating alterations occur very early during evolution, while MAP-kinase pathway mutations, such as BRAF V600E and NRAS hotspot mutations, can occur late and often result in striking intra-tumor heterogeneity.

  Study phs003451

• The Cancer Dependency Map (DepMap)

  The Cancer Dependency Map (DepMap) aims to accelerate precision cancer medicine by creating a comprehensive map of tumor vulnerabilities. The DepMap project genomically profiles a wide range of cancer models and characterizes them for their sensitivity to genetic and compound perturbations. The data is computationally analyzed to create a systematic overview of the genetic dependencies and compound sensitivities of cancer types and the predictive biomarkers that point to patient populations most likely to benefit from targeting of these vulnerabilities. The DepMap public portal has become a comprehensive resource to identify cancer vulnerabilities by providing datasets at scale, cutting-edge computational tools, and sophisticated visualization tools that together have accelerated the discovery of novel targets and biomarkers. Please visit Depmap.org to access the public portal.

  Study phs003444

• KDM6A Loss Triggers an Epigenetic Switch that Disrupts Urothelial Identity and Drives Cell Proliferation in Bladder Cancer

  Disruption of KDM6A, a histone lysine demethylase, is one of the most common somatic alternations in bladder cancer. How mutations of this chromatin modifier impact the epigenetic landscape to promote carcinogenesis is poorly understood. Here, we demonstrate that KDM6A loss triggers an epigenomic switch that disrupts urothelial identity and induces a neoplastic state characterized by increased cell proliferation. In bladder cancer cells with intact KDM6A, FOXA1 binds KDM6A at enhancers to activate genes instructing urothelial differentiation. In KDM6A-deficient cells, we observed simultaneous loss of FOXA1 target binding and genome-wide redistribution of the bZIP transcription factor ATF3, which in turn represses FOXA1 target genes and activates cell-cycle progression genes. Importantly, ATF3 depletion reverses the cell proliferation phenotype. These data establish that KDM6A loss creates an epigenetic state that drives tumor growth in an ATF3-dependent manner, forging a molecular vulnerability that can be targeted by novel therapeutic strategies.

  Study phs002801

• Inherited Genetic Susceptibility in Langerhans Cell Histiocytosis

  We recruited cases of Langerhans cell histiocytosis (LCH) who were recruited to the Children's Oncology Group Childhood Cancer Research Network, Project:EveryChild projects, or to a local patient biobank to conduct an expanded genome-wide association study for risk variants and to perform post-GWAS analysis of a previous hit in the SMAD6 gene. Publicly available control data were used for our analyses; however, here we provide the SNP array data and targeted SMAD6 sequence data for the LCH cases and some non-LCH cases included in the analysis.

  Study phs004547

• MP2PRT: Evaluation of an Inflammation Polygenic Risk Score (iPRS) to Predict Cancer Related Cognitive Impairment and Fatigue in Patients Receiving Chemotherapy for Non-Metastatic Breast Cancer in URCC0701 and URCC10055

  This study is a secondary analysis of cancer related cognitive impairment (CRCI) and cancer related fatigue (CRF) among participants in URCC0701 and URCC10055 from the University of Rochester NCI Community Oncology Research Program (NCORP) Research Base. CRCI and CRF are common, troublesome, and dose-limiting toxicities reported by patients undergoing breast cancer chemotherapy that have an etiologic basis linked to low-grade systemic inflammation. Chronic, low-grade systemic inflammation is, in part, genetically determined with common single nucleotide polymorphisms (SNPs) capturing variation across individuals. This study aimed to 1) determine whether an inflammation polygenic risk score (iPRS) is associated with CRCI or CRF, 2) determine whether the relationship between the iPRS and CRCI or CRF is modified by exercise at the time of cancer treatment, 3) identify SNPs associated with serum cytokines measured at the time of cancer treatment, and 4) identify novel CRCI- and CRF-associated risk SNPs via genome-wide association analyses. We found that there was a significant inverse correlation between the iPRS and change in fatigue score from pre-chemotherapy to post-chemotherapy while there was no statistically significant association between the iPRS and cognitive impairment score. The inverse relationship between the iPRS and fatigue may be explained in part by the finding that the iPRS was also significantly associated with greater pre-chemotherapy fatigue, suggesting that women with a genetic predisposition to low-grade systemic inflammation (i.e., high iPRS) have more fatigue at the time of breast cancer diagnosis and, therefore, are less likely to worsen over the course of treatment. In contrast, women with a low iPRS had significantly less fatigue pre-chemotherapy and a significant worsening of fatigue from pre- to post-chemotherapy. The relationship between the iPRS and fatigue remained after adjustment for patient and cancer treatment covariates and was most pronounced in women who reported regularly exercising for at least 6 months prior to starting their cancer treatment. Exploratory genome-wide analysis identified a novel risk locus on chromosome chr6q27, tagged by rs9365961, associated with CRCI. This locus is upstream of TBXT, which encodes an embryonic nuclear transcription factor previously associated with susceptibility to neural tube defects. The genome-wide SNP data, patient-reported CRCI and CRF outcome measures, and covariate data used in this analysis are available through dbGaP.

