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• 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

  Dataset EGAD00001007793

• SeqControl: Process Control for DNA Sequencing

  As next-generation sequencing (NGS) continues to increase in speed and throughput, routine clinical and industrial application draws steadily closer. These “production” uses of NGS will require enhanced quality-monitoring and quality-control to optimize output and reduce costs. We therefore developed a framework called SeqControl for predicting sequencing quality and coverage using a set of 15 metrics describing overall coverage, coverage distribution, base-wise coverage and base-wise quality. Using whole-genome sequences of 27 prostate cancers and 26 normal references we derive multivariate models that predict sequencing quality and depth. SeqControl robustly predicts how much sequencing is required to reach a given coverage depth (AUC = 0.993), accurately classifies clinically relevant formalin-fixed paraffin-embedded samples and makes predictions from as little as 1/8 of a lane of sequencing data (AUC = 0.967). These techniques can be immediately incorporated into existing NGS pipelines to monitor data quality in real-time. SeqControl represents a first step towards statistical process-control for NGS.

  Study EGAS00001000899

• Single nucleus RNA Seq of LUAD patient derived lung samples

  Fastq files of single nucleus RNA Sequencing data from 26 patients including 26 lung adenocarcioma and 12 matched healthy tissue samples for 8 young female never smokers, 8 young female smokers, 7 elderly female never smokers and 3 male never smokers.

  Dataset EGAD00001008955

• WGS of Multiple Myeloma/MGUS/SMM cases (germline) - VCF files (SNPs)

  WGS - PCR-free library preparation (whole blood gDNA), paired-end (2x100bp) sequencing on DNBseq sequencing platform (BGI) Number of samples: 26

  Dataset EGAD50000001800

• L1-Seq and Genome-Wide SNP Genotyping in a Multiethnic Asian Population

  Insertions of the human-specific subfamily of LINE-1 (L1) retrotransposon are highly polymorphic across individuals and can critically influence the human transcriptome. We hypothesized that L1 insertions could represent genetic variants determining important human phenotypic traits, and performed an integrated analysis of L1 elements and single nucleotide polymorphisms (SNPs) in several human populations. We found that a large fraction of L1s were in high linkage disequilibrium (LD) with their surrounding genomic regions and that they were well-tagged by SNPs. However, L1 variants were only partially captured by SNPs on standard SNP arrays, so that their potential phenotypic impact would be frequently missed by SNP array-based genome-wide association studies. We next identified potential phenotypic effects of L1s by looking for signatures of natural selection linked to L1 insertions; significant extended haplotype homozygosity (EHH) was detected around several L1 insertions. This suggests that some of these L1 insertions may have been the target of recent positive selection.

  Study phs000732

• Phenotype Risk Scores Identify Patients with Unrecognized Mendelian Disease Patterns

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

  Study phs001516

• Genomic Wide Scans for Female Osteoporosis Genes

  Osteoporosis is a condition of excessive skeletal fragility which results in high risk to low trauma fractures. It is the most prevalent metabolic bone disease and is a major public health problem which may result in devastating morbidity and mortality. The most powerful, measurable determinant of fracture risk is bone mineral density (BMD). More than 60% of BMD variation is attributable to genetic factors. There are gender differences in BMD that contribute to a substantially higher fracture risk among women than men. Genetic studies demonstrate that some osteoporosis risk genes/genomic regions are gender specific. However, specific such genes contributing to female BMD and to the sex differences of BMD are largely unknown. Recent rapid progresses in SNP genotyping technology, in our knowledge about human genome diversity and linkage disequilibrium (LD) patterns in the human genome as revealed have made it feasible and timely to pursue a powerful whole genome-wide association study (GWAS) to identify genes for BMD. The major goal of this project is to perform a powerful GWAS study in a large sample of US Caucasian subjects. Gender specific effects of the genetic variants will be examined. The significant genetic variants discovered will be used to design diagnostic DNA chips for prognosis for potential health problems of osteoporosis later in life.

  Study phs000390

• IMpower133 (GO30081) clinical data and biomarker data

  Relevant clinical data for IMpower133 (GO30081) including treatment arm, overall survival, progression-free survival, best overall response, PD-L1 IHC, molecular subtype, and baseline clinical features.

