Search Results - EGA European Genome-Phenome Archive

Heart Failure Network - Effectiveness of Ultrafiltration in Treating People with Acute Decompensated Heart Failure and Cardiorenal Syndrome (HFN CARRESS - BioLINCC)

ObjectiveThe CARRESS trial examined the effectiveness of ultrafiltration compared with a strategy of diuretic-based stepped pharmacologic therapy on renal function and weight loss in patients with heart failure who have worsening renal function and persistent congestion.BackgroundAcute cardiorenal syndrome is defined as worsening renal function in patients with acute decompensated heart failure. It occurs in 25 to 33% of patients and is associated with poor outcomes. Current heart failure treatments focus on removing excess fluid buildup, however administration of intravenous diuretics may contribute to worsening renal function. Venovenous ultrafiltration is one alternative therapy that may be effective in patients with acute decompensated heart failure complicated by acute cardiorenal syndrome and persistent congestionSubjectsA total of 188 patients were randomized.DesignHospitalized subjects were randomly assigned to receive either ultrafiltration therapy or pharmacologic therapy. Ultrafiltration was performed at a fluid-removal rate of 200 ml per hour and loop diuretics were discontinued for the duration of the intervention. The addition of intravenous vasodilators or positive inotropic agents was prohibited, unless they were deemed to be necessary as rescue therapy. Patients assigned to stepped pharmacologic therapy received intravenous diuretics to manage congestion and maintain a urine output of 3 to 5 liters per day. In both groups, the assigned treatment strategy was to be continued until the signs and symptoms of congestion in the patient were reduced as much as possible. The primary end points were baseline changes in serum creatinine and weight as assessed at 96 hours after treatment assignment.ConclusionsThe use of a stepped pharmacologic-therapy algorithm was superior to a strategy of ultrafiltration for the preservation of renal function, and there was a similar amount of weight loss between the two groups. Ultrafiltration was associated with a higher rate of adverse events (Bart, et al., 2012, PMID: 23131078).

Study phs003510

Genomic Profiling of Pediatric Tumors by Cell Free DNA Sequencing

BACKGROUND Analysis of cell-free DNA (cfDNA) from peripheral blood has been studied extensively for detection and monitoring therapy response in adult cancers, but utility in pediatric tumors is unclear. METHODS We studied 233 children with hematologic, solid and brain tumors. cfDNA was extracted from 1 mL of plasma collected at diagnosis. Circulating tumor DNA (ctDNA) in cfDNA was quantified and diverse classes of somatic genomic variants were detected using PeCan-Seq. PeCan-Seq findings were compared with matched tumor whole-genome and whole-exome sequencing data. Minimal residual disease (MRD) status was evaluated by cfDNA PeCan-Seq in 14 patients with B-cell acute lymphoblastic leukemia. RESULTS Plasma cfDNA yields at diagnosis were higher for hematologic malignancies than for solid and brain tumors. Patients with hematologic malignancy were 100% ctDNA-positive, the median ctDNA fraction in cfDNA was 0.77. We detected 97% variants that were present in tumors and covered by the capture panel, and 50 subclonal variants that were present in cfDNA only. Our approach enabled detection of sequence and structural variants in B-ALL ctDNA at varying levels of MRD. Nineteen of 38 patients with solid tumors were ctDNA-positive, with high prevalence in Ewing Sarcoma, liver tumors and osteosarcoma. One of 19 brain tumor patients was ct-DNA positive, indicating lack of utility for plasma-derived cfDNA in this disease. Notably, cfDNA analysis of a single plasma sample identified genomic features in ctDNA derived from B-ALL, concurrent primary neuroblastoma, and a later neuroblastoma relapse, indicating that genomic variations from multiple tumors could be detected simultaneously. CONCLUSIONS Pediatric patients with hematologic malignancy had an abundance of plasma ctDNA at diagnosis. Plasma ctDNA levels varied between different solid tumor types, more studies are needed to determine utility. Panel-based cfDNA sequencing could serve as a non-invasive approach for pediatric cancer diagnosis and disease monitoring.

Study EGAS50000000072

Gene expression signatures associated with chronic endometritis revealed by RNA sequencing

Chronic endometritis (CE) is a persistent inflammatory condition of the endometrium characterized by the infiltration of plasma cells. CD138 immunohistochemistry is considered to improve the CE diagnosis rate. Using the number of CD138-positive cells equal or greater than five as a diagnostic criterion for CE, we identified 24 CE and 33 non-CE cases among women with infertility. We conducted RNA-sequencing analysis for these 57 cases in total as an attempt to elucidate the molecular pathogenesis of CE and to search for new biomarkers for CE. By comparing CE and non-CE groups, we identified 20 genes upregulated in the endometria of CE patients, including 12 immunoglobulin-related genes and eight non-immunoglobulin genes as differentially expressed genes. The eight genes were MUC5AC, LTF, CAPN9, MESP1, ACSM1, TVP23A, ALOX15, and MZB1. By analyzing samples in the proliferative and secretory phases of the menstrual cycle separately, we also identified four additional non-immunoglobulin genes upregulated in CE endometria: CCDC13 by comparing the samples in the proliferative phase, and OVGP1, MTUS2, and CLIC6 by comparing the samples in the secretory phase. Although the genes upregulated in CE may serve as novel diagnostic markers of CE, many of them were upregulated only in a limited number of CE cases showing an extremely high number of CD138-positive cells near or over one hundred. Exceptionally, TVP23A was upregulated in the majority of CE cases regardless of the number of CD138-positive cells. The upregulation of TVP23A in the endometria of CE cases may reflect the pathophysiology of a cell-type or cell-types intrinsic to the endometrium rather than the accumulation of plasma cells. Our data, consisting of clinical and transcriptomic information for CE and non-CE cases, helped us identify gene expression signatures associated with CE.

Study JGAS000621

Population Structure and Genetic Diversity in Argentinean populations

Argentina was one of the last places peopled when humans entered the Americas. Its earliest archeological sites are dated from 13,000 years BP, and throughout its history the region has exhibited broad cultural diversity, involving both hunter-gatherer and agro-pastoral societies, different linguistic families, the Southern expansion of the Inca Empire, the arrival of the Spanish conquistadors and slave trade from Africa. More recently, Argentina has had the highest proportion of influx of transoceanic migration between 1850 and 1940 of any Latin American country. Furthermore, the geographical distribution of immigrants was oriented towards the Pampa region of central-eastern Argentina and the Northeast, so different patterns of mixed ancestry throughout the country are expected. In this present work we aim to describe the history and structure of the Argentinean population. Thus far, we have collected DNA samples from 2904 participants from 15 dispersed regions in Argentina, from the Andean populations in the Northwest to the river lands of the Northeast. Our preliminary data includes genome-scale Illumina Exome Array 250K genotypes, plus next-generation sequencing data from uniformly spaced genomic regions targeted with a genotype-by- sequencing strategy (which covers 1.5% of the genome), for 375 participants from 9 of the 15 populations. We will identify proportions and patterns of European, African and Indigenous American ancestry in the Argentinean cohort via local ancestry inference. The first series of analyses will focus on genomic tracts of Indigenous American ancestry for fine-scale examination of sub-continental structure by comparing to a panel of 493 samples from 52 Indigenous American populations from throughout the Americas. Furthermore, this work will serve as a test of different low-cost strategies (exome genotype array vs. genotype-by-sequencing) for accurate inference of population structure in extant populations.