  Study phs003688

• Single Cell DNA Methylation Analysis for Forensic Epigenetics

  As part of the Epigenetic CHaracterization and Observation (ECHO) program, the Genomic Analysis Laboratory at the Salk Institute generated the DNA methylation profiles of certain PBMC cell types to determine the change in methylation levels before, during or after exposure to certain biological or chemical agents. Samples from individuals who either handled anthrax in controlled environments or who tested positive to MRSA, MSSA, HIV, COVID-19 or exposed to Flu virus or organophosphates, or control samples were used in single-nucleus methylation (snmC-seq) assays to quantify DNA methylation levels of cytosine residues of the DNA. Around 5-10% cytosine sites were sampled in the assay. Using computational analyses, regions in the genome differentially methylated in response to the exposure were identified. This information can be used to develop diagnostic tools to predict the type of infection or time since exposure.

  Study phs003204

• Childhood Cancer Data Initiative (CCDI): A Cohort of Hispanic Children with Acute Lymphoblastic Leukemia; Bloom Syndrome in a Mexican American Family with Rhabdomyosarcoma

  Retrospective case-control genetic study of Hispanic children with acute lymphoblastic leukemia (ALL) treated 1994-2013, comparing 14 treatment-related pancreatitis (TRP) cases to 46 treatment-matched controls without pancreatitis. Targeted sequencing of 23 genes (pancreatitis-related and asparagine-metabolism genes) was performed from post-remission blood DNA; select HLA types were inferred from whole-exome data in cases. CFTR and ASNS variants were enriched in TRP (notably CFTR V470M, OR 4.27, p=0.025).

  Study phs002823

• Genetics of Growth Rates in Induced Pluripotent Stem Cells

  We quantified induced Pluripotent Stem Cells (iPSC) growth using a time-lapse imaging-based growth Area-Under-the-Curve (gAUC) metric and examined its relationship with gene expression and genetic variation across cell lines. Our study utilized measurements derived from cellular imaging, SNP genotyping, bulk RNA sequencing (RNA-Seq), and both genome and exome sequencing. Our differential expression analysis identified thousands of differentially-expressed genes associated with iPSC growth rate and identified WDR54, TMEM250, and C2orf81 as having putatively damaging missense variants associated with reduced growth rate. We are providing individual-level SNP genotype, RNA-Seq, and whole genome sequencing (WGS) data for iPSC cell lines generated from 335 subjects of the iPSCORE, GENESiPS, and HipSci consortia.

