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• Kids First and INCLUDE: Down Syndrome, Heart Defects, and Acute Lymphoblastic Leukemia

  This project is a collaboration with the trans-NIH INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE (INCLUDE) Project, which seeks to improve health and quality-of-life for individuals with Down syndrome, and NHLBI's TransOmics for Precision Medicine (TOPMed) program, which seeks to apply omics technologies to improve scientific understanding of the fundamental biological processes that underlie heart, lung, blood, and sleep (HLBS) disorders. The data is also available at the INCLUDE Data Hub. Down syndrome (DS), which occurs due to trisomy 21, is one of the strongest risk factors for both congenital heart disease (CHD) and acute leukemia. For instance, children with DS have a 2000-fold increased risk of atrioventricular septal defects (AVSD) and a 20-fold increased risk of acute lymphoblastic leukemia (ALL). An important and innovative aspect of the Kids First program is understanding the overlap between structural birth defects and childhood cancer. Notably, the background of DS predisposes children to both of these phenotypes, however, the genomic architecture of risk remains largely undiscovered. In this joint Kids First/TOPMed/INCLUDE project, we are currently including >2,000 samples for whole-genome sequencing, including: 1) paired germline-tumor samples from children with DS-ALL; and 2) samples from families with DS-CHD. This work will advance our understanding of the developmental pathways that may lead to both structural birth defects and childhood cancer. The objectives of this study are to determine the genetic variants underlying AVSD and ALL risk in children with DS. Therefore, the aims of our study are: 1) compare whole-genome sequencing (WGS) data between children with documented DS-AVSD and children with DS who have structurally normal hearts to identify genetic variants that perturb heart development; and 2) compare WGS data between children with documented DS-ALL and children (from Aim 1) with DS who do not have a known history of ALL. We will also examine associations between germline mutations and somatic genomic features. This study will address the fundamental question of why children with DS have an elevated risk of AVSD and ALL. Insights into the genes that drive DS-AVSD and DS-ALL may have implications for improved genetic counseling, surveillance, clinical management, and treatment strategies for these children. Additionally, our findings may inform targeted therapies or interventions for children without DS who are at risk for structural birth defects and cancer. Additional Pediatric Cardiac Genetics Consortium (PCGC) data from children affected with Down syndrome and congenital heart disease are accessible through two separate dbGaP studies: phs001138 (Kids First) and phs001194 (TOPMed).

  Study phs002330

• Transcriptome of human trophoblast stem cells derived from normal and HDP placentas

  Hypertensive disorders of pregnancy (HDP) is a disease driven by abnormal placenta formation, which is a leading cause of maternal and fetal death. For investigation of genetic and epigenetic regulation of human trophoblast differentiation, we have previously established human trophoblast stem cells (hTSCs) from first-trimester placentas. Those hTSCs were able to differentiate into extravillous trophoblasts (EVTs) and syncytiotrophoblasts (STs), and their transcriptome was similar to that of cytotrophoblasts in human placenta. However, since HDP happens in the second half of pregnancy, the conventional hTSC derivation method was not enough to investigate the nature of HDP trophoblasts. In this analysis, we improved the derivation method and successfully established the hTSCs from normal and HDP term placentas after delivery. We performed RNA-seq of normal and HDP hTSCs, and HDP hTSCs recapitulated abnormalities in gene expression reported in HDP placentas.

  Study JGAS000660

• Nicotine dependence GWAS meta-analysis across European and African American ancestries

  Cigarette smoking is the leading cause of preventable morbidity and mortality. Knowledge is evolving on genetics underlying initiation, regular smoking, nicotine dependence (ND), and cessation. We performed a genome-wide association study using the Fagerström Test for ND (FTND) in 58,000 smokers of European or African ancestry. Five genome-wide significant loci, including two novel loci MAGI2/GNAI1 (rs2714700) and TENM2 (rs1862416) were identified, and loci reported for other smoking traits were extended to ND. Using the heaviness of smoking index (HSI) in the UK Biobank (N=33,791), rs2714700 was consistently associated, but rs1862416 was not associated, likely reflecting ND features not captured by the HSI. Both variants were cis-eQTLs (rs2714700 for MAGI2-AS3 in hippocampus, rs1862416 for TENM2 in lung), and expression of genes spanning ND-associated variants was enriched in cerebellum. SNP-based heritability of ND was 8.6%, and ND was genetically correlated with 13 other smoking traits (rg=0.40-0.95) and co-morbid diseases. Our results emphasize the FTND as a composite phenotype that expands genetic knowledge of smoking, including loci specific to ND.

