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• The NCAA-DoD Concussion Assessment, Research, and Education (CARE) Consortium

  Study Description: Established in 2014, the U.S. Department of Defense (DoD) and the National Collegiate Athletic Association (NCAA) funded the Concussion Assessment, Research and Education (CARE) Consortium to inform science, clinical care and public policy related to concussion and repetitive head impact exposure (HIE) in U.S. Military Service Academy (MSA) cadets and collegiate student-athletes. The primary aims of the initial study were to: (1) establish a multisite research consortium to characterize the effects of concussion and repetitive head impact exposure on brain health, (2) characterize the clinical sequelae and natural history of concussion, (3) characterize the effect of concussion and repetitive head impacts on brain structure and brain function. The 30 member institutions of the CARE Consortium (26 civilian universities/colleges and 4 military service academies) agreed to invite all varsity athletes to undergo multimodal clinical assessments at preseason baseline, and at 5 additional timepoints after concussion diagnosis. At the service academies, non-varsity athlete cadets/midshipmen were also studied. Assessment Categories At Each Time Point Baseline: • Demographics • Personal and Family History • Neurocognitive Assessment • Neurological Status • Postural Stability • Symptoms ACUTE POST-INJURY FOLLOW-UP (CARE 1.0) (24 hrs; 48hrs; Asymptomatic; Unrestricted Return to Play (RTP); 6 mos) • Neurocognitive Assessment • Neurological Status • Postural Stability • Symptoms CUMULATIVE & PERSISTENT EFFECTS. (CARE 2.0) In-Person Exit Visit; Post-grad Online • Demographics • Personal and Family History • Neurocognitive Assessment • Neurological Status • Postural Stability • Symptoms • PROs • MROs (at academies only) LONG-TERM EFFECTS (CARE/SALTOS Integrated (CSI))Annual Online Assessment (at MSAs only); In-Person Research Visits • Demographics • Symptoms • Psychological health • PROs • MROs (at academies only)A subset of athletes at 6 of the CARE institutions underwent additional assessments including multimodal MRI, proteomic and genomic biomarker characterization, and head impact quantification (helmet-based sensors). Assessment time points for the ARC/pARC Neurocognitive and Behavioral Testing was done at Baseline, <48hrs Post-Injury, Cleared for Return to Play Progression (Asymptomatic), Unrestricted Return to Play, 7 days following Return to Play, and at >60 days after final game of junior year until end of collegiate career.Blood biomarker collection was done at Baseline, <48hrs Post-Injury, Cleared for Return to Play Progression (Asymptomatic), 7 days following Return to Play, and at >60 days after final game of junior year until end of collegiate career. Multi-modal MRI studies were done at Baseline, <48hrs Post-Injury, Cleared for Return to Play Progression (Asymptomatic), 7 days following Return to Play, and at >60 days after final game of junior year until end of collegiate career. However, please note that only athletes from one study performance site completed a multi-modal MRI study at baseline.

  Study phs002175

• Genome-wide genotyping and methylation data from Understanding Society

  Genome-wide genotyping and methylation data from Understanding Society. Please visit https://www.understandingsociety.ac.uk/ for further information.

  Study EGAS00001008417

• Germline RUNX1 Variation and Predisposition to Childhood Acute Lymphoblastic

  Somatic mutations of RUNX1, which encodes the myeloid and lymphoid transcriptional factor RUNX1, are common in both B- and T- acute lymphoid leukemia (ALL) and are associated with poor prognosis of T-ALL. However, there has been no comprehensive investigation of the pattern or prevalence of RUNX1 germline mutation in both B- and T-ALL. Here we report germline RUNX1 variants in 1.23% of B-ALL and 2.11% of T-ALL, identifying 31 unique variants in 62 B-ALL and 18 unique variants in 26 T-ALL children. The majority of frameshift and nonsense variants affected RUNX1 function in transcriptional regulation, hematopoiesis, and cellular proliferation. We identified JAK3 as the most frequent somatic mutation in T-ALL with RUNX1 variants. These results not only identify RUNX1 as a leukemia predisposition gene but also further underline the importance of germline genetic variants to the development of ALL

  Study EGAS00001005403

• The Mutational Landscape of CTCL and Sezary Syndrome

  Sezary syndrome is a leukemic and aggressive form of cutaneous T-cell lymphoma (CTCL) resulting from the malignant transformation of skin-homing central memory CD4+ T cells. To identify new genetic alterations involved in Sezary syndrome and CTCL transformation we performed whole-exome sequencing of tumor-normal sample pairs from 26 Sezary syndrome and 16 CTCL patients. These analyses revealed a distinctive pattern of somatic copy number alterations in Sezary syndrome including highly prevalent recurrent chromosomal deletions involving the TP53, RB1, PTEN, DNMT3A, and CDKN1B tumor suppressor genes. Mutation analysis identified a broad spectrum of somatic mutations involving key genes involved in epigenetic regulation (TET2, CREBBP, MLL3, BRD9, SMARCA4 and CHD3) and signaling, including mutations in MAPK1, BRAF, CARD11 and PRKG1 driving increased MAPK, NFKB and NFAT activity upon T-cell receptor stimulation. Collectively, our findings provide new insights into the genetics of Sezary syndrome and CTCL and support the development of personalized therapies targeting key oncogenically activated signaling pathways for the treatment of these diseases.

