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• Molecular origins of mpMRI visibility

  Multiparametric magnetic resonance imaging (mpMRI) has transformed the landscape of prostate cancer (PCa) management. Prostate Imaging Reporting and Data System (PI-RADSv2) scores reflect function and correlate phenotypic features with tumor aggressiveness, is an independent predictor of biochemical recurrence, and may distinguish low-risk tumors requiring no treatment from high-risk tumors requiring aggressive management. We hypothesize that differences in functional mpMRI of prostate tumors reflect the genetic and epigenetic heterogeneity of PCa. We profiled the genomes and transcriptomes of 40 Gleason score 3+4 tumors, of which 20 tumors were mpMRI invisible (not PI-RADSv2 3-5) and 20 tumors were visible (PI-RADSv2 5). Genomes of visible tumors were more unstable than those of invisible tumors. We identified 62 enriched transcripts, including numerous snoRNAs, Relaxin 1 and SCHLAP1, in visible tumors. These data suggest a confluence of aggressive pathological and microenvironmental phenomenon in PI-RADSv2 5 tumors reminiscent of nimbosus, while linking the molecular profiles of tumor aggressiveness with their functional features on mpMRI.

  Study EGAS00001003179

• Tumour gene expression signature in primary melanoma predicts long-term outcomes: A prospective multicentre study

  Adjuvant systemic therapies are now routinely used following resection of stage III melanoma, however accurate prognostic information is needed to better stratify patients. We used differential expression analyses of primary tumours from 204 RNA-sequenced melanomas within a large adjuvant trial, identifying a 121 metastasis-associated gene signature. This signature strongly associated with progression-free (HR=1.63, p=5.24x10-5) and overall survival (HR=1.61, p=1.67x10-4), and validated in 177 regional lymph nodes metastasis as well as two externally ascertained datasets. The machine learning classification models trained using the signature genes performed significantly better in predicting metastases than models trained with clinical covariates (pAUROC=0.02), or published prognostic signatures. The signature score negatively correlated with measures of immune cell infiltration (ρ=-0.75, p<2.2x10-16), with a higher score representing reduced lymphocyte infiltration and a higher 5-year risk of death in stage II melanoma. Our expression signature identifies melanoma patients at higher risk of metastases and warrants further evaluation in adjuvant clinical trials.

  Study EGAS00001004664

• RNA-seq of M-CSF differentiated human peripheral monocyte-derived macrophages (MDMs) - Validation macIDR

  Macrophages represent multifunctional leukocytes defined by their stimulus-specific transcriptional reprogramming. As in vivo macrophages are often difficult to obtain, in vitro macrophage models are often used. We aggregated public expression data to define consensus expression profiles for eight commonly-used in vitro macrophage models and built the classifier macIDR, capable of distinguishing macrophage subsets with high accuracy (>0.95). Classification of in vivo macrophages suggested that alveolar macrophages resembled interleukin-10 activated macrophages in general whereas chronic obstructive pulmonary disease patients displayed decreased similarity to interferon-γ stimulated macrophages. Adipose tissue-derived macrophages were classified as unstimulated macrophages, but would resemble LPS-stimulated macrophages more in diabetic-obese patients. Rheumatoid arthritic synovial macrophages were similar to macrophages stimulated with interleukin-10 or interferon-γ. Altogether, our results suggest that macIDR is capable of identifying in vitro macrophages. By projecting in vivo macrophages onto the in vitro macrophages, we were capable of elucidating macrophage-specific changes as a result of tissue and disease.

  Study EGAS00001003451

• DERMATLAS__Porocarcinoma_WES

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are porocarcinomas.

  Study EGAS00001005720

• DERMATLAS__Poroma_WES

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are poromas.

  Study EGAS00001007705

• Liverpool Preterm Birth Biomarker Study

  Preterm birth is a multifactorial condition defined as birth less than 37 weeks of gestation. This study aimed to identify early pregnancy biomarkers from maternal genome-wide and transcriptome-wide data of women experiencing two types of spontaneous PTB (sPTB): spontaneous preterm birth (SPTB) and preterm premature rupture of membranes (PPROM). Whole blood samples were obtained from women with singleton pregnancies (N=567) recruited at the Liverpool Women’s Hospital at 16 and 20 weeks of gestation. Women with a previous history of sPTB pregnancies <34 weeks were categorised on their index pregnancy outcome as spontaneous preterm birth (SPTB) and preterm premature rupture of membranes (PPROM) or high-risk term control (HTERM, ≥37 weeks). Women with no history of SPTB/PPROM and delivered at term were LTERM (≥39 weeks of gestation). DNA was genotyped on the UK Biobank Axiom™ array (Applied Biosystems™, Thermo Fisher Scientific) and RNA who processed using the Clariom™ D Human assay (Thermo Fisher Scientific). Genome-wide association analysis, differential expression analysis and expression quantitative trait loci (eQTL) were completed.

  Study EGAS00001005076

• DERMATLAS__Hidradenoma_papilliferum_RNAseq

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are hidradenoma papilliferums.

  Study EGAS00001005715

• Extensive three-dimensional intratumor proteomic heterogeneity revealed by multiregion sampling in high-grade serous ovarian tumor specimens

  Enriched tumor epithelium, tumor-associated stroma, and whole tissue were collected by laser microdissection from thin sections across spatially separated levels of ten high-grade serous ovarian carcinomas (HGSOCs) and analyzed by mass spectrometry, reverse phase protein arrays, and RNA sequencing. Unsupervised analyses of protein abundance data revealed independent clustering of an enriched stroma and enriched tumor epithelium, with whole tumor tissue clustering driven by overall tumor “purity.” Comparing these data to previously defined prognostic HGSOC molecular subtypes revealed protein and transcript expression from tumor epithelium correlated with the differentiated subtype, whereas stromal proteins (and transcripts) correlated with the mesenchymal subtype. Protein and transcript abundance in the tumor epithelium and stroma exhibited decreased correlation in samples collected just hundreds of microns apart. These data reveal substantial tumor microenvironment protein heterogeneity that directly bears on prognostic signatures, biomarker discovery, and cancer pathophysiology and underscore the need to enrich cellular subpopulations for expression profiling. (Companion proteomic data is available in the ProteomeXchange Consortium, PRIDE: PXD026570).

  Study EGAS00001005786

• DERMATLAS__SG_basal_cell_adenoma_and_adenocarcinoma_WES

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are SG basal cell adenomas and adenocarcinomas.

  Study EGAS00001007745

• DERMATLAS__Leiomyosarcoma_RNAseq

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are leiomyosarcomas.

  Study EGAS00001007631

• DERMATLAS__Hidradenoma_papilliferum_WES

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are hidradenoma papilliferums.

  Study EGAS00001005714

• DERMATLAS__Poroma_RNAseq

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are poromas.

  Study EGAS00001005759

• DERMATLAS__Leiomyosarcoma_WES

  irtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are leiomyosarcomas.

  Study EGAS00001007628

• DERMATLAS__SG_basal_cell_adenoma_and_adenocarcinoma_RNAseq

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are SG basal cell adenomas and adenocarcinomas.

  Study EGAS00001007746

• Cell-free DNA TAPS for early cancer detection

  Multimodal, genome-wide characterization of epigenetic and genetic information in circulating cell-free DNA (cfDNA) could enable more sensitive early cancer detection. However, due to technological challenges associated with DNA methylation sequencing in low input cfDNA samples, most studies have been limited by DNA damage caused by bisulfite sequencing, or the qualitative nature of enrichment-based sequencing. Recently, we developed TET-assisted Pyridine Borane Sequencing (TAPS), which is a mild, bisulfite-free method for base-resolution direct DNA methylation sequencing. Here we optimized TAPS for cfDNA (cfTAPS) to provide high-quality and high-depth whole-genome cell-free methylomes. We applied cfTAPS to 85 cfDNA samples from patients with hepatocellular carcinoma (HCC) or pancreatic ductal adenocarcinoma (PDAC) and non-cancer controls. From just 10 ng cfDNA (1-3 mL of plasma), we generated the most comprehensive cfDNA methylome to date. We demonstrated that cfTAPS provides multimodal information about cfDNA characteristics, including DNA methylation, tissue of origin, and DNA fragmentation. Integrated analysis of these epigenetic and genetic features enables accurate identification of early HCC and PDAC.

