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

• Long-Term Isolation and Archaic Introgression Shape Functional Genetic Variation in Near Oceania

  We generated 175 whole-genome sequences (WGS) from 12 populations across the Bismarck Archipelago and Bougainville (Papua New Guinea). We used these data to infer the evolutionary history of these populations, quantify levels of Neandertal and Denisovan ancestry, detect signatures of positive selection, and functionally characterize genetic variants introgressed from Neandertals and Denisovans. FASTQ files for 175 individuals and variant calls jointly genotyped with a larger dataset of worldwide humans are made available. These genotype calls include samples from the Human Genome Diversity Project (HGDP, PRJEB6463), HGDP samples sequenced by the Simons Genome Diversity Project (SGDP, PRJEB9586), as well as samples from Vernot et al. 2016 (phs001085.v1.p1) and Tucci et al. 2018 (phs001633.v1.p1).

  Study phs004464

• Childhood Cancer Data Initiative (CCDI): Texas Pediatric Patient Derived Xenograft 

  The DNA/RNA samples of patients for which PDX models were developed were from a population of children, adolescents, and young adults from South Texas. Consent was obtained for collection of malignant and non-malignant tissue samples for genetic analysis and for the development of models to study new ways to treat cancer. For additional details, please refer to these publications: PMID: 37915590; PMID: 37990009.

  Study phs003215

• Lipid Research Clinics - Prevalence Study (LRC-PS-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Objectives: The LRC Program began in 1971 under the sponsorship of the National Heart, Lung, and Blood Institute, National Institutes of Health. Part of this program was the Lipid Research Clinics Prevalence Study, a standardized series of cross-sectional surveys of various North American populations designed to determine the prevalence of dyslipidemias and to describe the distributions of lipids and lipoproteins in major ethnic and social groups. In addition to contributing to the aggregate analysis, each independent population-based study was designed with capabilities for separate analyses of lipid and lipoprotein distributions. The participating populations were not selected to be a probability sample representative of the North American population per se, but by virtue of their size and economic and geographical diversity, they provide a useful cross-sectional group. The Family Study was the third phase of the Lipids Research Clinics North American Population Studies. The Family Study was designed to obtain knowledge of the distribution of lipids and lipoproteins among family members and of the association of familial and genetic attributes to dyslipoproteinemias. Background: An association between serum cholesterol and coronary heart disease is well established. A system was developed for classifying hyperlipoproteinemias into six types of patterns, as a basis for characterizing lipoprotein disorders. The Lipid Research Clinics was thus created to improve the detection of and clinical management of hyperlipoproteinemias. The three primary objectives were: 1) to acquire data on the prevalence of different types of hyperlipoproteinemia in various age and ethnic groups, with special emphasis on the nature and frequency of genetic forms; 2) to collect reliable data on the prevalence and incidence of atherosclerosis in different types of hyperlipoproteinemia; and 3) to conduct an intervention trial to determine if lowering plasma lipid levels would reduce the risk of CHD. Participants: There were 60,495 participants. Conclusions: Data from this study confirm findings from earlier studies in developed countries, showing age-related differences in plasma lipid levels. However, for overall distributions, the LRC data showed slightly lower cholesterol and markedly higher trigylceride values than those previously reported for North America. Some variation in plasma lipid values was evident among the clinic populations. The large number of participants within most subgroups permitted a variety of analytic and comparative studies. For example, data from the large pediatric population revealed a drop in plasma cholesterol levels in adolescent males and females. Males aged 20-50 years had higher cholesterol levels than females in the same age group, and higher trigylceride levels between ages 20-70 years. Numbers were also significient for meaningful comparisons between lipid distributions of females who were taking sex hormones and those who were not; in females taking sex hormones, cholesterol and triglyceride levels were higher for subjects younger than 45 years, but slightly lower after age 45, than lipid levels in females not taking hormones (Circulation 1979; 60(2):427-439).

  Study phs003995

• Veterans Administration (VA) Million Veteran Program (MVP) Summary Results from Omics Studies

  MVP is an ongoing prospective cohort study and mega-biobank in the Department of Veterans Affairs Healthcare System designed to study genetic influences on health and disease among veterans.