  Dataset EGAD50000000195

• Gut metagenomic data of 2,338 Pinggu adults

  Here we exploited a Han Chinese population-based cohort with extensive host metadata established in the Pinggu (PG) district of Beijing, and investigated gut microbiota from 2,338 adults (26-76 years) by metagenomic sequencing, revealing associations of the gut microbiota with sex, sex hormones, age, and a number of clinical and metabolic parameters.

  Study EGAS00001004820

• GAW16 Framingham and Simulated Data

  Important links to apply for individual-level data Genetic Analysis Workshop Instructions to Request Authorized Access Data Use Certification Requirements (DUC) Apply here for controlled access to individual level data Research Use Statement Questions regarding GAW16 should be directed to Vanessa Olmo at vanessa@business-endeavors.com. Problem 2: Description of the Framingham Heart Study In GAW16, we use data drawn from the Framingham Heart Study. The Framingham Heart Study — under the direction of National Heart, Lung, and Blood Institute; NHLBI — began in 1948 with the recruitment of adults from the town of Framingham, Massachusetts. At the time, little was known about the general causes of heart disease and stroke, but the death rates for cardiovascular disease (CVD) had been increasing steadily since the beginning of the 20th century and had become an American epidemic. The Framingham Heart Study is now conducted in collaboration with Boston University. The objective of the Framingham Heart Study was to identify the common factors or characteristics that contribute to CVD by following its development over a long period of time in a large group of participants who had not yet developed overt symptoms of CVD or suffered a heart attack or stroke. Between 1948 and 1953 the researchers recruited 5,209 subjects (2,336 men and 2,873 women) between the ages of 29 and 62 from the town of Framingham, Massachusetts and began the first round of extensive physical examinations and lifestyle interviews that they would later analyze for common patterns related to CVD development. Subjects were recruited from lists of addresses recorded for the town. Two out of every three households were approached for participation in the study. While there was no intention to recruit families for family studies, the plan was to recruit all household members in the ages 30-60 within each house that was selected for study. Hence, many biologically related individuals were recruited, including 1644 spouse pairs. Since 1948, these participants have returned to the study every two years for a detailed medical history, physical examination, and laboratory tests. Now in 2008 at 60 years of follow up, there remain about 500 participants from this cohort. Between 1971 and 1975 the study enrolled a second-generation group — 5,124 of the original participants' children and the spouses of these children — to participate in similar examinations. 2,616 subjects are offspring of the original spouse pairs and 34 are stepchildren. A total of 898 offspring are children of cohort members where only one parent was a study participant and 1,576 are spouses of the offspring. The Offspring Cohort has been followed every four years through 2001 (except between Exams 1 and 2 with an intervening 8 years) using protocols similar to those used for study of the Original Cohort. Between 2002 and 2005 the study enrolled the third generation (Gen3) of the Framingham Heart Study - 4095 offspring of the second generation. None of their spouses were recruited. An additional 103 parents of this third generation, who were not recruited between 1971 and 1975, were also recruited at this time. The latter group is not included in the GAW16 data. With the recruitment of this third generation, the study has increasingly focused on genetic factors associated with the development of cardiovascular disease and its associated risk factors. To date, there is only one examination of this generation of participants. A description of the recruitment of this third generation and comparison with the earlier generations at their initial recruitment is presented in Splansky GL et al., 2007. Further information on the Study can be found at http://www.nhlbi.nih.gov/about/framingham/index.html. Genome-wide Dense SNP Scan in Framingham Heart Study Genetic studies did not begin in the FHS until the 1990s. In the late 1980s and through the 1990s DNA was extracted from blood samples of surviving FHS participants. In 2007, the FHS entered a new phase with the conduct of genotyping for the FHS SHARe (SNP Health Association Resource) project, for which dense SNP genotyping was performed using approximately 550,000 SNPs (GeneChip® Human Mapping 500K Array Set and the 50K Human Gene Focused Panel) in 10,775 samples (some duplicates) from the three generations of subjects (including over 900 pedigrees). Affymetrix conducted all genotyping for the FHS SHARe project, using the 250K Sty, 250K Nsp, and the supplemental 50K platforms. Eighty-nine percent of the DNA samples were collected during the 1990s. To maximize the power of the study, we also extracted DNA from 1133 blood samples, drawn from subjects who had no DNA, to include in the SHARe project. These samples had been sitting in our refrigerators for some time, a few as far back as the 1970s. We refer to these DNA samples as the legacy samples. These samples had a higher failure rate in the genotyping process (40%) than the other eighty-nine percent (3%). Affymetrix invoked its own criteria for a sample to succeed in genotyping. All non-legacy samples must succeed on all three platforms, while legacy samples needed to pass on at least one platform. When a sample failed, additional attempts were made. Samples that repeatedly failed 2-4 times were called failures. Other samples failed due to issues of genotyped sex identification not matching our records or low SNP concordance among SNPs common across arrays or contamination. Eighty-nine percent of the legacy samples for which genotyping results are available passed all three platforms. The genotyping data from the 10,043 samples from 9354 subjects that passed the Affymetrix criteria were additionally checked for gender consistency and consistency with family structure, resulting in genotyping data for 9,274 participants in FHS SHARe. Genotype calls were made with the BRLMM algorithm. The SHARe database is housed at the National Center for Biotechnology Information database of genotypes and phenotypes (NCBI dbGaP) and contains all ~550,000 SNPs. This genome-wide dense SNP scan and a subset of phenotypes from the Framingham Heart Study are the focus of the Genetic Analysis Workshop 16. Further information on the specific variables in the Problem 2 dataset can be found by clicking on the Documents tab at the top of the page. Problem 3: Description of the Simulated Data Set The focus of this simulation is gene discovery in genome-wide association scans (GWAS). The Framingham Heart Study data set (distributed as "Problem 2") is the basis for the FHS* simulated data. The pedigree structures are derived from the data distributed for Problem 2, and we distribute an accompanying triplet file (triplet_sim) containing person ID, father ID, mother ID, to ensure the identical subjects, pedigrees, and singletons are used in the simulated data analysis. Consistent with standard practice, founders and singletons are designated as subjects with both fshare and mshare equal to zero (missing). The simulated data includes a total of 6,479 subjects with both phenotype and genotype data, in 942 pedigrees distributed among 3 generations and 188 singletons. Data inclusion is consistent with the subjects' consent for use by both for-profit and not-for-profit researchers. The genotypes for all Problem 3 replicates are fixed as measured and distributed for Problem 2 for both the genomewide scan and the additional candidate gene SNPs, for a total of approximately 550,000 SNPs (GeneChip® Human Mapping 500K Array Set and the 50K Human Gene Focused Panel). Thus, to analyze the Problem 3 simulated data you also will need to download the Problem 2 genotypes. Note that there are slight discrepancies in counts between Problems 2 and 3 due to a change in consents between the two datasets. Several phenotypes that contribute to coronary heart disease (CHD) were simulated for all individuals with genotypes across three different time points, 10 years apart. All genotyped individuals have complete data; the effects of missing values can be investigated by user-specified missing value patterns. There are 200 longitudinal datasets created, based on the generating model, and each replication is found in a separate dataset. We suggest that if only one replication is to be analyzed, that it be replication 1 to enable more precise comparisons among analytical approaches. The 'shareid' will allow you to merge the simulated phenotype data with the Problem 2 genotype data, and reconstruction of the pedigrees using the distributed 'triplet_sim' file or for larger families' relationships with the triplet distributed with the Problem 2. The simulated data problem is further described in the associated readme file, and a data dictionary is provided defining all the variables. For disclosure of the generating model for these data, please contact Jean MacCluer at jean@sfbrgenetics.org.