  Study phs000994

• Molecular stratification of endometrioid ovarian carcinoma predicts clinical outcome

  Endometrioid ovarian carcinoma (EnOC) is an under-investigated type of ovarian carcinoma. Here, we report the largest genomic study of EnOCs to date, performing whole exome sequencing of 112 cases following rigorous pathological assessment. High frequencies of mutation were detected in CTNNB1(43%), PIK3CA(43%), ARID1A(36%), PTEN(29%), TP53(26%) and SOX8(19%), a novel target of recurrent mutation in EnOC. POLE and mismatch repair protein-encoding genes were mutated at lower frequency (6%, 18%) with significant co-occurrence. A molecular taxonomy was constructed using a novel algorithm (PRISTINE), identifying clinically distinct EnOC subtypes: TP53m cases demonstrated greater genomic complexity, were frequently FIGO stage III/IV at diagnosis (48%) and incompletely debulked (44%), and demonstrated inferior survival; conversely, CTNNB1m cases demonstrated low complexity and excellent clinical outcome, were predominantly stage I/II at diagnosis (89%) and completely resected (87%). Tumour complexity provides further resolution within the TP53wt/CTNNB1wt group. Moreover, we identify the WNT, MAPK/RAS and PI3K pathways as good candidate targets for molecular therapeutics in EnOC.

  Study EGAS00001004366

• A plasma protein biomarker signature that differentiates acute rheumatic fever from related clinical presentations

  Acute Rheumatic Fever (ARF) is a systemic inflammatory condition triggered by Group A Streptococcus infection, with timely diagnosis critical to prevent Rheumatic Heart Disease. ARF pathogenesis is poorly understood and diagnosis is based on clinical criteria. Here, we compared ARF cases and well-defined controls from two Uganda cohorts. We identified a 5-protein signature that discriminates ARF patients from clinically-similar conditions (receiver operating characteristic-area under the curve (ROC-AUC)=1.0, n=18 definite ARF vs n=9 known alternate diagnosis; ROC-AUC=0.97, n=18 definite ARF vs n=13 unknown alternate diagnosis), which retained very good diagnostic value in a validation cohort (ROC-AUC=0.83 n=26 definite ARF vs n=13 unknown alternate diagnosis). Pathway analysis identified the epithelial-mesenchymal transition pathway as highly-associated with acute ARF, suggesting that tissue damage and repair is central to ARF pathogenesis. Our findings require further validation, yet highlight the potential for proteomics to identify clinically useful diagnostic biomarkers that would revolutionise ARF diagnosis and treatment.

  Study EGAS00001008381

• Dataset for NSCLC-RNA

  Rare cancer sequencing data of 45 runs in tumor/control pairs, which were uploaded to umbrella studies. The sequencing was always paired

  Dataset EGAD00001008846

• Reasons for Geographic and Racial Differences in Stroke Cardiorenal GWAS

  REGARDS is a national, population-based, longitudinal study of incident stroke and associated risk factors including over 30,000 Black and White adults aged 45 years or older from all 48 contiguous U.S. states and the District of Columbia. The study was designed to investigate reasons underlying the higher rate of stroke mortality among Black participants compared to White participants and among residents of the Southeastern U.S. compared to other U.S. regions. By design, Black adults and residents of the deep south were oversampled. Between 2003 and 2007 (baseline visit) participants completed a computer-assisted telephone interview to collect demographic information and medication adherence, and an in-home visit for blood pressure measurements and collection of blood and urine samples. Following the baseline visit, participants have been contacted by phone at six-month intervals to obtain information on incident stroke or secondary outcomes. Additionally, samples and data were collected on about 50% of the original cohort during a second study visit an average of 10 years after the baseline visit. Genotyping was performed as part of an ancillary study on 10,788 (84% Black) participants using Illumina MEGA arrays.

  Study phs002719

• Paired-end Whole Exome-seq analysis of the 3D evolution of glioma cell populations. Part 2.

  Dataset contains paired-end Whole Exome sequencing data from 257 glioma samples from 28 patients. 26 normal blood samples are also included.

