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• Genetic Markers of Caries Risk in Diverse Underserved Children: CIDR

  The study Predicting Caries Risk In Underserved Children, From Toddlers To The School-age Years In Primary Healthcare Settings, is a renewal of an initial project designed to develop a dental caries risk tool for use in primary medical and dental healthcare settings to identify high dental caries risk children, expanding from the toddler (1-4 years old, referred to as Stage 1 grant) to the school-age years (6-9 years old, referred to as Stage 2 grant); and to determine the relationships between dental caries risk profiles and dental caries disease patterns. 1326 children, 12 +/- 3 months of age, and their primary caregivers, were enrolled in the study. This cohort represents a diverse population, including ethnic and racial minorities and low socio-economic status groups. There are a total of six in-person visits (at child age 1, 2.5, 4, 6.5, 8 and 9.5 years), and at each one the primary caregiver (PCG) completes a dental caries risk questionnaire, and the child receives a detailed dental caries examination. Saliva samples were collected during the age 8 visit (2019-2020) from 1,059 racially and ethnically diverse individuals (543 children and 516 PCGs) for the purposes of human genetic testing, to study the genetics of dental caries experience of children and their primary caregivers.

  Study phs003280

• Frequent germline mutations of HAVCR2 in sporadic subcutaneous panniculitis-like T-cell lymphoma.

  Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare subtype of peripheral T-cell lymphoma affecting younger cases and associated with hemophagocytic lymphohistiocytosis. To clarify the molecular pathogenesis of SPTCL, we analyzed paired tumor and germline DNAs from 13 patients by whole exome sequencing.

  Dataset EGAD00001004795

• Mutation analysis of 17 genes in plasma DNA of CRC patients using the AVENIO ctDNA Targeted Kit

  Mutation analysis of 17 genes (ALK, APC, BRAF, BRCA1, BRCA2, DPYD, EGFR, ERBB2, KIT, KRAS, MET, NRAS, PDGFRA, RET, ROS1, TP53, UGT1A1) in plasma DNA of CRC patients using the AVENIO ctDNA Targeted Kit.

  Dataset EGAD00001006103

• Single cell RNA sequencing of colorectal cancer patients (KUL5)

  All libraries were sequenced on Illumina NextSeq or NovaSeq6000 until sufficient saturation was reached.

  Dataset EGAD00001008585

• Sensitive and robust liquid biopsy-based detection of PIK3CA mutations

  Over the last years, the treatment of hormone receptor-positive metastatic breast cancer patients has dramatically changed. Combination strategies attempting to overcome resistance to endocrine therapy such as targeting the PI3 kinase pathway are gaining importance. The phase III SOLAR-1 trial demonstrated the benefit of the addition of alpelisib to fulvestrant, thereby providing further clinical evidence of the increasing importance of PIK3CA testing. Here, we performed a comparison of liquid biopsy and tissue-based detection of PIK3CA mutations in HR-positive metastatic breast cancer patients. Plasma samples and the latest available tumor tissue from 69 patients with metastatic hormone-receptor positive breast cancer were analyzed for PIK3CA hotspot mutations. A high-resolution NGS assay (SiMSen-Seq) was used for plasma samples covering 11 recurrent PIK3CA mutations, used for stratification in SOLAR-1. Additionally, mFAST-SeqS was used to estimate the tumor fractions in the plasma samples. For tumor tissue samples, targeted Ion Torrent NGS was employed. Matched tissue and plasma samples were available from 63 patients. PIK3CA mutations were detected in 46.1% of the tissue samples and in 50.7% of the plasma samples. The variant allele frequency (VAF) ranged from 4.36% to 72.93% with a median of 28.60% in tissue samples, and from 0.28% to 49.85% with a median of 1.17% in plasma samples. The most frequent variants in tissue and plasma were H1047R, E545K, and E542K. We detected at least one of 11 PIK3CA mutations from the SOLAR-1 trial in 51/63 patients, both in tissue and plasma. In 7 patients, such mutations were found only in plasma. In 5 patients, PIK3CA mutations found in tissue were not detectable in ctDNA, 2 of which had a low tumor fraction.Together, in 33/67 plasma samples without detectable PIK3CA mutations, 18 samples had elevated tumor fraction, implicating true negative results. In the remaining 15 patients with low tumor fraction, additional tissue analysis was needed. SiMSen-Seq-based detection of PIK3CA mutations in plasma shows advantageous concordance with the tissue analyses. A combination with an untargeted, mutation-independent approach for detecting ctDNA fractions may confirm a negative PIK3CA result and thereby enhance the performance of the SiMSen-Seq test. This combinatory approach for selecting suitable patients for alpelisib treatment should be validated in larger patient cohorts.

  Study EGAS00001004940

• Longitudinal snRNAseq and DNAseq of IDHmutant glioma

  We collected longitudinal glioma samples from 35 patients with an IDH-mutant oligodendroglioma (n = 13) or IDH-mutant astrocytoma (n = 22) diagnosis based on 2021 WHO glioma classification at two or three time points (n = 75 samples). For each patient, we designated the two earliest samples as the initial and recurrence for longitudinal analyses. In 17 of 35 longitudinal pairs, the initial sample was obtained at primary diagnosis, whereas the remaining 18 cases the initial samples were collected at a subsequent surgery. Between the initial and recurrence samples, 26 of 35 patients received radiotherapy and/or alkylating chemotherapy, whereas no adjuvant treatment was reported for the remaining patients. To comprehensively investigate IDH-mutant glioma evolution, we used snRNAseq and bulk DNA/RNA sequencing from the same resected glioma samples. A subset of these samples was profiled with simultaneous snRNA-ATAC sequencing (48 out of 75), including 21 matched longitudinal pairs,

  Dac EGAC50000000973

• Pediatric Whole Genome Sequencing Diagnostic Utility

  The standard of care for first-tier clinical investigation of the etiology of congenital malformations and neurodevelopmental disorders is chromosome microarray analysis (CMA) for copy number variations (CNVs), often followed by gene(s)-specific sequencing searching for smaller insertion-deletions (indels) and single nucleotide variant (SNV) mutations. We compared diagnostic rate of WGS to CMA and targeted gene testing of 100 patients referred to The Hospital for Sick Children Genetics clinic in 2014. WGS identified genetic variants meeting clinical diagnostic criteria in 34% of cases, representing a 4-fold increase in diagnostic rate over CMA (8%) (p-value = 1.42e-05) alone and >2-fold increase in CMA plus targeted gene sequencing (13%) (p-value = 0.0009). WGS identified all rare clinically significant CNVs that were detected by CMA. In an additional 26 patients, WGS revealed indel and missense mutations presenting in a dominant (63%) or a recessive (37%) manner. We found four subjects with mutations in at least two genes associated with distinct genetic disorders, including two cases harboring a pathogenic CNV and SNV. When considering medically actionable secondary findings in addition to primary WGS findings, 38% of patients would benefit from genetic counselling.

