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• Integrated targeted deep sequencing reveals unique tissue-of-origin and donor cell-free DNA signatures in transplant recipients

  We have developed a targeted deep methylation sequencing assay that integrates cell-free DNA (cfDNA) tissue-of-origin analysis with donor-derived cfDNA quantification to non-invasively monitor transplant health. In this study, liver and kidney transplant recipients were assessed in conjunction with healthy controls to characterize the dynamic patterns of cfDNA release and clearance, and to identify distinct tissue injury signatures throughout the transplant journey.

  Study EGAS50000000987

• Clinical validity of post-surgery circulating tumor DNA (ctDNA) in stage III colon cancer patients treated with adjuvant chemotherapy: the PROVENC3 study

  The PROVENC3 study aimed to determine the clinical validity of post-surgery ctDNA testing in patients with stage III colon cancer treated with adjuvant chemotherapy (ACT). Blood was collected pre-surgery, post-surgery and post-adjuvant chemotherapy. Tumor-informed plasma ctDNA detection was performed through integrated whole genome sequencing (WGS) analyses of formalin-fixed paraffin-embedded tumor tissue DNA (80x), white blood cell germline DNA (40x) and plasma cell-free DNA (30x). These raw WGS data for 209 patients are shared in .cram format in this EGA submission. For 196/209 of these patients there is overlapping FFPE tumor RNA sequencing data available, shared in .fastq format in this EGA submission.

  Study EGAS50000000804

• Whole genome sequencing, single-cell RNA sequencing, and ATAC sequencing of mesothelioma (patient, patient-derived xenograft and cell line)

  Malignant pleural mesothelioma is an aggressive pleural tumor with a poor prognosis, and elucidating its molecular mechanisms is essential for improving diagnosis and treatment. This study investigates key genes and pathways involved in tumor progression, with particular attention to the involvement of neutrophils in the tumor ecosystem of mesothelioma. We performed whole-genome sequencing and single-cell RNA sequencing (scRNA-seq) of one pleural mesothelioma tumor specimen, scRNA-seq of matched patient-derived xenograft tumors, scRNA-seq of mesothelioma-free pleural tissues from three patients, and assay for transposase-accessible chromatin using sequencing (ATAC-seq) of a patient-derived cell line.

  Study JGAS000859

• Detection of mutational patterns in cell free DNA (cfDNA) of colorectal cancer by custom amplicon sequencing

  Monitoring the mutational patterns of solid tumors during cancer therapy is a major challenge in oncology. Analysis of mutations in cell free (cf) DNA offers a non-invasive approach to detect mutations that may be prognostic for disease survival or predictive for primary or secondary drug resistance. A main challenge for the application of cfDNA as a diagnostic tool is the diverse mutational landscape of cancer. Here, we developed a flexible end-to-end experimental and bioinformatics workflow to analyze mutations in cfDNA using custom amplicon sequencing. Our approach relies on open software tools to select primers suitable for multiplex PCR using minimal cfDNA as input. In addition, we developed a robust linear model to identify specific genetic alterations from sequencing data of cfDNA. We used our method to design a custom amplicon panel suitable for detection of hotspot mutations relevant for colorectal cancer and analyzed mutations in serial cfDNA samples from 34 patients with advanced colorectal cancer. Our data demonstrates that recurrent and patient-specific mutational patterns can be reliably detected for the majority of patients. Furthermore, we show that the allele frequency of mutations in cfDNA correlates well with disease progression. Finally, we demonstrate that monitoring of cfDNA can outperform the predictive power of currently used tumor markers and reveal mechanisms of resistance to anti-EGFR antibody treatment.

  Study EGAS00001003382

• The dataset for Detection of brain cancer using genome-wide cell-free DNA fragmentomes

  The dataset for “Detection of brain cancer using genome-wide cell-free DNA fragmentomes” includes 310 bam files from whole genome next-generation sequencing on the Illumina Novaseq 6000. The dataset analyzed include plasma cfDNA samples from patients with cancer, patients with neurological conditions, and healthy individuals.

  Dataset EGAD50000001445

• Circulating, Cell-Free DNA Methylation Patterns Indicate Cellular Sources of Allograft Injury after Liver Transplant

  Post-transplant complications reduce allograft and recipient survival. Current approaches for detecting allograft injury non-invasively are limited and do not differentiate between cellular mechanisms. Here, we monitor cellular damages after liver transplants from cell-free DNA (cfDNA) fragments released from dying cells into the circulation. We analyzed longitudinal blood samples collected from patients at different time points after transplant. Sequence-based methylation of cfDNA fragments were mapped to an atlas of cell-type-specific DNA methylation patterns derived from 476 methylomes of purified cells. For liver cell types, DNA methylation patterns and multi-omic data integration show distinct enrichment in open chromatin and regulatory regions functionally important for the respective cell types. We find that multi-tissue cellular damage post-transplant recovers in patients without allograft injury during the first post-operative week. However, sustained elevation of hepatocyte and biliary epithelial cfDNA within the first month indicates early-onset allograft injury. Further, cfDNA composition differentiates amongst causes of allograft injury indicating the potential for non-invasive monitoring and timely intervention.

  Study phs003610

• Ultra-Low-Pass Whole Genome Sequencing of Cell-Free DNA for Large B-Cell Lymphoma

  While deep targeted DNA sequencing of liquid biopsies has shown prognostic utility in large B-cell lymphoma (LBCL), the routine clinical adoption of these assays remains limited due to their high costs. Here, leveraging a well-annotated cohort of encompassing both frontline and relapsed/refractory (R/R) LBCL, we profiled patient plasma samples with two complementary modalities – ultra-low-pass whole genome sequencing (ulpWGS) and deep targeted DNA sequencing, the former being a cost-effective method to profile large scale chromosomal abnormalities and estimate tumor burden. Our findings revealed a strong association of high cell-free tumor burden by both genomic profiling modalities with established measures of tumor burden and patient survival. Notably, the associations with survival remained statistically significant after accounting for international prognostic index scoring. Furthermore, we showed that del(17p) in circulating tumor DNA as detected by ulpWGS was strongly associated with TP53 mutation status and predicted for significantly inferior patient outcome in frontline but not R/R LBCL patients. Our study demonstrates that ulpWGS can provide robust prognostic biomarkers for both frontline and R/R LBCL, highlighting its broad applicability for risk stratification.

  Study EGAS50000001027

• The dataset for Single molecule genome-wide mutation profiles of cell-free DNA for non-invasive detection of cancer

  The dataset for Single molecule genome-wide mutation profiles of cell-free DNA for non-invasive detection of cancer includes 57 BAM files from whole genome next-generation sequencing on the Illumina HiSeq2500. The samples analyzed include plasma samples from individuals with and without cancer.

  Dataset EGAD00001010891

• Targeted plasma cell-free DNA sequencing for tissue-of-origin determination and donor-derived cell-free DNA quantification in organ transplant recipients and healthy controls

  The dataset comprises targeted deep methylation sequencing data used for both tissue-of-origin determination and donor-derived cfDNA quantification. It includes plasma cfDNA data from stable kidney transplant recipients (n = 31), stable liver transplant recipients (n = 20) and healthy controls (n = 23). In addition, plasma cfDNA samples collected early after transplantation were analyzed from kidney transplant recipients (n = 44) and liver transplant recipients (n = 40). The dataset also features genomic DNA data generated from whole blood (n = 10) and buffy coat (n = 3) from healthy controls, as well as from T cells (n = 1), B cells (n = 2), hepatocytes (n = 1) and kidney epithelium (n = 1). Lastly, genomic DNA data was generated from buffy coat of transplant recipients (n = 17). Here, “n” indicates the sample number.

  Dataset EGAD50000001446

• Atezolizumab Plus Personalized Neoantigen Vaccination in Patients with Urothelial Cancer: a Phase 1 Trial

  This is a phase 1 single center clinical trial evaluating a multi-peptide personalized neoantigen vaccine, PGV001, in combination with atezolizumab for patients with urothelial cancer. Patients were enrolled in either the adjuvant or metastatic setting. Those in the adjuvant setting included patients considered high risk of recurrence (pathological stage ypT2-T4 or ypN+ for those treated with prior neoadjuvant chemotherapy or pT3-T4 or pN+ for those not treated with prior neoadjuvant chemotherapy). Those in the metastatic setting included patients progressing after prior chemotherapy or those with at least stable disease after chemotherapy treated as “switch maintenance” therapy. The primary endpoint was feasibility (including the number of neoantigens identified per patient, vaccine production time, the proportion of patients consenting to the vaccine development phase for whom a vaccine product was prepared, and the proportion of patients eligible for the treatment phase who completed the priming cycle 1 of PGV001 plus atezolizumab) and safety. Secondary endpoints included the objective response rate, progression-free survival or disease-free survival, overall survival, and immunomodulatory effects of treatment. Urothelial tumor tissue and normal tissue or peripheral blood specimens were utilized for DNA sequencing. HLA typing was performed utilizing genomic DNA isolated from whole blood, and RNA sequencing was performed utilizing tumor tissue specimens. Neoantigen prediction and final selection for incorporation into the vaccine was determined by the OpenVax computational pipeline. 12 patients were initially enrolled into the vaccine development phase and 10 patients initiated the treatment phase. PGV001 was administered with poly-ICLC and tetanus peptide on subsequent days for up to 10 doses, including an initial priming cycle 1. Atezolizumab was administered every 3 weeks for up to 1 year in the adjuvant setting or 2 years in the metastatic setting. The vaccine was feasible and safe, the median vaccine production time was 20.3 weeks, and 100% of patients that initiated the treatment phase completed the priming cycle. The most common treatment-related adverse events were local grade 1 injection site reactions, fever, and fatigue. Three of the 4 patients in the adjuvant setting remained disease-free at median follow-up of 39.5 months. There was a 40% objective response rate among patients with measurable disease in the metastatic setting. The single patient treated as “switch maintenance” therapy remained with no evidence of disease at 39.4 month follow-up. All patients demonstrated on-treatment neoantigen-specific T cell reactivity, as measured by ELISPOT and flow cytometry assays. Overall, PGV001 plus atezolizumab was feasible, safe, and warrants further investigation. Whole exome sequencing from tumor tissue and normal tissue or whole blood specimens and RNA sequencing from tumor tissue specimens will be available through dbGaP.

