Search Results - EGA European Genome-Phenome Archive

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PAGE: The Charles Bronfman Institute for Personalized Medicine (IPM) BioMe BioBank

The Institute for Personalized Medicine (IPM) BioMe Biobank is a consented, EMR-linked medical care setting biorepository of the Mount Sinai Medical Center (MSMC) drawing from a population of over 70,000 inpatients and 800,000 outpatient visits annually. MSMC serves diverse local communities of upper Manhattan, including Central Harlem (86% African American), East Harlem (88% Hispanic Latino), and Upper East Side (88% Caucasian/white) with broad health disparities. IPM BioMe Biobank populations include 28% African American, 38% Hispanic Latino predominantly of Caribbean origin, 23% Caucasian/White. IPM BioMe Biobank disease burden is reflective of health disparities with broad public health impact. Biobank operations are fully integrated in clinical care processes, including direct recruitment from clinical sites waiting areas and phlebotomy stations by dedicated Biobank recruiters independent of clinical care providers, prior to or following a clinician standard of care visit. Recruitment currently occurs at a broad spectrum of over 30 clinical care sites. This study is part of the Population Architecture using Genomics and Epidemiology (PAGE) study (phs000356).

Study phs000925

FIGHT-207: Anonymized Genomic Alterations and Clinical Responses

Background: FIGHT-207 was a phase 2 study of the FGFR1-FGFR3 inhibitor pemigatinib in patients with previously treated, locally advanced/metastatic or unresectable solid tumor malignancies harboring activating fibroblast growth factor receptor (FGFR) gene alterations. Population information: 107 patients were divided into 3 cohorts: FGFR1–FGFR3 fusions/rearrangements; n=49 Activating FGFR1–FGFR3 non-kinase domain single nucleotide variants (SNVs); n=32 FGFR1–FGFR3 kinase domain mutations or variants of unknown significance (VUS) with potential pathogenicity; n=26 Participants on study had tumors that were grouped into the following histologies based on ≥ 5 patients: Cholangiocarcinoma, gynecologic cancers (cervical, endometrial, uterine), central nervous system (glioblastoma, low-grade pediatric glioma, astrocytoma), pancreatic cancer, breast cancer, urothelial tract/bladder cancer, non-small cell lung cancer, and other (adrenal cancer, anal cancer, cancer of unknown primary origin, colorectal cancer, gastric/gastroesophageal cancer, gallbladder cancer, giant cell bone tumor, head and neck cancer, lung neuroendocrine cancer, nasopharyngeal cancer, ovarian cancer, prostate cancer, renal cell cancer, sarcoma, solitary fibrous tumor). Among the efficacy-evaluable participants, 99 had both independent review committee (IRC) central best overall response (BOR) and tissue NGS- data; 2 additional patients had Not Evaluable (NE) as central BOR Baseline tissue targeted NGS data (F1CDx, Foundation Medicine Inc.) of genomic alterations are reported for N=101 participants Baseline plasma targeted NGS analysis (PredicineCare, Predicine Inc.) of genomic data are reported for N=83 participants; data at disease-progression are reported for N=78 participants. Principal Findings: The FIGHT-207 study provided evidence of clinical benefit of pemigatinib in multiple histologies, explored the clinical actionability of various FGFR1-FGFR3 gene alterations, and leveraged the depth of translational data from targeted NGS analysis of baseline samples and plasma samples obtained at baseline and end of treatment to provide key insights into the biology of FGFR inhibition and the clinical utility of FGFR inhibitors. The FIGHT-207 article (pending in Nat.Med. NMED-A128973B) reports evidence suggesting clinical acquired resistance to FGFR inhibition via secondary FGFR mutations as well as emerging co-mutations in other oncogenic and tumor suppressor pathways. This study also provides evidence of acquired resistance to FGFR inhibition in multiple histologies beyond cholangiocarcinoma and urothelial cancers in a systemic correlative analysis of post-progression ctDNA in a trial. Data available through dbGaP: Anonymized information for 101 participants with both IRC central BOR evaluation (including 2 patients with NE as BOR) and tissue NGS data, including tumor histology, enrollable FGFR alteration, and outcome. Genomic alterations determined by baseline tissue NGS (F1CDx, Foundation Medicine Inc.) Genomic alterations determined by plasma NGS analysis (PredicineCare, Predicine Inc.) of ctDNA analysis at baseline (n=83) and at end of treatment/ disease progression (n=78) including genomic alterations that were not assessed to be Germline SNPs.

Study phs003590

TNF-induced dynamic regulation of mRNA stabilome in rheumatoid arthritis fibroblast-like synoviocytes

During rheumatoid arthritis (RA), TNF activates fibroblast-like synoviocytes (FLS) inducing in a temporal order a constellation of genes, which perpetuate synovial inflammation. Although the molecular mechanisms regulating TNF-induced transcription are well characterized, little is known about the impact of mRNA stability on gene expression and the impact of TNF on decay rates of mRNA transcripts in FLS. To address these issues we performed RNA sequencing and genome-wide analysis of the mRNA stabilome in RA FLS. We found that TNF induces a biphasic gene expression program: initially, the inducible transcriptome consists primarily of unstable transcripts but progressively switches and becomes dominated by very stable transcripts. This temporal switch is due to: a) TNF-induced prolonged stabilization of previously unstable transcripts that enables progressive transcript accumulation over days and b) sustained expression and late induction of very stable transcripts. TNF- induced mRNA stabilization in RA FLS occurs during the late phase of TNF response, is MAPK-dependent, and involves several genes with pathogenic potential such as IL6, CXCL1, CXCL3, CXCL8/IL8, CCL2, and PTGS2. These results provide the first insights into genome-wide regulation of mRNA stability in RA FLS and highlight the potential contribution of dynamic regulation of the mRNA stabilome by TNF to chronic synovitis.

