3613 results for "*geneti*"

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• Prevention and Early Treatment of Acute Lung Injury (PETAL) Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) (PETAL CLOVERS-BioLINCC)

  Data Access NOTE: Please refer to the "Authorized Access" section below for information about how access to the data from this accession differs from many other dbGaP accessions. Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from PETAL CLOVERS include plasma, and whole blood. Please note that use of biospecimens in genetic research is subject to a tiered consent. Available Data: The data available for request now include Long Term Outcome data.Objectives: To compare the effects of a restrictive fluid strategy (with early use of vasopressors) to a liberal fluid strategy in participants with sepsis-induced hypotension.Background: Intravenous fluid resuscitation is a common therapy used in the initial treatment of participants with septic shock and sepsis-induced hypotension. The goal of initial fluid therapy is to increase depleted or functionally reduced intravascular volume that occurs in sepsis due to a vasodilated vascular network. However, intravenous fluid resuscitation can create dilutional coagulopathy, fluid overload, and pathogenic edema in the lungs and other organs. Vasopressor agents are also commonly used to treat hypoperfusion by inducing constriction of arterioles and venules and increasing cardiac contractility. Vasopressor therapy also comes with risks that include vasoconstriction resulting in tissue ischemia, increased cardiac workload, and arrhythmias. Clinicians have used these strategies, typically in combination, to provide supportive care for participants with sepsis-induced hypoperfusion. However, at the time of the CLOVERS study, there was limited data to guide specific use of these therapies, including fluid volumes, in the early care of participants with sepsis-induced hypotension. The CLOVERS study hypothesized that a restrictive fluid strategy used during the first 24-hours of resuscitation for sepsis-induced hypotension would lead to lower mortality before discharge home by day 90 than a liberal fluid strategy.Participants: A total of 1,563 participants, from 60 medical centers, of the planned 2,230 participants were enrolled, with 782 assigned to the restrictive fluid group and 781 to the liberal fluid group. Enrollment in the trial was ended after the second interim analysis due to a lack of significant difference observed between the two 24-hour strategies.Design: This study was a multi-center, prospective, phase 3 randomized non-blinded interventional trial of fluid treatment strategies in the first 24 hours for participants with sepsis-induced hypotension. Participants were randomly assigned in a 1:1 ratio to either a restrictive fluid strategy (with early vasopressor use) or a liberal fluid strategy. In each group, the assigned protocol was followed for a period of 24 hours. The restrictive fluid protocol prioritized vasopressors as the primary treatment for sepsis-induced hypotension, with 'rescue fluids' being permitted for prespecified indications that suggested severe intravascular volume depletion. The liberal fluid protocol consisted of a recommended initial 2000-ml intravenous infusion of isotonic crystalloid, followed by fluid boluses administered on the basis of clinical triggers (e.g., tachycardia) with 'rescue vasopressors' permitted for prespecified indications. A protocol amendment implemented in October, 2019, allowed for limiting the initial infusion to 1,000 ml if the participant's blood pressure and heart rate had stabilized and the clinical assessment was that the participant was unlikely to benefit from additional intravenous fluid administration. The clinical team could override the protocol-specified care instructions at any time if it was judged to be in the best interest of the participant.The primary outcome was death from any cause before discharge home by day 90. Secondary outcomes included 28-day measures of the number of days free from ventilator use, days free from renal-replacement therapy, days free from vasopressor use, days out of the ICU, and days out of the hospital. Conclusions: Among participants with sepsis-induced hypotension, the restrictive fluid strategy that was used in this trial did not result in significantly lower (or higher) mortality, or other measures of recovery such as length of hospital stay, before discharge home by day 90 than the liberal fluid strategy.

  Study phs004080

• Imaging Genetics of Spasmodic Dysphonia

  Laryngeal dystonia (LD), or spasmodic dysphonia, is isolated focal dystonia characterized by selective impairment of speech production due to involuntary spasms in the laryngeal muscles. Despite well-characterized clinical features of LD, its clinical management remains challenging due, in part, to the absence of objective measures (biomarkers) for early detection and differential diagnosis. This results in diagnostic inaccuracies, which have a negative impact on the patient's quality of life and healthcare costs. Importantly, delayed diagnosis leads to deferred treatment. The objective of this application is to conduct a series of studies that combine advanced machine-learning with neuroimaging and genetics to (1) identify the neural markers that accurately differentiate LD between its clinical phenotypes (adductor vs. abductor), genotypes (sporadic vs. familial), and comorbid disorders (voice tremor and muscle tension dysphonia); (2) determine the early predictive neural markers of LD development in at-risk individuals, and (3) validate associated LD gene mutations. Supported by our preliminary data, our central hypothesis is that brain abnormalities are shaped, in part, by underlying genetic factors and exhibit LD form-characteristic features, which can be used as differential diagnostic and early predictive biomarkers of this disorder. Data submitted to dbGaP consist of sequences and phenotype information.

