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• Gene expression profile of mesothelial cells from peritoneal adhesion biopsies

  RNA-sequencing analysis was carried out on mesothelial cells isolated from peritoneal adhesion biopsies and compared to control human peritoneal mesothelial cells to identify a mesothelial-to-mesenchymal transition (MMT)-related gene signature in patients.

  Dataset EGAD00001008324

• 2017_ AML WGS analysis result

  This data is belong to 2017 AML genome data which is aligned to human reference(human_g1k_v37.fasta). There are 10 paired tumor/normal samples from SNUH. All samples has passed QC and recalibration steps while aligning to reference.

  Dataset EGAD00001003599

• 2017_ AML prospective data analysis result

  This data is belong to 2017 AML prospective data which is aligned to human reference(human_g1k_v37.fasta). There are 10 paired tumor/normal samples from SNUH. All samples has passed QC and recalibration steps while aligning to reference.

  Dataset EGAD00001003598

• 2014 AML WES analysis result

  This data is belong to 2014 AML patients' exome data which is aligned to human reference(human_g1k_v37.fasta). There are 51 paired tumor/normal samples from SNUH. All samples has passed QC and recalibration steps while aligning to reference.

  Dataset EGAD00001003932

• Ovarian cancer/normal cell lines

  We performed whole genome sequencing of nine OC patient-derived cell lines and one normal cell line (HOSEpiC) to analyze if the cell lines harbor OC-typical genomic aberrations absent in normal cells and to relate genomic features to drug sensitivities.

  Dataset EGAD00001003146

• RNA bam files of Renal Cell Carcinoma patients

  the dataset contains RNA bam files of Renal Cell Carcinoma patients, which belongs to "An Empirical Approach Leveraging Tumorgrafts to Dissect the Tumor Microenvironment in Renal Cell Carcinoma Identifies Missing Link to Prognostic Inflammatory Factors"

  Dataset EGAD00001003895

• Whole Genome Sequencing of 18 sequential samples from 3 CLL patients

  Whole Genome Sequencing to track subclonal heterogeneity in 18 samples from 3 Chronic Lymphocytic Leukemia patients subjected to repeated cycles of therapy. NOTE: There are only 12 BAM files available to download. The other 6 files are missing.

  Dataset EGAD00001000972

• Transposome Bisulfite Sequencing

  DNA belonging to 16 tumour/normal samples were treated with bisulfite, then up to 5 different bisulfite PCRs were performed in each one of the samples. Amplicons form the same sample were pooled and submitted to sequencing on a MiSeq platform.

  Dataset EGAD00001001028

• NHLBI TOPMed: The Jackson Heart Study (JHS)

  Since there is a greater prevalence of cardiovascular disease among African Americans, the purpose of the Jackson Heart Study (JHS) is to explore the reasons for this disparity and to uncover new approaches to reduce it. The JHS is a large, community-based, observational study whose 5306 participants were recruited from among the non-institutionalized African-American adults from urban and rural areas of the three counties (Hinds, Madison, and Rankin) that make up the Jackson, MS, metropolitan statistical area (MSA). Jackson is the capital of Mississippi, the state with the largest percentage (36.3%) of African Americans in the United States. The JHS design included participants from the Jackson ARIC study who had originally been recruited through random selection from a drivers' license registry. Approximately six months before the JHS was to begin, an amendment to the federal Driver's Privacy Protection Act was passed that changed the level of consent for public release of personal information from driver's license lists from an "opt out" to an "opt in" basis. The Mississippi Highway Patrol was no longer able to release a complete listing of all persons with driver's licenses or state identification cards, which prevented its use in the JHS. New JHS participants were chosen randomly from the Accudata America commercial listing, which provides householder name, address, zip code, phone number (if available), age group in decades, and family components. The Accudata list was deemed to provide the most complete count of households for individuals aged 55 years and older in the Jackson MSA. A structured volunteer sample was also included in which demographic cells for recruitment were designed to mirror the eligible population. Enrollment was opened to volunteers who met census-derived age, sex, and socioeconomic status (SES) eligibility criteria for the Jackson MSA. In addition, a family component was included in the JHS. The sampling frame for the family study was a participant in any one of the ARlC, random, or volunteer samples whose family size met eligibility requirements. Eligibility included having at least two full siblings and four first degree relatives (parents, siblings, children over the age of 21) who lived in the Jackson MSA and who were willing to participate in the study. No upper age limit was placed on the family sample. Known contact information was obtained during the baseline clinic examination from the index family member with a verbal pedigree format to identify name(s), age(s), address (es), and telephone number(s). Recruitment was limited to persons 35-84 years old except in the family cohort, where those 21 years old and above were eligible. Only persons who otherwise met study criteria but were deemed to be physically or mentally incompetent by trained recruiters were excluded from study eligibility.1 1 Wyatt SB, Diekelmann N, Henderson F, Andrew ME, Billingsley G, Felder SH et al. A community-driven model of research participation: the Jackson Heart Study Participant Recruitment and Retention Study. Ethn Dis 2003; 13(4):438-455 (PMID: 14632263).

  Study phs000964

• Environmental Influences on Child Health Outcomes (ECHO) - PATHWAYS - Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE)

  Pregnant women are exposed daily to multiple chemical and non-chemical stressors, including air pollutants, phthalates, and psychosocial stress. The Developmental Origins of Health and Disease model (DOHaD) states that exposure to these stressors in pregnancy affects fetal development in a manner that impacts offspring health across the life course. Yet epidemiologic data in these areas is limited, particularly with U.S. samples. It is also poorly understood whether these exposures prenatally affect childhood neurodevelopment and airway health in an independent or combined manner, and likely moderators of effects, such as the sex of the child, are infrequently addressed. We propose to unify three diverse extant pregnancy cohorts: TIDES (N=717, 2010-12), GAPPS (N=1133, 2012-16), and CANDLE (N=1385, 2007-11), for a combined sample size of 3235 mother-child dyads in the PATHWAYS study. PATHWAYS will investigate how chemical (air pollutants and phthalates) and non-chemical (psychosocial stress) exposures during pregnancy are related to placental gene expression (transcriptome) and childhood neurodevelopment and airway health (at ages 4-6, 8-9, and 10-11 years). Each cohort has rich resources of prenatal data and banked specimens (urine, blood, and placenta) that will be harmonized for the PATHWAYS study and will contribute to the ECHO consortium. We will develop a national model with high spatiotemporal resolution of key air pollutants and assess urinary markers of maternal exposure. A composite measure will capture multilevel maternal psychosocial stress across pregnancy, and urinary phthalate and blood stress hormone [Corticotropin-releasing hormone (CRH)] levels in the second and third trimesters will provide individual assessment of those exposures in potential critical periods. We will characterize the placental transcriptome using RNA sequencing (RNA-Seq) and will assess neurodevelopment and airway health prospectively into middle childhood. PATHWAYS will examine how these prenatal exposures are related to the placental transcriptome and child health outcomes in main effect and interactive models, with emphasis on sex-specific associations. For both neurodevelopment and airway health, we propose to measure both phenotypic precursors of health outcomes (i.e. fluid cognition, lung function growth), which yield dimensional tests of proposed associations, as well as clinically meaningful and policy relevant outcomes (i.e. asthma, mental health). Our study is powered to assess interactive effects of chemical and non-chemical stressors and will be the first study to characterize how prenatal environmental exposures relate to placental transcriptome pathways in relation to childhood health outcomes. This represents a significant scientific advance in testing DOHaD hypotheses. Major contributions to the ECHO Consortium include: 1) the development of a state of the art national model of air pollution, 2) a large, diverse pregnancy cohort with extensive biorepositories and extant prenatal and postnatal biomarkers, placental transcriptome, psychosocial and environmental data, and 3) an experienced, interdisciplinary team that will contribute meaningfully to the ECHO program of work.The sequencing data in this submission pertains only to the 794 subjects from the CANDLE study for whom placental tissue transcriptomics was performed.

