The flashfm approach for fine-mapping multiple quantitative traits

Funder: “Expanding excellence in England” award from Research EnglandJoint fine-mapping that leverages information between quantitative traits could improve accuracy and resolution over single-trait fine-mapping. Using summary statistics, flashfm (flexible and shared information fine-mapping) fine-maps signals for multiple traits, allowing for missing trait measurements and use of related individuals. In a Bayesian framework, prior model probabilities are formulated to favour model combinations that share causal variants to capitalise on information between traits. Simulation studies demonstrate that both approaches produce broadly equivalent results when traits have no shared causal variants. When traits share at least one causal variant, flashfm reduces the number of potential causal variants by 30% compared with single-trait fine-mapping. In a Ugandan cohort with 33 cardiometabolic traits, flashfm gave a 20% reduction in the total number of potential causal variants from single-trait fine-mapping. Here we show flashfm is computationally efficient and can easily be deployed across publicly available summary statistics for signals in up to six traits.Wellcome Trust [WT107881

Interconnected Microphysiological Systems for Quantitative Biology and Pharmacology Studies

Microphysiological systems (MPSs) are in vitro models that capture facets of in vivo organ function through use of specialized culture microenvironments, including 3D matrices and microperfusion. Here, we report an approach to co-culture multiple different MPSs linked together physiologically on re-useable, open-system microfluidic platforms that are compatible with the quantitative study of a range of compounds, including lipophilic drugs. We describe three different platform designs - "4-way", "7-way", and "10-way" - each accommodating a mixing chamber and up to 4, 7, or 10 MPSs. Platforms accommodate multiple different MPS flow configurations, each with internal re-circulation to enhance molecular exchange, and feature on-board pneumatically-driven pumps with independently programmable flow rates to provide precise control over both intra- and inter-MPS flow partitioning and drug distribution. We first developed a 4-MPS system, showing accurate prediction of secreted liver protein distribution and 2-week maintenance of phenotypic markers. We then developed 7-MPS and 10-MPS platforms, demonstrating reliable, robust operation and maintenance of MPS phenotypic function for 3 weeks (7-way) and 4 weeks (10-way) of continuous interaction, as well as PK analysis of diclofenac metabolism. This study illustrates several generalizable design and operational principles for implementing multi-MPS "physiome-on-a-chip" approaches in drug discovery.United States. Army Research Office (Grant W911NF-12-2-0039

Personal radiofrequency electromagnetic field exposure of adolescents in the Greater London area in the SCAMP cohort and the association with restrictions on permitted use of mobile communication technologies at school and at home

Personal measurements of radiofrequency electromagnetic fields (RF-EMF) have been used in several studies to characterise personal exposure in daily life, but such data are limitedly available for adolescents, and not yet for the United Kingdom (UK). In this study, we aimed to characterise personal exposure to RF-EMF in adolescents and to study the association between exposure and rules applied at school and at home to restrict wireless communication use, likely implemented to reduce other effects of mobile technology (e.g. distraction). We measured exposure to RF-EMF for 16 common frequency bands (87.5 MHz–3.5 GHz), using portable measurement devices (ExpoM-RF), in a subsample of adolescents participating in the cohort Study of Cognition, Adolescents and Mobile Phones (SCAMP) from Greater London (UK) (n = 188). School and home rules were assessed by questionnaire and concerned the school's availability of WiFi and mobile phone policy, and parental restrictions on permitted mobile phone use. Adolescents recorded their activities in real time using a diary app on a study smartphone, while characterizing their personal RF-EMF exposure in daily life, during different activities and times of the day. Data analysis was done for 148 adolescents from 29 schools who recorded RF-EMF data for a median duration of 47 h. The majority (74%) of adolescents spent part of their time at school during the measurement period. Median total RF-EMF exposure was 40 μW/m2 at home, 94 μW/m2 at school, and 100 μW/m2 overall. In general, restrictions at school or at home made little difference for adolescents’ measured exposure to RF-EMF, except for uplink exposure from mobile phones while at school, which was found to be significantly lower for adolescents attending schools not permitting phone use at all, compared to adolescents attending schools allowing mobile phone use during breaks. This difference was not statistically significant for total personal exposure. Total exposure to RF-EMF in adolescents living in Greater London tended to be higher compared to exposure levels reported in other European countries. This study suggests that school policies and parental restrictions are not associated with a lower RF-EMF exposure in adolescents

