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• Coronary Artery Risk Development in Young Adults (CARDIA-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 CARDIA data available include:phs000236.v2.p2 PAGE: CALiCo: Coronary Artery Risk Development in Young Adults(CARDIA) phs000309.v3.p2 The CARDIA-GENEVA Study phs000399.v1.p2 NHLBI GO-ESP: Heart Cohorts Exome Sequencing Project (CARDIA) phs000613.v1.p2 NHLBI CARDIA Candidate Gene Association Resource (CARe) phs003675.v1.p1 CARDIA Multi-omics Obesity & CVD Substudy – Year 20 Untargeted Metabolomics Data phs001612.v3.p2 NHLBI TOPMed: CARDIA (Coronary Artery Risk Development in Young Adults) phs003045.v1.p1 Collaborative Cohort of Cohorts for COVID-19 Research (C4R): Coronary Artery Risk Development in Young Adults Study (CARDIA) phs000285.v4.p3 CARDIA_Cohort Available Data: Available data for request include exam data through Year 30 and outcomes and death data through 2022. Additionally, data from 28 ancillary studies are available for request.Objectives: The original objectives of CARDIA were to document levels of risk factors for coronary artery disease and potential determinants of these risk factors in young adults; to study the interrelationships of risk factors and lifestyles and to document behavioral and environmental changes during the transition from young adulthood to middle age; to compare cross-sectional and longitudinal data on age-related trends in cardiovascular disease risk factors; and to compare levels and evolution of risk factors between men and women, blacks and whites, and in groups of differing socioeconomic status. Goals of the study have evolved to emphasize understanding determinants of left ventricular mass, emerging obesity and hypertension, and sequelae of hypertension in pregnancy.Background: CARDIA is designed to increase understanding of contributors to changes in cardiovascular disease (CVD) risk factors during the critical years of transition from young adulthood to middle age. CARDIA was funded initially in 1983 for a five-year cycle that included two rounds of examinations. Contract renewals have allowed for subsequent re-examinations.Participants: Black and white men and women; ages 18-30 years at entry with a range of attained education; original sample size: 5,115.Design: CARDIA is a population-based observational study of 5,115 participants aged 18-30 years recruited in 1985-1986. The sample was designed to achieve approximately balanced subgroups of race, gender, education (high school or less and more than high school) and age (18-24 and 25-30). Forty percent of the cohort had no more than a high school education. A total of nine examinations have been completed in the cohort with examination cycles at year 2 of the project and years 5, 7, 10 , 15, 20, 25, and 30.In addition to standard measurements of blood pressure, anthropometry, blood lipids, smoking behavior, physical activity, diet, pulmonary function, and many psychological factors, CARDIA has other included measurements (in subsets or in the full cohort) to obtain unique information on other aspects of risk factor development and early morbidity. These have included: graded exercise treadmill testing; echocardiography, particularly for measurement of left ventricular mass; cardiovascular reactivity; serum cotinine; Lp(a), apoE phenotype, apolipoprotein A1 and B; homocysteine; skin reflectance; body composition by dual X-ray absorptiometry; glucose tolerance testing; vascular resistance and compliance; and plasma renin activity and sympathetic nervous system activity.