  Study phs001672

• KOLF2.1J iPSC and Differentiated Cell Types

  KOLF2.1J is a human induced pluripotent stem cell (iPSC) line that was selected and characterized by the iPSC Neurodegenerative Disease Initiative (iNDI) as a community reference line to support large-scale, collaborative research, with particular emphasis on neurodegenerative disease modeling. The line was generated as a sub-clone of the parental KOLF2-C1 iPSC line, which was originally reprogrammed from fibroblasts obtained from a male donor of European ancestry under informed consent and appropriate ethical approvals. During sub-cloning, a heterozygous 19-bp deletion in ARID2 present in the parental line was corrected, yielding a clonally derived line with a low burden of deleterious variants and no known high-risk alleles for neurodegenerative disease, making it well suited as a neutral genetic background for disease modeling.KOLF2.1J demonstrates robust and reproducible pluripotency, high genomic stability in culture and after gene editing, efficient CRISPR editing, and reliable tri-lineage differentiation potential, with performance validated across multiple independent laboratories. The KOLF2.1J has been chosen as a high-quality, broadly applicable reference iPSC line suitable for adoption as a common cellular substrate to reduce inter-line variability and facilitate cross-laboratory data integration. To enable widespread use, KOLF2.1J and a growing collection of gene-edited isogenic derivative clones have been made openly available to the research community. More details can be found in Pantazis et al., "A reference human induced pluripotent stem cell line for large-scale collaborative studies", Cell Stem Cell (2022); doi: https://doi.org/10.1016/j.stem.2022.11.004.Building on this foundation, the present study extends the genomic characterization of KOLF2.1J using long-read and long-range sequencing to generate a complete, telomere-to-telomere reference assembly, together with matched long-read genomic, epigenetic and long- and short-read based expression data from differentiated derivative cell types. This work is described in the accompanying preprint Alvarez Jerez et al., "The complete genome of the KOLF2.1J reference iPSC line", bioRxiv (2026); doi: https://doi.org/10.64898/2026.03.06.710144. Data available through this dbGaP study include newly generated long-read sequencing data of the parental KOLF2.1J iPSC line and the differentiated cell lines (astrocytes, cortical neurons, NGN2-derived neurons, microglia, and oligodendrocytes) derived from the parental KOLF2.1J, along with corresponding expression data, and the assembled Y chromosome sequence. The assembled Y chromosome will be shared under controlled access for research use only, given the heightened re-identification risk associated with Y chromosome sequence data. The full diploid assembly, excluding the Y chromosome, is available through GenBank under BioProject PRJNA1478016.

  Study phs004798

• Cutaneous Squamous Cell Carcinoma: Integrating Germline and Somatic Alterations that Underlie Tumor Progression

  Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer in the United States, affecting over a million people annually, and with significant mortality due to metastasis. The overall scientific objective of this study is to identify and integrate novel tumor mutational data with previously characterized information on host genetic risk factors and clinical risk factors to better understand how cancer risk alleles contribute to the development of cSCCs capable of metastasis. We analyze 290 cSCCs (145 primary cSCCs) that progressed to metastasis and 145 non-metastatic primary cSCCs arising in the well characterized GERA cohort to provide a comprehensive landscape of genomic alterations in cSCCs. The aims of the study are: a) characterize the somatic genome and transcriptome of metastatic and non-metastatic cSCCs, b) integrate somatic mutational analysis with environmental exposure data, and c) develop a risk prediction tool for metastatic-cSCC that integrate genomic and clinical data.

  Study phs003681

• NHLBI TOPMed: San Antonio Family Heart Study (SAFHS)