  Study EGAS00001004962

• Kalirin-RAC controls nucleokinetic migration in ADRN-type neuroblastoma

  The migrational propensity of neuroblastoma is affected by cell identity, but the mechanisms behind the divergence remain unknown. Using RNAi and time-lapse imaging, we show that ADRN-type NB cells exhibit RAC1- and kalirin-dependent nucleokinetic (NUC) migration that relies on several integral components of neuronal migration. Inhibition of NUC migration by RAC1 and kalirin-GEF1 inhibitors occurs without hampering cell proliferation and ADRN identity. Using three clinically-relevant expression dichotomies, we reveal that most of up-regulated mRNAs in RAC1- and kalirin-GEF1-suppressed ADRN-type NB cells are associated with low-risk characteristics. The computational analysis shows that, in a context of overall gene set poverty, the upregulomes in RAC1- and kalirin-GEF1-suppressed ADRN-type cells are a batch of AU-rich elements (ARE)-containing mRNAs, which suggests a link between NUC migration and mRNA stability. GSEA-based search for vulnerabilities reveals prospective weak points in RAC1- and kalirin-GEF1-suppressed ADRN-type NB cells, including activities of H3K27- and DNA methyltransferases. Altogether, these data support the introduction of NUC inhibitors into cancer treatment research.

  Study EGAS00001005023

• Interferon lambda 4 impairs viral antigen presentation and attenuates T cell responses

  Genetic variants of the interferon lambda (IFNL) gene locus are strongly associated with spontaneous and IFN treatment induced clearance of hepatitis C virus (HCV) infections. Individuals with the ancestral IFNL4-dG allele are not able to clear HCV in the acute phase and develop chronic hepatitis C (CHC) with more than 90% probability. Paradoxically, the IFNL4-dG allele encodes a fully functional IFNλ4 protein with antiviral activity against HCV and coronavirus. Here we describe a hitherto unknown effect of IFNλ4 on HCV antigen presentation. Only minor amounts of IFNλ4 are secreted, because the protein is largely retained in the endoplasmic reticulum (ER) where it induces ER stress. Stressed cells were significantly weaker activators of HCV specific CD8+ T cells. This was not due to reduced MHC I surface presentation or extracellular IFNλ4 effects, since T cell responses could be restored by exogenous loading of MHC with HCV antigens. Rather, IFNλ4 induced ER stress impaired HCV antigen processing and/or loading onto the MHC I complex. Our results provide a potential explanation for the IFNλ4 – HCV paradox.

  Study EGAS00001005396

• An instructive role for IL7RA in the development of human B-cell precursor leukemia

  Kinase signaling fuels growth of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Yet its role in leukemia initiation is unclear and has not been shown in primary human hematopoietic cells. We previously described activating mutations in interleukin-7 receptor alpha (IL7RA) in poor-prognosis “ph-like” BCP-ALL. Here we show that expression of activated mutant IL7RA in human CD34+ hematopoietic cells creates a preleukemic state in transplanted NOD/LtSz-scid IL2Rγnull mice, characterized by persistence of self-renewing Pro-B cells with non-productive V(D)J gene rearrangements. Preleukemic CD34+CD10highCD19+ cells evolved to a BCP-ALL with spontaneously acquired CDKN2A deletions as commonly observed in primary human BCP-ALL. CRISPR mediated silencing of CDKN2A in primary human CD34+ cells transduced with activated IL7RA resulted in robust development of BCP-ALLs in-vivo. Thus, we demonstrate for the first time that constitutive activation of IL7RA can initiate preleukemia in primary human hematopoietic progenitors and cooperates with CDKN2A silencing in progression into BCP-ALL.

  Study EGAS00001005347

• DERMATLAS__Porocarcinoma_RNAseq

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are porocarcinomas.

  Study EGAS00001005721

• A blood atlas of COVID-19 defines hallmarks of disease severity and specificity

  Treatment of severe COVID-19 is currently limited by clinical heterogeneity and incomplete understanding of potentially druggable immune mediators of disease. To advance this, we present a comprehensive multi-omic blood atlas in patients with varying COVID-19 severity and compare with influenza, sepsis and healthy volunteers. We identify immune signatures and correlates of host response. Hallmarks of disease severity revealed cells, their inflammatory mediators and networks as potential therapeutic targets, including progenitor cells and specific myeloid and lymphocyte subsets, features of the immune repertoire, acute phase response, metabolism and coagulation. Persisting immune activation involving AP-1/p38MAPK was a specific feature of COVID-19. The plasma proteome enabled sub-phenotyping into patient clusters, predictive of severity and outcome. Tensor and matrix decomposition of the overall dataset revealed feature groupings linked with disease severity and specificity. Our systems-based integrative approach and blood atlas will inform future drug development, clinical trial design and personalised medicine approaches for COVID-19.

  Study EGAS00001005493

• Multi-omic analysis of cell-of-origin and epigenomic state in pediatric H3K27M gliomas

  It is not known whether midline pediatric gliomas driven by Histone 3 K27M mutations (oncohistones) or EZHIP expression (oncohistone-mimics) share a common cell-of-origin, or arise from distinct cell types with unique vulnerabilities to PRC2 inhibition and partner alterations. Here, we define the etiological and oncogenic relationship between pediatric midline gliomas characterized by inhibition of K27M and K27M-like oncohistones. We assemble an extensive reference for gliogenesis from the developing mouse and human fetal brain. With bulk and single-cell transcriptomics and epigenomics, we profiled a large cohort of primary tumors comprising H3.1K27M and H3.3K27M pontine gliomas, H3.3K27M thalamic gliomas, and EZHIP+ posterior fossa ependymomas. We focus on differences across axes of location (thalamus vs. pons vs. posterior fossa), tumor type (diffuse midline gliomas vs. ependymomas), and oncohistone (H3.1/2K27M vs. H3.3K27M vs. EZHIP). We use tumor molecular features to delineate transcriptional states and cell-of-origin in each entity. Finally, we use culture models in isogenic contexts to interrogate the effect of each oncohistone or mimic.

  Study EGAS00001005773

• Epigenomic priming of immune genes implicates oligodendroglia in multiple sclerosissusceptibility

  Multiple sclerosis (MS) is characterized by a targeted attack on oligodendroglia (OLG)and associated myelin by immune cells, which are thought to be the main drivers of MS susceptibility. Assessing chromatin accessibility and the transcriptome simultaneously at the single cell level, we found that immune genes exhibit a primedchromatin state in mouse and human OLG in a non-disease context, compatible withrapid transitions to immune-competent states in MS. We identified transcription factors as BACH1 and STAT1 involved in immune gene regulation in oligodendrocyteprecursor cells (OPCs). A subset of immune genes present bivalency of H3K4me3/H3K27me3 in OPCs, with Polycomb inhibition leading to their increased activation upon interferon-gamma (IFNg) treatment. Some MS susceptibility single-nucleotide polymorphisms (SNPs) overlap with these regulatory regions in mouse andhuman OLG, and treatment of mouse OPCs with IFNg leads to chromatin architecture remodeling at these loci and altered expression of interacting genes. Our data indicates that susceptibility for MS may involve OLG, which therefore constitute novel targets for immunological-based therapies for MS.