  Study EGAS00001001623

• Genetics of Glucose Regulation in Gestation and Growth (Gen3G) Cohort - Placenta Transcriptomics RNA Sequencing

  The overarching goals of Genetics of Glucose regulation in Gestation and Growth (Gen3G) are to increase our understanding of biological, environmental, and genetic determinants of glucose regulation during pregnancy and their impact on fetal/child development. Gen3G is a prospective cohort study: we initially recruited 1,024 pregnant women between 2010-2013 at Blood Sampling in Pregnancy Clinic during the first trimester of pregnancy (median 9 weeks of gestation) in Sherbrooke, Québec, Canada. We assessed 898 pregnant women at second trimester (median 26 weeks of gestation), when participants completed a 75g oral glucose tolerance test (OGTT) as clinically indicated for screening of gestational diabetes mellitus (GDM). We collected data for 854 mother-child dyads at delivery (from medical records), in addition to placenta and/or cord blood samples in majority of newborns.The overall goal of the grant that supported data that is included in this dbGaP submission was to discover novel placental factors that regulate glucose metabolism in pregnancy and predict GDM by conducting genome-wide transcriptomics (RNA and miRNA) in carefully collected placenta samples from Gen3G.

  Study phs003151

• Center for Common Disease Genomics [CCDG] - Cardiovascular: Cardiology Biobanking for Biomarker Discovery

  This study is a part of NHGRI's Center for Common Disease Genomics, which is a collaborative large-scale genome sequencing effort to comprehensively identify rare risk and protective variants contributing to multiple common disease phenotypes. Current estimates anticipate that the CCDG program will sequence approximately 140K whole genomes and 225K whole exomes during the life of the project. The Cardiovascular Disease working group of the CCDG considered five diseases: early-onset coronary artery disease (EOCAD), stroke, atrial fibrillation, congestive heart failure and type 2 diabetes. Atrial fibrillation will affect between 6-12 million individuals in the US by 2050. AF also is associated with increased risks of stroke, dementia, heart failure, death, and high health care costs. Many risk factors for AF have been identified, including advancing age, cardiovascular disease (CVD), and CVD risk factors. However, there is little knowledge how to prevent AF. Furthermore, therapies for AF are only partially effective, and are themselves associated with substantial morbidity. Previously, heritable forms of AF have been considered rare; yet in the last decade, it has been established that AF, and in particular early-onset forms of AF, are heritable. Genome-wide association studies (GWAS) provide a powerful tool to identify common variants underlying disease risk. The AFGen Consortium currently consists of investigators from more than 25 studies with >20,000 individuals with AF and >100,000 without AF. In the latest analyses, 14 loci have been identified for AF1. Broadly, the loci implicate genes related to cardiopulmonary development, cardiac-expressed ion channels, and cell signaling molecules.Source: https://ccdg.rutgers.edu/sites/default/files/CCDG_CVD_EOAF_FINAL_w_link.pdfThe BioHEART study is a multi-center, prospective, observational cohort study to identify new biomarkers in stable coronary artery disease (CAD) and acute myocardial infarction (MI) (ACTRN12618001322224). Participants are recruited at time of clinically indicated computed tomography (CT) coronary angiogram (CTCA). 1,950 of 5,000 planned participants have been recruited and serum/plasma/erythrocytes/monocytes stored, with follow-up ongoing. CTCA imaging studies provides volumetric quantification of total calcified and non-calcified plaque, which is assessed using established and novel scoring systems. Comprehensive molecular phenotyping is performed on blood samples using state-of-the-art genomic, transcriptomic, proteomics, metabolomic, lipidomic, and immunophenotyping. Outcome data will be used to build improved risk models for CAD.Reference: http://www.anzctr.org.au/ - ACTRN12618001322224

  Study phs002726

• BLUEPRINT: RNA-seq of progenitor cells

  Data supporting the paper Transcriptional diversity during lineage commitment of human blood progenitors

  Dataset EGAD00001000745

• Cancerous Adaptive Dosing Melanoma WGS Dataset

  Illumina NovaSeq 6000 30x WGS of 26 samples, each with up to 5 matched timepoints. Timepoints A,B,C,D,and E correspond to Pretreatment, Week 3, Week 6, Week 9, and Week 12 after treatment, respectively. Additional sample metadata (sample recurrence, treatment course, age, sex, comorbidities, etc.) are present in sample description.

  Dataset EGAD00001010926

• Extensive and differential platinum chemotherapy mutagenesis in livers of children - Targeted NanoSeq

  Targeted NanoSeq using a bait set consisting of 285 genes, comprising mostly cancer genes, of a Validation cohort that includes platinum-exposed (n=195) and platinum naïve (n=60) samples from 26 individuals (children and foetal tissues). The samples are mainly liver samples (normal and cancer tissues) and obtained from children with liver cancer.

