3613 results for "*geneti*"

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• Somatic Mutations and Their Etiological Determinants for Breast Cancer in African American Women (B-CAUSE Study)

  The breast cancer health disparity between women of African ancestry (AA) and European ancestry (EA) remains a major public health challenge in the United States. AA women are afflicted by higher rate of triple-negative breast cancer (TNBC) and bear the highest mortality rate of all populations from the disease. Even within TNBC, some data suggest that AA women have poorer outcomes than EA women. Mounting evidence points to population differences in cancer biology, a fundamental question that remains unsettled. The disparity also manifests in representativeness in tumor sequencing projects, due to the low inclusion of AAs in genomic studies. A recent analysis of The Cancer Genome Atlas (TCGA) data revealed that the number of AA cases sequenced was sufficient only for studying frequently mutated genes (≥10%), and the power was worse for TNBC as a separate disease entity. As a result, the breast tumor mutational landscape elucidated to date is derived mostly from EA cases, and may not necessarily represent AA cancer genomes. Moreover, as discovery potential for new driver genes has come close to a plateau, cancer in AAs derived from distinct genetic and environmental contexts may provide a powerful venue for discovering mutations that are rare in EA cases. This is showcased in recent studies in colon and prostate cancer. Thus, we carried out a collaborative project, B-CAUSE, to characterize the mutational landscape of AA breast cancer genomes by pooling resources from five established studies, including the Women's Circle of Health Study (WCHS), the Black Women's Health Study (BWHS), the Southern Community Cohort Study (SCCS), the Nashville Breast Health Study (NBHS), and the Southern Tri-State Breast Health Study (STSBHS). This effort has created the largest AA-specific breast tumor mutation dataset to date in an efficient manner. The data deposited here are from the whole-exome sequencing (WES) of matched tumor-normal pairs of 462 TNBC in AA women from the B-CAUSE Study.

  Study phs003962

• A Scalable, GMP-Compatible, Autologous Organotypic Cell Therapy for Dystrophic Epidermolysis Bullosa

  Gene editing in induced pluripotent stem (iPS) cells has been hailed for enabling new cell therapies for various monogenetic diseases including dystrophic epidermolysis bullosa (DEB). However, manufacturing, efficacy, and safety roadblocks have limited the development of genetically corrected, autologous iPS cell-based therapies. Dystrophic Epidermolysis Bullosa Cell Therapy (DEBCT), is a new generation, Good Manufacturing Practice-compatible (cGMP), reproducible, and scalable platform to produce autologous clinical-grade iPS cell-derived organotypic induced skin composite (iSC) grafts to treat incurable wounds of patients lacking type VII collagen (C7). DEBCT uses a single step, combined, high-efficiency reprogramming, and CRISPR-based genetic correction to generate genome scar-free, COL7A1 corrected clonal iPS cells from primary patient fibroblasts. Validated iPS cells are converted into epidermal, dermal, and melanocyte progenitors with a novel 2D organoid differentiation protocol, followed by CD49f enrichment and expansion to minimize maturation heterogeneity. iSC product characterization by single cell transcriptomics was followed by mouse xenografting for disease correcting activity at 1 month and toxicology analysis at 1-6 months. Culture-acquired mutations, potential CRISPR-off target effects, and cancer-driver variants were evaluated by targeted and whole genome sequencing. iPS cell-derived iSC grafts were reproducibly generated from four recessive DEB patients with different pathogenic mutations. Organotypic iSC grafts onto immune-compromised mice developed into stable stratified skin with functional C7 restoration. Single cell transcriptomic characterization of iSCs revealed prominent holoclone stem cell signatures in keratinocytes and the recently described Gibbin-dependent signature in dermal fibroblasts. The latter correlated with enhanced graftability. Multiple orthogonal sequencing and subsequent computational approaches identified random and non-oncogenic mutations introduced by the manufacturing process. Toxicology revealed no detectable tumors after 3-6 months in DEBCT-treated mice. In conclusion, DEBCT successfully overcomes previous roadblocks and establishes a robust, scalable, and safe cGMP manufacturing platform for the production of a CRISPR-corrected autologous organotypic skin graft to heal DEB patient wounds.

  Study phs003271

• A Depression and Opioid Pragmatic Trial in Pharmacogenetics (ADOPT PGx): Chronic Pain Trial

  This study was comprised of three separate pharmacogenetic trials grouped into a single protocol due to similarities in the intervention, the hypotheses, and the trial design. The three trials are the Acute Pain Trial, the Chronic Pain Trial (this study), and the Depression Trial. Participants could enroll in only one of the three trials. Trial-specific outcomes will be compared between participants in the intervention arm and control arms who have an actionable phenotype.Chronic Pain Trial: A prospective, multicenter, two arm randomized pragmatic trial. Participants meeting eligibility criteria were randomly assigned to either immediate pharmacogenetic testing and genotype-guided opioid therapy (Intervention arm) or standard care with 6-month delayed pharmacogenetic testing (Control arm). Actionable phenotypes are defined as CYP2D6 intermediate metabolizers (IMs) and poor metabolizers (PMs) (i.e. CYP2D6 activity score ≤ 0.75) for the chronic pain trial. Approximately 1050 participants seen in primary care or pain specialty clinics who are already prescribed or anticipated to be prescribed tramadol, codeine, or hydrocodone for pain control.

  Study phs004059

• Pomalidomide for the Treatment of Bleeding in HHT (PATH-HHT)

  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 determine efficacy (reduction in severity of epistaxis), tolerability, and improvement in quality of life of pomalidomide compared to placebo after 24 weeks of treatment.Background: This study addresses the efficacy of pomalidomide in the treatment of epistaxis in patients with Hereditary Hemorrhagic Telangiectasia (HHT) who have anemia and/or require blood transfusion or iron infusion for treatment of bleeding-induced anemia and iron deficiency. HHT (also known as Osler-Weber-Rendu disease) is an inherited bleeding disorder. Over 95% of patients develop recurrent epistaxis, which may be severe and result in chronic anemia, need for iron infusions and blood transfusions, substantial psychiatric comorbidity (including depression and post-traumatic stress disorder) and reduction in health-related quality of life (HRQoL). HHT is clinically diagnosed using the Curacao criteria, which consists of 1) spontaneous and recurrent epistaxis, 2) telangiectasias at characteristic sites, 3) visceral arteriovenous malformations (AVMs) or telangiectasias, and 4) a first degree relative with HHT (inheritance is usually autosomal dominant). Patients with three criteria are considered to have definite HHT, and those with 2 criteria probable HHT. HHT affects approximately 1 in 3,800 individuals. Significant manifestations of HHT often do not appear until the third or fourth decades, sometimes later.Participants: 144 patients from 11 clinical centers were enrolled.Design: This is a multi-center, double blind, randomized placebo-controlled trial that investigated the efficacy and safety of pomalidomide in patients with HHT and chronic epistaxis leading to iron-deficiency anemia or requiring intravenous iron infusions or blood transfusion.Screening evaluation included the Epistaxis Severity Score (ESS) with three-month recall, which reflected the patient's history of epistaxis and bleeding over the prior three months, as well as detailed review of iron infusion and red cell transfusion over the preceding six months. Eligible patients were provided a diary to record the duration of each epistaxis event that occurred during the 4 weeks prior to the baseline visit, and then returned for the baseline randomization visit, at which time patients underwent genetic testing, if this had not been previously performed, and completed an ESS with 4-week recall and quality of life assessments. Patients were randomized 2:1, stratified by study site, to either pomalidomide 4 mg/day or matching placebo during each of six 28 day cycles (24 weeks). Patients were seen every four weeks during treatment, and at a 4-week post-treatment follow-up visit to measure the ESS (with 4-week recall), laboratory assessments including iron stores and need for iron infusion, CBC, and metabolic profile. Patients were assessed for adverse events (AE) throughout the study. Treatment dosage could be reduced, or temporarily or permanently discontinued following AE-specific guidelines related to fatigue, cytopenias or other toxicities.Quality of life assessments were completed at baseline, and the 12- and 24-week visits, and the 4-week post-treatment follow-up visit using validated NIH instruments of 1) Neuro-QOL satisfaction with social roles and activities, 2) PROMIS emotional distress – depression, and 3) PROMIS fatigue, and the HHT-specific quality of life instrument developed specifically for this study. The effect of pomalidomide on duration of epistaxis was assessed via diary between weeks 8-12, 20-24 and the 4-week post-treatment period.Conclusions: Among patients with HHT, pomalidomide treatment resulted in a significant, clinically relevant reduction in epistaxis severity. No unexpected safety signals were identified (Al-Samkari et al., 2024; PMID: 39292928)

  Study phs003948

• Human Epilepsy Genetics: Mosaic Mutations in Focal Epilepsy

  This study investigates the role of somatic mosaic mutations in human focal epilepsies, including focal cortical dysplasia (FCD) and mesial temporal lobe epilepsy (mTLE). It leverages genomic and single-cell transcriptomic data from surgically resected brain tissue to identify pathogenic variants and characterize their effects on specific cell types and molecular pathways. The study employs methods such as deep whole-exome and targeted sequencing, single-nucleus RNA sequencing (snRNA-seq), and integrated genotype-transcriptome profiling (e.g., GO-TEN) to define the cellular architecture and functional consequences of mosaic mutations. Data generated under this project aim to elucidate mechanisms of epileptogenesis and support discovery of potential therapeutic targets.

  Study phs004124

• Single Cell Profiling of Transcriptional and Epigenetic Differences Between Virus and Severity in Infants Infected with SARS-CoV-2 and RSV

  This study compares the transcriptional and epigenetic immune responses to SARS-CoV-2 and RSV in infant PBMCs across different disease severities. Infants and young children hospitalized with SARS-CoV-2 (n=30) or RSV (n=19) were enrolled from February 2019 through January 2022. Blood samples were obtained within 24 hours for peripheral blood mononuclear cell isolation. Healthy controls (n=17) enrolled pre COVID-19 pandemic were also enrolled for baseline comparisons. Infants with COVID-19 were classified as subacute (n=9); moderate (n=12), or severe (n=9) based on level of clinical care, viral loads, and days post-exposure to COVID-19. Four of the five infants with severe COVID-19 were treated with dexamethasone and were reclassified as severe treated. Infants with RSV were classified as mild (n=5), moderate (n=7), or severe (n=7) based on an established clinical disease severity score designed for assessing severity in RSV. In total, 66 samples were included for scRNA-seq, and 51 samples were included for snATAC-seq. New data to be submitted from this study includes data for 27 scRNA-seq and 53 snATAC-seq. Note: Two additional samples (1 healthy control and 1 subacute COVID-19) were later determined to have signatures of viral infection (healthy control sample) or co-infection with another virus (subacute COVID-19 sample) during downstream analysis. These samples (adding up to the total of 68 scRNA-seq and 53 snATAC-seq) were included for reproducibility.

