External quality assessment of tumour marker analysis: state of the art and consequences for estimating diagnostic sensitivity and specificity

This review shows the current analytical quality for the following analytes used as tumour markers in the external quality assessment (EQA)-programmes of Instand e.V., a national EQA-organiser in Germany: Corticotropin (ACTH), growth hormone (GH, hGH), prolactin (PRL), chorionic gonadotropin (CG, hCG), calcitonin (CT, hCT), thyroglobulin (Tg), carcinoembryonic antigen (CEA), CA-Antigens 125, 72-4, 15-3 and 19-9, alpha foetoprotein (AFP) and prostate-specific antigen (PSA)

The Health Status of Southern Children: A Neglected Regional Disparity

Purpose: Great variations exist in child health outcomes among states in the United States, with southern states consistently ranked among the lowest in the country. Investigation of the geographical distribution of children’s health status and the regional factors contributing to these outcomes has been neglected. We attempted to identify the degree to which region of residence may be linked to health outcomes for children with the specific aim of determining whether living in the southern region of the United States is adversely associated with children’s health status. Methods: A child health index (CHI) that ranked each state in the United States was computed by using statespecific composite scores generated from outcome measures for a number of indicators of child health. Five indicators for physical health were chosen (percent low birth weight infants, infant mortality rate, child death rate, teen death rate, and teen birth rates) based on their historic and routine use to define health outcomes in children. Indicators were calculated as rates or percentages. Standard scores were calculated for each state for each health indicator by subtracting the mean of the measures for all states from the observed measure for each state. Indicators related to social and economic status were considered to be variables that impact physical health, as opposed to indicators of physical health, and therefore were not used to generate the composite child health score. These variables were subsequently examined in this study as potential confounding variables. Mapping was used to redefine regional groupings of states, and parametric tests (2-sample t test, analysis of means, and analysis-of-variance F tests) were used to compare the means of the CHI scores for the regional groupings and test for statistical significance. Multiple regression analysis computed the relationship of region, social and economic indicators, and race to the CHI. Simple linear-regression analyses were used to assess the individual effect of each indicator. Results: A geographic region of contiguous states, characterized by their poor child health outcomes relative to other states and regions of the United States, exists within the “Deep South” (Mississippi, Louisiana, Arkansas, Tennessee, Alabama, Georgia, North Carolina, South Carolina, and Florida). This Deep-South region is statistically different in CHI scores from the US Census Bureau– defined grouping of states in the South. The mean of CHI scores for the Deep-South region was \u3e1 SD below the mean of CHI scores for all states. In contrast, the CHI score means for each of the other 3 regions were all above the overall mean of CHI scores for all states. Regression analysis showed that living in the Deep- South region is a stronger predictor of poor child health outcomes than other consistently collected and reported variables commonly used to predict children’s health. Conclusions: The findings of this study indicate that region of residence in the United States is statistically related to important measures of children’s health and may be among the most powerful predictors of child health outcomes and disparities. This clarification of the poorer health status of children living in the Deep South through spatial analysis is an essential first step for developing a better understanding of variations in the health of children. Similar to early epidemiology work linking geographic boundaries to disease, discovering the mechanisms/pathways/causes by which region influences health outcomes is a critical step in addressing disparities and inequities in child health and one that is an important and fertile area for future research. The reasons for these disparities may be complex and synergistically related to various economic, political, social, cultural, and perhaps even environmental (physical) factors in the region. This research will require the use and development of new approaches and applications of spatial analysis to develop insights into the societal, environmental, and historical determinants of child health that have been neglected in previous child health outcomes and policy research. The public policy implications of the findings in this study are substantial. Few, if any, policies identify these children as a high-risk group on the basis of their region of residence. A better understanding of the depth and breadth of disparities in health, education, and other social outcomes among and within regions of the United States is necessary for the generation of policies that enable policy makers to address and mitigate the factors that influence these disparities. Defining and clarifying the regional boundaries is also necessary to better inform public policy decisions related to resource allocation and the prevention and/or mitigation of the effects of region on child health. The identification of the Deep South as a clearly defined sub-region of the Census Bureau’s regional definition of the South suggests the need to use more culturally and socially relevant boundaries than the Census Bureau regions when analyzing regional data for policy development

