The distribution of maxima of approximately Gaussian random fields

Motivated by the problem of testing for the existence of a signal of known parametric structure and unknown ``location'' (as explained below) against a noisy background, we obtain for the maximum of a centered, smooth random field an approximation for the tail of the distribution. For the motivating class of problems this gives approximately the significance level of the maximum score test. The method is based on an application of a likelihood-ratio-identity followed by approximations of local fields. Numerical examples illustrate the accuracy of the approximations.Comment: Published in at http://dx.doi.org/10.1214/07-AOS511 the Annals of Statistics (http://www.imstat.org/aos/) by the Institute of Mathematical Statistics (http://www.imstat.org

Statistical corrections of linkage data suggest predominantly cis regulations of gene expression

Morley et al. (Nature 2004, 430:743–747) detected significant linkages to the expression levels of 142 genes (of 3554) at a reported threshold of genome-wide p = 0.001 (LOD ≈ 5.3), using 14 three-generation Centre d'Etude du Polymorphisme Humain pedigrees. Most of the linkages (77%) were trans, i.e., more than 5 Mb from the expressed gene. However, the analysis did not account for the expected anti-conservative effect of the skewed distribution of score- or regression-based statistics in large sibships, or for the possible variance distortion due to correlations among tests. Therefore, we re-analyzed their data, using a robust score statistic for the entire pedigrees and correcting the p-values for skewness. We found that a LOD of 5.3 had a skewness-corrected genome-wide p-value of 0.016 instead of 0.001 (a result that we confirmed using simulation), with around 50 expected false positives. We then further corrected for correlation among the (skew-corrected) p-values by using Efron's method for obtaining the empirical null distribution. Setting a threshold of FDR = 10% (Z = 6.4, LOD = 8.9), we detected linkage for the expression levels of 22 genes, 19 of which are cis. Limiting the analysis to cis regions, linkage was detected to the expression levels of 46 genes with 4.6 expected false positives (FDR = 10%)

Stochastic Model of Protein–Protein Interaction: Why Signaling Proteins Need to Be Colocalized

Colocalization of proteins that are part of the same signal transduction pathway via compartmentalization, scaffold, or anchor proteins is an essential aspect of the signal transduction system in eukaryotic cells. If interaction must occur via free diffusion, then the spatial separation between the sources of the two interacting proteins and their degradation rates become primary determinants of the time required for interaction. To understand the role of such colocalization, we create a mathematical model of the diffusion based protein–protein interaction process. We assume that mRNAs, which serve as the sources of these proteins, are located at different positions in the cytoplasm. For large cells such as Drosophila oocytes we show that if the source mRNAs were at random locations in the cell rather than colocalized, the average rate of interactions would be extremely small, which suggests that localization is needed to facilitate protein interactions and not just to prevent cross-talk between different signaling modules

Scanning a Poisson Random Field for Local Signals

The detection of local genomic signals using high-throughput DNA sequencing data can be cast as a problem of scanning a Poisson random field for local changes in the rate of the process. We propose a likelihood-based framework for such scans, and derive formulas for false positive rate control and power calculations. The framework can also accommodate modified processes that involve overdispersion. As a specific, detailed example, we consider the detection of insertions and deletions by paired-end DNA-sequencing. We propose several statistics for this problem, compare their power under current experimental designs, and illustrate their application on an Illumina Platinum Genomes data set

Possible detection of two giant extrasolar planets orbiting the eclipsing polar UZ Fornacis

We present new high-speed, multi-observatory, multi-instrument photometry of the eclipsing polar UZ For in order to measure precise mid-eclipse times with the aim of detecting any orbital period variations. When combined with published eclipse times and archival data spanning ~27 years, we detect departures from a linear and quadratic trend of ~60 s. The departures are strongly suggestive of two cyclic variations of 16(3) and 5.25(25) years. The two favoured mechanisms to drive the periodicities are either two giant extrasolar planets as companions to the binary (with minimum masses of 6.3(1.5)M(Jupiter) and 7.7(1.2)M(Jupiter)) or a magnetic cycle mechanism (e.g. Applegate's mechanism) of the secondary star. Applegate's mechanism would require the entire radiant energy output of the secondary and would therefore seem to be the least likely of the two, barring any further refinements in the effect of magnetic fieilds (e.g. those of Lanza et al.). The two planet model can provide realistic solutions but it does not quite capture all of the eclipse times measurements. A highly eccentric orbit for the outer planet would fit the data nicely, but we find that such a solution would be unstable. It is also possible that the periodicities are driven by some combination of both mechanisms. Further observations of this system are encouraged.Comment: 10 pages, 4 figures, 2 table

Spatial Regulation and the Rate of Signal Transduction Activation

Of the many important signaling events that take place on the surface of a mammalian cell, activation of signal transduction pathways via interactions of cell surface receptors is one of the most important. Evidence suggests that cell surface proteins are not as freely diffusible as implied by the classic fluid mosaic model and that their confinement to membrane domains is regulated. It is unknown whether these dynamic localization mechanisms function to enhance signal transduction activation rate or to minimize cross talk among pathways that share common intermediates. To determine which of these two possibilities is more likely, we derive an explicit equation for the rate at which cell surface membrane proteins interact based on a Brownian motion model in the presence of endocytosis and exocytosis. We find that in the absence of any diffusion constraints, cell surface protein interaction rate is extremely high relative to cytoplasmic protein interaction rate even in a large mammalian cell with a receptor abundance of a mere two hundred molecules. Since a larger number of downstream signaling events needs to take place, each occurring at a much slower rate than the initial activation via association of cell surface proteins, we conclude that the role of co-localization is most likely that of cross-talk reduction rather than coupling efficiency enhancement

