Search Results - EGA European Genome-Phenome Archive

Prognostic and therapeutic significance of leukemia subtypes and minimal residual disease measurements in pediatric acute lymphoblastic leukemia treated with contemporary risk-directed trial: a cohort study

Background Genomic analyses to identify leukemia subtypes and refinement of minimal residual disease (MRD) determination are two recent advances that would have substantial impact on the management of children with acute lymphoblastic leukemia (ALL). However, the combined application of these two approaches to determine the prognostic and therapeutic significance of MRD measurement and full spectrum of leukemia subtypes in the context of contemporary risk-directed therapy has not been studied comprehensively.MethodsBetween October 29, 2007 and March 26, 2017, 598 consecutive children with newly diagnosed ALL were enrolled in a clinical trial at St. Jude Children’s Research Hospital. Patients were provisional classified according to the presenting clinical and laboratory features including immunophenotype and cytogenetics. Patients with ETV6-RUNX1 and high hyperdiploid B-progenitor ALL were provisionally included in the low-risk groups; those with TCF3-PBX1, hypodiploidy and T-cell ALL in the standard (intermediate)-risk group; and patients with BCR-ABL1, KMT2A and early T-cell precursor ALL in the high-risk group. Final risk assignment was based primarily on MRD levels measured by flow cytometry on Day 15 (≥1%) and Day 42 (<0.01% or ≥1%) of remission induction. Using genomic classification based on cytogenetics and genomic analysis (single nucleotide polymorphism array analysis and transcriptome, exome, and genome sequencing), patients were classified into 17 subtypes. The primary aim was to determine the event-free survival, overall survival and cumulative risk of relapse according to specific leukemia subtypes and MRD levels on Days 8, 15 and 42 of remission induction. This clinical trial was registered at ClinicalTrials.gov, number NCT00549848.FindingsPatients with ETV6-RUNX1, high hyperdiploidy and DUX4-rearranged B-ALL all received low- or standard-risk therapy, and had the highest 5-year event-free survival rates: 98.4% (95% CI, 95.9-100), 95.3% (91.2-99.4), and 95.0% (84.2-100), respectively. All 142 patients with Day 8 MRD<0.01%, except two with KMT2A-rearranged ALL and one with TCF3-PBX1, were in continuous complete remission. The TCF3-PBX1, PAX5alt, T-cell, early T-cell precursor, iAMP21 and hypodiploid ALL had intermediate outcome with 5-year event-free survival rates ranging from 80.0% (39.4-100) to 88.2% (71.7-100). Patients with KMT2A-rearranged, BCR-ABL1, BCR-ABL1-like and ETV6-RUNX1-like ALL had the worst outcomes, with 5-year event-free survival rates between 64.1% (43.9-84.3) and 76.2% (51.9-100), despite most patients receiving standard- or high-risk therapy. Treatment intensification based on MRD and genotype improved outcome. Relapse did not occur in any of the patients with ETV6-RUNX1, DUX4-rearranged, TCF3-PBX1, iAMP21, ZNF384-rearranged, hypodiploid, or BCR-ABL1-like B-ALL who had day 15 MRD≥1% and received standard-risk therapy. However, day 42 MRD<0.01% did not preclude relapse in patients with intermediate-risk or unfavorable subtypes including TCF3-PBX1, PAX5alt, T-cell, iAMP21, BCR-ABL1, BCR-ABL1-like, ETV6-RUNX1-like, KMT2A-rearranged, and MEF2D-rearranged ALL, despite intensified treatment in the standard- or high-risk arms. InterpretationContemporary risk-directed treatment based on genotypes and MRD can cure virtually all patients with ETV6-RUNX1, hyperdiploid>50 and DUX4-rearranged ALL. While intensified treatment improve outcome for patients with high MRD during induction, substantial proportions of patients with intermediate-risk or unfavorable subtypes would still relapse even achieving negative MRD status at the end of induction and require novel therapeutics to improve outcome.

Study EGAS00001004739

QUANTitative Chest Computed Tomography UnMasking Emphysema Progression in Alpha-1 Antitrypsin Deficiency

AAT deficiency is a genetic disorder associated with emphysema. Spirometry, the lung function test that measures how well the lungs exhale air, is used to diagnose and track the progression of emphysema. Some studies have suggested that forced expiratory volume in 1 second (FEV1) measurements, a type of spirometry test, may lack accuracy in detecting disease progression in cases of severe AAT deficiency. Another method, high resolution chest CT scans, may be more accurate at measuring the progression of emphysema. The purpose of this study is to determine if high resolution CT scans are better at detecting the progression of emphysema than lung function tests. Results from this study may lead to the development of a more accurate way to assess lung tissue loss and may improve the understanding of lung destruction in AAT deficiency. This study will last 4 years and will enroll people with AAT deficiency who have nearly normal lung function test results. Study visits, each lasting about 4 hours, will occur at baseline and months 6, 12, 18, 24, and 36. At each visit, participants will undergo lung function tests, a CT scan, blood collection, and a physical exam. Female participants will have urine collected for a pregnancy test. All participants will also complete questionnaires to assess health status and lung function. Study researchers will call participants every 2 months to collect information on lung disease symptoms and medication changes.

Study phs000698

Framingham Heart Study-Cohort (FHS-Cohort) - Imaging

The Framingham Heart Study (FHS) is a population-based, observational cohort study initiated in 1948 to prospectively investigate the determinants of cardiovascular disease to guide public health prevention. The FHS began by recruiting an Original Cohort of 5,209 men and women between the ages of 30 and 62 from the town of Framingham, Massachusetts, who had not yet developed overt symptoms of cardiovascular disease or suffered a heart attack or stroke. The Original cohort Exam 1 took place between 1948 and 1953. Since that time the cohort has had a total of 32 biennial exams (ending in 2014) and event follow-up through 2022. In 1971, the FHS added the Offspring cohort, comprising 5124 children whose parents were enrolled in the Original cohort and the spouses of the children. This cohort on average has been examined every three to four years. However, there was an eight year gap between Exam 1 and Exam 2 and a seven year gap between Exam 7 and Exam 8. The latest exam (10) was completed in 2022. In 2002, the transgenerational FHS design was facilitated with the recruitment of 4095 children of the Offspring cohort (Third Generation), and 103 spouses of the Offspring who were not previously enrolled in the study (New Offspring Spouses, NOS). These cohorts have completed 3 exams through 2019. To reflect the changing demographic characteristics of the greater Framingham community, the FHS additionally recruited and enrolled 2 cohorts comprising racial and ethnic minority groups, termed Omni-1 and Omni-2, (n = 506 and 410, respectively) in 1995 and 2002, respectively. These cohorts included individuals of African American, Hispanic, Asian, Indian, Native American, and Pacific Islander descent. The OMNI-1 cohort have completed 5 exams through 2022. The OMNI-2 cohort have completed 3 exams through 2019. Data available for request include Echocardiogram images, available from the following exams in each cohort. Original Cohort: exams 18-32; Offspring cohort: exams 3-10; Third Generation, NOS and OMNI-2 cohorts: exams 1-3; OMNI-1 cohort: exams 1-5.CT image data at one or two timepoints were added for 4427 participants in the offspring, third generation, and OMNI1 and OMNI2 cohorts.Summary level phenotypes for the Framingham Cohort study participants can be viewed at the top-level study page phs000007 Framingham Cohort. Individual level phenotype data and molecular data for all Framingham top-level study and substudies are available by requesting Authorized Access to the Framingham Cohort study phs000007.