  The San Antonio Family Heart Study (SAFHS) is a complex pedigree-based mixed longitudinal study designed to identify low frequency or rare variants influencing susceptibility to cardiovascular disease, using whole genome sequence (WGS) information from 2,590 individuals in large Mexican American pedigrees from San Antonio, Texas. The major objectives of this study are to identify low frequency or rare variants in and around known common variant signals for CVD, as well as to find novel low frequency or rare variants influencing susceptibility to CVD. WGS of the SAFHS cohort has been obtained through three efforts. Approximately 540 WGS were performed commercially at 50X by Complete Genomics, Inc (CGI) as part of the large T2D-GENES Project. The phenotype and genotype data for this group is available at dbGaP under accession number phs000462. An additional ~900 WGS at 30X were obtained through Illumina as part of the R01HL113322 "Whole Genome Sequencing to Identify Causal Genetic Variants Influencing CVD Risk" project. Finally, ~1,150 WGS at 30X WGS were obtained through Illumina funded by a supplement as part of the NHLBI's TOPMed program. Extensive phenotype data are provided for sequenced individuals primarily obtained from the P01HL45522 "Genetics of Atherosclerosis in Mexican Americans" for adults and R01HD049051 for children in these same families. Phenotype information was collected between 1991 and 2016. For this dataset, the SAFHS appellation represents an amalgamation of the original SAFHS participants and an expansion that reexamined families previously recruited for the San Antonio Family Diabetes Study (R01DK042273) and the San Antonio Family Gall Bladder Study (R01DK053889). Due to this substantial examination history, participants may have information from up to five visits. The clinical variables reported are coordinated with TOPMed and include major adverse cardiac events (MACE), T2D status and age at diagnosis, glycemic traits (fasting glucose and insulin), blood pressure, blood lipids (total cholesterol, HDL cholesterol, calculated LDL cholesterol and triglycerides). Additional phenotype data include the medication status at each visit, classified in four categories as any current use of diabetes, hypertension or lipid-lowering medications, and, for females, current use of female hormones. Anthropometric measurements include age, sex, height, weight, hip circumference, waist circumference and derived ratios. PBMC derived gene expression assays for a subset of ~1,060 individuals obtained using the Illumina Sentrix-6 chip is also available from the baseline examination. The WGS data have been jointly called and are available in the current TOPMed accession (phs001215).

  Study phs001215

• Genes in Diabetic Retinopathy Project (DRCRnet-Genes)

  The "Genetics in Retinal Diseases Project" (Protocol-GEN) is an ongoing effort to create a repository of genetic material and clinical phenotype information as a resource for the research community, both public and private institutions. Blood samples are collected from consented participants from Diabetic Retinopathy Clinical Research (DRCR) Retina Network trials and sent to a qualified laboratory to harvest DNA and store the materials. This bioresource is available to the research community (e.g., government, academic centers, and industry) who may request samples, together with detailed clinical data, for genotypic analyses. When complete, the project will create a resource that combines high-quality genetic material and uniquely detailed phenotype information.The Network collaborated with Regeneron's Genetics Center for the sequencing of 2,084 samples, with both whole exome and genotype array data, as well as relevant