  Study phs004457

• Exploration of the Biologic Basis for Underperformance of Oral Polio and Rotavirus Vaccines in Bangladesh

  Oral polio and rotavirus vaccines are significantly less effective in children living in the developing world. Environmental enteropathy, which is associated with intestinal inflammation, decreased absorption and increased permeability, may contribute substantially to oral vaccine failure in developing country settings. The primary objective of the study was to determine the association of environmental enteropathy with the efficacy of oral polio and rotavirus vaccines in children in Bangladesh. Secondary and exploratory objectives were designed to address other possible causes of oral vaccine underperformance including malnutrition, interference with maternal or breastmilk antibodies, changes in gut microbiota, and genetic susceptibility. The PROVIDE (Performance of Rotavirus and Oral Polio Vaccines in Developing Countries) study was structured as a 2x2 clinical trial with a prospective birth cohort enrollment of 700 infants and their mothers in the urban slum of Mirpur, Dhaka, Bangladesh. All children received the full series of Bangladesh's Expanded Program on Immunization vaccines, including oral polio vaccine (OPV) and followed for their first 2 years of life. Half the children were randomized to receive an inactivated polio vaccine (IPV) for their 4th dose at 39 weeks instead of the standard OPV dose. In the other trial, half the infants received the 2-dose rotavirus vaccine (Rotarix) with delayed dosing at 10 and 17 weeks of age. A detailed description of the study design and procedures can be obtained from PROVIDE methods publication: Kirkpatrick B.D., Colgate R.E., Mychaleckyj J.C., Haque R., Dorothy D.M., Carmolli M.P., et al., 2015, PMID: 25711607 The Poliovirus trial and results are described in Mychaleckyj et al, 2016, PMID: 26643930 The Rotavirus trial and results are described in Colgate et al., 2016, PMID: 27217217 The PROVIDE infants were genotyped on a custom Affymetrix Axiom array (30K SNPs) at the University of Virginia Center for Public Health Genomics; and on a pre-production version of the Illumina MEGA v2 chip at the Wellcome Trust Sanger Institute, UK. The latter genotyping was performed under the auspices of the VaccGene Consortium. Molecular data on a sub-set of subjects (22) was funded by R21 AI103536 (to C.G.). Analyses are ongoing to identify variants associated with the included phenotypes. The genotyping methods and analysis are described in PMID: 29514873.

  Study phs001478

• Childhood Cancer Data Initiative (CCDI): Metastatic Osteosarcoma snMultiome Profiling

  Metastatic osteosarcoma is an aggressive bone malignancy affecting pediatric, adolescent, and young adults. While recent research has increasingly focused on understanding the complex biology of the osteosarcoma microenvironment, the tumor vasculature is understudied, especially in the context of metastatic disease. To address this, we performed single-nuclei multi-ome (RNA+ATAC) sequencing on a cohort of 24 human metastatic osteosarcoma specimens. Our data shows that endothelial cells universally exhibit a hybrid endothelial–mesenchymal state consistent with endothelial-to-mesenchymal transition (EndMT). Additionally, we uncovered that a subset of diploid endothelial cells adopts an osteoblastic cell fate as evidenced by gene expression and gene regulatory network (GRN) analysis. Joint copy-number analysis of our dataset identified a subset of osteosarcoma cells with endothelial transcriptional programs and GRNs, indicative of vascular mimicry. In vitro assays and in vivo lineage tracing experiments using syngeneic murine models validated both vascular mimicry and endothelial to-osteoblastic transdifferentiation. Collectively, these findings highlight the remarkable plasticity and lineage infidelity of both endothelial and osteosarcoma cells in patient specimens and a metastatic syngeneic murine model, provide novel insights into the functional role of endothelial cells in the metastatic osteosarcoma microenvironment, and challenge current understanding of osteosarcoma biology.