  Study phs000128

• HCI-PDX Trial Center for Breast Cancer Therapy

  The HCI-PDX Trial Center for Breast Cancer Therapy study is a collection of patient-tumor samples that are serially established as patient-derived tumor xenografts (human tumor in mouse) and matching organoids. For this study, we describe valuable methods and resources to generate organoids and use them as cost-effective models for precision drug screens. This study leveraged whole-exome sequencing, RNAseq, and SNP-array data to illustrate how the heterogeneity of tumors is preserved in xenograft and organoid models. Sequencing files are provided for whole-exome and RNAseq data. Processed copy number variant calls from the SNP arrays are also available. A full description of the study can be found in the article entitled, "A human breast cancer-derived xenograft and organoid platform for drug discovery and precision oncology," written by Guillen et al., 2022 in Nature Cancer (PMID: 35221336).

  Study phs002479

• POISED (Peanut Oral Immunotherapy: Safety, Efficacy, and Discovery)

  Phase 2 POISED (Peanut Oral Immunotherapy: Safety, Efficacy, Discovery) Study In this randomized, double-blind, placebo-controlled (DBPC) clinical trial, blinded placebo group received oat flour, whereas in active participants, dosage was built-up for over ~ 52 weeks and subsequently maintained on 4000 mg peanut protein, daily for next 52 weeks. 80 (98.77%) per-protocol active participants passed the food challenge at week 104. Subsequently, for 12 weeks, peanut ingestion was avoided in a randomized group of 51 blinded active participants (i.e., peanut avoidance group). 21 (41.2%) participants in the peanut avoidance group passed the 4000 mg double-blind, placebo-controlled food challenge (DBPCFC) without any allergic reaction at week 117, thus demonstrating sustained unresponsiveness. These 21 participants continued oral immunotherapy (OIT) for every three months and afterwards were allowed to continue peanut OIT discontinuation if they passed. 8 participants passed the DBPCFCs, 12 months after peanut discontinuation (week 156), i.e. they achieved long-term sustained unresponsiveness with no allergic reaction in response to food challenge. For detailed description, please refer to Chinthrajah et al., PMID: 31522849.

  Study phs003071

• Impact of Genetic Polymorphisms on Human Immune Cell Gene Expression

  While many genetic variants have been associated with risk for human diseases, how these variants affect gene expression in various cell types remains largely unknown. To address this gap, the DICE [Database of Immune Cell Expression, Expression quantitative trait loci (eQTLs) and Epigenomics] project was established. Considering all human immune cell types and conditions studied, we identified cis-eQTLs for a total of 12,254 unique genes, which represent 61% of all protein-coding genes expressed in these cell types. Strikingly, a large fraction (41%) of these genes showed a strong cis-association with genotype only in a single cell type. We also found that biological sex is associated with major differences in immune cell gene expression in a highly cell-specific manner. These datasets will help reveal the effects of disease risk-associated genetic polymorphisms on specific immune cell types, providing mechanistic insights into how they might influence pathogenesis.

  Study phs001703

• FLT3 is genetically essential for ITD-mutated leukemic stem cells but dispensable for human HSCs

  bulk RNA sequencing of AML patients It contains 18 samples from primary AML patients. Half of the samples are control samples and half of the samples are FLT3-ITD knock-out (edited for the FLT3-ITD mutation). It is using Illumina high-throughput technology

  Dataset EGAD50000000636

• scRNA-seq analysis of HGSC tumors, including immune TME, before and after NACT

  Gene expression profiles of single cells from 26 tumor and ascites samples samples from 17 patients

  Dataset EGAD50000000862

• A Randomized, Double-Blind, Crossover Study of Sodium Phenylbutyrate (Buphenyl) and Low-Dose Arginine (100 mg/kg/day) Compared to High-Dose Arginine (500 mg/kg/day) Alone on Liver Function, Ureagenesis and Subsequent Nitric Oxide Production in Patients with Argininosuccinic Aciduria (ASA)

