238 results for "site"

in 13.27 milliseconds.

• Cell and Circuit-Specific Exploration of HIV Neurogenomics in Context of Opiate and Cocaine Misuse

  Utilizing frozen postmortem brain tissue from the Manhattan HIV Brain Bank, we performed cell-type-specific, genome-wide sequencing of three different types: 1) single-nucleus RNA-sequencing (snRNA-seq), 2) in situ Hi-C, and 3) HIV integration site sequencing (IS-seq). We assayed tissue from three different donor types: 1) HIV-uninfected control (HIV-), HIV-infected (HIV+), and HIV-infected with HIV encephalitis (HIVE), who served as a positive control for active CNS viral infection. The diagnosis of HIVE was made by a board-certified neuropathologist on routine histopathology, based on the presence of a microglial nodule encephalitis with characteristic multinucleated syncytial cells and staining for HIV p24 antigen. Other HIV-infected individuals (the HIV+ group) did not have this histologic evidence of active HIV brain replication, and were variable with regard to cART status and virologic control prior to death. Donor characteristics, including ante-mortem plasma HIV loads, CD4 counts, and cART status, were documented. Quality controls were used for each assay: For snRNA-seq we applied filters to remove low quality nuclei from analysis and performed experiments in which mouse tissue was mixed with human tissue to determine a reliable HIV read count threshold. For Hi-C, we used paired HIV- and HIVE samples and processed all samples in parallel, at the same time. Correlation analysis was used to ensure biological replicates were aligned. For IS-seq, each time the assay was run, a positive and negative control were included. This allowed us to ensure a lack of contamination in IS-seq libraries and that, when a particular sample failed to yield library, this was due to low levels of HIV rather than a failure of the assay. Altogether, we built an integrative dataset from 79 sequencing files, including snRNA-seq, and cell type specific Hi-C, IS-seq, and ChIP-seq datasets. Human autopsy brain samples were collected by the Manhattan HIV Brain Bank (MHBB, U24MH100931), using protocols under the supervision of the Icahn School of Medicine at Mount Sinai (ISMMS) Institutional Review Board. Written informed consent was obtained either from decedents or their primary next of kin. Major Findings: Reorganization of open/repressive (A/B) compartment structures in HIVE microglia encompassing 6.4% of the genome was linked to transcriptional activation of interferon (IFN) signaling and cell migratory pathways and was partially recapitulated by IFN-gamma stimulation of cultured microglia. In contrast, decreased expression and repressive compartmentalization of genes regulating neuronal health and signaling was seen in both HIVE and HIV+ microglia. IS-seq recovered 1,221 integration sites in the brain that displayed distinct genomic patterns as compared to peripheral lymphocyte integration and were enriched for chromosomal domains newly mobilized into a permissive chromatin environment in HIVE microglia. Viral transcription occurred in a subset of highly activated microglia comprising 0.003% of all nuclei in HIVE brain. Our findings point to a disruption of microglia-neuronal interactions in the HIV infected brain and an interrelation of retroviral integration and expression with interferon-associated remodeling of the microglial 3D genome during progression to HIVE. Search terms: HIV, postmortem brain, microglia, substance abuse, viral integration, chromosomal conformation capture, Hi-C, chromatin, single nuclei RNA-seq, Irf8, NeuN, HIV encephalitis, neuron-microglia interaction, cytokine

  Study phs003080

• Resuscitation Outcomes Consortium (ROC) Cardiac Epidemiologic Registry (Cardiac Epistry) Version 3 (ROC-Cardiac Epistry 3-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. Available Data The ROC Cardiac Epistry version 3 include all cardiac arrest cases entered into the ROC database from April 1, 2011 to June 30, 2015. This is separate from versions 1 and 2 because of the major changes in how and which data were collected. Version 3 represents the following major changes to the structure and data collection: separate ED Arrival and Hospital Admits forms, mandatory ED and Hospital elements and a revamped CPR Process form. For ROC traumatic injury Epistry data please see: ROC-Trauma Epistry Objectives To build a prospective population-based registry of participants with out-of-hospital cardiac arrest responded to by Emergency Medical Services (EMS). Specific aims included: to establish whether the results of Resuscitation Outcomes Consortium (ROC) trials can be generalized to the larger population of participants that experience cardiac arrest; to more fully establish the burden of cardiac arrest; and to examine the relationships between variation in EMS structure and process, regional and periodic factors, and participant outcomes. Background Cardiac arrest is a common, serious, debilitating and costly public health problem. Although there has been a steady decline in morbidity and mortality from most cardiovascular diseases, high mortality rates for out-of-hospital cardiac arrests continue to pose a challenge for healthcare providers and a significant public health burden. The Resuscitation Outcomes Consortium (ROC) was established in 2004 to conduct clinical research in the areas of cardiopulmonary arrest and life-threatening traumatic injury with the overall goal of improving resuscitation outcomes. Participant and care characteristics can predict favorable outcomes in cardiac arrests, but there is still a wide variation in outcomes that is not well understood. EMS factors such as service level, number of responding providers, use of procedures or drugs in the field, training, quality assurance/feedback, and response time intervals also vary significantly by region. Variations in geographic, socioeconomic and periodic factors may also be associated with differences in outcomes. Prior to ROC Cardiac Epistry, there were no North American population-based registries for out-of-hospital cardiac arrests. Therefore there was a need for standardized data collection of out-of-hospital cardiac arrests in diverse geographic locations in order to identify the independent effects of prognostic or treatment factors accounting for variations in survival. Participants There were 120,306 participants. Design ROC Epistry collected standardized data regarding episode-specific factors, participant demographics, clinical information, pre-hospital interventions and disposition, hospital information, and participant outcome for all out-of-hospital cardiac arrests in the ROC regions. Each ROC site had to ensure capture of all eligible cases within the EMS service areas. Out-of-hospital data were extracted from existing databases whenever possible and augmented with targeted review of EMS reports. Hospital data were abstracted directly from the hospital file in most cases. Alternative methods included linkage to death registries and obituaries if the death occurred within 30 days. Sites submitted data using a web-based interface or batch uploads. Participants were not contacted directly.