LSST: from Science Drivers to Reference Design and Anticipated Data Products

(Abridged) We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). A vast array of science will be enabled by a single wide-deep-fast sky survey, and LSST will have unique survey capability in the faint time domain. The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the Solar System, exploring the transient optical sky, and mapping the Milky Way. LSST will be a wide-field ground-based system sited at Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg$^2$ field of view, and a 3.2 Gigapixel camera. The standard observing sequence will consist of pairs of 15-second exposures in a given field, with two such visits in each pointing in a given night. With these repeats, the LSST system is capable of imaging about 10,000 square degrees of sky in a single filter in three nights. The typical 5$\sigma$ point-source depth in a single visit in $r$ will be $\sim 24.5$ (AB). The project is in the construction phase and will begin regular survey operations by 2022. The survey area will be contained within 30,000 deg$^2$ with $\delta<+34.5^\circ$, and will be imaged multiple times in six bands, $ugrizy$, covering the wavelength range 320--1050 nm. About 90\% of the observing time will be devoted to a deep-wide-fast survey mode which will uniformly observe a 18,000 deg$^2$ region about 800 times (summed over all six bands) during the anticipated 10 years of operations, and yield a coadded map to $r\sim27.5$. The remaining 10\% of the observing time will be allocated to projects such as a Very Deep and Fast time domain survey. The goal is to make LSST data products, including a relational database of about 32 trillion observations of 40 billion objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures available from https://www.lsst.org/overvie

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Noble gas constraints on air-sea gas exchange and bubble fluxes

Author Posting. © American Geophysical Union, 2009. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research 114 (2009): C11020, doi:10.1029/2009JC005396.Air-sea gas exchange is an important part of the biogeochemical cycles of many climatically and biologically relevant gases including CO2, O2, dimethyl sulfide and CH4. Here we use a three year observational time series of five noble gases (He, Ne, Ar, Kr, and Xe) at the Bermuda Atlantic Time series Study (BATS) site in tandem with a one-dimensional upper ocean model to develop an improved parameterization for air-sea gas exchange that explicitly includes separate components for diffusive gas exchange and bubble processes. Based on seasonal timescale noble gas data, this parameterization, which has a 1σ uncertainty of ±14% for diffusive gas exchange and ±29% for bubble fluxes, is more tightly constrained than previous parameterizations. Although the magnitude of diffusive gas exchange is within errors of that of Wanninkhof (1992), a commonly used parameterization, we find that bubble-mediated exchange, which is not explicitly included by Wanninkhof (1992) or many other formulations, is significant even for soluble gases. If one uses observed saturation anomalies of Ar (a gas with similar characteristics to O2) and a parameterization of gas exchange to calculate gas exchange fluxes, then the calculated fluxes differ by ∼240% if the parameterization presented here is used compared to using the Wanninkhof (1992) parameterization. If instead one includes the gas exchange parameterization in a model, then the calculated fluxes differ by ∼35% between using this parameterization and that of Wanninkhof (1992). These differences suggest that the bubble component should be explicitly included in a range of marine biogeochemical calculations that incorporate air-sea gas fluxes.Funding from the National Science Foundation Chemical Oceanography program (OCE-0221247 and OCE-0623034)

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

The genomic landscape of 2,023 colorectal cancers

Colorectal carcinoma (CRC) is a common cause of mortality1, but a comprehensive description of its genomic landscape is lacking2–9. Here we perform whole-genome sequencing of 2,023 CRC samples from participants in the UK 100,000 Genomes Project, thereby providing a highly detailed somatic mutational landscape of this cancer. Integrated analyses identify more than 250 putative CRC driver genes, many not previously implicated in CRC or other cancers, including several recurrent changes outside the coding genome. We extend the molecular pathways involved in CRC development, define four new common subgroups of microsatellite-stable CRC based on genomic features and show that these groups have independent prognostic associations. We also characterize several rare molecular CRC subgroups, some with potential clinical relevance, including cancers with both microsatellite and chromosomal instability. We demonstrate a spectrum of mutational profiles across the colorectum, which reflect aetiological differences. These include the role of Escherichiacolipks+ colibactin in rectal cancers10 and the importance of the SBS93 signature11–13, which suggests that diet or smoking is a risk factor. Immune-escape driver mutations14 are near-ubiquitous in hypermutant tumours and occur in about half of microsatellite-stable CRCs, often in the form of HLA copy number changes. Many driver mutations are actionable, including those associated with rare subgroups (for example, BRCA1 and IDH1), highlighting the role of whole-genome sequencing in optimizing patient care