  Study EGAS00001005911

• Tumor-intrinsic expression of the autophagy gene Atg16l1 suppresses anti-tumor immunity in colorectal cancer

  The vast majority of colorectal cancer (CRC) patients fail to respond to immune checkpoint inhibitors (ICI). Understanding tumor-intrinsic determinants of immunotherapy resistance is critical to improve CRC patient outcomes. Here, we demonstrate that transcript levels of the core autophagy gene ATG16L1 are prognostic of poor outcome and predictive of ICI resistance in late-stage CRC. Deletion of Atg16l1 in murine CRC organoids markedly inhibited tumor growth in primary and metastatic niches in syngeneic hosts. ATG16L1 deficiency rendered CRC organoids more responsive to interferon (IFN) signaling and enhanced programmed cell death while decreasing tumor stem-like populations. IFN hypersensitivity consequently promoted cytotoxic anti-tumor immunity in vivo. In IMblaze370, a large phase III clinical trial of anti-PD-L1 in advanced metastatic CRC, low ATG16L1 levels identified patients with increased lymphocyte infiltration and improved outcome in a KRAS mutant setting. This work reveals autophagy as a clinically relevant immunosuppressive mechanism in CRC and provides a rationale for autophagy inhibition to boost immunotherapy responses in the clinic.

  Study EGAS00001005952

• Whole-exome sequencing of glioblastomas with long-term relapse interval

  Treatment options for GBM patients have not changed over the last 15 years, and the success of targeted therapy or immunotherapy has been disappointinglimited. Thus, the standard of care for GBM patients remains surgical resection followed by concomitant DNA alkylating agent therapy with temozolomide (TMZ) and radiation therapy (RT). However, the time to relapse is generally short (6.9 months on average) owing to the tumor’s ability to infiltrate normal parenchyma and its intrinsic resistance to radio-chemotherapy. Due to the lack of alternative treatment options, elucidating underlying resistance mechanism has come into major focus of research, with the hope for opening new ways of therapeutic intervention overcoming resistance. To explore therapy resistance driving events, we performed a study using a single-centric collective of matched pairs of therapy-naïve and post-therapeuticc tissue from GBM patients, selected based on a maximally long interval between resections of the initial and the recurrent tumors. This rare collective was analyzed by whole exome sequencing (WES), mRNA expression and miRNA expression profiling.

  Study EGAS00001006022

• Genetic and epigenetic variation at regulatory regions contribute to cancer evolution under endocrine treatment

  Comprehensive profiling of hormone-dependent breast cancer (HDBC) has identified hundreds of protein-coding alterations contributing to cancer initiation, but only a handful have been linked to endocrine therapy resistance, potentially contributing to 40% of relapses. If other mechanisms underlie the evolution of HDBC under adjuvant therapy is currently unknown. In this work, we employ integrative functional genomics to dissect the contribution of cis-regulatory elements (CREs) to cancer evolution by focusing on 12 megabases of non-coding DNA, including clonal enhancers, gene promoters, and boundaries of topologically associating domains. Massive parallel perturbation in vitro reveals context-dependent roles for many of these CREs, with a specific impact on dormancy entrance and endocrine therapy resistance9. Profiling of CRE somatic alterations in a unique, longitudinal cohort of patients treated with endocrine therapies identifies non-coding changes involved in therapy resistance. Overall, our data uncover actionable transient transcriptional programs critical for dormant persister cells and unveil new regulatory nodes driving evolutionary trajectories towards disease progression.

  Study EGAS00001006340

• Proteogenomics reveals two distinct biological pilocytic astrocytoma subgroups

  Pilocytic astrocytoma (PA) is the most common pediatric brain tumor and driven by aberrant MAPK signaling, typically mediated by BRAF alterations. While five-year overall survival rates exceed 95%, tumor recurrence constitutes a major clinical challenge in incompletely resected tumors despite chemotherapeutic or radiation based therapies. Therefore, we used proteogenomics to discern the biological heterogeneity of PA to improve classification of this tumor entity and identify novel therapeutic targets. Our proteogenomics approach integrates RNA sequencing and LC/MS-based proteomic profiling data from a cohort of 58 confirmed, primary PA samples. An integrative genomics approach was conducted to discern the biological heterogeneity of PA and to identify aberrant pathway activation in these biological subgroups. In summary, Pilocytic astrocytomas segregate into two groups where younger patients are significantly associated with Group 1. Importantly, we validate the two distinct biological subgroups in two non-overlapping cohorts. The biological heterogeneity seen here may improve biological classification and reveal novel therapeutic targets specifically useful for non-resectable tumors with high risk of recurrent or progressive disease.

  Study EGAS00001006402

• Multi-focal genomic dissection of synchronous primary and metastatic tissue from de novo metastatic prostate cancer

  De novo metastatic prostate cancer is highly aggressive, but the paucity of routinely-collected tissue in this setting has hindered genomic stratification and jeopardizes precision oncology efforts. Here, we leveraged a rare study of surgical intervention in 43 de novo metastatic prostate cancers to assess somatic genotype across 607 synchronous primary and metastatic tissue foci plus circulating tumor DNA. Intra-prostate heterogeneity was pervasive and impacted clinically-relevant genes, resulting in frequent discordance between select primary-restricted foci and synchronous metastases. Additional complexity was driven in several instances by polyclonal metastatic seeding from the reservoir of phylogenetically-related primary populations. When simulating standard clinical practice relying on a single tissue focus, genomic heterogeneity plus highly variable per-sample tumor fraction caused false genotyping of dominant disease. However, in silico modeling demonstrated that analysis of multiple biopsy cores can rescue misassigned somatic genotypes. Our results define the relationship between synchronous treatment-naive primary and metastatic lesions in de novo metastatic prostate cancer and provide a framework for implementing genomics-guided patient management.

  Study EGAS00001006466

• DERMATLAS__Tubular_adenoma

  IVirtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are tubular adenomas.

  Study EGAS00001006686

• DERMATLAS__Tubular_adenoma_RNAseq

  IVirtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are tubular adenomas.

  Study EGAS00001006685

• RNA sequencing of CCO- and CCO+ human hepatocytes

  RNAseq data from Passman et al 2023. Clonal CCO-deficient hepatocyte patches and nearby CCO-proficient hepatocytes were identified in morphologically normal human livers and sampled at varying distances along the PT-CV axis. Samples are named according to their location within the liver lobule, with "PT" denoting samples abutting the portal triad, "CV" denoting samples abutting the central hepatic vein, and "Mid" sampled acquired midway between these structures. Normal human liver is thought to be generally quiescent, however clonal hepatocyte expansions have been observed but neither their cellular source nor their expansion dynamics have been determined. Knowing the hepatocyte cell of origin, and their subsequent dynamics and trajectory within the human liver will provide an important basis to understand disease-associated dysregulation. Here we use in vivo lineage tracing and a combination of methylation sequence analysis to demonstrate normal human hepatocyte ancestry. We exploit next generation mitochondrial sequencing to determine hepatocyte clonal expansion dynamics across spatially-distinct areas of laser-capture microdissected clones, in tandem with computational modelling in morphologically-normal human liver.

  Study EGAS00001006984

• Modulation of the peripheral blood immune cell transcriptome by vitamin D3 supplementation in people with a first demyelinating event: a randomized placebo-controlled trial

  Vitamin D deficiency is a risk factor for developing multiple sclerosis (MS). Both in vitro and animal studies suggest an immunomodulatory effect of vitamin D. The PrevANZ trial, a phase IIb randomized placebo-controlled trial of oral vitamin D3 supplementation in people with a first demyelinating event (FDE), was conducted to determine if supplementation can prevent recurrent disease activity in this cohort at high risk of developing definite MS. As a sub-study of this trial, we used whole blood transcriptomic analyses to investigate the effect of vitamin D3 supplementation on peripheral immune cells in people with an FDE, and to gain insight into potential mechanisms by which vitamin D3 may regulate MS risk and disease activity. The PrevANZ trial randomized participants to 1000 IU, 5000 IU or 10,000 IU daily of oral vitamin D3 or placebo. Peripheral blood was collected at baseline and 12 weeks in PAXgene Blood RNA tubes. Transcriptomic datasets were generated by RNA sequencing.

  Study EGAS00001007346

• DERMATLAS__Leiomyoma_WES

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are leiomyomas.