  Study phs003619

• Lipid Research Clinics - Prevalence Study (LRC-PS-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 LRC Program began in 1971 under the sponsorship of the National Heart, Lung, and Blood Institute, National Institutes of Health. Part of this program was the Lipid Research Clinics Prevalence Study, a standardized series of cross-sectional surveys of various North American populations designed to determine the prevalence of dyslipidemias and to describe the distributions of lipids and lipoproteins in major ethnic and social groups. In addition to contributing to the aggregate analysis, each independent population-based study was designed with capabilities for separate analyses of lipid and lipoprotein distributions. The participating populations were not selected to be a probability sample representative of the North American population per se, but by virtue of their size and economic and geographical diversity, they provide a useful cross-sectional group. The Family Study was the third phase of the Lipids Research Clinics North American Population Studies. The Family Study was designed to obtain knowledge of the distribution of lipids and lipoproteins among family members and of the association of familial and genetic attributes to dyslipoproteinemias. Background: An association between serum cholesterol and coronary heart disease is well established. A system was developed for classifying hyperlipoproteinemias into six types of patterns, as a basis for characterizing lipoprotein disorders. The Lipid Research Clinics was thus created to improve the detection of and clinical management of hyperlipoproteinemias. The three primary objectives were: 1) to acquire data on the prevalence of different types of hyperlipoproteinemia in various age and ethnic groups, with special emphasis on the nature and frequency of genetic forms; 2) to collect reliable data on the prevalence and incidence of atherosclerosis in different types of hyperlipoproteinemia; and 3) to conduct an intervention trial to determine if lowering plasma lipid levels would reduce the risk of CHD. Participants: There were 60,495 participants. Conclusions: Data from this study confirm findings from earlier studies in developed countries, showing age-related differences in plasma lipid levels. However, for overall distributions, the LRC data showed slightly lower cholesterol and markedly higher trigylceride values than those previously reported for North America. Some variation in plasma lipid values was evident among the clinic populations. The large number of participants within most subgroups permitted a variety of analytic and comparative studies. For example, data from the large pediatric population revealed a drop in plasma cholesterol levels in adolescent males and females. Males aged 20-50 years had higher cholesterol levels than females in the same age group, and higher trigylceride levels between ages 20-70 years. Numbers were also significient for meaningful comparisons between lipid distributions of females who were taking sex hormones and those who were not; in females taking sex hormones, cholesterol and triglyceride levels were higher for subjects younger than 45 years, but slightly lower after age 45, than lipid levels in females not taking hormones (Circulation 1979; 60(2):427-439).

  Study phs003995

• Overcoming Clinical Resistance to EZH2 Inhibition Using Rational Epigenetic Combination Therapy

  Essential epigenetic dependencies have become evident in many cancers. Based on functional antagonism between BAF/SWI/SNF and PRC2 in SMARCB1-deficient sarcomas, we and colleagues recently completed the clinical trial of the EZH2 inhibitor tazemetostat, leading to its FDA approval. However, the principles of tumor response to epigenetic therapy in general and tazemetostat in particular remain unknown. Using functional genomics of patient tumors and diverse experimental models, we defined molecular mechanisms of tazemetostat resistance. We found distinct classes of acquired mutations that converge on the RB1/E2F axis, decoupling EZH2-dependent differentiation and cell cycle control. This allows tumor cells to escape tazemetostat-induced G1 arrest despite EZH2 inhibition and suggests a general mechanism for effective EZH2 therapy. Using RNA-sequencing of patient tumor specimens, we identified specific genes as markers of a deficient RB1/E2F axis, which we propose as prospective biomarkers for therapy stratification. This offers a paradigm for rational epigenetic combination therapy suitable for immediate translation to clinical trials.This study was performed on archived tumor tissue collected as part of the above clinical trial at Memorial Sloan Kettering Cancer Center. Patient tumors were classified into "Response" or "Progression" groups based on RECIST 1.1 criteria. "Response" included tumors exhibiting a complete response, partial response, or stable disease. All other tumors were classified under the "Progression" group. Archived frozen tumor samples were weighed and up to 20-30mg were homogenized in RLT buffer, followed by extraction using the AllPrep DNA/RNA Mini Kit (QIAGEN catalog 80204) according to the manufacturer's instructions. RNA was eluted in 13 μL nuclease-free water. After RiboGreen quantification and quality control by Agilent BioAnalyzer, 1 μg of total RNA with DV200 percentages varying from 78% to 100% underwent ribosomal depletion and library preparation using the TruSeq Stranded Total RNA LT Kit (Illumina catalog RS-122-1202) according to instructions provided by the manufacturer with 8 cycles of PCR. Samples were barcoded and sequenced using NovaSeq 6000 in a PE150 mode, with the NovaSeq 6000 S4 Reagent Kit (Illumina). On average, 84 million paired reads were generated per sample and 70% of the data mapped to mRNA. For analysis, read adaptors were trimmed and quality filtered using 'trim_galore' and mapped to GRCh38/hg19 reference genome using STAR v2.7.9 with default parameters.

  Study phs003188

• NHLBI GO-ESP: Heart Cohorts Exome Sequencing Project (Siblings with Ischemic Stroke Study, SWISS)

  The NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), a signature project of the NHLBI Recovery Act investment, was designed to identify genetic variants in coding regions (exons) of the human genome (the "exome") that are associated with heart, lung and blood diseases. These and related diseases that are of high impact to public health and individuals from diverse racial and ethnic groups will be studied. These data may help researchers understand the causes of disease, contributing to better ways to prevent, diagnose, and treat diseases, as well as determine whether to tailor prevention and treatments to specific populations. This could lead to more effective treatments and reduce the likelihood of side effects. GO-ESP is comprised of five collaborative components: 3 cohort consortia - HeartGO, LungGO, and WHISP - and 2 sequencing centers - BroadGO and SeattleGO. The Siblings with Ischemic Stroke Study (SWISS) is an affected sibpair (ASP) study of patients and their brothers/sisters who have had similar strokes. The study was conducted to determine the genes that contribute to an individual's risk of developing an ischemic stroke (a stroke due to sudden interruption of blood flow to a part of the brain). Over 600 people have participated in SWISS, with the coordination of the recruitment and flow of the samples occurring at the Mayo Clinic, Jacksonville, FL, under the direction of James F. Meschia, MD. The University of Virginia (Stephen S. Rich, PhD) served as the analytic site for the genetic data. Participants were excluded from SWISS if they had stroke following an invasive cerebrovascular or cardiovascular procedure, if their stroke occurred shortly following an aneurismal subarachnoid hemorrhage, if the stroke occurred in the setting of a mechanical aortic or mitral valve, if the patient had definite CNS vasculitis or if the patient had a Mendelian mitochondrial stroke disorder, including CADASIL, MELAS, Fabry disease, sickle cell anemia or homocysteinemia. For the NHLBI ESP, the youngest 51 ASPs (102 individuals) from SWISS were selected to undergo exome sequencing. These ASPs were selected from among all SWISS participants, excluding those pedigrees with individuals who had TOAST subtypes of stroke of other etiology or of stroke with undetermined etiology. In addition, the affected siblings were required to have the same TOAST subtype (both small vessel (lacunar) or both large vessel (atherosclerotic)). Of those selected, 98 samples passed initial quality control metrics, and 94 completed exome sequencing and were deposited in dbGaP. An additional set of 590 samples from the SWISS collection has been genotyped on the ExomeChip that contained a subset of rare/infrequent variants identified by exome sequencing. These samples include 495 affected individuals (from multiple affected family members) as well as 95 unaffected family members. These genetic and phenotypic data also will reside in dbGaP.