  Study phs004490

• OurHealth - Cardiovascular Disease in South Asians

  The OurHealth Study aims to build a biobank comprising South Asian samples from participants residing in the United States. Primary objectives are to (1) identify genetic and non-genetic drivers of cardiometabolic disease in South Asians, (2) engage participants and researchers in scientific advances and research opportunities to accelerate discovery, and (3) assess the impact of returning polygenic risk scores for cardiovascular-related health conditions. Participants use a web-based platform to complete electronic informed consent, and contribute data via (1) online health surveys, (2) mailed saliva biospecimens for sequencing, and (3) optional electronic health record sharing. Surveys capture medical history, medication data, lifestyle factors, family history, mental health history, and detailed information about cultural and ancestral background. Biospecimens, procured via saliva self-collection kits, undergo DNA isolation and are sequenced using the "blended genome exome" (BGE) method, which consists of sequencing on the NovaSeqX 10B Flowcell followed by Dynamic Read Analysis for GENomics (DRAGEN) analysis for alignment to GRCh38, mapping, and variant calling. BGE uses low-coverage whole genome sequencing (lcWGS) (2-3x) combined with deep-coverage exome sequencing (30-40x), improving on SNP arrays for common variant imputation across European and non-European populations while also capturing rare coding variants. Relative to array genotyping, coverage, genotyping breadth, imputation generalizability, and cost are more optimal.BGE requires imputation for which the 1000G + HGDP reference panel was used, and GLIMPSE2 was used for imputation emitting genotyping dosages (i.e., 0-2 multimodal continuous). Quality control (QC) included the following procedures. Sample QC excluded those with mean coverage 3% contamination from FREEMIX/VerifyBamID, sex aneuploidy and genotype/phenotype sex-mismatch due to potential phenotyping errors, fingerprinting discordance, and sample metric-level outliers were ancestry-aware, given expected distribution differences. Variant QC metrics including allele frequencies, imputation INFO scores, and Hardy-Weinberg Equilibrium (HWE) p-values are provided with the data; the genotype files provided are not filtered.For more information about the OurHealth study, navigate to the OurHealth study website. For more information about the OurHealth dataset, including working with OurHealth data in AnVIL, navigate to the PRIMED Consortium OurHealth webpage.

  Study phs003821

• Blood and Marrow Clinical Trials Network - Multicenter Phase II, Double-blind Placebo Controlled Trial of Maintenance Ixazomib After Allogeneic Hematopoietic Stem Cell Transplantation for High Risk Multiple Myeloma (BMT CTN-1302-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions.ObjectivesTo evaluate the efficacy of ixazomib maintenance therapy after reduced-intensity conditioning allogeneic stem-cell transplantation from HLA-matched donors in patients with high-risk multiple myeloma.BackgroundMultiple myeloma (MM) is considered incurable using conventional agents. High-dose chemotherapy with autologous hematopoietic cell transplantation (HCT) is considered the standard of care in transplant eligible patients. However, progression-free survival (PFS) remains at 40 to 50 months, even with lenalidomide maintenance. Myeloma patients with high-risk disease, commonly defined as the presence of high-risk cytogenetics or fluorescence in situ hybridization (FISH) findings such as 13q deletion by conventional cytogenetics, t(4;14), t(14;16), or del(17p), have much shorter PFS with inferior survival. While there is clinical data on proteasome inhibitors and immunomodulatory agents, there remains a significant unmet need to mitigate disease relapse and improve survival in high-risk patients.The BMT CTN 1302 study was initiated to determine if the addition of bortezomib to the conditioning regimen would optimize the anti-myeloma effect of fludarabine/melphalan and if post-HCT maintenance with the oral proteasome inhibitor, ixazomib, would further reduce the risk of disease relapse.ParticipantsEligible patients were age 18 to 70 years with a 6/6 sibling donor matched for HLA-A, -B, and HLA-DRB1; or an 8/8 related (other than a sibling) or unrelated donor matched for HLA-A, -B. -C, and -DRB1.Eligible disease conditions were (1) high-risk MM in partial response (PR) or better with no prior progression and ≤24 months from auto-HCT (single or planned tandem), or ≤24 months from initiation of systemic antimyeloma therapy with no auto-HCT; (2) high-risk MM in very good partial response (VGPR) or better with 1 prior progression occurring ≤24 months after auto­HCT (single or planned tandem), or ≤24 months after initiation of systemic antimyeloma therapy with no auto-HCT; (3) standard-risk MM in VGPR or better with 1 prior progression occurring ≤24 months from auto-HCT (single or planned tandem): and (4) Plasma cell leukemia (PCL) in VGPR or better with no prior progression and ≤18 months after auto-HCT, or ≤18 months after initiation of systemic anti-PCL therapy with no auto-HCT. High-risk MM was defined as one or more of the following detected at any time prior to enrollment: deletion of chromosome 13 by conventional karyotyping, hypodiploidy, chromosome 1q amplification, 1p deletion, t(4;14), t(14;16), t(14;20), or deletion of chromosome 17p by FISH or conventional karyotyping, or high-risk criteria based on gene expression profiling (GEP).Of the 52 enrolled patients who underwent allo­HCT, 43 proceeded to randomization. 21 patients were randomized to the ixazomib arm, and 22 patients were randomized to the placebo maintenance arm.DesignBMT CTN 1302 was a randomized phase 2, double-blinded, multicenter trial. The conditioning regimen consisted of fludarabine 30 mg/m2i.v. (reduced to 24 mg/m2 for creatinine clearance 40 to 70 mL/minute) from day -6 to day -3, melphalan 70 mg/m2i.v. on days -4 and -3, and bortezomib 1.3 mg/m2i.v. on day -3. The initial patients also received bortezomib on days +1, +4, and +7 after transplantation, but this was discontinued with a protocol amendment because of toxicity concerns. GVHD prophylaxis was provided with a combination of tacrolimus and methotrexate. Between day +60 and day +120 post-allo-HCT, eligible patients were randomized to either ixazomib maintenance therapy or placebo. The starting dose of ixazomib was 3 mg orally once daily on days 1, 8, and 15 of a 28-day cycle. After 3 cycles, the dose was escalated to 4 mg/day. A total of 12 cycles was planned. Ixazomib dosage adjustments were made for toxicities.The primary endpoint was PFS as a time to event endpoint from randomization. Secondary endpoints included GVHD, overall survival, toxicity, infection, and quality of life.ConclusionsBMT CTN 1302 demonstrated the feasibility of Flu/Mel/Bort reduced-intensity conditioning (RIC) regimen followed by HLA-matched related or unrelated donor HCT without post-HCT bortezomib for high-risk MM. The study was limited by early closure, which diminished the power to detect differences between the two randomized arms.Bashir Q, Nishihori T, Pasquini MC, et al. A Multicenter Phase II, Double-Blind, Placebo-Controlled Trial of Maintenance Ixazomib After Allogeneic Transplantation for High-Risk Multiple Myeloma: Results of the Blood and Marrow Transplant Clinical Trials Network 1302 Trial. Transplant Cell Ther. 2023;29(6):358.e1-358.e7. doi:10.1016/j.jtct.2022.07.007