Study phs001371

A system-wide approach to monitor responses to synergistic BRAF and EGFR inhibition in colorectal cancer cells

Molecular heterogeneity of tumors, epigenetic changes and a diverse range of molecular mechanisms are main contributors to drug resistance, which represents one of the great challenges in cancer treatment. A deeper understanding of the molecular biology of cancer has resulted in better targeted therapies, where one or multiple drugs are adopted in novel therapies to tackle resistance. This beneficial effect of using combination treatments has to some extent also been observed in colorectal cancer (CRC) patients harboring the BRAF(V600E) mutation, whereby dual inhibition of BRAF(V600E) and EGFR increases antitumor activity. Notwithstanding this success, it is not clear whether this combination treatment is the only or most effective treatment to block resistance. Here, we investigate molecular responses upon single and multi-target treatments, over time, using BRAF(V600E) mutant CRC cells as a well-define model system. Through integration of transcriptomic, proteomic and phosphoproteomics data we obtain a comprehensive overview, revealing both well-known and novel responses. We primarily observe widespread upregulation of tyrosine kinases (RTKs) and and metabolic pathways. This points to by which the treated cells switch energy sources as a defensive response entering a quiescent like state, while activating signalling to re-activate the MAPK pathway.

Study EGAS00001002654

Gynecology and Lubricant Effects (GALE) Study

The GALE study is a longitudinal study of the association between lubricant use and the vaginal microbiota in women receiving transvaginal ultrasound (TVUS) at the Diagnostic Radiology and Nuclear Medicine Department at the University of Maryland School of Medicine. Participants undergo a clinical exam at enrollment (at least 5 days prior to TVUS) and self-collect daily, mid-vaginal samples in the week leading up to TVUS, including immediately before the procedure. At the TVUS appointment, the sonographer applies a single-use packet of Glide lubricating jelly to the probe. The product was selected for study as it was currently being used in the TVUS clinic at the University of Maryland Medical Center and is a clinical lubricant which is very similar in composition to many sex lubricants. Participants collect samples the evening after TVUS and present for a follow-up clinical exam within a week of TVUS. Participants continue to sample twice weekly for an additional 8 weeks (returning completed kits each week), complete daily health and behavior diaries, and attend one final clinical exam at week 10. The clinician evaluates participants for bacterial vaginosis (BV) at each clinical visit using Amsel's criteria, and also looks for signs of vulvovaginal candidiasis (VVC) and trichomonas using a wet mount.

Study phs002211

Cincinnati Children's Hospital Medical Center (CCHMC) - eMERGE Phase IIIA Data

This submission includes genotyping or sequencing data from separate cohorts, each is described in separate paragraphs below. Extreme early onset obesity Obesity is a serious epidemic condition and on the rise in the United States. Today, nearly one out of three children is overweight or obese in this country. According to the Center for Disease Control, 35.7% of American adults and 17% of American children are obese. The medical costs associated with obesity are estimated to be in the billions. Without a doubt, interplay of additive genetic effects and common environmental effects influence this complex disease. However, despite being exposed to so-called "obesogenic environment", a large proportion of the population remains of normal weight. These observations suggest that innate, non-environmental, factors make some individuals more susceptible to obesity providing support for biological mechanisms, and thus genetic factors, to underlie the individual's response to the obesogenic environment. In young children with severe obesity the relative role of genetics and in utero programming are likely to outweigh the short duration of environmental and lifestyle exposures. This group is therefore an ideal one to study as they are likely enriched for variants that influence the risk of developing obesity. The purpose of this project is to further study and understand obesity in childhood and to develop a repository of samples for future studies into obesity. Eosinophilic Esophagitis (EoE) Eosinophilic Esophagitis (EoE) is one of the manifestations of eosinophilic gastrointestinal inflammation which have profound effects on a patient's health and development. Results of epidemiologic studies performed through our center demonstrate that eosinophil-associated gastrointestinal disease is not an uncommon entity. While the epidemiology of eosinophilic esophagitis has not been thoroughly studied until recently, there appears to be a significant increase in the diagnosis of EoE in the last decade. Based on our research, this mainly reflects increased disease recognition, but there is also a bona-fide increase in disease incidence which coincides with the increasing incidence of asthma and allergic diseases in the industrialized world. In addition, many patients with intractable symptoms thought in the past to represent atypical GERD or other disorders are now being recognized as having EoE. Diagnosis of EoE requires endoscopy and biopsies to document the characteristic histologic findings of esophageal eosinophilia. In general, this study proposed to elucidate the mechanisms underlying eosinophil growth, survival, migration, and function, and to investigate and further characterize the pathophysiology of, clinical manifestations of, and spectrum of disease severity of eosinophilic esophagitis in humans. The de-identified genotyping and genome wide association data generated as part of this research will be used for further genome research. Familial Sample Repository (FSR) and Directed Sample Repository (DSR) De novo mutations could cause many diseases, which has been demonstrated in mental retardation, autism and many rare genetic disorders. Family-based studies have a variety of advantages over case/control studies, including the elimination of analysis artifacts related to population stratification, the detection of genes that act through a recessive mechanism of inheritance and validation that the trait is not transmitted from a parent, something not possible using a case/control design. Additionally, DNA from families can be used to identify de novo mutations suggesting strong candidate causal polymorphisms. For this project, samples will be collected from families on an on-going basis. Families may be recruited because the patient either has a disease which is thought to be of genetic origin or from the general patient population to serve as controls or future identified diseases. Some phenotypes under study include fibroblastic rheumatism, diaphragmatic hernia, polymicrogyria, severe congenital neutropenia, primary sclerosing cholangitis and staph infection. CLRR-Cincinnati Lupus Registry and Repository Systemic lupus erythematosus (SLE) is a complex, partially understood autoimmune disorder. Genetic origins for SLE are supported by high heritability (> 66%), familial aggregation, increased monozygotic twin concordance, genetic linkages, and candidate gene genetic association, including HLA genes, Fc receptors, and complement components. Relevant environmental factors likely include infections (Epstein-Barr virus), therapeutics, personal habits (smoking), and diet. To continue a research resource facility for collection of well-characterized pedigrees containing a proband with systemic lupus erythematosus we develop this repository. Juvenile Idiopathic Arthritis (JIA) Juvenile Idiopathic Arthritis (JIA) is a debilitating complex genetic disorder characterized by inflammation of the joints and other tissues and shares histopathological features with other autoimmune diseases. It is considered complex genetic traits. There are more than 50,000 children with JIA in the USA, approximately 1 per 1000 births, which is about the same incidence as juvenile diabetes. It is believed that genes in the major histocompatibility complex (MHC) play a role in defining genetic risk, and it can be hypothesized that loci in other chromosomal regions are involved in conferring risk in JIA. These candidate chromosomal regions can be identified using genome-wide association analyses. The long-term goal is a comprehensive understanding of the genetic basis of these disabling arthropathies for which the molecular basis is not presently understood. These data will contribute to a national resource for the study of autoimmunity in children. Better Outcomes for Children-Cytogenetics Since 2007, more than 4000 samples, enriched with various rare or common genetic diseases as well as specific chromosomal abnormalities such as deletions and duplications have been genotyped for the purpose of subsequent GWAS and Phewas analyses and uncovering main genetic effects.

