14663 results for "PLOS+ONE+Pennsylvania+German+ACS+language+code+pdc+open+access+study"

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• Adipose Tissue Omics In Obesity

  This project used a multi-omics approach to study the adipose tissue transcriptome in humans with and without obesity. Our human cohort included males and females between the ages of 18-80 who underwent elective abdominal surgery at the University of Michigan and the Ann Arbor Veterans Affairs Healthcare System.Patients with advanced cancer or immuncompromised status were excluded. Visceral adipose tissue (VAT/omental) and subcutaneous adipose tissue (SAT/abdominal wall) were collected from subjects with obesity (BMI>=35) at the beginning of elective surgical procedures, placed on ice, and transported back to the laboratory for immediate processing. For adipose tissue stromal cells (ASC) isolation, adipose tissue was digested with Type II collagenase (2 mg/mL in PBS/2% BSA) at 37oC, 60min, centrifuged at 250 rcf, and the stromal-vascular cell pellet was retrieved, plated overnight, and the adherent cells passaged three times to enrich for ASC, which were then frozen in DMEM/F12, 15% fetal calf serum, and 10% DMSO in liquid nitrogen until use. Single nuclear sequencing was performed on preparations from intact adipose tissue. Bulk RNA sequencing and single cell sequencing were performed on ASC isolated from intact adipose tissue and cultured in 2D and 3D culture systems. We currently apply bulk, single cell, and single nuclear sequencing analyses to these tissues. One component of this project studies single nuclear sequencing in nuclei isolated from intact adipose tissues from human subjects with obesity, focusing on depot comparisons (VAT vs. SAT). This cohort also permits comparisons of adipose tissue transcriptomes between male and female subjects, controlling for age and BMI. Primary findings to date include identification of multiple ASC, adipocyte, and endothelial cell (EC) subpopulations, T-cell, and macrophage (MAC) populations that are in concordance with and expand upon other published datasets. Of two dominant ASC subpopulations, one (inflammatory-mesothelial, IM- ASC) is present in VAT, but absent in SAT, while the other (fibroadipogenic, FA-ASC) is present in both VAT and SAT. We identified multiple EC subtypes with features of lymphatic, venous, and arterial EC, and a PRDM16 expressing population with features of an EC progenitor. Immune cell populations match recent experimental validation of lipid-activated macrophage (LAM) phenotypes, TIM4 macrophages, and a prominent population of MRC1/CD206+ resident AT macrophages with expression signatures related to glucocorticoid activation. These data support depot-specific differences in ASC subpopulations and previously unrecognized EC heterogeneity within human AT, with the potential to shed light on functional differences in AT depot and disease state. Planned future studies include ATAC-Seq and other omics analyses. Another component of this project studies transcriptional responses of ASC in vitro to various stimuli, including different matrix environments. Current data includes bulk RNA Sequencing of human ASC from VAT and SAT differentiated into mature adipocytes in hydrogels of differing stiffness (3%, 5%, 10%) to define transcriptional responses to matrix environments of different stiffness. Primary findings to date include enrichment of adipogenesis and lipid and oxidative metabolic gene pathways in adipocytes in 5% relative to 3% hydrogels, while fibrotic gene pathways have been enriched in 3% hydrogels. These data demonstrate that intermediate density matrix promotes a more adipogenic, less fibrotic adipocyte phenotype geared towards increased lipid and aerobic metabolism. Planned future studies include expansion of intact tissues from our cohort studied with single nuclear sequencing, as well as further study of ASC responses in vitro to different biologic stimuli, including different matrix environments.

  Study phs003390

• Urethral Microbiome of Adolescent Males

  Urethral microbiome of adolescent males is designed to characterize the microbial communities resident in the urethra of young men, to identify differences in these communities as a function of race/ethnicity, circumcision status, sexual exposures, and uro-genital symptoms. We collect detailed sexual behavior and symptoms data using cellular telephones with Internet access. Specimens are routinely collected at monthly intervals, and intermittently following reported symptoms, specific sexual exposures, or identification of a sexually transmitted infection. We also collect periodic samples from the penile coronal sulcus to better characterize its relationship to the urethral micriobial communities. Participants are ages 14 - 17 at enrollment, and prior history of sexual exposure is not required for participation. Parental permission is obtained for each participant. The planned duration of followup is up to 4 years allowing for prospective observation of both physical and behavioral maturation from middle adolescence into young adulthood. The overall objectives of the project are to better characterize the healthy male urethral microbiome, and to use this information to better understand acquisition of urethritis and sexually transmitted infections, as well as chronic genital pain and prostatitis syndromes that become common among young adults.