Study phs003593

NHLBI TOPMed: Genetic Epidemiology Network of Arteriopathy (GENOA)

The Genetic Epidemiology Network of Arteriopathy (GENOA) is one of four networks in the NHLBI Family-Blood Pressure Program (FBPP). GENOA's long-term objective is to elucidate the genetics of target organ complications of hypertension, including both atherosclerotic and arteriolosclerotic complications involving the heart, brain, kidneys, and peripheral arteries. The longitudinal GENOA Study recruited European-American and African-American sibships with at least 2 individuals with clinically diagnosed essential hypertension before age 60 years. All other members of the sibship were invited to participate regardless of their hypertension status. Participants were diagnosed with hypertension if they had either 1) a previous clinical diagnosis of hypertension by a physician with current anti-hypertensive treatment, or 2) an average systolic blood pressure = 140 mm Hg or diastolic blood pressure = 90 mm Hg based on the second and third readings at the time of their clinic visit. Only participants of the African-American Cohort were sequenced through TOPMed. The Family Blood Pressure Program (FBPP), GENOA's parent program, is an unprecedented collaboration to identify genes influencing blood pressure (BP) levels, hypertension, and its target-organ damage. This program has conducted over 21,000 physical examinations, assembled a shared database of several hundred BP and hypertension-related phenotypic measurements, completed genome-wide linkage analyses for BP, hypertension, and hypertension associated risk factors and complications, and published over 130 manuscripts on program findings. The FBPP emerged from what was initially funded as four independent networks of investigators (HyperGEN, GenNet, SAPPHIRe and GENOA) competing to identify genetic determinants of hypertension in multiple ethnic groups. Realizing the greater likelihood of success through collaboration, the investigators created a single confederation with program-wide and network-specific goals. Comprehensive phenotypic data for GENOA study participants are available through dbGaP phs001238.

Study phs001345

A Phase I/II Trial of Sirolimus (Rapamune®) and Cyclosporine in Patients with Refractory Aplastic Anemia

The most successful treatment for aplastic anemia is bone marrow transplantation. However, few patients are eligible for this procedure. For others, treatment usually consists of immunosuppressive agents, such as antithymocyte globulin (ATG) and cyclosporine. Unfortunately, even with immunosuppressive therapy, relapse is common. New combinations of medications may offer alternative and more effective treatment options. Sirolimus and cyclosporine are two drugs routinely used to suppress the immune system and prevent rejection in patients who have received organ transplants. While cyclosporine has been proven effective for treating aplastic anemia, sirolimus has not been tested for this disease. This study will evaluate the safety and efficacy of sirolimus in combination with cyclosporine for treating individuals with aplastic anemia that have not responded to other treatments. This study will last at least 6 months. Participants will first be screened to verify diagnosis of aplastic anemia. The screening will include a physical examination, blood test, bone marrow biopsy from the pelvic bone, and review of medications and medical history. Individuals who are eligible will then start the first treatment period. Participants will receive two medications: cyclosporine will be taken twice a day and sirolimus will be taken once a day. Depending on side effects, the dose of either drug may be temporarily stopped or lowered. On Day 1, blood will be drawn and females will undergo a pregnancy test. Subsequent study visits will occur weekly for the first month, every 2 weeks for 2 months, and then once a month for the remainder of the study. Each visit will include a physical examination, vital sign assessment, and review of side effects and medications. Blood tests will be performed weekly for the first 3 weeks, and then every 2 weeks. After 6 months of treatment, if a participant has shown improvements in disease status without major side effects, the treatment will continue. Over time the doses may be lowered. If a participant has not improved while on the study medication, treatment will stop at 6 months. Whenever treatment is discontinued, the participant will again undergo a physical examination, blood tests, and bone marrow biopsy.

Study phs000695

NextGen Consortium: The iPSCORE (iPSC Collection for Omic Research) Resource for Studying the Impact of Genetic Variation on Molecular Phenotypes

The iPSC Collection for Omic Research (iPSCORE) Resource was created as part of the Next-Gen Consortium funded by NHLBI. The overarching purpose of the resource is to provide a large collection of human induced pluripotent stem cells (iPSCs) for use in studying the impact of genetic variation on molecular and physiological phenotypes. The resource has been used in a number of studies in the Dr. Kelly A. Frazer's Lab examining both the characteristics of human iPSCs and a variety of iPSC-derived cell types including cardiovascular progenitor cells (iPSC-CVPCs), pancreatic precursor cells (iPSC-PPCs), and retina pigment epithelium cells (iPSC-RPEs). We have shown that the iPSCs, CVPCs, and PPCs are suitable surrogate models to identify genetic factors active in early developmental processes because they exhibit fetal-like molecular properties. A total of 273 individuals have participated in the study, of which 222 have had iPSCs generated from fibroblasts. Of the 273 individuals, 181 are part of 55 families that include 24 monozygotic twin pairs and 5 dizygotic twin pairs, allowing for the incorporation of familial relationships into genetic analyses. Germline DNA has been sequenced from blood or fibroblast samples for all 273 individuals (available through dbGaP phs001325) and other genomic data (RNA-seq, DNA methylation, genotype arrays, ATAC-seq, H3K27ac ChIP-seq, HiC-seq) have been generated from the 222 iPSCs as well as derived cell types (available through dbGaP phs000924). QTL analyses were conducted for multiple omics data types and summary statistics are available through dbGaP phs0001325. Important note: Of the 273 individuals, 268 are consented for general research use and 5 are consented for cardiac research only. For detailed information about iPSCORE Collection including samples, methods used to generate the data, and how to access the datasets visit the Frazer lab website.The 222 well characterized iPSC lines that constitute the iPSCORE resource are available, please contact Dr. Kelly A. Frazer (kafrazer@health.ucsd.edu) if you are interested in obtaining the collection.

Study phs000924

NextGen Consortium: The iPSCORE (iPSC Collection for Omic Research) Resource for Studying the Impact of Genetic Variation on Molecular and Physiological Phenotypes - Whole Genome Sequence

The iPSC Collection for Omic Research (iPSCORE) Resource was created as part of the Next-Gen Consortium funded by NHLBI. The overarching purpose of the resource is to provide a large collection of human induced pluripotent stem cells (iPSCs) for use in studying the impact of genetic variation on molecular and physiological phenotypes. The resource has been used in a number of studies in the Dr. Kelly A. Frazer's Lab examining both the characteristics of human iPSCs and a variety of iPSC-derived cell types including cardiovascular progenitor cells (iPSC-CVPCs), pancreatic precursor cells (iPSC-PPCs), and retina pigment epithelium cells (iPSC-RPEs). We have shown that the iPSCs, CVPCs, and PPCs are suitable surrogate models to identify genetic factors active in early developmental processes because they exhibit fetal-like molecular properties.A total of 273 individuals have participated in the study, of which 222 have had iPSCs generated from fibroblasts. Of the 273 individuals, 181 are part of 55 families that include 24 monozygotic twin pairs and 5 dizygotic twin pairs, allowing for the incorporation of familial relationships into genetic analyses.Germline DNA has been sequenced from blood or fibroblast samples for all 273 individuals (available through dbGaP phs001325) and other genomic data (RNA-seq, DNA methylation, genotype arrays, ATAC-seq, H3K27ac ChIP-seq, HiC-seq) have been generated from the 222 iPSCs as well as derived cell types (available through dbGaP phs000924).QTL analyses were conducted for multiple omics data types and summary statistics are available through dbGaP phs0001325.Important note: Of the 273 individuals, 268 are consented for general research use and 5 are consented for cardiac research only.For detailed information about iPSCORE Collection including samples, methods used to generate the data, and how to access the datasets visit the Frazer lab website.The 222 well characterized iPSC lines that constitute the iPSCORE resource are available, please contact Dr. Kelly A. Frazer (kafrazer@health.ucsd.edu) if you are interested in obtaining the collection.