Study phs001011

Center for Common Disease Genomics [CCDG] - Cardiovascular: PEGASUS-TIMI 54

This study is a part of NHGRI's Center for Common Disease Genomics, which is a collaborative large-scale genome sequencing effort to comprehensively identify rare risk and protective variants contributing to multiple common disease phenotypes. Current estimates anticipate that the CCDG program will sequence approximately 140K whole genomes and 225K whole exomes during the life of the project. The Cardiovascular Disease working group of the CCDG considered five diseases: early-onset coronary artery disease (EOCAD), stroke, atrial fibrillation, congestive heart failure and type 2 diabetes. Atrial fibrillation will affect between 6-12 million individuals in the US by 2050. AF also is associated with increased risks of stroke, dementia, heart failure, death, and high health care costs. Many risk factors for AF have been identified, including advancing age, cardiovascular disease (CVD), and CVD risk factors. However, there is little knowledge how to prevent AF. Furthermore, therapies for AF are only partially effective, and are themselves associated with substantial morbidity. Previously, heritable forms of AF have been considered rare; yet in the last decade, it has been established that AF, and in particular early-onset forms of AF, are heritable. Genome-wide association studies (GWAS) provide a powerful tool to identify common variants underlying disease risk. The AFGen Consortium currently consists of investigators from more than 25 studies with >20,000 individuals with AF and >100,000 without AF. In the latest analyses, 14 loci have been identified for AF1 . Broadly, the loci implicate genes related to cardiopulmonary development, cardiac-expressed ion channels, and cell signaling molecules. Source: ccdg.rutgers.eduFor this study, The Broad Institute of MIT and Harvard generated genetic data for 7,481 individuals from the PEGASUS-TIMI 54 clinical trial run by Brigham and Women's Hospital TIMI study group using whole exome sequencing and whole genome genotyping (Infinium Global Screening Array); all samples serving as controls.  

Study phs002243

Center for Common Disease Genomics [CCDG] - Cardiovascular: ENGAGE Atrial Fibrillation-TIMI 48

This study is a part of NHGRI's Center for Common Disease Genomics, which is a collaborative large-scale genome sequencing effort to comprehensively identify rare risk and protective variants contributing to multiple common disease phenotypes. Current estimates anticipate that the CCDG program will sequence approximately 140K whole genomes and 225K whole exomes during the life of the project. The Cardiovascular Disease working group of the CCDG considered five diseases: early-onset coronary artery disease (EOCAD), stroke, atrial fibrillation, congestive heart failure and type 2 diabetes. Atrial fibrillation will affect between 6-12 million individuals in the US by 2050. AF also is associated with increased risks of stroke, dementia, heart failure, death, and high health care costs. Many risk factors for AF have been identified, including advancing age, cardiovascular disease (CVD), and CVD risk factors. However, there is little knowledge how to prevent AF. Furthermore, therapies for AF are only partially effective, and are themselves associated with substantial morbidity. Previously, heritable forms of AF have been considered rare; yet in the last decade, it has been established that AF, and in particular early-onset forms of AF, are heritable. Genome-wide association studies (GWAS) provide a powerful tool to identify common variants underlying disease risk. The AFGen Consortium currently consists of investigators from more than 25 studies with >20,000 individuals with AF and >100,000 without AF. In the latest analyses, 14 loci have been identified for AF1. Broadly, the loci implicate genes related to cardiopulmonary development, cardiac-expressed ion channels, and cell signaling molecules.Source: https://ccdg.rutgers.edu/sites/default/files/CCDG_CVD_EOAF_FINAL_w_link.pdfFor this study, The Broad Institute of MIT and Harvard generated genetic data for 13,667 individuals from the ENGAGE AF-TIMI 48 clinical trial run by Brigham and Women's Hospital TIMI study group using whole exome sequencing and whole genome genotyping (Infinium Global Screening Array); all cases with atrial fibrillation.

Study phs002774

eMERGE Geisinger eGenomic Medicine (GeM) - MyCode Project Controls

A research cohort of adult Geisinger Clinic patients was enrolled from community-based primary care clinics of the Geisinger Health System. Patients were eligible for enrollment if they were a primary care patient of a Geisinger Clinic physician and were scheduled for a non-emergent clinic visit. All participants provided written informed consent and HIPAA authorization. Consenting patient agreed to provide blood samples for broad biomedical research use, and permission to access data in their Geisinger electronic medical record for research. The enrollment rate was 90% of patients approached. The demographics of the cohort approximate those of the Geisinger Clinic outpatient population. Research blood samples were collected during an outpatient clinical phlebotomy encounter. Research blood samples are coded and stored in a central biorepository. Samples are linkable to clinical data in a de-identified manner for research via an IRB-approved data broker process. For genomic analysis, DNA is extracted from EDTA-anticoagulated whole blood. For the initial eMERGE Geisinger eGenomic Medicine (GeM) genotyping project, a subset of 1,232 unique samples were genotyped using Illumina HumanOmniExpress-12 v1.0 arrays, and used as population controls for other Geisinger Clinic case cohorts, including abdominal aortic aneurysm and gastric bypass surgery cases. These samples were selected from a larger subset of approximately 6,000 MyCode DNA samples using a partial matching algorithm that included age, sex, and body mass index as variables.