  Study phs000259

• eMERGE Phase III Clinical Center at Partners HealthCare

  The Partners HealthCare Biobank is a large research data and sample repository working within the framework of Partners Personalized Medicine. It provides researchers access to high quality, consented samples to help foster research, advance understanding of the causes of common diseases, and advance the practice of medicine. The Partners Biobank provides banked samples (plasma, serum and DNA) collected from consented patients. These samples are available for distribution to Partners HealthCare investigators with appropriate approval from the Partners Institutional Review board (IRB). They are linked to clinical data that originates in the Electronic Medical Record (EMR), as well as additional health information collected in a self-reported survey. The Partners Biobank will be genotyping 25,000 subjects with the Illumina Multiethnic Beadchip 1.6 million SNPs with exome and custom content (> 60,000 LoFs). Of the participants genotyped so far, 4929 of 4962 (99.3%) individuals have genotype data that passed the default quality thresholds for the Infinium array (call rate >= 0.99). We are submitting the genotype data to dbGaP for 4929 subjects with 12 phenotypes (based on icd9 codes). We will do annual releases until we reach the full 25,000 genotyped subjects.

  Study phs000944

• The proliferative history shapes the DNA methylome of B-cell tumor and predicts clinical outcome

  Here, we provide access to CLL and DLBCL DNA methylation and gene expression data in the context of a systematic analysis of the DNA methylation variability in 1,595 samples of normal cell subpopulations and 14 tumor subtypes spanning the entire human B-cell lineage. This approach showed that differential methylation among tumor entities relates to differences in cellular origin and to de novo epigenetic alterations, which allowed us to build an accurate machine learning-based diagnostic algorithm. We identify extensive patient-specific methylation variability in silenced chromatin associated with the proliferative history of normal and neoplastic B cells. Mitotic activity generally leaves both hyper- and hypomethylation imprints, but some B-cell neoplasms preferentially gain or lose DNA methylation. Subsequently, we construct a DNA methylation-based mitotic clock called epiCMIT, whose lapse magnitude represents a strong independent prognostic variable in B-cell tumors and is associated with particular driver genetic alterations. Our findings reveal DNA methylation as a holistic tracer of B-cell tumor developmental history, with implications in the differential diagnosis and prediction of clinical outcome.

  Study EGAS00001004640

• LCCC1122: Defining the Triple Negative Breast Cancer Kinome Response to GSK1120212

  In this study the investigators looked at adaptive reprogramming impact on the kinome when a MEK inhibitor called GSK1120212 (trametinib) was administered in a "window of opportunity" trial. GSK1120212 is not yet approved by the FDA for use in breast cancer patients. The investigators gave GSK1120212 for a short period of time (one week) to examine MEK and the other kinase expression in cancer cells both before and after the study drug is given. The investigators gave this drug for research purposes only. The length of time it was given is not intended to treat cancer. Recently researchers at UNC developed a process that can comprehensively profile the majority of the individual kinases in the kinome and examine the impact on kinase expression of kinase inhibitors (Duncan et al, Cell 2012, PMID: 22500798). This can tell us which kinases need to be concurrently blocked to augment responsiveness and prevent acquired resistance so that the investigators can design the best combinations of kinase blocking drugs for triple negative breast cancer. This is especially important for individuals with triple negative breast cancer (TNBC) because there are no targeted drugs available that can block molecules that affect tumor growth. The investigators believe that kinase-blocking drugs have the potential to be a more effective treatment for people with TNBC. In this recently published study (Zawistowski et al, Cancer Discovery 2017, PMID: 28108460), TNBC patients treated with trametinib for 7 days resulted in a transcriptional response characterized by significant reprogramming of the tyrosine kinome, and this adaptive bypass response in human tumors was found to be similar to that seen in preclinical models including TNBC cell lines and mouse xenografts. In this study we also examined whether reprogramming differed between TNBC molecular subtypes, finding that basal-like and claudin-low human TNBC cells and mouse tumor subtypes had different adaptive transcriptional responses to MEK-ERK inhibition. Mechanistically we found that genome-wide enhancer remodeling drove the adaptive transcriptional response, suggesting that epigenetic approaches to reprogramming may be more durable than kinase inhibitor polypharmacology.