  Study phs000327

• Kids First: Whole Genome Sequencing in Structural Defects of the Neural Tube

  Myelomeningocele (aka meningomyelocele, MM) is the most severe form of spina bifida, a neural tube defect (NTD) in humans and the most common CNS birth defect. MM is considered a genetically complex disease, and occurs in 3.72/10,000 live US birth, and is partly preventable with prenatal folate, but the genetic basis and the mechanisms by which folate work to reduce disease incidence remain obscure. MM is associated nearly uniformly with prenatal hydrocephalus and the Arnold-Chiari malformation, as well as paraplegia and lifelong neuromotor disability. The genes for several rare syndromic forms of NTDs are known, but the causes for the majority with sporadic MM remain unknown. Despite the importance of MM, most previous research has been limited to targeted sequencing and association studies of folate metabolism genes, or very small-scale exome sequencing. We hypothesize that de novo mutations (DNMs) produce likely gene disrupting (LGD) events that contribution to MM risk. Using conservative estimates of between 50-100 recurrently mutated discoverable genes contributing to risk, and our preliminary data demonstrating an excess of LGD DNMs in MM compared with control individuals, we estimate that with a cohort size of 1000 trios, we should uncover between 5-20 new recurrently mutated genes underlying MM, with minimal false-discovery. With this in mind, we formed the Spina Bifida Sequencing Consortium, and established a platform for data and sample sharing. Preliminary analysis of our first batch of 100 trios analyzed by WGS from GMKF suggests a wealth of important gene mutations. We have embarked on a new recruitment effort of an additional cohort of 400 new simplex MM trios, in collaboration with the US Spina Bifida Association, consented trios to allow for data sharing, and have performed detailed sample quality control. We also have preliminary data that use of dried bloodspot DNA from trios performs comparably to whole blood DNA, so will be happy to swap saliva for bloodspot recruitment at NIH's preference. This cohort is now half-way assembled, with the remaining cohort to be ascertained in the next 6 months. We have established a workflow for de novo SNP/INDEL/SV detection from WGS and have ample computer storage and nodes to see the project to completion. We also plan to continue recruitment into the future with the goal of 2000 trios in the next 5 years. We propose a detailed bioinformatics workflow to identify gene mutations within a statistical framework, considering detailed scRNA expression profiling from developing mammalian neural tube, and have developed a robust functional validation workflow using Xenopus and mouse gene targeting. Our project has the potential to uncover a host of causes for this most common of the CNS birth defects, paving the way for future breakthroughs in detection, treatment, and prevention.

  Study phs002591

• CTSP: Clinical Trial Sequencing Project

  For the Clinical Trials Sequencing Project (CTSP), National Cancer Institute (NCI) will utilize whole genome sequencing and/or whole exome sequencing in conjunction with transcriptome sequencing to try to identify recurrent genetic alterations (mutations, deletions, amplifications, rearrangements) and/or gene expression signatures that would be important to the hypothesis(es) submitted by the investigators. The samples will be processed and submitted for genomic characterization using pipelines and procedures established within The Cancer Genome Analysis (TCGA) project. Data analysis will be performed as a collaboration between the National Clinical Trials Network (NCTN) Group and its investigators submitting the proposal. The investigators at the NCI-sponsored Genomic Data Analysis Center (GDAC) will characterize the samples. The NCTN Group will be responsible for providing the clinical data needed for the proposal to the open clinical system maintained by NCI CCG's Biospecimen Core Resource (BCR) at Nationwide Children's Hospital in Columbus, Ohio. The project team (Network Group/investigators and GDAC) will analyze the data together. Additionally, clinical and genomic data related to the analyses will also need to be registered by NCI and will be made available to qualified researchers via a controlled-access database (e.g., dbGaP) upon publication of the primary analysis described in the study proposal. A substudy description and its molecular data information are provided under its own page: phs001184 CTSP Diffuse Large B-Cell Lymphoma (DLBCL) CALGB 50303

  Study phs001175

• The Pioneer 100 Wellness Project (P100)

  108 individuals (age 21-89+ years; 59% males, 41% females; 89% Caucasian; not recruited based on any specific phenotype) participated in an IRB-approved study from April 2014 to January 2015. Each individual had the genome sequenced in full. Blood was collected in clinics every three months. Additionally, participants completed at-home collections of saliva, stool, and first morning void urine every three months. Stool and saliva samples were shipped directly to the vendor by the participant, while urine was given back to the study coordinators for distribution to the proper sample vendor. For each successful participant in each round we carried out 218 clinical laboratory tests, measured up to 643 metabolites and 262 proteins, and measured the abundance of 4616 operational taxonomic units (OTUs) in the gut microbiome using 16S rRNA sequencing. The P100 study had four objectives: 1) Establish cost-efficient procedures for generating, storing and analyzing multiple sources of health data obtained over time from participants and analyzed in combination with genomic data; 2) Develop and deploy analytic tools for integrating these diverse datasets and deriving actionable information from their observed interrelationships; 3) Identify novel patterns within the streams of health data that indicate either wellness, or transitions between wellness and disease; 4) Learn how to best interface with and present longitudinal health information to individuals by studying the reactions and feedback from participants as they are presented actionable information.

  Study phs001363

• Genetics of Disorders Affecting Tooth Structure, Number, Morphology and Eruption

  The long-term objective of this research project is to discover the complete spectrum of genes that contribute to the etiologies of genetic disorders of dentition. Inherited tooth defects can be isolated (the only symptom) or syndromic (having additional symptoms), and can be caused by mutations in many different genes. Clinically, it can be difficult to distinguish among the diverse forms. Making an accurate diagnosis would be greatly improved if reliable tests could identify the specific genetic defect that causes the disease in each case. Current technology can identify the numerous sequence variations throughout a patient's exome, but the disease-causing variation among them cannot be identified unless it is already on the list of genes that potentially cause the disease. A diagnosis based upon the genetic defect that causes the disorder distinguishes between isolated and syndromic tooth defects. A precise diagnosis permits formulation of a more accurate prognosis, which informs treatment decisions. The benefits of accomplishing our aims are to 1) enable genetic testing to achieve a precise and accurate diagnosis, and thereby optimize treatment, and 2) improve our understanding of normal and pathological tooth formation, leading to future improvements in treatment and eventually cures. Our short-term objectives are to 1) recruit kindreds with inherited disorders affecting their dentition, characterize their dental phenotype (and non-dental phenotypes when applicable) and the distribution of the disorder throughout the family, and 2) determine the genetic etiology of their disorders.