  Study phs003726

• Resuscitation Outcomes Consortium (ROC) Cardiac Epidemiologic Registry (Cardiac Epistry) Versions 1 and 2 (ROC-Cardiac Epistry 1 and 2-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. Available Data: The ROC Cardiac Epistry versions 1 and 2 include all cardiac arrest cases entered into the ROC database from December 1, 2005 to April 1, 2011. ROC Cardiac Epistry 3 includes cardiac arrest cases captured between 2011 and 2015, and introduced significant changes in how and which data were collected.For ROC traumatic injury Epistry data, please see: ROC-Trauma Epistry Objectives: To build a prospective population-based registry of participants with out-of-hospital cardiac arrest responded to by Emergency Medical Services (EMS). Specific aims: to establish whether the results of Resuscitation Outcomes Consortium (ROC) trials can be generalized to the larger population of participants that experience cardiac arrest;to more fully establish the burden of cardiac arrest; and to examine the relationships between variation in EMS structure and process, regional and periodic factors, and participant outcomes.Background: Cardiac arrest is a common, serious, debilitating and costly public health problem. Although there has been a steady decline in morbidity and mortality from most cardiovascular diseases, high mortality rates for out-of-hospital cardiac arrests continue to pose a challenge for healthcare providers and a significant public health burden. The Resuscitation Outcomes Consortium (ROC) was established in 2004 to conduct clinical research in the areas of cardiopulmonary arrest and life-threatening traumatic injury with the overall goal of improving resuscitation outcomes. Participant and care characteristics can predict favorable outcomes in cardiac arrests, but there is still a wide variation in outcomes that is not well understood. EMS factors such as service level, number of responding providers, use of procedures or drugs in the field, training, quality assurance/feedback, and response time intervals also vary significantly by region. Variations in geographic, socioeconomic and periodic factors may also be associated with differences in outcomes.Prior to ROC Cardiac Epistry, there were no North American population-based registries for out-of-hospital cardiac arrests. Therefore there was a need for standardized data collection of out-of-hospital cardiac arrests in diverse geographic locations in order to identify the independent effects of prognostic or treatment factors accounting for variations in survival. Participants: The registry included 109,326 cardiac arrest events from 264 EMS agencies transporting to 287 acute care hospitals from the following regional centers: Birmingham, Alabama; Dallas, Texas; Iowa City, Iowa; Milwaukee, Wisconsin; Pittsburgh, Pennsylvania; Portland, Oregon; San Diego, California; Seattle/King County, Washington; Ottawa, Ontario; Toronto, Ontario; and Vancouver, British Columbia.Design: ROC Epistry collected standardized data regarding episode-specific factors, participant demographics, clinical information, pre-hospital interventions and disposition, hospital information, and participant outcome for all out-of-hospital cardiac arrests in the ROC regions. Each ROC site had to ensure capture of all eligible cases within the EMS service areas. Out-of-hospital data were extracted from existing databases whenever possible and augmented with targeted review of EMS reports. Hospital data were abstracted directly from the hospital file in most cases. Alternative methods included linkage to death registries and obituaries if the death occurred within 30 days. Sites submitted data using a web-based interface or batch uploads. Participants were not contacted directly.