phenotype data for the 8* completed studies (n = 2,074) are available for further analysis efforts. Of these, 850 samples of DME-only patients treated with anti-VEGF agents for 6 or 12 months were included in a GWAS study by the Network, in collaboration with the Mass Eye & Ear Infirmary (MEEI), for statistical analysis of the pharmacogenetics of treatment responses. Quality controlled genotypes from Illumina's Infinium Global Screening Array were imputed using the TOPMed reference panel. Both change in central subfield thickness (CST) and visual acuity (VA) were examined as co-primary phenotype endpoints, with several additional secondary outcomes and time to response. Linear and logistic regression were applied (PLINK2.0) to quantitative and dichotomous outcomes, respectively, on all samples and subpopulations (EUR, AFR, AMR) separately, adjusting for 10 genotype PCs, age, sex, HbA1c, diabetes type and duration, hypertension prior treatment, DR severity, baseline ETDRS and CST, and type/number of anti-VEGF agents received in 6 and 12 months. A cross-ancestry meta-analysis was performed on the 6-month time point using METAL. Replication of significant associations were pursued in a second independent sample set. To prioritize causal genes and pathways, gene and gene-set level association testing was performed using MAGMA. Colocalization analysis between expression and slicing QTLs (e/sQTLs) and significant GWAS loci was performed to further prioritize causal genes for genome-wide significant loci.Multiple loci were significant at a genome-wide significance (PPPIL3 and BICC1. Colocalization analyses with expression and splicing QTLs from GTEx tissues and retina further proposed putative causal genes for several loci. In replication analyses with a second, independent study, one locus on chromosome 5 passed genome-wide significance with a consistent direction of effect between the discovery cohort and replication cohort.Data available through dbGaP includes the entire genotype/sequencing dataset (2,084 samples), supporting documentation including SNP array and CNV calls derived from the sequencing, a linking table for accessing associated phenotype from the completed clinical trials (2,074 samples; URLs are listed in table below), and the GWAS/linkage results (851 samples). ProtocolProtocol DescriptionSamples AvailablePublic DatasetIIntravitreal Ranibizumab or Triamcinolone Acetonide in Combination with Laser Photocoagulation for Diabetic Macular Edema277DownloadMEffect of Diabetes Education during Retinal Ophthalmology Visits on Diabetes Control294DownloadSPrompt Panretinal Photocoagulation versus Intravitreal Ranibizumab with Deferred Panretinal Photocoagulation for Proliferative Diabetic Retinopathy196DownloadTA Comparative Effectiveness Study of Intravitreal Aflibercept, Bevacizumab and Ranibizumab for Diabetic Macular Edema460DownloadTXA Comparative Effectiveness Study of Intravitreal Aflibercept, Bevacizumab and Ranibizumab for Diabetic Macular Edema – Follow-up Extension Study5DownloadUShort-term Evaluation of Combination Corticosteroid+Anti-VEGF Treatment for Persistent Central-Involved Diabetic Macular Edema Following Anti-VEGF Therapy70DownloadVTreatment for Central-Involved Diabetic Macular Edema in Eyes with Very Good Visual Acuity423DownloadAAPeripheral Diabetic Retinopathy (DR) Lesions on Ultrawide-field Fundus Images and Risk of DR Worsening Over Time250DownloadABIntravitreous Anti-VEGF vs. Prompt Vitrectomy for Vitreous Hemorrhage from Proliferative Diabetic Retinopathy99Download*Protocol AD (PROMINENT-Eye Ancillary Study, NCT03345901) ended prematurely due to low recruitment. Samples were collected but insufficient clinical data is available to create a phenotype dataset.