  Individuals with Urea Cycle Disorders (UCD) cannot remove ammonia, a waste product, from the blood. At present there is little information on the use of sodium phenylbutyrate (Buphenyl™) in children with argininosuccinic aciduria (ASA). It is hoped that this drug may help lower ammonia and argininosuccinic acid levels in patients with ASA. Through this study we hope to learn whether the use of sodium phenylbutyrate (Buphenyl™) in patients with ASA, in addition to diet and arginine therapy, will decrease liver damage and the number of periods during which ammonia levels are high. The primary study objective is to determine if the treatment of ASA patients with sodium phenylbutyrate (Buphenyl™) in conjunction with lowered doses of arginine improves liver function as measured by short-term assessment of synthetic activity and the use of stable isotope tracers to assess ureagenesis and nitric oxide production. Twelve patients with ASA will be studied using a randomized, cross-over design. Medical records will be reviewed to confirm the diagnosis prior to enrollment. Patients will be on the each arm of the study for one week each preceded by a three day washout period. Patients will come to the Baylor College of Medicine General Clinical Research Center in Texas Children's Hospital for an inpatient hospitalization. This hospitalization is for diet control, clinical evaluation, and stable isotope infusions for measurement of in vivo rates of ureagenesis and nitric oxide production. During the washout periods Buphenyl™ or other alternative route medications, e.g., benzoate, will be discontinued and arginine will be administered at the standard therapeutic dose of 500 mg/kg/day or 10 grams/m2. Following randomization, subjects will be maintained on either high-dose arginine (500 mg/kg/day or 10 grams/m2) alone, or the alternative of low-dose arginine (100 mg/kg/d or 2 grams/m2) along with sodium phenylbutyrate (500 mg/kg/day or 10 grams/m2). For the second week they will be crossed over to the other arm of the study preceded by another three day washout. Previous medications and dietary protein intake (0.6 g/kg/day or current metabolic diet) will be continued during both arms of the study. The two arms may be performed as separate ten-day admissions. The decision to design the study with two arms, high-dose arginine and low-dose arginine/Buphenyl™, was reached after weighing several considerations. First, the current accepted practice for treatment of ASA is high-dose arginine. Based on metabolic flux studies, we have quantified the effects of this dose of arginine as compared to standard doses of Buphenyl™/phenylacetate on ureagenesis. Since the study is not designed or intended to address the independent effects of Buphenyl™ as compared to arginine alone, Buphenyl™ was added for safety reasons to accommodate loss of clearance of nitrogen by decreasing the arginine dose. Moreover, based on our experience with recruiting for previous versions of this study, most ASA patients with liver dysfunction are on an alternative route ammonia scavenger medication in addition to arginine. We found that this has in fact become an accepted practice. Hence, when considering study design from both a safety and recruitment perspective, it was most reasonable to design the study to investigate specifically the hypothesis that the production and presence of argininosuccinic acid leads to liver dysfunction. Since both low-dose arginine with Buphenyl™ and high-dose arginine alone lead to a decreased production of argininosuccinic acid, and both are currently accepted therapies in ASA and UCDs in general, the need to address their effects distinctly is not being investigated at this time. Sodium phenylbutyrate dosage will be 500 mg/kg/day in patients weighing less than 20kg and 10 g/m2/day in larger patients. Daily dosage will be given in equally divided doses 4 times per day. In order to ensure that the study remains double-blind to investigators, study staff and subjects, the Investigational Pharmacy Service at Texas Children's Hospital will dispense both the Buphenyl™ and arginine in powder form which is compounded into capsules or will be mixed with syrpalta (up to 5 grams will dissolve in 10cc liquid) and administered orally or through nasogastric or gastrostomy tube. No nasogastric tube should be placed or gastrostomy performed solely for the purpose of inclusion in this study. Because the reported adverse effects of sodium phenylbutyrate include gastritis, participants will be started on a standard dose of ranitidine (Zantac™), or comparable drug, during both arms of the study.

  Study phs001305

• Melanoma_post_mortem_analysis

  This is a targeted pulldown validation in support of the existing whole-genome sequencing study of melanoma metastases (Canapps ID:1888). We are studying the genomic evolution of cutaneous melanoma metastases. In this pulldown analysis we are specifically sequencing the subclonal variants that we believe account for the variability between the metastases.