  Dataset EGAD00001016120

• Transcriptomic Analysis of Human Hematopoietic Progenitors from Healthy Donors and Bone Marrow Failure Patients

  The purpose of this study was to define transcriptional changes that occur in the rare and heterogeneous bone marrow progenitors that are affected in Shwachman-Diamond Syndrome. Data are reported for four genetically confirmed SDS patients ranging from 11-26 years old, 3 male and 1 female, and four healthy donors ranging from 25-29 years old, 2 male and 2 female. Subjects provided written, informed consent in accordance with the Declaration of Helsinki's Ethical Principles of Medical Research Involving Human Subjects. Single CD34+ cells were purified from fresh bone marrow and cDNA libraries were prepared using the SMARTer Ultra Low RNA Kit (Clontech; pre-2015) or SMART-Seq v4 Ultra Low RNA Kit (Clontech; post-2015). Libraries were sequenced on a HiSeq 2500 Instrument (Illumina, San Diego, CA) to a read depth of ~3 M paired-end, 25 bp reads per single cell. Paired-end reads were mapped to the hg38 human transcriptome (Gencode v24) using STAR v2.4.2a.

  Study phs001845

• Circulating Tumor DNA as a Biomarker in Patients with Stage III and IV Wilms Tumor: Analysis from a Children's Oncology Group Trial, AREN0533

  We evaluated the utility of circulating tumor DNA (ctDNA) as a biomarker in the serum and urine of 50 patients with Stage III or Stage IV Wilms tumor (WT) that were enrolled on Children's Oncology Group (COG) trial AREN0533. 49 out of 50 patients had matched tumor samples available for comparison. We profiled samples with ultra-low pass whole genome sequencing (ULP-WGS) and detected ctDNA in 82% of serum samples and 26% of urine samples. We also identified copy-number changes and single-nucleotide variants in the serum and urine samples, and compared them to the tumor data. Our study highlights the advantages of using ctDNA as non-invasive prognostic biomarker with the potential to detect tumor heterogeneity in patients with WT. We believe that prospective validation of ctDNA as a prognostic biomarker in patients with WT is warranted. The ULP-WGS and targeted next-generation sequencing (OncoPanel) data are available in this study.

  Study phs002847

• International Age-Related Macular Degeneration Genomics Consortium - Exome Chip Experiment

  Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. To further our understanding of AMD genetics, we examined the contribution of common and rare genetic variation in the International AMD Genomics Consortium that included ~50,000 samples of 26 AMD case - control cohorts that were jointly genotyped. Analyzing 16,144 patients with late stage AMD and 17,832 controls, we identified 52 independently associated common and rare variants distributed across 34 loci. Besides these single variant signals, we also observed gene-based enrichment of very rare coding variants (frequency < 0.1%) in cases that implicated causal roles for CFH, CFI and TIMP3 in three of the known AMD risk loci. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.

  Study phs001039

• Functional Variant rs9344 at 11q13.3 Regulates CCND1 Expression in Multiple Myeloma with t(11;14)

  Multiple myeloma (MM) is a plasma cell (PC) malignancy characterized by cytogenetic abnormalities, such as t(11;14)(q13;q32), resulting in CCND1 overexpression. The rs9344 G allele within CCND1 is the most significant susceptibility allele for t(11;14). We have found the G risk allele is enriched in both healthy individuals of African ancestry and African American individuals with MM. The overall aim of this study was to identify the mechanism behind why the G allele is enriched in t(11;14) MM. To reach this goal, we performed ATAC-seq from 100,000 CD138+ tumor cells from 26 patients with MM. In addition, we performed ChIP-seq using antibodies against H3K4me1, H3K27ac and H3K4me3 from 100,000 CD138+ tumor cells from 8 patients with MM. We used these data to evaluate whether the G allele of rs9344 is associated with elevated chromatin accessibility, H3K27ac and H3K4me3 in t(11;14) MM.

  Study phs003997

• Whole exome and Transcriptome sequencing of treatment-naïve esophageal adenocarcinoma biopsies and matched peripheral blood mononuclear cells

  Exome sequencing was performed on n=28 treatment-naïve esophageal adenocarcinoma (EACs). Three to four biopsies sampling different areas of each tumor were pooled before nucleic acid extractions to mitigate the elevated heterogeneity described for EAC. WES was performed on EAC biopsies at 120X average coverage, with autologous PBMCs used as germline controls at 80X average coverage. Libraries were prepared from 30 ng of input DNA using the SureSelect QXT Human All Exon V7 kit (Agilent Technologies) and sequenced on the NextSeq 550 (Illumina), 2x150 bp. BCL files were demultiplexed to FastQ files using bcl2fastq2 software (Illumina). Three paired end sequencing batches were analyzed independently (Batch1: samples 8, 10, 11, 12, 15, 17, 18; Batch2: samples 20, 24, 25, 26, 27, 29, 30, 31, 33, 34 ; Batch3: samples 35, 37, 39, 40, 41, 43, 45, 48, 54, 55, 57). RNA sequencing was performed on n=26 treatment-naïve esophageal adenocarcinoma (EACs). Three to four biopsies sampling different areas of each tumor were pooled before nucleic acid extractions to mitigate the elevated heterogeneity described for EAC. RNAseq libraries were prepared on 50 ng of total RNA (with RNA integrity index RIN >=7) with the TruSeq Stranded mRNA library preparation kit (Illumina) in accordance with low-throughput protocol. After PCR enrichment (15 cycles) and purification of adapter-ligated fragments, the concentration and length of DNA fragments were measured using D1000 Screen Tape System (Agilent), obtaining a median insert size of 311 nucleotides. Then, RNAseq libraries were sequenced using the Illumina NovaSeq platform, 1x100 bp, obtaining on average 100 million single reads per sample.

  Dataset EGAD00001010876

• RNA-seq samples

  Raw FASTQ files obtained by RNA sequencing of tumor samples from patients (age 12-29) with newly diagnosed, recurrent intermediate or high-grade sarcoma.

  Dataset EGAD00001008393

• Whole-exome/genome sequencing of childhood acute leukemia in Iraq

  This dataset contains 26 whole-genome sequencing (13 paired tumor and normal), 106 whole-exome sequencing (53 paired tumor and normal), and 43 targeted sequencing data. Sequencing was performed using an Illumina platform. The data are BAM files aligned to the hg19 reference genome.

