An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Immunity to Bovine Herpesvirus 1: II. Adaptive Immunity and Vaccinology

Bovine herpesvirus 1 (BHV-1) infection is widespread and causes a variety of diseases. Although similar in many respects to the human immune response to human herpesvirus 1, the differences in the bovine virus proteins, immune system components and strategies, physiology, and lifestyle mean the bovine immune response to BHV-1 is unique. The innate immune system initially responds to infection, and primes a balanced adaptive immune response. Cell-mediated immunity, including cytotoxic T lymphocyte killing of infected cells, is critical to recovery from infection. Humoral immunity, including neutralizing antibody and antibody-dependent cell-mediated cytotoxicity, is important to prevention or control of (re-)infection. BHV-1 immune evasion strategies include suppression of major histocompatibility complex presentation of viral antigen, helper T-cell killing, and latency. Immune suppression caused by the virus potentiates secondary infections and contributes to the costly bovine respiratory disease complex. Vaccination against BHV-1 is widely practiced. The many vaccines reported include replicating and non-replicating, conventional and genetically engineered, as well as marker and non-marker preparations. Current development focuses on delivery of major BHV-1 glycoproteins to elicit a balanced, protective immune response, while excluding serologic markers and virulence or other undesirable factors. In North America, vaccines are used to prevent or reduce clinical signs, whereas in some European Union countries marker vaccines have been employed in the eradication of BHV-1 disease

Measurement of the cross-section and charge asymmetry of WW bosons produced in proton-proton collisions at s=8\sqrt{s}=8 TeV with the ATLAS detector

This paper presents measurements of the $W^+ \rightarrow \mu^+\nu$ and $W^- \rightarrow \mu^-\nu$ cross-sections and the associated charge asymmetry as a function of the absolute pseudorapidity of the decay muon. The data were collected in proton--proton collisions at a centre-of-mass energy of 8 TeV with the ATLAS experiment at the LHC and correspond to a total integrated luminosity of 20.2~\mbox{fb^{-1}}. The precision of the cross-section measurements varies between 0.8% to 1.5% as a function of the pseudorapidity, excluding the 1.9% uncertainty on the integrated luminosity. The charge asymmetry is measured with an uncertainty between 0.002 and 0.003. The results are compared with predictions based on next-to-next-to-leading-order calculations with various parton distribution functions and have the sensitivity to discriminate between them.Comment: 38 pages in total, author list starting page 22, 5 figures, 4 tables, submitted to EPJC. All figures including auxiliary figures are available at https://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/STDM-2017-13

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Search for chargino-neutralino production with mass splittings near the electroweak scale in three-lepton final states in √s=13 TeV pp collisions with the ATLAS detector

A search for supersymmetry through the pair production of electroweakinos with mass splittings near the electroweak scale and decaying via on-shell W and Z bosons is presented for a three-lepton final state. The analyzed proton-proton collision data taken at a center-of-mass energy of √s=13  TeV were collected between 2015 and 2018 by the ATLAS experiment at the Large Hadron Collider, corresponding to an integrated luminosity of 139  fb−1. A search, emulating the recursive jigsaw reconstruction technique with easily reproducible laboratory-frame variables, is performed. The two excesses observed in the 2015–2016 data recursive jigsaw analysis in the low-mass three-lepton phase space are reproduced. Results with the full data set are in agreement with the Standard Model expectations. They are interpreted to set exclusion limits at the 95% confidence level on simplified models of chargino-neutralino pair production for masses up to 345 GeV

Detecting referral and selection bias by the anonymous linkage of practice, hospital and clinic data using Secure and Private Record Linkage (SAPREL): case study from the evaluation of the Improved Access to Psychological Therapy (IAPT) service

Background: The evaluation of demonstration sites set up to provide improved access to psychological therapies (IAPT) comprised the study of all people identified as having common mental health problems (CMHP), those referred to the IAPT service, and a sample of attenders studied in-depth. Information technology makes it feasible to link practice, hospital and IAPT clinic data to evaluate the representativeness of these samples. However, researchers do not have permission to browse and link these data without the patients’ consent. Objective: To demonstrate the use of a mixed deterministic-probabilistic method of secure and private record linkage (SAPREL) - to describe selection bias in subjects chosen for in-depth evaluation. Method: We extracted, pseudonymised and used fuzzy logic to link multiple health records without the researcher knowing the patient’s identity. The method can be characterised as a three party protocol mainly using deterministic algorithms with dynamic linking strategies; though incorporating some elements of probabilistic linkage. Within the data providers’ safe haven we extracted: Demographic data, hospital utilisation and IAPT clinic data; converted post code to index of multiple deprivation (IMD); and identified people with CMHP. We contrasted the age, gender, ethnicity and IMD for the in-depth evaluation sample with people referred to IAPT, use hospital services, and the population as a whole. Results: The in IAPT-in-depth group had a mean age of 43.1 years; CI: 41.0 - 45.2 (n = 166); the IAPT-referred 40.2 years; CI: 39.4 - 40.9 (n = 1118); and those with CMHP 43.6 years SEM 0.15. (n = 12210). Whilst around 67% of those with a CMHP were women, compared to 70% of those referred to IAPT, and 75% of those subject to indepth evaluation (Chi square p< 0.001). The mean IMD score for the in-depth evaluation group was 36.6; CI: 34.2 - 38.9; (n = 166); of those referred to IAPT 38.7; CI: 37.9 - 39.6; (n = 1117); and of people with CMHP 37.6; CI 37.3- 37.9; (n = 12143). Conclusions: The sample studied in-depth were older, more likely female, and less deprived than people with CMHP, and fewer had recorded ethnic minority status. Anonymous linkage using SAPREL provides insight into the representativeness of a study population and possible adjustment for selection bias