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