  Study phs001405

• Identification of Somatic Changes in Tumors from Fanconi Anemia Patients

  This study focused on the identification of genomic signatures present in tumors from Fanconi anemia patients. Fanconi anemia is a rare hereditary disease caused by defects in DNA interstrand crosslink repair. The primary patient phenotypes are bone marrow failure and cancer predisposition. We concentrated on squamous cell carcinomas and used whole genome Illumina sequencing (22 tumor samples and 12 normal samples) , whole exome sequencing (37 tumor samples and 33 normal samples), PacBio long-read whole-genome (nine tumor and four normal samples),10X linked-read whole-genome sequencing, 10x single-cell/nuclei 3’ RNA sequencing (three tumor samples), 10x Visium spatial transcriptomics (one tumor sample), EPIC 850K methylation array (six samples), and bulk RNAseq (six tumor samples) to identify somatic changes present in tumors. The study aimed to identify changes that drive tumorigenesis in Fanconi anemia, give insight into the early development and aggressive nature of these tumors, and suggest therapeutic avenues for these patients. Another goal was to compare the genomic changes identified in tumors from Fanconi anemia patients with sporadic head and neck cancers. This study demonstrated that the tumors from Fanconi anemia individuals are generally not driven by HPV. Instead, they acquire mutations in the p53 tumor suppressor. The main characteristic of the tumors is the presence of a high number of structural variants in the form of small deletions, unbalanced translocations, and fold-back inversions, which often form complex rearrangements. These rearrangements result in amplifications and deletions of a multitude of oncogenes and tumor suppressors, respectively. The study also shows that lack of the Fanconi anemia DNA repair pathway leads to an epithelial-to-mesenchymal transition in a mouse model and in human samples that may influence the behavior of tumors in Fanconi anemia. Finally, comparing genomic changes in Fanconi anemia and sporadic tumors of the head and neck, we propose that the structural variants present in sporadic cancer result in a functional deficiency of the Fanconi anemia DNA repair pathway.

  Study phs002652

• 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

• Dataset of methylation data from whole blood DNA

  This dataset includes raw data (.idat) for the Illumina Human450k beadchip and methylation levels (.txt files). Methylation level were treated for normalization and background substraction. We removed probes with at least one of the following characteristics: (1) weak signal (p > 0.01) (2128 CpG sites), (2) SNP-enriched sites (4100 sites), (3) out of a CpG context (not on a CG) (3149 sites), or (4) located on sex chromosomes (11,129 sites). A total of 465,071 CpG sites were analyzed initially. Signal was then normalized, first by scaling to the internal controls using the methylumi R package, then by applying the method of subset-quantile within array normalization (SWAN) implemented in the minfi R package.

  Dataset EGAD00010001593

• Transcriptome of memory B cells with autoproliferation in MS

  Transcriptional profile of resting/hi and autoproliferating/Dim memory B cells in Multiple sclerosis patients. In brief, non-proliferating (CFSEhi) and AP+ (CFSEdim) CD19+ CD27+ B cells from PBMCs of 5 natalizumab-treated female RRMS (NAT) patients were sorted following 7 days of autoproliferation. Transcriptome libraries were constructed from the same samples, except for one sample pair, which was excluded due to limited input material (5 donors as for Methylome, D1; D2, D3, D5, D6; samples from donor D4 unfortunately technically failed). SMARTer Total Stranded RNA-seq library construction with ribosomal depletion was performed and then sequenced on NovaSeq S4 lane.