  Study phs003739

• Heart Failure Network - Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure (HFN RELAX-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 StudyEcho images are available through HFN RELAX-ImagingObjectivesThe RELAX trial tested the hypothesis that chronic phosphodiesterase type-5 inhibitor therapy with sildenafil would improve exercise capacity and clinical status in heart failure patients with normal ejection fraction, as compared to placebo. Background Heart failure (HF) with preserved ejection fraction (HFpEF) is a common and highly morbid condition that is characterized by chronic exercise intolerance, progressive functional decline and a high rate of readmission. At the time of the RELAX trial, clinical trials of renin-angiotensin system antagonists had not demonstrated improvement in outcomes or clinical status in HFpEF, and effective therapies were needed. Phosphodiesterase type-5 (PDE-5) metabolizes the nitric oxide (NO) and natriuretic peptide (NP) systems' second messenger cyclic guanosine monophosphate (cGMP), and thus may limit beneficial NO and NP actions in the heart, vasculature and kidney. Pre-clinical studies suggest that inhibition of PDE-5 reverses adverse cardiac structural and functional remodeling and enhances vascular, neuroendocrine and renal function. In clinical studies, PDE-5 inhibitor therapy improved exercise tolerance and clinical status in patients with idiopathic pulmonary arterial hypertension and in patients with HF and reduced ejection fraction (HFrEF). A small, single-center study in HFpEF observed improved hemodynamics, left ventricular (LV) diastolic function, right ventricular (RV) systolic function, LV hypertrophy and lung function with chronic PDE-5 inhibition as compared to placebo. In aggregate, these studies suggested the potential for PDE-5 inhibition to ameliorate several key pathophysiological perturbations in HFpEF, and thus improve exercise capacity and clinical status. ParticipantsA total of 216 participants were enrolled in the trial with 113 in the Sildenafil group and 103 in the placebo group. Design Participants who met screening criteria underwent baseline studies including a history and physical examination, cardiopulmonary exercise test (CPXT), six-minute walk distance, Minnesota Living with Heart Failure Questionnaire (MLWHFQ), echocardiography, cardiac magnetic resonance imaging, and phlebotomy for biomarkers. Subjects were then randomly assigned, in a 1:1 ratio, to either the sildenafil or placebo intervention group. The study drug was administered orally at 20 mg three times daily (TID) for 12 weeks. If the dose was well tolerated at 12 weeks, it was increased to 60 mg TID for another 12 weeks. If side effects developed, study staff could recommend discontinuation or return to a lower or previously tolerated dose of study drug. Sildenafil levels 2 hours after a scheduled dose of study drug were obtained at 12 and 24 weeks. The primary endpoint was exercise capacity determined by change in peak oxygen consumption during the CPXT after 24 weeks of therapy. Secondary endpoints included change in six-minute walk distance at 12 and 24 weeks, change in peak oxygen consumption at 12 weeks, and a three tier score reflective of clinical status where patients were ranked based on time to death (lowest tier), time to cardiovascular or cardiorenal hospitalization (middle tier), and change in the MLWHFQ for patients alive without cardiovascular or cardiorenal hospitalization after 24 weeks (highest tier). Conclusions Chronic phosphodiesterase type-5 inhibitor therapy with sildenafil for 24 weeks did not alter exercise capacity or clinical status compared to placebo in patients with heart failure and preserved ejection fraction.

  Study phs003565

• Targeting the p53 pathway to treat Malignant Rhabdoid and High-Risk Atypical Teratoid Rhabdoid Tumors

  Rhabdoid tumors (RTs) predominantly affect young children and are among the deadliest pediatric solid tumors. Despite multimodal therapy consisting of surgery, radiation, and chemotherapy, children with these tumors have median survival of less than one year. RTs can arise throughout the body, including the central nervous system (CNS) where they are called atypical teratoid rhabdoid tumors (AT/RTs), and in extra-CNS locations such as the kidneys and other soft tissues where they are designated malignant RTs (MRTs). We previously identified MDM2 and MDM4 as therapeutic vulnerabilities in RTs and showed that treatment with the MDM2 inhibitor idasanutlin increased survival in mice bearing MRT xenografts. However, the therapeutic potential of idasanutlin in CNS RT tumors is unknown. Single agent therapies are prone to resistance and show limited clinical benefit on their own. Therefore, we sought to identify combination strategies incorporating idasanutlin that would be effective in both CNS and extra-CNS RTs. Here, we show that the XPO1 inhibitor selinexor increased nuclear retention of p53 and potentiated idasanutlin-induced p53 pathway activation and cytotoxicity in AT/RT and MRT cell lines in vitro. Importantly, combination therapy limited acquired resistance through TP53 mutation. In vivo, combination therapy was well-tolerated, reduced tumor burden, and increased survival in orthotopic models of both AT/RT and MRT. Our results demonstrate that combining idasanutlin with selinexor is a promising therapeutic strategy for children with rhabdoid tumors.