Study phs000381

Warfarin Pharmacogenetics: Pharmacogenetic Optimization of Anticoagulant Response (POAT) and Genetic and Environmental Determinants of Warfarin Response (GEDWR)

Although the efficacy of warfarin in the treatment and prevention of thromboembolic disorders is proven, it is vastly underutilized with difficulties in management and risk of complications being the main deterrents. Recognition of genetic regulation of warfarin response has fueled efforts to quantify this influence, but the focus has been restricted to select genes and outcomes mainly in European Americans. Race appears to influence warfarin dose requirements with African Americans requiring larger and Asians requiring lower doses compared to Europeans. This variation in dose requirement by race may at least partially be explained by genetic differences. The Genetic and Environmental Determinants of Warfarin Response (GEDWR) and the Pharmacogenetic Optimization of Anticoagulation Therapy (POAT) are prospective cohort study aimed at defining the influence of CYP2C9, VKORC1 and other genes. All patients were followed at monthly intervals from initiation of therapy. At each visit factors influencing warfarin response such as warfarin dose, INR, concurrent medications, etc. were documented. Information on concurrent medications was updated at every clinic visit by self-report and verified by medical record review. Concomitant use of drugs such as drugs that alter warfarin pharmacokinetics, including CYP2C9 inhibitors (e.g., amiodarone), and pharmacodynamics such as antiplatelet agents (e.g. aspirin). Although the a priori hypothesis focused on the candidate-gene approach, with the recognition that the candidate-gene approach is bound by the assumption that our knowledge of genetic influences on warfarin response is complete. Among African Americans known variation in candidate genes (CYP2C9 and VKORC1) explain substantially less variability in warfarin dose requirements. Therefore a genome-wide association study (GWAS) was conducted on African American patients to identify novel variants associated with warfarin dose requirements.

Study phs000708

Potential Modulatory Role of Osteoprotegerin in Bone Metabolism of Patients with 21-Hydroxylase Deficiency

21-hydroxylase deficiency (21-OHD) is an inherited disorder that results from a mutation on the CYP21A2 gene. It affects the adrenal glands and is the most common cause of congenital adrenal hyperplasia (CAH). 21-OHD CAH causes the body to produce an insufficient amount of cortisol and an excess of androgen, the type of hormone that produces male characteristics. The primary treatment for 21-OHD CAH, glucocorticoid replacement therapy, has been shown to cause bone loss. However, the elevated hormone levels caused by 21-OHD CAH may increase production of the protein osteoprotegerin (OPG), which in turn may protect against bone loss. This study will compare bone density and OPG levels in women who have 21-OHD CAH and have undergone a lifetime of glucocorticoid replacement therapy to that in women who have neither of these criteria. In doing so, the study will aim to determine the relationship between OPG and bone loss. Because of the excess of androgen caused by 21-OHD CAH, women with CAH may exhibit some male-like characteristics. Glucocorticoids are a member of a class of drugs called corticosteroids, which are used in hormone replacement therapy. In order to counteract the effects of 21-OHD CAH, women with the disease are given hormone replacement therapy with glucocorticoids beginning at infancy. Glucocorticoids are known to cause bone loss. Despite many years of treatment with glucocorticoids, however, young women with 21-OHD CAH seem to be protected against bone loss. Researchers believe that the increased androgen levels in these women lead to increased estrogen levels, which in turn increase OPG production. The increase in OPG levels may protect women against bone loss. This study will evaluate bone density and OPG levels in women with and without 21-OHD CAH to determine the relationship between OPG and bone loss. Participants in this observational study will attend only one study visit. At this visit, they will undergo a blood draw; a scan of their lower spine, hip, and forearm; height and weight measurements; and a body fat analysis test. This last test will entail a weak and painless electrical signal being sent from foot to foot. Participants will not attend any follow-up visits for this study.

Study phs001314

INSIGHT (Intervention Nurses Start Infants Growing on Healthy Trajectories) Cohort

This is a study of the biological risk factors for children enrolled in the INSIGHT (Intervention Nurses Start Infants Growing on Healthy Trajectories) study. INSIGHT is a randomized, controlled trial testing a responsive parenting intervention designed for the primary prevention of childhood obesity against a safety control. These first-born children were deeply studied in this time period with data collected on a wide variety of variables including mode of delivery, gender, weight and height (collected at 7 time points), medication usage, diet information, and maternal health information (gestational weight gain, gestational diabetes, smoking during pregnancy). This study includes a survey of the oral and gut microbiota from 226 mother-child dyads. It was designed to investigate the relationship between a cross-sectional view of the child's microbiome (at two years of age) and the patterns of growth between birth and 2 years. Microbiome samples from children (buccal swab and stool sample) and their mothers (buccal swab) are collected at the children's 2-year clinical research visit. Stool metabolites have also been assayed for a subset of the 226 children using 1H-NMR. Additionally, we genotyped the same individuals for SNPs across the genome. For a subset of 48 individuals we have added second-born siblings. For these additional 48 children, we characterized the methylation pattern across the genome using cord blood and placenta samples.