  Study phs003859

• Remodeling of the Immune System across Human Lifespan at Single Cell Resolution

  The human immune system undergoes dynamic remodeling from infancy through old age. We profiled PBMCs from 167 healthy individuals (ages 2 months to 105 years): infants (n=36), children (n=26), adolescents (n=20), young adults (n=24), middle aged (n=16), older adults (n=33) and oldest old (n=12) using scRNA seq and snATAC seq (n=23). MAIT and γδ T cells showed a “rise and fall” pattern, rising in childhood, peaking in young adulthood, and declining with age. Conventional CD8⁺ T cells were most profoundly altered with age, with decreasing naïve and increasing GZMK⁺ and TEMRA cells. The oldest old had increased TEMRA, adaptive NK, and KLRF1⁺ γδ T cells. Infants showed increased CD16⁺ monocytes and pDCs, constitutive interferon stimulated gene expression, and expanded SOX4⁺ naïve T cells. Inflammatory and stress response pathways increased with age, while interferon pathways declined. This map provides insights into human immune system dynamics across the lifespan, emphasizing unique features of the infant immune system. This study includes 95 samples generated in-house (this submission) and 72 samples obtained from four publicly available datasets, for a total of 167 samples. Participants were grouped into seven age categories: • Infants (2 months–2 years): n = 36 • Children (2–12 years): n = 26 • Adolescents (12–18 years): n = 20 • Young adults (18–40 years): n = 24 • Middle-aged adults (45–65 years): n = 16 • Older adults (65–85 years): n = 33 • Oldest old (85–105 years): n = 12 The public datasets are described below: • Deng et al. (GSE231906): n = 21 • Wang et al. (syn61609846): n = 45 • Wang et al. (GSE168732): n = 3 • Zhong et al. (GSE206295): n = 3 For epigenetic analyses, single nucleus ATAC sequencing (snATAC seq) data from 23 healthy PBMC donors were utilized, distributed across age groups as follows: • Infants and children: n = 9 • Adolescents: n = 3 • Young and middle aged adults: n = 6 • Older adults: n = 5 The raw data (fastq files) from participants HY13, HY18 and HY19 will not be included in the dataset per consent. HI17 and HI23 samples originate from the same infant collected at two time points (2 months for HI17 and 11 months for HI23).

  Study phs003259

• Fusion Transcription Factor Dosage Controls Cell State in Rhabdomyosarcoma

  In the fusion-positive subset of rhabdomyosarcoma, the PAX3::FOXO1 oncoprotein is the most common fusion driver. We previously established a human myoblast system for inducible expression of PAX3::FOXO1. In this myoblast system, MYCN is constitutively expressed. In this current study, we aim to modulate PAX3::FOXO1 protein expression to understand the epigenetic and phenotypic functions at different PAX3::FOXO1 levels. Dosage-specific gene expression profiles in the human myoblast system with varying PAX3::FOXO1 expression were assessed by RNA sequencing.

  Study phs004381

• Divergent Control of Epithelial Homeostasis, Regeneration, and Inflammation by NEDD8 and SUMO2

  This study includes de-identified primary human keratinocytes derived from discarded neonatal foreskin collected under an IRB-approved biospecimen protocol. The submitted data are from in vitro assays in primary keratinocytes used to characterize how NEDD8 and SUMO2 related pathways regulate epithelial progenitor maintenance and differentiation. Sequencing based assays used in these primary cells include transcriptomic and functional genomic profiling of genetic and pharmacologic perturbations and associated limited sample metadata. Across these assays, loss of NEDD8 signaling promoted differentiation associated programs, whereas loss of SUMO2 machinery impaired differentiation associated programs. This identified opposite roles for these ubiquitin-like pathways in human keratinocyte state control. Data available through dbGaP will consist of de-identified human sequencing data and accompanying study metadata from these keratinocyte experiments.

  Study phs004614

• Prevention and Early Treatment of Acute Lung Injury Network - Vitamin D to Improve Outcomes by Leveraging Early Treatment (PETAL VIOLET-BioLINCC)

  Data Access NOTE: Please refer to the "Authorized Access" section below regarding accessing data through the BioData Catalyst ecosystem. The data from this accession is not available for download through dbGaP. Biospecimens: Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from PETAL VIOLET include Plasma and Whole Blood. Please note that use of biospecimens in genetic research is subject to a tiered consent. Specimens may not be used to produce commercial products.Objectives: To evaluate the effect of short-term vitamin D supplementation on mortality among critically ill patients with a vitamin D deficiency.Background: Observational data indicate that vitamin D deficiency is common among critically ill patients and constitutes a potentially modifiable risk factor associated with longer lengths of stay in the hospital and intensive care unit (ICU), lung and other organ injury, prolonged mechanical ventilation, and death. In a previous phase 2 trial, vitamin D supplementation administered to vitamin D-deficient, critically ill patients was associated with lower observed mortality than placebo at 28 days and at 6 months. Because of the need for a larger, phase 3 trial, the PETAL-VIOLET study was initiated to determine if early administration of high-dose vitamin D3 would reduce all-cause mortality among critically ill patients with a vitamin D deficiency.Participants: 1360 patients underwent randomization, 690 were assigned to the vitamin D group and 668 were assigned to the placebo group. Of the 1078 patients confirmed to have a vitamin D deficiency by liquid chromatography-tandem mass spectrometry (LC-MS-MS), 538 had been assigned to the vitamin D group and 540 had been assigned to the placebo group.Design: PETAL-VIOLET was a multicenter, double-blind, placebo-controlled, phase 3 trial. Patients were enrolled within 12 hours after the clinician's decision to admit the patient to the ICU from the emergency department, hospital ward, operating room, or outside facility. Patients were tested for vitamin D deficiency, with a threshold of plasma 25-hydroxyvitamin D level of less than 20 ng per milliliter. Patients were randomly assigned in a 1:1 ratio, stratified according to site, to receive either a single enteral (administered orally or through a nasogastric or orogastric tube) dose of 540,000 IU of vitamin D3 or matched placebo, in liquid form, administered within 2 hours after randomization.Conclusions: After the first interim analysis, the data and safety monitoring board recommended that the trial be stopped for futility.A single 540,000 IU enteral dose of vitamin D3 administered early during critical illness rapidly corrected vitamin D deficiency but did not provide an advantage over placebo with respect to mortality or other clinically important end points.

  Study phs003879

• Cognitively Affected DMD Patients have Unique Methylation Signatures Compared to Cognitively Normal DMD Patients

  The overarching goal of this project was to identify changes in methylation patterns in Duchenne muscular dystrophy (DMD) patients with discordant symptoms using whole genome bisulfite sequencing (WGBS) from genomic DNA isolated from whole serum. DMD siblings (biological brothers) had the same genetic mutation in the dystrophin gene but with discordance in symptoms such as ambulation, cardiopulmonary function, and cognition. Trios (DMD sibling brothers and biological mother or father) and quartets (DMD sibling brothers and biological mother and father) were recruited for this study for intra- and inter-familial comparisons of the methylation of gene bodies.

  Study phs003118

• MP2PRT: PI3K Pathway Activation and Its Associated Genomic Profile as Predictive Biomarkers of HPV-Related Oropharyngeal Cancer: Evaluation of NRG HN002 and RTOG 1016

  The Molecular Profiling to Predict Response to Treatment (MP2PRT) program is part of the NCI Cancer Moonshot Initiative. The aim of this program is the retrospective characterization and analysis of biospecimens collected from completed NCI-sponsored trials of the National Clinical Trials Network. This study, titled “PI3K Pathway Activation and Its Associated Genomic Profile as Predictive Biomarkers of HPV-Related Oropharyngeal Cancer: Evaluation of NRG-HN002 and RTOG 1016”, is one of the selected studies under this program. For this study, molecular characterization (i.e., WES, Total RNAseq, and multiplex immunofluorescence staining) was performed on formalin-fixed paraffin embedded tumor tissue and matching germline previously collected from patients with HPV-related oropharyngeal cancer. This project will investigate genomic alterations within the PI3K pathway (PIK3CA and PTEN). It is hypothesized that an improved understanding of this pathway in a specific genetic context may lead to the development of novel therapies to guide future clinical trials and improve the clinical outcomes of patients with HPV-positive oropharyngeal cancer.

  Study phs003089

• Analysis of Epigenomes and Genome Topology in Colorectal Cancer

  When diagnosing cancer, pathologists use nuclear morphology as a hallmark of tumor cells, but the topological changes linked to alterations in the shape of the nucleus were poorly understood. To uncover the molecular changes that occur in the 3D structure of cancer genomes, we integrated topological maps for colon tumors and normal colon tissues with epigenetic, transcriptional, and imaging data. We characterized tumor-associated changes in chromatin loops, topologically associated domains (TADs), and large-scale compartments. We found that chromatin loop rewiring contributes to oncogenic gene expression programs. Whereas TAD structures are largely stable, the spatial partitioning of the open and closed genome compartments is compromised in tumors and is accompanied by hypomethylation and histone mark rearrangements. We also identified a compartment that is reorganized in tumors and is at the interface between the canonical A and B compartments. Similar changes were evident in non-malignant cells that had accumulated excessive cellular divisions. Our analyses suggest that these compartment changes repress stemness and invasion programs while inducing immunity genes, and they may therefore restrain malignant progression.

  Study phs002288

• Retrovirus Epidemiology Donor Study-II (REDS II) Molecular Surveillance (MS) - (REDS_II_MS_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.Protocol Synopsis: We propose to conduct a genetic analysis of incident and prevalent strains of HIV, HCV and HBV by testing blood specimens from HIV, HCV or HBV positive blood donors who give blood at REDS-II, UBS, BCP, NYBC and ARC blood centers between 2006 and 2008. The frequency of the different genetic lineages of these viruses will be evaluated and compared between incident (recently acquired) and prevalent (more remotely acquired) infections. We will also evaluate if genotypic distributions vary by demographic characteristics and by geographical area. Informative viral genetic regions will be PCR amplified, sequenced and phylogenetically analyzed to determine genotypes and subtypes. Anti-viral drug and antibody neutralization resistance mutations will also be recorded. This study will provide an oversight of the genetic diversity of blood borne agents detected in the US using current NAT, antigen and serological assays. Using published data, this analysis of viruses in blood donors will allow us to also determine whether this population is infected with the same strains of viruses as seen in more at-risk populations. Genetic characterization of viruses in NAT-yield and recent seroconverting donations, which represent incident cases, will allow for characterization of circulating strains of viruses thus enabling early detection of rare variants and longitudinal tracking of changes in genotype frequency of actively transmitted strains. Because genetic variants of HIV, HCV and HBV appear to differ in properties such as pathogenicity, anti-viral therapy response and antibody neutralization properties, the genetic characterization of incident strains will also guide future anti-viral and vaccine research in the US.Objectives The objective of the study was to conduct a genetic analysis of incident and prevalent strains of HIV, HCV and HBV by testing blood specimens from HIV, HCV or HBV positive blood donors who gave blood at REDS-II centers, as well as at UBS, NYBC and ARC blood centers between 2006 and 2009. Background Genetic variations of human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis B virus (HBV) can affect diagnostic assays and therapeutic interventions. Recent changes in prevalence of subtypes/genotypes and drug/immune-escape variants were characterized by comparing recently infected vs. more remotely infected blood donors.ParticipantsThis study included qualifying donations from 1 January 2006 through 31 December 31 2009 from 3 Retrovirus Epidemiology Donor Study-II (REDS-II) blood centers (Blood Centers of the Pacific, Blood Center of Wisconsin, and Hoxworth Blood Center/University of Cincinnati), all American Red Cross Blood Services regions, United Blood Services regions and the New York Blood Center. Together, these centers account for approximately 70% of the US blood supply.DesignInfected donors were identified among approximately 34 million US blood donations, 2006–2009 based on screening and confirmatory tests for HIV and HCV nucleic acid testing, HIV and HCV antibody, HBsAg, and anti-HBV core antibody; incident infections were defined as having no or low antiviral antibody titers. Viral genomes were partially sequenced.ConclusionsViral genetic variant distribution in blood donors was similar to that seen in high-risk US populations. Blood-borne viruses detected through large-scale routine screening of blood donors can complement molecular surveillance studies of highly exposed populations. (Delwart et. al. 2012)

  Study phs004524

• Prematurity-Related Ventilatory Control: Role in Respiratory Outcomes (Pre-Vent-BioLINCC)