  Dataset EGAD00001007873

• Center for Common Disease Genomics [CCDG] - Cardiovascular: Genetic and Phenotypic Determinants of Blood Pressure and Other Cardiovascular Risk Factors

  This study is a part of NHGRI's Center for Common Disease Genomics, which is a collaborative large-scale genome sequencing effort to comprehensively identify rare risk and protective variants contributing to multiple common disease phenotypes. Current estimates anticipate that the CCDG program will sequence approximately 140K whole genomes and 225K whole exomes during the life of the project. The Cardiovascular Disease working group of the CCDG considered five diseases: early-onset coronary artery disease (EOCAD), stroke, atrial fibrillation, congestive heart failure and type 2 diabetes. Atrial fibrillation will affect between 6-12 million individuals in the US by 2050. AF also is associated with increased risks of stroke, dementia, heart failure, death, and high health care costs. Many risk factors for AF have been identified, including advancing age, cardiovascular disease (CVD), and CVD risk factors. However, there is little knowledge how to prevent AF. Furthermore, therapies for AF are only partially effective, and are themselves associated with substantial morbidity. Previously, heritable forms of AF have been considered rare; yet in the last decade, it has been established that AF, and in particular early-onset forms of AF, are heritable. Genome-wide association studies (GWAS) provide a powerful tool to identify common variants underlying disease risk. The AFGen Consortium currently consists of investigators from more than 25 studies with >20,000 individuals with AF and >100,000 without AF. In the latest analyses, 14 loci have been identified for AF1. Broadly, the loci implicate genes related to cardiopulmonary development, cardiac-expressed ion channels, and cell signaling molecules. Source: ccdg.rutgers.edu The GAPP study is an ongoing national population-based prospective cohort study conducted in the Principality of Liechtenstein. Between 2010 and 2014, all inhabitants of Liechtenstein aged 25-41 years old were asked to participate in the study, and 2170 could be enrolled. The aim of the study is to identify the determinants of blood pressure and other cardiovascular risk factors and their progression over time. A large number of baseline characteristics and health information as well as several blood, urinary and genetic markers were collected. The samples were sent to The Broad Institute of MIT and Harvard to generate genetic data using whole exome sequencing and whole genome genotyping (Infinium Global Screening Array); all samples serving as controls.

  Study phs002236

• Single cell RNAseq FASTQ files of three PDAC organoid lines (P28, P40, P47) using SORT-seq

  This dataset contains raw FASTQ files from single cell RNA sequencing of three patient-derived pancreatic ductal adenocarcinoma (PDAC) organoid lines (P28, P40, P47) cultured under standard conditions. For each line, single cells were FACS sorted into 384-well capture plates, with each well containing a 50nl droplet of barcoded primers. Plates were processed following an adapted SORT-seq protocol, and cDNA libraries were generated using CEL-Seq2 with TruSeq small RNA primers (Illumina). Sequencing was performed on an Illumina NextSeq500 platform using paired-end reads (read 1: 26 cycles, index read: 6 cycles, read 2: 60 cycles). Data are controlled-access and intended for single cell transcriptomic analysis of PDAC organoid heterogeneity and WNT pathway activity.

  Dataset EGAD50000002220

• Federated discovery and sharing of genomic data using Beacons

  The Beacon Project is a Global Alliance for Genomics & Health (GA4GH) initiative that enables genomic and clinical data sharing across federated networks. The project is working toward developing regulatory, ethics and security guidance to ensure proportionate safeguards for distribution of data according to the GA4GH-developed “Framework for Responsible Sharing of Genomic and Health-Related Data”. Within this Nature Biotechnology Correspondence a description of the Beacon protocol and how it can be used as a model for the federated discovery and sharing of genomic data is offered to the community. A Beacon is defined as a web-accessible service that can be queried for information about a specific allele. A user of a Beacon can pose queries of the form “Have you observed this nucleotide (e.g., C) at this genomic location (e.g., position 32,936,732 on chromosome 13)?” to which the Beacon responds with either “yes” or “no.” In this way, a Beacon allows allelic information of interest to be discovered by a remote searcher with no reference to a specific sample or patient, thereby mitigating privacy risks. The Beacon API (represented as a RESTful web application) provides a technical specification that a Beacon server must implement. The specification is open source and available online here. To simplify the process of lighting a Beacon, a free, open-source reference implementation of the latest specification has been developed. GA4GH is promoting different levels of data access (open, registered, and controlled) for convenience and for compatibility across its projects. Each so-called access tier has distinct visibility and requirements for authorization. For example, ‘open access’ Beacons are accessible to anonymous users of the internet, whereas ‘registered access’ Beacons are accessible to registered users (for example, bona fide researchers and clinicians) who have agreed to a set of conditions of data use. Many of the largest genomic archives, such as dbGaP, the European Genome-phenome Archive and the European Variation Archive, have provided access to variation data through Beacons for some or all of their datasets. Beacons can be interconnected through the Beacon Network, a directory and search engine for Beacons. Although individual Beacons answer the question “Have you observed this allele?”, the Beacon Network answers the question “Who has observed this allele?”. Beacons can be freely registered to the Beacon Network and can be searched independently or in aggregate with other connected Beacons.

  Blog federated-discovery-using-beacons

• EGA FUSE Client

  EGA FUSE Client What is EGA FUSE Client? The EGA FUSE Client is a Java Native Runtime (JNR) based Filesystem in Userspace (FUSE) client that allows users to access authorised EGA files by presenting them in a virtual directory. This means that users can use authorised EGA files like regular files without having to download them first. The EGA FUSE Client is a useful tool for researchers who need to access and work with large amounts of EGA data. Why use EGA FUSE Client? The EGA FUSE Client provides several benefits for researchers working with EGA data: Efficient use of storage space: With the EGA FUSE Client, users can access authorised EGA files without having to download them first. This means that users can save storage space on their local machines. Faster access to data: Since users can access authorised EGA files directly through the EGA FUSE Client, they can work with the data more quickly than if they had to download the files first. Simplified workflow: The EGA FUSE Client presents authorised EGA files in a virtual directory, allowing users to work with the files like regular files. This simplifies the workflow for researchers who need to access and work with large amounts of EGA data. Get started with EGA FUSE Client To get started with EGA FUSE Client visit the EGA FUSE Client GitHub repository for more information and installation instructions.