  Dataset EGAD50000001270

• 10X CD4 auto-antigens

  Ex vivo CD4 T-cells from 4 donors were stimulated with antigen-coupled beads to aCD3, ABD, EBNA1, ANO2 or CRYAB and the LiveCD3+CD4+CFSEdim cells were sorted by flow cytometry. Cells were labelled with barcoded antibodies to identify the original stimulus. All stimulations from each donor were pooled into four reactions, i.e. one reaction per donor. Libraries were assembled with the 10X Chromium Next GEM Single Cell 5’ Kit for TCR and transcriptome with feature barcodes. Dataset contains raw fastq reads as well as supplementary information needed to link fastq files to modality, i.e. gene-expression, protein or VDJ, and includes supplementary information to de-multiplex the reactions by stimulation condition.

  Dataset EGAD50000002201

• Preeclampsia InterPregGen Consortium: Whole Genome Sequencing of 100 unrelated Kazakhs (DNA samples from the Scientific Center of Obstetrics, Gynecology and Perinatology, Almaty, Kazakhstan; Gulnara Svyatova, Principal Investigator

  Whole genome sequencing of 100 unrelated Kazakhs in order to impute genotypes into PE cases and controls from Kazakhstan and to provide genetic data and infrastructure for future genetic studies in Kazakhstan and Central Asia more generally and to fill a gap in worldwide information as Central Asia is not adequately represented in available genomic data. This dataset is one component of the InterPregGen FP7 project. DNA samples for this component were collected by InterPregGen Consortium collaborators at the Scientific Center of Obstetrics, Gynecology and Perinatology, Almaty, Kazakhstan (Gulnara Svyatova, Principal Investigator)

  Dataset EGAD00001005467

• C9orf72 region reads of 3001 samples

  This dataset includes cram files from 3,001 samples. These cram files include all read pairs where at least one of the reads aligns within 1kb of the C9orf72 repeat expansion. Additionally, these cram files also contain reads that are aligned to any of 29 pre-determined off target locations where the aligners are known to mis-align reads associated with this repeat expansion. These samples were sequenced using a combination of 2x100bp reads on an Illumina HiSeq2000 and 2x150bp reads on an Illumina HiSeqX sequencer and aligned using the Isaac aligner.

  Dataset EGAD00001004834

• Inter and intra - tumor heterogeneity in Colorectal Cancer

  The dataset consists of two main sample groups. 1) The inter-tumour sample group contains a total of 97 samples from 27 patients. Each patient has a single normal and primary sample as well as one or more metastases. All samples were sequenced using IonTorrent PGM and a custom colorectal cancer (CRC) panel. 2) The intra-tumour sample group contains a total of 68 samples from a single tumour as well as a normal tissue sample. All 68 samples were sequenced using IonTorrent PGM and a custom CRC panel. Shallow whole genome sequencing was additionally applied to 10 of the samples using Illumina HiSeq 4000.

  Dataset EGAD00001003131

• ICR639 CPG NGS Validation series

  The dataset includes sequencing data generated using the TruSight Cancer Panel (TSCP) a targeted NGS assay for analysis of CPGs and orthogonally generated data supporting at least one pathogenic variant in a CPG for a total of 645 pathogenic CPG variants. The set of pathogenic CPG variants includes strong representation of some of the most challenging types of pathogenic variants, with 339 indels, including 16 complex indels and 24 insertions or deletions with length greater than 5bp, and 74 exon CNVs, including 23 single exon CNVs. There are 502 pathogenic variants in BRCA1 or BRCA2, making this an important first-line validation dataset for laboratories performing NGS testing of BRCA1 and BRCA2.

  Dataset EGAD00001004134

• LLDeep DAG2+: scRNA-seq in PBMCs

  Single cell transcriptomics of PBMCs of 47 donors from the Lifelines Deep cohort (general population, Northern part of the Netherlands). Cells of five or six different donors were pooled together in one sample pool, resulting in eight different sample pools. In total, 28.855 cells were captured and their transcriptomes were sequenced to an average depth of 74k. Genotype data was available for each donor, which allowed us to use the Demuxlet method that uses variable SNPs between the pooled individuals to determine which cell belongs to which individual. Since genotype information is lacking of 2 individuals, the transcriptome of only 45 individuals could be retrieved.