  Study EGAS00001007629

• GOSH_Childhood_Leukemia_Behjati_WellcomeCore_RNA

  Paediatric single-cell archival project This project is taking sequential samples of children with B-cell acute lymphoblastic leukaemia (B-ALL) treated at Great Ormond Street Hospital (GOSH) between 2011 and the present day. Patients selected, are those that have done badly (e.g. had to escalate treatment, relapsed or died) despite having apparently ""good"" or ""intermediate"" risk cytogenetics, and often also had immunotherapy (e.g., the bi-specific T-cell engager blinatumomab) because of this. Using samples from key treatment-points, we hope to better characterise their disease and treatment response, to re-define understandings of risk for patients who did unexpectedly poorly. Additionally, we hope to define the disease/immunological factors that determine response to increasingly used immunotherapies within the field of paediatric B-ALL. Each of the samples will be viably frozen bone marrow-derived mononuclear cells. They will come in Eppendorf's, frozen and de-anonymised, from GOSH. We plan to primarily do single cell analysis (GEX, BCR +/-TCR), and then tumour-only WGS and bulk-RNA expression on left-over

  Study EGAS00001007616

• DERMATLAS__Leiomyoma_RNAseq

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are leiomyomas.

  Study EGAS00001007630

• Selective targeting of TBXT with DARPins identifies regulatory networks and therapeutic vulnerabilities in chordoma

  The embryonic transcription factor TBXT (brachyury) drives chordoma, a spinal neoplasm without effective drug therapies. TBXT’s regulatory network is poorly understood, and strategies to disrupt its activity for therapeutic purposes are lacking. We developed designed ankyrin repeat proteins that block TBXT-DNA binding (T-DARPins). In chordoma cells, T-DARPins reduced cell cycle progression, spheroid formation, and tumor growth in mice and induced signs of senescence and differentiation. Transcriptomic and proteomic analyses identified gene networks involved in cell cycle regulation, embryonic cell identity, and interferon response and revealed features of regulome components, such as druggability for future translational studies and the fine-tuning of TBXT downstream effectors through IGFBP3. Finally, we found high interferon signaling in chordoma cell lines and patient tumors, which was promoted by TBXT and associated with sensitivity to JAK2 inhibitors. These findings demonstrate the potential of DARPins for probing nuclear proteins to understand the regulatory networks of transcription factor-driven cancers, including entry points for therapies that warrant testing in patients.

  Study EGAS00001008140

• Endocrine therapy reprogramming of breast cancer facilitates metastatic escape via upregulation of P-Rex1/Rac1 signalling

  The estrogen receptor (ER) drives growth in ~70% of breast cancers, and endocrine therapies prevent recurrence. However, 30% of patients recur, with many fatal cases occurring late (after >5 years), presenting a challenge due to their often non-proliferative nature and limited options. To study this, we generated slow-growing resistant cells that form small primary tumours but readily metastasize. Single-cell RNA sequencing (scRNAseq) revealed that endocrine therapy reprograms these cells, notably upregulating the Rac1 signalling component P-Rex1. We found in clinical cohorts that P-Rex1 in high in ER+ breast cancer. Intravital imaging demonstrated that Rac1 signalling is active in ER+ cells following endocrine therapy. Targeting the Rac1 pathway with small molecule inhibitors (NSC23766, R-ketorolac) reduced survival and motility in resistant cells, inhibited in vivo Rac1 activity, and reduced tumour burden when combined with tamoxifen in a drug-refractory patient-derived xenograft. This work identifies the P-Rex1/Rac1 axis, as a potential therapeutic target for late recurring ER+ breast cancer.

  Study EGAS00001008353

• Molecular risk stratification in patients with T1 colorectal cancer_WES

  The introduction of bowel cancer screening has led to a significant increase in the proportion of patients being diagnosed with asymptomatic, early-stage colorectal cancer (CRC). Although the majority of these patients are successfully treated with surgery alone, a small proportion of patients have 'born-to-be-bad' aggressive lesions with early dissemination leading to distant metastases. Current standard of care histological assessment is unable to distinguish between these aggressive versus non-aggressive early lesions which is essential to provide appropriate clinical management decisions. This study aims to carry out molecular and histological profiling of approximately 300 T1 CRCs in order to develop a molecular stratifier based on the risk of relapse in early-invasive CRC. This novel T1 cohort will represent the world's largest molecularly characterised T1 cohort of samples, with digital pathology assessment alongside whole exome sequencing, copy number variation analysis and 3' RNA-seq. This data will be used to generate a robust panel of molecular and/or histological markers applicable to formalin-fixed paraffin embedded (FFPE) archival tissue which discriminates between T1 lesions based on risk of relapse, which will ultimately be used to inform clinical management of CRC at the earliest stages of the disease.

  Dataset EGAD00001010890

• Somatic mutation and selection at epidemiological scale - Sanger_NanoSeq_RandD

  Bottleneck sequencing of human tissue including neurons, cord blood, sperm 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/. As we age, many tissues become colonised by microscopic clones carrying somatic driver mutations. Some of these clones represent a first step towards cancer whereas others may contribute to ageing and other diseases. However, our understanding of the clonal landscapes of human tissues, and their impact on cancer risk, ageing and disease, remains limited due to the challenge of detecting somatic mutations present in small numbers of cells. Here, we introduce a new version of nanorate sequencing (NanoSeq), a duplex sequencing method with error rates of less than 5 per billion base pairs, which is compatible with whole-exome and targeted gene sequencing. Deep sequencing of polyclonal samples with single-molecule sensitivity enables the simultaneous detection of mutations in large numbers of clones, yielding accurate somatic mutation rates, mutational signatures and driver mutation frequencies in any tissue. Applying targeted NanoSeq to 1,042 non-invasive samples of oral epithelium and 371 samples of blood from a twin cohort, we found an unprecedentedly rich landscape of selection, with 46 genes under positive selection driving clonal expansions in the oral epithelium, over 62,000 driver mutations, and evidence of negative selection in some genes. The high number of positively selected mutations in multiple genes provides high-resolution maps of selection across coding and non-coding sites, a form of in vivo saturation mutagenesis. Multivariate regression models enable mutational epidemiology studies on how carcinogenic exposures and cancer risk factors, such as age, tobacco or alcohol, alter the acquisition and selection of somatic mutations. Accurate single-molecule sequencing has the potential to unveil the polyclonal landscape of any tissue, providing a powerful tool to study early carcinogenesis, cancer prevention and the role of somatic mutations in ageing and disease.

  Dataset EGAD00001015624

• DNA methylation atlas of normal human cell types

  DNA methylation is a fundamental epigenetic mark that governs chromatin organization, cell identity, and gene expression. Here we describe a human methylome atlas, based on deep whole-genome bisulfite sequencing allowing fragment-level analysis across thousands of unique markers for 39 cell types sorted from 205 healthy tissue samples. Replicates of the same cell-type are >99.5% identical, demonstrating robustness of cell identity programs to genetic variation and environmental perturbation. Unsupervised clustering of the atlas recapitulates key elements of tissue ontogeny, and identifies methylation patterns retained since gastrulation. Loci uniquely unmethylated in an individual cell type often reside in transcriptional enhancers and contain DNA binding sites for tissue-specific transcriptional regulators. Uniquely hyper-methylated loci are rare and are enriched for CpG islands, polycomb targets, and CTCF binding sites, suggesting a novel role in shaping cell type-specific chromatin looping. The atlas provides an essential resource for interpretation of disease-associated genetic variants, and a wealth of potential tissue-specific biomarkers for use in liquid biopsies.