  Documentation access/download/visualisation/fuse-client

• Whole genome sequencing data of high-grade serous ovarian cancer samples (set 17)

  The dataset contains whole genome sequencing data of 26 high-grade serous carcinoma (HGSC) patients sequenced with Novoseq 6000. The 86 samples are either fresh frozen tumour samples or blood samples. The files provided are paired fastq files.

  Dataset EGAD50000002409

• WES of der(1;7)(q10;p10)

  This dataset contains the BAM files of WES of 26 myeloid neoplasm patients with der(1;7)(q10;p10)(+) cases. The dataset was used to identify key driver genes in patients with der(1;7)(q10;p10). Already known drivers along with novel driver genes were identified through the use of this WES.

  Dataset EGAD50000000986

• Center for Common Disease Genomics [CCDG] - Cardiovascular: The Genetics of Atrial Fibrillation

  This study is a part of NHGRI's Center for Common Disease Genomics, which is a collaborative large-scale genome sequencing effort to comprehensively identify rare risk and protective variants contributing to multiple common disease phenotypes. Current estimates anticipate that the CCDG program will sequence approximately 140K whole genomes and 225K whole exomes during the life of the project. The Cardiovascular Disease working group of the CCDG considered five diseases: early-onset coronary artery disease (EOCAD), stroke, atrial fibrillation, congestive heart failure and type 2 diabetes. Atrial fibrillation will affect between 6-12 million individuals in the US by 2050. AF also is associated with increased risks of stroke, dementia, heart failure, death, and high health care costs. Many risk factors for AF have been identified, including advancing age, cardiovascular disease (CVD), and CVD risk factors. However, there is little knowledge how to prevent AF. Furthermore, therapies for AF are only partially effective, and are themselves associated with substantial morbidity. Previously, heritable forms of AF have been considered rare; yet in the last decade, it has been established that AF, and in particular early-onset forms of AF, are heritable. Genome-wide association studies (GWAS) provide a powerful tool to identify common variants underlying disease risk. The AFGen Consortium currently consists of investigators from more than 25 studies with >20,000 individuals with AF and >100,000 without AF. In the latest analyses, 14 loci have been identified for AF1 . Broadly, the loci implicate genes related to cardiopulmonary development, cardiac-expressed ion channels, and cell signaling molecules.Source: https://ccdg.rutgers.edu/sites/default/files/CCDG_CVD_EOAF_FINAL_w_link.pdfFor this study, The Broad Institute of MIT and Harvard generated genetic data for UWO Genetic Investigation of Supraventricular Tachycardias.Patients confirmed to possess a supraventricular tachycardia and/or an accessory pathway at the time of invasive electrophysiology study at the London Health Sciences Centre, London, Ontario, Canada were eligible for enrollment. Potential supraventricular tachycardias included atrioventricular nodal reentrant tachycardia (AVNRT), atrioventricular reentrant tachycardia (AVRT), atrial tachycardia, junctional tachycardia, atriofascicular tachycardia, nodofascicular tachycardia, and nodoventricular tachycardia. Patients that did not have inducible supraventricular tachycardia, but had an accessory pathway that conducted antegrade, retrograde, or both, were also eligible for enrollment. All patients additionally underwent, at minimum, a clinical history, physical examination, 12-lead ECG, and echocardiogram. Study participants provided informed written consent under a protocol approved by the research ethics board of Western University.Raw sequencing data, metadata, vcf and phenotype data at individual level are available at https://anvilproject.org/data For questions about availability contact help@lists.anvilproject.org.

  Study phs002811

• Radiation-Related Genomic Profile of Papillary Thyroid Cancer after the Chernobyl Accident

  The April 26, 1986 accident at the Chernobyl nuclear power plant in northern Ukraine resulted in the release of radioactive contaminants, which were deposited in the surrounding areas in Ukraine, Belarus, and Russia. The main radiation-related health effect resulting from these exposures is the increased occurrence of thyroid cancer among individuals who were children at the time of the accident or born shortly thereafter. The purpose of this study was to conduct a comprehensive genomic landscape analysis of papillary thyroid tumors arising in individuals who were exposed as children to radioactive iodine (I-131) from the Chernobyl nuclear power plant accident.

  Study phs001134

• COVID-19-Induced Immune Alterations in Infants

  Although previous studies have described some overlap between COVID-19-induced immune alterations in adults and children, no systematic immune profiling studies have been reported in infants. We applied a multidimensional approach to decipher the immune responses to SARS-CoV-2 infected infants (n=26; 10 mild, 11 moderate and 5 severe) and healthy matched controls (n=14). Single-cell RNA-seq profiling (scRNA-seq) of PBMCs revealed alterations in cell composition upon infection, with most cell types demonstrating an interferon-stimulated gene (ISGhi) state. Our findings shed insight into the immune responses to SARS-CoV-2 in the first year of life.

  Study phs002655

• Peripheral blood DNA transcriptomics of ustekinumab treatment response in patients with Crohn's disease

  Data pertains longitudinal transcriptomic data measured from blood obtained from patients with Crohn's disease that were starting treatment with ustekinumab. Samples were obtained prior to treatment and approximately 26 weeks into treatment during response assessment. At response assessment, patients were classified as responders (R) or non-responders (NR) based on a strict combination of endoscopic, biochemical and clinical criteria: ≥50% reduction in the endoscopic SES-CD score, corticosteroid-free clinical remission (≥3 point drop98 in HBI or HBI ≤4 and no systemic steroids) and/or biochemical response (C-reactive protein (CRP) and fecal calprotectin reduction ≥50% or ≤5 mg/L and fecal calprotectin ≤250 µg/g). Modified response was defined as a combination of corticosteroid-free clinical- (HBI ≤4) and biochemical (CRP ≤5 mg/L and/or fecal calprotectin ≤250 µg/g) remission between week 26-52 without treatment change through week 52. Transcriptomic analyses was conducted through RNA sequencing, wherein mRNA was extracted utilizing the QIAsymphony system, converted into cDNA and sequenced in a paired-end format on the Illumina NovaSeq6000 at the Amsterdam UMC Core Facility Genomics, generating a dataset comprising 40 million 150 bp-reads.