  Dataset EGAD00001003459

• Single-cell RNA-seq of human kidney tumors

  Fresh nephrectomy samples were collected from a total of 5 untreated ccRCC patients. Out of these 5 patients, 7 samples were obtained. Two samples consisted of fresh versus frozen single cells from the primary tumor site of one patient. Two other samples consisted of matched primary and distant thrombus sites (the vena cava) of a second patient. The three remaining samples came from the primary tumor sites of three distinct ccRCC patients. Single-cells were captured into 10x barcoded gel beads and RNA-sequencing library preparation was done using Chromium Single Cell 3' v2 chemistry. Sequencing was performed on a Illumina HiSeq 4000 sequencer.

  Dataset EGAD00001009306

• Single cell RNA-seq, TCR-seq and bulk TCR-seq on HNSCC patients treated with ICB

  We performed single cell RNA- and TCR-sequencing (10x Genomics) on immune infiltrates (CD45+ cells) from 18 HNSCC patients enrolled in the IMCISION trial (Vos et al. 2021). Viable immune cells were isolated from pre-treatment and post-treatment primary tumor biopsies of 10 patients responding (1 partial pathological response and 9 major pathological responses) and 7 patients non-responding to anti-PD-1 and anti-CTLA4 combination immunotherapy. One patient treated with anti-PD-1 monotherapy (1 major pathological response) was included in the dataset. Bulk TCR-seq was performed on the PBMCs of responding patients, pre- and post-treatment.

  Dataset EGAD00001011311

• Women's Health Initiative Clinical Trial and Observational Study

  The Women's Health Initiative (WHI) is a long-term national health study that has focused on strategies for preventing heart disease, breast and colorectal cancer, and osteoporotic fractures in postmenopausal women. The original WHI study included 161,808 postmenopausal women enrolled between 1993 and 1998. The Fred Hutchinson Cancer Research Center in Seattle, WA serves as the WHI Clinical Coordinating Center for data collection, management, and analysis of the WHI. The WHI has two major parts: a partial factorial randomized Clinical Trial (CT) and an Observational Study (OS); both were conducted at 40 Clinical Centers nationwide. The CT enrolled 68,132 postmenopausal women between the ages of 50-79 into trials testing three prevention strategies. If eligible, women could choose to enroll in one, two, or all three of the trial components. The components are: Hormone Therapy Trials (HT): This double-blind component examined the effects of combined hormones or estrogen alone on the prevention of coronary heart disease and osteoporotic fractures, and associated risk for breast cancer. Women participating in this component with an intact uterus were randomized to estrogen plus progestin (conjugated equine estrogens [CEE], 0.625 mg/d plus medroxyprogesterone acetate [MPA] 2.5 mg/d] or a matching placebo. Women with prior hysterectomy were randomized to CEE or placebo. Both trials were stopped early, in July 2002 and March 2004, respectively, based on adverse effects. All HT participants continued to be followed without intervention until close-out. Dietary Modification Trial (DM): The Dietary Modification component evaluated the effect of a low-fat and high fruit, vegetable and grain diet on the prevention of breast and colorectal cancers and coronary heart disease. Study participants were randomized to either their usual eating pattern or a low-fat dietary pattern. Calcium/Vitamin D Trial (CaD): This double-blind component began 1 to 2 years after a woman joined one or both of the other clinical trial components. It evaluated the effect of calcium and vitamin D supplementation on the prevention of osteoporotic fractures and colorectal cancer. Women in this component were randomized to calcium (1000 mg/d) and vitamin D (400 IU/d) supplements or a matching placebo. The Observational Study (OS) examines the relationship between lifestyle, environmental, medical and molecular risk factors and specific measures of health or disease outcomes. This component involves tracking the medical history and health habits of 93,676 women not participating in the CT. Recruitment for the observational study was completed in 1998 and participants were followed annually for 8 to 12 years. Extension Studies: The original protocol allowed for follow-up until March 2005, after which participants were invited to enroll in the first WHI Extension Study for follow-up through 2010. Participants were invited again to participate in the second WHI Extension Study with continued follow up from 2010 to at least 2015. As of March 31, 2011 there were 93,122 women enrolled in the second extension. In Extension Study 2, the overall WHI study population was divided into two new subsamples, the Medical Records Cohort (MRC) and the Self-Report Cohort (SRC). The MRC consists of all former hormone trial participants and all African American and Hispanic participants from all study components. The SRC consists of the remaining participants. The extent of outcome information collected differs between the two cohorts, with more extensive outcomes information collection on the MRC. As part of Extension Study 2, selected older WHI participants were invited to participate in an In Person Visit (a.k.a., Long Life Study) at their homes during which additional blood samples were collected and various measurements were taken (such as blood pressure, height, weight, waist circumference, grip strength, etc.). In October 2015, Extension Study 2 was renewed with continued follow-up planned through October 2020, pending annual contract review and renewal. Additional Information: The WHI website, https://www.whi.org/about/SitePages/About%20WHI.aspx has much more information about the study. For WHI data collection forms used over the years, please see https://www.whi.org/researchers/studydoc/SitePages/Forms.aspx. For additional dataset documentation, see https://www.whi.org/researchers/data/Pages/Available%20Data.aspx. For data preparation and use, please refer to 'WHI dbGaP Cohort Data Release Data Preparation Guide May 2018' for additional details about the WHI data. The WHI Cohort is utilized in the following dbGaP substudies. To view genotypes, analysis, expression data, other molecular data, and derived variables collected in these substudies, please click on the following substudies below or in the "Substudies" box located on the right hand side of this top-level study page phs000200 WHI Cohort. phs000386 WHI SHARe phs000281 GO-ESP WHISP phs000315 WHI GARNET phs000503 WHISE phs000227 PAGE WHI phs000675 WHIMS+ phs000746 WHI Harmonized and Imputed GWAS phs001334 WHI Metabolomics of CHD phs001335 WHI BA23 phs001614 WHI LLS Phase III GWAS