  Study phs003803

• eMERGE Network Phase III: HRC SNV and 1000 Genomes SV Imputed Array Data of 105,000 Participants

  The Electronic Medical Records and Genomics (eMERGE) Network is a National Institutes of Health (NIH)-organized and funded consortium of U.S. medical research institutions. The primary goal of the eMERGE Network is to develop, disseminate, and apply approaches to research that combine biorepositories with electronic medical record (EMR) systems for genomic discovery and genomic medicine implementation research. eMERGE was announced in June 2007 and began its third phase in September 2015. eMERGE Phase III (June 2015 - June 2020) consists of 10 study sites, two central sequencing and genotyping facilities, and a coordinating center. Included in this study are: Human Reference Consortium (HRC) single nucleotide variants and 1000 Genomes structural variants imputed array data of 105,108 eMERGE participants from nine Phase III study sites and three Phase II study site collaborators. Corresponding demographics, body mass index measurements. Case/control status for the following phenotypes: Abdominal aortic aneurysm; Ace-Inhibitor/Cough; Attention Deficit Hyperactivity Disorder; Age-related macular disease; Appendicitis; Asthma; Atopic Dermatitis; Autism; Benign Prostatic Hyperplasia; Carotid artery disease as a Quantitative Measure; caMRSA; Cataract; Clostridium difficile colitis; Extreme Obesity; Chronic Kidney Disease; Chronic Kidney Disease and Type 2 Diabetes; Chronic Kidney Disease, Type 2 Diabetes and Hypertension; Colon Polyps; Cardiorespiratory Fitness; Dementia; Diverticulosis; Diabetic retinopathy; Gastroesophageal Reflux Disease; Glaucoma; Height; Heart failure; Hypothyroidism; Lipids; Ocular hypertension; Peripheral Arterial Disease; QRS duration; Red blood cell indices; Remission of Diabetes after ROUX-EN-Y gastric bypass surgery; Resistant hypertension; MACE while on Statins; Type 2 Diabetes; Venous Thromboembolism; White blood cell indices; and Zoster virus infection. Study sites and participants include: Boston Children's Hospital: The Gene Partnership (TGP) is a prospective longitudinal registry at Boston Children's Hospital (BCH) to study the genetic and environmental contributions to childhood health and disease, collect genetic information on a large number of children who have been phenotyped, and implement the Informed Cohort and the Informed Cohort Oversight Board (ICOB). The term "The Gene Partnership" reflects a partnership between researchers and participants. Children seen at BCH are offered enrollment, as are their parents and siblings. DNA is collected on all enrollees. BCH has a comprehensive EMR system, and virtually all inpatient and outpatient data are captured electronically. Clinical data in the BCH EMR is loaded in the i2b2 data warehouse which is available to investigators. Cases, phenotypes, and covariates are ascertained using the i2b2 database. Participants at BCH in TGP have consented to receive any research result and/or incidental finding that arises from studies using TGP that is approved by the Informed Cohort Oversight Board (ICOB) and is in accordance with the participants'preferences;results are returned through the Personally Controlled Health Record (PCHR). BCH and Cincinnati Children's Hospital Medical Center (CCHMC) have partnered as the Pediatric Alliance for Genomic and Electronic Medical Record (EMR) Research (PAGER) site for the eMERGE Phase II network for pediatric institutions, and the cohort for eMERGE at BCH is TGP. Children's Hospital of Pennsylvania (CHOP): The Center for Applied Genomics (CAG) at the Children's Hospital of Philadelphia (CHOP) is a high-throughput, highly automated genotyping and sequencing facility equipped with state-of-the-art genotyping and sequencing platforms. Children who are treated at the Children's Hospital Healthcare Network and their parents may be eligible to take part in a major initiative to collect more than 100,000 blood samples, covering a wide range of pediatric diseases. A large majority of participants consenting to prospective genomic analyses also consent to analysis of their de-identified electronic health records (EHRs). EHRs are longitudinal, with a mean duration of 6.5 years. Cincinnati Children's Hospital Medical Center/Boston's Children's Hospital (CCHMC/BCH): Cincinnati Children's Hospital Medical Center (CCHMC) is a pediatric institution dedicated to improving health and welfare of children and to the discovery and practical application of new genomic information to the ordinary care of children. CCHMC brings an extraordinary faculty to eMERGE III who are committed to gain a better understanding of the genesis of disease and to elucidate the mechanisms of diseases that afflict children, specifically pediatric disease phenotypes that will leverage the available eMERGE adult genomic data and electronic medical records (EMRs) to discover meaningful use results. Generation of EMR phenotype algorithms, informed by natural language processing, using heuristic and machine learning methods is ongoing. CCHMC has developed tools to evaluate adolescent return of results preferences, examined the ethical and legal obligations and potential to reanalyze results, and developed clinical decision support for phenotyping, test ordering, and returning sequencing results. The success of these eMERGE III studies is enhanced by the ongoing institutional investment made in the CCHMC Biobank, the comprehensive EMR (EPIC), the i2b2 de-identified medical record data warehouse, and hundreds of faculty and senior staff who make genomics or informatics an active focus of their research. Columbia University: Columbia University Medical Center/New York Presbyterian (CUMC/NYP) Hospital system is one of the nation's largest and most comprehensive hospital systems with over 2 million inpatient and outpatient yearly visits that serves a racially and ethnically diverse urban patient population. The Columbia University GENomic Integration with EHR (GENIE) research study contributed and shared phenotype and genotype data for individuals who were recruited as part of a diverse array of initiatives within the hospital, including Northern Manhattan Study (NOMAS), Pediatric Cardiac Genomic Consortium (PCGC), Caribbean Hispanics with Familial and Sporadic Late Onset Alzheimer's disease (AD), Alzheimer's Disease Sequencing Project (ADSP), and Genetics of Chronic Kidney Disease study. Some of these individuals had kidney or neurological problems, some were healthy adult volunteers with self-reported health status information from the medically underserved Northern Manhattan community, and others were pediatric patients with cardiac conditions. For the kidney disease cohort, patients with the diagnosis of Chronic Kidney Disease (CKD) and healthy controls were recruited to the Columbia University CKD biobank. For the NOMAS cohort, eligible participants were stroke-free, were 40 years old, and resided for at least 3 months in a Northern Manhattan household with a telephone. The PCGC study recruited parent-offspring trios with pediatric probands diagnosed with congenital heart defects (CHD). For the Caribbean Hispanics with Alzheimer's disease project, individuals from families affected by AD and with sporadic AD were recruited, along with unrelated