  ObjectivesTo develop a predictive model of short-term respiratory outcomes in extremely preterm infants, based on quantitative analysis of neonatal ICU cardiorespiratory monitoring data.BackgroundPreterm birth is a major cause of infant mortality and morbidity worldwide and a leading contributor to disability. Abnormal control of breathing is common in preterm infants and usually manifests as apnea, intermittent hypoxemia, bradycardia, and periodic breathing. Extremely preterm infants may also have impaired gas exchange caused by respiratory distress syndrome and subsequent bronchopulmonary dysplasia. The combination of apnea and lung disease often leads to more prolonged episodes of intermittent hypoxia. Such chronic intermittent hypoxia is associated with worse short-term outcomes (e.g., increased respiratory support, retinopathy of prematurity) and neurodevelopmental impairment that are difficult to predict in the neonatal ICU (NICU). The contribution of abnormal control of breathing to respiratory outcomes has not been determined. The Pre-Vent study was initiated to analyze cardiorespiratory continuous waveform monitoring data to delineate mechanisms of immature ventilatory control in preterm infants and identify predictive markers.ParticipantsInfants less than 29 weeks gestational age with continuously archived cardiorespiratory monitoring data were included. 717 total infants were evaluated.DesignPre-Vent was an observational multicenter prospective cohort study. Clinical data collected included respiratory support, medications, and co-morbidity data. Physiologic data consisted of variables extracted from cardiorespiratory monitoring data and quantified by count of events per day and duration per event. The extracted variables were apnea (≥20 seconds), periodic breathing (wavelet transform using a five-breath template), intermittent hypoxia events with oxygen saturation Infants discharged prior to 40 weeks post-menstrual age or inpatient infants at 40 weeks post-menstrual age had a favorable outcome if they were not on respiratory support or respiratory medications. Infants discharged prior to 40 weeks post-menstrual age or inpatient infants at 40 weeks post-menstrual age had an unfavorable outcome if they were on respiratory medications and/or respiratory support, or deceased. ConclusionsThe major findings of this study were that mathematical models based on cardiorespiratory bedside monitoring can identify alterations in physiologic measures that are independently associated with unfavorable respiratory outcomes in extremely preterm infants. Both physiologic and clinical variables contributed to good prediction models, with the contribution by physiologic variables increasing with postnatal age (Ambalavanan N, Weese-Mayer DE, Hibbs AM, et al. Am J Respir Crit Care Med. 2023;208(1):79-97.), (Weese-Mayer DE, Di Fiore JM, Lake DE, et al. Pediatr Res. 2024;95(4):1060-1069). 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 Pre-Vent include DNA. Please note that use of biospecimens in genetic research is subject to a tiered consent.

  Study phs004826

• Kidney Precision Medicine Project (KPMP)

  The Kidney Precision Medicine Project (KPMP) is a prospective cohort study, whose goal is to use deep molecular phenotypes of kidney biopsies, along with longitudinally collected clinical phenotypic data, in order to develop new disease ontologies, classification systems, and treatments for acute kidney injury (AKI) and chronic kidney disease (CKD). Since its inception, the KPMP has sought out and included substantive patient-representative feedback regarding disease experience, lack of innovation in new kidney disease therapies and patient tolerance for risk levels in balance with potential benefits both to the individual and society. As established in 2017, the objectives of the Kidney Precision Medicine Project (KPMP) are: • Diverse longitudinal cohort. Recruit adults from varied age, sex, racial, ethnic, socioeconomic, and geographic backgrounds with AKI and CKD to undergo protocol research biopsies linked to longitudinal clinical data and biosamples. • Public resource. Create a publicly available data hub with de-identified clinical, physiologic, imaging, cellular, and molecular data using FAIR principles (findable, accessible, interoperable, and reusable). • Kidney tissue atlas. Create a collection of maps to locate and classify different cell types and interstitial components accounting for health, disease, age, sex, race, ethnicity, socioeconomic, and geographic backgrounds. The atlas will help define disease subgroups and identify critical cells, interstitial components, pathways, and targets for novel therapies. • State/transition markers. Identify cellular and molecular markers that classify cells as healthy, injured, activated, or undergoing recovery via adaptive or maladaptive repair. • Clinical subgroups. Use all available data to define disease subgroups to allow for clinical stratification into distinct endophenotypes. • Molecular pathways. Identify and understand healthy and disease pathways that are activated in a cell type in a subgroup of people. • Biomarkers. Discover sets of subgroup and pathway biomarkers. Molecular and imaging data derived from kidney tissue will be integrated with clinico-pathologic and genetic information, as well as other data derived from analyses of fluid biospecimens, including peripheral blood, urine, and stool. Using advanced analytics to integrate the data, KPMP will aim to define kidney disease subgroups in molecular terms by identifying critical cells, pathways and targets for novel therapies. Patients with AKI or CKD will be recruited from clinical care encounters (e.g., clinic visits for CKD patients, hospitalization or emergency room visits for AKI patients) and from electronic resources (e.g., existing registries, electronic health records). All study procedures are designed to optimize participant safety and will be ethically conducted, ensuring subjects fully understand the scope of the study and any possible risks. For each participant, kidney tissue will be obtained for molecular phenotyping and clinical diagnosis. The diagnostic interpretation will be returned to the participant's primary caregiver to inform clinical care, but no treatment interventions will be prescribed by the KPMP. In addition to kidney biopsy, the study will involve collection of baseline (time of biopsy) and longitudinal biospecimens (including urine, plasma, serum, DNA and stool) and demographic, clinical, and laboratory data. Participants will be followed through scheduled in-person and remote (telephone) study visits, as well as through periodic review of electronic health records.Limited phenotype data and whole genome sequences will be made available in dbGaP. The KPMP will retain the more comprehensive data described above. Investigators may contact the KPMP for access to these data.

  Study phs004574

• International Cancer Proteogenome Consortium (ICPC): Proteogenomics of Oral Squamous Cell Carcinoma in Taiwan

  Oral cavity squamous cell carcinoma (OSCC) is the major subtype (~90%) of oral cancer, which is leading cancer with high mortality worldwide. The environmental risk factors associated with OSCC are quite different in Taiwan as compared to other populations. In most non-Taiwanese populations, OSCC is often associated with tobacco chewing, cigarette smoking, alcohol drinking, or human papillomavirus (HPV) infection. In Taiwan, in contrast, the OSCC occurs mainly in males aged 30 years or older who have habitual betel nut chewing, cigarette smoking, and alcohol drinking. To uncover molecular mechanisms and identify new therapeutic strategies of oral squamous cell carcinoma, this study recruited 112 treatment-naïve OSCC patients and generated multi-omics data, including WES, RNA-Seq, TMT-labeled proteomes, and phosphoproteomes from paired normal/tumor tissues. We have investigated our multi-omics data, covering molecular characterizations such as mutation signatures, impacts of mutations on RNA/protein/phosphoprotein, RNA-protein correlation, somatic copy number alteration, and the relationship with RNA & protein, proteome, and phosphoproteome analysis (T vs NAT), novel peptides (somatic variants, neoantigens, CT antigens, T cell receptors, etc.), as well as molecular subtyping (& pathway analysis). Notably, we have discovered a higher frequency of APOBEC3B deletion polymorphism in the Taiwanese population, and APOBEC3A is a potential prognostic biomarker. Our proteogenomic data enable us to further stratify patients into four groups based on APOBE3A expression level, which is found inversely correlated with EGFR expression. Therefore, the patients with high EGFR and low APOBEC3A expression may benefit from anti-EGFR therapy, while those with low EGFR and high APOBEC3A expression may benefit from immunotherapy. To clarify if there is an interaction between genetic polymorphisms and betel nut chewing habit in Taiwanese OSCC, we plan to concurrently evaluate the effect of habitual betel nut chewing on the gene mutation pattern, the dysregulated protein/phosphoproteins as novel biomarkers and/or therapeutic targets, and the molecular subtyping of patients for effective treatments. 

  Study phs002580

• Genetic Factors Associated with Anthracycline-Induced Cardiomyopathy (COG-ALTE03N1)

  We investigated the genetic mechanisms underlying anthracycline-induced cardiomyopathy, a serious long-term complication among childhood cancer survivors. We focused on the role of DNA damage response and repair (DDR) genes, which had not been previously studied in this context. A gene-based and pathway-based approach was applied to assess both the main effects and gene-by-anthracycline interaction effects of DDR genes on cardiomyopathy risk. The analysis was conducted using a matched case-control design within the COG-ALTE03N1 study, including 113 cases and 226 controls, all of whom were non-Hispanic White childhood cancer survivors exposed to anthracyclines. For each case, we randomly selected 1-3 childhood cancer survivors with no cardiomyopathy, matched on primary cancer diagnosis, year of diagnosis (±10y), and race/ethnicity. The selected controls had to have a longer duration of follow-up compared with time from cancer diagnosis to cardiomyopathy for the corresponding case. Participants provided blood or saliva for germline DNA isolation and genotyping. Genotyping was performed using Illumina HumanOmniExpress-12 v1.0 (709,358 SNPs) and IlluminaOmni5Exome-4 v1.3 arrays (4,293,368 SNPs), with merging of genotype data from the two arrays (683,781 overlapped SNPs) and quality control (QC) using PLINK. Of the 220 genes in the MD Anderson DDR gene website, 187 genes with 2,220 single nucleotide polymorphisms [SNPs] identified on our array data were included in the analyses. A total of 2,170 SNPs were retained in the final gene-based and pathway-based analysis in 339 anthracycline-exposed non-Hispanic White (NHW) patients (113 cases; 226 controls). Key findings included significant associations for FANCC and XRCC5 with cardiomyopathy risk (main effect), and a significant gene-environment interaction involving MGMT. The study also confirmed the involvement of DDR-related biological pathways through both genetic association and interaction analyses.Data Available Through dbGaP: • Genotype data (GWAS) for all study participants • Phenotype data: age at primary cancer diagnosis, sex, race/ethnicity, case-control status This dataset supports further research into genetic susceptibility to chemotherapy-induced adverse outcomes and enables cross-cohort comparisons in cardio-oncology.

  Study phs003792

• The Role of E2F4 in Controlling Resistance to Irinotecan (CPT-11) in Human Colon Cancer

  This study reports the results of RNA sequencing (RNA-seq) experiments performed on three isogenic clones of the human HT29 colon cancer cell line, genetically engineered to achieve the selective inactivation of the adenovirus early 2 (E2) gene transcription factor 4 (E2F4) protein, a key functional component of the multimeric transcriptional repression complex known as the dimerization partner (DP), retinoblastoma-like (RB-like), E2F and multi-vulva class B (MuvB) complex (DREAM). In previous studies, we identified E2F4 as a key regulator of colorectal cancer (CRC) resistance to irinotecan (CPT-11), a cytotoxic agent that stands at the backbone of multiple chemotherapy regimens for the treatment of metastatic CRCs. The molecular mechanisms linking E2F4 to irinotecan resistance, however, remain poorly understood. The present study was designed to identify which genes are under the transcriptional control of E2F4, either at baseline or following exposure to SN38 (i.e., the active metabolite of irinotecan, generated in vivo by biotransformation in the liver) in order to clarify the role played by E2F4 in shaping colon cancer resistance to chemotherapy. The cell line used for this study (HT29) is aneuploid and contains three copies of the E2F4 gene, because of a trisomy of chromosome 16, where the E2F4 gene is located (Kawai et al., Genes, Chromosomes & Cancer, 34:1-8, 2002; PMID: 11921276). HT29 cells were infected with lentivirus vectors encoding for CRISPR/Cas9 constructs designed to selectively inactivate the E2F4 gene, using three distinct guide-RNAs (gRNAs), each targeting a different sequence within the proximal exons of the E2F4 gene (exon 1, exon 2). Lentivirus-infected cells were sub-cloned by single-cell fluorescence-activated cell sorting (FACS), based on the differential expression of a fluorescent reporter (EGFP) expressed in tandem with the gRNAs. Isogenic clones (EGFP+) were then screened to identify those with a tri-allelic knock-out, as revealed by both genetic sequencing of the E2F4 gene (revealing the presence of three distinct frameshift mutations) and Western blot (revealing complete loss of E2F4 protein expression). The study includes twelve (n=12) RNA-seq experiments, representative of 3 experimental replicates (i.e., three distinct isogenic clones of the HT29 cell line, each displaying complete loss of E2F4 expression) and 3 negative controls (i.e., three independent preparations of the parent HT29 cell line, infected with a lentivirus vector encoding for a non-targeting gRNA) exposed to 2 distinct in vitro cell culture conditions: a) treatment with SN38 resuspended in dimethyl sulfoxide (DMSO); or b) treatment with DMSO alone (negative control). The in vitro treatment regimen used for SN38 (32 nM, 24 hours) was designed so that the exposure to SN38 experienced in vitro by HT29 cells would mirror the exposure to SN38 experienced in vivo by malignant tissues, as measured, for example, in metastatic CRC patients receiving a standard dose of irinotecan (180 mg/m2) administered by intravenous infusion over 90 minutes (Deyme et al., Cancer Chemotherapy and Pharmacology, 88:247-258, 2021; PMID: 33912999).