  Study EGAS00001006791

• Assessment of genetic and epigenetic variation in human IPS cells-RNA

  In order to progress human induced pluripotent stem cells (hiPSCs) towards the clinic, several outstanding questions must be addressed. It is possible to reprogram different somatic cell types into hiPSCs and from studies in the mouse, it appears that an epigenetic memory of the starting cell type is carried over to hiPSCs. However a comprehensive comparative study of the characteristics of these hiPSCs has been missing from the literature. Importantly studies which aimed to address these aspects of hiPSCs have used cells from different patients. In order to avoid this important confounding variable and to keep the genetic background constant, tissue samples were procured from the patients and reprogrammed to iPS cells. The transcriptomes of these iPS cells will be compared. Protocol: primary cultures of cells were reprogrammed to iPS cells. RNA was extracted using a standard column extraction kit.

  Dataset EGAD00001000604

• Tumor-resident T cells and dendritic cells form an in situ archetype during immunotherapy response in melanoma.

  Tumor-resident (TR) T cells, known as tissue-resident memory (TRM) T cells in mice, play a central role in melanoma immunosurveillance, yet their contribution to immune checkpoint inhibitors (ICI) therapy has not been comprehensively explored. We performed spatial and single-cell profiling on 32 metastatic melanoma lymph node samples, from treatment-naïve, ICI-resistant, or ICI-responsive patients. Here we show that tumor areas in ICI-responders were enriched in both CD8+ and CD4+ TR. CD8+ TR were hyperexpanded, and both CD8+ and CD4+ TR cells upregulated cytotoxicity-related gene expression, suggesting functional anti-tumor immunity. Conversely, ICI-resistant tumors displayed chronic IFN-γ response pathways, linked to T cell exhaustion. We further identified a spatially organized immune triad composed of CD8⁺ TR, CD4⁺ TR, and type-3 dendritic cells (DC3) that is exclusive to responding tumors. These findings define coordinated cellular interactions within the tumor microenvironment that underpin successful immunotherapy and provide a framework for spatial biomarkers of response.

  Study EGAS50000001722

• Reliable detection of somatic mutations in solid tissues by laser-capture microdissection and low-input DNA sequencing

  Somatic mutations accumulate in healthy tissues as we age, giving rise to cancer and potentially contributing to ageing. To study somatic mutations in non-neoplastic tissues, we developed a series of protocols to sequence the genomes of small populations of cells isolated from histological sections. Here, we describe a complete workflow that combines laser-capture microdissection (LCM) with low-input genome sequencing, whilst circumventing the use of whole-genome amplification (WGA). The protocol is subdivided broadly into 4 steps: tissue processing, LCM, low-input library generation and mutation calling and filtering. The tissue processing and LCM steps are provided as general guidelines which may require tailoring based on the specific requirements of the study at hand. Our protocol for low-input library generation utilises enzymatic rather than acoustic fragmentation to generate WGA-free whole-genome libraries. Finally, the mutation calling and filtering strategy has been adapted from previously published protocols to account for artefacts introduced via library creation. To date, we have used this workflow to perform targeted and whole-genome sequencing of small populations of cells (typically 100-1,000 cells) in thousands of microbiopsies from a wide range of human tissues. The low-input DNA protocol is designed to be compatible with liquid handling platforms and make use of equipment and expertise standard to any core sequencing facility. However, obtaining low-input DNA material via LCM requires specialized equipment and expertise. The entire protocol from tissue reception through whole-genome library generation can be accomplished in as little as a week, though 2-3 weeks would be a more typical turnaround time.

  Dataset EGAD00001006088

• The ITCC-P4 PDX platform of pediatric cancers for preclinical testing

  Cancer is the leading cause of disease-related deaths among children in high-income countries. Tumor heterogeneity and lack of mechanism-of-action-based therapeutic options are key challenges to overcome in order to improve pediatric cancer patients’ survival. Here, we report the EU-IMI-2 funded public-private partnership “ITCC-Pediatric Preclinical Proof-of-Concept Platform” (ITCC-P4), which has built a large repertoire of patient-derived xenograft (PDX) models, representing all major solid pediatric cancer types, for in vivo drug testing. Three-hundred-fifty-three PDX models from diagnostic and relapsed pediatric cancers have been established and molecularly characterized, together with matched germline/tumor samples. As proof-of-concept, we present in vivo drug screening data in neuroblastoma and rhabdomyosarcoma models. PDX data, accessible at http://r2platform.com/itcc-p4, allow the selection of models based on oncogenic drivers and/or potential biomarkers for preclinical testing. Operated by a non-profit entity (www.itccp4.com), this sustainable platform aids academic and industrial researchers in developing and prioritizing innovative therapies for pediatric cancer.

  Study EGAS00001008330

• National Human Genome Research Institute (NHGRI) GENEVA Genome-Wide Association Study of Venous Thrombosis (GWAS of VTE)

  Overview: Our overall long-term goal is to determine risk factors for the complex (multifactorial) disease, venous thromboembolism (VTE), that will allow physicians to stratify individual patient risk and target VTE prophylaxis to those who would benefit most. In this genome-wide association case-control study (1300 cases and 1300 controls) we hope to identify susceptibility variants for VTE. Mutations within genes encoding for important components of the anticoagulant, procoagulant, fibrinolytic, and innate immunity pathways are risk factors for VTE. We hypothesize that other genes within these four pathways or within other pathways also are VTE disease-susceptibility genes. Therefore, we performed a genome wide association (GWA) screen and analysis using the Illumina 660W platform to identify SNPs within 1,300 clinic-based, non-cancer VTE cases primarily from Minnesota and the upper Midwest USA, and 1300 clinic-based, unrelated controls frequency-matched on patient age, gender, myocardial infarction/stroke status and state of residence. This is a subset of a slightly larger candidate gene study using 1500 case-control pairs to identify haplotype-tagging SNPs (ht-SNPs) in a large set of candidate genes (n~750) within the anticoagulant, procoagulant, fibrinolytic, and innate immunity pathways. Study Populations. Cases. VTE cases were consecutive Mayo Clinic outpatients with objectively-diagnosed deep vein thrombosis (DVT) and/or pulmonary embolism (PE) residing in the upper Midwest and referred by Mayo Clinic physician to the Mayo Clinic Special Coagulation Laboratory for clinical diagnostic testing to evaluate for an acquired or inherited thrombophilia, or to the Mayo Clinic Thrombophilia Center. Any person contacted to be a control but discovered to have had a VTE was evaluated for inclusion as a case. Cases were primarily residents from Minnesota, Wisconsin, Iowa, Michigan, Illinois, North or South Dakota, Nebraska, Kansas, Missouri and Indiana. A DVT or PE was categorized as objectively diagnosed when (a) confirmed by venography or pulmonary angiography, or pathology examination of thrombus removed at surgery, or (b) if at least one non-invasive test (compression duplex ultrasonography, lung scan, computed tomography scan, magnetic resonance imaging) was positive. A VTE was defined as: Proximal leg deep vein thrombosis (DVT), which includes the common iliac, internal iliac, external iliac, common femoral, superficial [now termed "femoral"] femoral, deep femoral [sometimes referred to as "profunda" femoral] and/or popliteal veins. (Note: greater and lesser saphenous veins, or other superficial or perforator veins, were not included as proximal or distal leg DVT). Distal leg DVT (or "isolated calf DVT"), which includes the anterior tibial, posterior tibial and/or peroneal veins. (Note: gastrocnemius, soleal and/or sural [e.g., "deep muscular veins" of the calf] vein thrombosis was not included as distal leg DVT). Arm DVT, which includes the axillary, subclavian and/or innominate (brachiocephalic) veins. (Note: jugular [internal or external], cephalic and brachial vein thrombosis was not included in "arm DVT"). Hepatic, portal, splenic, superior or inferior mesenteric, and/or renal vein thrombosis. (Note: ovarian, testicular, peri-prostatic and/or pelvic vein thrombosis was not included). Cerebral vein thrombosis (includes cerebral or dural sinus or vein, saggital sinus or vein, and/or transverse sinus or vein thrombosis). Inferior vena cava (IVC) thrombosis Superior vena cava (SVC) thrombosis Pulmonary embolism Patients with VTE related to active cancer, antiphospholipid syndrome, inflammatory bowel disease, vasculitis, a rheumatoid or other autoimmune disorder, a vascular anomaly (e.g., Klippel-Trénaunay syndrome, etc.), heparin-induced thrombocytopenia, or a mechanical cause for DVT (e.g., arm DVT or SVC thrombosis related to a central venous catheter or transvenous pacemaker, portal and/or splenic vein thrombosis related to liver cirrhosis, IVC thrombosis related to retroperitoneal fibrosis, etc.), with hemodialysis arteriovenous fistula thrombosis, or with prior liver or bone marrow transplantation were excluded. Controls. A Mayo Clinic outpatient control group was prospectively recruited for this study. Controls were frequency-matched on the age group (18-29, 30-39, 40-49, 50-59, 60-69, 70-79, and 80+ years), sex, myocardial infarction/stroke status, and state of residence distribution of the cases. We selected clinic-based controls using a controls' database of persons undergoing general medical examinations in the Mayo Clinic Departments of General Internal Medicine or Primary Care Internal Medicine. Additionally persons undergoing evaluation at the Mayo Clinic Sports Medicine Center, and the Department of Family Medicine were screened for inclusion as controls. This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org) funded by the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to venous thrombosis through large-scale genome-wide association studies of 1,300 clinic-based, VTE cases and 1300 clinic-based, unrelated controls. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington.

