3613 results for "*geneti*"

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

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

  Study phs004705

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

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

  Study phs003419

• Uncovering Gene Regulatory Differences between Human and Chimpanzee Neural Cells

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

  Study phs004053

• NHLBI Growth and Health Study (NGHS-BioLINCC)

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

  Study phs004467

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

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

  Study phs003971

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

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

  Study phs004420

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

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

  Study phs004293

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

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

  Study phs003551

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

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

  Study phs004869

• REDIAL RNASeq Study

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

  Study phs004230