  Study phs004015

• Kids First: The Genomic Architecture of Hirschsprung Disease (HSCR)

  Hirschsprung disease (HSCR) is a male biased developmental disorder associated with a lack of innervation of the gastrointestinal tract. Genetic studies have been instrumental in understanding its multifactorial inheritance, high heritability, syndromic associations, and genetic heterogeneity with variable penetrance and expressivity. At least 24 genes and 9 loci with pathogenic alleles (PAs) are known to underlie HSCR pathogenesis and explain 62% of its population attributable risk (PAR). Despite this heterogeneity, there is functional unity in HSCR: ~53% of HSCR PAs disrupt RET and EDNRB signaling in the developing enteric nervous system (ENS) in which 11 genes comprising a gene regulatory network control RET and EDNRB gene expression. We propose to identify the remaining 30% PAR by studying 857 unrelated HSCR cases, their 125 affected and 1,446 unaffected firstdegree relatives by whole genome sequencing to increase statistical power of gene discovery through improved detection of all types of coding and regulatory PAs. HSCR arises from cell autonomous defects in enteric neural crest cell precursors (ENCCs) affecting their proliferation, differentiation and migration in the ENS, functional studies that will guide our detection of novel genes.

  Study phs003662

• Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Related Studies: Other SPIROMICS data available include: SPIROMICS (main, phs001119); NHLBI TOPMed SPIROMICS (phs001927); Genetics and genomics (SPIROMICS Genetics Genomics, phs002399), and C4R SPIROMICS (phs002909).Biospecimens: Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from SPIROMICS include: bronchial lavage, bronchial wash, oral wash, plasma, serum, sputum, and urine. Please note that use of biospecimens in genetic research is subject to a tiered consent.Available Data: Data available for request include SPIROMICS I main study data as well as SPIROMICS Bridge phone call follow-up period data (period between SPIROMICS I NIH contract and SPIROMICS II grant).Objectives: The SPIROMICS study sought to identify homogeneous subgroups of COPD patients for targeted enrollment in future therapeutic clinical trials, as well as to identify and conduct preliminary validation of intermediate biological or clinical outcomes for use as clinical trial endpoints.Background: Chronic obstructive pulmonary disease (COPD) is a chronic, usually progressive, lung disease characterized by incompletely reversible airflow obstruction. At the time of the SPIROMICS study, COPD affected between 12,000,000 and 24,000,000 people in the US, with no proven medical therapies that significantly reduce mortality, other than supplemental oxygen and smoking cessation. COPD is also a highly heterogeneous disease. For example, cigarette smoke-induced chronic bronchitis and emphysema are subsumed within the COPD definition, despite histological and clinical differences. The recognition of COPD as a systemic disease that affects extra-pulmonary systems, including cardiovascular, sleep and muscle function, further complicates disease classification. Because of clinical and pathological heterogeneity, individual patient subtypes may benefit from unique therapeutic regimens. Thus the SPIROMICS study was initiated to facilitate the identification of important COPD phenotypes, based on disease pathophysiology and biomarkers that track key pathophysiologic processes, in order to focus research efforts and improve treatment options.Participants: Eligible participants were between 40 and 80 years of age, and included never-smokers, current and former smokers without obstructive lung disease, and current and former smokers with COPD. Never smoker was defined as less than 1 pack-year smoking history, and current or former smoker were defined as more than 20 pack-years smoking history. Lung function was also part of the eligibility criteria and was assessed by spirometry with or without inhaled bronchodilators. Non-smokers were required to have pre-bronchodilator FEV1 (forced expiratory volume in one second)/FVC (forced vital capacity) > 0.7 and FVC > LLN (lower limit of normal). Current or former smokers without obstructive lung disease were required to have post-bronchodilator FEV1/FVC > 0.7 and FVC > LLN. Current or former smokers with obstructive lung disease were required to have post-bronchodilator FEV1/FVC 50% predicted.Major exclusion criteria included non-COPD obstructive lung disease or a history of diseases or treatments likely to interfere with interpretation of study tests, BMI > 40 kg/m2 at baseline, hypersensitivity to or intolerance of the bronchodilators used in study assessments, and diagnosis of unstable cardiovascular disease. Design: SPIROMICS was a prospective cohort study that enrolled approximately 2,981 participants at twelve clinical centers over five years. Participants were distributed across four enrollment strata; never-smokers, smokers without COPD, smokers with mild or moderate COPD, and smokers with severe COPD.There were baseline (Visit 1) and three annual in-person follow-up visits (Visits 2–4). Participants also received quarterly follow-up calls to assess health status and determine if an exacerbation occurred. Visits 1, 2 and 4, included anthropometry, seated blood pressure, spirometry, 6-minute walk test, biological specimen collection, and a series of questionnaires. Information was collected on medical history, respiratory exposures and current medications. Visits 1 and 2 included a thoracic computed tomography (CT) scan at maximum inspiration and expiration. Clinical outcomes, including hospitalizations and deaths, were adjudicated centrally. The primary outcome measures up to month 36 were (1) morbidity measured by assessing acute exacerbations, (2) lung function by using spirometry and plethysmography to measure FEV1, FVC, FRC (functional residual capacity), and IC (inspiratory capacity), and (3) mortality. There were several key sub-studies involving SPIROMICS participants. The Repeatability and Replicate Sub-study enrolled 98 participants and repeated the entire baseline clinic visit, including the CT scanning, in order to quantify reliability and short-term within-person variability of study procedures and assay methods. In addition, sites collected blinded replicate samples on 5% of each specimen type at the Baseline, Year 1, and Year 3 visits. The Bronchoscopy Sub-study enrolled a total of 250 participants to undergo bronchoscopy with bronchoalveolar lavage, epithelial brushings and bronchial biopsies. The Exacerbation Sub-study enrolled a total of 214 participants that were followed prospectively and had biological samples (not available via BioLINCC) and clinical information collected at the time of an acute exacerbation.

  Study phs004568

• Identifying and Understanding Drivers of Chemoresistance in Small Cell Lung Cancer

  Using patient derived models of small cell lung cancer (SCLC), either the KEAP1 gene or the USP22 gene was deleted using lentiviral expression of a vector expressing CAS9 and single guide RNA (sgRNA) targeting KEAP1 or USP22. Control vector expressing models were also generated. RNA-Seq analysis was performed to compare gene expression in tumors growing in vivo, comparing KEAP1 deleted or USP22 deleted to control tumors under saline-treated and cisplatin/etoposide-treated conditions. Similar experiments were performed overexpressing USP22 or a control vector in a USP22-deleted patient derived xenograft model of SCLC. For USP22-deleted models, we also performed CUT&TAG analyses to examine the impact of USP22 loss on histone modifications.