  Study phs001532

• CRC and UC WES samples

  This is the dataset used to produce results for the report "NOUS-209 off-the-shelf immunotherapy has the potential to hit primary and metachronous colorectal and urothelial cancer in Lynch syndrome"

  Dac EGAC50000000782

• Allele-specific expression of GATA2 due to epigenetic dysregulation in double mutated CEBPA AML

  Transcriptional deregulation is a central event in the development of acute myeloid leukemia (AML). To identify potential disturbances in gene regulation, we conducted an unbiased screen of allele-specific expression (ASE) in 209 AML cases. The gene encoding GATA binding protein 2 (GATA2) displayed ASE more often than any other myeloid or cancer-related gene. GATA2 ASE was strongly associated with CEBPA double mutations (CEBPA DM), with 95% of cases presenting GATA2 ASE. In CEBPA DM AML with GATA2 mutations, the mutated allele was preferentially expressed. We found that GATA2 ASE is a somatic event lost in complete remission, supporting the notion that it plays a role in CEBPA DM AML. Acquisition of GATA2 ASE involved silencing of one allele via promoter methylation, compensated by overactivation of the other allele, thereby preserving expression levels. Notably, promoter methylation was also lost in remission together with GATA2 ASE. In summary, we propose that GATA2 ASE is acquired by epigenetic mechanisms and is a prerequisite for the development of AML with CEBPA DM. This finding constitutes a novel example of an epigenetic hit cooperating with a genetic hit in the pathogenesis of AML.

  Study EGAS00001004684

• MUSIC: Long-TerM OUtcomes after the Multisystem Inflammatory Syndrome In Children

  This study is an observational cohort study that will use routinely-collected clinical and cardiac (EKG, echocardiogram, CMR, exercise testing) data to assess the association between MIS-C (multisystem inflammatory syndrome in children) and cardiac outcomes within the first year after hospital discharge. Research funding will be available for EKGs, echocardiograms and MRIs in protocol windows that are not ordered by primary caregivers. Our principal goal is to determine the spectrum and early time course of coronary artery involvement, LV systolic function, and arrhythmias or conduction system abnormalities, and, using these data, to define associated clinical and laboratory factors. We will include all eligible patients, including retrospective cases beginning January 1, 2020, with follow-up (in-person or telehealth) up to one year and annual medical history forms until up to 5 years have elapsed since illness onset. Because many patients will have been identified by retrospective review, we will obtain consent at different times in their illness course. For this reason, it may be hard to reach some patients and their families. Waiver of consent will be obtained after three attempts have been made to locate the patient and family without success, as well as for the rare child who dies before informed consent can be obtained. We will include a HIPAA-compliant cryptographic algorithm to create a sharable “hashed” identifier from patient information. If blood work for research purposes is added to usual clinically-indicated blood work during follow-up visits, this will be covered by other informed consent forms. Our primary outcomes are the largest proximal Left Anterior Descending Coronary Artery (LAD) or Right Coronary Artery (RCA) z score and lowest Left Ventricular Ejection Fraction (LVEF).

  Study phs002770

• A Multi-Gene Mutation Classification of 468 Colorectal Cancers Reveals a Prognostic Role for APC

  Colorectal cancer (CRC) is a highly heterogeneous disease, for which prognosis has been relegated to clinic-pathologic staging for decades. There is a need to molecularly stratify subpopulations of CRC to better predict outcome and assign therapies. Here we report targeted exome sequencing of 1,321 cancer-related genes on 468 tumor specimens, which identified a subset of 17 genes that best classify CRC, with APC (Gene ID: 324) playing a central role in predicting overall survival. APC may assume 0, 1, or 2 truncating mutations, each with a striking differential impact on survival. Tumors lacking any APC mutation carry a worse prognosis than single APC mutation tumors, but tumors with two APC mutations and KRAS (Gene ID: 3845) and TP53 (Gene ID: 7157) mutations confer the poorest survival among all the subgroups examined. Our study demonstrates a substantial prognostic role for APC and suggests that sequencing of APC may have clinical utility in the routine staging and potential therapeutic assignment for CRC.