  Dataset EGAD00001009496

• Osteoporotic Fractures in Men (MrOS)

  The Osteoporotic Fractures in Men Study (MrOS) is a multi-center prospective, longitudinal, observational study of risk factors for vertebral and all non-vertebral fractures in older men, and of the sequelae of fractures in men. The original specific aims of the study include: (1) to define the skeletal determinants of fracture risk in older men, (2) to define lifestyle and medical factors related to fracture risk, (3) to establish the contribution of fall frequency to fracture risk in older men, (4) to determine to what extent androgen and estrogen concentrations influence fracture risk, (5) to examine the effects of fractures on quality of life, (6) to identify sex differences in the predictors and outcomes of fracture, (7) to collect and store serum, urine and DNA for future analyses as directed by emerging evidence in the fields of aging and skeletal health, and (8) define the extent to which bone mass/fracture risk and prostate diseases are linked. The MrOS study population consists of 5,994 community dwelling, ambulatory men aged 65 years or older from six communities in the United States (Birmingham, AL; Minneapolis, MN; Palo Alto, CA; Monongahela Valley near Pittsburgh, PA; Portland, OR; and San Diego, CA). Inclusion criteria were designed to provide a study cohort that is representative of the broad population of older men. The inclusion criteria were: (1) ability to walk without the assistance of another, (2) absence of bilateral hip replacements, (3) ability to provide self-reported data, (4) residence near a clinical site for the duration of the study, (5) absence of a medical condition that (in the judgment of the investigator) would result in imminent death, and (6) ability to understand and sign an informed consent. To qualify as an enrollee, the participant had to provide written informed consent, complete the self-administered questionnaire (SAQ), attend the clinic visit, and complete at least the anthropometric, DEXA, and vertebral X-ray procedures. There were no other exclusion criteria. The baseline examination was completed over a 25-month period from March 2000 to April 2002. Participants completed questionnaires regarding medical history, medications, physical activity, diet, alcohol intake, and cigarette smoking. Objective measures of anthropometric, neuromuscular, vision, strength, and cognitive variables were obtained at a clinic visit. Skeletal assessments included DEXA, calcaneal ultrasound, and vertebral radiographs. Vertebral and proximal femoral QCT was performed on a subset (65%) of participants. Serum, urine, and whole blood specimens were collected. During the study period, participants complete a tri-annual questionnaire every four months that obtains information concerning the occurrence of incident falls and fractures. Follow-up is over 99% complete. All reported fractures are confirmed using physician review of radiology reports or study radiologist review of x-rays. All deaths are also centrally adjudicated using death certificates and recent hospitalization records. In additional to the baseline study visit and tri-annual questionnaires, all surviving active participants were invited to follow-up visits and questionnaires. A second comprehensive clinic visit was completed between March 2005 and May 2006 or about 4.5 years after baseline. Most baseline measures, including vertebral radiographs, were repeated at the second visit. A third comprehensive clinic visit was completed between March 2007 and March 2009 or about 7.0 years after baseline. Many baseline measures were repeated at the third visit. A measure of energy expenditure was also obtained utilizing an accelerometer based armband device. Surviving participants have also completed two extensive mailed questionnaires designed to updated information obtained at clinic visits. The first questionnaire was mailed between baseline and visit 2 between July 2002 and March 2004. The second questionnaire was mailed after the third questionnaire between March 2009 and February 2011. The MrOS Sleep Study, an ancillary study of the parent MrOS cohort, was conducted between December 2003 and March 2005 and recruited 3,135 MrOS participants for a comprehensive sleep assessment. Men were screened for nightly use of mechanical devices during sleep including pressure mask for sleep apnea (CPAP or BiPAP), mouthpiece for snoring or sleep apnea, or oxygen therapy and were generally excluded. The sleep visit included objective measures of sleep using actigraphy and polysomnography. Other measures at the sleep visit include neuropsychiatric measures, performance measures, health related questionnaires, routine exam measures previously completed at MrOS clinic visits and a urine and serum specimen collection. During the sleep study period, participants complete a tri-annual questionnaire every four months that contains information about incident cardiovascular events. All reported events are centrally adjudicated utilizing hospital records, study ECGs and other supporting documentation. The Hip Osteoarthritis study, another ancillary study of the parent MrOS cohort, was completed at the second clinic visit between March 2005 and May 2006. Participants were asked for consent for a hip x-ray and osteoarthritis measurements were obtained from these x-rays. DNA was extracted from baseline whole blood samples for use in genetic research. Consent for use of DNA was obtained through written consent. Raw GWAS data is housed at the study's coordinating center and not released as part of the dbGAP release. The raw data can be requested from the study's coordinating center. Only QC cleaned Plink files are available on dbGAP.

  Study phs000373