  Study phs000289

• Incentives and Case Management to Improve Cardiac Care: Healthy Lifestyle Program (HeLP)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this study.Objectives: The HeLP study assessed how early case management, financial incentives contingent on cardiac-rehabilitation attendance, or both impacted adherence to cardiac rehabilitation among patients with lower socioeconomic status (SES) who had a cardiac-rehabilitation-qualifying diagnosis. Background:Cardiovascular disease (CVD) is the leading cause of death in the United States. Regular attendance at cardiac rehabilitation (CR) is the number one recommendation for patients who have experienced a recent cardiac event. CR is a secondary prevention outpatient program involving an individually tailored structured exercise program along with counseling and encouragement regarding lifestyle changes to reduce the recurrence of major cardiac events.Despite the benefits of CR attendance, enrollment and adherence to the program are low. This is particularly true of individuals of lower socioeconomic status (SES), who also generally suffer a higher burden from CVD on account of higher-risk cardiac profiles. As these profiles are the result of modifiable behavior targeted by CR (i.e., smoking, obesity, lack of physical activity), methods of increasing CR attendance among this population are necessary.Case management and financial incentives contingent on CR attendance are two potential strategies for addressing this issue. Previous studies have shown how trained case managers can support and assist patients with attending CR and improving their cardiac health, and how financial incentives can promote various types of health-related behavior. The purpose of the present study was to evaluate how these two interventions, individually and in tandem, fared at improving CR adherence among individuals of lower SES specifically. Participants:A total of 314 participants were screened, and 209 were randomized. All consented to have their data shared for research purposes. Design:Eligible patients were approached either while still in the hospital or during initial visits to CR. After obtaining informed consent, clinical and demographic characteristics (i.e., age, sex, education, race and ethnicity, smoking status, and CR-qualifying diagnosis) and depressive symptoms were collected. Participants then were randomized 2:3:3:3 to usual care (UC), case management starting in hospital (CM), financial incentives for attending CR (FI), or financial incentives plus case management (FICM). For all participants regardless of condition, an appropriate referral for CR was confirmed after randomization. Over the course of the study participants completed three assessments – one at intake, one after four months, and one after one year. Clinical (i.e., cardiorespiratory fitness, body composition, and cardiac-related quality of life) and sociocognitive (i.e., Beck Depression Inventory, Achenbach System of Empirically Based Assessment, and Behavior Rating Inventory of Executive Function) measures were obtained at each assessment. Participants randomized to the UC condition were contacted weekly by study staff for adverse event checks, but received no additional intervention. Participants randomized to the CM condition were immediately assigned a case manager. Case managers met with their participants, usually within 24 hours of consent while they were still in the hospital, to introduce themselves during an initial check-in. Within the first week of consent they completed a longer, more thorough initial needs assessment with their participant and established behavioral goals. For the next 16 weeks, case managers met with their participants at least once a week, typically over the phone, to discuss progress on these goals and address any problems or barriers that had arisen. Case managers also were available via phone outside of these regular meetings during normal working hours and Saturday mornings. Participants randomized to the FI condition could earn money for completing an initial CR orientation and attending CR sessions. Twenty dollars could be earned for completing the CR orientation session. CR attendance was reinforced on an escalating schedule starting at $10. Payments increased by $2 for each successive session attended, and capped out at a maximum of $40 per session. Unexcused absences resulted in the incentives for that session not being earned, and the potential earnings for the next scheduled session being reset to $10. Successful participation of two consecutive sessions following the reset resulted in the incentives being returned to the amount prior to the reset. In total, participants could earn $1220 for attending the initial orientation and all 36 sessions of CR. The primary outcome of interest was the percentage of participants who completed at least 30 sessions of CR. Secondary outcomes included the number of sessions completed, cardiorespiratory fitness (peak VO2 and estimated metabolic equivalents (METs)), body composition (waist circumference and BMI), depression scores, and both general and cardiac-related qualify of life. Conclusions:The two interventions involving financial incentives (i.e., financial incentives alone and financial incentives plus case management) significantly improved CR adherence compared to usual care. Subsequent analyses revealed that the combination of financial incentives and case management led to greater improvements in CR attendance than financial incentives alone.

  Study phs003737

• Sleep Heart Health Study (SHHS-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.Related StudiesParent cohort phenotype data can be accessed through ARIC-BioLINCC, Framingham-BioLINCC, and CHS-BioLINCC. Objectives To determine the cardiovascular and other consequences of sleep-disordered breathing and to test whether sleep-disordered breathing is associated with an increased risk of coronary heart disease, stroke, all-cause mortality and hypertension by examining subjects from well-characterized and established epidemiologic cohorts. Background Obstructive sleep apnea syndrome (OSA) is a potentially debilitating condition characterized by repetitive episodes of apnea while asleep, nocturnal oxygen desaturation, excessive daytime sleepiness, and loud disruptive snoring. Epidemiologic data from middle-aged adults indicate that OSA is common, with prevalence rates of 4% in men and 2% in women. Prior studies implicated OSA as a risk factor for the development of hypertension, ischemic heart disease, congestive heart failure, stroke and consequently premature death. Questions arose as to whether an increased propensity for cardiovascular and cerebrovascular diseases was limited to only those with frank OSA or whether more subtle forms of sleep-disordered breathing (SDB) would also confer elevated risk. Further evidence was also needed to clarify whether, SDB, including OSA, is an independent risk factor for the development of cardiovascular or cerebrovascular disease. Known cardiovascular and cerebrovascular disease risk factors such as obesity and smoking are commonly present in those with SDB; therefore, apparent associations between SDB and cardiovascular and cerebrovascular diseases may have resulted from the effects of these concomitant risk factors. Moreover, there was no understanding as to whether such factors as race, age, gender, and prevalent cardiovascular or cerebrovascular disease might interact with SDB to alter future cardiovascular and cerebrovascular disease risk. Mechanisms underlying any propensity to develop cardiovascular or cerebrovascular disease with SDB had not been firmly established (Quan, et al., 1997, PMID: 9493915). Participants Participants in SHHS were recruited from nine existing NHLBI epidemiological studies in which data on cardiovascular risk factors had been collected previously. The “parent” cohorts included: Two sites of the Atherosclerosis Risk in Communities Study (ARIC) Three sites of the Cardiovascular Health Study (CHS) The Framingham Offspring Cohort The Strong Heart Study (SHS) sites in South Dakota, Oklahoma, and Arizona The New York Hypertension Cohorts The Tucson Epidemiologic Study of Airways Obstructive Diseases and the Health and Environment Study From these parent cohorts, a sample of participants who met the inclusion criteria (age 40 years or older; no history of treatment of sleep apnea; no tracheostomy; no current home oxygen therapy) was invited to participate in the baseline examination of the SHHS, which included an initial polysomnogram (SHHS-1). Several cohorts over-sampled snorers in order to increase the study-wide prevalence of sleep-disordered breathing. In all, 6441 individuals were enrolled between November 1, 1995 and January 31, 1998. During exam cycle 3 (January 2001-June 2003), a second polysomnogram (SHHS-2) was obtained in 3295 of the participants. Due to sovereignty issues, Strong Heart Study participants are not included in the shared SHHS data. Data from a total of 5839 participants (1920 ARIC, 1249 CHS, 997 Framingham Offspring and OMNI 1, and 1673 from other studies), consenting to share data are available. Design The Sleep Heart Health Study added in-home polysomnography to the data collected in each of the parent studies at a baseline SHHS exam and a follow-up approximately 4 years later. Using the Compumedics PS polysomnograph, sleep studies were obtained in an unattended setting, usually in the homes of the participants, by trained and certified technicians. The recording montage consisted of: C3/A2 and C4/A1 EEGs, sampled at 125 Hz right and left electrooculograms (EOGs), sampled at 50 Hz a bipolar submental electromyogram (EMG), sampled at 125 Hz thoracic and abdominal excursions (THOR and ABDO), recorded by inductive plethysmography bands and sampled at 10 Hz "airflow" detected by a nasal-oral thermocouple (Protec, Woodinville, WA), sampled at 10 Hz finger-tip pulse oximetry (Nonin, Minneapolis, MN) sampled at 1 Hz ECG from a bipolar lead, sampled at 125 Hz for most SHHS-1 studies and 250 Hz for SHHS-2 studies Heart rate (PR) derived from the ECG and sampled at 1 Hz body position (using a mercury gauge sensor) ambient light (on/off, by a light sensor secured to the recording garment)This montage provides data on the occurrence of sleep-disordered breathing, sleep stages, heart rate, oximetry and on arousals. Each participant in the parent studies was also asked to complete the Sleep Habits Questionnaire which covers usual sleep pattern, snoring, and sleepiness.