  Study phs001111

• MP2PRT: Evaluation of an Inflammation Polygenic Risk Score (iPRS) to Predict Cancer Related Cognitive Impairment and Fatigue in Patients Receiving Chemotherapy for Non-Metastatic Breast Cancer in URCC0701 and URCC10055

  This study is a secondary analysis of cancer related cognitive impairment (CRCI) and cancer related fatigue (CRF) among participants in URCC0701 and URCC10055 from the University of Rochester NCI Community Oncology Research Program (NCORP) Research Base. CRCI and CRF are common, troublesome, and dose-limiting toxicities reported by patients undergoing breast cancer chemotherapy that have an etiologic basis linked to low-grade systemic inflammation. Chronic, low-grade systemic inflammation is, in part, genetically determined with common single nucleotide polymorphisms (SNPs) capturing variation across individuals. This study aimed to 1) determine whether an inflammation polygenic risk score (iPRS) is associated with CRCI or CRF, 2) determine whether the relationship between the iPRS and CRCI or CRF is modified by exercise at the time of cancer treatment, 3) identify SNPs associated with serum cytokines measured at the time of cancer treatment, and 4) identify novel CRCI- and CRF-associated risk SNPs via genome-wide association analyses. We found that there was a significant inverse correlation between the iPRS and change in fatigue score from pre-chemotherapy to post-chemotherapy while there was no statistically significant association between the iPRS and cognitive impairment score. The inverse relationship between the iPRS and fatigue may be explained in part by the finding that the iPRS was also significantly associated with greater pre-chemotherapy fatigue, suggesting that women with a genetic predisposition to low-grade systemic inflammation (i.e., high iPRS) have more fatigue at the time of breast cancer diagnosis and, therefore, are less likely to worsen over the course of treatment. In contrast, women with a low iPRS had significantly less fatigue pre-chemotherapy and a significant worsening of fatigue from pre- to post-chemotherapy. The relationship between the iPRS and fatigue remained after adjustment for patient and cancer treatment covariates and was most pronounced in women who reported regularly exercising for at least 6 months prior to starting their cancer treatment. Exploratory genome-wide analysis identified a novel risk locus on chromosome chr6q27, tagged by rs9365961, associated with CRCI. This locus is upstream of TBXT, which encodes an embryonic nuclear transcription factor previously associated with susceptibility to neural tube defects. The genome-wide SNP data, patient-reported CRCI and CRF outcome measures, and covariate data used in this analysis are available through dbGaP.

  Study phs003688

• Genomic Studies of Bipolar Disorder in a Large Cohort from The Netherlands

  The transcriptomes of whole blood samples of a large cohort of individuals from the Netherlands were assayed using RNA-seq. These whole blood samples included patients diagnosed with schizophrenia or bipolar disorder, family members of patients, and healthy controls. Within the whole blood dataset, about 600 of the samples were sequenced to an average of 13.9 million mapped reads per sample, while about 2,000 were sequenced to an average of 5.9 million mapped reads per sample, in order to assess changes in power to detect eQTLs based on sample size. We find that expression, defined as the log transcripts per million reads (TPMs), is highly correlated when comparing the moderate (13.9M) and lower (5.9M) coverage datasets. Additionally, a subset of about 150 individuals provided fibroblast cell lines which were assessed for the levels of gene expression using RNA-seq at an average of 50 million mapped reads per sample. We use downsampling techniques to generate synthetic datasets derived from this real fibroblast RNA-Seq data to explore the relationship between coverage and number individuals in an eQTL analysis. Corresponding individual-level genotypes for the samples included in the expression matrix are also made available. The genotypes were derived from multiple other project cohorts, each using different genotyping platforms including OmniExpress Exome, Global Screening Array, Illumina550, and PsychChip. A Plink file set of these cohorts is provided here after merging the separate project file sets and extracting only the individuals who have expression data also provided here; quality control for SNP-missingness is recommended. We demonstrate in this study that given a fixed budget, eQTL discovery power can be increased by lowering the sequencing depth per sample to allow for an a greater number of individuals sequenced. 