  Study phs004887

• Elucidation of Genotype-Phenotype Relationships Using Human Stem Cell Models

  Our goal of this work is to determine how natural human genetic variation influences molecular and cellular phenotypes using human pluripotent stem cell (hPSC) cells and their derivatives. This project utilizes the “cell village” approach in which hPSCs (or their derivatives) from many different genetically-distinct donors are pooled together in shared in vitro environments for high throughput multi-modal phenotyping. Genotypes for each donor are collected prior to village construction using whole genome sequencing or SNP array profiling followed by whole genome imputation. Molecular phenotypes for each donor are ascertained via single-cell RNA sequencing followed by Dropulation-based donor de-multiplexing. Finally, cellular phenotypes are quantified using low coverage (0.5-1X) whole genome sequencing of the village followed by Census-seq computation of donor proportions. By capturing genetic, molecular, and cellular phenotyping heterogeneity in a uniform environment, we can detect relationships among alleles, molecules, and cellular traits. The project data registered with the study includes assessments of cell fitness, defined as a cell's ability to proliferate and survive: (1) Low coverage (0.5X-1x) whole genome sequencing data from a human embryonic stem cell (hESC)-derived neural progenitor cell village consisting of 38 donors that was harvested at multiple time points (Day 0, 1, 5, 6, and 10) to quantify differential baseline growth rates among donors.(2) Low coverage (0.5X-1x) whole genome sequencing data from a human embryonic stem cell (hESC)-derived neural progenitor cell village consisting of 38 donors that was harvested at multiple time points (Day 0, 4, and 7) after exposure to a vehicle control, 3 uM, or 10 uM lead (Pb) acetate to quantify differential Pb sensitivities across donors. (3) Low coverage (0.5X-1x) whole genome sequencing data from a human induced pluripotent stem cell (hiPSC)-derived neural progenitor cell village composed of eleven neurotypical controls and twelve 16p11.2 deletion patients harvested at multiple time points (Day 0, 1, 5, 6, 10) to quantify case-control differences in baseline growth rates.

  Study phs004608

• Lineage Heterogeneity and Plasticity in Lung Cancer

  Our previous studies found lung cancer cells harboring amplification of lineage oncogenes are specifically dependent on their expression for survival. The need for lineage amplified genes in a subset of cancers suggests unique vulnerabilities in cancer cells that may be poised on the brink of survival. However, these amplifications represent only a minor subset of the two major subtypes of lung cancers. Therefore, this study focuses on the lineage factors that are essential during the development and control cell identity in adult cells, in the remaining subsets of lung cancers. Through genome-wide profiling of a histone marks, we identified ‘super-enhancers' (SE) on lineage-defining transcription factor genes. Subsequent hierarchical clustering of lung cancer samples identified SEs specific to subsets of lung cancers. We aim to understand the significance of factors defining the lineage state of the newly defined subsets of lung cancers.

  Study phs004458

• Field Studies of Human Immunity to Amebiasis in Bangladesh

  Amebiasis is a common cause of diarrhea and is associated with malnutrition in grade-school aged children in an urban slum of Dhaka, Bangladesh. Field Studies of Human Immunity to Amebiasis in Bangladesh was designed to determine the contribution of amebiasis to illness in the first 2 years of life when most deaths due to diarrhea occur, and understand the immunologic and genetic factors that protect children from amebiasis. The hypothesis underlying the study is that susceptibility to amebiasis is determined by host innate and acquired immune responses that vary between individuals in part due to: human genetic polymorphisms; environmental influences including malnutrition and concurrent geohelminth infection; and virulence differences among Entamoeba histolytica genotypes. Specific aims proposed in the design of the study were to: a) Measure the incidence of amebiasis and correlate it with human and parasite genetic polymorphisms, immune responses, and environmental factors such as geohelminth infection and malnutrition; b) Test the hypothesis that protective immunity is mediated both by innate immune responses initiated via TLR stimulation as well as by mucosal IgA against the Gal/GalNAc lectin and systemic IFN-γ; c) Test for the association of common genetic polymorphisms in host innate and acquired immune genes with incidence of amebiasis. 629 newborn babies were enrolled and followed regularly through bi-weekly surveillance for diarrheal episodes, anthropometry at 3-month interval until 60 months of age. The infants that were consented for GWAS analysis were genotyped in 3 separate batches at different times, on 3 different arrays. Quality control was performed on the 3 separate data sets and then jointly after merging. Genetic data available on 447 infants together with their phenotype data is made available in this submission.