controls. Samples for the ADSP study have been selected from well-characterized cohorts of individuals with AD diagnosis. Geisinger Health System: 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 patients 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. Partners Health Care (Harvard): The Partners HealthCare Biobank is a large research program designed to help researchers understand how people's health is affected by their genes, lifestyle, and environment. This large research data and sample repository provides access to high-quality, consented blood samples to help foster research, advance our understanding of the causes of common diseases, and advance the practice of medicine. For the Partners research community (Massachusetts General Hospital and Brigham and Women's Hospital), the Biobank provides: Banked samples (plasma, serum, and DNA) collected from consented patients Blood samples that were discarded after clinical testing in the Crimson Cores maintained in the Brigham and Women's Hospital and Massachusetts General Hospital Pathology Departments Sample handling and preparation services Link to the biobank data to the Partners Research Patient Data Registry (RPDR) a research instance of our electronic clinical chart Data access through our research portal. To date, over 60,000 Partners patients have given their consent to enroll, give a blood sample, receive research results and agreed to be re-contacted for additional research studies. The Biobank has enabled Partners investigators to compete for nationally recognized grants in personalized medicine such as a clinical electronic Medical Records and Genomics network (eMERGE) site and the national All of US program. The Biobank currently supports over 120 Partners investigators and over 100 million dollars in NIH research. Kaiser Permanente Washington with the University of Washington and the Fred Hutchinson Cancer Research Center: KPWA participants were enrolled in the eMERGE Network through the Northwest Institute of Genetic Medicine (NWIGM) biorepository, and provided the appropriate consent to receive clinically relevant genetic results (N~8,073.) NWIGM is based at the University of Washington and co-managed by the University of Washington and KPWA. The purpose of the NWIGM biorepository is to build infrastructure and resources to carry out a broad range of future genetic research. KPWA members enrolled in the biorepository are asked to provide informed consent to providing a DNA sample for storage in the NWIGM biorepository. The consent is purposefully broad to serve the dual purpose of reducing the burden on researchers who wish to use this biorepository and the IRB committees who will be responsible for reviewing these requests in the future. Participants were eligible if aged 50 - 65 years old at the time of their enrollment into the NWIGM repository, living, enrolled in KPWA's integrated group practice, and had completed an online Health Risk Appraisal. The selection algorithm was based on several data sources from the EHR at KPWA. 1) Demographics - participants with self-reported race as Asian ancestry were prioritized and selected to enrich for non-European ancestry. The KPWA eMERGE cohort includes n=1,245 members of Asian ancestry. 2) Participants were also selected for a history of colorectal cancer (n=1,002), in order to allow us to enrich germline pathogenic variants. Essentia Institute of Rural Health, Marshfield Clinic, Pennsylvania State University (Marshfield): The Marshfield Clinic Personalized Medicine Research Project is a population-based biobank in central Wisconsin with more than 20,000 adult subjects who provided written, informed consent to access their medical records and provided a blood sample from which DNA was extracted and plasma and serum stored. In addition to an average of 30 years of medical history data, a questionnaire about environmental exposures, including a detailed food frequency questionnaire, is available to facilitate gene/environment studies. Mayo Clinic: The Mayo Vascular Disease Biorepository is a disease-specific biobank for vascular diseases including peripheral arterial disease (PAD). PAD patients were identified from individuals referred to the non-invasive vascular laboratory for lower extremity arterial evaluation. Since 1997, laboratory findings have been recorded into an electronic database employing an in-house software package for data archiving and retrieval;this data becomes part of the Mayo EMR. Patients referred to the center with suspected PAD undergo a comprehensive non-invasive evaluation including the ankle-brachial index (ABI) - the ratio of blood pressure measured in the upper arms divided by blood pressure measured at the ankles. Controls subjects are identified from patients referred to the Cardiovascular Health Clinic for stress ECG. The prevalence of PAD in patients with normal exercise capacity who do not have inducible ischemia on the stress ECG , was <1%. Data regarding risk factors for atherosclerosis such as diabetes, dyslipidemia, hypertension, and smoking are ascertained from the EMR. Case control study of venous thromboembolism (PI John Heit) Controls from a case control study of pancreatic cancer (PI Gloria Petersen) Mayo Clinic Biobank. Icahn School of Medicine at Mount Sinai School (Mt. Sinai): The Institute for Personalized Medicine (IPM) Biobank Project 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 Biobank populations include 28% African American (AA), 38% Hispanic Latino (HL) predominantly of Caribbean origin, 23% Caucasian/White (CW). IPM Biobank disease burden is reflective of health disparities with broad public health impact: average body mass index of 28.9 and frequencies of hypertension (55%), hypercholesterolemia (32%), diabetes (30%), coronary artery disease (25%), chronic kidney disease (23%), among others. 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. Northwestern University: The NUgene Project is a repository with longitudinal medical information from participating patients at affiliated hospitals and outpatient clinics from the Northwestern University Medical Center. Participants'DNA samples are coupled with data from a self-reported questionnaire and continuously updated data from our Electronic Medical Record (EMR) representing actual clinical care events. Northwestern has a state-of-the art, comprehensive inpatient and outpatient EMR system of over 2 million patients. NUgene has broad access to participant data for all outpatient visits as well as inpatient data via a consolidated data warehouse. NUgene participants consent to distribution and use of their coded DNA samples and data for a broad range of genetic research by third-party investigators. Vanderbilt University Medical Center: BioVU, Vanderbilt's DNA databank, was designed as an enabling resource for exploration of the relationships among genetic variation, disease susceptibility, and variable drug responses. BioVU acquires DNA from discarded blood samples collected from routine patient care. The biobank is linked to de-identified clinical data extracted from Vanderbilt's EMR, which forms the basis for phenotype definitions used in genotype-phenotype correlations. BioVU is currently the largest single site DNA collection world-wide, at >235,000 samples as of spring 2017.