  Study phs002856

• National Institute of Neurological Disorders and Stroke (NINDS), Family Study of Essential Tremor (FASET), Identification of Susceptibility Genes for Essential Tremor

  The Familial Study of Essential Tremor (FASET) was designed to identify susceptibility genes for Essential Tremor. ET is among the most common neurological diseases with a prevalence (age > 40 years) estimated to be 4.0% and prevalence in advanced age (> 90 years) exceeding 20%. ET, often referred to as "familial tremor", is generally regarded as a highly genetic disorder with families, with affected members over multiple generations, and twin studies show high concordance among monozygotic twins. Probands (affected with ET) and relatives were enrolled in a family study of ET at Columbia University, New York between 2011 - 2014. The study was approved by the Institutional Review Board at Columbia University and written informed consent was obtained from all enrollees. The criteria for enrollment were: 1) the proband had early-onset ET with age at onset < 50 years, 2) the proband had a diagnosis of definite or probable ET, 3) in addition to the proband, there were at least two affected relatives in the family, 4) additional affected and unaffected family members were willing to participate in the study, and 5) the families contained more than two affected individuals in different generations. Blood samples were also collected for genetic research. For the genetic analyses, we excluded enrollees that we or others had diagnosed with Parkinson's disease (PD) or dystonia. The final sample includes 52 families (52 probands [affected with ET]) and 155 relatives). The number of affected individuals enrolled per family ranged from 3 - 7 (mean = 4.1). Genetic samples from FASET were analyzed with whole genome SNP genotyping (for linkage analyses) and whole exome sequencing. It is hoped that this resource will better help researchers to understand the genetic causes of ET and underlying disease pathogenesis.

  Study phs000966

• Whole exome sequencing for clarification of rare causes of axonal Charcot-Marie-Tooth disease (2017-08-16)

  The project is focused on the axonal forms of Charcot-Marie-Tooth (CMT) disease. We have selected 13 families (7 from Spain and 6 from Czech Republic) that have been indepth clinically assessed and previously tested for mutations in known CMT genes without causal variants characterised. In these patients we expect to discover several CMT2 genes. Thus, we requested for exome sequencing of 45 DNAs:27 exomes in families from Spain and 18 exomes in the families from Czech Republic. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/ This dataset contains all the data available for this study on 2017-08-16.

  Dataset EGAD00001003565

• ATAC-SEQ MAIN - PHASE 1

  This is a study to test ATAC-seq protocols. CD4+ and CD8+ cells have been obtained from three different anatomical compartments. We aim to assay open-chromatin regions across these cells and perform comparative analyses.This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Dataset EGAD00001001320

• Genetic Studies of Homologous Recombination Deficiency in Hispanic Gastric Cancer

  Approximately 10% of gastric cancer cases show familial clustering and a hereditary cause is likely, however, only 1-3% cases result from known hereditary syndromes – which are predominantly associated with CDH1 and CTNNA1 genes. Hispanics are > 2 times more likely to be diagnosed and to die from gastric cancer compared to non-Hispanic whites. Not only does gastric cancer precision medicine lag behind other cancers – there is an urgent need to understand its etiology. Germline mutations in homologous recombination genes have been implicated as important risk factors for gastric cancer. The purpose of this study is to continue to generate knowledge to improve gastric cancer outcomes and disparities by 1) characterizing prevalence of germline mutations in homologous recombination genes and identify new genes associated with gastric cancer 2) perform molecular characterization of gastric tumors in Hispanic patients. Participants for germline analysis were enrolled from Chile, Colombia, Mexico, Portugal, Spain, Uruguay.Whole exome sequence capture was performed for all germline and somatic samples using Agilent SureSelect Human All Exon v7 Kit. All sequencing was performed on an Illumina NovaSeq 6000. Germline Analysis: Whole exome sequencing was performed on 536 Hispanic patients (290 males, 246 female)