  Study phs001491

• A Natural History Study of CMT1B, CMT2A, CMT4A and CMT4C

  Charcot Marie Tooth disease (CMT) is an umbrella term that covers any inherited peripheral neuropathy. People with CMT have a problem with the nerves that go to the feet and hands that cause muscle and sensation loss, as well as difficulty with balance. There are at least forty genes that, when mutated, cause CMT. The purpose of this study is to look at the natural history of CMT to see how it changes over time. Particular emphasis will be put on studying people with CMT1B, CMT2A, CMT4A, and CMT4C, though all people with CMT are encouraged to participate. Participants are invited back on a yearly basis to determine how the changes are occurring. Objectives: Determine the natural history and genotype-phenotype correlations of disease-causing mutations in CMT1B, CMT2A, CMT4A and CMT4C as well as other forms of CMT Determine the capability of the newly developed CMTPeds score and the Minimal Dataset to measure impairment and perform longitudinal measurements in patients with multiple forms of CMT over a ten-year window This is a longitudinal study of individuals with CMT. Study participants will be invited to be re-evaluated every year. Evaluations will consist of neurological histories and examinations, selected nerve conduction studies (NCS) as well as completion of assorted clinical outcome measures including the CMTNS, Minimal Dataset, and Peds CMT Scale. Selected CMT patients and controls will also receive glabrous skin biopsies.

  Study phs001419

• International Consortium on the Genetics of Systemic Lupus Erythematosus (SLEGEN)

  The genetic makeup of an individual strongly influences the risk of developing systemic lupus erythematosus (SLE). The identification of genes that predispose an individual to SLE will lead to earlier and better diagnosis, better treatments, and possibly prevention. To this end, the International Consortium on the Genetics of Systemic Lupus Erythematosus (SLEGEN) was formed in 2005 and is composed of lupus researchers who agreed to pool their knowledge and resources to search for genes that predispose to lupus. Eight laboratories contributed DNA samples for genotyping at the Broad Institute and association with SLE was performed by the Data Coordinating Center (Wake Forest University), as part of a four stage study design. Stages one and two of this design were graciously funded by the Alliance for Lupus Research (www.lupusresearch.org). In this stage of the study, approximately 767 SLE patients (cases) were compared to approximately 383 non-SLE patients (controls) for differences among the Illumina HumanHap300. The affected individuals are all females of European decent. 82% of the cases are the index case from multiplex pedigrees for SLE and the remaining 18% have self-reported first degree relatives with SLE. A detailed summary of the methods and results can be found in the manuscript in Nature Genetics February 2008 by SLEGEN "Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants ITGAM, PXK, KIAA1542 and other loci". (Please see also Study Accession: phs000202.v1.p1)

  Study phs000216

• Phenotype Risk Scores Identify Patients with Unrecognized Mendelian Disease Patterns

  This study was designed to assess the phenotypic effects of rare variants. Rare variants are difficult to study in a high-throughput manner because most cohorts are underpowered to detect associations. In order to gain power to test rare variants, we use Phenotype Risk Scores (PheRS) based on features of Mendelian diseases. PheRS is calculated using claims data from an EHR that is mapped to clinical features from OMIM's clinical descriptions of Mendelian disease. We calculated PheRS for 1,204 Mendelians diseases in a cohort of 21,701 individuals genotyped on the HumanExome BeadChip. We then tested for association between these diseases and rare variants in causal genes. A phenotype risk score is calculated as the weighted sum of features for a given disease. The features are defined as a set of phecodes (consolidated ICD codes) associated with a particular Mendelian disease as described in OMIM. The weights for each phecode are calculated as the log inverse prevalence of the phecode in our cohort. For an individual, their score equals the sum of the weights for each phecode that is present in their medical record. Our study was based on a cohort of individuals with genotype data linked to de-identified electronic health records (EHR) from Vanderbilt's BioVU resource. We hope that this method will help generate phenotype-genotype correlation data on rare variants which in turn may inform rare variant interpretations use for diagnostics.

  Study phs001516

• Whole Exome Sequencing of DNA from Pre-and Post-Chemotherapy Needle Biopsies of Triple Negative and Inflammatory Breast Cancers Enrolled in the S0800 Trial

  Purpose: The purpose of this study was to assess the somatic mutation landscape of breast tumors before and after neoadjuvant chemotherapy. The data includes whole exome sequencing of pre- and post- tissues that were collected in the context of an already published clinical trial SWOG S0800 (ZA Nahleh et al. Breast Cancer Research and Treatment. 158:485-495, 2016). The trial compared the efficacy of sequential nab-paclitaxel followed or preceded by doxorubicin/cyclophosphamide anthracycline chemotherapy with or without bevacizumab as preoperative therapy for stage II-III breast cancer. Experimental Design: 29 pre-treatment biopsies and 9 matching post-treatment surgically resected cancer tissues were available for analysis and were subjected to whole exome sequencing to identify mutational patterns associated with response to neoadjuvant chemotherapy. The 9 paired samples with residual invasive cancer after therapy were also analyzed to assess changes in mutational patterns in response to therapy. No matching normal tissues were available for germline sequencing and therefore we used n=7 post-treatment breast tissues without residual cancer (i.e. complete eradication of cancer by therapy) as a normal cohort to facilitate somatic variant calling.Conclusion: These results suggest that genomic disturbances in BRCA-related DNA repair mechanisms, reflected by a dominant mutational signature 3, confer increased chemotherapy sensitivity. Cancers that survive neoadjuvant chemotherapy, frequently have alterations in cell cycle regulating genes but different genes are affected in different patients.

  Study phs001883

• Whole Genome Sequencing Analysis in a Family of Discordant Twins With Non-Syndromic Microtia and Hemifacial Microsomia: Identification of Novel Candidate Genes and Variants

  This research is a non-NIH effort to discover the pathogenesis of non-syndromic microtia and to detect potential candidate genes. Microtia (OMIM 600674, 612290, 251800) is a spectrum of congenital anomalies and facial abnormalities, 90% of the cases followed by hearing loss. Two types of the disease are described in terms of connection to the affected syndromes: anomalies (syndromic) and only clinical manifestation (non-syndromic) associated with other symptoms. Though the exact pathogenesis of microtia remains unknown, pathogenic genes of majority of the microtia syndromic types have been identified. However, the genetic mutation of the non-syndromic microtia has not been confirmed. In this study, whole genome sequencing (WGS) was utilized to screen mutations in monozygotic discordant twins of congenital microtia-atresia and their family members. One of the twins, along with her grandfather, was discordant for microtia-atresia. By bioinformatic analysis of the WGS data from monozygotic twins with microtia and their non-microtia relatives, we proposed that among 28 identified potential genes, 4 of them (CNOT1, ODAD4, TBX15, and GIPC3) could be more responsible for non-syndromic microtia development and phenotypic features. Interested investigators may request to access the DNA genomic sequencing data of the study participants via dbGaP authorized access. In addition to raw genomic sequencing data, datasets of germline mutations and candidate gene mutations may also be available for investigators to request.