  Study phs003922

• Methylome sequencing of cell-free DNA and RRBS of solid tissue

  Early cancer detection by cell-free DNA (cfDNA) faces multiple challenges: low fraction of tumor cfDNA, molecular heterogeneity of cancer, and sample sizes not sufficient to reflect diverse patient population. We develop a cancer detection approach to address these challenges. It consists of an assay, cfMethyl-Seq, for cost-effective sequencing of cfDNA methylome (with >12-fold enrichment over whole genome bisulfite sequencing in CpG islands), and a computational method to extract methylation information and diagnose patients. Applying our system to 408 colon, liver, lung, and stomach cancer patients and controls, at 97.9% specificity we achieve 80.7% and 74.5% sensitivity in detecting all-stage and early-stage cancer, and 89.1% and 85.0% accuracy for locating tissue-of-origin of all-stage and early-stage cancer, respectively. Our approach cost-effectively retains methylome profiles of cancer abnormalities, thereby permitting the classification models to learn new features as training cohorts grow, and expanding their scope to other cancer types.

  Study EGAS00001006020

• The effect of pre-analytical and physiological variables on cell-free DNA fragmentation

  Background: assays that account for the biological properties and fragmentation of cell-free DNA (cfDNA) can improve the performance of liquid biopsy. However, pre-analytic and physiological differences between individuals on fragmentomic analysis are poorly defined. Methods: we analyzed the impact of collection tube, plasma processing time and physiology on the size distribution of cfDNA, their genome-wide representation and sequence diversity at the cfDNA fragment-ends using shallow Whole Genome Sequencing. Results: we observed that using different stabilizing collection tubes, or processing times does not affect the cfDNA fragment sizes, but can impact the genome-wide fragmentation patterns and fragment-end sequences of cfDNA. In addition, beyond differences depending on the gender, the physiological conditions tested between 63 individuals (age, body mass index, use of medication and chronic conditions) minimally influenced the outcome of fragmentomic methods. Conclusions: our results highlight that fragmentomic approaches have potential for implementation in the clinic, pending clear traceability of analytical and physiological factors.

  Study EGAS00001005748

• Assessment of RNA-Seq Sample Preparation Methodology

  The goal of this study was two-fold, to determine if common purification techniques have any effect on downstream differential expression analysis and to evaluate combinations of alignment and differential expression software for reliability. To this end, blood was collected from three individuals and pooled during and after extraction. After pooling and mixing was completed, samples were divided into three aliquots for testing. The first aliquot was a control and not purified or concentrated. It was diluted to produce samples of varying concentrations for testing. The second aliquot was diluted to 20 ng/μL and used to test six different variations on the AMPure XP bead purification procedure. The last aliquot was also diluted to varying concentrations of 60, 30, and 9.6 ng/μL and purified using MinElute columns. Samples were submitted for total RNA-Seq library preparation and sequencing. Library preparation was performed using the TruSeq Stranded Total RNA with Ribo-Zero Globin kit (20020612, Illumina Inc.), and 2x150 bp PE sequencing was done on an Illumina NovaSeq 6000 with the S4 reagent kit. Comparisons were made between methods (AMPure vs. unpurified, AMPure vs. MinElute, MinElute vs. unpurified) to assess the effects of purification method on downstream differential expression. Comparisons were also made within methods using the varying concentrations tested for unpurified samples and for MinElute purified samples to assess the effects of concentration on differential expression. Variations of the AMPure procedure were also compared to assess the effectiveness of the variations tested in comparison to the unmodified procedure. A subset of samples was selected for use with alignment and differential expression package comparison. Unpurified high concentration samples eluted in RNAse-free water were compared to unpurified high concentration samples eluted in BR5, a buffer from the PAXgene blood miRNA kit, with the expectation that there should be no or very few differentially expressed genes. Unpurified high concentration samples eluted in RNAse-free water were also compared to unpurified low concentration samples also eluted in RNAse-free water, with possibly a small number of differentially expressed genes anticipated. A third dataset of simulated RNA-seq data was created with a known rate of differential expression. These files were aligned using Bowtie2, HISAT2, kallisto, RSEM, Rsubread, Salmon, and STAR. Results were then analyzed for differential expression using ALDEx2, baySeq, DEGseq, DESeq2, edgeR, limma, NOISeq, PoissonSeq, and SAMseq. Differential expression results of all three comparisons were evaluated to determine which combinations provided the most reliable results for both real and simulated data.

  Study phs003001

• A prospective multicenter study of plasma ctDNA versus archival tumor tissue to guide FGFR-targeted therapy in metastatic urothelial cancer - Targeted

  Targeted sequencing data related to the publication titled "A prospective multicenter study of plasma ctDNA versus archival tumor tissue to guide FGFR-targeted therapy in metastatic urothelial cancer." FGFR alterations, seen in up to 25% of metastatic urothelial carcinoma, can be exploited with targeted therapy. Here, we perform targeted sequencing of cell-free DNA, archival FFPE, and white blood cell DNA to compare ctDNA versus tissue for FGFR biomarker status and monitor temporal changes to FGFR over the disease course, specifically after progressing on targeted therapy.

  Study EGAS50000001450

• Circulating tumour DNA abundance and potential utility in de novo metastatic prostate cancer

  Several systemic therapeutic options exist for metastatic castration sensitive prostate cancer (mCSPC). Circulating tumour DNA can profile metastatic castration resistant prostate cancer and influence treatment decisions, but remains untested in mCSPC. We set out to determine ctDNA abundance at de novo mCSPC diagnosis and whether ctDNA provides complementary clinically relevant information to a prostate biopsy. We collected and sequenced 77 plasma cell-free DNA samples from 53 newly diagnosed patients with mCSPC. Targeted sequencing was also performed on DNA from 48 diagnostic prostate tissue samples.

  Study EGAS00001003351

• Clinical utility of combined low-pass whole genome and targeted sequencing in liquid biopsies for diagnosis and monitoring of pediatric solid tumors

  We designed a liquid biopsy (LB) platform employing Low-Pass Whole Genome Sequencing (LP-WGS) and targeted sequencing of cell-free (cf) DNA isolated from plasma for detecting genome-wide copy number alterations and targeted gene fusions in pediatric solid tumors. A total of 143 plasma samples were analyzed from 19 controls (patients with non-oncologic diagnoses) and 73 patients, including 44 with bone or soft tissue sarcomas, 12 with renal tumors, 10 with germ cell tumors, 5 with hepatic tumors, and 2 with thyroid tumors.

  Study EGAS00001006913

• STARR-seq of ERa binding sites in MCF7 and Ishikawa cell lines

  A oligo-captured STARR-seq library was generated using as targets ERa binding regions indetified by ChIP-seq in Ishikawa (Endometrial cancer) and T47D (breast cancer) cell lines and, breast cancer primary tissues. STARR-seq assays have been performed in MCF-7 and Ishikawa cell lines. Cells have been cultured for 3 days in hormone deprivated (phenol-red free) media and stimulated for 6 hours by 10nM estradiol (E2) or DMSO (negative control).

  Dataset EGAD50000000015

• The dataset for Early detection of ovarian cancer using cell-free DNA fragmentomes and protein biomarkers

  The dataset for “Early detection of ovarian cancer using cell-free DNA fragmentomes and protein biomarkers” includes 409 cram files from whole genome next-generation sequencing on the Illumina HiSeq2500. The samples analyzed include plasma samples from healthy individuals and patients with cancer.

  Dataset EGAD50000000695

• Genome-wide cell-free DNA mutational integration enables ultra-sensitive cancer monitoring

  In many areas of oncology, we lack sensitive tools to track low burden disease. While cell-free DNA (cfDNA) shows promise in detecting cancer mutations, we found that the combination of low tumor fraction (TF) and limited number of DNA fragments restricts low disease burden monitoring through the prevailing deep targeted sequencing paradigm. We reasoned that breadth may supplant depth of sequencing to overcome the barrier of cfDNA abundance. Whole genome sequencing (WGS) of cfDNA allowed ultra-sensitive detection, capitalizing on the cumulative signal of thousands of somatic mutations observed in solid malignancies, with TF detection sensitivity as low as 10-5. The WGS approach enabled dynamic tumor burden tracking and post-operative residual disease detection, associated with adverse outcome. Thus, we present an orthogonal framework for cfDNA cancer monitoring via genome wide mutational integration, enabling ultra-sensitive detection, overcoming the limitation of cfDNA abundance, and empowering treatment optimization in low-disease burden oncology care

  Study EGAS00001004406

• DAC for cell free DNA TAPS study

  Dac EGAC00001001903

• Transrenal DNA Analysis

  Urinary cell-free DNA (ucfDNA) is an emerging marker in liquid biopsy. However, the characteristics of transrenal DNA and urinary-tract DNA are not fully understood. Therefore, we investigated the fragmentomic features and demonstrated the potential clinical utilities of ucfDNA in the current study.

  Study EGAS50000000766

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

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

  Study phs000924

• Cancer cell and tumor microenvironment biomarkers associated with disease-free survival with adjuvant nivolumab in the phase 3 CheckMate 274 trial

  In the CheckMate 274 trial, adjuvant nivolumab versus placebo demonstrated an improvement in the primary endpoint of disease-free survival (DFS) in patients with high-risk muscle-invasive urothelial carcinoma after radical resection. An extensive analysis of tumor biomarkers, including their associations with DFS, was performed. Analysis of genome-wide differential gene expression and known gene signatures found that immune-related genes and pathways, in particular an IFNγ signature, were predictive of DFS in nivolumab-treated patients. Predictive and prognostic associations, respectively, were found for tumor-infiltrating CD4 and CD8 T cells. Analysis of a composite predictive model suggested that CD4 gene expression and tumor cell PD-L1 expression had the greatest contributions to predicting outcomes in nivolumab-treated patients. These results reinforce recent studies establishing the importance of biomarkers of adaptive immunity, and in particular CD4 T cells, in influencing response to PD-1/PD-L1 blockade and establish the potential predictive rather than solely prognostic nature of such findings.

  Study EGAS50000000560

• cfRRBS methylation profiling of cfDNA from cerebrospinal fluid from pediatric CNS tumor patients

  In this study, we explore the potential of classifying pediatric brain tumors based on methylation profiling of the cell-free DNA in cerebrospinal fluid (CSF). For this proof-of-concept study, we collected 20 cerebrospinal fluid samples of pediatric brain cancer patients via a ventricular drain placed for reasons of increased intracranial pressure. For 11 patients in this study we collected matched tumor DNA. This cohort contains fastQ files of cfRRBS data of these samples.

  Dataset EGAD50000000554

• Whole genome sequencing of patients with or at risk for HCC

  Liver cancer is a major cause of cancer mortality worldwide. Screening individuals at high risk, including those with cirrhosis and viral hepatitis, provides an avenue for improved survival, but current screening methods are inadequate. In this study, we used whole-genome cell-free DNA (cfDNA) fragmentome analyses to evaluate 724 individuals from the United States, the European Union, or Hong Kong with hepatocellular carcinoma (HCC) or who were at average or high-risk for HCC. Using a machine learning model that incorporated multifeature fragmentome data, the sensitivity for detecting cancer was 88% in an average-risk population at 98% specificity and 85% among high-risk individuals at 80% specificity. We validated these results in an independent population. cfDNA fragmentation changes reflected genomic and chromatin changes in liver cancer, including from transcription factor binding sites. These findings provide a biological basis for changes in cfDNA fragmentation in patients with liver cancer and provide an accessible approach for noninvasive cancer detection.

