Multiple imputation for estimation of an occurrence rate in cohorts with attrition and discrete follow-up time points: a simulation study

<p>Abstract</p> <p>Background</p> <p>In longitudinal cohort studies, subjects may be lost to follow-up at any time during the study. This leads to attrition and thus to a risk of inaccurate and biased estimations. The purpose of this paper is to show how multiple imputation can take advantage of all the information collected during follow-up in order to estimate the cumulative probability <it>P(E) </it>of an event <it>E</it>, when the first occurrence of this event is observed at <it>t </it>successive time points of a longitudinal study with attrition.</p> <p>Methods</p> <p>We compared the performance of multiple imputation with that of Kaplan-Meier estimation in several simulated attrition scenarios.</p> <p>Results</p> <p>In missing-completely-at-random scenarios, the multiple imputation and Kaplan-Meier methods performed well in terms of bias (less than 1%) and coverage rate (range = [94.4%; 95.8%]). In missing-at-random scenarios, the Kaplan-Meier method was associated with a bias ranging from -5.1% to 7.0% and with a very poor coverage rate (as low as 0.2%). Multiple imputation performed much better in this situation (bias <2%, coverage rate >83.4%).</p> <p>Conclusions</p> <p>Multiple imputation shows promise for estimation of an occurrence rate in cohorts with attrition. This study is a first step towards defining appropriate use of multiple imputation in longitudinal studies.</p

Parallel Expansions of Sox Transcription Factor Group B Predating the Diversifications of the Arthropods and Jawed Vertebrates

Group B of the Sox transcription factor family is crucial in embryo development in the insects and vertebrates. Sox group B, unlike the other Sox groups, has an unusually enlarged functional repertoire in insects, but the timing and mechanism of the expansion of this group were unclear. We collected and analyzed data for Sox group B from 36 species of 12 phyla representing the major metazoan clades, with an emphasis on arthropods, to reconstruct the evolutionary history of SoxB in bilaterians and to date the expansion of Sox group B in insects. We found that the genome of the bilaterian last common ancestor probably contained one SoxB1 and one SoxB2 gene only and that tandem duplications of SoxB2 occurred before the arthropod diversification but after the arthropod-nematode divergence, resulting in the basal repertoire of Sox group B in diverse arthropod lineages. The arthropod Sox group B repertoire expanded differently from the vertebrate repertoire, which resulted from genome duplications. The parallel increases in the Sox group B repertoires of the arthropods and vertebrates are consistent with the parallel increases in the complexity and diversification of these two important organismal groups

Radiative properties of stellar plasmas and open challenges

The lifetime of solar-like stars, the envelope structure of more massive stars, and stellar acoustic frequencies largely depend on the radiative properties of the stellar plasma. Up to now, these complex quantities have been estimated only theoretically. The development of the powerful tools of helio- and astero- seismology has made it possible to gain insights on the interiors of stars. Consequently, increased emphasis is now placed on knowledge of the monochromatic opacity coefficients. Here we review how these radiative properties play a role, and where they are most important. We then concentrate specifically on the envelopes of $\beta$ Cephei variable stars. We discuss the dispersion of eight different theoretical estimates of the monochromatic opacity spectrum and the challenges we need to face to check these calculations experimentally.Comment: 6 pages, 5 figures, in press (conference HEDLA 2010

Differential Epigenetic Regulation of TOX Subfamily High Mobility Group Box Genes in Lung and Breast Cancers

Aberrant cytosine methylation affects regulation of hundreds of genes during cancer development. In this study, a novel aberrantly hypermethylated CpG island in cancer was discovered within the TOX2 promoter. TOX2 was unmethylated in normal cells but 28% lung (n = 190) and 23% breast (n = 80) tumors were methylated. Expression of two novel TOX2 transcripts identified was significantly reduced in primary lung tumors than distant normal lung (p<0.05). These transcripts were silenced in methylated lung and breast cancer cells and 5-Aza-2-deoxycytidine treatment re-expressed both. Extension of these assays to TOX, TOX3, and TOX4 genes that share similar genomic structure and protein homology with TOX2 revealed distinct methylation profiles by smoking status, histology, and cancer type. TOX was almost exclusively methylated in breast (43%) than lung (5%) cancer, whereas TOX3 was frequently methylated in lung (58%) than breast (30%) tumors. TOX4 was unmethylated in all samples and showed the highest expression in normal lung. Compared to TOX4, expression of TOX, TOX2 and TOX3 in normal lung was 25, 44, and 88% lower, respectively, supporting the premise that reduced promoter activity confers increased susceptibility to methylation during lung carcinogenesis. Genome-wide assays revealed that siRNA-mediated TOX2 knockdown modulated multiple pathways while TOX3 inactivation targeted neuronal development and function. Although these knockdowns did not result in further phenotypic changes of lung cancer cells in vitro, the impact on tissue remodeling, inflammatory response, and cell differentiation pathways suggest a potential role for TOX2 in modulating tumor microenvironment

Speckle Tracking Echocardiography for the Assessment of the Athlete's Heart: Is It Ready for Daily Practice?