Study phs001325

The British Autozygosity Populations BioResource (2022-04-26)

This data set contains whole exome sequences of individuals from 8086 (mostly British Pakistani/British Bangladeshi, mostly self-reported parentally related) individuals from the following studies: 1. 5236 British Pakistani/British Bangladeshi adults from East London Genes & Health, now known as Genes & Health 2. 2624 British South Asian mothers from Born in Bradford (mostly Pakistani) 3. 1061 British South Asian adults from Birmingham (mostly Pakistani) This dataset contains all the exome sequence data available for this study on 2022-04-26

Dataset EGAD00001008736

Broccoli Sprouts Extracts Trial (BEST-COPD-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: To establish a safe and tolerable dose of sulforaphane that effects in vivo antioxidants via Nrf2 for development as a potential novel treatment for participants with Chronic Obstructive Pulmonary Disease (COPD).Background: Chronic Obstructive Pulmonary Disease (COPD), caused primarily by smoking, is the third leading cause of death in the United States and world-wide. Surprisingly, there are few treatments available to address the pathobiology of COPD other than cessation of smoking. The development and progression of COPD are associated with increased inflammatory response(s) and increased oxidative stress in the lung. Thus, one approach to the development of novel therapies is the stimulation of endogenous antioxidant defense mechanisms.Nuclear factor erythroid-2-related factor 2 (NFE2L2/Nrf2) is a transcription factor activated by oxidative stress. Nrf2 activity promotes anti-oxidant enzymes, and anti-oxidant enzymes play key roles in cellular defenses. Sulforaphane, a derivative of broccoli and other cruciferous vegetables, has been shown to stimulate Nrf2 activity in both in vivo and in vitro experiments. For example, activation of Nrf2 protected mice from developing emphysema after chronic smoke exposure and decreased oxidative stress. Similarly, activation of Nrf2 in human COPD lung cells resulted in decreased oxidative stress. Therefore, this study was designed to assess whether daily ingestion of sulforaphane by COPD participants for four weeks increased Nrf2 activity in alveolar macrophages and bronchial epithelial cells. Participants: There were a total of 89 participants randomized to one of three treatment arms. Of these, 31 participants were randomized to the placebo arm, and 29 participants were randomized to the each of the sulforaphane arms. One participant withdrew from the placebo arm, therefore, a total of 88 participants completed the study.Design: Participants were assigned to receive sulforaphane at 25 micromoles (4.4mg), sulforaphane at 150 micromoles (26.6 mg), or placebo (microcellulose) once daily by mouth. Computer-generated treatment assignments were blinded to participants, clinical staff, and study staff. Doses were back-filled with methylcellulose and presented in similar capsules to compensate for appearance and weight differences in sulforaphane and placebo treatments arms.There were a total of five study visits over the six-week study period. Prior to randomization, participants were assessed for eligibility, which included baseline data collection. Participants provided medical histories, underwent a physical examination, pre-and-post bronchodilator spirometry, lung volume measurements, carbon monoxide diffusing capacity (DLCO), and pulse oximetry over the six-week study period. Follow up data and biospecimens were collected at the final visit, which was targeted for four weeks after randomization. Two fiberoptic bronchoscopies were performed under sedation to collect endobronchial brushings and bronchoalveolar lavage used to isolate alveolar macrophages and bronchial epithelial cells. The first bronchoscopy was performed on the day of randomization, and the second bronchoscopy was performed the day after the final visit. In addition, nasal brushings were obtained prior to bronchoscopy to isolate nasal epithelial cells. The primary outcomes were changes in Nrf2 target gene expression at four weeks in alveolar macrophages and bronchial epithelial cells. The target genes for the primary outcome were NQ01, H01, AKR1C1, and AKR1C3. Secondary outcomes included the evaluation of: expression of other genes in the Nrf2/Keap1 pathway (e.g. Nrf2/NFE2L2, KEAP1, and SLPI), markers of oxidative stress (e.g., isoprostane and thiobarbituric acid reactive substances) in plasma and expired breath condensate, and cytokine profiles in bronchoalveolar lavage fluid. Conclusions: Sulforaphane administered at four weeks doses of 25umoles and 150umoles to participants with COPD did not significantly increase Nrf2 target gene expression in alveolar macrophages or bronchial epithelial cells. In addition, changes in oxidative stress markers and the expression of other genes in the Nrf2/Keap1 pathway were not statistically significant between the treatment groups.Wise RA, Holbrook JT, Criner G, et al. Lack of Effect of Oral Sulforaphane Administration on Nrf2 Expression in COPD: A Randomized, Double-Blind, Placebo Controlled Trial. Vij N, ed. PLoS ONE. 2016; 11(11):e0163716. doi:10.1371/journal.pone.0163716 (PMID: 27832073; PMID: 28350841).

Study phs004022

16S-based fecal microbiota composition

The dataset reports the 16S rRNA gene sequencing of the fecal microbiota of donors from the Milieu Intérieur Cohort. The Milieu Intérieur cohort includes a total of 1,000 healthy individuals of western European ancestry, recruited in France as part of the Milieu Intérieur project. To assess their fecal microbiota composition, 16S rRNA profiles were generated from stool samples of 863 of the 1,000 donors. Human stool samples were produced at home no more than 24 hours before the scheduled medical visit and collected in a double-lined sealable bag maintaining strict anaerobic conditions. Upon reception at the clinical site, the fresh stool samples were aliquoted and stored immediately at -80°C. DNA was extracted from stool and barcoding PCR was carried out using indexed primers targeting the V3-V5 region of the 16S rRNA gene. Equal volumes of normalized PCR reaction were pooled and thoroughly mixed. The amplicon libraries were sequenced on Illumina MiSeq.

Dataset EGAD00001004979

TRanscriptomic ANalySis of left ventriCulaR gene Expression (TRANSCRibE)

Myocardial ischemia occurs when there is a mismatch between coronary oxygen delivery and metabolic requirements of the myocardium, which may be clinically manifested during angina, coronary angioplasty or cardiopulmonary bypass (CPB). Myocardial ischemia may lead to a spectrum of myocardial stunning, hibernating myocardium, and ultimately cell death if the ischemic insult is severe. In the human heart, irreversible damage begins after approximately 20 to 40 minutes of oxygen deprivation. Observed molecular and cellular changes of myocardial ischemia are characteristic of an inflammatory response, but the exact mechanisms that underlie this pathological process are unclear and may not be full emulated by animal models of ischemia or infarction. Thus, we felt it valuable to investigate a human ischemia model. During cardiac surgery, CPB with aortic cross-clamping (AoXC) and cardioplegic arrest is associated with excellent clinical outcomes and suitable operative conditions. However, despite the use of cardioprotective strategies, AoXc during CPB is accompanied by a variable, yet obligate ischemic period lasting 1 to 3 hours, resulting in hypoxia, metabolic substrate depletion, reperfusion injury, apoptosis, and necrosis. Cardiac specific biomarkers of ischemia and infarction, including troponin, are elevated even after routine coronary artery bypass graft surgery and correlate with the duration of ischemia from AoXc.This process of CPB provides us with the ability to examine the transcriptional profile before and after an expected, consistent, and reproducible human ischemic event, albeit induced by cold cardioplegic arrest and not coronary occlusion. In addition, the absence of reperfusion in this time period allows us to examine the transcriptomic response to intermittent ischemia, without having to account for the perturbations of reperfusion injury. Although various animal models have been used to examine the effects of ischemia on cardiac function, no human data exist which examine the early transcriptomic response to a left ventricular (LV) ischemic insult. We therefore characterized the effect of cold cardioplegia induced acute ischemia on the transcriptional profile of the LV by performing whole transcriptome next-generation RNA-sequencing (RNA-seq) in patients undergoing cardiac surgery by sampling human LV tissue prior to, and after, the obligate ischemia during AoXC. We hypothesized that the cold cardioplegia induced ischemic injury will dramatically alter transcription in the human myocardium, and that we would identify genes and pathways, which will identify interventional targets for pharmacological therapy. Methods:We have collected left ventricle tissue samples and blood sample from patients undergoing heart surgery. We obtained punch biopsies (~3-5μg total RNA content) from the site of a routinely placed surgical vent in the anterolateral apical left ventricular wall of patients undergoing elective aortic valve replacement surgery with cardiopulmonary bypass. After an average of 79 minutes of aortic cross-clamping with intermittent cold blood cardioplegia for myocardial protection every 20 minutes, a second biopsy was obtained in the same manner. Tissue samples were immediately placed in RNAlater® (Ambion, ThermoFisher Scientific, Waltham, MA), and after 48 hours at +4°C were stored at -80°C until RNA extraction. Total RNA was isolated with Trizol and RNA quality was assessed using the Agilent Bioanalyzer 2100 (Agilent, Santa Clara, CA). Libraries were prepared by poly(A) mRNA isolation and reverse transcription Polymerase Chain Reaction (RT-PCR), then sequenced on the Illumina HiSeq2000 or HiSeq2500 (Illumina, San Diego, CA). As samples were analyzed at different times, different read lengths were employed, initially using single-end reads (n=20) and then transitioning to paired end reads (n=216), ranging from 36 - 100 base pairs. Raw sequencing files were processed using Sickle, Skewer, and STAR software, and aligned to GrCh37 or UCSC Hg19. DNA was isolated from whole blood using standard methods. SNP genotyping was performed using the Illumina Omni2.5Exome-8 BeadChip array with additional exome content (Illumina, San Diego, CA) chip, version 1.1. We first phased and imputed 93 subjects using a phasing tool called SHAPEIT and an imputation tool called MINIMAC, with 1000 Genomes phase 1 version 3 for the reference panel. We then phased and imputed 26 more subjects using SHAPEIT, an imputation tool called IMPUTE2, and 1000 Genomes phase 3 version 5.