  Study EGAS00001007249

• Enhanced Detection of Landmark Minimal Residual Disease in Lung Cancer using Cell-Free DNA Fragmentomics

  The circulating tumor DNA (ctDNA) mutation-based approach shows limited performance in minimal residual disease (MRD) detection, especially for landmark MRD detection at an early-stage cancer after surgery. Here, A total of 87 NSCLC patients, who received curative surgical resections (23 patients relapsed during follow-up), enrolled in this study. A total of 163 plasma samples, collected at 7 days and 6 months postsurgical, were used for high-throughput sequencing.

  Dataset EGAD00001010300

• Size-tagged preferred ends in maternal plasma DNAshed light on the production mechanism and showutility in noninvasive prenatal testing

  Cell-free DNA molecules in the plasma of pregnant women exhibit nonrandom fragmentation with preferred end sites. We studied if such preferred end sites might bear any re- lationship with fragment lengths of plasma DNA. Short and long plasma DNA molecules were associated with different preferred DNA end sites. Analysis of size-tagged preferred ends could be used for measuring fetal DNA fraction and for facilitating fetal trisomy 21 detection. Fetal preferred end sites were generally located in the nucleosome cores, while the maternal ones were located in the linker regions. This con- ceptual framework provides an explanation of the relative shortness of fetal DNA in maternal plasma and brings us closer to understanding the biological mechanisms that influence plasma DNA fragmentation.

  Study EGAS00001002831

• Error-corrected flow-based sequencing at whole genome scale and its application to circulating cell-free DNA profiling

  Differentiating sequencing errors from true variants is a central genomics challenge calling for error suppression strategies that balance costs when sparse material or ultra-rare variants require high-accuracy methods. For example, circulating cell-free DNA (ccfDNA) sequencing for cancer monitoring is limited by sparsity of circulating tumor DNA (ctDNA), abundance of genomic material in samples, library preparation error rates and sequencing errors. Whole-genome sequencing (WGS) can overcome the low abundance of ccfDNA by integrating signal across the mutation landscape, but higher cost limits adoption compared with targeted panels, where ccfDNA abundance limits maximal coverage depths. Here we applied deep (~120x) lower-cost WGS (Ultima Genomics) with analytic error correction for tumor-informed ctDNA detection within the part-per-million range. We further developed high-coverage duplex error-corrected WGS of ccfDNA, achieving 7.7x10-8 error rates, to assess disease burden in melanoma and urothelial cancer patients without matched tumor sequencing. Together, we show that deeply sequenced error-corrected WGS accurately calls somatic variants, demonstrating the feasibility of WGS for tumor-informed and tumor-agnostic ctDNA detection.

  Study EGAS50000000844

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

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

  Study phs001325

• circulating cell-free RNAs, CF-miRNAs, Sequencing with Qiaseq and NextSeq 550

  This dataset includes small RNA sequencing data from circulating cell-free RNAs (CF-miRNAs). miRNA libraries were prepared using the Qiaseq miRNA Library Kit with adaptations for low RNA input and sequenced on the Illumina NextSeq 550 platform

  Dataset EGAD50000001503

• PCR-Free Shallow Whole Genome Sequencing for Chromosomal Copy Number Detection

  Archival peripheral blood or bone marrow plasma samples from non small-cell lung cancer, B-cell lymphoma and acute myeloid leukemia patients, and healthy donors. Shallow whole genome sequencing of 100 Samples by two distinct library preparation methods (PCR = 45, PCR-Free = 55). sWGS done for Chromosomal CN detection.

  Dataset EGAD50000001404

• Detection and localization of surgically resectable cancers with a multi-analyte blood test

  Earlier detection is key to reducing cancer deaths. Here we describe a blood test that can detect eight common cancer types through assessment of the levels of circulating proteins and mutations in cell-free DNA. We applied this test, called CancerSEEK, to 1,005 patients with clinically detected cancers of the ovary, liver, stomach, pancreas, esophagus, colorectum, lung, or breast. CancerSEEK tests were positive in a median of 70% of the eight cancer types. The sensitivities ranged from 69% to 98% for the detection of five cancer types (ovary, liver, stomach, pancreas, and esophagus) for which there are no screening tests available for average-risk individuals. The specificity of CancerSEEK was > 99%: only 7 of 812 healthy controls scored positive. In addition, CancerSEEK localized the cancer to a small number of anatomic sites in a median of 83% of the patients.

  Study EGAS00001002764

• Differential Presence of Exons in Cell-Free DNA Reveals Different Patterns in Colorectal Cancer Between Metastatic and Non-Metastatic Patients

  Dac EGAC00001000749

• End structure of DNA in plasma: detection, characterizationand diagnostic applications

  The physical properties of cell-free DNA fragments in plasma, such as fragment sizes and ends, have attracted much recent interest, leading to the emerging field of fragmentomics. This study attempted to further characterize the end structure of plasma DNA.

  Study EGAS00001004080

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

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

  Study phs000928

• Genomic sequencing of Pediatric Rhabdomyosarcoma

  Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood accounting for approximately 350 newly diagnosed cases yearly in the United States. With the development of multimodal chemotherapy regimens, relapse-free survival rates have improved to 70-80% in patients with localized disease albeit with significant toxicity. Unfortunately, despite aggressive treatment, patients with metastatic or recurrent disease continue to suffer from high mortality. Further characterization of the genetic events underlying this tumor type is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. In a collaborative effort between the National Cancer Institute, the Children's Oncology Group, and the Broad Institute, we use a combination of whole-genome and whole-exome sequencing to characterize the landscape of somatic alterations in 147 tumor/normal pairs.

  Study phs000720

• A fast, affordable and minimally-invasive diagnostic test for Cancer of Unknown Primary (CUP) using DNA methylation profiling

  CUP diagnosis on FFPE tissue and liquid biopsies (blood, pleural and peritoneal effusions) using cfRRBS (cell-free reduced representation bisulfite sequencing), a technique that allows for identification of the methylation profile starting from minimal amounts of highly fragmented DNA.

  Study EGAS50000000257

• MicroRNA profiling by next-generation sequencing for colorectal cancer screening

  The dataset contains raw miRNA sequencing data of plasma samples from 20 newly diagnosed colorectal cancer cases and 20 controls free of colorectal neoplasms matched by age and sex. It includes files in the FASTQ compressed (.gz) format.

  Dataset EGAD00001006966

• Differential Presence of Exons in Cell-Free DNA (NIMGenetics/IIS-FJD)

  Dac EGAC00001002885

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

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

  Study phs000981

• Cell-free DNA methylation profiling of sepsis patients

  This data set contains paired-end NGS files (in FASTQ format) generated from a methylation profiling experiment of cell-free DNA derived from the plasma of sepsis patients and healthy controls. Methylation profiling was performed using the TET-assisted pyridine borane sequencing (TAPS) protocol.

  Dataset EGAD50000001505

• Single Nucleus Transcriptomes from the Ventral Midbrain of Opioid Overdose Cases and Controls

  We generated ventral midbrain single nuclei RNA-seq libraries for 95 brain donors, including 45 subjects with documented histories of opioid abuse and overdose, and 50 demographically-matched, opioid-free control subjects, collected from two geographically distinct regions within the U.S. (greater Detroit area, Michigan and Miami, Florida). Each sample included both substantia nigra and the adjacent ventral tegmental area. Nuclei were processed in pools of 3-4 brains using the 10X Chromium system followed by Illumina sequencing, read alignment and processing by 10X Cellranger.

  Study phs003260

• Clonal selection after gene therapy in sickle cell disease

  While gene therapy (GT) provides a potentially curative treatment option for patients with sickle cell disease (SCD), the occurrence of myeloid malignancies in clinical trials has prompted concern. To interrogate potential mechanisms underlying increased cancer risk, we used hematopoietic stem cell (HSC) clonal tracking by whole genome sequencing (WGS) to map the somatic mutation and clonal landscape of 2,592 gene modified as well as unmodified single stem and progenitor cells from six SCD patients undergoing gene therapy (7-26 years old, average 12.7× depth). Pre-GT phylogenetic trees in SCD were highly polyclonal and mutation burdens per cell were elevated in some, but not all, patients. Post-GT, no clonal expansions were identified. However, an increased frequency of driver mutations associated with myeloid neoplasms or clonal hematopoiesis (DNMT3A- and EZH2-mutated clones in particular) were seen in both genetically modified and unmodified cells suggested positive selection of mutant clones during gene therapy. This work sheds light on the mutation landscape and HSC clonal dynamics in gene therapy for SCD and highlights enhanced fitness of some HSCs harboring pre-existing driver mutations following gene therapy. Future studies should define the long-term fate of mutant clones including any contribution to expansions associated with myeloid neoplasms.

  Dataset EGAD00001010913

• Identification of hypermutation and defective mismatch repair in ctDNA from metastatic prostate cancer

  DNA mismatch repair defects (MMRd) and tumor hypermutation are rare and under-characterized in metastatic prostate cancer. Furthermore, since hypermutated MMRd prostate cancers can respond to immune checkpoint inhibitors, there is an urgent need for practical detection tools. We analyzed cell-free DNA targeted sequencing data from 434 metastatic prostate cancer patients with circulating tumor DNA (ctDNA) purity above 2%. Samples with somatic hypermutation were subjected to 150x whole exome sequencing. These data allowed us to interrogate the salient genomic properties of this rare prostate cancer subtype and correlate findings with patient clinical outcomes.

