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• Hematopoietic Cell Transplant for Sickle Cell Disease (HCT for SCD)

  The Center for International Blood and Marrow Transplant Research (CIBMTR) is a hematopoietic cell transplant registry that was established in 1972 at the Medical College of Wisconsin. The overarching goal of the registry is to study trends in transplantations and to advance the understanding and application of allogeneic hematopoietic cell transplantation for malignant and non-malignant diseases. Included in this dataset are children, adolescents and young adults with severe sickle cell disease who received an allogeneic hematopoietic cell transplant in the United States and provided written informed consent for research.Hematopoietic cell transplant for sickle cell disease is curative. Offering this treatment for patients with severe disease is challenging as only about 20-25% of patients expected to benefit have an HLA-matched sibling. Consequently, several transplantations have utilized an HLA-matched or mismatched unrelated adult donor and HLA-mismatched relative. Transplantation strategies have also evolved over time that has included transplant conditioning regimens of varying intensity, grafts other than bone marrow and novel approaches to overcome the donor-recipient histocompatibility barrier and limit graft-versus-host disease. The data that is available for sickle cell disease transplants have been utilized to report on outcomes after transplantation and compare outcomes after transplantation of grafts HLA-matched related, HLA-mismatched related, HLA-matched and HLA-mismatched unrelated donors. Collectively, these data have advanced our knowledge and understanding of hematopoietic cell transplant for this disease. These data can also serve as "contemporaneous controls" for comparison with other more recent curative treatments like gene therapy and gene editing.Data available for request include allogeneic hematopoietic cell transplants for sickle cell disease (Hb SS and Hb Sβ thalassemia) in the United States from 1991 to 2019. Follow-up data through December 2020 are available.Instructions for requesting individual-level data are available on BioData Catalyst at https://biodatacatalyst.nhlbi.nih.gov/resources/data/. Apply for data access in dbGaP. Upon approval, users may begin accessing requested data in BioData Catalyst. For questions about availability, you may contact the BioData Catalyst team at https://biodatacatalyst.nhlbi.nih.gov/contact.

  Study phs002385

• Columbia-Yale-Bilkent Study: Genetics Study of Essential Tremor

  This is a research development/planning grant application to initiate collaborative studies with investigators at Bilkent University in Turkey to study the genetics of Essential Tremor (ET). ET is one of the most common neurological diseases, with an estimated 7 million affected individuals in the United States. The most characteristic clinical feature of ET is a kinetic tremor in the hands or arms, which is mild early in the disease process. As the disease progresses, tremor becomes more severe and more anatomically widespread (e.g., head, trunk). Aside from tremor, patients with ET may also present with other motor features including gait ataxia. Non-motor features can include psychiatric manifestations, cognitive decline and dementia. Despite its extraordinarily high prevalence, the genetic causes of ET are largely unknown. We propose to develop a genetic study of ET focusing on consanguineous families in Turkey. Turkey with a population of about 70 million has a high rate of consanguineous marriages. The rate of consanguinity is estimated to be as much as 20-25% with approximately 70% of all consanguineous marriages involving first cousins. Studying the genetics of ET in the Turkish population, particularly in large consanguineous families, may identify novel genetic causes of ET that are also relevant to ET populations in the United States and worldwide. The proposed research has a high probability of success with our collaborators Drs Ozcelik and Tekinay's expertise in human genetics and functional studies together with an established resource of large consanguineous ET families. The specific aims of this planning grant are to: (1) further develop and solidify collaborations with the team in Bilkent and define the scope of the research that will be the focus of an R01 application, (2) assess the Bilkent team's resources and needs in order to successfully conduct the research, (3) implement cross-training between the United States and Turkish groups in the areas of human genetics, genetic epidemiology and risk factor assessment, genomics, clinical diagnosis, functional studies and personalized genomic medicine, and (4) conduct pilot studies to generate preliminary data necessary for an R01 application.