  Dataset EGAD50000000386

• Peripheral blood DNA transcriptomics of vedolizumab treatment response in patients with Crohn's disease

  Data pertains longitudinal transcriptomic data measured from blood obtained from patients with Crohn's disease that were starting treatment with vedolizumab. Samples were obtained prior to treatment and approximately 26 weeks into treatment during response assessment. At response assessment, patients were classified as responders (R) or non-responders (NR) based on a strict combination of endoscopic, biochemical and clinical criteria: ≥50% reduction in the endoscopic SES-CD score, corticosteroid-free clinical remission (≥3 point drop98 in HBI or HBI ≤4 and no systemic steroids) and/or biochemical response (C-reactive protein (CRP) and fecal calprotectin reduction ≥50% or ≤5 mg/L and fecal calprotectin ≤250 µg/g). Modified response was defined as a combination of corticosteroid-free clinical- (HBI ≤4) and biochemical (CRP ≤5 mg/L and/or fecal calprotectin ≤250 µg/g) remission between week 26-52 without treatment change through week 52. Transcriptomic analyses was conducted through RNA sequencing, wherein mRNA was extracted utilizing the QIAsymphony system, converted into cDNA and sequenced in a paired-end format on the Illumina NovaSeq6000 at the Amsterdam UMC Core Facility Genomics, generating a dataset comprising 40 million 150 bp-reads.

  Dataset EGAD50000000385

• Pre-existing immunity drives the response to neoadjuvant chemotherapy in esophageal adenocarcinoma

  Esophageal adenocarcinoma (EAC) is a highly aggressive tumor. Patients with locally advanced disease undergo neoadjuvant chemotherapy (nCT) before surgery, however fewer than 30% of treated patients achieve a pathological complete response associated with increased 5-year overall survival. We set out to elucidate the mechanisms the response to nCT by multi-dimensional profiling of pre-treatment tumor biopsies and blood samples from EAC patients. In particular we performed whole exome sequencing (WES) and RNAseq on n=26 baseline EAC tumor; two additional EAC samples underwent only WES. WES on matched peripheral blood mononuclear cells (PBMCs) were used as germline control.

  Study EGAS00001007245

• 10x Genomics raw data of intestinal plasma cells

  The dataset contains raw fastq files (fastq.gz) for Chromium Single Cell 5’ gene expression (GEX), human B cell VDJ and feature barcode (CSP) sequencing from transglutaminase 2-specific and other small intestinal plasma cells isolated from four untreated celiac disease patients. Single cell 5’ gene expression, V(D)J-enriched and cell surface protein libraries were generated using Chromium single cell kits, and barcoded cDNA from a total of 5,000-10,000 cells per sample was generated using the 10x Genomics Chromium Controller. The libraries were pooled prior to sequencing on a NovaSeq 6000 instrument (Illumina) using the following configuration: read 1: 26 cycles, read 2: 89 cycles, index read 1: 8 cycles.

  Dataset EGAD50000000342

• fragmentomic features of individuals with different cfDNA concentrations

  The uploaded data includes sequencing data of 862 individuals from the nasopharyngeal carcinoma (NPC) screening study. Samples from this cohort were sequenced using targeted sequencing methods for the Epstein Barr Virus (EBV) and selected autosomal DNA, but only ‘off-target’ reads were used for fragmentomic analyses. We have also performed genome-wide (non-targeted sequencing) for 1) Individuals with the highest and lowest cell-free DNA concentration (40 individuals); 2) A subsequent collection of the subjects with the highest and lowest DNA concentrations after six years (26 individuals); 3) 30 cases of pregnancy and 4) 20 patients with hepatocellular carcinoma. All sequencing data are of extracted plasma cfDNA from human subjects. The targeted sequencing samples from 862 individuals were sequenced on the NextSeq500 System (Illumina) and aligned to the EBV genome (AJ507799.2) and the human genome (hg19). The alignments were provided in bam format. The original fastq files of the remaining non-target sequencing samples were provided.

  Dataset EGAD50000000970

• Center for Common Disease Genomics [CCDG] - Cardiovascular: Pharmacokinetic Polymorphisms in Japanese General Population

  This study is a part of NHGRI's Center for Common Disease Genomics, which is a collaborative large-scale genome sequencing effort to comprehensively identify rare risk and protective variants contributing to multiple common disease phenotypes. Current estimates anticipate that the CCDG program will sequence approximately 140K whole genomes and 225K whole exomes during the life of the project. The Cardiovascular Disease working group of the CCDG considered five diseases: early-onset coronary artery disease (EOCAD), stroke, atrial fibrillation, congestive heart failure and type 2 diabetes. Atrial fibrillation will affect between 6-12 million individuals in the US by 2050. AF also is associated with increased risks of stroke, dementia, heart failure, death, and high health care costs. Many risk factors for AF have been identified, including advancing age, cardiovascular disease (CVD), and CVD risk factors. However, there is little knowledge how to prevent AF. Furthermore, therapies for AF are only partially effective, and are themselves associated with substantial morbidity. Previously, heritable forms of AF have been considered rare; yet in the last decade, it has been established that AF, and in particular early-onset forms of AF, are heritable. Genome-wide association studies (GWAS) provide a powerful tool to identify common variants underlying disease risk. The AFGen Consortium currently consists of investigators from more than 25 studies with >20,000 individuals with AF and >100,000 without AF. In the latest analyses, 14 loci have been identified for AF1 . Broadly, the loci implicate genes related to cardiopulmonary development, cardiac-expressed ion channels, and cell signaling molecules.Source: https://ccdg.rutgers.edu/sites/default/files/CCDG_CVD_EOAF_FINAL_w_link.pdfAnalysis of 165 pharmacokinetic-related gene polymorphisms (the number of polymorphisms may increase) using DNA derived from the blood of approximately 1,000 Japanese general populations. Tokai University School of Medicine Molecular Life Sciences 2 Isogo Lab has been trying to find new genes which contribute to the development of multiple diseases and to develop new methods for human genome diversity analysis that will lead to the development of technology for disease screening by finding genes related to diseases and incorporating gene analysis technology. Using this method, we are trying to clarify the relationship between the characteristics of rheumatoid arthritis and psoriasis vulgaris and genes to seek effective treatments and prevention methods. Raw sequencing data, metadata, vcf and phenotype data at individual level are available at https://anvilproject.org/data. For questions about availability contact help@lists.anvilproject.org.