  Study phs001476

• CIDR/NICHD Genetic Basis of Recessive Pediatric Brain Diseases

  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 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 phs001060

• HIV Associated Reservoirs and Comorbidities Study (HARC)

  Despite effective antiretroviral therapy (ART), people with HIV (PWH) are at risk for central nervous system (CNS) abnormalities, including cognitive impairment. B cells and antibodies are key mediators of adaptive immunity in neuroinflammatory disorders and crucial for viral control, but their role in HIV-associated CNS pathology is unknown. Here, we apply multimodal transcriptomic, epigenetic, and B-cell receptor profiling of B cells across cerebrospinal fluid (CSF), choroid plexus, and blood from ART-treated PWH and people without HIV, alongside neurocognitive assessments. In ART-suppressed PWH, CSF resting memory B cells exhibit impaired pathogen responsiveness, and high antibody gene mutations, suggesting CNS-restricted antigenic adaptation. Choroid plexus B cells exhibit similar transcriptomic immune perturbations despite viral suppression. Notably, CNS-specific B-cell molecular alterations are associated with poorer neurocognitive performance. These findings suggest that, despite long-term ART suppression, CNS memory B cells show suppressed antiviral pathways but increased antigen experience and trafficking, indicating dysregulated CNS immune surveillance and positioning them as key contributors to HIV-associated neuroimmune dysfunction.

  Study phs004745

• Defining Intrinsic and Acquired Mechanisms of Immune Checkpoint Blockade Resistance in Glioblastoma

  To systematically investigate the genomic features associated with benefit from anti-PD(L)1 in isocitrate dehydrogenase (IDH)-wildtype glioblastoma (GBM), we profiled 181 GBM cases (43 newly diagnosed, 138 recurrent) by whole exome sequencing (WES), targeted panel sequencing, and bulk RNA-sequencing (RNA-Seq). In multivariate survival analysis, baseline tumor transcriptional subtype and presence of their associated genetic lesions emerged as key features predicting overall survival (OS) among newly-diagnosed GBM treated with anti-PD(L)1, with the mesenchymal (MES) subtype associated with improved OS and the proneural subtype associated with poorer OS. Exposure to immune checkpoint blockade (ICB) was associated with outgrowth of subclones harboring lesions associated with non-MES subtype (CDKN2A deletions, PDGFRA gain-of-function mutations), which was not observed in analogous analyses of an external ICB-naive cohort. Our studies support the notion of an MES to non-MES transition as a common trajectory following ICB treatment for GBM.

  Study phs003614

• Circulating, Cell-Free DNA Methylation Patterns Indicate Cellular Sources of Allograft Injury after Liver Transplant

  Post-transplant complications reduce allograft and recipient survival. Current approaches for detecting allograft injury non-invasively are limited and do not differentiate between cellular mechanisms. Here, we monitor cellular damages after liver transplants from cell-free DNA (cfDNA) fragments released from dying cells into the circulation. We analyzed longitudinal blood samples collected from patients at different time points after transplant. Sequence-based methylation of cfDNA fragments were mapped to an atlas of cell-type-specific DNA methylation patterns derived from 476 methylomes of purified cells. For liver cell types, DNA methylation patterns and multi-omic data integration show distinct enrichment in open chromatin and regulatory regions functionally important for the respective cell types. We find that multi-tissue cellular damage post-transplant recovers in patients without allograft injury during the first post-operative week. However, sustained elevation of hepatocyte and biliary epithelial cfDNA within the first month indicates early-onset allograft injury. Further, cfDNA composition differentiates amongst causes of allograft injury indicating the potential for non-invasive monitoring and timely intervention.

  Study phs003610

• CIDR-Whole Genome Sequencing: Prospective Birth Cohort to Elucidate Etiology of ADHD in US Minority Children

  Attention Deficit Hyperactivity Disorder (ADHD) is the most common pediatric developmental disability, affecting at least 6 million U.S. children; children from minority racial and ethnic populations, such as Black children, are at even higher risk. A major challenge in preventing and treating ADHD is that the causes remain unclear. Available data suggest that both genetic and early life environmental factors may play a role. On the genetics forefront, although an increasing number of genome-wide association studies (GWAS) have been conducted, and many genetic variants have been linked to risk of ADHD, these loci only explain a small fraction of ADHD. One puzzle has been the substantial discrepancy in estimated heritability of ADHD by GWAS (10% to 28%) vs. family-based studies (~80%). This so called “missing heritability” could be due to limitations of available arrays for conducting GWAS. For example, loci identified by GWAS could simply be surrogates for causal variants and/or functional genes associated with ADHD, and important single nucleotide variations (SNVs) or genetic structural variants (SVs) are not captured by GWAS. To advance the field, we integrated whole genome sequencing (WGS) with a well-established and well-phenotyped prospective Boston Birth Cohort (BBC) comprised of predominantly US, Black children from under-resourced urban settings. These children were enrolled at birth and followed up to age 21 years. We performed WGS for 500 Black children, about half with clinically diagnosed ADHD and another half neurotypical children. WGS offers an unprecedented opportunity to examine the entire genome, including rare SNVs (including insertion or deletions), SNVs in the noncoding region (a potentially large and hitherto unexplored class of variations), and SVs (including copy number variations) not captured by current arrays for GWAS. We anticipate that this study will enable us to gain deeper insight into the genetic architecture underlying the development of ADHD, its findings will be directly relevant to reduce the health disparity of ADHD in the United States.

  Study phs003431