  Study phs000200

• Cooperative Study of Sickle Cell Disease (CSSCD)

  The Cooperative Study of Sickle Cell Disease was initiated in 1977 to determine the natural history of sickle cell disease (SCD) from birth to death in order to identify those factors contributing to the morbidity and mortality of the disease. Specific objectives included: 1) to study the effect of sickle cell disease on growth and development from birth through adolescence 2) to study the conditions or events that may be related to the onset of painful crises 3) to obtain data on the nature, duration, and outcome of major complications of SCD 4) determine the nature, prevalence, and age- related incidence of organ damage due to SCD, and 5) study the role of SCD and its interaction with selected health events.Phases 2 and 3 of the study involved followup of the infant cohort. A total of 709 infants (age less than 6 months) were enrolled during Phase 1 of the Cooperative Study of Sickle Cell Disease (CSSCD), and Phases 2 and 3 of the CSSCD was designed to follow these children for an additional 10 years. The study objectives included: 1) define prospectively the natural history of sickle cell disease; 2) determine the relationships between cognitive and academic functioning and brain status as determined by MRI; 3) determine the cognitive or behavioral markers of silent infarct; 4) determine the relationship of family functioning on the Family Environment Scale (FES) to brain status, cognitive functioning, and social and demographic factors; 5) continue studies that will enhance the state of knowledge on the influence of sickle cell disease on the psychosocial adjustment of children and adolescents. Phase 2A of the study sought to examine the progression of organ damage in the heart, lung, kidney, and liver in adult cohort patients (born before 1/1/56) enrolled in phase 1 of the study between 3/79 and 5/81. A total of 620 patients from 11 centers were eligible for phase 2A.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 phs002362