  Study phs002985

• Longitudinal sampling in relapsed and refractory Hodgkin lymphoma

  Ultra-deep next-generation panel-sequencing on 59 FFPE-samples (20 LTR, 26 relapsed (rHL: 11 initial-diagnosis, 15 relapse) and 13 primary-refractory (prHL: 8 initial-diagnosis, 5 progression) from 44 cHL-patients applying a hybrid-capture approach. Data was processed as described in the publication and mark duplicated bam files were uploaded.

  Dataset EGAD50000000210

• Finnish_population_cohort_genotyping_B

  The FINRISK cohorts comprise the respondents of representative, cross-sectional populationsurveys that are carried out every 5 years since 1972, to assess the risk factors of chronicdiseases (e.g. CVD, diabetes, obesity, cancer) and health behavior in the working agepopulation, in 3-5 large study areas of Finland. DNA samples were collected in the followingsurvey years: 1987, 1992, 1997, 2002, 2007, and 2012. The MONICA and EHES (EU)procedures were applied in phenotype collection (cf. MORGAM) and a wide spectrum oflaboratory tests was carried out from serum and plasma samples. Background information onsocioeconomic status, medical history, diet, exercise, measured anthropometric measures,etc. was collected by questionnaires and during a clinical visit. Plasma/serum samples arestill available for the 2002-2012 cohorts. The cohort sizes are 6000-8800 per survey. Thecohorts have been followed up by linking them to the national hospital discharge register,causes-of-death register and cancer register.This project is an extension to previous efforts to build a catalogue of Finnish genome widedata on population-based Finsrisk samples with rich phenotypic characterisations and healthregistry link-up. These samples will extend the current Sequencing Initiative Suomi (SISu)samples with a combination of genotyping using Illumina HumanCoreExome array and SISu-based imputation. This will lead to high confidence common and low frequency variantcatalogue. The project will be funded by Aarno Palotie’s remaining faculty fundscomplemented by Finnish funding from FIMM.

  Study EGAS00001001047

• Platinum Genomes

  Improvement of variant calling in next-generation sequence data requires a comprehensive, genome-wide catalogue of high-confidence variants called in a set of genomes for use as a benchmark. We generated deep, whole-genome sequence data of seventeen individuals in a three-generation pedigree and called variants in each genome using a range of currently available algorithms. We used haplotype transmission information to create a phased "platinum" variant catalogue of 4.7 million single nucleotide variants (SNVs) plus 0.7 million small (1-50bp) insertions and deletions (indels) that are consistent with the pattern of inheritance in the parents and eleven children of this pedigree. Platinum genotypes are highly concordant with the current catalogue of the National Institute of Standards and Technology for both SNVs (>99.99%) and indels (99.92%), and add a validated truth catalogue that has 26% more SNVs and 45% more indels. Analysis of 334,652 SNVs that were consistent between informatics pipelines yet inconsistent with haplotype transmission ("non-platinum") revealed that the majority of these variants are de novo and cell-line mutations or reside within previously unidentified duplications and deletions. The reference materials from this study are a resource for objective assessment of the accuracy of variant calls throughout genomes.

  Study phs001224

• Spatiotemporal Genomic Profiling of Intestinal Metaplasia Reveals Clonal Dynamics of Gastric Cancer Progression

  Intestinal metaplasia (IM) is a pre-malignant condition of the gastric mucosa associated with increased gastric cancer (GC) risk. We analyzed 1256 gastric samples (1152 IMs) from 692 subjects from a 10-year prospective study. We identified 26 IM driver genes in diverse pathways including chromatin regulation (ARID1A) and intestinal homeostasis (SOX9), largely occurring as subclonal events. Analysis of clonal dynamics between and within subjects, and also longitudinally across time, revealed that IM clones are likely transient but increase in size upon progression to dysplasia, with eventual transmission of genetic events to paired GCs. Single-cell and spatial profiling highlighted changes in tissue ecology and lineage heterogeneity in IM, including an intestinal stem-cell dominant cellular compartment linked to early malignancy. Expanded transcriptome profiling revealed expression-based molecular subtypes of IM, including a body-resident “pseudoantralized” subtype associated with incomplete histology, antral/intestinal cell types, ARID1A mutations, inflammation, and microbial communities normally associated with the healthy oral tract. We demonstrate that combined clinical-genomic models outperform clinical-only models in predicting IMs likely to progress. Our results raise opportunities for GC precision prevention and interception by highlighting strategies for accurately identifying IM patients at high GC risk and a role for microbial dysbiosis in IM progression.

  Study EGAS00001007067

• Dataset for NSCLC-RNA

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

  Dataset EGAD00001008846

• The Mutational Landscape of CTCL and Sezary Syndrome

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

  Study phs000994

• Molecular stratification of endometrioid ovarian carcinoma predicts clinical outcome

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

  Study EGAS00001004366

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

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

  Study EGAS00001008381

• Whole Exome Sequencing of paired gDNAs and PPGL tumor DNA from patients with cyanotic congenital heart disease

  Fastq files from Whole Exome Sequencing of 12 paired germline DNA (from blood/saliva) and 14 PPGL tumor DNA (from formalin-fixed paraffin-embedded (FFPE) blocks from surgery) from patients with cyanotic congenital heart disease (CCHD) and pheochromocytoma and paraganglioma (PPGL). Sequencing was performed using the Illumina HiSeq4000.