Study phs001679

Count Me In (CMI): The Metastatic Prostate Cancer (MPC) Project (CMI-MPCproject)

Count Me In - The Metastatic Prostate Cancer Project: A Patient-Driven Research Initiative to Accelerate Metastatic Prostate Cancer Research The Metastatic Prostate Cancer Project (MPCproject; http://mpcproject.org/) is a research study that empowers men with metastatic and advanced prostate cancer to partner directly with researchers by sharing their samples and clinical information, with the ultimate goal of accelerating scientific discoveries that have clinical impact. The MPCproject enables any man with metastatic or advanced prostate cancer in the US and Canada to participate in cutting-edge genomic and molecular research, regardless of where they live. Metastatic or advanced prostate cancer patients visit the project website and complete an online questionnaire of basic information about themselves and their cancer. Enrolled patients are mailed saliva and blood draw kits, which can be used to extract germline DNA and cell-free DNA (cfDNA), respectively. The study team contacts participants' healthcare institutions to obtain medical records and a portion of archived tumor samples. Whole exome sequencing is performed on tumor DNA, germline DNA, and cfDNA, and transcriptome sequencing is performed on tumor RNA. De-identified data, including linked genomic, clinical, and patient-reported data, are shared via public databases on a recurring pre-publication basis. Participants are regularly provided with updates on the study.

Study phs001939

Lactobacillus rhamnosus GG ATCC (LGG) as an immune adjuvant for influenza vaccination in the elderly

Double blind Randomized Controlled trial to evaluate the safety of Lactobacillus rhamnosus GG ATCC 53103 (LGG) vs placebo in elderly receiving Trivalent Inactivated Influenza Vaccine (TIV) (study 1) or Double blind Randomized Controlled trial to evaluate the safety of Lactobacillus rhamnosus GG ATCC 53103 (LGG) vs. placebo in elderly subjects receiving Live Attenuated Influenza vaccine (LAIV) (study 2). Healthy elderly volunteers, ages 65-80 were enrolled as outpatients in two clinical studies in which they received the TIV vaccine (study 1, n=28) or the LAIV vaccine (study 2, n=30). In each of the 2 studies, subjects were randomized to receive either LGG capsules containing 1 x 1010 CFU, twice daily for 28 days, or matching placebo capsules twice daily for the same period of time. The study subjects completed a daily diary, telephone calls, and study visits at the Massachusetts General Hospital Clinical Research Centers at baseline, days 21, 28 and 56 and month 5 for the TIV study and baseline, days 21, 28, and 56 for the LAIV study. During each visit, the subject diary, interim history, potential adverse effects and concomitant medications were reviewed and vital signs and a physical examination were performed. Routine blood tests were obtained to monitor for safety during visits and nasopharyngeal and stool samples were collected for microbiome analysis. Volunteers in both studies who were interested in participating in the effect of LGG probiotic on the Human whole Blood Transcriptome substudy also had blood drawn for DNA and RNA extraction, after signing the substudy consent form. The main objectives of the TIV and LAIV studies were to assess the safety and tolerability of 2 x 1010 CFU LGG administered orally to elderly subjects for 28 days after administration of TIV (study 1) or LAIV (study 2). Secondary objectives were to evaluate the richness and microbial diversity in nasopharyngeal and stool specimens using pyrosequencing, and to compare cytokine production in response to bacterial stimulation by following the kinetics of mRNA expression of pro and anti-inflammatory genes and different signaling pathways, in relation to changes in stool Bifidobacterium and Lactobacillus spp. The studies were reviewed and approved by the Partners Human Research Committee (TIV study IRB # 2010p001694 and LAIV study IRB # 2011p002849) and were registered at ClinicalTrials.gov (NCT01368029 and NCT01545349, respectively).

Study phs000981

Genetic Epidemiology Network of Arteriopathy (GENOA)

The Genetic Epidemiology Network of Arteriopathy (GENOA) is one of four networks in the NHLBI Family-Blood Pressure Program (FBPP). GENOA's long-term objective is to elucidate the genetics of target organ complications of hypertension, including both atherosclerotic and arteriolosclerotic complications involving the heart, brain, kidneys, and peripheral arteries. The longitudinal GENOA Study recruited European-American and African-American sibships with at least 2 individuals with clinically diagnosed essential hypertension before age 60 years. All other members of the sibship were invited to participate regardless of their hypertension status. Participants were diagnosed with hypertension if they had either 1) a previous clinical diagnosis of hypertension by a physician with current anti-hypertensive treatment, or 2) an average systolic blood pressure ≥ 140 mm Hg or diastolic blood pressure ≥ 90 mm Hg based on the second and third readings at the time of their clinic visit. The Family Blood Pressure Program (FBPP), GENOA's parent program, is an unprecedented collaboration to identify genes influencing blood pressure (BP) levels, hypertension, and its target-organ damage. This program has conducted over 21,000 physical examinations, assembled a shared database of several hundred BP and hypertension-related phenotypic measurements, completed genome-wide linkage analyses for BP, hypertension, and hypertension associated risk factors and complications, and published over 130 manuscripts on program findings. The FBPP emerged from what was initially funded as four independent networks of investigators (HyperGEN, GenNet, SAPPHIRe and GENOA) competing to identify genetic determinants of hypertension in multiple ethnic groups. Realizing the greater likelihood of success through collaboration, the investigators created a single confederation with program-wide and network-specific goals.