  Study EGAS00001003531

• Cardiovascular Cell Therapy Research Network (CCTRN): A Phase II, RCT of Mesenchymal Stem Cells & Cardiac Stem Cells in Subjects With Ischemic HF (CONCERT HF-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. ObjectivesTo assess the feasibility, safety, and efficacy of autologous mesenchymal stromal cells (MSCs) and c-kit positive cardiac cells (CPCs), alone or in combination, in participants with ischemic heart failure.Background The prognosis of heart failure (HF) caused by chronic ischemic cardiomyopathy (coronary artery disease and prior myocardial infarction), hereby referred to as “ischemic HF”, remains poor. Many studies have explored the use of various types of stem or progenitor cells in participants with chronic ischemic HF, with encouraging results. Several clinical trials have suggested that MSCs and CPCs are both safe and beneficial in participants with ischemic HF. At the time of this study, no information was available on the efficacy of MSCs and CPCs in humans, however, both cell types have been shown to attenuate left ventricle (LV) dysfunction in animal models. Preclinical models indicate that combining MSCs and CPCs increases the therapeutic effects, but this had not yet been tested in humans. The CONCERT-HF study was initiated to assess whether autologous MSCs and CPCs, alone or in combination, can be manufactured and delivered to participants with ischemic HF; are well-tolerated; and improve LV function, quality of life, and functional capacity, and/or reduce scar size. Participants A total of 125 participants were randomized with 33 participants randomized to the MSCs and CPCs group, 29 participants to the MSCs alone group, 31 participants to the CPCs alone group, and 32 participants to the placebo group. Design The CONCERT-HF study was a multi-center Phase II, double-blind, randomized, placebo-controlled trial designed to evaluate the feasibility, safety, and efficacy of MSCs alone, CPCs alone, and their combination compared with placebo as well as each other in patients with ischemic HF. In Stage 1 (open label, lead-in study) participants were randomized 1:1 to either a standard-of-care control group (i.e., they did not undergo harvest, mapping, or injection procedures) or combination therapy (MSCs + CPCs, as described for Stage 2) to complete safety assessments. Once approval was granted for Stage 2, participants were randomized (1:1:1:1) to one of four treatments: placebo, autologous MSCs (target dose, 150 × 106 cells), autologous CPCs (target dose, 5 × 106 cells), or a combination of autologous MSCs and CPCs. At the harvest visit, right ventricular endocardial biopsy (EMB) was performed in participants randomized to receive CPCs alone or a combination of MSCs and CPCs. Participants randomized to receive MSCs alone or placebo had a sham procedure (right heart catheterization without EMB). All participants underwent a bone marrow aspiration and approximately 14 weeks later had transendocardial, electromechanically-guided injections of study product. Visits occurred at 1 day, 1 week, and 1, 3, 6, and 12 months after study product injection. A telephone contact took place at 24 months to assess the participant's current medications, as well as morbidity and mortality. Study endpoints included measures of safety, feasibility, and efficacy. Safety outcomes included all adverse events grade 2 and higher, including major adverse cardiac events (MACE) related to HF (death, hospitalization for worsening HF, and HF exacerbation not requiring hospitalization). Efficacy endpoints included quality of life, MRI measures of LV function and structure, functional capacity, and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. Conclusions In patients with ischemic HF, autologous MSCs and CPCs, alone or in combination, are safe and feasible; CPCs were associated with a reduction in the incidence of MACE related to HF compared to placebo; MSCs, either alone or in combination with CPCs, were associated with improved quality of life; these seemingly beneficial effects of CPCs and MSCs on clinical outcome were not associated with changes in LV function or structure; and combination therapy with MSCs and CPCs was associated with the best clinical outcomes with respect to both MACE related to HF and quality of life.

  Study phs004055

• NHLBI TOPMed - NHGRI CCDG: The Vanderbilt AF Ablation Registry

  The Vanderbilt Atrial Fibrillation Ablation Registry (VAFAR) was founded in 2011. Patients with AF referred for AF ablation are prospectively enrolled. A detailed clinical history is recorded, along with imaging data (cardiac MRI or CT). Blood samples are obtained for DNA extraction at the time of ablation. Details of the ablation procedure are recorded. Patients are longitudinally followed to monitor for AF recurrence. VAFAR contributed 171 samples submitted to dbGaP for WGS: 115 were from male subjects, of which 113 were white/non-Hispanic and 2 were Hispanic; 56 were from females, of which all 56 were white/non-Hispanic.

  Study phs000997

• Genetic Analysis of Skin Cells

  Cutaneous squamous cell carcinoma (cSCC) is a form of skin cancer originating from keratinocytes in the skin. They have high mutation burdens, primarily driven by UV-radiation-induced DNA damage. The order in which mutations undergo selection during the evolution of cSCC is not known. A subset of cSCCs grow out of benign neoplasms called actinic keratoses. To better understand the evolution of cSCC, we identified cases of cSCCs adjacent to actinic keratoses. From these cases, we separately microdissected the surrounding normal skin, the actinic keratosis, and the cSCC, and we performed targeted DNA-sequencing on the tissue from each area. We reconstructed tumor phylogenies and performed spatial transcriptomics on the 10X FFPE Visium platform on a subset of cases. Collectively, these studies revealed the mutational and gene expression changes that arise during the evolution of cSCC.

  Study phs003282

• Illumina HumanCoreExome genotyping data from the British Society for Surgery of the Hand Genetics of Dupuytren’s Disease consortium (BSSH-GODD consortium) collection

  Dupuytren's Disease (DD - OMIM126900) is the most common heritable disorder of connective tissue. It is a fibroproliferative disorder of the palmer fascia, causing flexion contractures of affected digits. DD affects men more commonly than women. DD is an archetypal complex disease, with multiple genetic and environmental factors affecting the final expression of the disease phenotype. The incidence increases with age, and the prevalence of DD is therefore increasing as the UK population ages. Half of all patients present before age 60. DD causes significant functional impairment, and severe contractures can lead to permanent disability. The mainstay of current treatment is surgery, but recurrence and complications are both high. For severe contractures, the only suitable treatment option is amputation. The direct costs to the NHS are high, and underestimate the true economic costs to society. We collected salivary samples from adults in the UK who have had surgery for DD. We have genotyped these samples using the Illumina HumanCoreExome Beadchips. https://research.ndorms.ox.ac.uk/public/dupuytrens/what-is-dupuytrens-disease/