  Study phs001507

• Kids First: Whole Genome Sequencing in Recessive Structural Brain Defects

  Almost 5% of all live births in the US (1:20 births) display an inborn defect, including both structural and functional/metabolic abnormalities. These are among the most common causes of Infant mortality in the developed world and underlie nearly half of hospitalizations in the first 3 years of life. Of the 35 major defects observable at birth from the International Clearinghouse for Birth Defects Surveillance Program (www.icbdsr.org, external link), about half involve the nervous system. Many of these result in lifelong neurodevelopmental disorders. Structural Brain Defects (SBDs) result from errors in development of the central nervous system, including defects in the forebrain, midbrain and hindbrain. Many SBDs arise as the consequence of a single gene bi-allelic mutation, and for this reason, occur more commonly in populations or communities with elevated consanguinity.Our lab has identified dozens of novel SBD genes using WES/WGS in consanguineous SBD families. Importantly, the genes that we and others have identified in these unique families are then used to advance diagnosis in pediatric SBDs around the world. We have built an enormous cohort of SBD families, including newly recruited families not yet studied genetically, and previous families that were negative for cause following WES analysis. Here we propose to collaborate with the Gabriella Miller Kids First Pediatric Research Program (X01) to have sequencing performed in individuals from a total of 200 families with genetically undiagnosed SBDs. The Gleeson Lab team of researchers is dedicated to the field of SBDs, with an outstanding track record of high-impact science, and a collaborative approach to discovery. We have 150 newly recruited families that we propose to study by WES by sequencing blood-derived DNA from two affected patients, or the parents and one affected patient. We also have 50 families in which WES was negative, which we propose to study in a multi-omics approach combining WGS from blood-derived DNA. We anticipate that this study will lead to the identification of many new molecular causes of SBDs, as well as uncover new genotype-phenotype correlations and new disease mechanisms, paving the way for future breakthroughs in detection, treatment and prevention.

  Study phs002590

• Rapid Acceleration of Diagnostics - Digital Health Technologies (RADx-DHT): NIH Digital Health Solutions for COVID-19: Team SAE

  The goal of this project is to develop a smartphone-based platform to monitor and support individuals with COVID-19 symptoms (who may need testing) and those who have already tested positive. The app will integrate a Bluetooth-enabled thermometer and pulse oximeter into an approach uniquely designed for low-resource settings and underserved populations. This project will focus on the American Indian/Alaskan Native (AI/AN) underserved population and will determine the feasibility of the digital health solution to collect symptom survey data and vital data including temperature, pulse, and oxygen saturation level. The complete study will include 300 participants 100% medically underserved with at least 51% from the AI/AN community. A combination of hard and soft data will be collected consisting of vital data, medical history and questionnaire data, and participant COVID-19 viral and antibody testing results collected during the study.DOI: https://rapids.ll.mit.edu/10.57895/wv88-by98

  Study phs002534

• Quick Guide for data submission

  Quick Guide This is a quick guide to submit data to the EGA. Please select data type to display the right detailed instructions. Sequence data Array-based data Get your submission account You first need to create your EGA user. Then, once your account has been verified by the Help Desk team, request your submission account and provide details of the data type and platform(s) in your submission. Register Study/DAC Use Submitter Portal to register your study, samples, Data Access Committee (DAC) and Policy. Upload data Encrypt your data files using the and upload it to your inbox using SFTP. Register experiments and runs Associate each data file to a registered sample and study by Linking files to samples. Details of the experimental procedure you followed must be provided. Finalise your submission Group your runs/analysis into datasets and link them to your new or existing DAC and policy using DAC Portal. Data request are done at a dataset level, thus files within a datasets must share release conditions. Release and admin When finalising the submission, set a released date to instruct our Helpdesk to release your study. All registered studies are automatically placed on hold until the named submission or DAC contact instructs our Helpdesk for the study to be released. Get your submission account Fill the submission form and provide details of the data type and platform(s) in your submission. Register Study/DAC Use EGA Programmatic submission to register your study, samples, Data Access Committee (DAC) and Policy. Upload data Encrypt your data files using the EgaCryptor and upload it using default FTP clients or Aspera. Complete the Array-Format (AF) spreadsheet Download the AF spreadsheet and complete all four sections. Return the spreadsheet to the EGA helpdesk. Release and admin Instruct our Helpdesk to release your study. All registered studies are automatically placed on hold until the named submission or DAC contact instructs our Helpdesk for the study to be released.