• CRU-Ukrainian National Research Center for Radiation Medicine Trio Study

  Data on transgenerational effects following nuclear accidents are important for understanding fully the consequences of parental exposure to ionizing radiation. Few studies to date have had adequate statistical power to detect effects of the magnitude expected based on animal data, and most have not been of low-dose, protracted exposures associated with nuclear accidents and their aftermath. Although, to date, scant use has been made of the new genomic technologies, in Chernobyl-exposed areas of Ukraine and Belarus, excess minisatellite mutations have been seen in children born after the accident. We propose a study of parent-child trios in which at least one parent was exposed to Chernobyl radiation as a clean-up worker (mean dose>=100 mGy) and/or evacuee from a contaminated area (mean >=50 mGy). The specific aims are to investigate the transgenerational and de novo mutation rates of the spectrum of genetic variants in trios, in particular looking at effects in children and mapping them to possible parental origin of the chromsoome. Together with long-term collaborators at the Research Center for Radiation Medicine (RCRM) in Kiev, epidemiologic data will be collected for up to 450 trios of parents with preconceptional doses and their unexposed offspring. We will use state-of-the-art genomic technologies to characterize the landscape of the genomes of the trios to determine whether parental radiation exposure is associated with genetic mutations transmitted to the offspring, by examining de novo mutation rates, minisatellite mutations, copy number alterations, and variations in telomere length. The analysis will be conducted in peripheral blood and/or buccal samples (when blood is not available) from complete father-mother-child trios. Doses to the gonads from the time of the accident to the time of conception will be reconstructed for all parents using existing records supplemented by interview data. Trio subjects will be selected from representative populations exposed to radiation from Chernobyl who are under active follow-up in the Clinico-Epidemiologic Registry at RCRM. To help identify specific effects of paternal and maternal radiation exposure, we will initially select sets of trio subjects in five categories: (1) exposed father, unexposed mother; (2) unexposed father, exposed mother; (3) both parents exposed; (4) both parents unexposed; and (5) a group of high dose "emergency workers" with acute radiation syndrome. All trio members will be invited to the RCRM outpatient clinic for collection of a 20 ml blood sample (or buccal cells for those who refuse phlebotomy). Both parents will be asked to complete a general questionnaire to obtain demographic and lifestyle data. Then one or both will complete detailed dosimetry questionnaires, based on forms used in previous collaborations with RCRM and administered by specially trained interviewers. Once 50 trios have been recruited (10 from each of the 5 exposure categories), we will conduct an interim evaluation of participation rates, sample collection and quality, and dose reconstruction in order to modify the protocol as needed. The analytical approach will be to correlate the extent, especially for de novo events of genetic alterations in the offspring with parental pre-conceptional radiation dose overall and by parental origin. The statistical power in relation to de novo mutations is very high, in excess of 90%, but somewhat lower for trends in minisatellite mutations. Study findings will contribute importantly to knowledge of the heritable effects of moderate- and low-dose radiation exposure in humans and to radiation risk projection. Eventually data from the Trio Study may be shared with the international community through dbGap.

  Study phs001163

• Comprehensive cancer predisposition gene testing in an adult multiple primary tumor series shows a broad range of deleterious variants and atypical tumor phenotypes

  Multiple primary tumors (MPT) affect a substantial proportion of cancer survivors and may result from various causes including inherited predisposition. Currently, germline genetic testing of MPT cases for cancer predisposition gene (CPG) variants is mostly targeted by tumor type. We ascertained pre-assessed MPT cases from genetics centers (defined as ≥2 primaries by age 60 years or ≥3 by 70) and performed whole genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment/molecular investigations, pathogenic variants in moderate and high-risk CPGs were detected in 67/440 (15.2%) of probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies including structural variants at low frequency (6/440 (1.4%) of probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant) the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice site CPG variants and at least one discordant tumor type was significantly higher than a control population (χ2=43.642 P=<0.0001). 2/67 (3%) of probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Summing together variant detection rates from a similarly ascertained previous MPT case series, the present results suggest that first-line comprehensive CPG analysis in a clinical genetics referral-based MPT cohort would detect a deleterious variant in about a third of cases.

