Simpler Evaluation of Predictions and Signature Stability for Gene Expression Data

Scientific advances are raising expectations that patient-tailored treatment will soon be available. The development of resulting clinical approaches needs to be based on well-designed experimental and observational procedures that provide data to which proper biostatistical analyses are applied. Gene expression microarray and related technology are rapidly evolving. It is providing extremely large gene expression profiles containing many thousands of measurements. Choosing a subset from these gene expression measurements to include in a gene expression signature is one of the many challenges needing to be met. Choice of this signature depends on many factors, including the selection of patients in the training set. So the reliability and reproducibility of the resultant prognostic gene signature needs to be evaluated, in such a way as to be relevant to the clinical setting. A relatively straightforward approach is based on cross validation, with separate selection of genes at each iteration to avoid selection bias. Within this approach we developed two different methods, one based on forward selection, the other on genes that were statistically significant in all training blocks of data. We demonstrate our approach to gene signature evaluation with a well-known breast cancer data set

h-Profile plots for the discovery and exploration of patterns in gene expression data with an application to time course data

<p>Abstract</p> <p>Background</p> <p>An ever increasing number of techniques are being used to find genes with similar profiles from microarray studies. Visualization of gene expression profiles can aid this process, potentially contributing to the identification of co-regulated genes and gene function as well as network development.</p> <p>Results</p> <p>We introduce the h-Profile plot to display gene expression profiles. Thumbnail versions of plots of gene expression profiles are plotted at coordinates such that profiles of similar shape are located in the same sector, with decreasing variance towards the origin. Negatively correlated profiles can easily be identified. A new method for selecting genes with fixed periodicity, but different phase and amplitude is described and used to demonstrate the use of the plots on cell cycle data.</p> <p>Conclusion</p> <p>Visualization tools for gene expression data are important and h-profile plots provide a timely contribution to the field. They allow the simultaneous visualization of many gene expression profiles and can be used for the identification of genes with similar or reversed profiles, the foundation step in many analyses.</p

Alignment-free sequence comparison for biologically realistic sequences of moderate length

The D2 statistic, defined as the number of matches of words of some pre-specified length k, is a computationally fast alignment-free measure of biological sequence similarity. However there is some debate about its suitability for this purpose as the variability in D2 may be dominated by the terms that reflect the noise in each of the single sequences only. We examine the extent of the problem and the effectiveness of overcoming it by using two mean-centred variants of this statistic, D2* and D2c. We conclude that all three statistics are potentially useful measures of sequence similarity, for which reasonably accurate p-values can be estimated under a null hypothesis of sequences composed of identically and independently distributed letters. We show that D2 and D2c, and to a somewhat lesser extent D2*, perform well in tests to classify moderate length query sequences as putative cis-regulatory modules.This work was funded in part by ARC discovery grant DP098729

Approximate word matches between two random sequences

Given two sequences over a finite alphabet $\mathcal{L}$, the $D_2$ statistic is the number of $m$-letter word matches between the two sequences. This statistic is used in bioinformatics for expressed sequence tag database searches. Here we study a generalization of the $D_2$ statistic in the context of DNA sequences, under the assumption of strand symmetric Bernoulli text. For $k<m$, we look at the count of $m$-letter word matches with up to $k$ mismatches. For this statistic, we compute the expectation, give upper and lower bounds for the variance and prove its distribution is asymptotically normal.Comment: Published in at http://dx.doi.org/10.1214/07-AAP452 the Annals of Applied Probability (http://www.imstat.org/aap/) by the Institute of Mathematical Statistics (http://www.imstat.org

Valuing Compromise for the Common Good

Pursuing the common good in a pluralist democracy is not possible without making compromises. Yet the spirit of compromise is in short supply in contemporary American politics. The permanent campaign has made compromise more difficult to achieve, as the uncompromising mindset suitable for campaigning has come to dominate the task of governing. To begin to make compromise more feasible and the common good more attainable, we need to appreciate the distinctive value of compromise and recognize the misconceptions that stand in its way. A common mistake is to assume that compromise requires finding the common ground on which all can agree. That undermines more realistic efforts to seek classic compromises, in which each party gains by sacrificing something valuable to the other, and together they serve the common good by improving upon the status quo. Institutional reforms are desirable, but they, too, cannot get off the ground without the support of leaders and citizens who learn how and when to adopt a compromising mindset