  Study phs003560

• Developing Allelic Imbalance Analysis from Single-Nucleus RNA-Seq Data

  Single-cell RNA-seq (scRNA-seq) is emerging as a powerful tool for understanding gene function across diverse cells. Recently, this has included the use of allele-specific expression (ASE) analysis to better understand how variation in the human genome affects RNA expression at the single-cell level. We reasoned that, because intronic reads are more prevalent in single-nucleus RNA-Seq (snRNA-Seq) and introns are under lower purifying selection, and are thus enriched for genetic variants, that snRNA-seq should facilitate single-cell analysis of ASE. Here we demonstrate how experimental and computational choices can improve the results of allelic imbalance analysis. We explore how experimental choices, such as RNA source, read length, sequencing depth, genotyping, etc., impact the power of ASE-based methods. We developed a new suite of computational tools to process and analyze scRNA-seq and snRNA-seq for ASE. As hypothesized, we extracted more ASE information from reads in intronic regions than those in exonic regions and show how read length can be set to increase power. Additionally, hybrid selection improved our power to detect allelic imbalance in genes of interest. We also explored methods to recover allele-specific isoform expression levels from both long- and short-read snRNA-seq. Overall, we provide an end-to-end experimental and computational approach for future studies.

  Study phs003749

• Type 1 Diabetes TrialNet

  Type 1 Diabetes TrialNet (TrialNet) is an international network of researchers established in 2003 for the purpose of conducting studies designed to evaluate new approaches to prevent, delay and reverse the progression of type 1 diabetes. These include interventions designed to decrease β-cell destruction and/or enhance β-cell survival. TrialNet engages in new onset diabetes trials to assess safety and to determine whether interventions can lead to preservation of C-peptide. Positive results from new onset trials are then evaluated as to whether the intervention can be brought into the prevention space for further evaluation. Other TrialNet goals include characterization of diabetes risk and pathophysiology through genetic, immunologic, and metabolic studies in participants participating in clinical studies. TN01 Bulk mRNA – RNA Sequencing The TrialNet “Key Question 1” study investigates immune system alterations associated with Type 1 Diabetes (T1D) progression using a retrospective, longitudinal nested case-control approach. It analyzes immune phenotype and gene expression changes in 178 individuals (89 cases, 89 controls). Cases include islet autoantibody-positive individuals from the TN01 Pathway to Prevention trial who developed T1D within a three year observation period, while controls are non-progressors matched by age, sex, and sampling timepoints. Serial blood samples were collected over three years, from pre-T1D to clinical diagnosis. Analyses include mass cytometry and transcriptomics. The RNA Sequencing portion of the study examines gene expression in five purified immune cell types: CD4+ T memory cells, CD8+ T memory cells, CD4+ T regulatory (Treg) memory cells, CD19+ B memory cells, and Natural Killer (NK) cells. RNA sequencing, with spike-in control RNA (ERCC), is used to control for batch variation. Whole Blood Genotyping – ExomeChip DNA from whole blood samples from TrialNet study participants was obtained and used for genotyping. Individuals included participants from TN01 Pathway to Prevention study and the following interventional trials: TN07 Oral Insulin, TN10 Anti-CD3 Prevention, TN18 Abatacept Prevention, TN20 Immune Effects of Oral Insulin, and TN22 Hydroxychloroquine Prevention. All interventional trial participants originated from TN01 Pathway to Prevention. Genotyping was performed by the University of Virginia using the Illumina TEDDY-T1DExome array. The TEDDY-T1DExome array is a custom chip that contains 550,601 markers from the Infinium CoreExome-24 v1.1 BeadChip and an additional 90,214 tagSNPs specifically selected by the TEDDY investigators based on their associations with nutrients, vitamins, type 2 diabetes, autoimmune diseases, body-mass index, or other exposures and phenotypes measured by TEDDY study. The Illumina GenTrain2 algorithm was used for genotype calling. Sample quality control metrics included sample call rate, heterozygosity rate and concordance of gender between the information reported and genotyped.

  Study phs004311

• Cryptococcosis in Previously Healthy Adults

  Cryptococcus is a fungus that causes infections most commonly in immunocompromised patients, such as those with AIDS and solid organ transplant recipients and is currently responsible for an estimated 15% of all AIDS-related deaths globally. However, in developed countries, approximately one-third of cases fall outside these groups such that cryptococcal meningoencephalitis (CM) has become the most common cause of non-viral meningitis in the U.S. Within the U.S., approximately 15-20% have no readily identifiable immune defect and cryptococcal infection in these hosts has a mortality rate of 30-50% despite optimal antifungal therapy. NIH Clinical Study Protocol 93-I-0106 (NCT00001352). The objectives of this protocol can be broadly categorized as: 1) Characterize the immunologic and genetic mechanisms predisposing to disease acquisition; 2) Understand the post-infectious inflammatory response and distinguish its consequences from those directly due to fungal growth; and 3) Management of post-infectious neuro-inflammatory syndromes associated with cryptococcal meningitis (CM). This protocol recruits patients who have microbiological evidence of cryptococcal neurologic or non-CNS disease (typically pulmonary or bone). Cerebrospinal fluid (CSF) and blood samples collected during clinical care are used to measure serum and CNS cellular and soluble cytokines as well as to perform in-situ immunohistochemistry. CSF and blood samples are also collected to measure transcriptional (gene expression), proteomic (protein), and lipidomic (lipids) changes that occur throughout disease and treatment. Observational data detailing audiological, ophthalmological and neurocognitive deficits in these patients is also recorded. We have recently described a post-infectious inflammatory syndrome (PIIRS) associated with cryptococcal meningoencephalitis (CM) which can be best described as a neuro-inflammatory state during which CM patients present with altered mental status (Montreal Cognitive Assessment Score As part of the protocol, we treat patients for either microbiological failure or neuroinflammatory sequelae by conventional therapies utilizing FDA-approved pharmaceuticals at FDA-approved doses. To understand and identify the predominant biological pathways responsible for PIIRS neuroinflammation, we examined patient CSF at baseline (at time of PIIRS diagnosis) and post-treatment with different FDA-approved pharmaceuticals at FDA-approved doses compared to CSF from non-PIIRS donors. Upstream pathway analysis of differentially expressed genes in the CSF of PIIRS patients revealed a prominent role for the JAK/STAT pathway in the pathogenesis of PIIRS and support the use of the JAK inhibitor, ruxolinib, as a pathway-instructed therapy to treat PIIRS patients. Data available through dbGaP: single cell RNA sequencing (scRNA-seq) data from CSF cells of a patient with PIIRS at the time of diagnosis and following treatment with steroids (1g solumedrol/day) and NanoString transcriptional data from CSF cells of patients with PIIRS at the time of diagnosis compared to CSF cells from non-PIIRS donors.

  Study phs003871

• Genetic and Epigenetic Screens in Primary Human T Cells Link Candidate Causal Autoimmune Variants to T Cell Networks

  We aimed to define the target genes and pathways in which autoimmune disease-associated genetic variants operate. We performed single cell-CRISPR-interference screens in primary human T cells and bulk RNA-seq on T cells containing CRISPRi and single gRNAs to assess how T cell regulatory regions containing autoimmune-associated genetic variants affect nearby gene expression and cellular programs.

  Study phs004072

• Prostate Cancer Upgrading Reference Set

  This study aimed to investigate clinical, demographic, and molecular features of men diagnosed with low-risk prostate cancer [ISUP Grade Group 1 (GG1)] at biopsy who underwent radical prostatectomy, and for whom an increased tumor grade (ISUP Grade Group 2 or above) was subsequently detected in the resected prostate. This phenomenon is termed upgrading. In collaboration with the Early Detection Research Network (EDRN), a blinded reference set was established to facilitate upgrading biomarker detection and validation. A prospective, multi-institutional, cohort of men with the GG1 prostate cancer and intention to undergo prostatectomy was recruited. Biospecimens (blood, urine) were collected and this biorepository comprises the official EDRN Upgrading Reference Set (URS). Recording of case-control status (case = upgrading at prostatectomy, control = no upgrading at prostatectomy) was coordinated by the Data Management and Coordinating Center (DMCC) of the EDRN, who ensured blinding of all participating researchers. A subset of the reference set (n = 192) was chosen to undergo whole genome sequencing (WGS) for the investigation of a germline genomic biomarker of upgrading. Variant calls from all sequenced URS whole genomes are available through dbGaP, with the exception of one sample for which sequencing was not successful. Among investigated clinical features, prostate-specific antigen (PSA) density and percent of cancer in pre-prostatectomy positive biopsy cores were significantly associated with upgrading. Two polygenic risk score-based biomarkers were computed in the genetic sub-cohort and tested against case-control status. Neither was predictive of upgrading.

  Study phs003670

• Cystic Kidney Disease: Disease Spectrum and Genotype-Phenotype Correlations

  This study seeks to characterize the genetic landscape of Autosomal Dominant Polycystic Kidney Disease (ADPKD). Sequencing data is primarily derived from a short-read targeted-Next Generation Sequencing (tNGS) custom panel of known and candidate genes towards polycystic kidney/liver diseases and ciliopathies. To understand the severity of the disease in individual patients, we have provided relevant phenotype information when available. This study is part of a multi-year effort; all submissions will be tied to this overarching dbGaP study to ensure continuity and facilitate integrated data access. Version 1 contains the tNGS sequencing data (BAM, gVCF, VCF) of Mayo Clinic patients with cystic kidney and/or cystic liver disease that were either negative for PKD1 or PKD2 pathogenic changes but had pathogenic changes detected in one of the minor ADPKD genes, such as IFT140, DNAJB11, ALG8, or ALG9. These individuals have been featured in publications detailing with monoallelic variants in these genes. The PubMed IDs are 39899384, 34890546, 29706351, and 32631624. Version 2 contains all data from Version 1. Version 2 additionally contains the tNGS sequencing data (BAM, gVCF, VCF) of Mayo Clinic patients with cystic kidney and/or cystic liver disease with pathogenic changes linked to NEK8 ADPKD and biallelic C2CD3 ciliopathy-based disorder. In addition, a pediatric cohort of cystic kidney-affected individuals as well as an Adult-Onset ARPKD phenotype cohort of individuals are featured in this version. These individuals have been featured in publications with respect to the phenotype and cohort group. The PubMed IDs are 41790507, 37598857, and 30097616. Subjects in the Adult-Onset ARPKD phenotype group are currently undergoing publication and this study will be updated to reflect this.