Study phs001238

Transcriptomic Profile of Whole Blood Cells from Elderly Subjects fed Probiotic Bacteria Lactobacillus rhamnosus GG ATCC 53103 (LGG) in a Phase I Open Label Study

Open label study to evaluate the safety of Lactobacillus rhamnosus GG ATCC 53103 (LGG) in elderly subjects. Fifteen healthy elderly volunteers, ages 65-80 were enrolled in a study in which they received LGG capsules containing 1 x 1010 CFU, twice daily for 28 days and were followed through day 56. The study subjects completed a daily diary, a telephone call on study days 3, 7 and 14 and study visits at the Massachusetts General Hospital Clinical Research Center at baseline, day 28 and day 56. During each visit, the subject diary, interim history, potential adverse effects and concomitant medications were reviewed and vital signs and a physical examination were performed. Routine blood tests were obtained to monitor for safety during visits and nasopharyngeal and stool samples were collected for microbiome analysis. Volunteers interested in participating in the effect of LGG probiotic on the Human whole Blood Transcriptome substudy also had blood drawn for DNA and RNA extraction, after signing the substudy consent form. The main objective of the study was to assess the safety and tolerability of 2 x 1010 CFU LGG administered orally to elderly subjects for 28 days. Secondary objectives were to evaluate the richness and microbial diversity in nasopharyngeal and stool specimens using pyrosequencing, and to compare cytokine production in response to bacterial stimulation by following the kinetics of mRNA expression of pro and anti-inflammatory genes and different signaling pathways, in relation to changes in stool Bifidobacterium and Lactobacillus spp. The study was reviewed and approved by the Partners Human Research Committee (IRB # 2010P001695) and was registered at ClinicalTrials.gov (NCT01274598). The main results regarding the clinical signs and safety of intervention is published in PLoS One. 2014 Dec 1;9(12):e113456. doi: 10.1371/journal.pone.0113456. eCollection 2014. PMID: 25438151. RNA sequencing for transcriptome analysis was only done in 11 of the 15 subjects as RNA integrity and quantity had to be optimal for the three times where blood was collected in order for a subject to be included in the study. The information regarding the microbiome data associated with this study is presented in a separate paper, which can be found at dbGaP study accession, phs000896, and PMID: 25873374.

Study phs000928

GEnomics and Transcriptomics of Human INsulinoma (GETHIN)

The Genomics and Transcriptomics of Human Insulinoma (GETHIN) The common forms of diabetes - Types 1 and 2 - ultimately result from a deficiency of insulin-producing pancreatic beta cells. The Genomics and Transcriptomics of Human Insulinoma (GETHIN) study was performed in order to identify novel approaches to inducing human pancreatic beta cells to replicate and regenerate. As a corollary, developing drugs that are able to expand human beta cell mass in people with diabetes should reverse diabetes. Unfortunately, identifying druggable pathways that can enhance human beta cell replication has been a major challenge. In 2017, there is only one class of drugs - the harmine analogues - that can induce human beta cells to replicate, and in this case, higher replication rates are desirable. Thus, identifying additional drugs and druggable pathways is a priority in diabetes research. Insulinomas are rare, benign adenomas of the pancreatic beta cell that cause excess insulin production and hypoglycemia: exactly the opposite of Types 1 and 2 diabetes. Beta cell proliferation rates in insulinomas are abnormally high. Thus, the premise for The Genomics and Transcriptomics of Human Insulinoma study is that benign human insulinomas hold the genomic and transcriptomic "recipe", and the repertoire of druggable pathways, that can be exploited to induce regeneration or replication of human beta cells in diabetes. Because, insulinomas are so rare, are almost always benign (non-malignant), and are easily resected by laparoscopic surgery, little attention has been paid to understanding the genomics or transcriptomics of insulinoma. There are at present only three published studies employing next-gen sequencing in insulinoma (PMID:24326773; PMID:25787250; and PMID:25763608). These studies contained 10, 7 and 8 insulinomas, respectively, and highlighted likely mutations in YY1 and MEN1. Our goal was to markedly expand the database and to add RNAseq to these earlier studies. The GETHIN study reports next-gen sequencing on 38 insulinomas, by far the largest series of human insulinomas subjected to next-gen sequencing (see the Selected publications section for reference). This includes paired (genomic plus tumor) whole exome sequencing on 26 human insulinomas (22 sequenced at Mount Sinai, 4 downloaded from Cao et al, PMID:24326773), and 25 sets of RNAseq from insulinomas, some of which also had paired whole exome sequencing, and some of which did not. The insulinoma RNAseq was compared to RNAseq from 22 sets of FACS-sorted normal human beta cells. Since insulinomas are so rare, the 38 insulinomas were collected by several investigators at several institutions over several decades, but most (22 whole exome sets, and all RNAseq) were sequenced at the Icahn School of Medicine at Mount Sinai in New York. The current dataset contains whole exome sequencing and RNAseq on the 11 insulinomas harvested at Mount Sinai. The four from Cao et al can be retrieved from Cao et al PMID:24326773. Fastq files from the remaining 23 insulinomas will be added as the local IRBs and Institutional Certifications are acquired. Complete patient data are provided in our Nature Communications report. Going forward, our intention is to expand this series, with the goal of sequencing 100 human insulinomas. These will be added to dbGaP as they accrue. Paired-end whole exome sequencing (mean usable sequencing depth 79X and 105X for blood and insulinoma, respectively) was performed using an Illumina HiSeq 2500. Insulinoma and sorted normal beta cell RNAseq was performed on Ribozero and polyA paired end libraries using the Illumina HiSeq 2500. Complete sequencing and bioinformatic details are provided in our Nature Communications report. The principal findings from the study are that although each insulinoma has a different set of presumptive driver mutations, the majority converge on genes that are members of the Polycomb Complex, Trithorax Complex and other epigenetic modifying enzymes. In addition, 20% of insulinomas have copy number loss or loss of heterozygosity of all or most of chromosome 11, and the majority display abnormalities in CpG methylation and imprinting control on the imprinted Chr 11 p15.5-15.4 region that contains INS, IGF2, CDKN1C, KCNQ1, and other genes involved in beta cell specification and proliferation.

Study phs001422

Center for Common Disease Genomics [CCDG] - Cardiovascular: SWISS-AF/SWISS-AF-PVI/BEAT-AF

This study is a part of NHGRI's Centers for Common Disease Genomics (CCDG), which is a collaborative large-scale genome sequencing effort to comprehensively identify rare risk and protective variants contributing to multiple common disease phenotypes. Current estimates anticipate that the CCDG program will sequence approximately 140K whole genomes and 225K whole exomes during the life of the project. The Cardiovascular Disease working group of the CCDG considered five diseases: early-onset coronary artery disease (EOCAD), stroke, atrial fibrillation (AF), congestive heart failure and type 2 diabetes. AF will affect between 6-12 million individuals in the US by 2050. AF is also associated with increased risks of stroke, dementia, heart failure, death, and high health care costs. Many risk factors for AF have been identified, including advancing age, cardiovascular disease (CVD), and CVD risk factors. However, there is little knowledge how to prevent AF. Furthermore, therapies for AF are only partially effective, and are themselves associated with substantial morbidity. Previously, heritable forms of AF have been considered rare; yet in the last decade, it has been established that AF, and in particular early-onset forms of AF, are heritable. Genome-wide association studies (GWAS) provide a powerful tool to identify common variants underlying disease risk. The AFGen Consortium currently consists of investigators from more than 25 studies with >20,000 individuals with AF and >100,000 without AF. In the latest analyses, 14 loci have been identified for AF1. Broadly, the loci implicate genes related to cardiopulmonary development, cardiac-expressed ion channels, and cell signaling molecules. Source: https://ccdg.rutgers.edu/sites/default/files/CCDG_CVD_EOAF_FINAL_w_link.pdf Three collections were brought together to form Swiss atrial fibrillation cases: SWISS-AF, SWISS-AF-PVI, and BEAT-AF. SWISS-AF is a prospective observational, multicentric cohort study in Switzerland to increase our knowledge on structural brain damage and its changes over time in patients with atrial fibrillation. Overall, 2400 patients with documented atrial fibrillation aged >65 years will be included and followed on a yearly basis. SWISS-AF-PVI is a registry of patients with atrial fibrillation undergoing catheter-based ablation of atrial fibrillation (pulmonary vein isolation) to determine long-term success rates of catheter-based ablation of atrial fibrillation (pulmonary vein isolation) and to evaluate factors associated with long-term success of catheter-based ablation of atrial fibrillation (pulmonary vein isolation). BEAT-AF is a prospective observational, multicenter cohort study in Switzerland. Overall, 1550 patients with documented atrial fibrillation were enrolled in seven study centers. The main aim of this study is to investigate the therapy and the medical consequences of patients with atrial fibrillation. Samples from all three collections were sent to The Broad Institute of MIT and Harvard to generate genetic data using whole exome sequencing and whole genome genotyping (Infinium Global Screening Array); all cases with atrial fibrillation.