  Study EGAS00001003899

• The data access committee for Genome-wide analyses of cell-free DNA for therapeutic monitoring of patients with pancreatic cancer

  Dac EGAC50000000588

• The G2 gene expression signature and MYC overexpression are independent poor prognostic factors in childhood high-grade osteosarcoma

  Purpose In high-grade osteosarcoma, prognostic factors at diagnosis are insufficient for stratifying patients into relevant subgroups. Recently, a transcriptomic study developed the G1/G2 gene expression signature, in which the G2 signature was associated with unfavorable survival. An orthogonal study identified MYC amplification as an unfavorable prognostic factor using targeted next-generation sequencing. The purpose of this study was to validate the independent prognostic value and to investigate the combined prognostic value of the G1/G2 signature with, MYC amplification and/or MYC expression for survival prediction. Material and methods This study included pediatric and adolescent patients with high-grade osteosarcoma. RNA sequencing was performed in 48 patients. Whole-exome sequencing was performed in 40 patients. Gene expression signature scores, MYC amplification (defined as > 7 copies) and MYC expression levels were calculated. Multivariable Cox proportional hazards analysis was performed for event-free survival (EFS) (primary endpoint) and overall survival (OS) (secondary endpoint). Results In the full cohort, the 3-year event-free survival rate was 37%. In multivariable Cox regression analysis with metastatic disease stage (n=21, 44%) as covariate, the G2 signature and MYC expression were independently associated with worse outcomes in terms of EFS (Hazard ratio (HR) 3.32, 95% confidence interval (CI) 1.34-8.21 and HR 3.38, 95%-CI 1.71-6.66, respectively) and OS (HR 4.07, 95%-CI 1.19-13.9 and HR 2.88, 95%-CI 1.22-6.76, respectively). MYC amplification was not associated with EFS or OS in univariable analysis (HR 1.88, 95% -CI 0.74-4.77 and HR 0.79, 95%-CI 0.21-3.05, respectively). Conclusion The G2 gene expression signature and MYC expression were independently associated with unfavorable outcomes in a pediatric cohort of patients with high-grade osteosarcoma. The combined prognostic value warrants further prospective validation and could potentially serve as a stratification marker for future osteosarcoma treatment protocols.

  Study EGAS00001008073

• Targeted sequencing of 72 prostate cancer driver in 712 plasma cell free DNA samples

  Dataset contains targeted sequencing data of 712 plasma cell free DNA samples and 428 white blood cell samples collected from 428 men with metastatic prostate cancer. Target capture was performed using a hydridization-based custom Roche SeqCap EZ Choice kit, designed to capture all exons of 72 prostate cancer driver genes. Cell free DNA was extracted from 10 mL blood samples. Libraries were sequenced using Illumina HiSeq 2500 or Illumina MiSeq instruments to a median coverage of 750x. 62% of samples had ctDNA fraction above 2% of total cfDNA. Note that "Dataset type" is erroneously listed as "Amplicon sequencing", because "Captured-based targeted sequencing" or "Hybridization-based targeted sequencing" were not available options in EGA at the time of submission.

  Dataset EGAD00001004208

• Liquid-based genomic profiling in high-risk localized prostate cancer.

  In this study, we evaluated the feasibility and performance of tissue and liquid-based genomic profiling in patients with high-risk localized prostate cancer. Genomic DNA from 12 FFPE tissue samples and cell-free DNA from 27 plasma samples were analyzed using Illumina TruSight Oncology (TSO) 500 panels.

  Study EGAS50000001712

• The data access committee for Single molecule genome-wide mutation profiles of cell-free DNA for non-invasive detection of cancer

  Dac EGAC00001003253

• The Human Phenotype Project (HPP) is a large-scale deep-phenotype prospective longitudinal and ethnically diverse cohort

  The Human Phenotype Project (HPP) is a large-scale deep-phenotype prospective longitudinal and ethnically diverse cohort and biobank that we established. To date, approximately 28,000 participants have enrolled in the study, with over 13,000 having completed their initial visit. The project is aimed at identifying novel molecular signatures with diagnostic, prognostic and therapeutic value, and at developing AI-based predictive models for disease onset and progression. A unique feature of the HPP is its deep and longitudinal profiling that includes medical history, lifestyle and nutritional habits, vital signs, anthropometrics, blood tests, continuous glucose and sleep monitoring, imaging modalities and molecular profiling of the transcriptome, genetics, gut, vaginal and oral microbiome, metabolome and immune system. For several of these modalities, the HPP is the first or largest cohort of its kind. Our analyses of this data provide novel insights into the variation of phenotypes with age and ethnicity, highlighting the importance of having ethnically diverse cohorts and the need for establishing age-dependent norms. We demonstrate how the HPP can be used to unravel personalized molecular signatures of disease by comparison to patient-specific and disease-specific matched healthy controls. Leveraging the extensive dietary and lifestyle HPP data, we systematically identify associations between lifestyle factors and health outcomes. Finally, we present a multi-modal foundation AI model that is trained using self-supervised learning on diet and CGM data and outperforms existing methods in predicting future onset of disease. We extend this AI framework to integrate all data modalities of each subject as a continuous sequence of diverse medical events, creating a digital twin that can simulate interventions and predict health trajectories and outcomes.

  Study EGAS00001008040

• Dataset for the study - Detection of cell-free DNA fragmentation and copy number alterations in cerebrospinal fluid from glioma patients

  FASTQ files from sequencing to < 0.4x depth of coverage of thirteen glioma patients. Indexed sequencing libraries were prepared using a commercially available kit (ThruPLEX-Plasma Seq, Rubicon Genomics). Libraries were pooled in equimolar amounts and sequenced on a HiSeq 4000 (Illumina) generating 150-bp paired-end reads.

  Dataset EGAD00001004425

• DPY30_ChIP_seq

  H9 human embryonic stem cells (hESCs) were cultured in feeder-free chemically-defined conditions in medium containing 10ng/ml Activin A and 12ng/ml FGF2 (Vallier L. 2011, Methods in Molecular Biology, 690: 57–66). Chromatin immunoprecipitation was performed as described in Brown S. et al. 2011. Stem Cells 29: 1176–85 by using 5ug of anti-DPY30 antibody (Sigma, cat. number HPA043761). This protocol was performed in control hESCs (expressing a scrambled shRNA) and in hESCs stably expressing an shRNA against DPY30 (Sigma, clone n. TRCN0000131112).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/

  Study EGAS00001001132

• The data access committee for Detecting Liver Cancer Using Cell-Free DNA Fragmentomes

  Dac EGAC00001003279

• Linguistic utterance counts for The admixture histories of Cabo Verde

  Datasets used in the article "The genetic and linguistic admixture histories of the islands of Cabo Verde" by Laurent R et al. eLife 2023 (DOI: https://doi.org/10.7554/eLife.79827 - URL: https://elifesciences.org/articles/79827) File name "eGAdeposit_225CaboVerde_FreeSpeech_Utterance_counts_FINAL_01062022.txt" Column 1 corresponds to individual alphanumeric codes as in the "eGAdeposit_233CaboVerde_GenotypeFile_FINAL_01062022.vcf" genotype file. Note that only 225 unrelated Cabo Verdean-born individuals are considered here, out of the 233 individuals in the genotype file. See Material and Methods in Romain Laurent et al. 2022 - doi pending Each 4831 other column correspond to the respective individual's utterance count in the free speech transcribed in ALUPEC and provided as column header. See See Material and Methods in Romain Laurent et al. 2022 - doi pendingColumn 1 corresponds to individual alphanumeric codes as in the "eGAdeposit_233CaboVerde_GenotypeFile_FINAL_01062022.vcf" genotype file. Note that only 225 unrelated Cabo Verdean-born individuals are considered here, out of the 233 individuals in the genotype file. See Material and Methods in Romain Laurent et al. 2022 - doi pending Each 4831 other column correspond to the respective individual's utterance count in the free speech transcribed in ALUPEC and provided as column header. See Material and Methods in Laurent R et al. eLife 2023

  Dataset EGAD00001008978

• Sensitive and reproducible cell-free methylome quantification with synthetic spike-in controls

  Study EGAS00001005069

• DAC for Early detection of ovarian cancer using cell-free DNA fragmentomes and protein biomarkers

  Ovarian cancer is a leading cause of death from gynecological malignancies worldwide. No effective screening methods exist resulting in tumor detection at advanced stages where treatment is less effective. In this study, we used whole-genome cell-free DNA (cfDNA) fragmentome and protein biomarker (CA-125 and HE4) analyses to evaluate 591 women, mostly post-menopausal, from the European Union or the United States with ovarian cancer, benign adnexal masses, or without ovarian lesions. Using a machine learning model that incorporated multi-analyte fragmentome data and protein measurements, we evaluated the detection of ovarian cancer in two clinical settings, detection of ovarian cancers among a healthy population, and classification of adnexal masses as benign or malignant. The combined approach detected ovarian cancer with specificity >99% and sensitivity of 72%, 69%, 87%, and 100% for stages I–IV, respectively (AUC=0.96, 95% CI: 0.94-0.99), including 90% of high grade serous ovarian cancers. At the same specificity, CA-125 alone detected 34%, 62%, 63%, and 100% of ovarian cancers for stages I–IV (p=0.001, two-sided test of equal proportions). Additionally, our approach differentiated benign masses from ovarian cancers with high accuracy (AUC of 0.88, 95% CI=0.83-0.92). These results were validated in an independent population. These findings show that integrated cfDNA fragmentome and protein analyses detect ovarian cancers with high performance, enabling a new accessible approach for noninvasive ovarian cancer screening and diagnostic evaluation.

  Dac EGAC50000000332

• DirectHRD Enables Sensitive Scar-Based Classification of Homologous Recombination Deficiency (HRD)

  Homologous recombination deficiency (HRD)-induced genomic scars are an FDA-approved biomarker for identifying cancers likely to respond to PARP inhibitors. However, detecting HRD scars from blood biopsies has been challenging due to the low tumor content in blood samples. To address this limitation, we developed DirectHRD, a genomic scar-based HRD classifier leveraging whole-genome sequencing (WGS) data for non-invasive blood biopsy testing. DirectHRD was applied to 90 cell-free DNA (cfDNA) samples across four cancer types: breast, ovarian, prostate, and pancreatic. The method achieved an AUC of 0.87 and demonstrated the ability to detect HRD at tumor fractions as low as 1%, offering a tenfold increase in sensitivity compared to state-of-the-art methods.

  Study phs003760

• Association studies using the Metabochip array - Samples analysed by the WTCCC (1958 British Birth Cohort (58BC), Hypertension cohort (HT), Type 2 Diabetes Cohort (T2D) and Coronary Artery Disease (CAD) cohort)

  Genomewide association studies (GWAS) have proven a powerful hypothesis-free method to identify common disease-associated variants. Even quite large GWAS, however, have only at best identified moderate proportions of the genetic variants contributing to disease heritability. To provide cost-effective genotyping of common and rare variants to map the remaining heritability and to fine-map established loci, the Metabochip Consortium has developed a 200,000 SNP chip that has been produced in very large numbers for a fraction of the cost of GWAS chips. This chip provides a powerful tool for genetic studies of metabolic, cardiovascular and anthropometric traits (Voight et al., in press PLoS Genetics).

  Study EGAS00000000115

• Genome-wide NanoRCS sequencing of cfDNA and ctDNA from liquid biopsies of healthy individuals and cancer patients

  Levels of circulating tumor DNA (ctDNA) in liquid biopsies may serve as a sensitive biomarker for real-time, minimally-invasive tumor diagnostics and monitoring. However, detecting ctDNA is challenging, as much fewer than 5% of the cell-free DNA in the blood typically originates from the tumor. To detect lowly abundant molecules, extremely sensitive sequencing methods are required. We developed a new technique, NanoRCS, which is based on Oxford Nanopore sequencing of concatenated copies of a single DNA molecule for genome-wide sequencing, and applied this to plasma of healthy individuals, Esophageal cancer patients and Granulosa cell tumor patients and ascites of Ovarian cancer patients. We also sequenced these samples on Illumina Novaseq, to compare the two techniques.

