Deriving chemosensitivity from cell lines: Forensic bioinformatics and reproducible research in high-throughput biology

High-throughput biological assays such as microarrays let us ask very detailed questions about how diseases operate, and promise to let us personalize therapy. Data processing, however, is often not described well enough to allow for exact reproduction of the results, leading to exercises in "forensic bioinformatics" where aspects of raw data and reported results are used to infer what methods must have been employed. Unfortunately, poor documentation can shift from an inconvenience to an active danger when it obscures not just methods but errors. In this report we examine several related papers purporting to use microarray-based signatures of drug sensitivity derived from cell lines to predict patient response. Patients in clinical trials are currently being allocated to treatment arms on the basis of these results. However, we show in five case studies that the results incorporate several simple errors that may be putting patients at risk. One theme that emerges is that the most common errors are simple (e.g., row or column offsets); conversely, it is our experience that the most simple errors are common. We then discuss steps we are taking to avoid such errors in our own investigations.Comment: Published in at http://dx.doi.org/10.1214/09-AOAS291 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

High Dimensional Data Enrichment: Interpretable, Fast, and Data-Efficient

High dimensional structured data enriched model describes groups of observations by shared and per-group individual parameters, each with its own structure such as sparsity or group sparsity. In this paper, we consider the general form of data enrichment where data comes in a fixed but arbitrary number of groups G. Any convex function, e.g., norms, can characterize the structure of both shared and individual parameters. We propose an estimator for high dimensional data enriched model and provide conditions under which it consistently estimates both shared and individual parameters. We also delineate sample complexity of the estimator and present high probability non-asymptotic bound on estimation error of all parameters. Interestingly the sample complexity of our estimator translates to conditions on both per-group sample sizes and the total number of samples. We propose an iterative estimation algorithm with linear convergence rate and supplement our theoretical analysis with synthetic and real experimental results. Particularly, we show the predictive power of data-enriched model along with its interpretable results in anticancer drug sensitivity analysis

Bumps, breathers, and waves in a neural network with spike frequency adaptation

In this Letter we introduce a continuum model of neural tissue that include the effects of so-called spike frequency adaptation (SFA). The basic model is an integral equation for synaptic activity that depends upon the non-local network connectivity, synaptic response, and firing rate of a single neuron. A phenomenological model of SFA is examined whereby the firing rate is taken to be a simple state-dependent threshold function. As in the case without SFA classical Mexican-Hat connectivity is shown to allow for the existence of spatially localized states (bumps). Importantly an analysis of bump stability using recent Evans function techniques shows that bumps may undergo instabilities leading to the emergence of both breathers and traveling waves. Moreover, a similar analysis for traveling pulses leads to the conditions necessary to observe a stable traveling breather. Direct numerical simulations both confirm our theoretical predictions and illustrate the rich dynamic behavior of this model, including the appearance of self-replicating bumps

Sources of variation in false discovery rate estimation include sample size, correlation, and inherent differences between groups

BACKGROUND: High-throughtput technologies enable the testing of tens of thousands of measurements simultaneously. Identification of genes that are differentially expressed or associated with clinical outcomes invokes the multiple testing problem. False Discovery Rate (FDR) control is a statistical method used to correct for multiple comparisons for independent or weakly dependent test statistics. Although FDR control is frequently applied to microarray data analysis, gene expression is usually correlated, which might lead to inaccurate estimates. In this paper, we evaluate the accuracy of FDR estimation. METHODS: Using two real data sets, we resampled subgroups of patients and recalculated statistics of interest to illustrate the imprecision of FDR estimation. Next, we generated many simulated data sets with block correlation structures and realistic noise parameters, using the Ultimate Microarray Prediction, Inference, and Reality Engine (UMPIRE) R package. We estimated FDR using a beta-uniform mixture (BUM) model, and examined the variation in FDR estimation. RESULTS: The three major sources of variation in FDR estimation are the sample size, correlations among genes, and the true proportion of differentially expressed genes (DEGs). The sample size and proportion of DEGs affect both magnitude and precision of FDR estimation, while the correlation structure mainly affects the variation of the estimated parameters. CONCLUSIONS: We have decomposed various factors that affect FDR estimation, and illustrated the direction and extent of the impact. We found that the proportion of DEGs has a significant impact on FDR; this factor might have been overlooked in previous studies and deserves more thought when controlling FDR

CYLINDER SEALS IN THE COLLECTIONS OF IZIKO MUSEUMS OF SOUTH AFRICA IN CAPE TOWN AND THE DEPARTMENT OF ANCIENT STUDIES OF STELLENBOSCH UNIVERSITY

This paper studies the cylinder seals in the collections of IzikoMuseums of South Africa in Cape Town and the Department ofAncient Studies of Stellenbosch University. The individual seals aredescribed and there is an iconographic analysis of the scenes andmotifs depicted on each seal, with comparisons to other artefacts.These seals date from the Early Dynastic period until the Persianperiod (ca. 3100-332 BC) and represent motifs such as deities,mythological beings and the ‘master of animals’, and scenes such asthe contest scene and presentation scene

Bumps and rings in a two-dimensional neural field: splitting and rotational instabilities

In this paper we consider instabilities of localised solutions in planar neural field firing rate models of Wilson-Cowan or Amari type. Importantly we show that angular perturbations can destabilise spatially localised solutions. For a scalar model with Heaviside firing rate function we calculate symmetric one-bump and ring solutions explicitly and use an Evans function approach to predict the point of instability and the shapes of the dominant growing modes. Our predictions are shown to be in excellent agreement with direct numerical simulations. Moreover, beyond the instability our simulations demonstrate the emergence of multi-bump and labyrinthine patterns. With the addition of spike-frequency adaptation, numerical simulations of the resulting vector model show that it is possible for structures without rotational symmetry, and in particular multi-bumps, to undergo an instability to a rotating wave. We use a general argument, valid for smooth firing rate functions, to establish the conditions necessary to generate such a rotational instability. Numerical continuation of the rotating wave is used to quantify the emergent angular velocity as a bifurcation parameter is varied. Wave stability is found via the numerical evaluation of an associated eigenvalue problem

Life in Anticipation of Wind Power Development: Three Cases from Coastal Norway

Wind power development, whilst welcomed by many as a potentially green source of energy, also gives rise to considerable local resistance. Drawing on three case studies from coastal Norway (Frøya, Haramsøy, and Egersund), the present article sets out to reflect on life in anticipation of wind power development. Reflecting on the nature of life in anticipation of undesired wind power developments, with implications for how life is lived in dread of imminent adversities in general (such as climate change, pandemics, and disaster risks), these case studies focus on how communities relate to the future and how they perceive and strive to organise so as to shape outcomes. A central point raised in this article is that wind power projects could become more socially, environmentally and economically sustainable if greater attention is paid to working with communities to reduce distrust and uncertainties before, during and after such projects. Hence, relational work carried out that may shape the affective state of anticipation prior to and during wind farm construction can be understood as crucial to the sustainability of large-scale green infrastructure projects.publishedVersio