  Study EGAS00001007680

• Atypical B cells and impaired SARS-CoV-2 neutralisation following heterologous vaccination in the elderly

  Age is a major risk factor for hospitalization and death after SARS-CoV-2 infection, even in vaccinees. Suboptimal responses to a primary vaccination course have been reported in the elderly, but there is little information regarding the impact of age on responses to booster third doses. Here we show that individuals 70 or older who received a primary two dose schedule with AZD1222 and booster third dose with mRNA vaccine achieved significantly lower neutralizing antibody responses against SARS-CoV-2 spike pseudotyped virus compared to those below 70 at one month post booster. Neither the concentration of serum binding anti spike IgG antibody, nor the frequency of spike- specific B cells showed differences by age grouping. Impaired neutralization potency and breadth post-third dose in the elderly was associated with enrichment of circulating “atypical” spike-specific B cells expressing CD11c and FCRL5. Presence of these atypical B cells was confirmed by scRNA seq. However, when considering individuals who received three doses of mRNA vaccine, we did not observe statistically significant differences in neutralization or enrichment in atypical B cells by age grouping following dose 3. Together, our data reveal impaired neutralising antibody responses in the elderly after heterologous vaccination with AdV followed by mRNA booster dose, but not in homologous three dose mRNA vaccination highlighting that different vaccine formats differentially instruct the memory B cell response.

  Study EGAS00001007385

• 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

• WGS data from LCNEC patient derived tumor organoids (PDTOs) and matched parental tumors - SA

  The dataset includes cram files from WGS of 2 LCNEC tumors and matched PDTOs. For all tumors, cram files from WGS of matched normal tissue derived organoids from the corresponding patients is included. Analysis VCF files are also included in the dataset. The sequencing was done with a NovaSeq 6000 instrument.

  Dataset EGAD00001009990

• Transcriptomics-driven classification of ALAL

  Acute leukemia of ambiguous lineage (ALAL) is a rare, poor-prognosis subtype of acute leukemia that cannot be assigned to a single hematopoietic lineage. Although ALAL patients are typically treated with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) regimens, optimal treatment choice is hindered by their lineage ambiguity. Therefore, we investigated the added value of transcriptomics for improving lineage assignment, currently based mainly on surface markers. First, we used an in-house pipeline to comprehensively detect genetic lesions in RNA-sequencing data (n=23) with a sensitivity >90%, as confirmed by targeted DNA sequencing. Second, we compared ALAL gene expression profiles (GEPs) with representative AML (n=145), B-ALL (n=223) and T-ALL (n=85) cases. In a principal component analysis, ALALs did not form a separate group, but clustered with AML, B-ALL or T-ALL. Accordingly, a machine learning classifier trained with GEPs of acute leukemias segregated 20/23 ALALs into myeloid-, B- or T-lymphoid leukemia. These 20 cases harbored genetic abnormalities consistent with the classifier-assigned leukemia. Furthermore, ALAL GEPs were deconvoluted with single-cell transcriptional profiles of normal hematopoietic cells using CIBERSORTx, revealing enrichment for signatures of lineages corresponding to the leukemic type predicted by our algorithm. The classifier was validated on an external ALAL cohort (n=24), assigning 75% of the patients to a lineage matching their immunophenotypic and methylation profiles. In conclusion, integrative analysis of RNA-sequencing data can accurately classify most ALAL cases. The pipeline and classifier developed in our study are valuable tools to improve ALAL diagnosis and guide therapeutic decisions.

  Study EGAS00001007967

• 3/7 Psychiatric Genomics Consortium: Finding Actionable Variation

  The goal of this study was to generate new therapeutic hypotheses by targeted sequencing of 161 genes most likely to harbor schizophrenia (SCZ) causal variants in multi-ancestry schizophrenia case-control cohorts. The gene panel was intended to contain putative SCZ risk genes, from within which, the majority of new discoveries from additional WES/WGS would come. To this end, we integrated current knowledge of the genetic architecture of SCZ (results from The Schizophrenia Exome Sequencing Meta-Analysis Consortium, or SCHEMA) and gene membership in gene sets that have been implicated in SCZ using a Bayesian framework. A total of 23,352 individuals selected to be non-overlapping with SCHEMA, as well as other previous and ongoing sequencing efforts in the field, were identified from over 20 individual study sites. Sequencing of the exonic regions of 161 prioritized genes was performed on the Ion Torrent platform in between June 2018 and April 2019. Sequencing plates were matched with respect to ancestry and case/control composition whenever possible. The average sequencing depth across all samples was 224x. Single sample calling was performed using Torrent Variant Caller v5.8.0, which is specially optimized to exploit the underlying flow signal information generated by the Ion Torrent sequencing. The schizophrenia case-control status was obtained from each original study site.

