Coherent Functional Modules Improve Transcription Factor Target Identification, Cooperativity Prediction, and Disease Association

Transcription factors (TFs) are fundamental controllers of cellular regulation that function in a complex and combinatorial manner. Accurate identification of a transcription factor's targets is essential to understanding the role that factors play in disease biology. However, due to a high false positive rate, identifying coherent functional target sets is difficult. We have created an improved mapping of targets by integrating ChIP-Seq data with 423 functional modules derived from 9,395 human expression experiments. We identified 5,002 TF-module relationships, significantly improved TF target prediction, and found 30 high-confidence TF-TF associations, of which 14 are known. Importantly, we also connected TFs to diseases through these functional modules and identified 3,859 significant TF-disease relationships. As an example, we found a link between MEF2A and Crohn's disease, which we validated in an independent expression dataset. These results show the power of combining expression data and ChIP-Seq data to remove noise and better extract the associations between TFs, functional modules, and disease

An integrative method for scoring candidate genes from association studies: application to warfarin dosing

BackgroundA key challenge in pharmacogenomics is the identification of genes whose variants contribute to drug response phenotypes, which can include severe adverse effects. Pharmacogenomics GWAS attempt to elucidate genotypes predictive of drug response. However, the size of these studies has severely limited their power and potential application. We propose a novel knowledge integration and SNP aggregation approach for identifying genes impacting drug response. Our SNP aggregation method characterizes the degree to which uncommon alleles of a gene are associated with drug response. We first use pre-existing knowledge sources to rank pharmacogenes by their likelihood to affect drug response. We then define a summary score for each gene based on allele frequencies and train linear and logistic regression classifiers to predict drug response phenotypes.ResultsWe applied our method to a published warfarin GWAS data set comprising 181 individuals. We find that our method can increase the power of the GWAS to identify both VKORC1 and CYP2C9 as warfarin pharmacogenes, where the original analysis had only identified VKORC1. Additionally, we find that our method can be used to discriminate between low-dose (AUROC=0.886) and high-dose (AUROC=0.764) responders.ConclusionsOur method offers a new route for candidate pharmacogene discovery from pharmacogenomics GWAS, and serves as a foundation for future work in methods for predictive pharmacogenomics

Crossing the Communication Chasm: Challenges and Opportunities in Transitions of Care from the Hospital to the Primary Care Clinic

Background Transitions of care from specialty and acute settings to primary care abound. Compared to the continuity in end-of-shift handoffs, care transitions involve provider communication between practices and facilities with their own cultures and bureaucracies. Using the transition from acute care to outpatient primary care for stroke/transient ischemic attack (TIA) patients as a case study, this qualitative research explored communication practices and institutional arrangements among clinical providers responsible for longitudinal management of hypertension. In this study, researchers investigated the barriers and facilitators of effective communication between acute stroke/TIA inpatient and primary care providers at a Veterans Affairs Medical Center. Methods A multidisciplinary team conducted consensus-based coding and thematic analysis of semistructured interviews with 21 clinical providers (9 with primary responsibilities for inpatient care and 12 with primary responsibilities in outpatient, primary care). Results Thematic analysis of responses identified three factors that influenced communication between clinical providers: (1) consistent, concise but complete medication and treatment plans; (2) reliable, standardized discharge documentation; (3) use of multiple modes of communication. Participants identified cultural barriers, including challenges with rotating providers at a teaching hospital and local discharge practices. Conclusion Ambiguity about who is being handed off to and time pressures in the acute setting may lead inpatient providers to give lower priority to discharge communication, leaving outpatient providers with low-quality information. While electronic templates have standardized key components of discharge documentation, improvement opportunities remain. Increased awareness of the challenges and opportunities on each side of the care transfer could foster communication practices that systematically account for the information needs of inpatient and outpatient providers

Aperture Photometry Tool

Aperture Photometry Tool (APT) is software for astronomers and students interested in manually exploring the photometric qualities of astronomical images. It is a graphical user interface (GUI) designed to allow the image data associated with aperture photometry calculations for point and extended sources to be visualized and, therefore, more effectively analyzed. The finely tuned layout of the GUI, along with judicious use of color-coding and alerting, is intended to give maximal user utility and convenience. Simply mouse-clicking on a source in the displayed image will instantly draw a circular or elliptical aperture and sky annulus around the source and will compute the source intensity and its uncertainty, along with several commonly used measures of the local sky background and its variability. The results are displayed and can be optionally saved to an aperture-photometry-table file and plotted on graphs in various ways using functions available in the software. APT is geared toward processing sources in a small number of images and is not suitable for bulk processing a large number of images, unlike other aperture photometry packages (e.g., SExtractor). However, APT does have a convenient source-list tool that enables calculations for a large number of detections in a given image. The source-list tool can be run either in automatic mode to generate an aperture photometry table quickly or in manual mode to permit inspection and adjustment of the calculation for each individual detection. APT displays a variety of useful graphs with just the push of a button, including image histogram, x and y aperture slices, source scatter plot, sky scatter plot, sky histogram, radial profile, curve of growth, and aperture-photometry-table scatter plots and histograms. APT has many functions for customizing the calculations, including outlier rejection, pixel “picking” and “zapping,” and a selection of source and sky models. The radial-profile-interpolation source model, which is accessed via the radial-profile-plot panel, allows recovery of source intensity from pixels with missing data and can be especially beneficial in crowded fields