  Dataset EGAD00001004088

• CIDR: NINDS High Throughput Genotyping Resource Access for Structural Hindbrain Disorders

  Recessive forms for many structural brain disorders (SBDs), including cerebellar hypoplasia (CBH), corpus callosum hypoplasia (CCH), cobblestone lissencephaly (COB), classical lissencephaly (LIS), microcephaly (MIC), and pontocerebellar hypoplasia (PCH), have been described. Patients usually present to the clinic with neurodevelopmental disorders (NDDs), including autism, epilepsy, intellectual disability, and cerebral palsy. Subsequent brain MRI usually leads to the diagnosis of an SBD. While a handful of genes that cause these diseases have been identified, most patients do not have mutations in these genes, suggesting that there is still much work to be done in identifying the genetic causes of these disorders. We have recruited a cohort of families with inherited SBDs, most from families with documented parental consanguinity with more than one affected member. Current approaches utilizing exome sequencing of SBD affected members still leave most cases unsolved, in part because there are too many possible variants to consider. Linkage analysis will allow us to extract all the useful genetic information from the family, taking advantage of each genetically informative meiosis in each family. We propose to analyze up to 100 SBD families for 500 samples per year for 4 years, through the CIDR SNP Genotyping Service, in parallel with already-funded exome sequencing of affects, leveraging off an already funded Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) effort to identify new causes of SBDs. Understanding the pathogenetic mechanisms underlying recessive pediatric SBDs will lead to better diagnostic and therapeutic opportunities for patients, and may shed light on complex NDDs. Ultimately, this work will identify new genetic disease loci to provide insight into pediatric SBD, with the hope to mitigate the impact of SBD worldwide.Public Health Significance: NDDs affect approximately 4-­6% of the general population, most notably children, and are evident in disorders, such as intellectual disability, epilepsy, and autism, with estimated yearly costs of $51.2B for intellectual disability, $11.5B for cerebral palsy, and $2.5B for visual impairment, making up >5% of total health care costs. Recessive NDDs impose enormous personal, social, and economic costs because of the early onset and the lifetime of medical dependence that often ensues. Genetic testing is critical to the diagnosis and treatment of these diseases. Many of the diseases under study have no treatment or cure. Structural brain diseases (SBDs) underlie a large percentage of these diseases, and are defined loosely as any condition in which defects in the structure or volume of a key brain component. SBDs are divided into major categories based upon the anatomical brain location. The major types involve the anatomical structures of the developing neural tube, forebrain, hindbrain, cerebral cortex, and those affecting overall brain size. For the purposes of this application, we have excluded SBDs resulting from environmental causes (i.e. prematurity-­induced), those below the brainstem, or those unlikely to be due to a germline or de novo mutation (i.e. focal SBDs or simplex disease).

  Study phs002621

• Whole Exome Sequencing of One Nuclear Family with Non-syndromic Sensorineural Hearing Loss

  Our goal is to find genes responsible for non-syndromic sensorineural hearing loss. Blood samples were collected from the JS6 family affected with hearing loss. The family is of Caribbean Hispanic ethnicity. Family JS6 consisted of two deaf siblings, JS6.001 (Male) and JS6.002 (Female) and healthy parents, JS6.100 (mother) and JS6.200 (father). The siblings had no other medical findings. Audiometry tests and Rinne and Weber tuning fork tests identified sensorineural hearing loss in the two siblings. We performed whole exome sequencing of the four individuals and identified a recessive mutation, p.(Arg186Trp), in the CIB2 gene in the two affected siblings. Both parents were unaffected carriers.

  Study phs000969

• CyTOF of 27 DLBCLs

  Diffuse large B-cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin lymphoma and is notorious for its clinical heterogeneity. Patient outcomes can be predicted by cell-of-origin (COO) classification, demonstrating that the underlying transcriptional signature of malignant B-cells informs biological behavior in the context of standard combination chemotherapy regimens. In the current study, we used mass cytometry (CyTOF) to examine tumor phenotypes at the protein level with single cell resolution in a collection of 27 diagnostic DLBCL biopsy specimens from treatment naïve patients. We found that malignant B-cells from each patient occupied unique regions in 37-dimensional phenotypic space with no apparent clustering of samples into discrete subtypes. Interestingly, variable MHC class II expression was found to be the greatest contributor to phenotypic diversity. Within individual tumors, a subset of cases showed multiple phenotypic subpopulations, and in one case we were able to demonstrate direct correspondence between protein-level phenotypic subsets and DNA mutation-defined subclones. In summary, CyTOF analysis can resolve both inter- and intra-tumoral heterogeneity among primary samples, and reveals that each case of DLBCL is unique and may be comprised of multiple, genetically distinct subclones.

  Dataset EGAD00001005419

• 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