  Study phs004705

• BLUE CORAL: Biology and Longitudinal Epidemiology of PETAL COVID-19 Observational Study

  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.Available Data: Long Term Follow-up data has been added with version 2. Biospecimens: Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from PETAL BLUE CORAL include: Bronchial Lavage, Plasma, Tracheal Aspirate, Urine, Whole Blood Buffy Coat, DNA, Plasma, Serum, Urine, and Whole Blood. Please note that use of biospecimens is tiered for both non-genetic and genetic research.Objectives: To measure the incidence and changes over time in symptoms, disability, and financial status after COVID-19–related hospitalization.Background: For many individuals, the effects of COVID-19 persist after the acute phase and result in prolonged symptoms and disability. This has led to widespread efforts to characterize the epidemiologic characteristics of such post-COVID-19 sequelae. However, accurate data were limited, hindering the ability to counsel patients, caregivers, and policy makers and to plan relevant recovery-focused clinical research. Thus, the BLUE CORAL study was intended to address the knowledge gaps and provide critical data to help guide clinical care, public health, and scientific efforts.Participants: A total of 1376 COVID-19 patents were enrolled, with 825 (444 male, and 379 female) that completed at least one follow-up survey.A subset of the BLUE CORAL adult participants were enrolled in the extension study, FIRE CORAL. FIRE CORAL was a multicenter prospective cohort study of participants recovering from COVID-19 disease after discharge from the hospital. Design: BLUE CORAL was a prospective cohort study. Participants were enrolled between August 24, 2020, and July 20, 2021, with follow-up occurring through March 30, 2022. Posthospital surveys were administered by trained interviewers in English or Spanish to patients or their proxies at 1, 3, and 6 months after enrollment. Cardiopulmonary symptoms were assessed using the Airways Questionnaire 20, the Kansas City Cardiomyopathy Questionnaire, and the Seattle Angina Questionnaire. Fatigue was assessed using the Patient Health Questionnaire-9. Disability was assessed by self-report of limitations in activities of daily living (ADLs) or instrumental activities of daily living (IADLs). Financial problems were assessed using the World Health Organization Disability Assessment Schedule 2.0 question and questions regarding job changes, time off work, and insurance coverage developed with the Mi-COVID-19 study using qualitative interviews. Quality of life was measured using the European Quality of Life 5-dimension 5-level instrument.The primary outcomes were new or worsened cardiopulmonary symptoms, financial problems, functional impairments, perceived return to baseline health, and quality of life. Symptoms that were not present before hospitalization or specifically reported as increased in severity were counted as new or worsened. Conclusions: The findings of this cohort study of people discharged after COVID-19 hospitalization suggest that recovery in symptoms, functional status, and fatigue was limited at 6 months, and some participants reported new problems 6 months after hospital discharge.