  Dataset EGAD50000001201

• RNA-seq of atypical 3q26 samples

  RNA was isolated using phenol-chloroform extraction followed by DNase digestion or using the Qiagen Allprep DNA/RNA kit and protocol (Qiagen, #80204). cDNA synthesis was done using the SuperScript II Reverse Transcriptase kit (Invitrogen). Quantitative real-time PCR was performed by using primers as described previously13,21 on the 7500 Fast Real-time PCR System (Applied Biosystems). Relative levels of gene expression were calculated using the ΔΔCt method

  Dataset EGAD00001006106

• Whole Genome Sequencing of Therapy-Related Myeloid Neoplasms

  The dataset consists of: 51 paired tumor/normal WGS samples (26 tumors and 25 normals), and 13 normal targeted samples.

  Dataset EGAD00001010026

• Identification of putative multiple myeloma (MM) susceptibility genes

  We sought to identify novel MM susceptibility genes using a collection of families with multiple cases of MM/MGUS, including 189 affected individuals from 40 families, and index cases from an additional 88 families, along with 170 early-onset (EO) MM cases (≤ 55 years). We analyzed a total of 347 affected individuals using whole exome (N=321) and whole genome (N=26) sequencing. Samples were identified and collected through nation-wide efforts in France, Sweden and Greece. We focused on rare (MAF<0.5%) germline protein truncating and likely deleterious missense variants in genes harboring variants in at least two families showing variant-disease segregation, and in additional index (≥2) and/or early-onset (≥2) cases.

  Study EGAS50000001259

• Single cell targeted DNA-sequencing (and antibody sequencing) of high hyperdiploid B-ALL

  This dataset contains all sequencing data of the publication "Single-cell DNA and Surface Protein Characterization of High Hyperdiploid Acute Lymphoblastic Leukemia at Diagnosis and During Treatment". We provide both the raw fastq-files as well as the processed data in the form of .h5 files. There are 13 patients: XJ176, XH135, XJ180, XI145, XI148, XI167, XI150, XJ175, XJ178, XI162, XF98, XG111 and XG115. Of 9 patients, also follow-up samples during/after treatment were sequenced: XJ180, XI145, XI148, XI167, XI150, XJ175, XJ178, XI162 and XG111. To identify the cell types and distinguish between normal and leukemic cells, cell surface proteins were also captured for 6 samples: XF98, XG111 (at diagnosis and during treatment), XG115, XI162 (after treatment) and XJ175 (after treatment). All samples were processed on the MissionBio platform with a custom amplicon panel, and DaB-seq for the combined targeted DNA and protein sequencing.

  Dataset EGAD50000000829

• NHLBI TOPMed: GOLDN Epigenetic Determinants of Lipid Response to Dietary Fat and Fenofibrate

  The GOLDN study was initiated to assess how genetic factors interact with environmental (diet and drug) interventions to influence blood levels of triglycerides and other atherogenic lipid species and inflammation markers (registered at clinicaltrials.gov, number NCT00083369). The study recruited Caucasian participants primarily from three-generational pedigrees from two NHLBI Family Heart Study (FHS) field centers (Minneapolis, MN and Salt Lake City, UT). Only families with at least two siblings were recruited and only participants who did not take lipid-lowering agents (pharmaceuticals or nutraceuticals) for at least 4 weeks prior to the initial visit were included. The diet intervention followed the protocol of Patsch et al. (1992). The whipping cream (83% fat) meal had 700 Calories/m2 body surface area (2.93 mJ/m2 body surface area): 3% of calories were derived from protein (instant nonfat dry milk) and 14% from carbohydrate (sugar). The ratio of polyunsaturated to saturated fat was 0.06 and the cholesterol content of the average meal was 240 mg. The mixture was blended with ice and flavorings. Blood samples were drawn immediately before (fasting) and at 3.5 and 6 hours after consuming the high-fat meal. The diet intervention was administered at baseline as well as after a 3-week treatment with 160 mg micronized fenofibrate. Participants were given the option to complete one or both (diet and drug) interventions. Of all participants, 1079 had phenotypic data and provided appropriate consent, and underwent whole genome sequencing through the Trans-Omics for Precision Medicine (TOPMed) program. Comprehensive phenotypic and pedigree data for GOLDN study participants are available through dbGaP phs000741.

  Study phs001359

• 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

• Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus Trial (The MILES Trial)

  Lymphangioleiomyomatosis (LAM) is an uncommon, progressive, cystic lung disease that predominantly affects young women. It is believed to be caused by defects within cellular pathways that regulate nutrient uptake, cell size, cell migration, and cell proliferation. The disease is caused by mutations in tuberous sclerosis complex (TSC) genes. Individuals with Lymphangioleiomyomatosis (LAM) often experience pneumothorax and chylothorax, as well progressive loss of lung function. Lymphangioleiomyomatosis (LAM) is frequently fatal and existing therapies for the disease have not proven effective. Lung transplantation can be considered as a last option, but alternative treatments are needed. Sirolimus is an immunosuppressive drug that is often used in people who have had kidney transplants. It directly affects the genetic pathway that causes Lymphangioleiomyomatosis (LAM). This study will evaluate the safety and effectiveness of sirolimus in stabilizing or improving lung function in people with Lymphangioleiomyomatosis (LAM). Individuals interested in participating in this 2-year, double-blind study will first report to the study sites for pulmonary function testing to determine their eligibility for participation. Participants deemed eligible will be randomly assigned to receive either sirolimus or placebo for 1 year. Sirolimus or placebo will be administered in 2 tablet doses (2 mg for sirolimus) for the duration of the study. Study visits will occur at baseline, Week 3, every 3 months for 12 months, and Months 18 and 24. Study visits will include a physical exam, questionnaires, a pregnancy test, blood and urine collection, and functional lung tests. A 6-minute walk test will occur at most study visits; a chest x-ray will be taken at baseline and Month 24; and a volumetric computed tomography scan will occur at baseline Month 12, and Month 24. Adverse events, medication side effects, and lung function will be assessed at each visit.

  Study phs000605