Study EGAS00001001663

Intra-tumor heterogeneity of localized lung adenocarcinomas defined by multi-region sequencing

Background: Intra-tumor heterogeneity (ITH) may have profound impacts on biopsy strategy, characterization of actionable targets, treatment planning, and drug resistance. ITH of lung cancers has not been well studied. Methods: We performed multi-region whole exome sequencing (average sequencing depth 277x) on 48 tumor regions from 11 resected lung adenocarcinomas (8 stage I, 2 stage II and one stage III tumors) followed by deep sequencing validation (average sequencing depth 863x). Results: All tumors showed clear evidence of spatial ITH. On average, 76% of all mutations and 20/21 known cancer gene mutations were present in all regions of individual tumors (trunk mutations). Copy number analysis did not show substantial difference in large-scale chromosome aberrations. A canonical KRAS p.G12C mutation was detected in only 1 of 4 tumor regions (branch mutations) at exome depth but detected in all four tumor regions (trunk mutations) at increased sequencing depth. In addition, many heterogeneous branch mutations defined by exome sequencing were detectable in all regions of individual tumors with increasing sequencing depth. Significant differences in mutational spectrum were observed in 6 tumors indicating that specific mutational processes were likely operative at different times during development of these tumors. With a median follow up of 21 months post surgery, 3 patients have relapsed and all 3 patients presented with significantly larger fractions of subclonal mutations in their primary tumors. Conclusions: Although multi-region sampling is still required to fully assess ITH complexity, single biopsy analysis at appropriate depth might be sufficient to identify the majority of known cancer gene mutations in localized lung adenocarcinomas. Larger subclonal mutation fractions may be associated with increased likelihood of postsurgical relapse in patients with localized lung adenocarcinomas. Studies on larger cohort, ideally with comprehensive clinical annotation and repeat biopsy at relapse are needed to fully understand the clinical impact of ITH.

Study EGAS00001000930

Bulk-RNA Sequencing of high-grade pancreatic and non-pancreatic Neuroendocrine Neoplasms

Therapeutic decisions in oncology depend on a precise pathological classification of individual neoplasms. Recent years have seen an intensification of research activities aimed at the extraction of clinically relevant information from patient-derived 'omics' data based on Machine-Learning models. However, a comprehensive training of Machine-Learning models requires sufficiently large numbers of training samples, which are usually not available for rare cancer types. The problem is worsened when individual tissues segregate into different cancer subtypes, as their discrimination would require even more training samples. Methods: Here, we report on a new data-augmentation technique to support the training of Machine-Learning models on ‘omics’ data from pancreatic neuroendocrine neoplasms (panNEN). PanNENs display all properties described above: Only about 2-3% of all pancreatic neoplasms are neuroendocrine and they fall into different subtypes with distinctly different prognosis, which makes the precise classification of such samples both difficult and important for therapy decisions. The approach reconstructs a given transcriptome based on healthy pancreatic cell type signatures and creates a Machine-Learning model that integrates the observed reconstruction error and predicted cell type proportions as features. Results: A benchmark of the deconvolution model predictions with the ground-truth found that the model could efficiently predict the sample grading, disease-related patient survival time, and differentiate between different subtypes in four panNEN and one mixed panNEN and non-pancreatic NENs dataset. We compared the predictive performance of the deconvolution-trained model to that of a model trained directly on the transcriptomic data, under inclusion of the Ki-67 classification gold standard biomarker, and found the performances to be comparable. Conclusion: Our approach serves as a data-augmentation technique to facilitate the training of Machine Learning models for rare cancer types via utilization of data from healthy origin. Additionally, the deconvolution results were clinically interpretable and further research can render the deconvolution approach an effective complementary asset for the clinical classification of neoplasms.

Study EGAS00001004861

Reduced Representation Bisulfite Sequencing (RRBS) in various tissues to discover DNA methylation markers for the diagnosis of breast and ovarian cancer.

Despite a myriad of attempts in the last three decades to diagnose ovarian cancer (OC) earlier, this clinical aim still remains a significant challenge. In addition, monitoring treatment and early detection of fatal breast cancer (BC) remains a major unmet need. Aberrant methylation patterns of linked CpGs analyzed in DNA fragments shed by cancers into the bloodstream (i.e. cell-free DNA) can provide highly specific signals indicating cancer presence.In order to discover the most relevant CpG regions, we used RRBS and analysed several tissue samples: 11 prospectively collected invasive epithelial ovarian cancer samples (high grade serous n=8, low grade serous n=1, endometrioid n=1, mucinous n=1, mean age = 54.7 years), 8 prospectively collected invasive ductal breast cancer samples (2/8 triple negative; mean age = 56.6 years), one benign tumor (papillary serous cystadenoma, age = 86 years), 18 non-neoplastic tissue samples (breast n=7 and adnexal n=11, mean age = 60.2 years), two non-neoplastic endometrial tissues (mean age = 68 years) and twenty three white blood cell samples (mean age = 57.8 years) were assessed by RRBS. Genome wide methylation analysis was performed by Reduced Representation Bisulfite Sequencing (RRBS) at GATC Biotech. DNA was digested with MspI followed by size selection of the library, providing enhanced coverage for the CpG-rich regions. The digested DNA was adapter ligated, bisulfite modified and PCR amplified. The libraries were sequenced on Illumina’s HiSeq 2500. Analysis of the first samples sequenced with 100bp paired-end mode showed that the library insert size was small. Therefore, the remaining samples were sequenced with 50 bp paired-end mode. Using Genedata Expressionist® for Genomic Profiling v9.1, we established a bioinformatics pipeline for the detection of cancer specific differentially methylated regions (DMRs). The most promising DMRs were taken forward for the development and validation of serum based clinical assays.