  Study phs003251

• Genome-wide study of the effect of blood collection tubes on the cell-free DNA methylome

  Background The methylation pattern of cfDNA, isolated from liquid biopsies, is gaining substantial interest for diagnosis and monitoring of diseases. We have evaluated the impact of type of blood collection tube and time delay between blood draw and plasma preparation on bisulfite-based cfDNA methylation profiling. Methods 15 tubes of blood were drawn from three healthy volunteer subjects (BD Vacutainer K2E EDTA spray tubes, Streck Cell-Free DNA BCT tubes, PAXgene Blood ccfDNA tubes, Roche Cell-Free DNA Collection tubes and Biomatrica LBgard blood tubes in triplicate). Samples were either immediately processed or stored at room temperature for 24 or 72 hours before plasma preparation. DNA fragment size was evaluated by capillary electrophoresis. Reduced representation bisulfite sequencing was performed on the cell-free DNA isolated from these plasma samples. We evaluated the impact of blood tube and time delay on several quality control metrics. Results All preservation tubes performed similar on the quality metrics that were evaluated. Furthermore, a considerable increase in cfDNA concentration and the fraction of it derived from NK cells was observed after a 72-hour time delay in EDTA tubes. Conclusion The methylation pattern of cfDNA is robust and reproducible in between the different preservation tubes. EDTA tubes processed as soon as possible, preferably within 24 hours, are the most cost effective. If immediate processing is not possible, preservation tubes are valid alternatives.

  Study EGAS00001004271

• NHLBI: Genetic modifiers of sickle cell anemia severity and fetal hemoglobin expression in the Cooperative Study of Sickle Cell Disease (CSSCD)

  Phenotypic heterogeneity is characteristic of sickle cell anemia, a Mendelian disorder caused by homozygosity for the sickle HBB gene (glu6val). Patients have different rates of hemolysis/vasculopathy and viscosity/vasoocclusion-related complications. These complications account for a substantial reduction in life expectancy. In 1994, the median life expectancy for men and women with sickle cell anemia was 42 and 48 years, respectively, and despite many advances in care, the annual mortality still approaches 4%. Fetal hemoglobin (HbF) is one of the most studied markers of severity of sickle cell anemia, and detailed longitudinal measurements were taken on subjects enrolled in the Cooperative Study of Sickle Cell Disease (CSSCD). Cubic root transformation of the median values from follow-up in 848 African American subjects is the phenotype data used in the GWAS of fetal hemoglobin. The analysis was adjusted by sex. Details are in Solovieff et al., Blood 2010 [PMID: 20018918]. To integrate individual disease complications into a comprehensive measure of severity, we developed a model of the associations among clinical and laboratory variables that scored disease severity as the risk of death within 5 years. This network was developed using data obtained from more than 3,400 subjects from the CSSCD, and its accuracy was validated in two unrelated sets of sickle cell patients. Recently, the network was also validated in a small European cohort of patients with sickle cell anemia. We used extreme values of disease severity as cases and control in the GWAS of severity of sickle cell anemia. We conducted the GWAS in 1,265 patients with either "severe" (177) or "mild" disease (1088) based on a network model of disease severity. Details are in Sebastiani et al. Am J Hematol, 2010 [PMID: 20029952].

  Study phs000366

• Next Generation Mendelian Genetics: Auriculocondylar syndrome (ACS)

  This project is part of an ongoing project to identify the molecular genetic basis of rare craniofacial disorders. This specific project involved the collection of DNA samples from four probands with severe manifestations of auriculocondylar syndrome and their parents. Detailed clinical phenotypic data is available on each proband. The sole purpose of this research is to identify the molecular cause(s) of auriculochondylar syndrome.