  Study EGAS50000000154

• cfDNA methylation profiling in Metastatic Cancer and Cancer of Unknown Primary

  This study contains methyl-binding domain sequencing and shallow whole genome sequencing from circulating cell-free DNA (cfDNA) for 143 patients with metastatic cancer of known type, 41 patients with Cancer of Unknown Primary (CUP) and 27 non-cancer controls.

  Dataset EGAD00001011178

• STAMPEED: Cardiovascular Health Study (CHS) GWAS to identify genetic variants associated with aging and CVD risk factors and events

  The primary aim of the study is to conduct a genome-wide association study to identify genetic variants associated with the incidence of myocardial infarction (MI), stroke, and heart failure (HF) among participants enrolled in the Cardiovascular Health Study (CHS) who were free of clinical cardiovascular disease at baseline. The secondary aim is to conduct genome-wide association study of other phenotypes in CHS. The study is an ancillary study to CHS. CHS is a population-based cohort study of risk factors for heart disease and stroke among older adults recruited at 4 US sites in 1989-1990. Subjects underwent an extensive baseline examination, and annual follow-up examinations through 1988-1999.

  Study phs000226

• Division of Cancer Epidemiology and Genetics (DCEG) Imputation Reference Dataset

  We have built a new resource for imputation of SNPs for existing and future genome-wide association studies (GWAS), known as the Division of Cancer Epidemiology and Genetics (DCEG) Reference Set. The first build of the data set includes 728 cancer-free individuals of European descent from three large prospectively sampled studies, 98 African-American individuals from the Prostate, Lung, Colon, and Ovary Cancer Screening Trial (PLCO), 74 Chinese individuals from a Chinese clinical trial in Shanxi, China (SHNX), and 349 unrelated individuals from the HapMap Project (see Molecular Data Section for details on arrays used). The final harmonized dataset includes 2.8 million autosomal polymorphic SNPs on 1,249 subjects after rigorous quality control metrics were applied.

  Study phs000396

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

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

  Study phs000695

• Whole transcriptome profiling of liquid biopsies from tumour xenografted mouse models: validation cohort

  While cell-free DNA (cfDNA) in liquid biopsies is widely being used and investigated, free circulating RNA (extracellular RNA, exRNA) has the potential to improve therapy response monitoring and cancer detection due to its dynamic nature. A fundamental open question hampering the initiation of large-scale liquid biopsy collections for tumour exRNA analysis is that it remains unclear in which blood subcompartment tumour-derived exRNAs primarily reside. We set out to develop a host-xenograft deconvolution framework, exRNAxeno, with cDNA mapping strategies to either a combined human-mouse reference genome or both species genomes in parallel, that can be applied to exRNA sequencing data from liquid biopsies of human xenograft mouse models, enabling to distinguish (human) tumoural RNA from (murine) host RNA, and as such to specifically analyse tumour-derived exRNA. Subsequently, the preferred exRNAxeno combination pipeline was applied to total exRNA sequencing data from blood platelets and three plasma fractions from a breast cancer patient-derived and neuroblastoma cell line-derived xenograft mouse model. We show that tumoural exRNA concentrations are not determined by plasma platelet levels, while host exRNA concentrations increase with platelet content. Furthermore, a large variability in exRNA levels and gene content across individual mice is observed. In general, the tumoural gene detectability in plasma is correlated with the RNA expression levels in the tumour tissue or cancer cell line. Our results unravel new aspects of tumour-derived exRNA biology in xenograft mouse models.

  Study EGAS00001006582

• DAC - A standardised framework for robust fragmentomic feature extraction from cell-free DNA sequencing data

  Dac EGAC00001003530

• Single cell transcriptomic analysis of the immune cell compartment in the human small intestine and in Celiac disease

  Celiac disease is an autoimmune disorder in which ingestion of dietary gluten triggers an immune reaction in the small intestine leading to destruction of the lining epithelium. Current treatment focusses on lifelong adherence to a gluten-free diet. Gluten-specific CD4+ T cells and cytotoxic intraepithelial CD8+ T cells have been proposed to be central in disease pathogenesis. Here we use unbiased single-cell RNA-sequencing and explore the heterogeneity of CD45+ immune cells in the human small intestine. We show altered myeloid cell transcriptomes present in active celiac lesions. CD4+ and CD8+ T cells transcriptomes show extensive changes and we define a natural intraepithelial lymphocyte population that is reduced in celiac disease. We show that the immune landscape in Celiac patients on a gluten-free diet is only partially restored compared to control samples. Altogether, we provide a single cell transcriptome resource that can inform the immune landscape of the small intestine during Celiac disease.

  Study EGAS00001003751

• Serial assessment of measurable residual disease in medulloblastoma liquid biopsies

  Nearly one-third of children with medulloblastoma, a malignant embryonal tumor of the cerebellum, succumb to their disease. Conventional response monitoring by imaging and cerebrospinal fluid (CSF) cytology remains challenging and a marker for measurable residual disease (MRD) is lacking. Here, we show the clinical utility of CSF-derived cell-free DNA (cfDNA) as a biomarker of MRD in serial samples collected from children with medulloblastoma (123 patients, 476 samples) enrolled on a prospective trial. Using low-coverage whole-genome sequencing, tumor-associated copy-number variations (CNVs) in CSF-derived cfDNA are investigated as an MRD surrogate. MRD is detected at baseline in 85% and 54% of patients with metastatic and localized disease, respectively. The number of MRD-positive patients decline with therapy, yet those with persistent MRD have significantly higher risk of progression. Importantly, MRD detection precedes radiographic progression in half who relapse. Our findings advocate for the prospective assessment of CSF-derived liquid biopsies in future trials for medulloblastoma.

  Study EGAS00001005592

• Development and Use of Network Infrastructure for High-Throughput GWA Studies

  The "Development and Use of Network Infrastructure for High-Throughput GWA Studies" project is collaboration between Group Health Cooperative (GH), the University of Washington (UW), and the Fred Hutchinson Cancer Research Center (FHCRC). It is one of 5 sites participating in The Electronic Medical Records and Genomics (eMERGE) Network funded by the National Human Genome Research Institute (NHGRI) with additional funding from the National Institute of General Medical Sciences (NIGMS). The overall eMERGE project is designed to assess whether linking biorepositories of patients in healthcare delivery systems with electronic medical records (EMRs) is an efficient strategy for high-throughput genome wide association (GWA) studies and whether information can be pooled across sites. The primary phenotype in the Group Health/UW Aging and Dementia eMERGE study project is dementia. Phenotyped participants originated from four population-based sources. Seattle-area members of GH (a large integrated health care system in Washington State) consented and enrolled in 1) the University of Washington Alzheimer's Disease Patient Registry (ADPR) and 2) the Adult Changes in Thought (ACT) study, 3) Marshfield Clinic Personalized Medicine Research Project (PMRP), a population-based DNA, plasma and serum biobank of 20,000 adults, 4) Vanderbilt's BioVU, a de-identified DNA biobank. The ADPR (PI: Eric B. Larson; NIH/NIA U01 AG 006781) is a population-based registry of incident dementia cases designed to identify all new dementia cases within GH from 1987 to 1996. Potential dementia cases were identified through referrals from primary care physicians, mental health services, and neurologists, as well as review of CT scans, neurology, emergency room, geriatrician, and mental health clinic logs, and hospital discharge diagnoses. Medical history, physical, laboratory testing, and neuropsychological testing were performed on all consenting potential cases. These data were reviewed by a consensus conference including a neuropsychologist, study physicians, and an epidemiologist. After discussion of the case, dementia status is assigned using DSM-III-R criteria. Alzheimer's disease status was assigned using the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria. The study base of the ADPR population was stable with an attrition rate of less than 1%/year. The ACT study (PI: Eric B. Larson; NIH/NIA U01 AG 006781) is an ongoing community-based cohort study designed to determine the incidence of Alzheimer's Disease (AD), other types of dementia, and cognitive impairment and to determine risk factors for these conditions. The original cohort of 2,581 was enrolled in 1994-1996. An expansion cohort of 811 was enrolled in 2000-2002. Continuous enrollment to keep 2,000 persons enrolled and at-risk for dementia outcomes was begun in 2005. To date the study has accrued more than 4,000 participants. Dementia-free participants are enrolled in this cohort and evaluated every two years by study personnel with many evaluations including an assessment of cognitive functioning using the Cognitive Abilities Screening Instrument (CASI), which is an extended version of the Mini-Mental State Examination that has been widely used in epidemiological studies of the elderly. Persons with CASI scores lower than 86 or in whom interviewers suspect unusual cognitive decline are followed up with dementia diagnostic evaluations which include physical and neurological examinations and neuropsychological tests. Medical records are reviewed, and laboratory tests and neuroimaging are obtained if not available. The dementia diagnoses and dementia subtypes are determined during a consensus conference attended by the examining clinicians and other study physicians, a neuropsychologist, and research nurse. After discussion of the case, dementia status is assigned using DSM-IV criteria. Alzheimer's disease status was assigned using NINCDS-ADRDA criteria. Individuals diagnosed with dementia are seen again one year following diagnosis using the same procedures. Individuals not diagnosed with dementia are returned to the pool of at-risk individuals and are seen at their next routinely scheduled biennial visit. The ACT sub-sample is stable; for the original cohort, median enrollment in GH was 19 years prior to joining the ACT study, and 85% of the cohort has ≥ 10 years of GH enrollment. DNA for the ADPR participants were obtained through a companion study, Genetic Differences in Cases and Controls (PI: Walter Kukull; NIH/NIA R01 AG007584). DNA obtained through both studies were extracted from blood using Gentra Systems Puregene methods. DNA concentration is determined by UV optical density. All samples are checked for quality by OD 260/280 ratio. For long-term storage, samples are aliquoted and stored at -70°C. The Marshfield study, Personalized Medicine Research Project (PMRP), a population-based DNA, plasma and serum biobank of 20,000 adults. PMRP was started in 2002 as a 3 Phase project. Completed in April 2004, the objectives of Phase I were to build and develop a large population-based biobank with DNA, plasma and serum samples to facilitate genomics research. Phase 1 was also to educate, inform and consult with the Marshfield Epidemiologic Study Area population and communities concerning potential studies, create the DNA foundation of the personalized medicine database and build the bioinformatics tools to store securely and analyze genotypic and phenotypic data. Phase I tasks included operation of the ethics and security advisory board, scientific advisory board and community advisory group. More than 18,000 residents aged 18 and above from 19 different zip codes surrounding Marshfield, WI were invited to participate in Phase I. After providing written informed consent, participants completed brief questionnaires that included questions about demographics, some environmental exposures, family history of disease, and adverse drug reactions, as well as family members living in the area. Participants provided 50ml of blood from which DNA was extracted and plasma and serum samples were stored. The informed consent process allowed access to electronic medical records and included language about non-disclosure of personal research results. A tick-off box was included so that participants could either allow or decline subsequent recontact for future research studied. The objectives of Phase II are to create the phenotypic database, establish the scientific and administrative infrastructure to support genetic mapping of the DNA and the initial discovery projects and genotype a sufficient portion of the genetic material to support these discovery projects. The objectives of Phase III are to expand the discovery projects, complete the genotyping of the genetic database and expand physician/health care provider education and community consultation. The Vanderbilt BioVU model uses discarded blood leftover from clinical care and de-identified clinical information, both of which are tracked with a Research Unique Identifier that is permanently disconnected from the medical record number used to generate it. The Vanderbilt IRB determined that the project does not qualify as "human subject" research under §46.102(f)(1)(2). The program has been reviewed by OHRP twice (the latest immediately prior to launch), and the determination of the Vanderbilt IRB that the project is consistent with the 8/10/2004 guidance has been validated. The model includes a simple opt out mechanism developed for patients who do not wish to have their samples included. Planning (including community involvement, ethics and IRB discussions, focus groups, development of operating procedures and pilot studies to assess them) began in May 2004, and the resource commenced sample collection in February 2007 and as of May 2009 contains approximately 56,000 samples. The current resource will be available to all Vanderbilt investigators who sign a Data Use Agreement. The resource represents Vanderbilt's broad patient population and thus provides a potential resource for research in a range of common and rare diseases as well as drug response or medication safety. BioVU patient protection model: There has been extensive involvement by the ethics community and the IRB to put in place procedures to provide privacy protection. The overall protection plan is multifaceted and includes a combination of technology and policy: (1) creation of the SD described above; (2) return of only the specific clinical data items requested by investigators (rather than the complete de-identified chart); (3) submission of any specific proposed project to the IRB and to a separate protocol review committee, both of which must approve; (4) implementing a Data Use Agreement that permits only approved queries and data analyses, specifically prohibits attempts at re-identification (at the risk of institutional sanctions), and mandates redeposit of all genetic information generated in a research study back into a genomic database; and (5) tracking and auditing all use.