  Study phs003216

• NIAID Centralized Sequencing Program

  Investigators at the National Institute of Allergy and Infectious Diseases (NIAID) use next-generation sequencing technologies to help determine genetic contributions to immune diseases. These efforts have increased rates of molecular diagnosis for a subset of NIAID participants as well as uncovered fundamental insights into the cellular and signaling pathways in host defense and immune regulation. Despite these successes, analysis and interpretation of genomic data remain a substantial challenge. Simply, researchers do not understand the functional and clinical consequences of most human genetic variation. Making progress in this area requires a coordinated, systematic, and transparent approach to clinical genomics research. This protocol is specific to genetic testing and explicitly aims to both strengthen clinical care and enhance research. Probands provide biological specimens for genetic testing and primary clinical and research evaluations are completed via a research protocol at NIAID. This protocol serves as a vehicle for a programmatic effort that includes standardized phenotyping, test ordering through the Clinical Research Information System (CRIS) at the National Institutes of Health Clinical Center, sample collection and isolation, nucleic acid analysis, bioinformatics, clinical interpretation, reporting in CRIS, genetic counseling, and supporting effective use of genomics as a research tool throughout the institute. Overall, increased process standardization will support data integrity and efficiency while still accommodating the need for investigator flexibility. This study aims to generate and analyze evidence regarding the genetic contribution to diverse immune diseases studied by the NIAID intramural research program.

  Study phs001899

• MAP Kinase-Mutant Hematologic Malignancies and Their Therapeutic Resistance

  The Mitogen-Activated Protein Kinase (MAPK) signaling pathway has been critically important in understanding pathology and developing targeted therapy for many cancers, but high frequency mutations in this pathway in hematopoietic malignancies were unknown until a series of sequencing studies from our group and others revealed a high frequency of activating mutations in BRAF (GeneID:673), MAP2K1 (GeneID:5604), and other key components of the MAPK pathway in two groups of rare and poorly studied blood cancers: hairy cell leukemia (HCL) and the systemic histiocytoses (SH). Although HCL and the SH both share common gene mutations in BRAF (BRAFV600E) and MAP2K1, these are distinct blood cancers with different clinical behaviors; however, their actual developmental cellular origins, genomic, and pathogenic differences are poorly understood, which led to our project goal of determining how BRAFV600E, MAP2K1, and other MAPK pathway mutations contribute to the pathogenesis of distinct blood cancers and affect their clinical responses to MAPK pathway inhibitors. This study proposal seeks to advance our understanding of the actual cells of origin of cancer-causing MAPK mutations in HCL and the SH, to determine why BRAFV600E and MAP2K1 mutations can cause two distinct blood cancers, and to understand how these mutations in HCL and SH influence responses to MAPK pathway inhibitor drugs and other receptor tyrosine kinase (RTK) inhibitors such as RET and ALK inhibitors that could potentially become effective therapy for these poorly understood blood cancers.

  Study phs001864

• Reference Standards for Mosaic Variant Detection

  After conception, postzygotic mutations continuously occur throughout life in humans, causing somatic mosaicism in an individual. The variant type, time of origination, and locations of the mosaic mutations result in unique mosaic patterns in a combinatorial manner and further affect phenotypes, including various noncancerous diseases. Several efforts have, thus, been made to identify the mutational landscape and mechanisms underlying the mosaic mutations. From a technical aspect, the accurate detection of mutations is at the core of the mosaicism research, and the construction of a standard reference is a critical first step to serve as the basis for analytical validation and benchmarks for germline and somatic mutation detection. Furthermore, a reference standard for mosaic mutations is urgently needed to enable more advanced research.Herein, we generated robust, large-scale, and cell line mixture-based reference standards that contain abundant mosaic SNVs and INDELs along with wild-type sites and germ line variants. Moreover, the whole reference standard set mimics the cumulative aspect of mosaic variant acquisition in the early developmental stage through a progressive cell line mixing with confirmed genotypes. It can be used for optimizing the current use of mosaic variant detection strategies, as well as developing algorithms for future improvements.We previously generated an NCBI BioProject (PRJNA758606) to release much of these data. Only the data that are subject to authorized access constraints have been included in this submission to dbGaP. The two data sources are thus, complementary to each other.

  Study phs003399

• Center for Sub-Cellular Genomics

  A cell is a highly complex system with distributed molecular physiologies in structured sub-cellular compartments whose interplay with the nuclear genome determine the functional characteristics of the cell. A classic example of distributed genomic processes is found in neurons. Learning and memory require modulation of individual synapses through RNA localization, localized translation, and localized metabolites, such as those from dendritic mitochondria. Dendrites of neurons integrate distributed synaptic signals into both electrical and nuclear transcriptional response. Dysfunction of these distributed genomic functions in neurons can result in a broad spectrum of neuropsychiatric diseases such as bipolar and depressive disorders, autism, among others. The Center for Sub-Cellular Genomics' (CSG) mission is to develop new technologies to enable the dissection of complex genomic interactions within a single cell. New technologies include methods to target DNA and RNA sampling at sub-cellular resolution in live cells; high-throughput isolation and microfluidics chemistry for sub-cellular fractions; sub-cellular resolution mass-spectrometry; and computational tools for analysis of sub-cellular genomics data. The new technologies developed by CSG will enable the broader genomics community to associate sub-cellular processes to cell function and dysfunction. These technologies will be utilized in the center to generate a comprehensive atlas of genomic signatures of sub-cellular compartments in the mammalian neuron system. The technologies and neuron-focused data obtained here will be relevant to neurodegenerative and neuropsychiatric diseases including schizophrenia, depression, autism spectrum disorder, traumatic brain injury, and Alzheimer's.

  Study phs002120

• Esophageal Squamous Cell Carcinoma Precursor Study

  Esophageal cancer is the sixth most common cause of cancer death in the world. High-risk areas occur across central Asia and from eastern to southern Africa, and in these populations, nearly all of the cases are esophageal squamous cell carcinoma (ESCC). ESCC has a dismal prognosis, largely because symptoms usually appear late in the course of the disease, when the tumors are incurable. Early detection and treatment of curable precursor lesions and early invasive ESCC in asymptomatic high-risk adults offers the potential for long-term survival and reduced mortality from this disease. Previous studies have shown that routine cytology of non-endoscopically collected esophageal cell samples is not sensitive and specific enough to be clinically useful, so we are now looking for molecular markers of high-grade esophageal squamous dysplasia (HGD), the proven clinically important precursor lesion of ESCC, that can be used to increase the accuracy and utility of this initial screening exam. National Cancer Institute (NCI) and Cancer Institute and Hospital, Chinese Academy of Medical Sciences (CAMS) began collaborative studies of ESCC since the mid-1980s in China. The present proposal is designed to characterize the type and prevalence of DNA mutations in tissue samples of HGD and to establish biologic and questionnaire resources for further study. The proposed study has two components, a field study to obtain questionnaire data and biological samples, and a genomic analysis to perform sequencing of the biological samples and bioinformatics analysis of the sequencing. 