Comparison and visualisation of agreement for paired lists of rankings

Output from analysis of a high-throughput ‘omics’ experiment very often is a ranked list. One commonly encountered example is a ranked list of differentially expressed genes from a gene expression experiment, with a length of many hundreds of genes. There are numerous situations where interest is in the comparison of outputs following, say, two (or more) different experiments, or of different approaches to the analysis that produce different ranked lists. Rather than considering exact agreement between the rankings, following others, we consider two ranked lists to be in agreement if the rankings differ by some fixed distance. Generally only a relatively small subset of the k top-ranked items will be in agreement. So the aim is to find the point k at which the probability of agreement in rankings changes from being greater than 0.5 to being less than 0.5. We use penalized splines and a Bayesian logit model, to give a nonparametric smooth to the sequence of agreements, as well as pointwise credible intervals for the probability of agreement. Our approach produces a point estimate and a credible interval for k. R code is provided. The method is applied to rankings of genes from breast cancer microarray experiments

Mupirocin for the reduction of colonization of internal jugular cannulae: a randomized controlled trial

In a prospective study, 218 cardiothoracic patients, in whom 'Abbocath-T' cannulae had been inserted preoperatively into the internal jugular vein, were randomized to receive skin preparation of the insertion site with tincture of iodine (108 controls) or tincture of iodine followed by application of sterile 2% calcium mupirocin ointment (110 test patients). Cannulae were usually removed within 48 h of the operation. Patients receiving mupirocin were less likely to develop significant colonization of one or more of their cannulae as judged by Maki's criterion of a yield of greater than 15 colony forming units (cfu) from a cannula segment rolled on an agar plate (17% of mupirocin treated patients compared with 54% of the controls, P less than 0.001). Coagulase-negative staphylococci, micrococci, or both, were the commonest isolates and were cultured from 70% of the 186 control cannulae compared with 24% of 172 cannulae inserted through mupirocin-treated skin (P less than 0.001). A count of more than 15 cfu was found on the tips of 25% control cannulae compared with 5% of the cannulae from mupirocin-treated patients, an effect which was independent of in-situ time (P less than 0.001). For cannulae with colonized tips, the same species was isolated from the skin of the insertion site in 67%, from the exterior of the hub in 61% and from the lumen in only 15%. There were no side effects attributed to mupirocin or superinfection with resistant organisms. We conclude that in cardiothoracic patients the application of mupirocin after standard skin preparation with tincture of iodine significantly reduces the colonization of central venous cannulae by organisms derived from the skin insertion site

Enhanced mtDNA repair and cellular survival following oxidative stress by targeting the hOGG repair enzyme to mitochondria.

Oxidative damage to mtDNA has been implicated as a causative factor in many disease processes and in aging. We have recently discovered that different cell types vary in their capacity to repair this damage, and this variability correlates with their ability to withstand oxidative stress. To explore strategies to enhance repair of oxidative lesions in mtDNA, we have constructed a vector containing a mitochondrial transport sequence upstream of the sequence for human 8-oxoguanine glycosylase. This enzyme is the glycosylase/AP lyase that participates in repair of purine lesions, such as 8-oxoguanine. Western blot analysis confirmed this recombinant protein was targeted to mitochondria. Enzyme activity assays showed that mitochondrial extracts from cells transfected with the construct had increased enzyme activity compared to cells transfected with vector only, while nuclear enzyme activity was not changed. Repair assays showed that there was enhanced repair of oxidative lesions in mtDNA. Additional studies revealed that this augmented repair led to enhanced cellular viability as determined by reduction of tetrazolium compound to formazan, Trypan blue dye exclusion, and clonogenic assays. Therefore, targeting of DNA repair enzymes to mitochondria may be a viable approach for the protection of cells against some of the deleterious effects of oxidative stress