  Study phs000437

• Bone Microarchitecture

  Osteoporosis affects more than 28 million people in the United States and the lifetime risk for osteoporosis-related morbidity is higher than a woman's combined risk for breast cancer, endometrial cancer and ovarian cancer. Health care expenditures for osteoporotic patients in this country are currently nearly 13 billion dollars per annum and are predicted to increase markedly in the next decades due the aging of the population; therefore, it is important to understand the factors that contribute to bone strength and fracture risk. With the advent of skeletal imaging modalities such as high resolution peripheral quantitative computed tomography (HR-pQCT), it is now possible to study the genetics of more highly refined peripheral skeletal microarchitecture phenotypes. Because these refined phenotypes have not been measured in many cohort studies, this project was a collaborative effort to include almost all the existing data on HR-pQCT of the radius and tibia, and genetics from around the world. Cohorts involved in the discovery included: 1) Framingham Osteoporosis Study, 2) Mayo Clinic cohort; 3) Geneva Retirees cohort; 4) OFELY cohort from Lyon France; 5) STRAMBO cohort from Lyon France; 6) Swedish Male cohorts. Replication cohorts undergoing de novo genotyping include: 1) QUALYOR cohort from Lyon France; 2) CaMOS cohort from Canada. Other than the Framingham cohort and the Swedish male cohorts, all discovery cohorts underwent genome wide genotyping with the Affymetrix Axiom Biobank array that had common variants along with exome content based on the early findings from the Exome Sequencing Project. All genotype data from the discovery cohorts were then imputed using the Haplotype Reference Consortium reference panel. Variants for replication genotyping using the Kasp technology were selected based on novelty compared with previously identified loci using DXA phenotypes, minor allele frequency, underlying LD structure within a locus, and likelihood of a variant being functional as assessed using various algorithms for coding and non-coding variants.    

  Study phs002102

• CONNECTS Master Protocol for Clinical Trials targeting Macro- and Micro-Immuno-Thrombosis, Vascular Hyperinflammation, and Hypercoagulability and Renin-Angiotensin-Aldosterone System (RAAS) in Hospitalized Patients with COVID-19 (ACTIV-4 Host Tissue)

  ACTIV 4 Host Tissue is a shared-placebo clinical trial platform evaluating therapies targeting the host response to COVID-19 in hospitalized patients. The overarching goal of the platform was to find effective strategies for inpatient management of patients with COVID-19. Therapeutic goals for patients hospitalized for COVID-19 include hastening recovery and preventing progression to critical illness, multiorgan failure, or death. Our objective is to determine whether modulating the host tissue response improves clinical outcomes among patients with COVID-19. Three trials were implemented to investigate three agents: TXA-127, TRV-027, and Fostamatinib. These agents all impact the host tissue response in COVID-19 via a number of unique mechanisms, including potential beneficial effects on the RAAS system and formation of neutrophil extracellular traps (NETs). Each trial evaluated the efficacy of these agents' ability to impact the host tissue response and improve outcomes in patients hospitalized with COVID-19. We found no evidence that any of the three agents significantly improved clinical outcomes as measured by the primary outcome, oxygen free days through day 28.

  Study phs003708

• INCLUDE Data Hub: NDA GUIDs for Down Syndrome Research

  The INCLUDE (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE) Project is an NIH-wide collaboration that seeks to improve health and quality of life for people with Down syndrome. The INCLUDE Project Data Coordinating Center (DCC) and partners created the INCLUDE Data Hub, a centralized data resource that allows access to large-scale clinical and multi-omics datasets specific to Down syndrome and supports collaborative, cloud-based analysis to accelerate scientific discoveries related to Down syndrome and its co-occurring conditions. The INCLUDE Data Hub includes an innovative researcher data repository, a portal, and a cloud-based platform for data analysis. The portal provides access to de-identified demographics and clinical metadata, as well as multi-omics datasets, including whole genome sequences, transcriptomes, proteomes, and metabolomes. The INCLUDE Data Hub uses a 'registered access' model, whereby users can access the portal and associated data after agreeing to terms of use. From the Data Hub, users can also reach 'controlled access' data (e.g., whole genome sequences) only for those studies for which they have obtained approval by an NIH Data Access Committee through the corresponding dbGaP study. A thoughtful linkage strategy to identify duplicate participants across studies enables researchers to merge multiple datasets and data types to create richer datasets and reduce costly redundancies in large-scale data generation (e.g., -omics) while mitigating potential risks introduced by linkage.Based on recommendations from the NICHD Office of Data Science and Sharing, which completed a comprehensive assessment of existing Privacy Protecting Record Linkage (PPRL) and associated data governance solutions, the INCLUDE DCC and the associated NIH Steering Committee have implemented NIMH Data Archive Global Unique Identifiers (NDA GUIDs) in the INCLUDE Data Hub. The NDA GUID Tool is a government-owned and operated PPRL technology that enables researchers to link data from multiple sources to the same individual without revealing personally identifiable information (PII). With the NDA GUID Tool, the same participant information will return the same GUID whenever or wherever it is entered. The GUID itself is not personally identifiable information or protected health information. Sharing data with NDA GUIDs allows approved researchers to link together data on a single participant, even if the data were collected at different locations or through different studies or are distributed from different data repositories. This dbGaP study enables researchers to access an INCLUDE GUID Mapping File that includes all available NDA GUIDs and their associations to study-specific Participant IDs across studies in the INCLUDE Data Hub. This dbGaP study only distributes NDA GUIDs associated with the INCLUDE Data Hub datasets. To access the associated controlled-access datasets, add the corresponding dbGaP studies to your Data Access Request. A list of these studies is available on the INCLUDE Data Hub Portal: https://portal.includedcc.org/studies.

