Gene set bagging for estimating replicability of gene set analyses

Background: Significance analysis plays a major role in identifying and ranking genes, transcription factor binding sites, DNA methylation regions, and other high-throughput features for association with disease. We propose a new approach, called gene set bagging, for measuring the stability of ranking procedures using predefined gene sets. Gene set bagging involves resampling the original high-throughput data, performing gene-set analysis on the resampled data, and confirming that biological categories replicate. This procedure can be thought of as bootstrapping gene-set analysis and can be used to determine which are the most reproducible gene sets. Results: Here we apply this approach to two common genomics applications: gene expression and DNA methylation. Even with state-of-the-art statistical ranking procedures, significant categories in a gene set enrichment analysis may be unstable when subjected to resampling. Conclusions: We demonstrate that gene lists are not necessarily stable, and therefore additional steps like gene set bagging can improve biological inference of gene set analysis.Comment: 3 Figure

CMB Likelihood Functions for Beginners and Experts

Although the broad outlines of the appropriate pipeline for cosmological likelihood analysis with CMB data has been known for several years, only recently have we had to contend with the full, large-scale, computationally challenging problem involving both highly-correlated noise and extremely large datasets ($N > 1000$). In this talk we concentrate on the beginning and end of this process. First, we discuss estimating the noise covariance from the data itself in a rigorous and unbiased way; this is essentially an iterated minimum-variance mapmaking approach. We also discuss the unbiased determination of cosmological parameters from estimates of the power spectrum or experimental bandpowers.Comment: Long-delayed submission. In AIP Conference Proceedings "3K Cosmology" held in Rome, Oct 5-10, 1998, edited by Luciano Maiani, Francesco Melchiorri and Nicola Vittorio, 343-347, New York, American Institute of Physics 199

Accounting for cellular heterogeneity is critical in epigenome-wide association studies

Background: Epigenome-wide association studies of human disease and other quantitative traits are becoming increasingly common. A series of papers reporting age-related changes in DNA methylation profiles in peripheral blood have already been published. However, blood is a heterogeneous collection of different cell types, each with a very different DNA methylation profile. Results: Using a statistical method that permits estimating the relative proportion of cell types from DNA methylation profiles, we examine data from five previously published studies, and find strong evidence of cell composition change across age in blood. We also demonstrate that, in these studies, cellular composition explains much of the observed variability in DNA methylation. Furthermore, we find high levels of confounding between age-related variability and cellular composition at the CpG level. Conclusions: Our findings underscore the importance of considering cell composition variability in epigenetic studies based on whole blood and other heterogeneous tissue sources. We also provide software for estimating and exploring this composition confounding for the Illumina 450k microarray

Improved Method for Detecting Local Discontinuities in CMB data by Finite Differencing

An unexpected distribution of temperatures in the CMB could be a sign of new physics. In particular, the existence of cosmic defects could be indicated by temperature discontinuities via the Kaiser-Stebbins effect. In this paper, we show how performing finite differences on a CMB map, with the noise regularized in harmonic space, may expose such discontinuities, and we report the results of this process on the 7-year Wilkinson Microwave Anisotropy Probe data.Comment: 5 pages, 6 figures; Text has been edited, in line with the PRD articl

Large Isospin mixing in phi radiative decay and the spatial size of the f0(980)- a0(980) meson

The measured rate for phi to gamma f0(980) appears to be larger than allowed on rather general grounds. We show that mixing between the f0(980) and a0(980), due to their dynamical interaction with the nearby KKbar thresholds, radically affects some existing predictions of their production in phi radiative decay. We predict that Gamma(phi to gamma f0)/Gamma(phi to gamma a_0) approx 3; that sum (b.r.(phi to gamma f0) + b.r. (phi to gamma a_0)) < 5 x 10^-4 with probable individual branching ratios 2 x 10^-4 and 0.7 x 10^-4 respectively.Comment: 7 pages, Late

Constraining Large Scale Structure Theories with the Cosmic Background Radiation

We review the relevant 10+ parameters associated with inflation and matter content; the relation between LSS and primary and secondary CMB anisotropy probes; COBE constraints on energy injection; current anisotropy band-powers which strongly support the gravitational instability theory and suggest the universe could not have reionized too early. We use Bayesian analysis methods to determine what current CMB and CMB+LSS data imply for inflation-based Gaussian fluctuations in tilted $\Lambda$CDM, $\Lambda$hCDM and oCDM model sequences with age 11-15 Gyr, consisting of mixtures of baryons, cold (and possibly hot) dark matter, vacuum energy, and curvature energy in open cosmologies. For example, we find the slope of the initial spectrum is within about 5% of the (preferred) scale invariant form when just the CMB data is used, and for $\Lambda$CDM when LSS data is combined with CMB; with both, a nonzero value of $\Omega_\Lambda$ is strongly preferred ($\approx 2/3$ for a 13 Gyr sequence, similar to the value from SNIa). The $o$CDM sequence prefers $\Omega_{tot}<1$, but is overall much less likely than the flat $\Omega_\Lambda \ne 0$ sequence with CMB+LSS. We also review the rosy forecasts of angular power spectra and parameter estimates from future balloon and satellite experiments when foreground and systematic effects are ignored.Comment: 20 pages, LaTeX, 5 figures, 2 tables, uses rspublic.sty To appear in Philosophical Transactions of the Royal Society of London A, 1998. "Discussion Meeting on Large Scale Structure in the Universe," Royal Society, London, March 1998. Text and colour figures also available at ftp://ftp.cita.utoronto.ca/bond/roysoc9