  Study phs004088

• Multicenter Hemophilia Cohort Studies (MHCS-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 MHCS include DNA, Peripheral Blood Mononuclear Cells, Plasma, Red Blood Cells, and Serum. Please note that use of biospecimens in genetic research is subject to a tiered consent. Objectives The First Multicenter Hemophilia Cohort Study (MHCS-I) evaluated and prospectively followed patients with hemophilia or a related coagulation disorder. Initiated in 1982, this study particularly sought to understand the cause and natural history of HIV infection and AIDS in this population which was at high risk for development of AIDS. The Second Multicenter Hemophilia Cohort Study (MHCS-II) evaluated and prospectively followed a cohort of subjects with hemophilia who were exposed to hepatitis C virus (HCV). The primary objectives were to quantify the rates of liver decompensation, hepatocellular carcinoma, and non-Hodgkin lymphoma and to evaluate candidate clinical, genetic, virologic, serologic and immunologic markers that are likely to be on the causal pathway for these conditions, identify predictive clinical and laboratory markers and follow the markers over time, identify host genes that confer susceptibility or resistance to HCV and HIV infections or to the diseases that result from these infections and to identify response and complication rates of various anti-HCV and anti-HIV regimens in the setting of comprehensive clinical care of persons with hemophilia. Background Treatment of hemophilia patients with contaminated plasma products before 1990 resulted in extraordinary prevalence rates of human immunodeficiency virus (HIV) and hepatitis B and C viruses (HBV, HCV). The first cases of acquired immunodeficiency syndrome (AIDS) were reported in the United States in 1981 and the first cases of AIDS in hemophilia patients were reported one year later. In contrast to HIV-1, HBV, HCV were present in the human population and HBV and HCV were almost certainly was always a contaminant of blood and plasma donated for transfusion prior to the development of diagnostic tests to screen blood donors. Participants Adults and children who had a congenital coagulation disorder [hemophilia A or B (congenital factor VIII or IX deficiency)] von Willebrand's disease, or other were enrolled from 8 collaborating hemophilia centers in the US between 1982 and 1985. Four additional centers from the US and 4 centers from Europe joined the study between 1987 and 1990. In MHCS-II, 52 collaborating hemophilia centers in North and South America and Europe, enrolled patients who had a congenital coagulation disorder [hemophilia A or B (congenital factor VIII or IX deficiency), von Willebrand's disease, or other], who had reached 13 years of age, and who had serological or molecular evidence of HCV or HIV-1 infection. The majority of subjects consisted of a "HCV cohort" of whom a portion was co-infected with HIV, the "HIV cohort". Design In MHCS-I, subjects were evaluated semiannually with a standardized physical examination, abstraction of medical records, and phlebotomy. In MHCS-II, The natural time scale was used, beginning with the estimated date of HCV or HIV infection to an event of interest, death, or censoring. Time initiated on the estimated date of HCV infection (HCV cohort) or HIV infection (HIV cohort) but follow-up was defined as the date of the first blood sample collected for the MHCS-I or -II. The main outcomes were liver decompensation, hepatocellular carcinoma and non-Hodgkin lymphoma. Measures included HCV viral load, anti-HCV levels and other markers of the primary outcomes such as serum cholesterol and inflammatory cytokine levels; host genetic polymorphism. Conclusions Nearly one-third of the MHCS-II participants were infected with HIV-1, many of whom were infected in childhood and all of whom have survived with HIV-1 for more than 15 years. As survivors, relatively few of them had an AIDS-defining opportunistic infection or malignancy (17%) or laboratory-defined AIDS. In contrast to use of HAART for HIV-1 infection, only a minority of MHCS-II participants had been treated for their HCV infection. In the MHCS-II cohort of HCV-seropositive people with hemophilia and related coagulation disorders, the prevalence rates of ascites, hepatomegaly, splenomegaly and persistent jaundice were 2- to 3-fold higher with HIV-1, when adjusted for age and most could not be ascribed to HAART or other anti-HIV-1 regimens. In the MHCS-II, 74% of the HIV-1-positive and 51% of the HIV-1-negative participants had evidence of current or previous HBV infection. In MHCS-I, the risk of decompensated end stage liver disease was increased 8.1-fold for carriers of hepatitis B surface antigen (HBsAg) and 3.4-fold for the much larger group of hemophiliacs who had cleared HBsAg. Publications Melendez-Morales L, Konkle BA, Preiss L, Zhang M, Mathew P, Eyster ME, Goedert JJ. Chronic hepatitis B and other correlates of spontaneous clearance of hepatitis C virus among HIV-infected people with hemophilia. AIDS. 2007; 21(12):1631-6. Goedert JJ; Second Multicenter Hemophilia Cohort Study. Prevalence of conditions associated with human immunodeficiency and hepatitis virus infections among persons with haemophilia, 2001-2003. Haemophilia. 2005; 11(5):516-28. Engels EA, Frisch M, Lubin JH, Gail MH, Biggar RJ, Goedert JJ. Prevalence of hepatitis C virus infection and risk for hepatocellular carcinoma and non-Hodgkin lymphoma in AIDS. J Acquir Immune Defic Syndr. 2002; 31(5):536-41. Goedert JJ, Eyster ME, Lederman MM, Mandalaki T, De Moerloose P, White GC 2nd, Angiolillo AL, Luban NL, Sherman KE, Manco-Johnson M, Preiss L, Leissinger C, Kessler CM, Cohen AR, DiMichele D, Hilgartner MW, Aledort LM, Kroner BL, Rosenberg PS, Hatzakis A. End-stage liver disease in persons with hemophilia and transfusion-associated infections. Blood. 2002; 100(5):1584-9. O'Brien TR, Blattner WA, Waters D, Eyster E, Hilgartner MW, Cohen AR, Luban N, Hatzakis A, Aledort LM, Rosenberg PS, Miley WJ, Kroner BL, Goedert JJ. Serum HIV-1 RNA levels and time to development of AIDS in the Multicenter Hemophilia Cohort Study. JAMA. 1996; 276(2):105-10. Ehmann WC, Eyster ME, Wilson SE, Andes WA, Goedert JJ. Relationship of CD4 lymphocyte counts to survival in a cohort of hemophiliacs infected with HIV. Multicenter Hemophilia Cohort Study. J Acquir Immune Defic Syndr. 1994;7(10):1095-8. Goedert JJ, Cohen AR, Kessler CM, Eichinger S, Seremetis SV, Rabkin CS, Yellin FJ, Rosenberg PS, Aledort LM. Risks of immunodeficiency, AIDS, and death related to purity of factor VIII concentrate. Multicenter Hemophilia Cohort Study. Lancet. 1994; 344(8925):791-2. Erratum in: Lancet 1994; 344(8931):1238. Eyster ME, Fried MW, Di Bisceglie AM, Goedert JJ. Increasing hepatitis C virus RNA levels in hemophiliacs: relationship to human immunodeficiency virus infection and liver disease. Multicenter Hemophilia Cohort Study. Blood. 1994; 84(4):1020-3. Goedert JJ, Kessler CM, Aledort LM, Biggar RJ, Andes WA, White GC 2nd, Drummond JE, Vaidya K, Mann DL, Eyster ME, et al. A prospective study of human immunodeficiency virus type 1 infection and the development of AIDS in subjects with hemophilia. N Engl J Med.1989; 321(17):1141-8. Lozier JN, Rosenberg PS, Goedert JJ, Menashe I. (2011), A case–control study reveals immunoregulatory gene haplotypes that influence inhibitor risk in severe haemophilia A. Haemophilia, 17: no. doi: 10.1111/j.1365-2516.2010.02473.x

  Study phs004485

• Next Generation Sequencing to Predict Risk of Events from Coronary Artery Disease

  Coronary artery disease (CAD) and myocardial infarction (MI) remain the leading cause of death worldwide and in the US. In recent years, clinical studies that considered intermediate phenotypes (phenotypic or genomic data isolated between DNA and the main disease phenotype) have greatly enhanced our understanding of complex traits like CAD by enabling inference of biological networks from the combination of genetic and genomic datasets isolated from disease-relevant tissue(s). The NGS-PREDICT study used whole transcriptome sequence data generated from primary macrophages derived in vitro from venous blood that was obtained from CAD cases and non-CAD controls. This study provided a valuable resource for the validation of biomarkers identified in STARNET NGS data from macrophages obtained from patients with and without CAD. It also can be used as a reference dataset for the study of metabolic syndrome as well as other systemic inflammatory diseases.

  Study phs003883

• Platinum Pedigree Consortium Long-Read Sequencing

  Platinum Pedigree Consortium includes whole genome sequencing of blood-derived DNA using five technologies on a 4-generation family. This is the CEPH-Utah (CEU) family 1463 and includes 4 grandparents from 1st generation, 2 parents from 2nd generation, 5 children from 3rd generation, 9 individuals from the 4th generation representing 2 branches of the 3rd generation, and their 2 additional parents. Family was not selected for disease, rather large size to study genetic transmission and human variation.Data available through dbGaP include raw sequence data: PacBio HiFi reads in unaligned BAM formats, Ultra-Long Oxford Nanopore (ONT) reads in FASTQ formats, Illumina sequencing, strand-seq and Element sequencing data in FASTQ format. Additionally, alignment files for HiFi reads mapped to the GRCh38 and CHM13v2.0 reference genomes, as well as de novo genome assemblies generated for this project are included.

  Study phs003793

• TET2 Loss Triggers ssDNA Gap Accumulation and Heightened PARP Inhibitor Sensitivity

  Here we sought to understand the molecular effects of TET2 knock out (KO) in U2OS cells. TET2 catalyzes the conversion of 5-methyl-cytosine to 5-hydroxy-methyl-cytosine (5hmC). We thus mapped 5hmC genome-wide using bACE-seq (bisulfite APOBEC-coupled epigenetic sequencing) in TET2 wild-type (WT) and KO. TET2 KO U2OS cells were engineered to remove ~42kb of TET2. TET2 KO was confirmed by PCR, western blot, and sequencing. bACE-seq analysis was then performed on genomic DNA isolated from three independent plates of WT and KO U2OS cells. Our subsequent analysis identified 4182 differentially hypo-hydroxy-methylated regions (hypo-hDMRs) and 651 hyper-hydroxy-methylated DMRs, confirming an overall reduction in the genomic levels of cytosine hydroxy-methylation upon TET2 loss. Hypo-hDMRs were spread across the chromosomes, and we did not observe specific chromosomal regions having preferential hDMR concentration. Moreover, we did not observe localization of hDMRs to any specific genomic compartment such as promoters, enhancers, or UTRs. Using previously published replication initiation and termination zones defined by OK-seq we observed that in WT cells initiation zones showed a slight reduction in 5hmC levels relative to randomized genomic control regions and termination zones. In TET2 KO cells, the difference at initiation zones was dampened as likely all genomic regions have reduced 5hmC. Here we provide bACE-seq hmC mapping data for TET2 WT and KO U2OS cells for three replicates of each condition.

  Study phs004658

• Genome-Wide Association Study of the Taste and Hedonic Ratings of the Low-Calorie Sweetener Acesulfame Potassium

  Acesulfame potassium (Ace-K) is a low-calorie sweetener (LCS) widely used as an additive in foods and beverages and an excipient in pediatric medicines. Because genetic variants play a role in individual variation in the taste of Ace-K, we sought to identify genetic contributions to its taste using a genome-wide association study (GWAS). 141 adult panelists rated the taste of an aqueous solution of Ace-K using the general labelled magnitude scale (gLMS) and its palatability using the hedonic gLMS. Genotypes were assayed on the Infinium Global Screening Array. Imputation of genotypes was performed on the Michigan Imputation Server with 1000 Genomes Project phase 3 genotype data as reference. Linear regression was performed to test genetic associations between genotyped and imputed variants with three gLMS ratings (bitterness (square-root-transformed), hedonic, sweetness) of Ace-K using PLINK2, adjusting for standardized age, sex, and the first 10 principal components of genetic ancestry. We identified that a locus spanning several TAS2R (Taste receptor 2) genes was associated with bitterness ratings of Ace-K and a locus within the gene ELMO1 (Engulfment and Cell Motility Protein 1) was associated with hedonic ratings of Ace-K (p-values 40594245).