Study phs001498

Count Me In (CMI): The Metastatic Breast Cancer (MBC) Project (CMI-MBCproject)

Count Me In - The Metastatic Breast Cancer Project: A Patient-Driven Research Initiative to Accelerate Metastatic Breast Cancer Research The Metastatic Breast Cancer Project is a research study that directly engages patients with metastatic breast cancer via social media and advocacy groups and empowers them to accelerate cancer research by sharing their samples and clinical information. Our goal is to create a publicly available dataset of genomic, molecular, clinical, and patient-reported data to enable research. Patients in the US or Canada may register online. Registered patients are sent an online consent form that asks for permission to obtain and analyze their medical records, tumor tissue, saliva, and blood samples. Once enrolled, patients are sent a saliva kit and asked to mail back a saliva sample, which is used to extract germline DNA. Study staff contact participants' medical providers and obtain medical records and a portion of their stored tumor biopsies. Patients may be asked to mail in a blood sample, which is used to extract cell free DNA (cfDNA). Whole exome sequencing (WES) is performed on tumor DNA, germline DNA, and cfDNA; transcriptome sequencing is performed on tumor RNA. Clinically annotated genomic data are used to study specific patient cohorts (including outliers) and to identify mechanisms of response and resistance to therapies. All de-identified data, including genomic, clinical, and patient-reported data, are shared via public databases on a pre-publication and recurring basis as it is generated. The latest data release in cBioPortal is available here. Study updates are shared with participants regularly.

Study phs001709

Multi-site tumor sampling highlights molecular intra-tumor heterogeneity in malignant pleural mesothelioma

Background:Malignant pleural mesothelioma (MPM) is a heterogeneous cancer. Better knowledge of molecular and cellular intra-tumor heterogeneity throughout the thoracic cavity is required to develop efficient therapies. This study focuses on molecular intra-tumor heterogeneity using the largest series to date in MPM and is the first to report on the multi-omics profiling of a substantial series of multi-site tumor samples. Methods:Intra-tumor heterogeneity was investigated in 16 patients from whom biopsies were taken at distinct anatomical sites. The paired biopsies collected from apex, side wall, costo-diaphragmatic or highest metabolic sites as well as 5 derived cell lines were screened using targeted sequencing. Whole exome sequencing, RNA sequencing, and DNA methylation were performed on a subset of the cohort for deep characterization. Molecular classification, recently defined histo-molecular gradients, and cell populations of the tumor microenvironment were assessed. Results:Sequencing analysis identified heterogeneous variants notably in NF2, a key tumor suppressor gene of mesothelial carcinogenesis. Subclonal tumor populations were shared among paired biopsies, suggesting a polyclonal dissemination of the tumor. Transcriptome analysis highlighted dysregulation of cell adhesion and extracellular matrix pathways, linked to changes in histo-molecular gradient proportions between anatomic sites. Methylome analysis revealed contribution of epigenetic mechanisms in two patients. Finally, significant changes in the expression of immune mediators and genes related to immunological synapse, as well as differential infiltration of immune populations in the tumor environment were observed and led to a switch from a hot to a cold immune profile in three patients. Conclusions:This comprehensive analysis reveals patient-dependent spatial intra-tumor heterogeneity at the genetic, transcriptomic and epigenetic levels and in the immune landscape of the tumor microenvironment. Results support

Study EGAS00001005328

EGA QuickView

EGA QuickView Secure and Remote Access to EGA Files What is EGA QuickView? EGA QuickView is a FUSE file system that allows secure and remote access to EGA files. It is a hybrid of sshfs and crypt4ghfs, which means it uses ssh to connect to the EGA distribution servers, downloads data in Crypt4GH format, and transparently decrypts those files. It is compatible with Linux and macOS 12. Why use EGA QuickView? EGA QuickView is a highly useful and convenient tool for anyone who needs to access EGA files remotely and securely. The software offers a quick and convenient way to browse through EGA files without the need for complete downloads, thus saving bandwidth and time. Whether you are a medical professional requiring access to sensitive patient data or a research scientist working on a project that involves EGA files, EGA QuickView provides a highly useful solution. The software boasts advanced security features, ensuring that your data is safe and protected at all times. Get started with EGA QuickView To get started with EGA QuickView, visit the EGA QuickView GitHub repository for more information and installation instructions.

Documentation access/download/visualisation/ega-quickview

Viral Respiratory Pathogens Genetics

The overall purpose of this study is to investigate the host genetic factors in response to influenza virus infection, with the focus on influenza vaccination in the first substudy "Adult Influenza Vaccine Genetics" and with the focus on influenza natural infection and other acute respiratory infections (ARIs) in the second substudy "Acute Viral Respiratory Infection Genetics". In the first substudy, healthy adults were enrolled in 2008 (male cohort) and 2010 (female cohort) and immunized with seasonal influenza vaccine. In the second substudy, healthy adults were invited to enroll to be followed for acute respiratory illness through two consecutive influenza seasons 2009-2010 and 2010-2011. Peripheral blood genomic DNA samples were collected from all the subjects, and time-series RNA and serum samples were obtained pre- and post- immunization/infection. Genotyping was carried out on peripheral blood genomic DNA samples using Illumina HumanOmniExpress-12 v1 arrays. Peripheral blood RNA samples obtained at each visit were analyzed using Illumina Human HT-12 (for all the samples) and HiSeq 2000 (for 130 samples in the "Acute Viral Respiratory Infection Genetics" study). Serum specimens were tested using hemagglutination-inhibition (HAI) antibody assay for Influenza H1N1, H3N2, and Influenza B strains. A detailed description of each substudy is provided under their own pages below and via the grouping tool in the right-hand box: phs000635 Adult Influenza Vaccine Genetics phs001031 Acute Viral Respiratory Infection Genetics