  Study phs000234

• Cardiovascular disease biomarkers derived from circulating cell-free DNA methylation

  Acute coronary syndrome (ACS) remains a major cause of worldwide mortality. The syndrome occurs when blood flow to the heart muscle is decreased or blocked, causing muscle tissues to die or malfunction. There are three main types of ACS: Non-ST-elevation myocardial infarction, ST-elevation myocardial infarction, and unstable angina. The treatment depends on the type of ACS, and this is decided by a combination of clinical findings, such as electrocardiogram and plasma biomarkers. Circulating cell-free DNA (ccfDNA) is proposed as an additional marker for ACS since the damaged tissues can release DNA to the bloodstream. We used ccfDNA methylation profiles for differentiating between the ACS types and provided computational tools to repeat similar analysis for other diseases. We leveraged cell type specificity of DNA methylation to deconvolute the ccfDNA cell types of origin and to find methylation-based biomarkers that stratify patients. We identified hundreds of methylation markers associated with ACS types and validated them in an independent cohort. Many such markers were associated with genes involved in cardiovascular conditions and inflammation. ccfDNA methylation showed promise as a non-invasive diagnostic for acute coronary events. These methods are not limited to acute events, and may be used for chronic cardiovascular diseases as well.

  Study EGAS00001007263

• Case Study of Acquired Resistance to FGFR Inhibition in Cholangiocarcinoma using Targeted DNA and RNA Sequencing

  Targeted sequencing was performed on blood, tumor, and cell free DNA samples from an FGFR2-fusion positive cholangiocarcinoma patient before and after treatment with an FGFR targeted therapy.

  Study phs001924

• Tumor Profiler Project - OV cell-free DNA data

  The dataset contains amplicon sequencing data from 48 samples from 35 different patients with ovarian cancers. Cell free DNA was collected from plasma. Sequencing was performed on an Ion Torrent platform and the sequencing data is provided in bam format.

  Dataset EGAD50000001410

• Circulating tumor DNA in urine and plasma of glioma patients - sequencing data

  Dataset consisting of sequence data from 36 glioma patients. Data includes; -Whole exome sequencing of tumour tissue and matched germline -Shallow whole genome sequencing of urine cell-free DNA -Targeted capture sequencing of plasma and CSF cell-free DNA Additional sequencing data are provided from non-glioma and healthy controls

  Dataset EGAD00001006156

• INSPIRE multi-timepoint cfMeDIP dataset

  This dataset contains raw sequencing data from multi-timepoint cell-free methylated DNA immunoprecipitation and sequencing (cfMeDIP-seq) of plasma samples from the INSPIRE study (NCT02644369). Details about the study, including inclusion/exclusion criteria and interventions are available at https://clinicaltrials.gov/study/NCT02644369. Briefly, five cohorts were included, INS-A (head & neck squamous cell carcinoma), INS-B (triple-negative breast cancer), INS-C (high-grade serous ovarian cancer), INS-D (melanoma), and INS-E (mixed solid tumors). All patients in the study were diagnosed with advanced cancer and received treatment with pembrolizumab. Plasma samples were collected at baseline and every 3 cycles until disease progression, death, loss of follow-up, or completion of the study. Plasma samples were first processed for cell-free DNA mutations and remaining samples were then processed by cfMeDIP-seq, prioritizing baseline and post-cycle 3 samples. In total, data from 204 timepoints from 87 distinct patients are deposited.

  Dataset EGAD00001011312

• Scalable Whole-Exome Sequencing of Cell-Free DNA Reveals High Concordance with Metastatic Tumors

  We performed whole genome sequencing and whole-exome sequencing of cell-free DNA (cfDNA) and whole-exome sequencing of matched tumor biopsies and germline DNA from patients with metastatic cancer. Using ichorCNA, a software tool that quantifies tumor content in ultra-low pass whole genome sequencing (~0.1x) of cfDNA without prior genomic characterization of the tumor, we show genome-wide concordance between cfDNA and tumor biopsies and detectability of high tumor fractions (>0.1) in the cfDNA of many patients with metastatic cancer. We then established that whole-exome sequencing of cfDNA can enable comprehensive profiling of tumors from blood, with high tumor-content cfDNA samples demonstrating concordance of clonal somatic mutations, copy number alterations, mutational signatures, and neoantigens with matched tumor biopsies. This study introduces a new method to identify patients that could be eligible for tumor profiling from cfDNA and sheds light on the concordance between metastatic tissue and blood biopsies.

  Study phs001417

• Detection of ctDNA in Plasma of Patients with Clinically Localised Prostate Cancer is Associated with Rapid Disease Progression

  Purpose: DNA originating from degenerate tumour cells can be detected in the circulation in many tumour types, where it can be used as a marker of disease burden as well as to monitor treatment response. Although circulating tumour DNA (ctDNA) measurement has prognostic/predictive value in metastatic prostate cancer, its utility in localised disease is unknown. Patients and Methods: We performed whole genome sequencing of tumour-normal pairs in eight patients with clinically localised disease undergoing prostatectomy, identifying high confidence genomic aberrations. A bespoke DNA capture and amplification panel against the highest prevalence, highest confidence aberrations for each individual was designed and used to interrogate ctDNA isolated from plasma prospectively obtained pre- and post- (24 hours and 6 weeks) surgery. In a separate cohort (n=189) we identified the presence of ctDNA TP53 mutations in pre-operative plasma in a retrospective cohort, and determined its association with biochemical- and metastasis-free survival. Results: Tumour variants in ctDNA were positively identified pre-treatment in two of eight patients, which in both cases remained detectable postoperatively. Patients with tumour variants in ctDNA had extremely rapid disease recurrence and progression compared to those where variants could not be detected. In terms of aberrations targeted, single nucleotide and structural variants outperformed indels and copy number aberrations. Detection of ctDNA TP53 mutations was associated with a significantly shorter metastasis-free survival (6.2 vs. 9.5 years (HR 2.4; 95% CIs 1.2-4.8, p = 0.014)). Conclusions: CtDNA is uncommonly detected in localised prostate cancer but its presence portends more rapidly progressive disease.

  Study EGAS00001004636

• The data access committee for Detection and characterization of lung cancer using cell-free DNA fragmentomes

  Dac EGAC00001002184

• ARDSNet 07-08: Randomized, Blinded, Placebo-Controlled, Multi-Center Trial of Omega-3 Fatty Acid, Gamma-Linolenic Acid, and Antioxidants in Acute Lung Injury or ARDS (OMEGA) (ARDSNet-Omega-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. Biospecimens: Access to Biospecimens is through the NHLBI Biologic Specimen and Data Repository Information Coordinating Center (BioLINCC). Biospecimens from ARDSNet-Omega include bronchial lavage, plasma, urine, and DNA. Please note that use of biospecimens in genetic research is subject to a tiered consent.Objectives: To determine if dietary supplementation of omega-3 (n-3) fatty acids, γ-linolenic acid and antioxidants to participants with acute lung injury would increase ventilator-free days to study day 28.Background: Early acute lung injury (ALI) is characterized by neutrophilic lung inflammation, permeability, and intravascular and alveolar fibrin deposition. The type and inflammatory activity of eicosanoids liberated during inflammation depends on the membrane phospholipid composition: omega 6 (n-6) fatty acid arachidonate yields highly reactive and inflammatory dienoic prostaglandins and series 4 leukotrienes, whereas omega-3 (n-3) fatty acids favor production of less active and potentially anti-inflammatory trienoic prostaglandins and series 5 leukotrienes. Participants at risk of developing ALI have n-3 levels approximately 25% of normal and those with established ALI have n-3 levels as low as 6% of normal, suggesting a potential role for n-3 dietary supplementation in participants with ALI.Three randomized controlled studies, conducted in participants with ALI or sepsis-induced respiratory failure, demonstrated an association between the administration of an enteral formula enriched in n-3 fatty acids, GLA, and antioxidants and improved oxygenation and respiratory physiology compared with an unenriched, high-fat formula. However, interpretation of these results is limited by the small sample sizes and as-treated analyses of only those participants who tolerated full enteral nutrition. Participants: The total number of participants in the study was 272.Design: Participants were stratified by hospital and the presence of shock at baseline and then randomized to receive either twice-daily enteral supplementation of n-3 fatty acids, GLA, and antioxidants (n-3 supplement) or an isocaloric-isovolemic carbohydrate-rich control. Participants were also simultaneously randomized to a separate ongoing trial (the EDEN study) comparing low- vs full-calorie enteral nutrition in a 2×2 factorial design.The n-3 or control supplement was administered enterally as twice-daily boluses of 120 mL beginning within 6 hours of randomization. Dosing continued until the earliest of 21 days, 48 hours of unassisted breathing, or extubation. The energy provided by the boluses supplemented that provided by each primary physician's choice of standard continuous non–n-3-enriched enteral formula. The rate of continuous enteral feeding was managed by a protocol with an algorithm for gastrointestinal intolerances. The supplement was administered even if enteral nutrition was interrupted, as long as the patient was tolerating enteral medications. Conclusions: The study was stopped by the DSMB for futility at the first interim analysis after 143 participants had been randomized to receive the n-3 supplement and 129 to receive the isocaloric control. Despite an 8-fold increase in plasma eicosapentaenoic acid levels, participants receiving the n-3 supplement had fewer ventilator-free days, intensive care unit–free days, and nonpulmonary organ failure-free days.