  Study phs002814

• A Phase I Study with a Personalized Neoantigen Cancer Vaccine in Melanoma

  Effective anti-tumor immunity in humans has been associated with presence of T cells targeting neoantigens that arise from non-silent tumor-specific mutations. Here we conducted whole-exome sequencing of tumor and normal cells from individual patients to identify mutations. We assessed the expression of mutated alleles by RNA-sequencing of tumor. We demonstrated the feasibility, safety and immunogenicity of a vaccine that targets up to 20 personal neoantigens predicted to be presented by the autologous patient tumor.Antigen-specific CD8+ T cells that can recognize and eliminate cancer cells play a crucial role in anti-tumor immune responses. Here we conducted single-cell sequencing of cells infiltrating melanoma specimens originating from 4 patients and determine the TCR clonality of the CD8+ tumor infiltrating cells. We investigated the relationship between T cell clonality and phenotypic cell states coupling single-cell transcriptome to single-cell TCR seq. The surface expression of a panel of protein was detected in parallel using CITE-Seq antibodies. Sorted tumor and peripheral blood specimens were processed in parallel.In order to discover cancer antigens derived from annotated and unannotated protein-coding regions of the genome, we carried out matched ribosome profiling (Ribo-seq), RNA-sequencing, and whole genome sequencing on one of the patients, as well as Ribo-seq on an additional patient. We used it to discover novel or unannotated open reading frames (nuORFs), their expression levels, as well as somatic mutations within them to predict potential neoantigens.

  Study phs001451

• HuBMAP: A Spatially Resolved Molecular Atlas of Human Endothelium

  The human circulatory system plays a vital role in the proper functioning of every organ in the human body. Because vascular related diseases, such as atherosclerosis, do not occur homogeneously throughout the vascular tree, differences in the endothelium of various organs must exist. There is even evidence of heterogeneity of adjacent endothelial cells. We are studying normal endothelium throughout the body and across individuals of different ages to characterize these differences. The first step will be to procure normal tissue samples from a wide range of organs. From disaggregated samples of these tissues, we will perform single cell combinatorial indexing (sci-) to generate chromatin accessibility (sci-ATAC-seq) and transcriptome (sci-RNA-seq) data from millions of single cells across hundreds of samples.  Molecular heterogeneity might correlate with multiple facets of the anatomical distribution of endothelium, including vascular vs. lymphatic, arteries vs. veins, capillaries vs. larger vessels, differences between organs, organ zonation, cell-to-cell differences, etc. Based on heterogeneous markers defined from deep profiling of disaggregated cells, we will employ seqFISH to spatially relate the distinct endothelial subpopulations arising from the single nuclei data to histologic preparations. For example, this will allow us to identify subpopulations with particular markers as arterial, capillary, venous, or lymphatic. The end product will include multiparameter images in which the complete gene expression and chromatin accessibility profile can be interactively visualized for every cell.

  Study phs002267

• Systematic Growth Factor Profiling Platform for 3D Tumor Models Reveals EstradiolResponsive Cellular Mechanisms of Immunotherapy Resistance

  Epithelial ovarian cancer (EOC) exhibits significant molecular heterogeneity, which is thought to be influenced by the tumor microenvironment (TME). However, the specific factors driving this heterogeneity remain poorly understood. In this study, we integrated growth factoromics and genomic data to identify TME factors contributing to EOC heterogeneity and immunosuppression. Our analysis revealed distinct subgroups of EOC samples with differential responsiveness to specific growth factors, particularly estradiol and R-spondin. Notably, samples with high responsiveness to estradiol and Wnt (C1 cluster) were enriched in the Mesenchymal (MES) molecular subtype, while samples with high responsiveness to R-spondin (C2 cluster) were associated with the Differentiated (DIF) and Immunoreactive (IMR) subtypes. We discovered that the G protein-coupled estrogen receptor (GPER), rather than the classical estrogen receptor alpha (ERα), was the key mediator of estrogen responsiveness and a determinant of molecular subtype classification. Single-cell sequencing analysis identified subsets of estrogen-responsive malignant cell (MAL.PDCD5) and cancer-associated fibroblast (FB.TNFSF10), which were associated with immunosuppressive patterns in the TCGA cohort. Importantly, the interaction between these cell populations significantly increased upon estrogen treatment, suggesting a potential mechanism by which estrogen signaling may contribute to the development of an immunosuppressive TME. Our findings highlight the critical role of estrogen signaling in shaping the molecular heterogeneity and immunosuppressive TME of EOC and provide novel insights into potential therapeutic targets for overcoming immunosuppression in this malignancy.

  Study EGAS50000000422

• Open_Targets_020_Epigenomes_of_Cell_Lines

  There is currently a drive to establish cell based assay systems of greater human biological and disease relevance through the use of well characterised transformed cell lines, primary cells and complex cellular models (e.g. co-culture, 3D models). However, although the field is gaining valuable experience in running more non-standard & complex cell assays for target validation and compound pharmacology studies, there is the lack of a systematic approach to determine if this expansion in cell assay models is reflected in increased human biological and disease relevance. The increasing wealth of publically available transcriptomic, and epigenome (ENCODE and Epigenome Roadmap) data represents an ideal reference mechanism for determining the relationship between cell types used for target & compound studies to primary human cells and tissues from both healthy volunteers & patients. The CTTV020 epigenomes of cell line project aims to generate epigenetic and transcriptomic profiles of cell lines and compare these with existing and newly generated reference data sets from human tissue and cell types. The aim is to identify assay systems which will provide greater confidence in translating target biology and compound pharmacology to patients. Multiple cell types commonly used within research have been grouped according to biology. Examples include erythroid, lung epithelial, hepatocyte cell types and immortalised models of monocyte / macrophage biology. 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 please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001003138

• DNA methylation analysis on PBL obtained from male patients with UC-PSC, UC and HC

  Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease affecting the intra- and extrahepatic bile ducts, and is strongly associated with ulcerative colitis (UC). In this study, we explored the peripheral blood DNA methylome and its immune cell composition in patients with PSC-UC, UC, and healthy controls (HC) with the aim to develop a predictive assay in distinguishing patients with PSC-UC from those with UC alone. The peripheral blood DNA methylome of male patients with PSC and concomitant UC, UC and HCs was profiled using the Illumina HumanMethylation Infinium EPIC BeadChip (850K) array. Differentially methylated CpG position (DMP) and region (DMR) analyses were performed alongside gradient boosting classification analyses to discern PSC-UC from UC patients. As observed differences in the DNA methylome could be the result of differences in cellular populations, we additionally employed mass cytometry to characterize the immune cell compositions. Genome wide methylation analysis revealed no differentially methylated positions between PSC-UC and UC patients. Nonetheless, using gradient boosting we were capable of discerning PSC-UC from UC with an area under the receiver operator curve (AUROC) of 0.80. Four CpG sites annotated to the NINJ2 gene were found to strongly contribute to the predictive performance. While mass cytometry analyses corroborated the largely similar blood cell composition among patients with PSC-UC, UC and HC, a higher abundance of myeloid cells was observed in UC compared to PSC-UC patients.