Study phs001030

AIDS Linked to the Intravenous Experience (ALIVE) Cohort

The AIDS Linked to the Intravenous Experience (ALIVE) Study is a long-standing community based research effort that includes past and current injection drug users (IDUs). ALIVE has been ongoing since 1988 and is one of the longest-running community-based cohorts of IDUs in existence. The primary objectives when the study started were to characterize the incidence and natural history of HIV among injection drug users (IDUs). At each study visit, participants undergo a series of questionnaires that elicit information about substance use (including drugs used and route of administration) and a blood draw. A subsample of 1200 subjects was selected for genotyping for the NIDA Smokescreen effort who report heroin injection and have existing peripheral blood samples (isolated buffy coat). In addition to injected heroin, ALIVE subjects are assessed on lifetime and previous six months use of marijuana (76.3%), crack (55.5%), snorted cocaine (48.3%), injected cocaine (89.9%), injected speedball (87.0%), and smoking heroin (9.0%). The sample is 33.4% female, ~85% African-American and assessed through a mean maximum age of 49.9 years old. Importantly, subjects are not assessed to meet DSM criteria, but all subjects report having injected drugs. We provide demographic data (age at assessment, sex, self-reported race) and drug use data (lifetime "use" ever endorsed) for each drug class/route described above for each subject

Study phs001494

National Heart, Lung, and Blood Institute (NHLBI) Bench to Bassinet Program: The Pediatric Cardiac Genetics Consortium (PCGC) Study

Multi-center, prospective observational cohort study of individuals with congenital heart defects (CHD). Phenotypic data and source DNA derived from 10,000 probands, parents, and families of interest are being collected to investigate relationships between genetic factors and phenotypic and clinical outcomes in patients with CHD. Phenotype data will be stored at dbGaP, while molecular and sequence data will be stored at BioData Catalyst. The PCGC Cohort is utilized in the following dbGaP substudies. Please click on the following substudies below or in the "Substudies" section of this top-level study page phs001194 PCGC Cohort. phs000571 PCGC: whole exome sequences, whole genome sequences, targeted sequences, MIP sequences, and SNP array data phs001843 PCGC-CMG Collaboration: whole genome sequences The Gabriella Miller Kids First Pediatric Research Program (Kids First) subset of the PCGC project (phs001194) is now accessible through a separate dbGaP study accession: phs001138. To access this dataset, please submit a Data Access Request (DAR) for phs001138. Approval of this DAR will be expedited for approved users of phs001194. To learn about other Kids First datasets visit https://kidsfirstdrc.org/.NHLBI's TOPMed program has provided additional Whole Genome Sequencing for PCGC participants - that data is accessible through a separate dbGaP sudy accession: phs001735. Access to this data set should be requested through a Data Access Request (DAR) for phs001735.

Study phs001194

The Natural History of Mucolipidosis Type IV

Mucolipidosis type IV (MLIV) is an autosomal recessive disorder typically characterized by severe psychomotor delay evident by the end of the first year of life and slowly progressive visual impairment during the first decade as a result of a combination of corneal clouding and retinal degeneration. The purpose of this research study is to look at the brain and eye in patients with mucolipidosis type IV (MLIV). MLIV is a lysosomal storage disease that primarily affects the brain and the eyes. The disease is caused by a defect in a gene called MCLON1 that makes a protein called mucolipin-1. Patients with MLIV do not make enough normal mucolipin. The disease begins early in life and the neurological problems seem to stabilize later in life. On the other hand, the eye abnormalities usually progresses over time. The exact course of the disease has not been determined, and until now, no study has addressed this question carefully. The research objectives are: To learn about the natural history of cognitive function for individuals with mucolipidosis type IV. To measure brain volume over time in individuals with mucolipidosis type IV This is an observational study of individuals with MLIV disorder. Those participating in this study will be evaluated annually for five years following a baseline visit.

Study phs001329

Carolina Breast Cancer Study (CBCS)

The Carolina Breast Cancer Study (CBCS), phase III, is a population-based study aiming to understand the social and molecular correlates of breast cancer outcomes, particularly among Black and young women. CBCS recruited first primary breast cancer cases from 44 North Carolina counties between 2008-2013. All cases were between age 20 and 74 and self-identified as female. Black women and young women were systematically oversampled by randomized recruitment such that the study includes approximately 50% Black women and approximately 50% women diagnosed before age 50. A total of 2,998 participants were enrolled. In the ten years following diagnosis, women completed surveys approximately every 1-2 years and diagnoses of subsequent distant local recurrence and second primary tumors were ascertained via linked medical records. We identified records of women who developed secondary breast tumors (including second primary tumors, contralateral breast cancers, and locoregional recurrences), and these participants were oversampled for targeted DNA sequencing using the UNCseq panel (~1200 genes).CBCS germline pathogenic mutations cannot be investigated because participants were consented between 2008 and 2013 with specific language prohibiting this. However, germline data can be used to call somatic mutations or to standardize somatic genomic data.For sharing of study data not included here, please visit unclineberger.org for instructions on submitting a data use agreement.

Study phs003725

Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS)