  Study EGAS00001001206

• Youth-GEMs, the project using data to define the mental health trajectories of young people

  Mental health trajectories are shaped by genetic, cognitive, social, and environmental factors that are particularly influential during human development. How exactly the interplay between these factors is impacting mental health, however, is yet unknown. The project “Gene Environment interactions in Mental health trajectories of Youth (Youth-GEMs)”, funded by the European Commission under the Horizon Europe programme, aims to help reducing mental suffering among European youth. How do Youth-GEMs contribute to bettering mental health in young people? Youth-GEMs aims to identify specific neurological, (epi)genetic and environmental drivers on mental health trajectories of young people. To do so, the project is working on a public knowledge base on functional genomics of the developing human brain, between birth and 24 years old. Reliable predictive models for trajectories of onset and course of mental illness in young people of the general population in Europe will be developed. Additionally, a secure and FAIR data infrastructure in mental health is being produced. Engaging and empowering young people Youth-GEMs is also working on the engagement of young people in the scientific field of Psychiatry. For that, the project is developing initiatives such as Science Café, intended to create a learning community where ideas and stories are shared. The 10th Science Café will take place today, with the participation of Lauren Fromont from the EGA. How do the EGA contribute to Youth-GEMs? The contributions require careful data management and harmonisation: we are dealing with an extraordinary amount of data types, sources, and time points (since the studies are longitudinal). To analyse them together and to determine which factors and interactions are truly key to account for mental health trajectories, the variables need to be transformed in a common “language”, i.e., harmonised under a common data model. Further, to guarantee FAIRness of data storage and sharing for future projects that will further advance our knowledge in the mental health field, we are ensuring that data are processed securely but can also be discovered easily. Find out more information about the project in the Youth-GEMs website.

  Blog youth-gems-mental-health

• Unrelated Donor Reduced Intensity Bone Marrow Transplant for Children with Severe Sickle Cell Disease (BMT CTN-0601-BioLINCC)