  Study phs004031

• Transcriptional Response to Hypoxia in iPSC-Derived Endothelial Cells from a High Altitude Adapted Population

  We established lymphoblastoid cell lines from 10 adult individuals of Tibetan ancestry living in the Chicago area. These lines were reprogrammed to induced pluripotent stem cells (iPSC). We validated genetic ancestry by genome-wide SNP array genotyping and population genetic analyses. After being subjected to standard quality control testing iPSCs were differentiated into endothelial cells. Following differentiation, endothelial cells were isolated via a pull down protocol using beads coated with an antibody for a canonical surface cell marker of the vascular endothelium (CD144). Purified vascular endothelial cells were cultured in parallel in normoxia (20% O2) and hypoxia (1% O2) for 48 hours prior to harvesting and processing for bulk RNA-sequencing. We provide imputed genotype data and bulk RNA-sequencing data in normoxia and in hypoxia for each of the 10 individuals. We also provide multiplexed scRNA-sequencing data for the 10 Tibetan individuals pooled with 10 CHB individuals from the 1000 Genome Project. Additionally, we provide scRNAseq data for the cardiomyocytes derived from the same iPSC lines from the Tibetan individuals pooled together with cardiomyocytes derived from iPSC lines of 10 CHB individuals from the 1000 Genome Project. Lymphoblastoid cell lines from the CHB were reprogrammed to iPSCs and differentiated to cardiomyocytes using the same protocols as used for the Tibetans. The batches of 4 lines were balanced by sex and population. These iPSC-derived cardiomyocytes were cultured in hypoxia (1% O2) for 48 hours and subjected to scRNAseq in pooled batches of 3 or 4 lines. The CHB individuals included in this analysis were: NA18528, NA18531, NA18557, NA18596, NA18606, NA18608, NA18614, NA18619, NA18633, and NA18748.

  Study phs003758

• Testicular Cancer Consortium WES

  We have leveraged our previous collaborative research to better understand the genetic underpinnings of testicular germ cell tumor (TGCT), and have completed whole exome sequencing on the DNA of patients at high risk for TGCT. Specifically, we conducted a study of high-risk individuals using data from Penn Medicine and the NCI. We collected germline DNA from blood or saliva samples from men with bilateral TGCT, and a family history consisting of at least one first to third degree relative diagnosed with the disease. The goal of the study was to identify coding genomic variation associated with predisposition to TGCT. Whole exome sequencing and gene burden analyses were performed on 293 men with a family history of TGCT or bilateral disease. 228 unique families were represented in this sample. Our results found a missense variant in the hinge domain of proto-oncogene PIM1. Several more candidates were identified via gene burden association, including loss-of-function variants in NIN and QRSL1. We also identified an association with variants in CFTR using gene-specific analysis. There was no association with sex and germ cell development pathways or regions identified by GWAS previously. We identified associations with three major pathways including, mitosis/cell cycle, co-translational protein targeting, and sex differentiation. Our results showed associations with variants in several genes, which suggests a multigenic heritability. We also found potential association with CFTR, co-translational protein targeting, and chromosomal segregation in sex determination. Our results suggest potential drug targets for TGCT prevention or treatment, e.g., PIM1, and the co-translational targeting pathway. To our knowledge, our study is the largest to date of men with high risk TGCT.

  Study phs003107

• Omic Studies in Children's Respiratory and Environmental Workgroup (CREW) Cohorts

  Children's Respiratory Research Workgroup (CREW) is an NIH-funded project consisting of multiple individual U.S. cohorts and three scientific centers working together to identify phenotypes and causes of childhood asthma. CREW will include data from a large number of children and their families, with broad diversity in terms of ethnicity, family characteristics, neighborhoods and geographic locations. One of the primary goals of CREW is to put together sets of data and samples of participating cohorts to identify phenotypes of childhood asthma (i.e. specific subtypes of asthma that can be distinguished by clinical features such as natural history, triggers, exacerbation frequency, concurrent allergies, lung function, sex, etc). Omics studies will include genotyping, methylation, and RNA sequencing. By integrating the DNA genotyping with the expression, immunologic and clinical data, we will identify eQTL, inflammation QTL, and lung function QTL, as well as QTL associated with other biomarkers. Analyses will identify genetic, epigenetic, transcriptional and protein/metabolite profiles that are associated with specific exposures or phenotypes. As we obtain mechanistic insights about personal and early life risk factors, we will connect asthma phenotypes with underlying causes and pathogenic mechanisms to define endotypes of childhood asthma.

  Study phs004036

• Genomics of Substance Use Disorders in Latin American Populations

  This is a subsample of the National Survey of Drug, Alcohol, and Tobacco Use, administered in 2016 between August and October to participants aged 12-65 in urban and rural Mexican households, named Mexican Genomic Database for Addiction Research (MxGDAR). The objective of the survey was to evaluate the patterns of use of different psychoactive substances and mental health problems in Mexico. The sample universe was made up of primary sampling units (PSUs) that were the sum of basic statistical geographic areas, stratified by state and urban-rural communities. An adult aged 18-65 was chosen randomly from each household, and an adolescent aged 12-17 was also chosen randomly from the household which has at least one member under 18. The second administration of the survey included a subsample of 13,130 respondents who agreed to give a saliva sample for DNA analysis, to be used in analyzing the relationship of mental health, addiction, and genetics. This sample was weighted according to selection probability to be representative on the national level. Mental health symptomatology for these individuals was evaluated using the Diagnostic Interview for Psychosis and Affective Disorders (DI-PAD) using the operational criteria for psychotic disorders (OPCRIT v.4.0), administered by interviewers trained in its use. It includes the evaluation of symptomatology of psychosis, depression, anxiety, obsession/compulsion, mania/hypomania, and post-traumatic stress. The study seeks to replicate genetic associations with substance use (LINC01622), psychiatric disorders (PTPRM), or comorbidity between both (MGMT) reported in following paper: https://pubmed.ncbi.nlm.nih.gov/33762635/. Funding for genotyping was provided by the National Institute on Drug Abuse (NIDA), one of the National Institutes of Health (NIH).

  Study phs003558

• Precision High Intensity Training Through Epigenetics (PHITE)

  Exercising regularly promotes health, but these benefits are complicated by acute inflammation induced by exercise. A potential source of exercise-induced inflammation is cell-free DNA (cfDNA), yet the cellular origins, molecular causes, and immune system interactions of exercise-induced cfDNA are unclear. To study these, 10 healthy individuals were randomized to a 12-week exercise program of either high-intensity tactical training (HITT) or traditional moderate-intensity training (TRAD). Blood plasma was collected pre- and post exercise at weeks 0 and 12 and after 4 week of detraining upon program completion. Whole-genome enzymatic methylation sequencing (EM-seq) with cell-type proportion deconvolution was applied to cfDNA obtained from the 50 plasma samples and paired to concentration measurements for 90 circulating cytokines. Acute exercise increased the release of cfDNA from neutrophils, dendritic cells (DCs), and macrophages proportional to exercise intensity (HITT > TRAD). Exercise training reduced cfDNA released in HITT participants but not TRAD and from DCs and macrophages but not neutrophils. For most participants, training lowered mitochondrial cfDNA at rest, even after detraining. Using a sequencing analysis approach we developed, we concluded that rapid extracellular traps (ETosis) was the likely source of cfDNA, demonstrated by enrichment of nuclear DNA. Further, several cytokines were induced by acute exercise, such as IL-6, IL-10, and IL-16, and training attenuated the induction of only IL-6 and IL-17F. Cytokine levels were not associated with cfDNA induction, suggesting that these cytokines are not the main cause of exercise-induced cfDNA. Overall, exercise intensity and training modulated cfDNA release and cytokine responses, contributing to the anti-inflammatory effects of regular exercise. One additional subject was also used in the methyl-seq data as a control for comparing bisulfite-sequencing to enzymatic methyl sequencing. DNA methylation for MPO gene was found to be significantly different as well, in line with interpretation that neutrophils are primarily undergoing ETosis.

  Study phs003873

• Gene-Specific RNA Sequencing in PLCG2-Associated Immune Dysregulation with Cold Urticaria

  This study utilized gene-specific RNA-sequencing of PLCG2 to screen for disease causing in-frame exon-skipping transcripts of PLCG2 in a collection of 9 subjects with cold urticaria, 2 subjects with known PLCG2-associated antibody deficiency and immune dysregulation (PLAID)-causing deletions of PLCG2 (positive controls) and 3 healthy subjects (negative controls). Full length cDNA of PLCG2 was generated using gene specific reverse transcription of peripheral blood mononuclear cell RNA. The full length PLCG2 cDNA was used as the template to create Illumina sequencing libraries. To identify the underlying genetic basis for the exon-skipping transcripts, trio-based whole genome sequencing was performed for probands in whom in-frame exon-skipping transcripts of PLCG2 were identified.

  Study phs003807

• CIDR NICHD Genetic Basis of Recessive Pediatric Brain Disease - Group 3

  The purpose of this study is to identify new genetic causes of recessive forms of pediatric neurodevelopmental disorders (NDDs) including Cerebellar hypoplasia (CBH), Lissencephaly (LIS), Microcephaly (MIC), Corpus callosum hypoplasia (CCH), Pontocerebellar hypoplasia (PCH), Pontine tegmental cap dysplasia (PTCD), and Aicardi syndrome among many others. Using whole exome sequencing (WES) on one or two affected members per family, we are able to identify many pathogenic genes for these families. Using Human SNP Linkage Scans, which takes advantage of the Illumina HumanCore Array, and parametric linkage analysis software (Genehunter, Allegro, and others), we seek to identify pathogenic loci utilizing 60-70 families per year. Through the combination of parametric linkage analysis with exome sequencing and bioinformatics approaches, we will refine our search for superior sensitivity and accuracy when investigating candidate genes and identifying causative mutations for disease.

  Study phs001510

• Black Representation in Genomic Research Whole Blood eQTL Study

  This dataset contains whole genome sequencing (WGS) results, as well as mRNA-seq of RNA extracted from a venous blood sample, from 23andMe research participants of African ancestry. This dataset facilitates the study of gene expression, genetic variation and the genetic architecture of gene expression in individuals of African ancestry.