  Study phs003419

• Uncovering Gene Regulatory Differences between Human and Chimpanzee Neural Cells

  A major challenge in human evolutionary biology is to pinpoint the genetic differences that underlie phenotypic changes in the human lineage, such as increased neuron number and a prolonged period of neuronal maturation. Here, we used human-chimpanzee tetraploid cells to distinguish changes in gene expression due to cis-acting sequence variants that change local gene regulation, from trans expression changes due to species differences in the cellular environment, in neural progenitor cells and excitatory neurons using RNA-seq and ATAC-seq. Using a CRISPR inhibition screen with scRNA-seq, transcription factor motif analyses with CUT&Tag, and downstream single-locus studies with RNA-seq, we further characterized cis-acting gene regulatory differences, including changes to FOS, TNIK, FOSL2, and MAZ, that influence neurogenesis and neuronal maturation. This study identifies specific genomic changes that may contribute to human neural specializations and provides a general framework for understanding genetic differences that underlie human traits.

  Study phs004053

• NHLBI Growth and Health Study (NGHS-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions.ObjectivesTo investigate racial differences in dietary, physical activity, family, and psychosocial factors associated with the development of obesity from pre-adolescence through maturation between African-American and white girls. Secondarily, the NGHS sought to examine the effects of obesity on cardiovascular disease risk factors.BackgroundObesity is a major contributing factor to several predictors of coronary heart disease such as hypertension, a poor lipid profile and diabetes. Both genetic and environmental factors play a significant role in the development of obesity, and there is evidence to suggest that obesity in childhood will likely carry over into adulthood. Prevention of obesity in early childhood could provide significant long term health benefits. A greater understanding of the factors contributing to childhood obesity is required for the establishment of effective weight reduction intervention programs. To this end, the NHLBI Growth and Health Study was initiated in 1985 as a multicenter study of the development of obesity among black and white pre-adolescent girls.ParticipantsThe NHLBI Growth and Health Study recruited girls 9 and 10 years of age in two communities (Richmond, California and Cincinnati, Ohio) and also from families enrolled in a health maintenance organization in the Washington, D.C. area. A total of 2,379 girls were enrolled in the study between 1987-88 and were followed for 9 years. Slightly more than half of the cohort was African-American. Subjects had annual examinations, and data collected included: physical examination, anthropometric measurements, dietary information including food pattern and nutrient intake, physical activity, lipid, lipoprotein, and apolipoprotein profiles, family socioeconomic status, and psychosocial information.

  Study phs004467

• Trio Analysis of Recurrent Pregnancy Loss Integrated Bioinformatics Genomics Study (TRIOS)

  The overall goal of the study “Trio Analysis of Recurrent Pregnancy Loss Integrated Bioinformatics Genomics Study (TRIOS)”, supported by NICHD (5R01HD105256-04), is to identify genetic risk factors associated with pregnancy loss. The dataset has been derived from multi-site collection of clinical information and samples from families affected by recurrent miscarriages. Genome sequencing has been performed on euploid product of conception (POC) samples and biological parent(s), including quad families (mother, father, and two POCs), trios (mother, father, and POC), and duos (a parent and POC). DNA from parental blood or saliva and POC DNA from chorionic villi tissue, fetal organ tissue or amniotic fluid were used for Genome sequencing. A panel of fifteen short tandem repeat (STR) polymorphic markers was used to confirm biological relatedness in each family. Genome sequencing libraries were prepared using the Kapa EvoPlus V2 library preparation kit (Roche). Genome sequencing was performed using the Illumina NovaSeq 6000 instrument. Variant call format (VCF) files for single nucleotide variants (SNV) are provided in this dataset.