  ObjectivesThe primary objective is to determine event-free survival (EFS) at 1 year after unrelated donor (URD) hematopoietic stem cell transplantation (HCT) using bone marrow (BM) in patients with sickle cell disease (SCD).BackgroundSickle cell disease (SCD), also known as sickle cell anemia, is an inherited blood disease that can cause organ damage, stroke, and intense pain episodes. Children with sickle cell disease experience organ damage, impaired quality of life, and premature mortality. A blood stem cell transplant is a treatment option for someone with a severe form of the disease. Prior to undergoing a transplant, people typically receive a conditioning regimen of high doses of chemotherapy and other medications to prepare the body to accept the transplant. This type of conditioning regimen is known as a myeloablative conditioning regimen, but it can result in toxicities and sterility. A conditioning regimen that uses lower doses of chemotherapy and medications may be safer for transplant recipients. This type of regimen is known as reduced intensity conditioning (RIC) regimen. RIC has a more favorable toxicity profile but is associated with higher rates of graft rejection (GR), especially with graft sources such as umbilical cord blood This study evaluated the safety and effectiveness of blood stem cell transplants, using bone marrow from unrelated donors, in children with severe SCD who receive a RIC regimen prior to the transplant.SubjectsPatients 3.0-19.75 years old with symptomatic SCD AND one or more of the following complications: (1)-(i) a clinically significant neurologic event (stroke) or any neurologic defect lasting > 24 hours and accompanied by an infarct on cerebral magnetic resonance imaging (MRI); OR, (ii) patients who have a Transcranial Doppler (TCD) velocity that exceeds 200 cm/sec by the non-imaging technique (or TCD measurement of >185 cm/sec by the imaging technique) measured at a minimum of 2 separate occasions one month or more apart; OR, (2) Minimum of two episodes of acute chest syndrome within the preceding 2-year period defined as new pulmonary alveolar consolidation involving at least one complete lung segment (associated with acute symptoms including fever, chest pain, tachypnea, wheezing, rales, or cough that is not attributed to asthma or bronchiolitis) despite adequate supportive care measures; OR, (3) History of 3 or more severe pain events (defined as new onset of pain that lasts for at least 2 hours for which there is no other explanation) per year in the 2 years prior to enrollment despite adequate supportive care measures (if patients are receiving hydroxyurea and compliant with therapy, being symptomatic is an indication for transplantation; however, if patients decline hydroxyurea or non-compliant with this therapy, they would still remain eligible for study if pain criteria as described above are met). Lansky/Karnofsky performance score must be ≥ 40. Hemoglobin S must be ≤ 45%. Patients must have an unrelated adult bone marrow donor who is HLA-matched at 8 of 8 HLA-A, -B, -C and -DRB1 at high resolution using DNA-based typing. Patients with bridging fibrosis or cirrhosis of the liver, with uncontrolled bacterial, viral, or fungal infection in the past month, or seropositivity for HIV are excluded. Patients with HLA-matched family donors, or who have received prior HCT, and females who are pregnant or breast feeding are excluded. Thirty patients were enrolled on this study and of these, 29 patients met the criteria and proceeded to the study transplant.DesignParticipants attended a study visit prior to the transplant to undergo a blood collection, neurocognitive testing to measure learning and brain function, magnetic resonance angiogram (MRA) and magnetic resonance imaging (MRI) scans. Questionnaires to assess quality of life were also completed. All patients received erythrocyte transfusions before transplant. Twenty-two days (-22) before the transplant, participants began receiving a reduced intensity conditioning regimen of chemotherapy and medications. On days -21, -20, and -19 participants weighing 10 kg or more received 10 mg, 15 mg, and then 20 mg of Alemtuzumab intravenously (IV) followed by 30 mg/m2/day IV on days -8 through -4 of Fludarabine. Eight days (-8) before the transplant, participants were admitted to the hospital to continue the conditioning regimen which included 140 mg/m2 IV of Melphalan on day -3. Participants received the bone marrow transplant on day 0. Prophylaxis for GVHD consisted of a calcineurin inhibitor (tacrolimus or cyclosporine) administered from day -3 through day 100 after graft infusion, with subsequent taper through day 180; methotrexate 7.5 mg/m2 on days 1, 3, and 6; and methylprednisolone 1 mg/kg per day from days 7 through 28, with subsequent taper by 20% per week. One week after the transplant continuing until the WBC is normal, participants received granulocyte-colony-stimulating factor (G-CSF). After leaving the hospital, participants attended study visits weekly during weeks 1 to 8, at day 60, weekly during weeks 9 to 14, at Day 100, at month 6, and at years 1 and 2. At all study visits, a blood collection, medical history review, and physical exam occurred. In addition, at day 100, month 6, and years 1 and 2, questionnaires to assess quality of life were completed. At select visits the following procedures were conducted: lung function testing, heart function testing, MRA and MRI scans, and neurocognitive testing.The primary outcome was 1-year EFS. Death, disease recurrence or graft rejection by 1 year were considered events for this endpoint.ConclusionsThe trial met its prespecified 1-year EFS, and significantly improved HRQL was reported posttransplant. However, although the Reduced-intensity conditioning (RIC) provided successful engraftment in most patients, the regimen cannot be considered safe for widespread adoption without modification due to the regimen-related toxicity (RRT) and high rate of chronic GVHD, which was the predominant cause of mortality.

  Study phs003470

• Single cell RNA sequencing data of advanced melanoma patients treated with checkpoint inhibitor immunotherapy

  Single cell RNA libraries were prepared using 10x Genomics Chromium Next GEM Single Cell 3’ v2 reagents. The samples were barcoded and each library were pooled with two samples at equimolar concentrations. The pooled libraries (n=4) were sequenced on the NextSeq 500 machine (Illumina) with paired-end sequencing and dual indexing as recommended in the manufacturer’s protocol; 26 and 98 cycles for the respective Read 1 and 2, and 8 cycles for i7 index.

  Dataset EGAD50000000493

• Evolution of GBM through therapy

  Primary glioblastoma (GBM) tumours recur following treatment. This is likely due to intratumour heterogeneity (ITH), which reduces the effectiveness of cancer therapies by enabling therapy-driven tumour evolution: Darwinian selection of genotypically and/or phenotypically distinct cells (subclones) that resist treatment to seed regrowth of an even less treatable recurrence. To investigate this we sequenced a pilot cohort of nine paired primary and locally recurrent GBM tumours, alongside matched blood samples, in order to begin characterising therapy resistant cells and thereby infer the mechanisms by which they evaded treatment. These data were included in the first data release from the Glioma Longitudinal AnalySiS (GLASS) consortium.

  Study EGAS00001003546