  Documentation submission/quickguide

• NHLBI GO-ESP: Lung Cohorts Exome Sequencing Project (Lung Health Study of Chronic Obstructive Pulmonary Disease)

  The NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), a signature project of the NHLBI Recovery Act investment, was designed to identify genetic variants in coding regions (exons) of the human genome (the "exome") that are associated with heart, lung and blood diseases. These and related diseases that are of high impact to public health and individuals from diverse racial and ethnic groups will be studied. These data may help researchers understand the causes of disease, contributing to better ways to prevent, diagnose, and treat diseases, as well as determine whether to tailor prevention and treatments to specific populations. This could lead to more effective treatments and reduce the likelihood of side effects. GO-ESP is comprised of five collaborative components: 3 cohort consortia - HeartGO, LungGO, and WHISP - and 2 sequencing centers - BroadGO and SeattleGO. The Lung Health Study I was a randomized multicenter clinical trial with 5887 participants carried out from October 1986 to April 1994, designed to test the effectiveness of smoking cessation and bronchodilator administration in smokers aged 35 to 60 with mild lung function impairment. Participants were randomly assigned to one of three groups: usual care, who received no intervention smoking intervention with the inhaled bronchodilator ipratroprium bromide smoking intervention with an inhaled placebo The effect of intervention was evaluated by the rate of decline of forced expiratory volume in one second (FEV1).

  Study phs000291

• Multimodal Immune Profiling to Determine Mechanisms of COVID-19 Clinical Trajectory in Uganda

  We conducted a prospective cohort study of adults (RESERVE-U-C19) admitted to Entebbe Regional Referral Hospital (ERRH), a national COVID-19 referral center, across three viral variant-driven phases of the pandemic in Uganda. In this cohort, which reflects the entire spectrum of SARS-CoV-2 infection, we integrated clinical data with serum proteomics (N=306) and whole-blood transcriptomics (N=100) to determine a range of host responses associated with COVID-19 severity, SARS-CoV-2/HIV co-infection, and circulating viral variants. Beyond the prognostic importance of myeloid cell-driven immune activation and lymphopenia, we show that multifaceted impairment of host protein synthesis and extensive redox imbalance define core metabolic signatures of severe COVID-19, with central roles for IL-7, IL-15, and lymphotoxin-α in COVID-19 respiratory failure. While prognostic signatures were generally consistent in SARS-CoV-2/HIV-coinfection, type I interferon responses uniquely scaled with COVID-19 severity in persons living with HIV. Throughout the pandemic, COVID-19 severity peaked during phases dominated by A.23/A.23.1 and Delta B.1.617.2/AY variants, with Delta phase COVID-19 distinguished by exaggerated pro-inflammatory myeloid cell and inflammasome activation, NK and CD8+ T-cell depletion, impaired host protein synthesis, and upregulation of viral cell entry and trafficking pathways. Data from this study available through dbGaP include raw RNA-Seq data from whole-blood of adult participants (N=100).