Study EGAS00001002609

The Human Virome in Children and its Relationship to Febrile Illness

Definition of the human microbiome is an important scientific priority. This study will expand the scope of the investigation to include viruses, which account for a substantial proportion of infectious disease morbidity and mortality, especially in children. The long-term goal of this project is to describe the human virome in children and to investigate its relevance to febrile illnesses in children. The project will also seek to understand the relationship of the immune system to the composition of the virome. Thus, the project's specific aims are 1) To elucidate the spectrum of viruses that can be detected using non-biased, high throughput sequencing on samples of blood, respiratory, and gastrointestinal secretions from healthy children and to use this information as a basis for understanding the role of viruses in acute febrile illnesses without an obvious source, and 2) to investigate the effect of various forms of immunosuppression on the spectrum of viruses detected in children, and to use this information as a basis for understanding the role of viruses in acute febrile illnesses occurring in these children. Our preliminary studies show that diverse viruses can be detected in children having undiagnosed fever. To carry out the specific aims, well children will be enrolled prior to having elective surgery, and febrile otherwise well children will be enrolled from the Emergency Department at St. Louis Children's Hospital. Immunocompromised children will be recruited from hematopoietic stem cell and solid organ transplant clinics, the HIV/AIDS clinic, and the rheumatology/immunology clinic from the same hospital. Children with fever will have samples obtained at the time of the febrile illness and at 1 and 6-month follow-up visits. Selected samples from each study group will be analyzed at the Genome Center at Washington University (GCWU) using next generation 454 high throughput sequencing to detect and sequence all viral sequences present. We anticipate detecting and sequencing a broad range of viruses, including previously unrecognized agents. A variety of techniques will be used to investigate the significance of viruses detected. Virus-specific PCR assays will be used to determine the frequency and extent of viruses detected by sequencing, using the full range of samples collected. Host response to the detected viruses will be investigated using serologic analysis, cytokine profiling, and microarrays to characterize host gene expression. These studies will take advantage of follow-up samples to compare the acute response with the response in the convalescent period. This study will draw upon the expertise and technological assets of one of the world's most powerful sequencing centers to provide the research community with a comprehensive sequence data base of the viruses that are present in children, which can be used to improve our understanding of the causes of febrile illnesses in young children, many of which are currently undiagnosed.

Study phs000264

Thymic epithelial transplantation for complete DiGeorge syndrome: RNA (2025-07-22)

Single cell transcriptomics study of thymic transplant biopsies Allogeneic thymus transplantation is the only curative therapy for complete DiGeorge Syndrome (cDGS), a rare severe primary immunodeficiency characterised by athymia. GOSH is one of only two centres worldwide to offer this treatment. Despite a lack of major histocompatibility complex (MHC)-matching between donor and host, transplanted thymus becomes repopulated by recipient bone marrow derived precursor cells and supports development of functional T-cells. The mechanisms underlying thymopoiesis in this context are poorly understood, but over time we observe reconstitution of T-cell immunity, with the ability to produce host naïve T-cells showing a broad T-cell receptor (TCR) repertoire and to generate MHC-restricted T-cell proliferative responses. Although lifesaving, the achieved immunological reconstitution is typically not complete with circulating T-cell numbers usually remaining below the age related normal ranges. Additionally, we observe persistence of donor-derived T-cells of unknown clinical significance. To gain more insight into the mechanisms by which MHC-mismatched transplanted thymus supports T-cell development with self-tolerance, as well as into the basis of suboptimal T-cell immunity, we now aim to investigate immune reconstitution after thymus transplantation in further detail by using single-cell transcriptomics, applied to thymic transplant biopsies and peripheral blood samples collected during standard post-transplant patient care. By identifying which lineages of host- derived cells repopulate the thymic tissue after transplantation, we will be able to address the role of MHC in positive and negative T-cell selection during T-cell differentiation. We will also be able to clarify the exact ontogeny of the persistent donor T-cells, as well as their possible role. Understanding the mechanisms of action of HLA-mismatched transplanted thymus will contribute to treatment optimisation. Additionally, our research provides a unique opportunity to further investigate key immunological concepts, such as tolerance and autoimmunity, challenging existing paradigms in thymus immunology. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/ . This dataset contains all the data available for this study on 2025-07-22.

Dataset EGAD00001015648

Kids First: Genomic Studies of Orofacial Cleft Birth Defects

The Gabriella Miller Kids First Pediatric Research Program (Kids First) is a trans-NIH effort initiated in response to the 2014 Gabriella Miller Kids First Research Act and supported by the NIH Common Fund. This program focuses on gene discovery in pediatric cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource). Both childhood cancers and structural birth defects are critical and costly conditions associated with substantial morbidity and mortality. Elucidating the underlying genetic etiology of these diseases has the potential to profoundly improve preventative measures, diagnostics, and therapeutic interventions. WGS and phenotypic data from this study are accessible through dbGaP and kidsfirstdrc.org, where other Kids First datasets can also be accessed. The Kids First study of nonsyndromic orofacial cleft birth defects (OFCs) is a whole genome sequencing study of 415 White parent-case trios drawn from ongoing collaborations led by Dr. Mary L. Marazita of the University of Pittsburgh Center for Craniofacial and Dental Genetics, including collaborations with Dr. George Wehby of the University of Iowa, Dr. Jacqueline Hecht of the University of Texas, and Dr. Terri Beaty of Johns Hopkins University. Sequencing was done by the Washington University McDonell Genome Institute. The case in each of the Kids First trios has cleft lip (CL, Figure A), cleft palate (CP, Figure B), or both (CL+CP, Figure C): OFCs are genetically complex structural birth defects caused by genetic factors, environmental exposures, and their interactions. OFCs are the most common craniofacial anomalies in humans, affecting approximately 1 in 700 newborns, and are one of the most common structural birth defects worldwide. On average a child with an OFC initially faces feeding difficulties, undergoes 6 surgeries, spends 30 days in hospital, receives 5 years of orthodontic treatment, and participates in ongoing speech therapy, leading to an estimated total lifetime treatment cost of about $200,000. Further, individuals born with an OFC have higher infant mortality, higher mortality rates at all other stages of life, increased incidence of mental health problems, and higher risk for other disorders (notably including breast, brain, and colon cancers). Prior genome-wide linkage and association studies have now identified at least 18 genomic regions likely to contribute to the risk for nonsyndromic OFCs. Despite this substantial progress, the functional/pathogenic variants at OFC-associated regions are mostly still unknown. Because previous OFC genomic studies (genome-wide linkage, genome-wide association studies (GWAS), and targeted sequencing) are based on relatively sparse genotyping data, they cannot distinguish between causal variants and variants in linkage disequilibrium with unobserved causal variants. Moreover, it is unknown whether the association or linkage signals are due to single common variants, haplotypes of multiple common variants, clusters of multiple rare variants, or some combination. Finally, we cannot yet attribute specific genetic risk to individual cases and case families. Therefore, the goal of the current study is to identify specific OFC risk variants in Whites by performing whole genome sequencing of parent-case trios.