  Study phs003744

• Distribution of ctDNA levels in plasma of early-stage non-small cell lung cancer patients measured using personalised ctDNA analysis

  Blood-based assays have shown increasing ability to detect circulating tumour DNA (ctDNA) in patients with early-stage cancer. However, detection of ctDNA in patients with non-small cell lung cancer (NSCLC) has continued to prove challenging. We performed retrospective analysis to quantify ctDNA levels in a cohort of 100 patients with early-stage NSCLC prior to treatment with curative intent. Where tumour tissue was available for whole exome sequencing, mutations identified were used to define patient-specific sequencing assays. For those 90 patients, plasma cell-free DNA was sequenced to high depth across capture panels targeting a median of 328 mutations specific to each patient. Data was analysed using Integration of Variant Reads (INVAR), detecting ctDNA in 66.7% of patients, including 52.7% (29 of 55) patients with stage I disease and >88% detection for patients with stage II and III disease (16/18 and 15/17). ctDNA was detected in plasma at fractional concentrations as low as 9.1x10-6, and in patients with tumour volumes as low as 0.23 cm3. A 36-gene sequencing panel (InVisionFirst-LungTM) was used to analyse plasma DNA in 27 samples including the 10 cases without tumour exome data, and detected ctDNA in 59% of samples tested (16 of 27). Across the entire cohort, detection rates were higher in squamous cell carcinoma patients compared to adenocarcinoma patients (81% vs. 59%). Detection of ctDNA prior to treatment was associated with significantly shorter time free from relapse, across all patients and in patient subgroups, with Hazard Ratios ranging from 2.25 to >11. Our analysis indicates that for patients with stage I NSCLC, the median ctDNA fraction in plasma is approx. 12 parts per million (0.0012%). This indicates the limits of detection that would be required for ctDNA-based liquid biopsies to detect ctDNA in the majority of patients with early-stage NSCLC.

  Dataset EGAD00001006230

• Cell-free DNA cleavages analysis (human)

  Cell-free DNA cleavages analysis (human)

  Study EGAS00001006701

• Fragmentomic features of individuals with different cfDNA concentrations

  The goal of this study is to explore fragmentomic patterns that vary between individuals of different concentrations of total cell-free DNA in plasma. We have selected a large cohort of individuals (ethnically Chinese men with a median age of 54 years, IQR 49-57) who were part of a screening of a large-scale clinical study to screen for nasopharyngeal carcinoma. Differences in fragmentomic features provided insights into the modulation of cfDNA levels in blood circulation. Fragmentomic and machine learning systems adopted in this study have also been applied to assess the quantity of cfDNA species of clinical interest, including the fraction of circulating fetal and tumor DNA, from pregnancy cases and individuals with hepatocellular carcinoma, respectively.

  Study EGAS50000000692

• Plasma mutation profile of precursor lesions and colorectal cancer using the Oncomine Colon cfDNA Assay

  Colorectal cancer (CRC) is the second leading cause of cancer death worldwide. Early detection of precursor lesions or early-stage cancer could hamper cancer development or improve survival rates. Liquid biopsy, which detects tumor biomarkers, such as mutations, in blood, is a promising avenue for cancer screening. To assess the presence of genetic variants in plasma cell-free tumor DNA from patients with precursor lesions and colorectal cancer using the commercial Oncomine Colon cfDNA Assay. Cell-free DNA (cfDNA) samples from the blood plasma of 52 Brazilian patients were analyzed. Eight patients did not have any significant lesions (five normal colonoscopies and three hyperplastic polyps), 24 exhibited precursor lesions (13 nonadvanced adenomas, ten advanced adenomas, and one sessile serrated lesion), and 20 patients with cancer (CRC). The mutation profile of 14 CRC-associated genes were determined by next-generation sequencing (NGS) using the Oncomine Colon cfDNA Assay in the Ion Torrent PGM/S5 sequencer.

  Dataset EGAD50000000679

• ucfDNA workflows for molecular profiling of malignant disease

  Urinary cell-free DNA (ucfDNA) is a promising liquid biopsy analyte obtained by a non-invasive sampling method, particularly valuable in urological cancers due to the proximity of biofluids to the tumor site. However, extremely high fragmentation and low abundance of ucfDNA pose significant analytical challenges. Improper handling and storage can severely affect ucfDNA quality, necessitating optimized pre-analytical workflows for clinical applications. We evaluated multiple pre-analytical workflows, including urine stabilization approaches against unstabilized urine samples. Our results demonstrated that without stabilization, ucfDNA degraded rapidly and minimal quantities remaining after 72 hours. In contrast, urine stabilization preserved ucfDNA integrity, enabling successful downstream analyses, including digital PCR and next-generation sequencing, for mutation detection in cancer-related genes and genome wide copy number profiling. These findings underscore the critical role of stabilization for a reliable ucfDNA analysis and highlight its potential in molecular diagnostics as a complementary tool to plasma-based liquid biopsies.

  Study EGAS50000001093

• The European MAPPYACTS trial: Precision Medicine Program in Pediatric and Adolescent Patients with Recurrent Malignancies

  MAPPYACTS (NCT02613962) is an international prospective precision medicine trial aiming to define tumor molecular profiles in pediatric patients with recurrent/refractory malignancies, in order to suggest the most adapted salvage treatment. From February 2016 to July 2020, 787 patients were included in France, Italy, Ireland and Spain. At least one genetic alteration leading to targeted treatment suggestion was identified in 436 patients (69%) with successful sequencing; 10% of these were considered "ready for routine use". Of 356 patients with follow-up beyond 12 months, 107 (30%) received one or more matched targeted therapies, 56% of them within early clinical trials, mainly in the AcSé-ESMART platform trial (NCT02813135). Overall, matched treatment resulted in a 17% objective response rate, those of patients with "ready for routine use" alterations was 38%. In patients with extra-cerebral tumors, 76% of actionable alterations detected in tumor tissue were also identified in circulating cell free DNA (cfDNA).

  Study EGAS00001005935

• C3 SNPs and outcome after lung transplantation

  Background: Development of chronic rejection is still a severe problem and causes high mortality rates after lung transplantation (LTx). Complement activation is important in the development of acute rejection (AR) and bronchiolitis obliterans syndrome, with C3 as a key complement factor. Methods: Since a single nucleotide polymorphism (SNP) in the C3 gene (rs2230199) is associated with long-term outcome after solid organ transplantation, we investigated this SNP in relation to LTx. In addition, we looked at local production of C3 by analyzing bronchoalveolar lavage fluid (BALF) of LTx patients using isoelectric focusing (IEF). Results: We demonstrated the presence of C3 in BALF and showed that this is produced by the donor lung based on the genotype of SNP rs2230199. We also analyzed donor and patient SNP configurations and observed a significant association between the SNP configuration in patients and episodes of AR during 4-years follow-up. Survival analysis showed a lower AR-free survival in homozygous C3 slow patients (p=0.005). Furthermore, we found a significant association between the SNP configuration in donors and BOS development. Patients receiving a graft from a donor with at least one C3 fast variant for rs2230199 had an inferior BOS-free survival (p=0.044). Conclusions: In conclusion, our data indicate local C3 production by donor lung cells. In addition, a single C3 SNP present in recipients affects short-term outcome after LTx, while this SNP in donors has an opposite effect on long-term outcome after LTx. These results could contribute to an improved risk stratification after transplantation.

  Study EGAS00001003843

• Molecular Analysis of Alliance A031201 Study

  This is the first study examining the relationship between clonal hematopoiesis and clinical outcomes in prostate cancer patients. We used a targeted gene sequencing panel to identify patients in the A031201 clinical trial with and without clonal hematopoiesis. We found that clonal hematopoiesis did not affect overall or progression free survival in A031201 but was associated more adverse cardiac events.

  Study phs003717

• Circulating RNAs prior to endometrial cancer diagnosis

  We analyzed circulating RNA levels using small RNA sequencing, targeting RNA in the size range 17 to 47 nucleotides, in samples collected prior to endometrial cancer diagnosis compared to cancer-free controls. The analysis included 316 cases with samples collected 1-11 years prior to diagnosis , and 316 matched controls, both from the Janus Serum Bank Cohort in Norway.

  Study EGAS50000000267

• Differential Presence of Exons in Cell-Free DNA Reveals Different Patterns in Colorectal Cancer Between Metastatic and Non-Metastatic Patients

  Tumor genotyping during disease follow-up is gaining an increasing interest for monitoring and clinical management in colorectal cancer (CRC). Growing evidences suggest that single biopsies are inefficient for molecular profiling, due to clonal evolution and intratumoral heterogeneity of primary tumors and/or metastasis. Circulating free DNA (cfDNA) has emerged as an alternative source of genetic material that seems to be representative of the continuously changing tumor molecular features. Thus, the so-called 'liquid biopsy' also offers the additional advantages of accessibility and non-invasiveness for the patient. Novel strategies based on next-generation sequencing (NGS) of cfDNA are being currently developed, with most studies focusing on targeted deep sequencing panels of potential clinically actionable genes. Here we describe an alternative approach, consisting of exome-sequencing in cfDNA at a relatively shallower depth to provide a more general overview of the circulating genome. In this study, two groups of colorectal cancer patients, with either disseminated (M) or localized disease (N), were compared using whole-exome sequencing and a RNA-seq bioinformatics analysis pipeline. Thus, a set of 379 exons present at different levels in cfDNA from both groups were identified, giving rise to a completely new concept in this field, termed as 'Differential Presence of Exons'. Differentially present exons (DPEs) were subsequently used for M and N patients clustering and classification, allowing for the design of a predictive algorithm with encouraging preliminary results in a small subset of patients that could not be initially classified attending to the selection criteria (U group, unassignable).