  Study phs003971

• Single-Cell eQTL and isoQTL Profiling of Normal Lung Tissues from Never-Smoking Korean Women

  This study was performed to identify cell-type-specific genetic regulation of gene expression in human lung tissues. All 129 participants are Korean female never-smokers who underwent lobectomey with a curative aim for lung adenocarcinoma at Yonsei University Health System, Severance Hospital, in Seoul, Korea. We performed single-cell short-read and long-read RNA sequencing of barcode-matched cDNAs from tumor/lesion-distant normal lung tissues. Germline genotypes were profiled using matched blood DNA on Illumina Infinium Global Screening Array (v2) and imputed using 1000 Genomes (v5) EAS populations as a reference. We identified cell-type-specific eQTLs and full-length isoform level isoQTLs using pseudobulk linear model or negative binomial model from each lung cell type. Individual-level imputed germline genotypes will be available through dbGaP.

  Study phs004420

• NIMH Alzheimer's Disease Genetics Initiative Family-Based Whole Genome Sequencing Dataset

  Samples were obtained at three sites with funding from the National Institute of Mental Health (NIMH). This was a family study known as the National Institute of Mental Health (NIMH) Genetics Initiative. We have been working with these samples since the study's inception and have carried out several GWAS studies on these samples as part of 2R01MH060009-14 “Identification of Functional Genome Variants in Alzheimer's Disease”. Several years ago we performed one of the first sets of whole genome sequencing, which was based on the full NIMH family-based dataset using funding from Cure Alzheimer's Fund. Whole genome sequencing was done at Illumina, Inc. Variants were jointly called for each family using FreeBayes (v0.9.9.2-18) and GATK (v3.0) best practices method as part of the bcbio-nextgen workflow.This study shares overlapping subjects with phs000483. Subjects with identical dbGaP subject IDs represent the same individuals across both studies. phs000483.v1.p1 provides SNP array data, while the current study provides whole genome sequencing data.

  Study phs004293

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

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

  Study phs003551

• Spindle Assembly Checkpoint Competency Determines Sensitivity to KIF18A Inhibition in Small-Cell Lung Cancer

  This study examined the biological determinants of response to KIF18A inhibition in small-cell lung cancer (SCLC), a chromosomal instability-high cancer. The study used patient tumor datasets, SCLC cell line models, genomic and transcriptomic profiling, drug sensitivity testing, live-cell imaging, genetic perturbation, and pharmacologic inhibition to assess chromosomal instability, mitotic regulation, and spindle assembly checkpoint function. Although KIF18A expression was elevated in SCLC and associated with chromosomal instability, proliferation, and neuroendocrine transcriptional programs, these features did not predict drug sensitivity. Instead, response to KIF18A inhibition was primarily determined by spindle assembly checkpoint competency, with SAC-proficient cells undergoing sustained mitotic arrest and apoptosis and SAC-defective cells showing resistance. The dbGaP-accessible data will include de-identified RNA-seq-derived expression data and associated sample metadata for the NIH/NCI patient-derived SCLC cell line component of the study. These data were used to assess selected gene expression features, including KIF18A-related expression and a neuroendocrine-related score based on Neuroendocrine-associated genes. No direct participant identifiers will be included.

  Study phs004869

• REDIAL RNASeq Study

  We seek to characterize the genomics of acute lymphoblastic leukemia (ALL) in children of Hispanic ethnicity. We hypothesize that certain molecular subtypes of ALL are over- or under-represented in Hispanics compared to patients of other genetic ancestries. Utilizing the REDIAL Study cohort, we performed genomic profiling (e.g., RNAseq) to determine fusion genes, global expression profiles, genetic ancestry, and other molecular features.

  Study phs004230