This pharmacogenomic study focused on the response of patients with MDD to an 8-week course of treatment with citalopram or escitalopram. Briefly, clinical assessments and research assessments were performed at each study visit as summarized in Table 1. Many patients continued on antidepressant medication after the 8 week study. Table 1: Study timeline and patient contacts. Week Consent/Med Hx Write Rx SI Qx SCID HRS-D17 QIDSC16 CGI-I 0 SC RC RC SC SC SC 4 RC RC SC SC RC 8 RC RC SC SC RC HRS-D17=Hamilton Rating Scale for Depression, QIDS-C16=Quick Inventory of Depressive Symptomatology, CGI-I=Clinical Global Impression-Improvement, SCID=Structured Clinical Interview for DSM-IV, SC=Study Coordinator, RC=Research Clinician. Enrollment and baseline assessment. Upon initial intake, the Study Coordinator (SC) obtained informed consent as well as clinical and demographic information, including history of bone marrow or liver transplant or blood transfusion within the previous 6 weeks, and prior history of treatment during the current major depressive episode. The SC completed the Structured Clinical Interview for DSM-IV (SCID), the HRS-D17 (17-item Hamilton Rating Scale for Depression) and the QIDS-C16 (Quick Inventory of Depressive Symptomatology) and reviewed the inclusion/exclusion criteria. After review with the Research Clinician (RC) and when appropriate, after a negative pregnancy test, the SC invited the subject to participate in the study if entry criteria were met. If the subject agreed, he/she received treatment according to the study protocol. Treatment schedule. Participants selected for inclusion in the study were seen at weeks 0, 4, and 8. The appropriate treatment antidepressant (citalopram or escitalopram) was determined following discussion between the patient and RC concerning medical, financial, and insurance considerations. The study medication citalopram was given in tablet or liquid form, depending on the patient's need. A fixed-flexible dose schedule was employed with the possibility of a dose escalation. In particular, the initial dose of citalopram was 20 mg and escitalopram was 10 mg. This dose was increased to 40 mg and 20 mg, respectively, after 4 weeks if the subject had a score of >/= 6 on the QIDS-C16 and the RC concluded that the subject could tolerate the increase. If necessary, dose was reduced at the discretion of the RC. The importance of medication compliance was discussed with the subject, and subjects were asked to bring in the medication at each visit for the purpose of counting remaining pills to assess compliance. Participants may have had an abbreviated course of therapy if they were clearly intolerant of the drug or failed to respond to a 40 mg dose of citalopram or a 20 mg dose of escitalopram. They then received standard treatment from a primary physician or psychiatrist with different medications and/or therapeutic modalities (e.g. psychotherapy). Special attention was given to subjects with suicidal ideation. Those subjects were offered additional appointments as needed to ensure their safety. Participants were also contacted by telephone at week 1 and week 2 by the Clinical Nurse Specialist (CNS) or other study personnel to ensure medication compliance and patient safety. The CNS was supervised by the study psychiatrist and principal investigator and deferred to the physician's judgment as needed. The SC was trained to notify the RC at the time of the clinical visits or the phone interviews if the subject endorsed any suicidal ideation or plans. For those subjects who were unable to attend the follow-up visits as scheduled, the patient was contacted by phone to complete the HRS-D17/QIDS-C16. The participant was also asked to return to the clinic to complete a final blood draw for the study. Adjunctive and concurrent medications. Adjunctive treatments were those used to manage transient associated symptoms (e.g., insomnia) or transient or longer-term medication side effects (e.g., sexual dysfunction). Adjunctive treatments that were not used to treat depression were allowed during the study. However, drugs in the exclusion criteria for this study were not used as adjunctive therapies. Subjects were allowed to participate in the study while receiving concurrent medications for general medical conditions as long as there was no contraindication to use while taking citalopram or escitalopram. Drug efficacy phenotype evaluation. The change in QIDS-C16 score and change in HRS-D17 score were used as the major research outcome measures to assess drug response. At each clinical research visit, the RC also completed the Clinician Global Impression of Improvement (CGI-I) scale. For the primary genome-wide association analyses, dichotomous outcome variables, remission and response, were defined based on the QIDS-C16 last visit score. Remission was defined as a QIDS-C16 score of 5 or less, while response was defined as at least a 50% reduction in the QIDS-C16 score from baseline. Specimen collection. Specimen collections were obtained by the General Clinical Research Center (GCRC) at St. Mary's Hospital (SMH). Subjects had blood drawn on an outpatient basis at GCRC-SMH on three separate occasions - baseline (0), week 4 and week 8 visits. Prior to sample collection, date and time of last dose of study medication was gathered at the 4 and 8 week visits. For those patients who were unable to complete the regularly scheduled visits, a dismissal blood draw was requested. GCRC then shipped samples to Mayo Clinic's Biospecimens Accessioning and Processing Lab. Genotyping and biomarker assays. DNA from 529 patients was genotyped by the RIKEN Center for Genomic Medicine (Yokohama, Japan) using Illumina Human610-Quad BeadChips (Illumina, San Diego, CA). The study also included the determination of plasma drug levels at weeks 4 and 8, and metabolite levels at baseline and weeks 4 and 8 for a subset of subjects. The primary genome-wide association study based on these data, which includes a summary of the protocol, subject description, selection of subjects for genetic analyses, and definitions of clinical outcomes, was published in the Pharmacogenomics Journal (Ji et al., 2012).

Study phs000670

Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT-BioLINCC)