  Study phs003637

• Genome-Wide Association Study of Hypertriglyceridemia in Mexicans

  Coronary artery disease (CAD) is the number one cause of death and mortality world-wide. High levels of serum triglycerides (TGs) and low levels of serum high-density lipoprotein cholesterol (HDL-C) are major risk factors for CAD. Previous epidemiological studies have shown that these two lipid disturbances are highly common dyslipidemias in Mexicans. However, the genetic factors underlying high serum TGs and low HDL-C are underinvestigated and poorly identified in Mexicans. As the Mexican-American and the genetically related Latin-American populations represent the fastest growing minority in the United States, elucidation of the unknown genetic factors influencing the increased susceptibility of Mexicans to these common dyslipidemias is of great relevance to these U.S. minorities and the American healthcare system. This study is a research collaboration between investigators at the University of California, Los Angeles (UCLA) and Instituto Nacional de Ciencias Médicas y Nutrición (INCMN), Mexico City, to perform a two-stage genome-wide association study (GWAS) for hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C) in Mexicans (Weissglas-Volkov et al. 2013, PMID: 23505323). This study was funded by an RO1 grant from NIH/NHLBI (PI Paivi Pajukanta; PI of the subaward Teresa Tusie-Luna). In stage 1 of the GWAS, we tested all GWAS SNPs from the Illumina Infinium Human610-Quad platform that passed quality control for association in ~2,200 hypertriglyceridemia cases and controls. In stage 2, we genotyped the ~1,200 positive signals of stage 1 in additional ~2,200 hypertriglyceridemia cases and controls, and performed a combined analysis of the two stages to identify genome-wide significant variants. The subjects were recruited at the INCMN. The DNA isolation and clinical laboratory measurements of the case-control study samples were performed at INCMN using standardized procedures. Genotyping and statistical analyses of the data were performed at UCLA. A summary of this GWAS can be found in Weissglas-Volkov et al. 2013 Journal of Medical Genetics, PMID: 23505323. Briefly, using the two-stage GWAS design, we identified a novel Mexican-specific genome-wide significant locus for serum TG levels close to the Niemann-Pick type C1 protein (NPC1) gene (Weissglas-Volkov et al. 2013, PMID: 23505323). Of the European lipid GWAS loci, three TG loci (APOA5, GCKR, and LPL) and four HDL-C loci (ABCA1, CETP, LIPC and LOC55908) resulted in genome-wide significant signals in Mexicans. Furthermore, our cross-ethnic mapping narrowed three European TG GWAS loci, APOA5, MLXIPL, and CILP2 that exhibited long range LD and a large number of candidate SNPs in the European GWAS scan. In the apolipoprotein A1C3A4A5 gene cluster region, the cross-ethnic fine mapping and LD comparisons reduced the number of candidate variants to one SNP, rs964184. We also found that although 52% of the associations from European lipid GWAS meta-analysis could be generalized to Mexicans, in 82% of the European GWAS loci, a different variant other than the European lead SNP provided the statistically strongest evidence of association in the Mexican scan (Weissglas-Volkov et al. 2013, PMID: 23505323). Taken together, our Mexican GWAS for lipids identified a novel Mexican-specific locus for high serum TGs; restricted three European GWAS loci; and investigated which European lipid GWAS variants extend to the Mexican population (Weissglas-Volkov et al. 2013, PMID: 23505323). This NHLBI sponsored RO1 project aimed to identify genetic variants contributing to serum lipid levels in Mexicans. In addition to de-identified genome wide genotypic data, a selected list of de-identified phenotypic data related to hypertriglyceridemia and related metabolic traits are also available in dbGaP.

  Study phs000618

• CRU-Ukrainian National Research Center for Radiation Medicine Trio Study

  Data on transgenerational effects following nuclear accidents are important for understanding fully the consequences of parental exposure to ionizing radiation. Few studies to date have had adequate statistical power to detect effects of the magnitude expected based on animal data, and most have not been of low-dose, protracted exposures associated with nuclear accidents and their aftermath. Although, to date, scant use has been made of the new genomic technologies, in Chernobyl-exposed areas of Ukraine and Belarus, excess minisatellite mutations have been seen in children born after the accident. We propose a study of parent-child trios in which at least one parent was exposed to Chernobyl radiation as a clean-up worker (mean dose>=100 mGy) and/or evacuee from a contaminated area (mean >=50 mGy). The specific aims are to investigate the transgenerational and de novo mutation rates of the spectrum of genetic variants in trios, in particular looking at effects in children and mapping them to possible parental origin of the chromsoome. Together with long-term collaborators at the Research Center for Radiation Medicine (RCRM) in Kiev, epidemiologic data will be collected for up to 450 trios of parents with preconceptional doses and their unexposed offspring. We will use state-of-the-art genomic technologies to characterize the landscape of the genomes of the trios to determine whether parental radiation exposure is associated with genetic mutations transmitted to the offspring, by examining de novo mutation rates, minisatellite mutations, copy number alterations, and variations in telomere length. The analysis will be conducted in peripheral blood and/or buccal samples (when blood is not available) from complete father-mother-child trios. Doses to the gonads from the time of the accident to the time of conception will be reconstructed for all parents using existing records supplemented by interview data. Trio subjects will be selected from representative populations exposed to radiation from Chernobyl who are under active follow-up in the Clinico-Epidemiologic Registry at RCRM. To help identify specific effects of paternal and maternal radiation exposure, we will initially select sets of trio subjects in five categories: (1) exposed father, unexposed mother; (2) unexposed father, exposed mother; (3) both parents exposed; (4) both parents unexposed; and (5) a group of high dose "emergency workers" with acute radiation syndrome. All trio members will be invited to the RCRM outpatient clinic for collection of a 20 ml blood sample (or buccal cells for those who refuse phlebotomy). Both parents will be asked to complete a general questionnaire to obtain demographic and lifestyle data. Then one or both will complete detailed dosimetry questionnaires, based on forms used in previous collaborations with RCRM and administered by specially trained interviewers. Once 50 trios have been recruited (10 from each of the 5 exposure categories), we will conduct an interim evaluation of participation rates, sample collection and quality, and dose reconstruction in order to modify the protocol as needed. The analytical approach will be to correlate the extent, especially for de novo events of genetic alterations in the offspring with parental pre-conceptional radiation dose overall and by parental origin. The statistical power in relation to de novo mutations is very high, in excess of 90%, but somewhat lower for trends in minisatellite mutations. Study findings will contribute importantly to knowledge of the heritable effects of moderate- and low-dose radiation exposure in humans and to radiation risk projection. Eventually data from the Trio Study may be shared with the international community through dbGap.