Membrane connectivity estimated by digital image analysis of HER2 immunohistochemistry is concordant with visual scoring and fluorescence in situ hybridization results: algorithm evaluation on breast cancer tissue microarrays

<p>Abstract</p> <p>Introduction</p> <p>The human epidermal growth factor receptor 2 (HER2) is an established biomarker for management of patients with breast cancer. While conventional testing of HER2 protein expression is based on semi-quantitative visual scoring of the immunohistochemistry (IHC) result, efforts to reduce inter-observer variation and to produce continuous estimates of the IHC data are potentiated by digital image analysis technologies.</p> <p>Methods</p> <p>HER2 IHC was performed on the tissue microarrays (TMAs) of 195 patients with an early ductal carcinoma of the breast. Digital images of the IHC slides were obtained by Aperio ScanScope GL Slide Scanner. Membrane connectivity algorithm (HER2-CONNECT™, Visiopharm) was used for digital image analysis (DA). A pathologist evaluated the images on the screen twice (visual evaluations: VE1 and VE2). HER2 fluorescence <it>in situ </it>hybridization (FISH) was performed on the corresponding sections of the TMAs. The agreement between the IHC HER2 scores, obtained by VE1, VE2, and DA was tested for individual TMA spots and patient's maximum TMA spot values (VE1max, VE2max, DAmax). The latter were compared with the FISH data. Correlation of the continuous variable of the membrane connectivity estimate with the FISH data was tested.</p> <p>Results</p> <p>The pathologist intra-observer agreement (VE1 and VE2) on HER2 IHC score was almost perfect: kappa 0.91 (by spot) and 0.88 (by patient). The agreement between visual evaluation and digital image analysis was almost perfect at the spot level (kappa 0.86 and 0.87, with VE1 and VE2 respectively) and at the patient level (kappa 0.80 and 0.86, with VE1max and VE2max, respectively). The DA was more accurate than VE in detection of FISH-positive patients by recruiting 3 or 2 additional FISH-positive patients to the IHC score 2+ category from the IHC 0/1+ category by VE1max or VE2max, respectively. The DA continuous variable of the membrane connectivity correlated with the FISH data (HER2 and CEP17 copy numbers, and HER2/CEP17 ratio).</p> <p>Conclusion</p> <p>HER2 IHC digital image analysis based on membrane connectivity estimate was in almost perfect agreement with the visual evaluation of the pathologist and more accurate in detection of HER2 FISH-positive patients. Most immediate benefit of integrating the DA algorithm into the routine pathology HER2 testing may be obtained by alerting/reassuring pathologists of potentially misinterpreted IHC 0/1+ versus 2+ cases.</p

Stream Bank Stability in Eastern Nebraska

Dredged and straightened channels in eastern Nebraska have experienced degradation leading to channel widening by bank failure. Degradation has progressed headward and affected the drainage systems upstream from the modified reaches. This report describes a study that was undertaken to analyze bank stability at selected sites in eastern Nebraska and develop a simplified method for estimating the stability of banks at future study sites. Bank cross sections along straight reaches of channel and geotechnical data were collected at approximately 150 sites in 26 counties of eastern Nebraska. The sites were categorized into three groups based on mapped soil permeability. With increasing permeability of the soil groups, the median cohesion values decreased and the median friction angles increased. Three analytical methods were used to determine if banks were stable (should not fail even when saturated), at risk (should not fail unless saturated), or unstable (should have already failed). The Culmann and Agricultural Research Service methods were based on the Coulomb equation and planar failure; an indirect method was developed that was based on Bishop’s simplified method of slices and rotational failure. The maximum angle from horizontal at which the bank would be stable for the given soil and bank height conditions also was computed with the indirect method. Because of few soil shear-strength data, all analyses were based on the assumption of homogeneous banks, which was later shown to be atypical, at least for some banks