  Study phs003678

• Evaluating potential drug candidates for the treament of Henamgiopericytoma on patient derived cell line models

  Solitary fibrous tumor/Hemangiopericytoma (SFT/HPC) is a rare subtype of soft tissue sarcoma associated with NAB2-STAT6 gene fusions. This study established and characterized a novel SFT/HPC patient-derived cell line called SFT-S1. Potential drug candidates that could be repurposed for the treatment of SFT/HPC were screened.

  Study EGAS50000000027

• Immunological hallmarks for clinical response to BCG in bladder cancer

  Intravesical Bacillus Calmette-Guerin (BCG) is an effective immunotherapy for non-muscle invasive bladder cancer (NMIBC). However, recurrence and progression remain frequent warranting deeper insights into its mechanism. We herein comprehensively profiled blood and tissues obtained from NMIBC patients before, during and after BCG treatment using cytometry by time-of-flight (CyTOF) and RNA sequencing to identify the key immune subsets crucial for anti-tumour activity.

  Study EGAS00001004764

• Idiopathic Pulmonary Fibrosis Network (IPFNet) Sildenafil Trial of Exercise Performance in Idiopathic Pulmonary Fibrosis (IPFNet-STEP-IPF-BioLINCC)

  Data Access NOTE: Please refer to the "Authorized Access" section below for information about how access to the data from this accession differs from many other dbGaP accessions. Objectives: The STEP-IPF study sought to evaluate whether treatment with sildenafil would improve walk distance, dyspnea, and quality of life in participants with advanced idiopathic pulmonary fibrosis (IPF).Background: IPF is a chronic, progressive lung disease of unknown cause that is characterized by the histopathologic pattern of usual interstitial pneumonia. Progression to end-stage respiratory insufficiency and death within 5 years after the onset of symptoms is characteristic. To date, no pharmacologic therapies have definitively been shown to improve survival or quality of life in participants with this disease.Participants with severe IPF have abnormalities of the pulmonary vasculature leading to decreased levels of resting and exercise-induced production of nitric oxide. Since nitric oxide is a potent pulmonary vasodilator, reduced levels are associated with pulmonary vasoconstriction and impaired gas exchange. Sildenafil (Revatio, Pfizer) is a phosphodiesterase-5 inhibitor that stabilizes the second messenger of nitric oxide, cyclic guanosine monophosphate, which leads to pulmonary vasodilatation. Such vasodilatation could improve ventilation–perfusion matching and thus gas exchange in with IPF.Design: STEP-IPF was a double-blind, randomized, placebo-controlled trial of oral sildenafil (20 mg three times daily). Participants meeting eligibility criteria were randomly assigned in a 1:1 ratio to receive sildenafil or matched placebo with the use of a permuted-block design, with stratification according to clinical center. The primary outcome was the presence or absence of an improvement of at least 20% in the 6-minute walk distance at 12 weeks, as compared with baseline. Key secondary outcomes included changes in the 6-minute walk distance, degree of dyspnea, and quality of life.Screening procedures included the taking of a detailed history, a physical examination, spirometry, echocardiography, CT imaging, and measurements of lung volume on plethysmography, carbon monoxide diffusion capacity, and arterial blood gases. Eligible participants returned for an enrollment visit within 6 weeks after screening. All participants received an initial dose of a study drug at this visit and were monitored for 60 minutes for adverse effects. Follow-up visits were scheduled at 1, 6, and 12 weeks. After completion of the 12-week visit, all participants were started on treatment with open-label sildenafil. Visits were scheduled at 13, 18, and 24 weeks; at 28 weeks, serious adverse events and vital status were documented. Testing of the 6-minute walk distance was performed with the use of a standardized protocol at the time of screening and enrollment and at study visits at 6, 12, 18, and 24 weeks. Participants with pulse oxygen saturation below 88% received supplemental oxygen. Conclusions: This study did not show a benefit for sildenafil for the primary outcome. The presence of some positive secondary outcomes creates clinical equipoise for further research. There were small but significant differences in arterial oxygenation, carbon monoxide diffusion capacity, degree of dyspnea, and quality of life favoring the sildenafil group.