  Study phs001163

• The UCSD / O'Connor "TSP" (Twin/Sibling/Pedigree) Resource in Hypertension

  Study Design: The UCSD / O'Connor "TSP" (Twin/Sibling/Pedigree) Resource in Hypertension contains N=797 participants. At the time of recruitment individuals ranged from 15-84 years of age and had varying ethnic backgrounds (Whites, African-Americans and Hispanics). The cohort was developed to study the genetic basis of autonomic dysfunction in human essential hypertension (reviewed in Zhang et al. Curr Hypertens Rep. 2011 13: 36-45. PMID: 21104344) and contains cross-sectionally collected phenotypes related to blood pressure regulation.  Phenotypes: Phenotype data specifically focuses on the sympathetic branch of the autonomic system, which is a key regulator of blood pressure. Data includes circulating concentrations of the secretory "quantum" (catecholamines, neuropeptides, chromogranins) which influence vascular responses to sympatho-adrenal activation resulting in blood pressure. Other measures on the twins and a subset of family members include a standard urine panel with absolute concentrations of potassium, sodium, uric acid, phosphorous; DynaPulse acquired heart rate and blood pressure measures including systolic and diastolic blood pressure, mean arterial pressure, heart rate, Left Ventricular (LV) ejection time, LV contractility, cardiac output, stroke volume data including; and absolute concentrations of plasma aldosterone, endothelin, leptin, and insulin. Phenotype data is included for the 697 individuals sequenced here and 100 family members.  Whole Genome Sequence Data Generation: Whole genome sequencing (20X coverage) was conducted on plasma-derived DNA. The WGS was generated using the Illumina HiSeq X Ten sequencing platform with variants called by Human Longevity, Inc (HLI; Ref 1). Preparation of sample libraries was conducted by mechanical shearing of gDNA (100-800 bp), isolation of DNA fragments 300-500bp in size, followed by library PCR amplification employing high-fidelity, low-bias PCR to amplify library fragments consisting of appropriate adapter sequences on both ends. BAM files were created by alignment of sequence reads to the reference genome (GRCh38) using iSAAC-01.14.02.06 (Python2.7). Note: The user may want to realign the sequence data and recall variants. In total, the WGS dataset contains 30 monozygotic twin pairs represented by one member of the twin pair, 133 monozygotic twin pairs with both individuals sequenced, 7 dizygotic twin pairs represented by one member of the twin pair, 67 dizygotic twin pairs with both individuals sequenced, 8 twin pairs with undetermined zygosity (both individuals sequenced) and 1 triplet with mother (all individuals sequenced). The dataset also contains sequences of 260 family members of twins including their mother, father, non-twin sibling, and offspring. Table 1 describes the composition of families ("sibling" refers to a non-twin sibling in the cohort). Note: We suggest users check gender and family relatedness. Table 1: Description of the families with sequence data                                                                                                               Units with:Twin PairsTwin (no pairs)No twinSibshipsMother and Father511Mother only1222Father only113One or more siblings22133Mother and siblings132Father and siblings(s)211Offspring of twins11Non twin siblings2Sib with unknown relative1Only one member of8The UCSD/O'Connor "TSP" (Twin/Sibling/Pedigree) Resource in Hypertension is now being managed at the UCSD School of Medicine's Institute for Genomic Medicine (IGM). The TSP Resource has collected a wide range of information (phenotypic, genotypic, demographic, metabolomic) and reagents (blood, plasma, urine, DNA, human induced pluripotent stem cells). For additional information about the resource, including other data types available as well as references and links to data from studies with previous collaborators, please go to the resource website at IGM [http://igm.ucsd.edu/research/twins-resource.shtml] or contact Dr. Brinda Rana at UCSD [bkrana@ucsd.edu]. 

  Study phs002230

• Systolic Blood Pressure Intervention Trial (SPRINT-BioLINCC)

  Available DataThe available data include all elements of the previously released SPRINT Primary Outcome Paper (SPRINT-POP) data, the full SPRINT clinical data including the MRI and MIND data, and select ancillary study data (Ambulatory Blood Pressure Monitoring, APOL1, Acute Kidney Injury, ASK, Heart, FAST, PWV, Renal Resistance, Biomarkers, Plasma AD).ObjectiveThe Systolic Blood Pressure Trial (SPRINT) was conducted to test the hypothesis that treating systolic blood pressure to a target of less than 120 mm Hg, as compared to a target of less than 140 mm Hg, would reduce the incidence of cardiovascular disease.BackgroundHypertension is a highly prevalent condition among adults and is a leading risk factor for myocardial infarction and stroke. Further, isolated systolic hypertension is the most common form of hypertension in adults over 50 years of age. Observational studies have shown a monotonic increase in cardiovascular risk with systolic blood pressures above 115 mm Hg; however, general population clinical trials have only documented the benefits of lowering systolic blood pressure to a target of 150 mm Hg. A 2007 expert panel sponsored by the National Heart, Lung, and Blood Institute designated the hypothesis that lowering the systolic blood pressure goal to a level SubjectsA total of 9361 participants were enrolled, with 4,678 randomized to the intensive-treatment group and 4,683 randomized to the standard-treatment group.DesignSPRINT was a randomized, single blinded (outcome adjudicators were blinded to treatment assignment) treatment trial with participants randomized to a systolic blood-pressure target of either less than 140 mm Hg (the standard-treatment group) or less than 120 mm Hg (the intensive-treatment group). Following randomization, baseline hypertensive regimens were adjusted in accordance with study treatment algorithms established for each group. The study formulary included all major classes of antihypertensive agents. Investigators could prescribe other antihypertensive medications, but the use of drug classes with the strongest evidence for reduction in cardiovascular outcomes was encouraged. This included thiazide-type diuretics as the first-line agent, loop diuretics for participants with advanced chronic kidney disease, and beta-adrenergic blockers for participants with coronary artery disease. Medications for participants in the intensive-treatment group were adjusted on a monthly basis to target a systolic blood pressure of less than 120 mm Hg. Medications for participants in the standard-treatment group were adjusted to target a systolic blood pressure of 135 to 139 mm Hg, and the dose was reduced if systolic blood pressure was less than 130 mm Hg on a single visit or less than 135 mm Hg on two consecutive visits. Lifestyle modification was encouraged as part of the management strategy.Participants were seen monthly for the first 3 months and every 3 months thereafter. Demographic data were collected at baseline. Clinical and laboratory data were obtained at baseline and every 3 months thereafter. A structured interview was used in both groups every 3 months to obtain self-reported cardiovascular disease outcomes. Medical records and electrocardiograms were obtained for documentation of events. Incidences of hypotension, syncope, injurious falls, electrolyte abnormalities, and bradycardia that were evaluated in an emergency department were included in adverse event reporting. Occurrences of acute kidney injury or acute renal failure requiring hospitalization were also monitored. The primary outcome was a composite outcome of myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes.ConclusionsThe blood pressure intervention was stopped in August of 2015 (median follow-up of 3.26 years) after the cardiovascular outcome results exceeded the boundary for efficacy at two consecutive time points. Compared with a systolic blood pressure target of less than 140 mm Hg, an intensive systolic blood pressure target of 120 mm Hg resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause. Significantly higher rates of some adverse events were observed in the intensive-treatment group.

  Study phs003483