D-cycloserine augmentation of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders: a systematic review and meta-analysis of individual participant data

Importance: Whether and under which conditions D-cycloserine (DCS) augments the effects of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders is unclear. Objective: To clarify whether DCS is superior to placebo in augmenting the effects of cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders and to evaluate whether antidepressants interact with DCS and the effect of potential moderating variables. Data Sources: PubMed, EMBASE, and PsycINFO were searched from inception to February 10, 2016. Reference lists of previous reviews and meta-analyses and reports of randomized clinical trials were also checked. Study Selection: Studies were eligible for inclusion if they were (1) double-blind randomized clinical trials of DCS as an augmentation strategy for exposure-based cognitive behavior therapy and (2) conducted in humans diagnosed as having specific phobia, social anxiety disorder, panic disorder with or without agoraphobia, obsessive-compulsive disorder, or posttraumatic stress disorder. Data Extraction and Synthesis: Raw data were obtained from the authors and quality controlled. Data were ranked to ensure a consistent metric across studies (score range, 0-100). We used a 3-level multilevel model nesting repeated measures of outcomes within participants, who were nested within studies. Results: Individual participant data were obtained for 21 of 22 eligible trials, representing 1047 of 1073 eligible participants. When controlling for antidepressant use, participants receiving DCS showed greater improvement from pretreatment to posttreatment (mean difference, -3.62; 95% CI, -0.81 to -6.43; P = .01; d = -0.25) but not from pretreatment to midtreatment (mean difference, -1.66; 95% CI, -4.92 to 1.60; P = .32; d = -0.14) or from pretreatment to follow-up (mean difference, -2.98, 95% CI, -5.99 to 0.03; P = .05; d = -0.19). Additional analyses showed that participants assigned to DCS were associated with lower symptom severity than those assigned to placebo at posttreatment and at follow-up. Antidepressants did not moderate the effects of DCS. None of the prespecified patient-level or study-level moderators was associated with outcomes. Conclusions and Relevance: D-cycloserine is associated with a small augmentation effect on exposure-based therapy. This effect is not moderated by the concurrent use of antidepressants. Further research is needed to identify patient and/or therapy characteristics associated with DCS response.2018-05-0

The Apache Point Observatory Galactic Evolution Experiment (APOGEE)

The Apache Point Observatory Galactic Evolution Experiment (APOGEE), one of the programs in the Sloan Digital Sky Survey III (SDSS-III), has now completed its systematic, homogeneous spectroscopic survey sampling all major populations of the Milky Way. After a three-year observing campaign on the Sloan 2.5 m Telescope, APOGEE has collected a half million high-resolution (R ~ 22,500), high signal-to-noise ratio (>100), infrared (1.51–1.70 μm) spectra for 146,000 stars, with time series information via repeat visits to most of these stars. This paper describes the motivations for the survey and its overall design—hardware, field placement, target selection, operations—and gives an overview of these aspects as well as the data reduction, analysis, and products. An index is also given to the complement of technical papers that describe various critical survey components in detail. Finally, we discuss the achieved survey performance and illustrate the variety of potential uses of the data products by way of a number of science demonstrations, which span from time series analysis of stellar spectral variations and radial velocity variations from stellar companions, to spatial maps of kinematics, metallicity, and abundance patterns across the Galaxy and as a function of age, to new views of the interstellar medium, the chemistry of star clusters, and the discovery of rare stellar species. As part of SDSS-III Data Release 12 and later releases, all of the APOGEE data products are publicly available

Sloan Digital Sky Survey IV: Mapping the Milky Way, Nearby Galaxies, and the Distant Universe

We describe the Sloan Digital Sky Survey IV (SDSS-IV), a project encompassing three major spectroscopic programs. The Apache Point Observatory Galactic Evolution Experiment 2 (APOGEE-2) is observing hundreds of thousands of Milky Way stars at high resolution and high signal-to-noise ratios in the near-infrared. The Mapping Nearby Galaxies at Apache Point Observatory (MaNGA) survey is obtaining spatially resolved spectroscopy for thousands of nearby galaxies (median $z\sim 0.03$). The extended Baryon Oscillation Spectroscopic Survey (eBOSS) is mapping the galaxy, quasar, and neutral gas distributions between $z\sim 0.6$ and 3.5 to constrain cosmology using baryon acoustic oscillations, redshift space distortions, and the shape of the power spectrum. Within eBOSS, we are conducting two major subprograms: the SPectroscopic IDentification of eROSITA Sources (SPIDERS), investigating X-ray AGNs and galaxies in X-ray clusters, and the Time Domain Spectroscopic Survey (TDSS), obtaining spectra of variable sources. All programs use the 2.5 m Sloan Foundation Telescope at the Apache Point Observatory; observations there began in Summer 2014. APOGEE-2 also operates a second near-infrared spectrograph at the 2.5 m du Pont Telescope at Las Campanas Observatory, with observations beginning in early 2017. Observations at both facilities are scheduled to continue through 2020. In keeping with previous SDSS policy, SDSS-IV provides regularly scheduled public data releases; the first one, Data Release 13, was made available in 2016 July