  Study phs004085

• AML_controls

  Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy that is most similar in expression profiles to plasmacytoid dendritic cells. However, patients often exhibit features of AML and can progress to AML. In this project, we will determine the differentially and commonly expressed genes between BPDCN and AML specimens. Available BPDCN and TET2-mutated AML specimens were taken for transcriptome microarray analysis.

  Dataset EGAD00010001726

• Whole transcriptome profiling of liquid biopsies from tumour xenografted mouse models: validation cohort

  While cell-free DNA (cfDNA) in liquid biopsies is widely being used and investigated, free circulating RNA (extracellular RNA, exRNA) has the potential to improve therapy response monitoring and cancer detection due to its dynamic nature. A fundamental open question hampering the initiation of large-scale liquid biopsy collections for tumour exRNA analysis is that it remains unclear in which blood subcompartment tumour-derived exRNAs primarily reside. We set out to develop a host-xenograft deconvolution framework, exRNAxeno, with cDNA mapping strategies to either a combined human-mouse reference genome or both species genomes in parallel, that can be applied to exRNA sequencing data from liquid biopsies of human xenograft mouse models, enabling to distinguish (human) tumoural RNA from (murine) host RNA, and as such to specifically analyse tumour-derived exRNA. Subsequently, the preferred exRNAxeno combination pipeline was applied to total exRNA sequencing data from blood platelets and three plasma fractions from a breast cancer patient-derived and neuroblastoma cell line-derived xenograft mouse model. We show that tumoural exRNA concentrations are not determined by plasma platelet levels, while host exRNA concentrations increase with platelet content. Furthermore, a large variability in exRNA levels and gene content across individual mice is observed. In general, the tumoural gene detectability in plasma is correlated with the RNA expression levels in the tumour tissue or cancer cell line. Our results unravel new aspects of tumour-derived exRNA biology in xenograft mouse models.

  Study EGAS00001006582

• Familial psychosis associated with a missense mutation at MACF1 gene combined with the rare duplications DUP3p26.3 and DUP16p23.3, affecting the CNTN6 and CDH13 genes

  Psychosis is a highly heritable and heterogeneous psychiatric condition. Its genetic architecture is thought to be the result of the joint effect of common and rare variants. Families with high prevalence are an interesting approach to shed light on the rare variant's contribution without the need of collecting large cohorts. To unravel the genomic architecture of a family enriched for psychosis, with four affected individuals, we applied a system genomic approach based on karyotyping, genotyping by whole-exome sequencing to search for rare single nucleotide polymorphisms (SNPs) and SNP array to search for copy-number variants (CNVs). We identified a rare non-synonymous variant, g.39914279 C>G, in the MACF1 gene, segregating with psychosis. Rare variants in the MACF1 gene have been previously detected in SCZ patients. Besides, two rare CNVs, DUP3p26.3 and DUP16p23.3, were also identified in the family affecting relevant genes (CNTN6 and CDH13, respectively). We hypothesize that the co-segregation of these duplications with the rare variant g.39914279 C>G of MACF1 gene precipitated with schizophrenia and schizoaffective disorder.

  Study EGAS00001004791