Study phs002242

Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C)

Reprinted from http://www.haltctrial.org/ Purpose The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial is a randomized controlled trial designed to evaluate the safety and efficacy of long-term use of pegylated interferon for the treatment of chronic hepatitis C in patients who failed to respond to previous interferon therapy. The HALT-C Trial was developed to determine whether prolonged interferon therapy altered histological and clinical outcomes in a group of patients who had failed to eradicate hepatitis C virus with previous interferon treatment. Study Hypotheses In patients with chronic hepatitis C and bridging fibrosis who failed to eradicate the virus with previous interferon therapy, long-term treatment with interferon is safe and can prevent progression to cirrhosis. In patients with cirrhosis secondary to chronic hepatitis C who failed to eradicate the virus with previous interferon therapy, long-term treatment with interferon is safe and can reduce the risks of hepatic decompensation or of hepatocellular carcinoma. Study Design 1145 patients with chronic HCV and advanced hepatic fibrosis (Ishak stage 3-6) who failed to respond to previous treatment with interferon were enrolled at 10 clinical centers and entered into a Lead-in phase. They were treated with a combination of pegylated interferon (Pegasys®, Hoffmann-La Roche) 180 µg/week and ribavirin (1000-1200 mg/day) for 24 weeks. Patients who had no detectable HCV-RNA at week 20 continued on combination therapy until week 48. 662 patients who did not clear virus were randomly assigned at week 24 to either continue treatment with pegylated interferon alone (90 µg/week) for an additional 42 months, or to have treatment discontinued. All patients were followed at 3-month intervals following randomization. Liver biopsy was performed at baseline and after 1.5 and 3.5 years of treatment. Because of slower than expected enrollment and the approval by the FDA of peginterferon alfa-2b after the start of the trial, we modified the study protocol in three ways. First, criteria for admission to the trial were liberalized to allow patients to enter the trial with lower platelet and white blood cell counts than had been initially considered safe or tolerable. Second, 151 Lead-in patients and those continuing on therapy after 24 weeks who demonstrated return of viremia during or after their 48-week treatment period (called "Breakthrough" or "Relapse" patients, respectively) were allowed to return to enter the randomized trial. Third, 237 patients treated with peginterferon alfa-2b (or with peginterferon alfa-2a in licensing trials) outside the HALT-C Trial who in other respects met all study criteria, having received the equivalent of Trial Lead-in period therapy, were allowed to enter the long-term trial as "Express" patients. A total 1050 patients were randomized. Those patients who completed Month 48 were offered an "extended follow-up (observation only)" until October 2009. These visits will primarily be to identify outcome events, and to provide information to patients concerning the current status of the trial. Some questionnaires, blood tests, and an ultrasonogram will be performed. Quarterly (every 3 months) Interval history of complications, adverse events Current medications Brief physical examination Laboratory tests: liver panel, CBC, INR, AFP Child-Pugh Score Stored serum Annual Complete physical examination Ultrasound of liver 1.5 years (M24 visit, middle of study) Liver biopsy: formalin fixed histology, frozen liver tissue (subset of patients) 3.5 years (M48, end of study) Liver biopsy: formalin fixed histology, frozen liver tissue (subset of patients) Endoscopy: evaluate esophageal varices and portal hypertension After Month 48 Observation only (no treatment) to determine clinical outcomes Clinic visit every 6 months with current medications, brief PE, liver panel, CBC, AFP, stored Serum Ultrasound of liver every 6 months Outcome Variables Primary outcome variables to be assessed in the two groups of patients include: Development of cirrhosis on liver biopsy (progression of Ishak fibrosis score by 2 points or more) Development of hepatic decompensation, as shown by: Sustained increase in the Child-Turcotte-Pugh score to 7 points or higher Variceal hemorrhage Ascites Spontaneous bacterial peritonitis Hepatic encephalopathy Development of hepatocellular carcinoma Death Secondary outcomes include quality of life, serious adverse events, events requiring dose reductions, and development of presumed hepatocellular carcinoma.

Study phs000430

Natural History and Structural Functional Relationships in Fabry Renal Disease

Fabry disease is a rare genetic disease with deficient activity of an enzyme, which leads to accumulation of inclusions in different organs including kidney, heart and vessels. The purpose of the study is to conduct a cross-sectional investigation of the natural history of Fabry renal disease and measure renal function and renal structure in male and female Fabry's patients. The study will utilize the resultant cross-sectional information to determine the renal structural parameters or composite of parameters that most closely relates to the onset and progression of clinical renal disease in Fabry patients. This is an observational, cross-sectional study of 60 individuals with Fabry disease. Those participating in the study will be evaluated during a one day visit and on a PRN basis. The primary study objectives are as follows: To study the natural history of Fabry renal disease and measure renal function and renal structure in male and female Fabry's patients. These patients would encompass the broad age range from childhood to adulthood and from normal renal function to moderate renal insufficiency [serum creatinine (SCr) ≤ 2.5mg/dl (chronic kidney disease or CKD3)]. To utilize the resultant cross-sectional information to determine the renal structural parameters or composite of parameters that most closely relates to the onset and progression of clinical renal disease in Fabry patients.

Study phs001333

CSER: Clinical Implementation of Carrier Testing Using Next Generation Sequencing (NextGen)

We will investigate the clinical implementation of genome sequencing (GS) for carrier screening to aid reproductive decision-making in adults. The study is organized into three inter-related Projects. The study population will include women and their partners who receive pre-conception testing. In Project 1, we will conduct a Randomized Clinical Trial to test clinical implementation of WGS compared with usual care. We will integrate WGS results with the electronic medical record (EMR), and measure outcomes from patient and physician perspectives. In Project 2, we will perform whole genome sequencing, including validation and interpretation of the identified variants to identify "actionable variants", meaning variants deemed worthy of reporting. This will include a robust approach using a Return of Results Committee (RORC) for determination of reportable results. In Project 3, we will evaluate the ethical and psychosocial implications of expanded carrier screening using WGS for the return of carrier status and secondary findings, and measure the impact on downstream healthcare utilization and cost. Two groups of women are identified through the electronic medical record. The first group has a clinical carrier screening test, usually Cystic Fibrosis (CF), ordered and completed as part of a preconception planning visit. The second group has a carrier screening test, usually CF, performed during pregnancy, they have delivered their baby and are planning a future pregnancy. Eligible women are randomized to either usual care or genome sequencing (GS). Women randomized into the usual care arm have already received their clinical genetic test. These women will not receive genome sequencing. Women in the GS arm will receive their carrier status results for about 700 gene/condition pairs approximately three months after randomization. If there are results to return, women come in for a genetic counseling session. If there are no results, a letter is sent in the mail. Incidental findings (IF) are returned about one month later. As with the carrier status results, all IF are returned in person, and if there are no results a letter is sent in the mail. If a participant is found to be a carrier of an autosomal recessive condition, her male partner is then eligible and invited to participate in the study and receive GS.