  Study phs002969

• ARDSNet 07-08: Randomized, Blinded, Placebo-Controlled, Multi-Center Trial of Omega-3 Fatty Acid, Gamma-Linolenic Acid, and Antioxidants in Acute Lung Injury or ARDS (OMEGA) (ARDSNet-Omega-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-Omega include bronchial lavage, plasma, urine, and DNA. Please note that use of biospecimens in genetic research is subject to a tiered consent.Objectives: To determine if dietary supplementation of omega-3 (n-3) fatty acids, γ-linolenic acid and antioxidants to participants with acute lung injury would increase ventilator-free days to study day 28.Background: Early acute lung injury (ALI) is characterized by neutrophilic lung inflammation, permeability, and intravascular and alveolar fibrin deposition. The type and inflammatory activity of eicosanoids liberated during inflammation depends on the membrane phospholipid composition: omega 6 (n-6) fatty acid arachidonate yields highly reactive and inflammatory dienoic prostaglandins and series 4 leukotrienes, whereas omega-3 (n-3) fatty acids favor production of less active and potentially anti-inflammatory trienoic prostaglandins and series 5 leukotrienes. Participants at risk of developing ALI have n-3 levels approximately 25% of normal and those with established ALI have n-3 levels as low as 6% of normal, suggesting a potential role for n-3 dietary supplementation in participants with ALI.Three randomized controlled studies, conducted in participants with ALI or sepsis-induced respiratory failure, demonstrated an association between the administration of an enteral formula enriched in n-3 fatty acids, GLA, and antioxidants and improved oxygenation and respiratory physiology compared with an unenriched, high-fat formula. However, interpretation of these results is limited by the small sample sizes and as-treated analyses of only those participants who tolerated full enteral nutrition. Participants: The total number of participants in the study was 272.Design: Participants were stratified by hospital and the presence of shock at baseline and then randomized to receive either twice-daily enteral supplementation of n-3 fatty acids, GLA, and antioxidants (n-3 supplement) or an isocaloric-isovolemic carbohydrate-rich control. Participants were also simultaneously randomized to a separate ongoing trial (the EDEN study) comparing low- vs full-calorie enteral nutrition in a 2×2 factorial design.The n-3 or control supplement was administered enterally as twice-daily boluses of 120 mL beginning within 6 hours of randomization. Dosing continued until the earliest of 21 days, 48 hours of unassisted breathing, or extubation. The energy provided by the boluses supplemented that provided by each primary physician's choice of standard continuous non–n-3-enriched enteral formula. The rate of continuous enteral feeding was managed by a protocol with an algorithm for gastrointestinal intolerances. The supplement was administered even if enteral nutrition was interrupted, as long as the patient was tolerating enteral medications. Conclusions: The study was stopped by the DSMB for futility at the first interim analysis after 143 participants had been randomized to receive the n-3 supplement and 129 to receive the isocaloric control. Despite an 8-fold increase in plasma eicosapentaenoic acid levels, participants receiving the n-3 supplement had fewer ventilator-free days, intensive care unit–free days, and nonpulmonary organ failure-free days.

  Study phs003744

• Registry Evaluation of Vital Information for VADs in Ambulatory Life (REVIVAL-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 provide a greater understanding of the clinical trajectory of ambulatory patients with chronic, advanced, systolic heart failure that may benefit from ventricular assisted device (VAD) therapy and determine the relationship between baseline clinical measures and prognosis.BackgroundIdentification of patients at high risk for mortality is vital to advance cardiac therapies. Heart failure scores based on results from earlier clinical trials have generally underestimated mortality in advanced heart failure. Breakthroughs in mechanical circulatory support (MCS) have extended survival and quality of life measures in the most advanced heart failure patients. Increased survival of advanced heart failure patients combined with shortages of donor organs resulted in the United Network to Organ Sharing (UNOS) limiting priority to hospitalized patients or those on MCS. Consequently, those patients who were "less sick" were de-prioritized for transplantation, which resulted in a need to decrease mortality and morbidity through other therapies. There was limited evidence on the clinical characteristics of patients that would benefit the most from MCS compared to new medical therapies such as Left-ventricular assisted device (LVAD). The REVIVAL study was initiated with the broader goal of improving prognostic assessment in chronic, ambulatory, advanced systolic heart failure and to better inform the selection of appropriate candidates for future studies on additional strategies.ParticipantsREVIVAL enrolled 400 subjects from participating study sites.Selected subjects were aged 18-80 and diagnosed with ambulatory chronic systolic heart failure for more than 12 months. They were under the care of a cardiologist at selected study sites on appropriate evidenced -based heart failure medications and willing to continue to receive care from the enrolling advanced heart failure clinic over 2 years. Additional criteria included: NYHA class II -IV for at least 45 of the last 60 days; documented left ventricular ejection fraction ≤ 35% by any imaging modality; ICD or CRT-D.Subjects were excluded for the following reasons: a known serious medical problem other than heart failure that would be expected to limit 2-year survival (≥50% mortality within 2 years from non-heart failure diagnosis); current hospitalization, current use of an intravenous inotrope; uncorrected thyroid disorder; pregnancy. Subjects were excluded for additional medical or diagnostic criteria that would affect participation in the study.DesignThe REVIVAL registry was a prospective, observational, multicenter patient cohort derived from 25 US clinical sites. Medical records were reviewed to assess for potential enrollment into the study. Heart failure subjects that meet all eligibility criteria were approached to consent for this study. Consented patients participated in the following clinic visits over the course of 2 years: Baseline A, Baseline B and follow up visits at 6,12,18 and 24 months. All study visits were conducted in person.The following assessments were conducted at all visits: 6-minute walk test, bloodwork, concomitant medications, directed history and physical exams (including NYHA and INTERMACS profiles), gait speed test, handgrip strength test, and Quality of Life (QOL) and health utility questionnaires. A patient diary was distributed at the Baseline A visit.Additional assessments included: biomarker and genetic testing (Baseline B); caregiver questionnaire (all visits except Baseline A); demographics (Baseline A); ECG (Baseline A, Baseline B, and 12-month visit); Heart Failure Survival Score (Baseline B); maximal treadmill CPX test (Baseline B); Seattle Heart Failure Model Score (Baseline A, Baseline B, and 12-month visit); transthoracic Echo (Baseline B); outcome assessments (all visits except Baseline A).

  Study phs004738

• Comprehensive Genomic Characterization of Translocation Renal Cell Carcinoma

  Xp11 translocation renal cell carcinoma (tRCC) is a rare, female-predominant cancer driven by a fusion between the TFE3 gene on chromosome Xp11.2 and a partner gene on either chrX or an autosome. It remains unknown what types of rearrangements underlie TFE3 fusions, whether fusions can arise from both the active (chrXa) and inactive X (chrXi) chromosomes, and whether TFE3 fusions from chrXi translocations account for the female predominance of tRCC. To address these questions, we performed haplotype-specific analyses of chrX rearrangements in tRCC whole genomes. We show that TFE3 fusions universally arise as reciprocal translocations and that oncogenic TFE3 fusions can arise from chrXi:autosomal translocations. Female-specific chrXi:autosomal translocations result in a 2:1 female-to-male ratio of TFE3 fusions involving autosomal partner genes and account for the female predominance of tRCC. Our results highlight how X chromosome genetics uniquely constrains somatic chrX alterations and underlies cancer sex differences.This version of the dbGaP study provides a comprehensive set of whole genome data and tables with clinical information collected for the 16 patients (15 pateints as tRCC and 1 patient as ccRCC) in the study cohort. The data also contains 12 RNA-seq samples used in the study and analyses. We anticipate that this data will considerably advance our molecular and genetic understanding of oncogenic translocations in TFE3-tRCC involving inactive chromosome X and its role in cancer sex bias.

  Study phs003008

• DNA-Sequencing of Baseline and Progression Plasma from the Phase III Alliance A031201 Trial

  Circulating tumor DNA (ctDNA) in plasma cell free DNA (cfDNA) of cancer patients is associated with poor prognosis, but is challenging to detect from low plasma volumes. In metastatic castration-resistant prostate cancer (mCRPC), ctDNA assays are needed to prognosticate outcomes of patients treated with androgen receptor (AR) inhibitors. We developed a custom targeted cfDNA sequencing assay, named AR-ctDETECT, to detect ctDNA in limiting plasma cfDNA available from mCRPC patients in the Alliance A031201 randomized phase 3 trial of enzalutamide with or without abiraterone. For the AR ctDETECT assay, DNA-seq libraries were constructed from cfDNA using Takara ThruPLEX Tag-Seq or Plasma-Seq kits, and subjected to hybridization enrichment using a custom-designed Agilent SureSelect bait panel. Post-capture DNA-seq libraries were pooled and sequenced on an Illumina HiSeq 2500 or an Illumina NovaSeq 6000 SP using 2x150 bp settings. ctDNA positivity was defined by samples harboring high ctDNA aneuploidy as measured by a modified ichorCNA algorithm, or samples harboring low ctDNA aneuploidy but displaying AR gain or genomic structural rearrangement (AR-GSR), MYC/MYCN gain, or a pathogenic mutation. We used the AR-ctDETECT assay to analyze plasma collected at baseline from 776 patients, and found that 59% were ctDNA-positive. Patients who were ctDNA-positive at baseline had significantly worse median overall survival than patients who were ctDNA-negative at baseline. We also used the AR-ctDETECT assay to analyze plasma collected at progression from 431 patients. Relative to baseline cfDNA, progression cfDNA exhibited enrichment of features associated with poor prognosis, including elevated cfDNA concentrations and increased ctDNA positivity. AR alterations were enriched at progression relative to baseline, primarily driven by AR-GSRs, including those predicted to truncate the AR ligand binding domain and originate from AR amplification on extrachromosomal DNA. Stratification by radiographic progression-free survival revealed that patients with rapid progression were enriched for non-AR gene alterations, while patients with initially durable responses showed selective enrichment of AR alterations. These results indicate that non-AR genetic alterations in ctDNA are associated with primary resistance to AR pathway inhibitors in first-line mCRPC, while AR alterations are associated with secondary resistance, even in patients who initially respond. .

  Study phs003325

• Trisomy 21 Dosage Compensation Map (T21DoCoMap)

  Excess gene dosage from human chromosome 21 (HSA21), due to trisomy or translocation of HSA21 material, causes Down syndrome (DS). We derived trisomy 21 (T21) induced pluripotent stem cells (iPSCs) alongside otherwise isogenic euploid controls from mosaic DS fibroblasts (GM00260, first described in Lubiniecki et al., PMID: 225951) of the NIGMS genetic cell repository, to enable analysis of whole-chromosomal and individual gene dosage imbalance in the context of in vitro models of DS development. Virtual karyotyping (by Infinium CytoSNP-850k), and phased genotyping (by linked-read whole-genome sequencing) of the resulting iPSC lines provide a deeply-characterized genomic platform for dissection of HSA21 gene dosage. We apply this highly unique resource to allelic analysis of mRNA sequencing of iPSCs and differentiated neural lineages, and demonstrate its utility in the context of inducible HSA21 dosage compensation. To this end, we equipped one distinct HSA21 copy with a doxycycline-inducible XIST transgene, which endogenously silences one X in 46,XX females. Standard and allele-specific RNA-seq analysis confirms mono-allelic T21 silencing to be virtually complete and irreversible, further supported by DNA methylation data (Infinium methylEPIC). This full-length HSA21 map of phased single-nucleotide and insertion/deletion variants enables allele-specific applications for gene-level dissection T21 dosage effects. Because our XIST remains inducible in post-mitotic T21 neurons and astrocytes, we perform single-nuclei RNA-seq to demonstrate XIST efficiently represses genes even after terminal differentiation.