Non-coding Class Switch Recombination-Related Transcription in Human Normal and Pathological Immune Responses

Antibody class switch recombination (CSR) to IgG, IgA, or IgE is a hallmark of adaptive immunity, allowing antibody function diversification beyond IgM. CSR involves a deletion of the IgM/IgD constant region genes placing a new acceptor Constant gene, downstream of the VDJH exon. CSR depends on non-coding (CSRnc) transcription of donor Iμ and acceptor IH exons, located 5′ upstream of each CH coding gene. Although, our knowledge of the role of CSRnc transcription has advanced greatly, its extension and importance in healthy and diseased humans is scarce. We analyzed CSRnc transcription in 70,603 publicly available RNA-seq samples, including GTEx, TCGA, and the Sequence Read Archive using recount2, an online resource consisting of normalized RNA-seq gene and exon counts, as well as, coverage BigWig files that can be programmatically accessed through R. CSRnc transcription was validated with a qRT-PCR assay for Iμ, Iγ3, and Iγ1 in humans in response to vaccination. We mapped IH transcription for the human IGH locus, including the less understood IGHD gene. CSRnc transcription was restricted to B cells and is widely distributed in normal adult tissues, but predominant in blood, spleen, MALT-containing tissues, visceral adipose tissue and some so-called “immune privileged” tissues. However, significant Iγ4 expression was found even in non-lymphoid fetal tissues. CSRnc expression in cancer tissues mimicked the expression of their normal counterparts, with notable pattern changes in some common cancer subsets. CSRnc transcription in tumors appears to result from tumor infiltration by B cells, since CSRnc transcription was not detected in corresponding tumor-derived immortal cell lines. Additionally, significantly increased Iδ transcription in ileal mucosa in Crohn's disease with ulceration was found. In conclusion, CSRnc transcription occurs in multiple anatomical locations beyond classical secondary lymphoid organs, representing a potentially useful marker of effector B cell responses in normal and pathological immune responses. The pattern of IH exon expression may reveal clues of the local immune response (i.e., cytokine milieu) in health and disease. This is a great example of how the public recount2 data can be used to further our understanding of transcription, including regions outside the known transcriptome

Bending of Light by Gravity Waves

We describe the statistical properties of light rays propagating though a random sea of gravity waves and compare with the case for scalar metric perturbations from density inhomogeneities. For scalar fluctuations the deflection angle grows as the square-root of the path length $D$ in the manner of a random walk, and the rms displacement of a ray from the unperturbed trajectory grows as $D^{3/2}$. For gravity waves the situation is very different. The mean square deflection angle remains finite and is dominated by the effect of the metric fluctuations at the ends of the ray, and the mean square displacement grows only as the logarithm of the path length. In terms of power spectra, the displacement for scalar perturbations has $P(k) \propto 1/ k^4$ while for gravity waves the trajectories of photons have $P(k) \propto 1/k$ which is a scale-invariant or `flicker-noise' process, and departures from rectilinear motion are suppressed, relative to the scalar case, by a factor $\sim (\lambda / D)^{3/2}$ where $\lambda$ is the characteristic scale of the metric fluctuations and $D$ is the path length. This result casts doubt on the viability of some recent proposals for detecting or constraining the gravity wave background by astronomical measurements.Comment: 14 pages, aastex, submitted to Astrophysical Journa

The X-ray Emissions from the M87 Jet: Diagnostics and Physical Interpretation

We reanalyze the deep Chandra observations of the M87 jet, first examined by Wilson & Yang (2002). By employing an analysis chain that includes image deconvolution, knots HST-1 and I are fully separated from adjacent emission. We find slight but significant variations in the spectral shape, with values of $\alpha_x$ ranging from $\sim 1.2-1.6$. We use VLA radio observations, as well as HST imaging and polarimetry data, to examine the jet's broad-band spectrum and inquire as to the nature of particle acceleration in the jet. As shown in previous papers, a simple continuous injection model for synchrotron-emitting knots, in which both the filling factor, $f_{acc}$, of regions within which particles are accelerated and the energy spectrum of the injected particles are constant, cannot account for the X-ray flux or spectrum. Instead, we propose that $f_{acc}$ is a function of position and energy and find that in the inner jet, $f_{acc} \propto E_\gamma^{-0.4 \pm 0.2} \propto E_e^{-0.2 \pm 0.1}$, and in knots A and B, $f_{acc} \propto E_\gamma^{-0.7 \pm 0.2} \propto E_e^{-0.35 \pm 0.1}$, where $E_\gamma$ is the emitted photon energy and and $E_e$ is the emitting electron energy. In this model, the index $p$ of the injected electron energy spectrum ($n(E_{e}) \propto E_{e}^{-p}$) is $p=2.2$ at all locations in the jet, as predicted by models of cosmic ray acceleration by ultrarelativistic shocks. There is a strong correlation between the peaks of X-ray emission and minima of optical percentage polarization, i.e., regions where the jet magnetic field is not ordered. We suggest that the X-ray peaks coincide with shock waves which accelerate the X-ray emitting electrons and cause changes in the direction of the magnetic field; the polarization is thus small because of beam averaging.Comment: Accepted for publication in ApJ; 21 pages, 9 figures, 2 tables; abstract shortened for astro-ph; Figures 1, 7 and 8 at reduced resolutio