Study phs001168

Long-Term Outcome in Offspring and Mothers of Dexamethasone-Treated Pregnancies at Risk for Classical Congenital Adrenal Hyperplasia Owing to 21-Hydroxylase Deficiency

Summary The purpose of this study is to perform the first long-term follow up study both of adolescents and young adults with a history of prenatal treatment with dexamethasone and of their mothers and to test for adverse medical or behavioral side effects. The emphasis will be on the outcome of this prenatal treatment in those fetuses who are not affected with steroid 21-hydroxylase deficiency (21OHD) form of congenital adrenal hyperplasia (CAH) and are either heterozygotes or homozygote-unaffected. Prenatal treatment of 46,XX fetuses with 21OHD (via administration of dexamethasone to the pregnant mother) has been shown to reduce the masculinization of the genitalia and, thereby, the later need for 'corrective' feminizing genital surgery and potential impairment of sexual functioning. Along with the suppression of excess prenatal androgen production and reduction of prenatal masculinization of the genitalia in 46,XX fetuses with 21OHD, prenatal dexamethasone treatment may reduce the behavioral masculinization that is well documented in untreated 46, XX patients with 21OHD. Those fetuses who are partially treated until diagnosis of an unaffected status (heterozygous or homozygous-unaffected) will be studied as well. This latter group is of importance because these fetuses are being unnecessarily treated, but we have no way of diagnosing the unaffected status before the 8th week of gestation when treatment must begin for the female fetus who is affected. As treatment is necessary only until term in the female fetus affected with classical CAH, male fetuses and unaffected or heterozygous female fetuses do not require treatment. Thus, only one out of eight fetuses will require prenatal treatment until term. Findings of adverse effects of glucocorticoid treatment in non-human mammals [1, 2] have raised concerns among other clinicians and investigators about potential adverse side effects of such treatment on the developing human. Thus, this study will address this concern and investigate the potential adverse side effects of prenatal treatment. Detailed Description Females with classical CAH owing to 21-hydroxylase deficiency are born with ambiguous genitalia due to the production of excess androgens in utero. Prenatal treatment with dexamethasone was inaugurated in 1978 by Maguelone Forest and has been the standard of practice in the United States since 1986. Dexamethasone, which crosses the placental barrier, suppresses the fetal adrenal gland production of androgens, thus preventing ambiguous genitalia in the affected female. Children of both sexes are prenatally treated as soon as pregnancies at risk are confirmed. Treatment in females with 21OHD continues to term, but is discontinued in males and unaffected females. To date, 685 pregnancies have been diagnosed, of which 366 fetuses were treated. These investigators will study prenatally treated adolescents and adults 12 years and older with respect to medical and behavioral outcomes (see Table 5). In addition, mothers of children prenatally treated for varying periods of time for suspected 21OHD will be studied for long-term side effects of dexamethasone treatment administered during pregnancy. The long-term outcome in these children and their mothers has never before been studied.

Study phs001317

The Genomic Landscape of Mongolian Hepatocellular Carcinoma

Background and Hypotheses: Mongolia has the highest reported incidence of - and mortality from - hepatocellular carcinoma (HCC) in the world, which is between three and seven times higher than that observed in other high-incidence populations, such as South Korea, Thailand, and China. Although its causative factors and underlying tumor biology remain unknown, risk factors such as chronic hepatitis B virus and/or hepatitis C virus infection are highly prevalent. Moreover, Mongolia has an extraordinarily high prevalence of hepatitis delta virus (HDV), more than ten times above the global estimate, which we hypothesize as a major driver of Mongolian hepatocarcinogenesis. By performing a comprehensive and integrative genomic characterization, we aimed to identify robust molecular subclasses and driver features informative of the etiology and progression of the disease. This study, the first one of this nature ever to be conducted on a Mongolian cohort, identifies similarities to previous studies performed on other populations (which reflect general characteristics of liver carcinogenesis) as well as unique features of Mongolian HCC. Study Design and Methods: Clinical information and paired tumor/non-tumor liver tissue samples were obtained from 76 HCC patients undergoing surgery at the National Cancer Center of Mongolia. Transcriptome sequencing and whole exome sequencing were performed on all tumor and non-tumor samples, followed by bioinformatics processing and quality control. Consensus clustering and regularized Cox regression analyses were performed on transcriptome data. Driver mutations and mutational signatures were assessed. These results were compared to those from 373 HCC patients of different races and ethnicities and diverse etiologies. Furthermore, molecular subclass gene signatures from multiple previous studies were assessed for validation. Results and Conclusions: Using a transcriptomics-based unsupervised approach, we identified four molecular subclasses among Mongolian HCC cases, which were associated with different patient survival outcomes. These molecular subclasses were mapped to signatures reported in other HCC cohorts, showing significant associations consistent with survival outcomes. A supervised analysis determined risk scores strongly associated with survival, consistent with the four molecular subclasses. Mutational signature analysis using recently published COSMIC and Environmental Agents Compendia identified signatures with distinct prevalence among HDV+ and HVD- groups. Signatures differentially associated with HDV+ include mutational patterns linked to alkylating agents (such as temozolomide), tobacco chewing and exposures to 1,8-Dinitropyrene and furan, whereas HDV- appeared differentially associated with aristolochic acid II. In addition to common driver mutations (TP53, CTNNB1) frequently found in pan-cancer analysis, Mongolian HCC exhibits several unique drivers (most notably GTF2IRD2B, PNRC2, and SPTA1), the latter of which may be linked to HDV infection. These results suggest the existence of new molecular mechanisms at play in Mongolian hepatocarcinogenesis.