  Study EGAS00001002687

• Genome-wide cell-free DNA fragmentation in patients with cancer

  Cell-free DNA (cfDNA) in the blood provides a noninvasive diagnostic avenue for patients with cancer. However, characteristics of the origins and molecular features of cfDNA are poorly understood. We developed an approach to evaluate fragmentation patterns of cfDNA across the genome and found that cfDNA profiles of healthy individuals reflected nucleosomal patterns of white blood cells, while patients with cancer had altered fragmentation profiles. We applied this method to analyze fragmentation profiles of 236 patients with breast, colorectal, lung, ovarian, pancreatic, gastric, or bile duct cancers and 245 healthy individuals. A machine learning model incorporating genome-wide fragmentation features had sensitivities of detection ranging from 57% to >99% among the seven cancer types at 98% specificity, with an overall AUC of 0.94. Fragmentation profiles could be used to identify the tissue of origin of the cancers to a limited number of sites in 75% of cases. Combining our approach with mutation based cfDNA analyses detected 91% of cancer patients. The results of these analyses highlight important properties of cfDNA and provide a proof of principle approach for screening, early detection, and monitoring of human cancer.

  Study EGAS00001003611

• The Genomic Map of Poland in Open Access

  The main goal is to prepare and share WGS/WES of Polish population In this project NGS (next generation sequencing) was performed using Illumina NOVASEQ 6000 and Illumina DRAGEN aligner was used. Shared BAM and BAM.BAI files Library Construction Protocol: Illumina DNA PCR-Free Prep, Tagmentation. Reference Genome: GRCh37.

  Study EGAS50000000096

• NIPT samples for systematic evaluation of BinDel, a software tool for detecting clinically significant microdeletions in low-coverage WGS-based NIPT samples

  This dataset contains three sets of samples. The first sample set contains euploid fetus pregnancies reported by NIPTIFY screening test and postnatal evaluation. Dataset was processed similarly to previously published guidelines from KU Leuven, with modifications [1]. Briefly, peripheral blood samples were collected in cell-free DNA BCT tubes (Streck, USA), and plasma was separated with standard dual centrifugation. Cell-free DNA was extracted from 3 ml plasma using MagMAX Cell-Free DNA Isolation Kit (ThermoFisher Scientific). Whole-genome libraries were prepared using the FOCUS (Fragmented DNA Compact Sequencing Assay, Competence Centre on Health Technologies, Estonia) NIPT method protocol with 12 cycles for the final PCR enrichment step. In the following quantification, equal amounts of 36 samples were pooled, and the quality and quantity of the pool were assessed on Agilent 2200 TapeStation (Agilent Technologies, USA). Whole genome sequencing was performed on the NextSeq 550 instrument (Illumina Inc.) with an average coverage of 0.32× (minimum 0.08 and maximum 0.42) and producing 85 bp single-end reads. The second sample set contains a single NIPT sample postnatally diagnosed with Prader-Willi syndrome. The sample was sequenced with Illumina NextSeq 500 platform, producing 85 bp single-end reads with an average per-sample coverage of 0.32× at the University of Tartu, Institute of Genomics Core Facility, according to the manufacturer’s standard protocols, as described previously [2]. The third sample set contains samples SC005 (SeraCare Life Sciences Inc lot #10446565), SC0042 (#10571706), and SC016 (#10560229). These are SeraCare Life Sciences Inc circulating cell-free DNA (ccfDNA) like mixture of human genomic DNA that consists of matched maternal and fetus. SC005 and SC0042 consist of matched DNA of maternal and fetus with DiGeorge Syndrome. SC016 is a custom-ordered DNA Mix with fetus DNA having a pathogenic loss of the terminal region of 20p13 and a pathogenic 3q29 duplication. SC016 was processed as the first sample set was processed, and SC0042 was processed as the second sample set was processed. Sample SC005 was processed once as was sample set 1 and once as was sample set 2 processed. This study was performed with the approval of the Research Ethics Committee of the University of Tartu (#352/M-12). 1. Bayindir B, Dehaspe L, Brison N, Brady P, Ardui S, Kammoun M, et al. Noninvasive prenatal testing using a novel analysis pipeline to screen for all autosomal fetal aneuploidies improves pregnancy management. Eur J Hum Genet. 2015;23: 1286– 1293. doi:10.1038/ejhg.2014.282 2. Žilina O, Rekker K, Kaplinski L, Sauk M, Paluoja P, Teder H, et al. Creating basis for introducing noninvasive prenatal testing in the Estonian public health setting. Prenat Diagn. 2019;39: 1262–1268. doi:10.1002/pd.5578

  Dataset EGAD00001009512

• Colon Cancer Organoid Cultures and Tumors Whole Genome Sequencing Data

  Five hundred nanograms of genomic DNA was fragmented by Covaris S2, the fragmented DNAs were performed end-repair, A-tailing at the 3 prime end, adaptors ligation with an IDT dual-indexed UMI adaptor system at the terminal ends. The adapter ligated library with size range 300-750bp were selected by dual-SPRI method. Twenty percent of the size selected PCR-free libraries were enriched by 5 PCR cycles prior to library size assessment by Bioanalyzer Fragment Analyzer. The PCR-free libraries were quantified by qPCR.The PCR-free libraries were denatured and diluted to optimal concentration. Illumina NovaSeq 6000 was used for Pair-End 151bp sequencing.

  Dataset EGAD00001005759

• Comprehensive benchmarking of methods for mutation calling in circulating tumor DNA

  This study provides a comprehensive benchmarking resource for somatic variant detection in cell-free DNA (cfDNA) from cancer patients. Longitudinal plasma samples from colorectal and breast cancer cohorts were selected to create patient-matched dilution series spanning ultra-low to high circulating-tumour-DNA (ctDNA) fractions, while preserving each individual’s germline and clonal haematopoiesis background. Deep whole-genome sequencing (150×) and ultra-deep whole-exome sequencing (2,000×) generated a reference call set of ~37,000 single-nucleotide variants and ~58,000 insertions/deletions. These data enabled systematic evaluation of nine somatic variant callers across variable ctDNA levels and sequencing depths, and were further used to explore machine-learning–guided parameter tuning. The resulting dataset offers an openly accessible framework for developers and clinicians to assess and optimize somatic variant calling in liquid biopsy applications.

  Study EGAS50000001313

• Whole blood RNAseq from a large ALS case-control study at Univ of Michigan

  This dataset consists of 694 bulk RNA-seq data (sorted aligned BAM files) from whole blood of ALS participants meeting the Gold Coast definition of ALS during their clinical visit (n=422) and healthy controls (n=272) at the University of Michigan (UM). Samples were collected as part of the UM Pranger ALS Clinic between 2011-2021, and prepared either using poly-A selection of rRNA depletion (see Experiments). RNAseq was performed on the NovSeq 6000 S4 at the UM Advanced Genomics Core, resulting in 150bp paired-end reads. Raw reads were trimmed using Cutadapt (v2.3) and aligned to hg38 using STAR (v2.5.3a). Age provided is the age at blood sample collection date.

  Dataset EGAD50000001488

• GEnomics and Transcriptomics of Human INsulinoma (GETHIN)

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

  Study phs001422

• The effect of blood tube and time delay on the genome-wide methylation pattern of cfDNA

  In this study, we evaluated the effect of preservation agens on the effect of the methylation pattern of cell-free DNA. The methylation pattern was assessed with cell-free reduced representation sequencing (cf-RRBS). All 45 samples were sequenced on a NovaSeq6000, and samples are provided as raw fastq files.

  Dataset EGAD00001006007

• Nuclease deficiencies alter plasma cell-free DNA methylation profiles (Human samples)

  The dataset contains 2x75bp paired-end sequencing data in DNASE1L3-deficient human subjects. We performed bisulfite sequencing of plasma samples from three DNASE1L3-deficient subjects and one heterozygous parent to investigate how nuclease deficiencies alter plasma cell-free DNA methylation profiles.

  Dataset EGAD00001007750

• MicroRNA profiling by next-generation sequencing for colorectal cancer screening

  The study was conducted as the marker discovery phase to identify potential microRNA (miRNA) candidates for colorectal cancer (CRC) screening. Genome-wide profiling with next-generation sequencing (NGS) was performed using plasma samples from 20 newly diagnosed CRC cases and 20 controls free of colorectal neoplasms matched by age and sex.

  Study EGAS00001005030

• cell-Free DNA Genomic Profiling and its Clinical Implementation in Advanced Prostate Cancer

  Sixty-eight patients with advanced prostate cancer in castration-resistant or castration-sensitive settings undergoing treatment at the University Hospital Basel or the St. Claraspital Basel (Switzerland) were selected for targeted parallel sequencing analysis on liquid biopsy (plasma cfDNA) and matched formalin-fixed, paraffin-embedded (FFPE) tumor tissue samples.

  Study EGAS50000000234

• NEOPREDICT-Lung: Neoadjuvant Immunotherapy for Resectable NSCLC

  Links via: DOI: https://doi.org/10.1038/s41591-024-02965-0 PubMed: https://pubmed.ncbi.nlm.nih.gov/38689060/ Journal: https://www.nature.com/articles/s41591-024-02965-0 Abstract Antibodies targeting the immune checkpoint molecules PD-1, PD-L1 and CTLA-4 administered alone or in combination with chemotherapy are standard of care in most patients with metastatic non-small cell lung cancers. When given prior to curative surgery, tumor responses and improved event-free survival are achieved. New antibody combinations may be more efficacious and tolerable. In an ongoing, open-label phase II study, 60 biomarker-unselected, treatment-naïve patients with resectable non-small cell lung cancer were randomized to receive two preoperative doses of nivolumab (anti-PD-1) with or without relatlimab (anti-LAG-3) antibody therapy. The primary study endpoint was feasibility of surgery within 43 days, which was met by all patients. Curative resection was achieved in 95% of patients. Secondary endpoints included pathological and radiographic response rates, pathologically complete resection rates, disease-free and overall survival rates, and safety. Major pathological (≤10% viable tumor cells) and objective radiographic responses were achieved in 27% and 10% (nivolumab), and 30% and 27% (nivolumab and relatlimab) of patients, respectively. In 100% (nivolumab) and 90% (nivolumab and relatlimab) of patients tumors and lymph nodes were pathologically completely resected. With 12 months median duration of follow-up, disease-free survival and overall survival rates at 12 months were 89% and 93% (nivolumab), and 93% and 100% (nivolumab and relatlimab). Both treatments were safe with grade ≥ 3 treatment-emergent adverse events reported in 10% and 13% of patients per study arm. Exploratory analyses provided insights into biological processes triggered by preoperative immunotherapy. This study establishes the feasibility and safety of dual targeting of PD-1 and LAG-3 prior to lung cancer surgery.

  Study EGAS00001007753

• Natural History and Structural Functional Relationships in Fabry Renal Disease

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

  Study phs001333