  Study EGAS00001005832

• Ultra-long sequencing for contiguous haplotype resolution of the human immunoglobulin heavy chain locus

  Genetic diversity within the human immunoglobulin heavy chain (IGH) locus influences the expressed antibody repertoire and susceptibility to infectious and autoimmune diseases. However, repetitive sequences and complex structural variation pose significant challenges for large-scale characterization. Here, we introduce a method that combines Oxford Nanopore ultra-long sequencing and adaptive sampling with a bioinformatic pipeline to produce haplotype-resolved, annotated IGH assemblies. Notably, our strategy overcomes prior limitations in phasing resolution, enabling single-contig haplotype assemblies that span the entire IGH locus. We applied this method to four individuals and validated the accuracy of the IGH assemblies using Pacific Biosciences HiFi reads, demonstrating near-complete sequence congruence, detecting only indels with a high degree of confidence. Moreover, when applied to the reference material HG002, our pipeline revealed no base differences and a limited number of indels compared with the Telomere-to-Telomere genome benchmark across the IGH region. Importantly, in the four individuals, our approach uncovered 30 novel alleles and previously uncharacterized large structural variants, including a 120 kb duplication spanning IGHE to IGHA1 and an expanded seven-copy IGHV3-23 gene haplotype. These findings underscore the power of our method to resolve the full complexity of the IGH locus and uncover previously unrecognized variants that may affect immune function and disease susceptibility. Thus, our method provides a strong basis for future immunological research and translational applications.

  Study EGAS50000001042

• Collaborative Study of Genes, Nutrients and Metabolites (CSGNM)

  While many genetic and metabolic studies focus on understanding disease states, this genome wide association study (GWAS) was designed to understand the influence of genetic variants on circulating metabolites and factors in normal, healthy individuals. Over 2500 healthy, ethnically Irish college students attending Trinity College Dublin completed a health and diet questionnaire and provided a non-fasting blood sample to be used for genetic and metabolic analysis. The questionnaire was designed to collect information on age, sex, height, weight, medical conditions, smoking, dietary habits, and consumption of alcohol, fortified foods, and supplements. Extracted DNA was genotyped using the Illumina HumanOmni1-Quad Beadchip. Metabolites were measured using a number of methods and focused on those relevant to the folate/vitamin B12 pathway.

  Study phs000789

• Episodic Ataxia Syndrome: Longitudinal Study

  Individuals with episodic ataxia experience recurrent attacks of dizziness and incoordination; between attacks patients are typically normal. The majority of cases are likely caused by an inherited genetic mutation. However, in some patients we are unable to identify the mutation. So far, 2 genes have been identified which cause different types of episodic ataxia. Ultimately, when the actual mutation is identified the protein product of the gene can be studied and specific medications can be designed. During this study, we will clinically evaluate patients with EA and follow them over time to help us better characterize the disease. We will also obtain blood samples to test for the known genetic mutations. In the future, we plan to coordinate trials of medications for the treatment of these disorders.

  Study phs000521

• DNA Replication Timing Alterations in Genetic Diseases

  This study contains a collection of lymphoblastoid cell line (LCL) and induced pluripotent stem cell (iPSC) whole genome sequencing from individuals with an without a diagnosed genetic disease. Several types of genetic diseases are included such as translocations, repeat expansions, and heritable or spontaneous mutations of genes. We used the whole genome sequencing to generate DNA replication timing profiles for these individuals and compared the profiles of diseased individuals to presumed healthy samples. We aimed to identify replication timing alteration linked to a specific genetic disease and therefore elucidate trans-acting factors of DNA replication timing. We found that replication timing was highly consistent across almost all diseased samples. Only one genetic disease, a mutation in MCM10, demonstrated an altered profile of replication timing.

  Study phs002597

• Next Generation Mendelian Genetics: Malignant Hyperthermia

  Malignant hyperthermia (MH) is a genetic disorder that causes a profound metabolic derangement following exposure to certain anesthetics. While approximately half of all cases are associated with ryanodine receptor-1 gene (RYR1) mutations, many cases have an unknown genetic cause. We sought to identify rare variants in novel MH candidate genes by sequencing the protein-coding regions of the genomes of individuals whose disease was either ruled in or out by the gold-standard diagnostic test. We also carefully selected individuals from well-characterized families to use gene-sharing information and maximize efficiency in the study design. Exome sequencing has helped identify the causes of over a dozen Mendelian disorders, has high power at low sample sizes, and is cost-efficient compared to whole-genome sequencing.

  Study phs000405

• Hyperdiploid Acute Lymphoblastic Leukemia RNA-Seq

  Few genetic drivers of children with hyperdiploid precursor B-cell acute lymphoblastic leukemia (ALL) have been identified to date. In an effort to detect novel genomic rearrangements that could be promoting leukemogenesis in this subset of patients, we sequenced ribosomal RNA-depleted transcriptomes isolated from 5 hyperdiploid acute lymphoblastic leukemia samples. In addition to looking for novel genomic rearrangements, we also sought to identify transcripts that could be created as a result of a novel posttranscriptional process. Surprisingly, we identified transcripts created as the result of exon circularization. The results of our studies are present in the paper "Circular RNAs Are the Predominant Transcript Isoform from Hundreds of Human Genes in Diverse Cell Types" published in PLoS ONE (PMID: 22319583).

  Study phs000522

• Multimodal Profiling of 500,000 Memory T Cells from a Tuberculosis Cohort Identifies Cell State Associations with Demographics, Environment, and Disease

  We conducted CITE-seq to measure whole transcriptome gene expression and surface expression of 31 proteins. We assayed >500K memory T cells from 259 donors from a tuberculosis progression cohort (128 cases: former progressors and 131 controls: non-progresssors/latent infection) >4 years post-infection after returning to immune steady state. We defined 31 memory T cell states influenced by age, sex, genetic ancestry, and season. After correcting for these covariates, we found that one cell state (C-12), resembling the T helper cells Th17s, were depleted in cases compared to controls. When sorted ex vivo, this state responds to polyclonal or Mycobacterium tuberculosis (Mtb) peptide antigen stimulation with interleukin-17 (IL-17) or interferon gamma (IFNg).

  Study phs002467

• Single Cell Genomic Analysis of Lymphoma

  Our study aimed to define the extent of heterogeneity between anatomically separated tumor manifestations in follicular lymphoma at single-cell resolution. We subjected single-cell suspensions derived from nodal, synchronously-acquired fine needle aspirations from two distinct tumor sites to high-throughput microfluidics-based single-cell RNA sequencing. By comparing the relative composition of the tumor subpopulations between the two tumor sites, we found that some patients can exhibit site-to-site differences. While the overall composition of the tumor microenvironment did not differ significantly between sites, we did detect a specific correlation between site-to-site tumor heterogeneity and T follicular helper cell abundance. Our study demonstrates the significant limitations of a solitary biopsy in defining the full scope of a patient's disease.

  Study phs002188

• Filtering and Annotation of Variants That Are Rare (FAVR)

  The project developed a suite of new methods (FAVR) designed to assist the shortlisting of genetic variants under a rare variant-phenotype/disease model. The methods were designed to work with commonly used massively parallel sequencing analysis pipelines, such as the GATK or ANNOVAR, and have been made publically available as a suite of software tools (https://github.com/bjpop/favr). The FAVR methods use signatures in comparator sequence alignment files to facilitate the filtering of mapping artifacts and common genetic variants, and annotation of genetic variants based on evidence of co-occurrence in individuals. As relevant, FAVR methods can also be used to filter out artifacts derived from imbalanced paired-end sequencing. Pope et al., BMC Bioinformatics, accepted Dec 2012.