Study phs002000

INCLUDE: The Epidemiology of Transient Leukemia in Newborns with Down Syndrome

The INCLUDE (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE) Project is an NIH-wide collaboration that seeks to improve health and quality-of-life for people with Down syndrome. The INCLUDE Project Data Coordinating Center and partners created the INCLUDE Data Hub, a centralized data resource that allows access to large-scale clinical and multi-omics datasets specific to Down syndrome and supports collaborative, cloud-based analysis to accelerate scientific discoveries related to Down syndrome and its co-occurring conditions.Down syndrome (DS) is associated with a remarkably high risk of childhood acute myeloid leukemia (AML), with an approximately 500-fold increased risk of the rare subtype acute megakaryoblastic leukemia. Though largely treatable, a proportion of myeloid leukemia in DS (ML-DS) patients relapse with dismal survival. ML-DS is preceded by a preleukemia, transient abnormal myelopoiesis (TAM), which presents clinically at birth and is driven by somatic truncating mutations in the erythro-megakaryocytic transcription factor gene GATA1. Up to 15% of DS newborns have TAM, and this can be fatal in up to 20% of cases. A further 10-15% of newborns with DS harbor subclonal GATA1 mutations with clinically silent disease (i.e., Silent TAM). Of the DS newborns with either TAM or Silent TAM (i.e., transient leukemia), up to 15% will acquire additional somatic mutations and progress to ML-DS. We predict that germline variation modifies the risk of developing somatic truncating GATA1 mutations, the first step towards ML-DS, however this has yet to be examined. To address this, the main aim of this X01 study is to perform the first genetic association study of GATA1 mutations in DS, through whole-genome sequencing (WGS) of 470 DS newborns in the Oxford Down Syndrome Cohort Study (ODSCS). Targeted sequencing of GATA1 has already been performed in the 470 DS newborns in the ODSCS, with 130 (28%) confirmed to harbor a somatic truncating GATA1 mutation. We will perform a genome-wide association study (GWAS) of GATA1 mutations to assess genetic variation genome-wide, in particular focusing on variants in candidate genes on the trisomic chromosome 21, RUNX1, ERG, ETS2, and DYRK1A, which have previously been associated with upregulation of GATA1. We will also carry out a chromosome X-wide association study (XWAS) to investigate genetic variation at the GATA1 gene, which resides on chromosome X. WGS data will also enable us to assess the potential role of copy number variation in the risk of transient leukemia in DS. Discovering genetic risk factors for GATA1 mutations in DS may reveal targets for new targeted therapies for TAM, and also inform the etiology of ML-DS as well as AML in the non-DS population. Finally, the ODSCS includes rich phenotypic data for the 470 DS newborns, including clinical diagnosis of TAM and other hematologic complications, complete blood counts, maternal pregnancy complications, and information on congenital heart disease and other birth defects. Thus, whole genome sequencing data in DS newborns from the ODSCS will provide a rich resource for the DS research community.

Study phs002982

The EGA joins EUCAIM, the European project powering AI and imaging in cancer research

EUCAIM (EUropean Federation for CAncer IMages) is the cornerstone of the European Cancer Imaging Initiative, one of the flagships of the Europe’s Beating Cancer Plan (EBCP). The European Genome-Phenome Archive (EGA), as member of the EUCAIM consortium, attended the kick-off meeting organized this week in Brussels for the launch of the Initiative. The EGA will contribute to the project with the experience gained in the deployment of our federated network, the Federated EGA (FEGA), and the experience gained as partners of EuCanImage (AI4HI initiative) contributing to the definition of common data models, ontologies and data standards. The ultimate goal of the project is to unlock the power of imaging and Artificial Intelligence for the benefit of cancer patients, clinicians and researchers. The consortium will deploy a pan-European digital federated infrastructure hosting cancer-related images, and associated pathology, molecular and laboratory data from Real-World. This endeavour will provide a comprehensive dashboard for imaging data discovery, federated search, metadata harvesting, annotation and distributed data processing. EUCAIM joins 76 partners, gathering the experience and previous effort made by the different repositories of the AI4HI initiative, European Research Infrastructures and national/regional repositories. Find out more information about the EUCAIM launch here

Blog the-ega-joins-eucaim

Development, maturation and maintenance of human prostate inferred from somatic mutations

Stem cells within prostate epithelium frequently undergo malignant transformation, but there is limited information on their clonal dynamics and mutation burden in healthy human prostates. We sequenced whole genomes from 409 microdissections of prostate epithelium across 8 donors, using phylogenetic reconstruction with spatial mapping in a 59-year-old man’s prostate to provide high-resolution reconstruction of tissue dynamics across the lifespan. Somatic mutation burden increases linearly with age, at ~16 mutations/year/clone, and is higher in peripheral than peri-urethral regions. The 24-30 independent glandular subunits are established as rudimentary ductal structures during fetal development by 5-10 embryonic cells each. Puberty induces formation of further side branches and terminal acini by local stem cells disseminated through the rudimentary ducts during development. During adult tissue maintenance, clonal expansions are small, with limited geographic scope and minimal migration. Driver mutations are rare in normal ageing prostate epithelium, but the one canonical driver we did observe generated a sizable intraepithelial clonal expansion. By resolving unbiased, continuously occurring lineage-marking mutations, we define stem cell dynamics through embryogenesis, puberty and ageing, with relevance for prostate cancer.

Dataset EGAD00001006591

Ethiopia Genome Project (high coverage)

The Ethiopian area stands among the most ancient ones ever occupied by human populations and their ancestors. Particularly, according to archaeological evidences, it is possible to trace back the presence of Hominids up to at least 3 million years ago. Furthermore, the present day human populations show a great cultural, linguistic and historic diversity which makes them essential candidate to investigate a considerable part of the African variability. Following the typing of 300 Ethiopian samples on Illumina Omni 1M (see Human Variability in Ethiopia project, previously approved by the Genotyping committee) we now have a clearer idea on which populations living in the area include the most of the diversity. This project therefore aims to sequence the whole genome of 300 individuals at low (4-8x) depth belonging to the six most representative populations of the Ethiopian area to produce a unique catalogue of variants peculiar of the North East Africa. Furthermore 6 samples (one from each population) will also be sequenced at high (30x) depth to ensure full coverage of the diversity spectrum. The retrieved variants will be of great help in evaluating the demographic dynamics of those populations as well as shedding light on the migrations out of Africa.

Dataset EGAD00001000696

P647 Targeted resequencing project

In collaboration with Dr Robert Semple we have identified a family harbouring an autosomal dominant variant, which leads to severe insulin resistance (SIR), short stature and facial dysmorphism. This family is unique within the SIR cohort in having normal lipid profiles, preserved adiponectin and normal INSR expression and phosphorylation. DNA is available for 7 affected and 7 unaffected family members across 3 generations. All 14 samples have been genotyped using microsatellites and the Affymetrix 6.0 SNP chip. Linkage analysis identified an 18.8Mb haplotype on chromosome 19 as a possible location of the causative variant. However, Exome sequencing of 3 affected and 1 unaffected family members has not identified the causative variant suggesting the possibility of an intronic or intergenic variant in this region or elsewhere in the genome. We propose to conduct whole genome sequencing of 5 members of the pedigree at a depth of 20X. The chosen samples are two sets of parents plus one member of an unaffected branch of the pedigree who shares the risk haplotype on chromosome 19. Sequencing of the two sets of parents will be used along with the genome-wide SNP data to impute 4 affected children giving an effect sample size of 6 affected individuals.