  Study phs004087

• ChiLDReN/BA: Genetic Studies of Biliary Atresia in the Childhood Liver Disease Research Network

  Biliary atresia (BA) is a progressive necroinflammatory process initially involving the extra-hepatic biliary tree. Little is known about the factors that cause BA or the factors that influence disease progression. A variety of genetic, autoimmune, and environmental influences have been hypothesized to be important. Most studies to date have focused on the neonate and young child with BA, yet the older surviving child with BA can provide important information about genetics as well as natural history.The Childhood Liver Disease Research Network (ChiLDReN) conducts two longitudinal and observational studies that include BA patients: Biliary Atresia Study in Infants and Children (BASIC) and A Prospective Database of Infants with Cholestasis (PROBE). Using samples from participants in these two protocols, we have formed the largest known data set of biliary atresia patients in the world. ChiLDReN is performing a series of genomic analyses, with subsequent analyses being released as subsequent versions of this registration, phs003356. Version 1 concerns PKD1L1.About the PKD1L1 Analysis (phs003356.v1): While multiple factors have been implicated in the perinatal biliary injuries that characterize BA, a definitive etiology has not yet been established. This study is part of a larger project to characterize the largest cohort of pediatric BA patients through whole-exome sequencing (WES). In this analysis, we examine the WES of those with various laterality defects to determine whether genetic factors could be identified to explicate the etiopathogenesis of BA in biliary atresia splenic malformation (BASM) syndrome. We specifically explored variations in the PKD1L1 gene, which recently has been identified in mouse models as playing a role in laterality.

  Study phs003356

• Retrovirus Epidemiology Donor Study-II (REDS II) Donor Iron Status Evaluation Study (RISE) (REDS_II_RISE -BioLINCC)