Data Access NOTEPlease refer to the "Authorized Access" section below for information about how access to the data from this accession. Access differs from many other dbGaP accessions. BiospecimensAccess to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from TOPCAT include Buffy Coat, DNA, Plasma, Serum, Urine, and Whole Blood. Please note that use of biospecimens in genetic research is subject to a tiered consent. Objectives The TOPCAT trial evaluated the effectiveness of aldosterone antagonist therapy in reducing cardiovascular mortality, aborted cardiac arrest, and heart failure hospitalization in patients who have heart failure with preserved systolic function. Background Many patients with heart failure have a normal, or near-normal, left ventricular ejection fraction (LVEF). Such patients share similar signs and symptoms as patients who have heart failure and a reduced LVEF, as well as an impaired quality of life and a poor prognosis. However, at the time of TOPCAT, the benefit of medical therapies for heart failure were limited to those with a reduced LVEF. Due to a lack of favorable evidence from clinical trials, clinical guidelines offered no specific recommendations for the management of heart failure in patients with preserved LVEF, except for attention to coexisting conditions. Among patients with heart failure and a reduced LVEF and those with myocardial infarction complicated by heart failure and left ventricular dysfunction, mineralocorticoid receptor antagonists have been shown to be effective in reducing overall mortality and hospitalizations for heart failure. In small mechanistic studies involving patients with heart failure and preserved left ventricular function, mineralocorticoid receptor antagonists improved measures of diastolic function. However, rigorous testing was needed regarding their effect on clinical outcomes in patients with preserved LVEF. Therefore, the TOPCAT trial was initiated to determine whether treatment with spironolactone, an aldosterone antagonist, would improve clinical outcomes in patients with symptomatic heart failure and a relatively preserved LVEF. Participants A total of 3445 participants were enrolled, with 1722 assigned to the spironolactone group and 1723 assigned to the placebo group. Among these, 2464 participants were enrolled via the hospitalization stratum and 981 were enrolled via the BNP stratum. Design TOPCAT was a phase 3, multicenter, international, randomized, double-blind, and placebo controlled trial. Eligible participants were randomly assigned to receive either spironolactone or placebo in a 1:1 ratio. Randomization was stratified according to whether the patient met the criterion for previous hospitalization or BNP elevation. The baseline visit included assessment of socio-demographics, physical characteristics, medical history, lifestyle factors, laboratory measures, electrocardiography variables and health-related quality of life and functional status. Study drugs were initially administered at a dose of 15 mg once daily, which was increased as tolerated to a maximum of 45 mg daily during the first four months after randomization. Subsequent dose adjustments were made as required and subjects continued to receive other treatments for heart failure and co-existing illnesses. Measurement of potassium and creatinine levels was required within 1 week after a change in the study-drug dose and at each scheduled study visit. Follow-up visits to monitor symptoms, medications, and events and to dispense study drug were scheduled every four months during the subject's first year on the study, and every six months thereafter. The mean follow-up interval was 3.3 years in each study group. Repository blood and urine samples were collected at the baseline and 1 year visits from consenting subjects. The primary endpoint was a composite of cardiovascular mortality, aborted cardiac arrest or hospitalization for the management of heart failure. Secondary endpoints included all-cause mortality, hospitalization for heart failure management, new onset of diabetes mellitus or atrial fibrillation, and quality of life. A subset of subjects also participated in the Echocardiography or Echocardiography and Vascular Stiffness ancillary studies. Echocardiography, and additionally tonometry in the Echocardiography and Vascular Stiffness study, were performed at baseline and at either 12 or 18 months following randomization. If the subject was already enrolled in the TOPCAT trial at the time the ancillary study was initiated, but had not yet reached the 18 month visit, baseline was determined via a retrospective analysis performed on any echocardiographic images completed within 60 days prior to TOPCAT enrollment and no tonometry was performed if applicable. Conclusions In patients with heart failure and a preserved ejection fraction, treatment with spironolactone did not significantly reduce the incidence of the primary composite outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure. However, the drug reduced the secondary endpoint of heart failure hospitalization incidence.

Study phs003665

Sleep Abnormalities in Rare Genetic Disorders: Angelman Syndrome, Rett Syndrome, and Prader-Willi Syndrome

This research study will investigate sleep behavior in the rare neurological disorders Angelman Syndrome (AS), Rett Syndrome (RTT), Prader-Willi Syndrome (PWS) and Early-onset Morbid Obesity (EMO). Sleep is very important to proper health and plays a critical role in learning, memory, brain development and brain function. Sleep disturbances can have negative effects on health and the quality of life of children and their families. Sleep disorders are common in individuals with AS, RTT, PWS and EMO. As a result, individuals with AS, RTT, PWS and EMO are at risk for sleep-related health problems that can worsen existing daytime behaviors and lead to additional problems with learning and memory. The principal objectives of the study are to: Characterize sleep behavior in individuals with Angelman Syndrome, Rett Syndrome, Prader-Willi Syndrome and Early-onset Morbid Obesity. Compare sleep behavior in these individuals with sleep behavior in normal controls Assess the natural history of sleep behavior in individuals with Angelman Syndrome, Rett Syndrome, Prader-Willi Syndrome and Early-onset Morbid Obesity About this Study This is a questionnaire study that will evaluate the sleep behavior of individuals with AS, RTT or PWS (participants), or unaffected siblings of individuals with AS, RTT or PWS (controls). Those participating in the study will already be registered with the Rare Disease Clinical Research Network (RDCRN) and have a confirmed diagnosis of AS, RTT or PWS or be an unaffected sibling. We will look at the medical records on file with the RDCRN to confirm diagnosis of AS, RTT or PWS. Study participants will participate in the study at their regularly scheduled RDCRN clinic visits. Participants will be asked to complete questionnaires at the study visits that will document their sleep behaviors. The questionnaires are not difficult and participants should be able to complete them in approximately 15-30 minutes. Parents and legal guardians are allowed to assist participants or answer on their behalf. Questionnaires will be administered at the initial study visit and at a 12 month follow-up visit to document any changes in sleep behavior. We hope to enroll approximately 1400 individuals with either AS, RTT or PWS or their unaffected siblings.

Study phs001292

Oxidative phosphorylation is a key ontogenetic feature of monocyte immunometabolism promoting myeloid differentiation after birth

Neonates primarily rely on innate immunity, yet their inflammatory responses to microbes, particularly those of monocytes, are usually restricted compared to adults. This is controversially interpreted as immaturity increasing the risk of sepsis or essential programming allowing immune adaptation after birth. Which changes the cellular immunometabolism undergoes after birth and its role in these concepts are poorly defined. Here, we applied transcriptomic, metabolic, and immunological approaches and found that monocytes exhibit an inverse ontogenetic balance of immunometabolism. Our data show that glycolysis in monocytes increases within the first year of life and fuels their inflammatory responsiveness. In contrast, oxidative phosphorylation (OXPHOS) is high in neonatal monocytes supporting myeloid differentiation but declines only gradually during the first five years of life. Treatment of neonatal monocytes with lipopolysaccharide induces an adult-like immunometabolic phenotype. Ketogenic diet restricts glycolysis in adult monocytes, but cannot reactivate OXPHOS and revive a neonatal-like immunometabolic phenotype, suggesting that neonatal metabolism is hardwired and cannot be restored by simple dietary changes. Transcriptional network and population-wide human variation analyses identified E2F1, MYB, STAT1 and FLI1 as important regulators of age-dependent cell functions and related energy demands in human monocytes. Collectively, our findings show that restricted glycolysis and increased OXPHOS are a physiological programming in neonatal monocytes. Premature switching to an adult-like metabolism could untimely enhance inflammatory responses and disrupt important myeloid differentiation, whereas microbial challenges accumulating during childhood seem to induce an essential gradual metabolic switch.

Study EGAS00001007555

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