Dataset EGAD00001000383

Partner independent fusion gene detection by multiplexed CRISPR Cas9 enrichment and long read Nanopore sequencing (FUDGE)

Targeted long-read nanopore sequencing. Abstract: Fusion genes are hallmarks of various cancer types and important determinants for diagnosis, prognosis and treatment. Fusion gene partner choice and breakpoint-position promiscuity restricts diagnostic detection, even for known and recurrent configurations. To accurately and impartially identify fusions, we developed FUDGE: FUsion Detection from Gene Enrichment. FUDGE couples target-selected and strand-specific CRISPR/Cas9 activity for fusion gene driver enrichment - without prior knowledge of fusion partner or breakpoint-location – to long-read Nanopore sequencing with the bioinformatics pipeline NanoFG. FUDGE has flexible target-loci choices and enables multiplexed enrichment for simultaneous analysis of several genes in multiple samples in one sequencing run. We observe on-average 665 fold breakpoint-site enrichment and identify nucleotide resolution fusion breakpoints - within two days. The assay identifies cancer cell line and tumor sample fusions irrespective of partner gene or breakpoint-position. FUDGE is a rapid and versatile fusion detection assay, providing unparalleled opportunity for diagnostic pan-cancer fusion detection.

Dataset EGAD00001006111

Ethiopia Genome Project (low coverage)

The Ethiopian area stands among the most ancient ones ever occupied by human populations and their ancestors. Particularly, according to archaeological evidences, it is possible to trace back the presence of Hominids up to at least 3 million years ago. Furthermore, the present day human populations show a great cultural, linguistic and historic diversity which makes them essential candidate to investigate a considerable part of the African variability. Following the typing of 300 Ethiopian samples on Illumina Omni 1M (see Human Variability in Ethiopia project, previously approved by the Genotyping committee) we now have a clearer idea on which populations living in the area include the most of the diversity.This project therefore aims to sequence the whole genome of 300 individuals at low (4-8x) depth belonging to the six most representative populations of the Ethiopian area to produce a unique catalogue of variants peculiar of the North East Africa. Furthermore 6 samples (one from each population) will also be sequenced at high (30x) depth to ensure full coverage of the diversity spectrum.The retrieved variants will be of great help in evaluating the demographic dynamics of those populations as well as shedding light on the migrations out of Africa.

Dataset EGAD00001000598

Epidemiological study comparing rates and risk factors for dementia in African Americans in Indianapolis and Yoruba living in Ibadan, Nigeria

In 1991 collaboration between researchers at Indiana University School of Medicine and the University of Ibadan, Ibadan, Nigeria established the Indianapolis-Ibadan Dementia Project. It is a longitudinal, prospective population-based comparative epidemiological study of the prevalence and incidence rates and risk factors of Alzheimer's disease and other age associated dementias. The project compares samples of community-dwelling elderly (age > 70 years) African Americans living in Indianapolis to Yoruba living in Ibadan, Nigeria, employing the same research design, methods, and investigators. It initially reported significantly lower prevalence rates of disorders in the Yoruba compared to the African Americans. In subsequent waves of the study (1994-1995, 1997-1998) incidence rates, rates of newly diagnosed cases, were also found to be significantly lower in the Yoruba. In genetic studies, the frequency of the APOE 4 allele was about the same in the two groups. APOE 4 was a significant risk factor for Alzheimer's disease and dementia in the Americans, while no association was found for the Yoruba. The APOE 2 allele appears to be protective in the Americans, but not the Yoruba. A constellation of factors often associated with vascular risk including a history of hypertension, diabetes, and high cholesterol levels is less common in the Yoruba than in the American group. An interaction was observed between cholesterol, APOE genotype and Alzheimer's disease in both study groups. In 2001-2002 survivors of the original cohort were once again evaluated (N~800 in each site) and 2,000 additional individuals age 70 years and older were enrolled in each site. Blood samples were collected from approximately 1,500 study participants in each site for genetic studies and analysis of biochemical risk factors for vascular disease. Subsequent waves of field work were conducted in 2004, 2007, 2009, and 2011. This fieldwork followed the classic two-stage study design. The study design involves an in-home screening interview with the study participant, which includes a cognitive assessment, medical history and current medications, brief neurological examination, height and weight, blood pressure measurement and assessment of social involvement. There is also a screening interview with a close relative of the study participant to assess activities of daily living, personality change, and medical history of the study participant. On the basis of the screening interview a sample of study participants (N~500 in each site) is selected for a full clinical diagnostic dementia work up which includes a neurological test battery, extensive interview with a family member and examination by a clinician. Diagnoses are made in a consensus diagnosis conference using the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III R) and International Classification of Diseases 10th Revision (ICD-10) for dementia. The criteria of the National Institute for Neurological and Communicative Disease and Stroke-Alzheimer's Disease and Related Disorders Association were used to diagnose possible and probable Alzheimer's disease. The focus of the study is risk factors for dementia and Alzheimer's disease, but also of particular importance is the question of mild cognitive impairment. This refers to the condition of having some decline in cognition but the decline is not sufficient to meet the criteria for dementia. We have studied this over the course of this project. In follow up studies of individuals who have this diagnosis about one third of them are better at follow up, about a third are about the same, and about a third decline more to meet the criteria for dementia. This is a very important issue for researchers because the ultimate goal of the research is to figure out how to identify the individuals who will definitely progress to dementia. If there are clear identifiers, it would be possible to make interventions, while individuals still function well, and possibly prevent the development of dementia altogether or delay the onset significantly. This is crucial because at the moment individuals usually do not enter into the medical care system until the dementia symptoms are quite severe, and the pathological damage to the brain cannot be undone.

Study phs000378

DKFZ-HIPO Data Access Committee of Heidelberg Center for Personalized Oncology

Dac EGAC00001000452

A Study to Assess the Cardiovascular, Cognitive, and Subjective Effects of Atomoxetine in Combination with Intravenous Methamphetamine