Study phs000927

NHLBI TOPMed: San Antonio Family Heart Study (SAFHS)

The San Antonio Family Heart Study (SAFHS) is a complex pedigree-based mixed longitudinal study designed to identify low frequency or rare variants influencing susceptibility to cardiovascular disease, using whole genome sequence (WGS) information from 2,590 individuals in large Mexican American pedigrees from San Antonio, Texas. The major objectives of this study are to identify low frequency or rare variants in and around known common variant signals for CVD, as well as to find novel low frequency or rare variants influencing susceptibility to CVD. WGS of the SAFHS cohort has been obtained through three efforts. Approximately 540 WGS were performed commercially at 50X by Complete Genomics, Inc (CGI) as part of the large T2D-GENES Project. The phenotype and genotype data for this group is available at dbGaP under accession number phs000462. An additional ~900 WGS at 30X were obtained through Illumina as part of the R01HL113322 "Whole Genome Sequencing to Identify Causal Genetic Variants Influencing CVD Risk" project. Finally, ~1,150 WGS at 30X WGS were obtained through Illumina funded by a supplement as part of the NHLBI's TOPMed program. Extensive phenotype data are provided for sequenced individuals primarily obtained from the P01HL45522 "Genetics of Atherosclerosis in Mexican Americans" for adults and R01HD049051 for children in these same families. Phenotype information was collected between 1991 and 2016. For this dataset, the SAFHS appellation represents an amalgamation of the original SAFHS participants and an expansion that reexamined families previously recruited for the San Antonio Family Diabetes Study (R01DK042273) and the San Antonio Family Gall Bladder Study (R01DK053889). Due to this substantial examination history, participants may have information from up to five visits. The clinical variables reported are coordinated with TOPMed and include major adverse cardiac events (MACE), T2D status and age at diagnosis, glycemic traits (fasting glucose and insulin), blood pressure, blood lipids (total cholesterol, HDL cholesterol, calculated LDL cholesterol and triglycerides). Additional phenotype data include the medication status at each visit, classified in four categories as any current use of diabetes, hypertension or lipid-lowering medications, and, for females, current use of female hormones. Anthropometric measurements include age, sex, height, weight, hip circumference, waist circumference and derived ratios. PBMC derived gene expression assays for a subset of ~1,060 individuals obtained using the Illumina Sentrix-6 chip is also available from the baseline examination. The WGS data have been jointly called and are available in the current TOPMed accession (phs001215).

Study phs001215

Expanding the SPTBN1 Spectrum: A Case of Neurodevelopmental Disorder with GI and Musculoskeletal Involvement

Background: Mutations in the SPTBN1 gene, which encodes the βII-spectrin protein, are associated with a recently described neurodevelopmental syndrome characterized by developmental delay, intellectual disability, autistic traits, seizures, and dysmorphic features. While the phenotypic spectrum continues to evolve, gastrointestinal (GI) involvement and vertical transmission remain rarely reported features. Case Presentation: We describe a 13-year-old male from Georgia with a heterozygous missense mutation in SPTBN1 (c.3799C>G, p.Leu1267Val), inherited from his clinically unaffected mother. The patient presented with cognitive and motor delays, autistic traits, behavioral challenges, feeding difficulties, growth delay, musculoskeletal anomalies (pectus excavatum, pes planus), and persistent GI symptoms including abdominal pain and gallbladder sludge. Despite therapy with ursodeoxycholic acid and nutritional counseling, the gallbladder abnormalities persisted over a 12-month follow-up. Feeding therapy could not be initiated due to access barriers, although parental efforts led to modest dietary improvement. Upon recent visit pes planus was also confirmed. Conclusion: This case contributes to the growing body of literature on SPTBN1-related neurodevelopmental disorders, highlighting the potential for a broader phenotypic spectrum than currently recognized. In addition to the well-documented behavioral, cognitive, and musculoskeletal features, our patient presented with notable gastrointestinal involvement—specifically, gallbladder sludge and feeding disorder—which are not commonly reported in association with SPTBN1 mutations. Although causality cannot be established from a single case, the observed GI manifestations may be indirectly related to underlying neurobehavioral features such as ASD and associated eating disorders. The identification of a vertically transmitted missense variant (c.3799C>G, p.Leu1267Val) adds to the limited but growing evidence of inherited SPTBN1 mutations, expanding our understanding of transmission patterns. Given the novelty of the findings, we emphasize the need for multidisciplinary management, including feeding and behavioral therapy, as well as longitudinal follow-up to assess developmental, nutritional, and hepatobiliary outcomes. Future studies and case series are warranted to determine whether pes planus, pectus excavatum, gastrointestinal symptoms, including biliary tract involvement, represent an underrecognized component of the SPTBN1 phenotypic spectrum.

Study EGAS50000001213

A Genome-Wide Association Study in Patients Experiencing Musculoskeletal Adverse Events on NCIC CTG Trial MA.27 Evaluating Aromatase Inhibitors as Adjuvant Therapy in Early Breast Cancer. A Collaboration Between the NIH Pharmacogenetics Research Network and the RIKEN Yokohama Institute Center for Genomic Medicine.

Source of Patients The source of the patients for this genome-wide case control study was MA.27, which was conducted as a multi-cooperative group effort under the auspices of the NCI Breast Cancer Intergroup of North America. The NCIC Clinical Trials Group (CTG) serves as the coordinating group, with participation by the NCI-sponsored North Central Cancer Treatment Group, Eastern Cooperative Oncology Group (ECOG), Southwest Oncology Group, and Cancer and Leukemia Group B (CALGB). MA.27 involved postmenopausal women with histologically confirmed and completely resected invasive breast cancer with surgical margins clear of invasive carcinoma and DCIS in the following TMN categories (AJCC Version 6): pT1, pT2, pT3; pNx, pN0, pN1, pN2, pN3 (only when the sole basis is presence of 10 or more involved axillary nodes); MO. The primary tumor must have been ER and/or progesterone receptor positive. Patients were stratified by lymph node status at diagnosis, prior adjuvant chemotherapy, and trastuzumab use and were randomized to 5 years of adjuvant therapy with anastrozole or exemestane. The trial was activated on May 26, 2003, and reached its accrual objectives on July 31, 2008, after the randomization of 6827 North American patients, with the majority (79%) providing DNA and consent for genetic testing. Non-North American patients were also entered by the International Breast Cancer Study Group but they did not contribute DNA. From 2003 to December 21, 2004, patients also underwent a second randomization to celecoxib 400 mg twice daily or placebo but, after the entry of 1,622 patients, this treatment was discontinued because of reports of increased cardiovascular risk associated with celecoxib. Case Definition for Musculoskeletal Adverse Events Cases were defined to have had at least one of the following six MSAE): 1. pain - joint, 2. pain - muscle, 3. pain - bone, 4. arthritis, 5. joint - function, 6. musculoskeletal - other. Cases were required to have at least grade 3 toxicity, according to the NCI Common Terminology Criteria for Adverse Events v3.0, or go off treatment for any grade of the six MSAEs; and were required to have had an MSAE within the first two years (i.e., a MSAE occurring after 2 years was not be considered a case). Subjects were excluded from the case group who met the case definition while on celecoxib or in the three months after stopping celecoxib but subjects were allowed to be cases if they developed their first MSAE more than three months after stopping celecoxib. Study Design The design was a nested matched case-control study with two controls selected for each case. Random matching from the potential control group (i.e., risk-set sampling such that controls had at least the same length of followup as the timing of the case event) was done by matching the case on the following factors: 1. treatment arm (exemestane vs. anastrozole, blinded), 2. prior adjuvant chemotherapy (yes vs. no), 3. age at start of treatment (+/- 5 years), 4. Celecoxib allocation (yes vs. no). Attempts were made to exactly match each case with two controls according to the above criteria. If, however, controls could not be exactly matched, "close" matching was used to define a distance between each case and all potential controls in an optimal matching algorithm. Race is a potential confounding factor, and 94% of the MA.27 population is Caucasian, 3% are Black, 1% Asian, 1% American Indian, and 1% are of unknown race. Because there are so few non-Caucasian participants, was restricted to only Caucasians. Following identification of cases and controls, the list was sent to the CALGB Pathology Coordinating Office (PCO) at Ohio State University Medical Center for plating of the samples. Other patient factors that might influence the association of SNP genotypes with a MSAE, either as confounding factors or as effect modifiers, were included as investigational covariates. These include 1. body mass index (BMI), 2. bisphosphonate use, 3. fractures in past 10 years, 4. baseline ECOG performance status, 5. prior hormone replacement therapy, 6. prior adjuvant radiotherapy, and 7. prior taxane treatment. An Honest Broker Process was utilized to ensure patient confidentiality. Genotype Assays and Quality Control A GWAS was performed with the Illumina Human610-Quad at the RIKEN Center for Genomic Medicine. The DNA for all of the samples were adjusted to a concentration of 50 to 100 ng/µL in a final volume of 50 µL. The 96-well plates were designed to have a unique distribution pattern with x duplicates per plate to evaluate genotype concordance. Samples with <98% call rate were removed from analyses. SNPs with ambiguous call will be excluded using the following criteria: 1. low signal intensity of each allele, 2. low cluster separation score, 3. SNP call rate <0.98, 4. SNPs with Hardy Weinberg Equilibrium p-value <0.001 were excluded. X-chromosome SNPs were used to validate female sex and quality control measures were examined across the different submitting centers. For all pairs of subjects, the percentage of matching genotypes were computed to screen for unexpected duplicate samples. All SNPs found to be associated with MSAE were subjected to visual inspection of the cluster plots to verify that the genotype clustering was adequate.