Peak-flow frequency relations and evaluation of the peak-flow gaging network in Nebraska

Estimates of peak-flow magnitude and frequency are required for the efficient design of structures that convey flood flows or occupy floodways, such as bridges, culverts, and roads. The U.S. Geological Survey, in cooperation with the Nebraska Department of Roads, conducted a study to update peak-flow frequency analyses for selected streamflow-gaging stations, develop a new set of peak-flow frequency relations for ungaged streams, and evaluate the peak-flow gaging-station network for Nebraska. Data from stations located in or within about 50 miles of Nebraska were analyzed using guidelines of the Interagency Advisory Committee on Water Data in Bulletin 17B. New generalized skew relations were developed for use in frequency analyses of unregulated streams. Thirty-three drainage-basin characteristics related to morphology, soils, and precipitation were quantified using a geographic information system, related computer programs, and digital spatial data. For unregulated streams, eight sets of regional regression equations relating drainage-basin to peak-flow characteristics were developed for seven regions of the state using a generalized least squares procedure. Two sets of regional peak-flow frequency equations were developed for basins with average soil permeability greater than 4 inches per hour, and six sets of equations were developed for specific geographic areas, usually based on drainage-basin boundaries. Standard errors of estimate for the 100-year frequency equations (1percent probability) ranged from 12.1 to 63.8 percent. For regulated reaches of nine streams, graphs of peak flow for standard frequencies and distance upstream of the mouth were estimated. The regional networks of streamflow-gaging stations on unregulated streams were analyzed to evaluate how additional data might affect the average sampling errors of the newly developed peak-flow equations for the 100-year frequency occurrence. Results indicated that data from new stations, rather than more data from existing stations, probably would produce the greatest reduction in average sampling errors of the equations

<title>Novel spectral bioimaging system as an imaging oximeter in intact rat brain</title>

The use of reflection spectrophotometry to measure the spectra of oxy-hemoglobin and deoxy- hemoglobin, strong absorbers of light in the visible region of the spectrum, is a well established method for determining tissue oxygenation. This type of spectral measurement is typically made with a point-spectrometer and provides information only at a single point. An imaging spectrometer, on the other, can measure the hemoglobin spectra at every pixel in the image, thus providing a two-dimensional (spatial) map of tissue ischemia. A novel spectral bio-imaging system based on the SpectraCube technology, an optical method based on proven Fourier transform (FT) spectroscopy, has been applied successfully in intact rat brain to measure oxy- and deoxy-hemoglobin spectra. Spectral images containing 10,000 spectra were acquired in a rat ventilated with 30% O , and repeated when the inspired gas mixture was switched for 45 seconds to 100% nitrogen. Differences in hemoglobin spectra corresponding to real differences in tissue oxygenation are readily apparent under these two conditions. There is also some evidence that information concerning cytochromes is present in these spectral images, and algorithms are currently being developed to extract the signatures of cytochromes. Details of the spectral bio-imaging system and the results of the measurements made in intact rat brain are discussed

Peak-flow frequency relations and evaluation of the peak-flow gaging network in Nebraska /

Includes bibliographical references.Mode of access: Internet

Transport of agricultural chemicals in surface flow, tileflow, and streamflow of Walnut Creek Watershed near Ames, Iowa, April 1991-September 1993 /

Shipping list no.: 97-0008-P.Includes bibliographical references (p. 38-39).Mode of access: Internet