The Study to Assess the Cardiovascular, Cognitive, and Subjective Effects of Atomoxetine in Combination with Intravenous Methamphetamine started in 2007 and ended in 2011. It was a small pilot study that included methamphetamine abusing individuals and healthy control participants aged 18-50 years. Participants who qualified over the telephone were scheduled to visit the London Laboratory at the UCLA Semel Institute for Neuroscience and Human Behavior for the In-Person Screening Phase. The screening procedures, usually scheduled over two visits, determined if participants were eligible to complete the subsequent study visits. Both groups completed identical screening procedures, including a SCID diagnostic interview to rule out any major psychiatric disorders. Methamphetamine users also answered questionnaires specific to their drug use. Urine toxicology for marijuana, opiates, cocaine, methamphetamine, and benzodiazepines were monitored at the beginning and throughout the study. Additionally, participants had blood samples to test for Rapid Plasma Reagin (exposure to syphilis), purified protein derivative (PPD), HIV and Hepatitis-C (HCV). Positive test results were relayed by a study physician and resulted in termination from continuing in the study. The inpatient portion of the study lasted a total of 24 days. To confirm compliance with abstinence from illicit and prescription drug use for the duration of the study, urine and breath alcohol testing was performed for both inpatient (methamphetamine users) and outpatient (healthy control) groups. Each subject was randomized to receive either atomoxetine (80 mg daily) or placebo. During inpatient days of the study, a study physician oversaw research subjects daily and experimental procedures were conducted in the General Clinical Research Center (GCRC). During drug administration sessions, heart rate and blood pressure were assessed at frequent intervals. Experimental sessions lasted around three hours and were conducted at approximately the same time of day for a given participant. Lunch was provided to participants at 11:30am with the prohibition of caffeine on study days involving methamphetamine administration. Participants were provided with smoke breaks as needed to assure that acute nicotine withdrawal did not negatively impact performance on cognitive testing. The following outlines the day to day procedures for a methamphetamine inpatient: Phase I Inpatient Study (15 days total) Days 1-3: On the day of admission, participants received blood tests and an EKG in order to determine that they had no occult medical conditions which would make their participation in the study medically contraindicated. A three day washout period was provided at the beginning of the study to establish an appropriate methamphetamine-free baseline for testing. Days 4-6: Participants completed cognitive test batteries to assess inhibitory control including self-report measures and cognitive testing, as well as up to three MRI scanning sessions. Day 7: On day 7, at 9AM and 1PM, participants received methamphetamine in a single-blinded condition. It was administered as two IV infusions of 15mg separated by a 60min break. The total dose of IV methamphetamine was 30mg. Participants were clinically evaluated by continuous cardiac telemetry, serial EKG and measurement of vital signs, during and after infusions, in order to determine the medical safety of methamphetamine infusion in the absence of study medication. Day 8: On day 8 we evaluated the safety and residual effects of the methamphetamine administered on the previous day. Days 9-10: After demonstrating medical and psychiatric stability of the initial methamphetamine infusion, participants were then randomized to receive placebo or atomoxetine (0 or 40mg) under double-blind conditions, which would be given at 8AM on both study days. Days 11-12: On days 11 and 12, participants remained in the GCRC and took two doses of test compound atomoxetine (0 or 40mg) at 8AM and 8PM. On the morning of day 12, participants completed a series of cognitive testing. Day 13: On day 13, participants remained in the GCRC, and took two doses of the test compound atomoxetine (0 or 40mg) at 8AM and 8PM. At 9AM and noon, they received methamphetamine under double-blind conditions administered non-contingently as two infusions of 0 or 15mg by IV (intravenously), with each infusion separated by 60min. The total dose of IV methamphetamine that each participant received was 30mg. As before, participants were clinically evaluated by continuous cardiac telemetry, serial EKG and measurement of vital signs, during and after infusions, in order to determine the medical safety of methamphetamine infusion in those participants receiving study medication. Day 14: On day 14 at 8AM, participants received their final dosing of the first test compound (atomoxetine 0 or 40mg). At 9AM and 1PM, participants selected between methamphetamine infusion or money using double-blind conditions in a multiple-choice self-administration paradigm. Participants were able to take up to two infusions of 0 or 15mg of methamphetamine, separated by 60min. The total dose of IV methamphetamine that each participant received on day 14 was 30mg. Participants were clinically evaluated by continuous cardiac telemetry, serial EKG and measurement of vital signs, during and after infusions, in order to determine the medical safety of methamphetamine infusion in those participants receiving study medication. At 5pm on day 14 discharge laboratory studies were drawn. Day 15: On day 15, a final EKG was performed as well as a review of discharge laboratory studies, including review of the EKG and continued medical and psychiatric stability. Upon clearance from a physician, participants were discharged on day 15. Participants spent at least 2 weeks (14 days) out of the hospital prior to returning to the UCLA GCRC for inpatient Phase II. Phase II Inpatient Study (9 days total) Day 1-2: On the day of re-admission, participants received blood tests and an EKG. A two day washout period was provided at the beginning of the study to establish an appropriate methamphetamine free condition for safe administration of the second test compound condition. Days 3-4: On days 3 and 4, given medical stability, participants were then switched to the opposite test compound (atomoxetine 0 or 40mg) under double-blind conditions, in the same manner as in Days 9-10 in Phase I. Days 5-6: Same procedure as in Days 11-12 in Phase I but with opposite medication condition. Day 7: Same procedure as in Day13 in Phase I but with opposite medication condition. Day 8: Same procedure as in Day14 in Phase I but with opposite medication condition. Day 9: Same procedure as in Day14 in Phase I but with opposite medication condition. For healthy control participants, the study consisted of 30 days or fewer of out-patient testing. Healthy control participants had an extensive screening, including a history and physical exam performed by a study physician, an EKG, and laboratory studies performed to assess for medical or psychiatric conditions. Control participants meeting criteria were invited back to UCLA to undergo cognitive testing, and some participants received fMRI scans. Participants were required to refrain from illicit and prescription drug use for the duration of the study, which was confirmed with urine toxicology and breath alcohol level testing on examination days. Caffeine was restricted on study days for least 2 hours prior to cognitive testing and MRI scans. Participants were permitted to drink their normal daily intake of caffeine, given the caveat above. On study days, cigarette smoking was permitted to match conditions used with methamphetamine users. The incorporation of smoke breaks during the test day assured that acute nicotine withdrawal did not negatively impact performance on cognitive tests or neuroimaging. The following outlines procedures for healthy control participants: For normal controls, participation involved one day of outpatient screening, and one day of baseline cognitive testing and possible MRI scans. After these procedures were completed, participants were randomized to the first test compound (atomoxetine 40mg or placebo), to be taken once daily in the morning for 2 days. It was then increased to twice daily for the next 3 days, followed by a final dose (40mg or placebo) on the sixth day of study medication. Participants were also asked to bring their pill packages to assess compliance with the study medication. Additionally, control participants completed a series of repeated-measures cognitive testing (on placebo or atomoxetine, respectively) and possibly two fMRI sessions (separated by a short break). After at least a four-day washout period, control participants were instructed to start the opposite test compound (atomoxetine 40mg or placebo), again to be taken once daily in the morning for two days, then twice daily for 3 days, reaching the final dose (40mg or placebo) of the second test compound in the morning. Participants were again asked to bring their pill packages to assess compliance and had blood drawn to assess atomoxetine levels. Control participants then completed another series of cognitive testing and fMRI testing sessions. They were subsequently discharged from the study. Normal control participants returned two weeks after completion of both study phases in order to complete assessments to their physical and psychological status following treatment.