  Study phs000601

• Whole exome sequencing in multiplex cleft families from a consortium

  Building upon our previous linkage and association studies, we will use whole exome sequencing studies of second and third degree affected relatives drawn from multiplex families. Our specific aims are: 1) To conduct whole exome sequencing on affected members (2° and 3° relatives) drawn from multiplex cleft families from a consortium to identify novel genes causing non-syndromic oral clefts; 2) To confirm and test the role of rare variants in these novel genes through confirmatory Sanger sequencing, plus linkage information using additional members available in these multiplex families. This whole exome sequencing approach will combine evidence from linkage studies and large scale sequencing to identify novel genes causing oral clefts in multiplex cleft families.

  Study phs000459

• Center for Common Disease Genomics (CCDG) - Cardiovascular: BioImage Cohort

  The genetic basis of cardiovascular disease in individuals of non-European ancestry remains largely unknown. Availability of ethnically diverse study populations is essential to fully investigate the underlying causes of disease. The BioImage Study enrolled adults aged 55-80 in a prospective observational study. Subjects had no prior history of cardiovascular disease, but were identified to be at intermediate to high risk for atherosclerotic cardiovascular events (PMID: 25790876). The recruiting target was a cohort with similar demographics to the US population in terms of race and ethnicity. Produced as part of the NHGRI Centers for Common Disease Genomics, this study contains whole genome sequence data and variant calls from 922 African American participants of the BioImage Study.

  Study phs002325

• Low Density Genotyping from the Fragile Families and Child Wellbeing Study

  The Fragile Families and Child Wellbeing Study (FFCWS) is based on a stratified, multistage sample of 4898 children born in large U.S. cities (population over 200,000) between 1998 and 2000, where births to unmarried mothers were oversampled by a ratio of 3 to 1. This sampling strategy resulted in the inclusion of a large number of Black, Hispanic, and low-income families. The project “Low Density Genotyping from the Fragile Families & Child Wellbeing Study” uses saliva collected from a subset of FFCWS children at Year 9 and from teens at Year 15 to examine genetic variation using a genome-wide assay (Illumina PsychChip). In addition to the genotype data, a limited set of self reported and anthropomorphic measures are included.

  Study phs002417

• NHLBI TOPMed - NHGRI CCDG: The Vanderbilt University BioVU Atrial Fibrillation Genetics Study

  Atrial fibrillation (also called AFib or AF) is a quivering or irregular heartbeat (arrhythmia) that can lead to blood clots, stroke, heart failure and other heart-related complications. At least 2.7 million Americans are living with AFib. Individuals with early onset atrial fibrillation (AF) are included in this study of cases from the BioVU sample repository. BioVU is Vanderbilt's biobank of DNA extracted from leftover and otherwise discarded clinical blood specimens. BioVU operates as a consented biorepository; all individuals must sign the BioVU consent form in order to donate future specimens. BioVU subjects are de-identified and linked to the Synthetic Derivative enabling researchers to access genetic data/DNA material as well as dense, longitudinal electronic medical record (EMR) information.

  Study phs001624

• Cross-site Concordance Evaluation of Tumor DNA and RNA Sequencing Platforms of CIMAC-CIDC Network

  The Cancer Immune Monitoring and Analysis Centers (CIMACs) and the Cancer Immunologic Data Commons (CIDC)  has engaged in efforts to harmonize Whole-exome (WES) and RNA-sequencing (RNA-seq) data from three different experimental platforms (MD Anderson, NCI MoCha lab, and Broad Institute) and are using a series of developed pipelines to process the early trial samples. To evaluate the consistency of tumor WES and RNA-seq profiling platforms across different centers, the CIMACs-CIDC conducted a systematic harmonization study. DNA and RNA were centrally extracted from fresh frozen (FF) and formalin-fixed paraffin-embedded (FFPE) non-small cell lung carcinoma (NSCLC) tumors and distributed to three centers for WES and RNA-seq profiling

  Study phs002295

• HuBMAP: A 3-D Tissue Map of the Human Lymphatic System

  The major goal of the 3-D Tissue Map of the Human Lymphatic System is to use microscopic and biomolecular procedures to facilitate co-registration pipelines and common 3D reconstruction algorithms. Tissue collected from human spleen, thymus and lymph node will be spatially resolved at the single cell level both within and across individuals. The approach employed involves sequencing of transcriptomes of dissociated cells and mapping to histological sections using CO-Detection by indEXing (CODEX) and /or Imaging mass spectroscopy, two highly multiplexed methods employing antibody-tagged target epitopes. Additionally, light sheet fluorescent microscopy is used to provide a higher level context for structural localization on a larger volume. The molecular data provided by this project is obtained through single-cell RNA-seq.

  Study phs002268

• DNA Repair Capacity for Lung Disease Risk Assessment

  A focus of this work was to address the extent to which susceptibility for lung cancer varies by gene-environment-phenotype interactions involving DNA repair capacity and differences in risk from environmental stressors. GWAS from a subset of subjects from the Lovelace Smokers Cohort and New Mexico Lung Cancer cohort were used to derive polygenic risk scores for DNA repair pathways (nucleotide excision, base excision, single strand break, non-homologous, homologous recombination). Logistic regression analysis was used to examine the association between polygenic risk score and lung cancer status. Polygenic risk scores were grouped by quartiles. Only diminished base excision repair was associated with increased risk for lung cancer at the 25-50% quartile and approached significance at the 50-75% quartile.

  Study phs004063

• APOBEC Mutagenesis, Kataegis, Chromothripsis in EGFR-Mutant Osimertinib-Resistant Lung Adenocarcinomas

  Expanding on studies investigating apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC) mutagenesis in histological transformation of epidermal growth factor receptor (EGFR)-mutant lung cancers, it has been hypothesized that mutational signature analysis may help better understand acquired resistance to targeted therapies. Using mutational signature analysis in Receptor Tyrosine Kinase (RTK) driven lung adenocarcinomas, more specifically EGFR mutant lung cancer, APOBEC dominant mutational signatures were noted more frequently in subclonal post Tyrosine Kinase Inhibitor (TKI) treatment biospecimen samples and in the presence of large-scale genomic rearrangements. This is hypothesized to be due to the pressure of treatment with TKIs; a fact that should be further explored and can be potentially manipulated in order to overcome drug resistance.

  Study phs003812

• The PRIME-AIR Study: Positive End-Expiratory Pressure, Recruitment, Incentive Spirometry, Muscle Relaxant Optimization, Preoperative Education, Postoperative Early Ambulation, Individualized, and Reinforced

  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.The PRIME-AIR study ("Positive end-expiratory pressure, Recruitment, Incentive spirometry, Muscle relaxant optimization, preoperative Education, postoperative early Ambulation, Individualized, and Reinforced") was a prospective multi-center randomized controlled pragmatic trial, with a blinded assessor, to compare post-operative pulmonary complications (PPCs) in patients with an individualized anesthetic-centered intervention (including individualized mechanical ventilation positive end-expiratory pressure (PEEP) management to maximize respiratory system compliance and minimize driving pressures, a neuromuscular agent and subsequent reversal, and post-operative lung expansion and early mobilization) versus usual care.

  Study phs003926