  Study phs002397

• Temptation Resistance Failures: Transdiagnostic Features and Influences

  Multiple forms of psychopathology involve problems with resisting temptations and urges. This study utilizes experience sampling (ES) methodology to assess temptation resistance across different classes of temptations and urges including both common everyday temptations and more disorder-specific temptation classes. The study tests the hypothesis that the broad ability to successfully resist temptations and urges across temptation classes is a common features of the externalizing superspectrum (factor) of psychopathology, particularly the disinhibition spectra as defined by the Hierarchical Taxonomy of Psychopathology (HiTOP). Additional associations are expected to arise between reduced temptation resistance success for specific temptation classes and narrower symptom domains associated with the externalizing and internalizing spectra (e.g., binge eating, and nonsuicidal self-harm among internalizing symptoms). The study further tests genetic and environmental influences on temptation strength and resistance ability with a focus on polygenic scores, adverse childhood experiences and childhood neighborhood deprivation variables that have previously been related to externalizing. To address these issues, we will study up to 1200 subjects (minimum 1000) selected with enrichment for psychopathology. Subjects will be recruited from a combination of ResearchMatch, and targeted contact with Reddit groups, and targeted social media/online advertisements, with targeted recruitment of at least 150 subjects who indicate problems with SUD, alcohol use disorder (AUD) or nicotine dependence, 70 who indicate problems with gambling or other impulse control problems, 70 subjects with criminal/legal problems, and 70 subjects based on binge eating episodes 70 with self-injurious behavior, and 70 with obsessive-compulsive disorder. Subjects will complete the (Externalizing Spectrum Inventory-BF and HiTOP-SR) to measure externalizing and internalizing spectra. Diagnoses in key categories will be confirmed with structured diagnostic interviews. Subjects also complete information on childhood adversity and geocoding is used to assess environment during development. The two-week ES regimen collects data on the strongest types of temptations and urges experienced by the subject, their subjective strength, the goal of the urge (pleasure/relief from negative feelings), the level of conflict with other goals, whether the person attempted to resist the temptation, the resistance strategy, and resistance success, to allow assessment of the extent to which differences in each of these facets (and calculated temptation resistance efficacy) are related to narrow or broad dimensions of psychopathology. Whole genome sequencing with .5x coverage and imputation will be performed to allow generation of polygenic scores for externalizing and addiction in order to test the hypothesis that externalizing polygenic scores are related to poor temptation resistance efficacy across temptation classes.

  Study phs004064

• Cardiovascular Health Study (CHS-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Related Studies having other CHS data available include:phs003639.v1.p1 Cardiovascular Health Study (CHS) – Imagingphs003637.v1.p1 Sleep Heart Health Study (SHHS-BioLINCC)phs001368.v4.p2 NHLBI TOPMed: Trans-Omics for Precision Medicine (TOPMed) Whole Genome Sequencing Project: Cardiovascular Health Studyphs000287.v7.p1 Cardiovascular Health Study (CHS) Cohort: an NHLBI-funded observational study of risk factors for cardiovascular disease in adults 65 years or olderphs000667.v4.p1 Building on GWAS for NHLBI-Diseases: The U.S. CHARGE Consortium - Sequencing (CHARGE-S): CHSphs000400.v6.p1 NHLBI GO-ESP: Heart Cohorts Exome Sequencing Project (CHS)phs000377.v6.p1 NHLBI Cardiovascular Health Study (CHS) Candidate Gene Association Resource (CARe)phs000301.v6.p1 PAGE: CALiCo: Cardiovascular Health Study (CHS)phs000226.v7.p1 STAMPEED: Cardiovascular Health Study (CHS)Biospecimens: Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from CHS include EDTA Plasma, Citrated Plasma, Serum, 2 Hour Serum, DNA, and Urine. Please note that use of biospecimens in genetic research is subject to a tiered consent.Available Data: The CHS-BioLINCC data package includes follow-up data through year 35, events data through 6/30/2015, and many ancillary studies.Objectives: The Cardiovascular Health Study (CHS) is a study of risk factors for development and progression of CHD and stroke in people aged 65 years and older. The objectives of the Cardiovascular Health Study are to: 1) quantify associations of conventional and hypothesized risk factors with CHD and stroke; 2) assess the associations of non-invasive measures of subclinical disease with the incidence of CHD and stroke; 3) quantify the associations of risk factors with subclinical disease; 4) characterize the natural history of CHD and stroke, and identify factors associated with clinical course; and 5) describe the prevalence and distributions of risk factors, non-invasive measures of subclinical disease, and clinical CHD and stroke.Background: The study originated in 1988 from the recommendations of an NHLBI workshop on the management of CHD in the elderly. This is the most extensive study undertaken by the NHLBI to study CVD exclusively in an elderly population. Initially funded for six years, CHS was renewed multiple times for additional examinations and continued morbidity and mortality follow-up.Participants: The 5,888 study participants were recruited from four U.S. communities and have undergone extensive clinic examinations for evaluation of markers of subclinical cardiovascular disease. The original cohort totaled 5,201 participants. A new cohort was recruited in 1992. The 687 participants in the new cohort are predominately African-American and were recruited at three of the four field centers.Design: The 2,962 women and 2,239 men were examined yearly from 1989 through 1999. The added minority cohort of 256 men and 431 women was examined from 1992 to 1999. Examination components have included medical history questionnaires, measurement of ankle-brachial index, abdominal and carotid ultrasound studies, echocardiograms, ambulatory electrocardiograms, cerebral magnetic resonance imaging, spirometry and retinal photographs over the past decade. The most extensive evaluations were at study entry (baseline) and again in 1992-1993 to assess change in subclinical disease measures. CHS has undertaken extensive follow-up for ascertainment of cardiovascular events including incident claudication, myocardial infarction, congestive heart failure, stroke and death.

  Study phs004879

• Pharmacogenomics and Pharmacometabolomics of Acamprosate Treatment Outcome

  Design and aims:The overarching goal of the study was to identify genetic markers associated with response to acamprosate treatment of alcohol use disorder (AUD). Specifically, the study aimed to enroll patients with AUD and randomize them to acamprosate or placebo treatment to allow identification of genetic markers associated with treatment outcomes, including acamprosate-specific pharmacogenomic effects. Genome-wide association analyses were completed using the newly collected data; subsequently, meta-analyses were performed to combine the new data with data from a prior genome-wide association study (GWAS) of AUD treatment outcomes that included the Mayo Clinic Center for Individualized Treatment of Addiction (CITA1) study, the COMBINE study and the PREDICT study (Biernacka et al., Neuropsychopharmacology, 2021). Here, the newly collected sample is referred to as CITA2. For CITA2, participants with AUD were recruited from Mayo Clinic sites in Rochester, MN and Albert Lea, MN (Fountain Center Residential Treatment Program), as well as Hazelden-Betty Ford affiliated treatment facilities in Center City, MN and Newberg, OR. Participants with comorbid depression and/or anxiety were treated with escitalopram or other SSRIs. Participants were randomized to acamprosate vs. placebo treatment, using stratified randomization within sites and within antidepressant (vs. no antidepressant) groups. Study participants and clinical personnel remained blinded to acamprosate or placebo assignment. Participants were evaluated by Psychiatric Research Interview for Substance and Mental Disorders (PRISM) at baseline to confirm alcohol use disorder diagnosis, and no secondary diagnosis of active other substance use disorder was present. Additional testing was done to rule out subjects with renal impairment or advanced liver disease. Participants were required to be willing to stop chronic/daily use of prescribed benzodiazepines, opioids, stimulants, cannabis related medication such as CBD or medical marijuana during participation. Review of medications including anti-depressants was done. Alcohol consumption was assessed by Timeline Follow Back (TLFB) at baseline and 1, 2 and 3 months during treatment. Treatment outcomes were derived from TLFB data and included continuous sobriety (yes/no) during 3 months of treatment, as well as the number of days until first alcohol use, the number of days until first relapse (≥ 5 drinks/day for men and ≥ 4 drinks/day for women) , and cumulative abstinence duration proportion, defined as the proportion of days over the length of follow-up during which a participant was completely abstinent from alcohol use.Population information: The total number of subjects that consented for the study was 379, with 288 randomized to acamprosate or placebo.Molecular Technologies: DNA was extracted and genotyping was performed using the Illumina Infinium Global Diversity Array. Principal Findings: Genome-wide association analyses were performed for time until relapse to any drinking ("time until relapse"), and time until relapse to heavy drinking ("time until heavy relapse") across all treatment groups. The analyses of the newly collected (CITA2) data identified no genome-wide significant associations with time until relapse or time until heavy relapse. Meta-analyses with data previously analyzed in Biernacka et al. (Neuropsychopharmacology, 2021) also did not identify significant associations with time until relapse or time until heavy relapse in the primary analyses. Data available: Genome-wide genetic data for participants recruited for this study will be available in dbGaP, along with demographic data and AUD treatment outcomes data.

  Study phs004068

• Epigenetic Control of Topoisomerase 1 by MacroH2A1.1

  DNA transactions introduce torsional constraints that pose an inherent risk to genome integrity. While topoisomerase 1 (TOP1) activity is essential for removing DNA supercoiling, aberrant stabilization of TOP1:DNA cleavage complexes (TOP1ccs) can result in cytotoxic single-stranded DNA lesions (SSLs). What protects the genome from aberrant TOP1 activity remains unknown. Using a combination of CUT&RUN and TOP1 Covalent Adduct Detection (CAD) Seq in MDA-MB-231 breast cancer cells (American Type Culture Collection, ATCC), we identified chromatin context as an essential means to ensure TOP1cc resolution at TOP1 hot spots. Through its ability to bind poly(ADP-ribose) (PAR), a protein modification required for TOP1cc repair, the histone variant macroH2A1.1 establishes a TOP1-permissive chromatin environment, while the alternatively spliced macroH2A1.2 isoform is unable to bind PAR or protect from TOP1ccs. MacroH2A1 isoform-specific analyses were based on reconstitution of macroH2A1.1 knockout cells with wild-type or PAR binding-deficient FLAG-tagged macroH2A1.1 in human breast cancer cells. Mechanistically, we find that macroH2A1.1 facilitates the recruitment of the TOP1cc repair factor XRCC1 in response to both endogenous and drug-induced topological stress. Impaired macroH2A1.1 splicing, a frequent cancer feature, was predictive of increased sensitivity to TOP1 poisons in a pharmaco-genomic screen in breast cancer cells, and macroH2A1.1 inactivation mirrored this effect in breast and ovarian cancer cells. Consistent with this, low macroH2A1.1 expression correlated with improved survival in cancer patients treated with TOP1 inhibitors (TOP1i). We propose that macroH2A1 alternative splicing serves as an epigenetic modulator of TOP1-associated genome maintenance and a potential cancer vulnerability.

  Study phs003729

• Genomic Landscape of Apical Periodontitis

  We undertook the first genome-wide association (GWAS) study of apical periodontitis, enrolling 932 patients with deep carious lesions at UTHealth School of Dentistry and the University of Pittsburgh School of Dental Medicine. We used a case-control design to compare those with apical periodontitis to those without. Genotype data was generated for all participants and imputed using the TOPMed reference panel. We performed a single-variant association testing, a subphenotype analysis, and a genetically regulated expression association analysis, and generated a polygenic risk score and performed phenome-wide association analysis. We identified eight near-genome-wide significant loci for our primary outcome, eight genes where genetically regulated expression was associated with apical periodontitis status, and 33 phecodes that were associated with the generated polygenic risk score. We also replicated three loci previously reported in the literature. Genotype, phenotype, and results from the primary association analysis will be available via dbGaP.

  Study phs003252

• Combined Genomic and Phenotypic Classification of Inherited and Acquired Genetic Disease with Long-Read Sequencing

  This study investigates the use of paired long read genetic and epigenetic sequencing in cell type deconvolution and the identification of cellular pathologies with absent or expanded populations. The data submitted to dbGaP contains sequencing read data generated by the pooling of samples from healthy individuals, sorting by flow cytometry into the key leukocyte populations of monocytes, CD4 T cells, CD8 T cells, NK cells, B cells, in addition to primary neutrophils acquired commercially, and sequencing by a PromethION sequencer (Oxford Nanopore Technologies). This allowed for the generation of data for both purified cell populations, as well as in silico synthetic mixture of defined compositions for evaluating epigenetic methods for cell type deconvolution.

  Study phs004480

• Pilot Study of Genetic Alterations and Clonal Evolution of Relapsed Refractory Adult ALL in Patients Receiving KTE-X19 CAR-T in ZUMA-3 (ZUMA3 Sequencing)

  This study is from the ZUMA-3 Phase 1/2 study of adults with relapsed/refractory B-cell acute lymphoblastic leukemia. Patients were treated with KTE-X19, an autologous anti-CD19 CAR T-cell therapy under investigation.

  Study phs002721