The Palomar Transient Factory Orion Project: Eclipsing Binaries and Young Stellar Objects

The Palomar Transient Factory (PTF) Orion project is an experiment within the broader PTF survey, a systematic automated exploration of the sky for optical transients. Taking advantage of the wide field of view available using the PTF camera at the Palomar 48" telescope, 40 nights were dedicated in December 2009-January 2010 to perform continuous high-cadence differential photometry on a single field containing the young (7-10Myr) 25 Ori association. The primary motivation for the project is to search for planets around young stars in this region. The unique data set also provides for much ancillary science. In this first paper we describe the survey and data reduction pipeline, and present initial results from an inspection of the most clearly varying stars relating to two of the ancillary science objectives: detection of eclipsing binaries and young stellar objects. We find 82 new eclipsing binary systems, 9 of which we are candidate 25 Ori- or Orion OB1a-association members. Of these, 2 are potential young W UMa type systems. We report on the possible low-mass (M-dwarf primary) eclipsing systems in the sample, which include 6 of the candidate young systems. 45 of the binary systems are close (mainly contact) systems; one shows an orbital period among the shortest known for W UMa binaries, at 0.2156509 \pm 0.0000071d, with flat-bottomed primary eclipses, and a derived distance consistent with membership in the general Orion association. One of the candidate young systems presents an unusual light curve, perhaps representing a semi-detached binary system with an inflated low-mass primary or a star with a warped disk, and may represent an additional young Orion member. Finally, we identify 14 probable new classical T-Tauri stars in our data, along with one previously known (CVSO 35) and one previously reported as a candidate weak-line T-Tauri star (SDSS J052700.12+010136.8).Comment: 66 pages, 27 figures, accepted to Astronomical Journal. Minor typographical corrections and update to author affiliation

The PTF Orion Project: a Possible Planet Transiting a T-Tauri Star

We report observations of a possible young transiting planet orbiting a previously known weak-lined T-Tauri star in the 7-10 Myr old Orion-OB1a/25-Ori region. The candidate was found as part of the Palomar Transient Factory (PTF) Orion project. It has a photometric transit period of 0.448413 +- 0.000040 days, and appears in both 2009 and 2010 PTF data. Follow-up low-precision radial velocity (RV) observations and adaptive optics imaging suggest that the star is not an eclipsing binary, and that it is unlikely that a background source is blended with the target and mimicking the observed transit. RV observations with the Hobby-Eberly and Keck telescopes yield an RV that has the same period as the photometric event, but is offset in phase from the transit center by approximately -0.22 periods. The amplitude (half range) of the RV variations is 2.4 km/s and is comparable with the expected RV amplitude that stellar spots could induce. The RV curve is likely dominated by stellar spot modulation and provides an upper limit to the projected companion mass of M_p sin i_orb < 4.8 +- 1.2 M_Jup; when combined with the orbital inclination, i orb, of the candidate planet from modeling of the transit light curve, we find an upper limit on the mass of the planetary candidate of M_p < 5.5 +- 1.4 M_Jup. This limit implies that the planet is orbiting close to, if not inside, its Roche limiting orbital radius, so that it may be undergoing active mass loss and evaporation.Comment: Corrected typos, minor clarifications; minor updates/corrections to affiliations and bibliography. 35 pages, 10 figures, 3 tables. Accepted to Ap

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

Pathway analysis of genome-wide data improves warfarin dose prediction

Background: Many genome-wide association studies focus on associating single loci with target phenotypes. However, in the setting of rare variation, accumulating sufficient samples to assess these associations can be difficult. Moreover, multiple variations in a gene or a set of genes within a pathway may all contribute to the phenotype, suggesting that the aggregation of variations found over the gene or pathway may be useful for improving the power to detect associations. Results: Here, we present a method for aggregating single nucleotide polymorphisms (SNPs) along biologically relevant pathways in order to seek genetic associations with phenotypes. Our method uses all available genetic variants and does not remove those in linkage disequilibrium (LD). Instead, it uses a novel SNP weighting scheme to down-weight the contributions of correlated SNPs. We apply our method to three cohorts of patients taking warfarin: two European descent cohorts and an African American cohort. Although the clinical covariates and key pharmacogenetic loci for warfarin have been characterized, our association metric identifies a significant association with mutations distributed throughout the pathway of warfarin metabolism. We improve dose prediction after using all known clinical covariates and pharmacogenetic variants in VKORC1 and CYP2C9. In particular, we find that at least 1% of the missing heritability in warfarin dose may be due to the aggregated effects of variations in the warfarin metabolic pathway, even though the SNPs do not individually show a significant association. Conclusions: Our method allows researchers to study aggregative SNP effects in an unbiased manner by not preselecting SNPs. It retains all the available information by accounting for LD-structure through weighting, which eliminates the need for LD pruning