  Study phs001584

• ICGC Data Access Compliance Office

  To access Controlled Access ICGC data at the EGA you must first apply for access on the DACO form. Instructions on this process is available from this web site: http://docs.icgc.org/portal/access/

  Dac EGAC00001000010

• Kids First: Genomics of Orofacial Cleft Birth Defects in Latin American Families

  The Gabriella Miller Kids First Pediatric Research Program) (Kids First) is a trans-NIH effort initiated in response to the 2014 Gabriella Miller Kids First Research Act and supported by the NIH Common Fund. This program focuses on gene discovery in pediatric cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource). Both childhood cancers and structural birth defects are critical and costly conditions associated with substantial morbidity and mortality. Elucidating the underlying genetic etiology of these diseases has the potential to profoundly improve preventative measures, diagnostics, and therapeutic interventions. All of the WGS and phenotypic data from this study are accessible through dbGaP and https://kidsfirstdrc.org, where other Kids First datasets can also be accessed. The Kids First study of nonsyndromic orofacial cleft (OFC) birth defects in Latin American families is a whole genome sequencing study of 283 Latin-American parent-case trios drawn from ongoing collaborations led by Dr. Mary L. Marazita of the University of Pittsburgh Center for Craniofacial and Dental Genetics, and including a collaboration with Dr. Lina Moreno Uribe and Dr. Andrew Lidral of the University of Iowa. All families were ascertained through the Clinica Noel where patients with OFCs receive care from the Antioquia University School of Dentistry in Medellin, Colombia (key on-site colleagues included Dr. Luz Consuelo Valencia-Ramirez and Dr. Mauricio Arcos-Burgos). Genetic studies have shown that this population is comprised of an admixture of immigrant male Caucasians (mainly Spaniards and Basques) and native Amerindian females. Every subject has had a genetic evaluation, including a pedigree analysis for a family history of clefting and other birth defects, a pregnancy history for environmental exposures, and a complete physical exam to rule out suspected or known syndromes or environmental phenocopies. Sequencing was done by the Broad Institute sequencing center funded by the Kids First program (grant number U24-HD090743). The case in each of the Kids First OFC trios has cleft lip (CL, Figure A below), cleft palate (CP, Figure B), or both (CL+CP, Figure C): OFCs are genetically complex structural birth defects caused by genetic factors, environmental exposures, and their interactions. OFCs are the most common craniofacial anomalies in humans, affecting approximately 1 in 700 newborns, and are one of the most common structural birth defects worldwide. On average a child with an OFC initially faces feeding difficulties, undergoes 6 surgeries, spends 30 days in hospital, receives 5 years of orthodontic treatment, and participates in ongoing speech therapy, leading to an estimated total lifetime treatment cost of about $200,000. Further, individuals born with an OFC have higher infant mortality, higher mortality rates at all other stages of life, increased incidence of mental health problems, and higher risk for other disorders (notably including breast, brain, and colon cancers). Prior genome-wide linkage and association studies have now identified at least 18 genomic regions likely to contribute to the risk for nonsyndromic OFCs. Despite this substantial progress, the functional/pathogenic variants at OFC-associated regions are mostly still unknown. Because previous OFC genomic studies (genome-wide linkage, genome-wide association studies (GWAS), and targeted sequencing) are based on relatively sparse genotyping data, they cannot distinguish between causal variants and variants in linkage disequilibrium with unobserved causal variants. Moreover, it is unknown whether the association or linkage signals are due to single common variants, haplotypes of multiple common variants, clusters of multiple rare variants, or some combination. Finally, we cannot yet attribute specific genetic risk to individual cases and case families. Therefore, the goal of the current study is identify specific OFC risk variants in Latin American families by performing whole genome sequencing of parent-case trios.