  Study phs003138

• National Cancer Institute (NCI) TARGET: Therapeutically Applicable Research to Generate Effective Treatments

  The Therapeutically Applicable Research to Generate Effective Treatments (TARGET) Initiative seeks to accelerate research in novel marker and drug development, along with understanding the molecular basis of pediatric malignancy, through identification of genomic changes associated with the following childhood cancers: Acute Lymphoblastic Leukemia (ALL) - A fast-growing type of blood cancer in which too many immature white blood cells are found in the blood and bone marrow. Acute Myeloid Leukemia (AML), including AML Induction Failure cases (AML-IF) - Another type of blood cancer marked by too many myeloblasts, an alternate type of immature white blood cell, are found in the blood and bone marrow. Upon diagnosis, AML patients without high-risk genetic markers undergo standard chemotherapy regimen, called the primary induction phase, to eliminate most cancer cells and induce a remission state. Clear Cell Sarcoma of the Kidney (CCSK) - A rare type of kidney cancer, in which the inside of the cells looks clear when viewed under a microscope. Clear cell sarcoma can spread from the kidney to other organs, most commonly the bone, but also including the lungs, brain, and soft tissues of the body. Neuroblastoma (NBL) - Cancer of cells of the sympathetic nervous system. Cancer Model Systems (MDLS), including PPTP - MDLS includes acute leukemia cell lines and xenografts with matched primary and/or relapsed tumor information, NBL cell lines and xenografts with matched controls, kidney tumor cell lines, normal brain tissues, and embryonic stem cell lines that were sequenced for some TARGET disease projects. Osteosarcoma (OS) - A cancer of the bone that primarily affects children and adolescents. Rhabdoid Tumor (RT) - A rare, fast-growing cancer that usually forms in the kidney or central nervous system (the brain and spinal cord) but can also form in soft tissues in other areas of the body. Rhabdoid tumors tend to spread quickly, are hard to treat, and have a poor prognosis. Wilms' Tumor (WT) - A cancer of cells in the kidney that can spread to the liver, lung and lymph nodes. More information can be found about each TARGET subproject by following the links on the top of this page. Together these cancers account for the majority of the more than 10,000 childhood cancer cases diagnosed in the United States each year. TARGET has employed a set of advanced and complementary genome analysis technologies, including large scale 2nd and 3rd generation genome sequencing, to strategically characterize alterations in both gene expression and in genomic structure (such as deletions and amplification) that are involved in childhood cancers. The goal of this coordinated effort has been to create a comprehensive genomic and transcriptomic profile of each cancer. Integrated analysis of the TARGET data has identified those genes that are either altered in their expression level or mapped to the chromosome regions of deletion/amplification/translocation, as these genes represent strong candidates for therapeutic targeting. To learn more about the TARGET project, which is now completed, visit the website at https://www.cancer.gov/ccg/research/genome-sequencing/target. TARGET data is accessible at the NCI's Genomic Data Commons (GDC) via the GDC's Data Portal and from each of the TARGET Publication Pages at the GDC (Please see the "Supplemental Links" section of any TARGET publication's "Publication Information and Associated Data Files page" at the GDC.). Available datasets include raw sequencing data, datasets generated by the original TARGET research teams (fully annotated clinical information and higher-level/analyzed molecular characterization data - gene expression, copy number variation, epigenetics, targeted sequencing), as well as higher level data generated by the GDC. Please see the TARGET Use and Publication Guidelines for updated details on the sharing of any TARGET substudy data, including how to cite TARGET.

  Study phs000218

• The Mood and Methylation Study (MMS)

  The Mood Methylation Study (MMS) is an observational study designed to understand epigenetic mechanisms underlying major depression symptoms (MDD) using a co-twin control design. Twins enrolled in the MMS were monozygotic (MZ) twin pairs discordant on lifetime history of MDD. All twins were members of the Washington State Twin Registry (WSTR), a community-based twin registry consisting of over 10,000 twin pairs. Lifetime and current MDD diagnoses were determined using the Structured Clinical Interview for DSM-IV Research Version (SCID-4-RV). DNA methylation in blood monocytes was measured using the Infinium HumanMethylationEPIC BeadChip. Monocyte gene expression was quantified by paired end RNA-seq (50 PE). Zygosity of the twin pairs included in the MMS was self-reported and confirmed using the polymorphic SNPs included in the DNA methylation array.

  Study phs002858