Study phs000210

National Sleep Research Resource (NSRR): Cleveland Family Study (CFS)

The Cleveland Family Study (CFS) is a family-based study of sleep apnea, consisting of 2,284 individuals (46% African American) from 361 families studied on up to 4 occasions over a period of 16 years. The study began in 1990 with the initial aims of quantifying the familial aggregation of sleep apnea. National Institutes of Health (NIH) renewals provided expansion of the original cohort, including increased minority recruitment, and longitudinal follow-up, with the last exam occurring in February 2006. The CFS was designed to provide fundamental epidemiological data on risk factors for sleep disordered breathing (SDB). The sample was selected by identifying affected probands who had laboratory diagnosed obstructive sleep apnea. All first-degree relatives, spouses and available second-degree relatives of affected probands were studied. In addition, during the first 5 study years, neighborhood control families were identified through a neighborhood proband, and his/her spouses and first-degree relatives. Each exam, occurring at approximately 4-year intervals, included new enrollment as well as follow up exams for previously enrolled subjects. For the first three visits, data, including an overnight sleep study, were collected in participants' homes while the last visit occurred in a general clinical research center (GCRC). Phenotypic characterization of the entire cohort included overnight sleep apnea studies, blood pressure, spirometry, anthropometry and questionnaires. Currently, data of 710 individuals are available for use through BioData Catalyst (with genotype data available through dbGaP).The National Sleep Research Resource (NSRR) is a NIH-supported sleep data repository that offers free access to large collections of de-identified physiological signals and related clinical data from a large range of cohort studies, clinical trials and other data sources from children and adults, including healthy individuals from the community and individuals with known sleep or other health disorders. The goals of NSRR are to facilitate rigorous research that requires access to large or more diverse data sets, including raw physiological signals, to promote a better understanding of risk factors for sleep and circadian disorders and/or the impact of sleep disturbances on health-related outcomes. Data from over 15 data sources and more than 40,000 individual sleep studies, many linked to dozens if not hundreds of clinical data elements, are available (as of Feb. 2022). Query tools are available to identify variables of interest, and their meta-data and provenance.

Study phs002715

Alzheimer's Disease Sequencing Project (ADSP)

NOTICE OF CHANGE IN LOCATION FOR ALZHEIMER'S DISEASE SEQUENCING PROJECT (ADSP) GENETIC AND PHENOTYPIC DATA: ADSP whole exome and whole genome sequence data that are shared through dbGaP were mapped to the Genome Reference Consortium human genome GRCh37 (build 37). These data are from the Discovery Phase of the project (described below) and will continue to be available at this site. Please see the ADSP Design page for the complete study description. All data that are mapped to GRCh38 (hg38) are being shared through the NIA Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) Data Sharing Service (DSS). For instructions on how access the ADSP Build 38 data that are shared through NIAGADS DSS, visit the Application Instructions page. STUDY DESCRIPTION FOR dbGaP BUILD 37 ADSP DATA: The overarching goals of the Alzheimer's Disease Sequencing Project (ADSP) are to: (1) identify new genomic variants contributing to increased risk of developing Alzheimer's Disease (AD), (2) identify new genomic variants contributing to protection against developing AD, and (3) provide insight as to why individuals with known risk factor variants escape from developing AD. These factors will be studied in multi-ethnic populations in order to identify new pathways for disease prevention. Such a study of human genomic variation and its relationship to health and disease requires examination of a large number of study participants and needs to capture information about common and rare variants (both single nucleotide and copy number) in well phenotyped individuals. Using existing samples from NIH funded and other studies, three NHGRI funded Large Scale Sequencing and Analysis Centers (LSAC) - Broad, Baylor, and Washington University - produced the DNA sequence data. Variant call data are being made available to the scientific community through NIH-approved data repositories. Statistical analysis of the sequence data is anticipated to identify new genetic risk and protective factors. The ADSP will conduct and facilitate analysis of sequence data to extend previous discoveries that may ultimately result in new directions for AD therapeutics. Analysis of ADSP data will be done in two phases. The Discovery Phase analysis (2014-2018) is funded under PAR-12-183. The entire Discovery dataset contains whole-genome sequencing data on 584 subjects from 113 families, and pedigree data for > 4000 subjects; whole exome sequencing data on 5096 cases 4965 controls; and whole exome sequence data on an additional 853 (682 Cases [510 Non-Hispanic, 172 Hispanic]), and 171 Hispanic Control subjects from families that are multiply affected with AD. The Replication Phase (2016-2021) analysis will be funded under RFA-AG-16-001 and RFA-AG-16-002 and is expected to include a combination of genotyping and sequencing approaches on at least 30,000 subjects. Targeted sequencing will be done by the LSACs. GRCh37 Data Releases The first ADSP data release occurred on November 25, 2013. It included the whole-genome sequencing data in BAM file format on 410 individuals. The second ADSP data release occurred on March 31, 2014, and included the whole-genome sequencing data in BAM file format for an additional 168 individuals. The third ADSP data release occurred on November 03, 2014 and included whole-exome sequencing data in BAM file format for 10,939 individuals. The fourth ADSP data release occurred on February 13, 2015 and included revised ethnic data for subjects with whole-exome sequencing data. The fifth ADSP data release occurred on July 13, 2015 and included whole-genome genotypes and updated phenotypes as well as changes to pedigree structures and sample IDs. The sixth ADSP data release occurred on December 8, 2015, and included whole-exome genotypes and updated phenotypes as well as changes to subject IDs. This seventh ADSP data release on April 12, 2016 includes: (1) WES and WGS SNV VCF files (2) WES and WGS Indel PLINK files ADSP Data Available through dbGaP: ADSP - Whole Genome Sequencing ADSP - Whole Exome Sequencing Comments DNA-Seq (BAM) n=578 n=10913 Sequence data available (plus n=38 replications w/out genotype data) Concordant SNV Genotypes (PLINK format) N/A n=10913 QC'ed genotypes that are concordant between the Atlas (Baylor's) and GATK (Broad's) calling pipelines (a subset of the consensus genotype set) Consensus Genotypes (PLINK and VCF format) n=578 n=10913 QC'ed genotypes that are concordant between Atlas and GATK pipelines as well as those that that were called uniquely by Atlas or GATK Concordant Indel Genotypes (PLINK format) n=578 n=10913 QC'ed genotypes that are concordant between the Atlas and GATK calling pipelines Phenotype Data n=4735 n=10913 Data of n=53 phenotype variables available (plus administrative data), including APOE genotype. WGS phenotypes include data of connecting family members. Please use the release notes provided by dbGaP to obtain detailed information about study release updates. The ADSP data portal provides a customized interface for users to quickly identify and retrieve files by covariates, phenotypes, and data properties such as sequencing facility or coverage. For more information about the ADSP study and the data portal, please visit https://www.niagads.org/adsp/.

Study phs000572

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