Study phs001195

Successful Clinical Response in Pneumonia Therapy (SCRIPT)

The goal of this study is to iteratively identify, validate and refine biomarkers to predict clinical failure, and identify novel targets for therapy, beyond traditional antibiotics, for patients with severe pneumonia requiring intubation, including severe community-acquired pneumonia (CAP), hospital-acquired pneumonia, and ventilator-associated pneumonia (HAP/VAP). We hypothesize that factors within the alveolar microenvironment in many patients with pneumonia prevent the active process of pneumonia resolution.The major emphasis will be on HAP. Mechanically ventilated CAP patients are a very high-risk group for subsequent VAP, and therefore CAP samples will be included to determine baseline bacteria, microbiome, and host defense patterns for those that do or do not develop HAP/VAP. Hospital-acquired pneumonia is the leading cause of death from nosocomial infections. Even in patients receiving pathogen-appropriate therapy, reported clinical failure rates are increasing, approaching 50% in recent clinical trials. Current approaches to improve outcomes in patients with pneumonia almost exclusively focus on the development of antibiotics to address the problem of resistance. However, the prevalence of antibiotic-resistant pathogens is insufficient to explain the high rates of clinical failure. Instead, we hypothesize that factors within the alveolar microenvironment in many patients with pneumonia prevent the active process of pneumonia resolution. These factors include pathogen-specific adaptations to the injured lung that modulate the innate and adaptive immune response, as well as changes to the alveolar microbiome, driven by selective pressure within our modern intensive care units. Understanding this complex adaptive system requires the integration of clinical information with unbiased measures of the host, pathogen, and microbiome changes within the alveolar microenvironment. These measures must be repeated over time to identify factors that distinguish successful from failed therapy for pneumonia sufficiently early during the clinical course to allow for effective interventions. To address this challenge, we have assembled a talented group of investigators in the Successful Clinical Response In Pneumonia Therapy (SCRIPT) Systems Biology Center. We will leverage our routine clinical practice of safe alveolar sampling in mechanically ventilated patients with pneumonia with repeated non-bronchoscopic bronchoalveolar lavage (NBBAL) sampling over the course of pneumonia. From this fluid, we will combine flow cytometry with multi-omic technologies (cell population-specific transcriptomics, epigenomics, shotgun microbiome sequencing, and pathogen-specific sequencing). Our systems scientists will integrate these genomic data with robust clinical -omics with the goal of identifying biomarkers that can be prospectively tested in patients and causally evaluated in humanized mouse models.The addition of a pooled sample artificially increases the number of automatically computed subjects by one.

Study phs002300

Mucociliary Clearance Consortium (MCC) Rare Genetic Disorders of the Airways: Cross-section Comparison of Clinical Features, and Development of Novel Screening and Genetic Test

We have established a consortium of 7 geographically-dispersed clinical research sites that are designed to study rare diseases of the airways, which involve defects in clearance of mucus secretions from the airways (defective "mucociliary clearance"). These sites will collaborate in diagnostic, genetic, and other studies in patients with impairments of mucociliary clearance, including primary ciliary dyskinesia (PCD), variant cystic fibrosis (CF), and pseudohypoaldosteronism (PHA). These disorders reflect genetic defects in airway host-defense, and typically result in chronic infection of the airways. Patients with these disorders of the conducting airways and sinuses have delayed (or incorrect) diagnoses, because diagnostic tests are not readily available. These patients may also have sub-optimal management of their clinical disease, because the cause of these disorders is not well-defined, and treatment regimens are usually not driven by evidence-based medicine. This current protocol is designed to employ a systematic approach to the diagnostic evaluation of these patients with chronic airways disease, which will yield precise diagnoses in individual patients, and will be associated with development of better diagnostic techniques, including genetic testing. In addition, we will compare/contrast clinical features (phenotype) across these disorders. A rigorous cross-sectional comparison of the clinical features will provide better understanding of the clinical disease of these disorders; in turn, this will lead not only to a better standard of clinical care, but will also assist in the identification of novel therapeutic approaches. The patient population for these studies includes individuals carrying a tentative diagnosis of the three disorders (PCD, variant CF or PHA), plus individuals suspected to have one of these disorders, but with inadequate or inconclusive diagnostic tests. Individuals in this latter category must have a preliminary clinical evaluation to evaluate for other more common disorders that may have similar manifestations including classical CF, immunodeficiency, asthma, and severe gastroesophageal reflux. We have an informal agreement with a network of pulmonologists across the United States to perform clinically-indicated (not research) preliminary clinical testing, if not directly available to patients who inquire about these studies. Blood will be collected for DNA to test for genetic mutations. The blood samples will be processed to establish a cell line (lymphocyte transformation) for a source of DNA for future genetic studies, in participants with disease. For participants unable to provide a blood sample, a buccal sample will be obtained for DNA.

Study phs000595

Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) - OncoArray Genotypes

Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) was one of five projects funded in 2010 as part of the NCI's Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative (http://epi.grants.cancer.gov/gameon/). GAME-ON's overall goal was to foster an intra-disciplinary and collaborative approach to the translation of promising research leads deriving from the initial wave of cancer GWAS. Specific goals included replication of previous GWAS findings and identification of new susceptibility loci through meta analyses of existing GWAS data and fine mapping of identified loci to better pinpoint causal variants; and identify germline variants that are associated with risk of multiple cancers. The other four funded GAME-ON projects were: the ColoRectal TransdisciplinaryStudy (CORECT), Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE), Follow-up of Ovarian Cancer Genetic Association and Interaction Study (FOCI), and Transdisciplinary Research in Cancer of the Lung (TRICL). To identify additional cancer risk loci, improve the precision of fine-mapping, and facilitate cross-cancer analyses, the GAME-ON projects and other consortia formed the OncoArray network (http://epi.grants.cancer.gov/oncoarray/), which developed and genotyped a new custom genotyping array (the "OncoArray") in large numbers of cancer cases and controls (over 400,000 samples). The OncoArray is a custom array manufactured by Illumina. The array includes a backbone of approximately 260,000 SNPs that provide genome-wide coverage of most common variants, together with markers of interest for each of the five GAME-ON cancers identified through genome-wide association studies (GWAS), fine-mapping of known susceptibility regions, sequencing studies, and other approaches. The array also includes loci of interest identified through studies of other cancer types, and other loci of interest to multiple cancer types (including loci associated with cancer related phenotypes, drug metabolism and radiation response). Additionally, SNPs relating to quantitative phenotypes such as body mass index (BMI), height, and breast density that correlate with common cancer risks are also included. The DRIVE data included under this dbGAP submission include OncoArray data from 60,015 breast cancer cases and controls genotyped at the Center for Inherited Disease Research (CIDR), University of Cambridge, National Cancer Institute, University of Copenhagen, University of Southern California and Mayo Clinic. Details on an additional approx. 80,000 breast cancer cases and controls genotyped at other centers can be found at http://bcac.ccge.medschl.cam.ac.uk/bcacdata/oncoarray/.

Study phs001265

14666 results for "PLOS+ONE+Pennsylvania+German+ACS+language+code+pdc+open+access+study"

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