  Study phs003246

• A super-enhancer associated with CD47 links pro-inflammatory signaling to CD47 upregulation in breast cancer

  CD47 is a cell surface molecule that inhibits phagocytosis of cells that express it by binding to its receptor, SIRPα, on macrophages and other immune cells. CD47 is expressed at different levels in normal cells, however, in cancer cells, CD47 transcript and protein expression is aberrantly increased. Here we sought to uncover the regulators of CD47 transcription, including active enhancers that increase its aberrant expression in cancer cells, in order to reveal mechanisms by which different neoplastic cells generate this dominant 'don't eat me' signal. Enhancers are genomic regions, often referred to as "switches", that can turn on or off the transcription of target genes. Recently the discovery of super-enhancers (SEs) has given more insight into the regulatory architecture of key genes that are highly expressed in a specific cell type, during a particular developmental stage or in disease. By analyzing the CD47 regulatory genomic landscape, we discovered: i) A distinct super-enhancer (SE) is associated with CD47 upregulation in breast cancer cells ii) Disruption of CD47 SEs by using the BRD4 inhibitor JQ1 robustly reduces CD47 gene expression; and iii) The TNF-NFKB1 signaling pathway is directly involved in the regulation of CD47 by interacting with a distal downstream constituent enhancer located within a CD47-associated SE specific to breast cancer. Our results describe a novel mechanism that cancer cells have evolved to drive CD47 overexpression to escape immune surveillance.

  Study phs001264

• A New Pipeline to Predict and Confirm Tumor Neoantigens Predicts Better Response to Checkpoint Blockade

  Mutations that drive oncogenesis in cancer can generate neoantigens that may be recognized by the immune system. Identification of these neoantigens remains challenging due to the complexity of the major histocompatibility complex (MHC) antigen and T-cell receptor interaction. Here we describe the development of a systematic approach to efficiently identify and validate immunogenic neoantigens. Whole exome sequencing of tissue from a melanoma patient was used to identify nonsynonymous mutations, followed by MHC binding prediction and identification of tumor clonal architecture. The top 18 putative class I neoantigens were selected for immunogenicity testing via a novel in vitro pipeline in HLA-A201 healthy donor blood. Naive CD8 T cells from donors were stimulated with allogeneic dendritic cells pulsed with peptide pools and then with individual peptides. The presence of antigen-specific T cells was determined via functional assays. We identified one putative neoantigen that expanded T cells specific to the mutant form of the peptide and validated this pipeline in a subset of patients with bladder tumors treated with durvalumab (N = 5). Within this cohort, the top predicted neoantigens from all patients were immunogenic in vitro. Finally, we looked at overall survival in the whole durvalumab-treated bladder cohort (N = 37) by stratifying patients by tertile measure of tumor mutation burden (TMB) or neoantigen load. Patients with higher neoantigen and TMB load tended to show better overall survival.

  Study phs002269

• Collagen XVII Promotes Pancreatic Cancer Through Regulation of PIK3R5

  Pancreatic ductal adenocarcinoma (PDAC) contains a desmoplastic stroma that promotes the aggressive biology of this disease. While the varied mechanisms by which fibrillar collagens contribute to PDAC have been defined, little is known about the contribution of transmembrane collagens. Among this class of collagens, Collagen XVII uniquely contains an extensive intracellular domain that connects intracellular cytoplasmic components with the extracellular matrix. Collagen XVII is best characterized as the defining component of the type I hemidesmosome, an anchoring complex that attaches epithelial cells to the underlying basement membrane. In this study, we characterize the expression of collagen XVII in PDAC and the mechanisms by which it contributes to PDAC biology. We demonstrate that crosstalk between PDAC cells and cancer associated fibroblasts drive collagen XVII expression in vitro and xenograft tumor models in vivo. Genetic depletion of collagen XVII in low-passage patient derived cell lines diminishes their metastatic potential and ability to form tumors in mice. Whole transcriptome sequencing of tumors formed by cells with diminished collagen XVII levels revealed dramatically lower levels of PIK3R5, a regulatory subunit of class IB phosphatidylinositol-3-kinase (PI3K) that interacts with G protein-coupled receptors. Consistent with this, collagen XVII-deficient tumors exhibited lower levels of phosphorylated AKT, a downstream effector of PI3K. The studies highlight the importance of collagen XVII signaling in PDAC and define a novel mechanism by which collagen XVII mediates activation of PI3K.

  Study phs003641