  Study phs001420

• Sporadic ALS Australia Systems Genomics Consortium (SALSA-SGC)

  In 2016 we established the Sporadic ALS Australia Systems Genomics Consortium (SALSA-SGC) funded by the Ice Bucket Challenge Grant administered by the Motor Neurone Disease Research Institute of Australia. The goals of the SALSA-SGC are to collect biological samples from clinics across Australia with matched in depth clinical and self-report phenotypes and to generate multiple levels of genetic and genomic data. In this first data generation exercise of the SALSA-SGC the majority of the samples were collected prior to the formal establishment of SALSA-SGC from clinics across Australia.Briefly, the cohort includes the University of Sydney’s Australian Motor Neuron Disease DNA Bank (MND Bank) cohort recruited April 2000 to June 2011), with study protocol approved by the Sydney South West Area Health Service Human Research Ethics Committee (HREC). Cases were recruited from around Australia via state-based MND associations with diagnosis verified by a neurologist. The remainder of the cases were recruited from clinics across Australia between 2015 and 2017 under HREC approvals from Royal Brisbane and Women’s Hospital, Macquarie University Multidisciplinary Motor Neurone Disease Clinic,  Calvary Health Care Bethlehem in Melbourne , Fiona Stanley Hospital in Perth, and from 2016 under HREC approvals at each site for the sporadic ALS Australia Systems Genomics Consortium (SALSA-SGC). The ALS cases were diagnosed with definite or probable ALS according to the revised El Escorial criteria. Some controls were recruited as either partners or friends of patients, healthy individuals free of neuromuscular diseases. We are providing GWAS and MWAS data in this dataset. Individual level GWAS data were generated using Illumina Infinium CoreExome-24 version 1.1 chips for N= 846 cases and N=665 controls. Individual MWAS data was generated using the Illumina Human methylation 450K array for N=782 cases and N=613 controls. There 1315 individuals where GWAS and MWAS data has been generated and is available. Further information on these data sets can be found: Paper 1: Restuadi, R, Garton, FC, Benyamin, B, Lin, T, et al. Amyotrophic Lateral Sclerosis Genetic Correlation with Cognitive Performance, educational attainment and schizophrenia: evidence from polygenic risk score analysis. (submitted) Paper 2: Nabais, MF, Lin, T, Benyamin, B et al. Significant out-of-sample classification from methylation profile scoring for amyotrophic lateral sclerosis. 2020. NPJ genomic medicine. 5(10). Files provided in this submission include: GWAS: This folder contains QCed genotype for the Australian ALS case-control cohort. Contains PLINK files for genotyping data (not imputed yet). The individuals selected here have: good consistency on phenotype data ethics approval registered as part of sporadic ALS studies unrelated by GRM cut-off 0.05 No ancestry QC yet MWAS: This folder contains the IDAT and post-QC normalized DNAm (beta) for the Australian ALS case-control cohort. 2019_AUS_ALS_PCTG_DNAm.tar.gz - IDATS for 1315 individuals analyzed in the MWAS study normalized_beta_values - Binary files (created with the OSCA software) containing information on the individuals, probes and the DNAm (beta) values obtained after QC phenotype_file - contains all the covariates analysed in the MWAS including: case-control status, coded 0 = Control and 1 = ALS, predicted age, predicted cell-type proportions, predicted smoking scores, slide and chip position and sex Important Notes: The DNAm data were normalized together with samples that were not part of this ALS case/control study and thus, the normalization procedure may not be 100% reproducible using only the IDAT files uploaded here. Summary data has been made publicly available and can be accessed directly: Data collection and sample processing were performed at several clinics across Australia. Genotyping and DNA methylation arrays were performed by the Human Studies Unit, at the Institute for Molecular Bioscience (University of Queensland). Quality control of the genotypic, phenotypic and DNA methylation data was done by the Program of Complex Traits Genomics, at the Institute for Molecular Bioscience (University of Queensland).