  Data Access NOTE: Please refer to the "Authorized Access" section below for information about how access to the data from this accession differs from many other dbGaP accessions.Objectives The Retrovirus Epidemiology Donor Study-II (REDS-II) Donor Iron Status Evaluation Study (RISE) was designed to evaluate the effects of blood donation intensity on iron and hemoglobin (Hb) status, assess factors that could modify that relationship, and provide data to help formulate optimal whole blood donation frequency. Background Previous studies have shown that regular blood donors are at risk of iron deficiency. Also, a polymorphism in transferrin, which increases the likelihood that menstruating women will be iron deficient, and several genes for hemochromatosis were described in other previous studies. Findings from these studies lead to the possibility that genetic markers might define “at-risk” and “protected” donor groups with respect to iron depletion in blood donors. In addition, none of the previous donor studies had assessed the influence of racial/ethnic or socioeconomic factors, nor behavioral variables and dietary intake. Also, the availability of new tests of body iron status provided further opportunities to detect or prevent this problem. For these reasons, the National Heart, Lung, and Blood Institute's (NHLBI) Retrovirus Epidemiology Donor Study – II (REDS-II) program conducted the REDS-II Donor Iron Status Evaluation (RISE) whereby blood donors were followed prospectively for 15-24 months to provide an in-depth and contemporary evaluation of iron status in a US blood donor population.ParticipantsThe RISE study was a longitudinal multi-center study conducted between 2007 and 2009. All six REDS-II blood centers participated in the study: American Red Cross New England Region, Dedham, MA; the American Red Cross Southern Region, Atlanta, Georgia; the Blood Center of Wisconsin, Milwaukee, Wisconsin; the Hoxworth Blood Center/University of Cincinnati Medical Center, Cincinnati, Ohio; the Institute for Transfusion Medicine, Pittsburgh, Pennsylvania; and the Blood Centers of the Pacific, San Francisco, California. Two cohorts (2,425 whole blood or double red blood cell donors total) were established; one consisted of 888 first-time (FT) or reactivated (RA) donors and the other consisted of 1,537 frequent donors. The FT/ RA cohort consisted of men and women who had either never given blood before (FT) or had not given a donation in the two years before enrollment (RA). The frequent donor cohort consisted of men who had given the equivalent of ≥ 3 and women who had given ≥ 2 red blood cell units in the last year (or equivalent double-red blood cell donations). Male and females donors were recruited equally for each cohort. Most sites where donors were recruited were fixed rather than mobile sites. Only individuals who successfully donated whole blood or double-RBC units, were not deferred at their enrollment visit, and had agreed to donate frequently in the following 24 months were included in the study.DesignData on previous blood donation history; smoking history; diet; use of vitamins, supplements, and aspirin; and reproductive history (female donors) were collected through a self-administered enrollment questionnaire. Also, blood donation activity before and after enrollment, height, weight, country of birth, race and/or ethnicity, and highest educational level were compiled from blood center records and the donor information form that donors completed at the time of donation at the REDS-II centers. At enrollment, ferritin, soluble transferrin receptor (sTfR), and fingerstick and venous hemoglobin were determined. Models to predict two measures of iron deficiency, absent iron stores (AIS) and iron-deficient erythropoiesis (IDE), and hemoglobin deferral were developed. Absent iron stores (AIS) were indicated by a ferritin level of less than 12 ng/mL and iron-deficient erythropoiesis (IDE) by a log(sTfR/ferritin) value of 2.07 or greater, corresponding to the 97.5 percentile of the distribution of the log (sTfR/ferritin) in FT/RA males at enrollment. For hemoglobin deferral, a donor was deferred by current standards if their hemoglobin was ConclusionsA large proportion of both female and male frequent blood donors have iron depletion. Strong associations between higher prior donation intensity and a shorter time since last donation and iron depletion were observed. Iron depletion also developed in a high proportion of returning FT/RA donors (51% of females and 20% of male had IDE on follow up). Other than donation intensity and time since last donation, gender, weight, age, and the use of self-administered iron supplements were found to be important independent predictors of AIS and/or IDE. Time since last red cell donation was a highly significant factor for hemoglobin deferral as were black race, female gender and younger age in women. Reducing the frequency of blood donation is likely to reduce the prevalence of iron deficiency among blood donors, as might implementing routine iron supplementation.

  Study phs004507

• Tumor detection by analysis of both symmetric- and hemi-methylation of plasma cell-free DNA

  Aberrant DNA methylation plays a critical role in tumorigenesis. While DNA methylation has been used for cancer detection and classification, DNA hemi-methylation, a novel epigenetic mark has not been analyzed extensively in cancer epigenomes. Here we report a strand-specific (ss) sequencing method (MeDIP-Seq) for plasma cell free (cf) DNA (sscf-MeDIP-Seq), which can analyze both symmetrically methylated DNA regions (DMRs) as well as hemi-methylated regions (DHMRs). Using the sscf-MeDIP-Seq method, we analyzed plasma cfDNA methylomes of 271 samples from subjects with liver cancer and brain cancer and from individuals without cancer (controls). Among them, 215 samples were chosen as the discovery cohort for the identification of DMRs and DHMRs specific in each subject group and for the training of machine learning models of multi-cancer detection (MCD) using DMRs, DHMRs and DMRs+DHMRs as inputs. These models were then used to predict the 56 samples in the validation cohort. We found that models trained with DMRs+DHMRs as inputs in general outperformed models trained with DMRs or DHMRs alone, with AUROC being 0.971, 0.981, and 0.99 in predicting control, liver and brain cancer samples in the validation cohort, respectively, by the DMR+DHMR-trained models.

  Study phs003462

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

  This study description pertains to the ADOPT PGx Acute Pain Trial.The overall ADOPT PGx 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 (this study), the Chronic Pain Trial, 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. Acute 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 post-surgical opioid therapy (Intervention arm) or standard care and pharmacogenetic testing after 6 months (Control arm). Actionable phenotypes are defined as CYP2D6 intermediate metabolizers (IMs) and poor metabolizers (PMs) (i.e. CYP2D6 activity score ≤ 0.75) for the acute pain trial. This study includes approximately 1,610 participants with planned/elective surgery who are anticipated to start a pain control medication with existing CPIC guidelines after their surgery.

  Study phs004058