  Study phs002068

• T2D-GENES Project 2: San Antonio Mexican American Family Studies

  The Type 2 Diabetes (T2D) Genetic Exploration by Next-generation sequencing in Ethnic Samples (T2D-GENES) Consortium is a collaborative international effort to identify genes influencing susceptibility to T2D in multiple ethnic groups using next generation sequencing. T2D-GENES Project 2 is a complex pedigree-based study designed to identify low frequency or rare variants influencing susceptibility to T2D, using whole genome sequence (WGS) information from 1,043 individuals in 20 Mexican American T2D-enriched pedigrees from San Antonio, Texas. The major objectives of this study are to identify low frequency or rare variants in and around known common variant signals for T2D, as well as to find novel low frequency or rare variants influencing susceptibility to T2D. The sampled individuals are obtained from two studies: the San Antonio Family Heart Study (SAFHS) and the San Antonio Family Diabetes/Gallbladder Study (SAFDGS), collectively referred to as the San Antonio Mexican American Family Studies (SAMAFS). The strategy is to sequence approximately 600 individuals at an average of 50x coverage across the entire genome, then impute genome wide genotypes for about 440 additional family members. The 600 sequenced individuals are specifically chosen for their value in imputing sequence information into other family members. By studying large pedigrees, we expect to find multiple individuals carrying each genetic variant, even if this variant is very rare in the population at large. Thus, a pedigree-based approach provides an excellent opportunity for identifying rare novel variants influencing risk of T2D and quantitative variation in T2D-related phenotypes. The whole genome sequencing has been done commercially by Complete Genomics, Inc. (CGI). The final data set includes whole genome sequence data for 607 individuals. After quality control, 585 sequenced individuals provide data for family based imputation, using Merlin linkage analysis software, into approximately 440 additional family members for whom chip based genotypes are available to indicate which parental haplotype is transmitted. Extensive phenotype data is provided for 1048 individuals. These include 5 sequenced individuals who do not belong to any of the 20 large pedigrees. Phenotype information was collected between 1991 and 2011 in the two contributing longitudinal studies. SAFHS participants may have information from up to 5 visits, and SAFDGS participants may have up to 4 visits. The clinical variables reported are coordinated with T2D-GENES Project 1 (multi-ethnic exome sequencing) and include T2D status and age at diagnosis, glycemic traits (fasting and 2 hour glucose and insulin), blood pressure, blood lipids (total cholesterol, HDL cholesterol, calculated LDL cholesterol and triglycerides), clinical chemistry (cystatin c, glutamic acid decarboxylase antibody titer (GadAb), creatinine, adiponectin and leptin). Glycated hemoglobin (HbA1c) was not measured for these individuals and insulin C-peptide is not included in this data set. Additional phenotype data include the medication status at each visit, classified in four categories as any current use of diabetes, hypertension or lipid-lowering medications, and, for females, current use of female hormones. Anthropometric measurements include age, sex, height, weight, hip circumference, waist circumference and derived ratios. Each phenotype variable has an initial summary column containing the most recent non-missing measurement for each individual, followed by the five potential time points for each individual, the number of non-missing measurements, and the age and year for the most recent non-missing measurement. For historical reasons, the order in which variables are presented on the dbGaP web site differs from their order in the data download file. When reading the comment fields for each variable, please note that commas are omitted to support data exchange in .csv format.

  Study phs000462

• Resuscitation Outcomes Consortium (ROC) Amiodarone, Lidocaine or Neither for Out-Of-Hospital Cardiac Arrest Due to Ventricular Fibrillation or Ventricular Tachycardia (ALPS)(ROC-ALPS-BioLINCC)

  Accessing Data Please refer to “Authorized Access” below regarding accessing data through the BioData Catalyst ecosystem. The data from this accession is not available for download through dbGaP. Objective To compare the effects of amiodarone, lidocaine, and placebo on survival to hospital discharge after out-of-hospital cardiac arrest due to shock-refractory ventricular fibrillation or pulseless ventricular tachycardia. Background Ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT) are common causes of out-of-hospital cardiac arrest, but are considered the most responsive to shock and therefore the most treatable. Nonetheless, most defibrillation attempts do not result in sustained return of spontaneous circulation, and VF or VT may persist or recur after shock. There is also evidence that longer durations of VF or VT are associated with decreases in the likelihood of resuscitation. Amiodarone and lidocaine are commonly used to promote successful defibrillation of shock-refractory VF or VT and prevent recurrences. Previous trials have shown amiodarone to be more effective than placebo or lidocaine for return of spontaneous circulation and survival at hospital admittance. This study sought to further extend the research and examine whether amiodarone would improve survival to hospital discharge and neurologic outcomes, as compared to placebo or lidocaine. Participants 3,026 eligible participants were enrolled, with 974 assigned to amiodarone, 993 assigned to lidocaine, and 1,059 assigned to placebo. An additional 1,627 participants that received a study intervention, but did not meet eligibility criteria, were included in analysis of the intention-to-treat population. Design The study interventions (amiodarone, lidocaine, and saline) were packaged in indistinguishable sealed kits and randomly distributed in to Emergency Medical Services (EMS) providers in a 1:1:1 ratio, stratified by participating site and agency. Each kit contained three syringes, and each syringe held 3 ml of colorless fluid containing 150 mg of amiodarone, 60 mg of lidocaine, or normal saline. Participants with out-of-hospital cardiac arrest were treated in accordance with local EMS protocols, in compliance with American Heart Association (AHA) guidelines. If VF or VT persisted or recurred after one or more shocks, eligible participants received a vasopressor and the masked kit containing amiodarone, lidocaine, or placebo. Approximating current clinical practice, the initial dose consisted of two syringes administered by rapid bolus. If the estimated body weight of the patient was less than 100 lbs., then one syringe was used. If VF or VT persisted, standard resuscitation measures, additional shocks, and an additional syringe of the study drug were administered. At that point the trial interventions were completed and standard interventions for advanced life support were employed. Upon arrival at the hospital, providers were notified of the patient's enrollment in the trial and encouraged to provide usual care in accordance with AHA guidelines, including open-label amiodarone or lidocaine if necessary. Components of hospital care were monitored but not standardized by the trial protocol. Participants, providers, and trial personnel were blinded to the trial drug assignments, with the exception of treating physicians if emergency un-blinding was required for care. Data from pre-hospital patient care records, CPR process measures, and hospital medical records were collected. The primary outcome of the trial was survival to hospital discharge, and the secondary outcome was survival with favorable neurologic status at discharge, defined as a score on the modified Rankin scale of 3 or less. Conclusions Neither amiodarone nor lidocaine resulted in a significantly higher rate of survival to hospital discharge or favorable neurologic outcome, as compared to placebo, among participants with out-of-hospital cardiac arrest due to initial shock-refractory ventricular fibrillation or pulseless ventricular tachycardia.

  Study phs003784

• Pomalidomide for the Treatment of Bleeding in HHT (PATH-HHT)

  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: To determine efficacy (reduction in severity of epistaxis), tolerability, and improvement in quality of life of pomalidomide compared to placebo after 24 weeks of treatment.Background: This study addresses the efficacy of pomalidomide in the treatment of epistaxis in patients with Hereditary Hemorrhagic Telangiectasia (HHT) who have anemia and/or require blood transfusion or iron infusion for treatment of bleeding-induced anemia and iron deficiency. HHT (also known as Osler-Weber-Rendu disease) is an inherited bleeding disorder. Over 95% of patients develop recurrent epistaxis, which may be severe and result in chronic anemia, need for iron infusions and blood transfusions, substantial psychiatric comorbidity (including depression and post-traumatic stress disorder) and reduction in health-related quality of life (HRQoL). HHT is clinically diagnosed using the Curacao criteria, which consists of 1) spontaneous and recurrent epistaxis, 2) telangiectasias at characteristic sites, 3) visceral arteriovenous malformations (AVMs) or telangiectasias, and 4) a first degree relative with HHT (inheritance is usually autosomal dominant). Patients with three criteria are considered to have definite HHT, and those with 2 criteria probable HHT. HHT affects approximately 1 in 3,800 individuals. Significant manifestations of HHT often do not appear until the third or fourth decades, sometimes later.Participants: 144 patients from 11 clinical centers were enrolled.Design: This is a multi-center, double blind, randomized placebo-controlled trial that investigated the efficacy and safety of pomalidomide in patients with HHT and chronic epistaxis leading to iron-deficiency anemia or requiring intravenous iron infusions or blood transfusion.Screening evaluation included the Epistaxis Severity Score (ESS) with three-month recall, which reflected the patient's history of epistaxis and bleeding over the prior three months, as well as detailed review of iron infusion and red cell transfusion over the preceding six months. Eligible patients were provided a diary to record the duration of each epistaxis event that occurred during the 4 weeks prior to the baseline visit, and then returned for the baseline randomization visit, at which time patients underwent genetic testing, if this had not been previously performed, and completed an ESS with 4-week recall and quality of life assessments. Patients were randomized 2:1, stratified by study site, to either pomalidomide 4 mg/day or matching placebo during each of six 28 day cycles (24 weeks). Patients were seen every four weeks during treatment, and at a 4-week post-treatment follow-up visit to measure the ESS (with 4-week recall), laboratory assessments including iron stores and need for iron infusion, CBC, and metabolic profile. Patients were assessed for adverse events (AE) throughout the study. Treatment dosage could be reduced, or temporarily or permanently discontinued following AE-specific guidelines related to fatigue, cytopenias or other toxicities.Quality of life assessments were completed at baseline, and the 12- and 24-week visits, and the 4-week post-treatment follow-up visit using validated NIH instruments of 1) Neuro-QOL satisfaction with social roles and activities, 2) PROMIS emotional distress – depression, and 3) PROMIS fatigue, and the HHT-specific quality of life instrument developed specifically for this study. The effect of pomalidomide on duration of epistaxis was assessed via diary between weeks 8-12, 20-24 and the 4-week post-treatment period.Conclusions: Among patients with HHT, pomalidomide treatment resulted in a significant, clinically relevant reduction in epistaxis severity. No unexpected safety signals were identified (Al-Samkari et al., 2024; PMID: 39292928)

  Study phs003948