PURPOSE OF REVIEW: To describe the use of speckle tracking echocardiography (STE) in the biventricular assessment of athletes' heart (AH). Can STE aid differential diagnosis during pre-participation cardiac screening (PCS) of athletes? RECENT FINDINGS: Data from recent patient, population and athlete studies suggest potential discriminatory value of STE, alongside standard echocardiographic measurements, in the early detection of clinically relevant systolic dysfunction. STE can also contribute to subsequent prognosis and risk stratification. Despite some heterogeneity in STE data in athletes, left ventricular global longitudinal strain (GLS) and right ventricular longitudinal strain (RV ɛ) indices can add to differential diagnostic protocols in PCS. STE should be used in addition to standard echocardiographic tools and be conducted by an experienced operator with significant knowledge of the AH. Other indices, including left ventricular circumferential strain and twist, may provide insight, but further research in clinical and athletic populations is warranted. This review also raises the potential role for STE measures performed during exercise as well as in serial follow-up as a method to improve diagnostic yield

Tracing the Origin of the Fungal α1 Domain Places Its Ancestor in the HMG-Box Superfamily: Implication for Fungal Mating-Type Evolution

BACKGROUND: Fungal mating types in self-incompatible Pezizomycotina are specified by one of two alternate sequences occupying the same locus on corresponding chromosomes. One sequence is characterized by a gene encoding an HMG protein, while the hallmark of the other is a gene encoding a protein with an α1 domain showing similarity to the Matα1p protein of Saccharomyces cerevisiae. DNA-binding HMG proteins are ubiquitous and well characterized. In contrast, α1 domain proteins have limited distribution and their evolutionary origin is obscure, precluding a complete understanding of mating-type evolution in Ascomycota. Although much work has focused on the role of the S. cerevisiae Matα1p protein as a transcription factor, it has not yet been placed in any of the large families of sequence-specific DNA-binding proteins. METHODOLOGY/PRINCIPAL FINDINGS: We present sequence comparisons, phylogenetic analyses, and in silico predictions of secondary and tertiary structures, which support our hypothesis that the α1 domain is related to the HMG domain. We have also characterized a new conserved motif in α1 proteins of Pezizomycotina. This motif is immediately adjacent to and downstream of the α1 domain and consists of a core sequence Y-[LMIF]-x(3)-G-[WL] embedded in a larger conserved motif. CONCLUSIONS/SIGNIFICANCE: Our data suggest that extant α1-box genes originated from an ancestral HMG gene, which confirms the current model of mating-type evolution within the fungal kingdom. We propose to incorporate α1 proteins in a new subclass of HMG proteins termed MATα_HMG

Steroid Hormone Control of Cell Death and Cell Survival: Molecular Insights Using RNAi

The insect steroid hormone ecdysone triggers programmed cell death of obsolete larval tissues during metamorphosis and provides a model system for understanding steroid hormone control of cell death and cell survival. Previous genome-wide expression studies of Drosophila larval salivary glands resulted in the identification of many genes associated with ecdysone-induced cell death and cell survival, but functional verification was lacking. In this study, we test functionally 460 of these genes using RNA interference in ecdysone-treated Drosophila l(2)mbn cells. Cell viability, cell morphology, cell proliferation, and apoptosis assays confirmed the effects of known genes and additionally resulted in the identification of six new pro-death related genes, including sorting nexin-like gene SH3PX1 and Sox box protein Sox14, and 18 new pro-survival genes. Identified genes were further characterized to determine their ecdysone dependency and potential function in cell death regulation. We found that the pro-survival function of five genes (Ras85D, Cp1, CG13784, CG32016, and CG33087), was dependent on ecdysone signaling. The TUNEL assay revealed an additional two genes (Kap-α3 and Smr) with an ecdysone-dependent cell survival function that was associated with reduced cell death. In vitro, Sox14 RNAi reduced the percentage of TUNEL-positive l(2)mbn cells (p<0.05) following ecdysone treatment, and Sox14 overexpression was sufficient to induce apoptosis. In vivo analyses of Sox14-RNAi animals revealed multiple phenotypes characteristic of aberrant or reduced ecdysone signaling, including defects in larval midgut and salivary gland destruction. These studies identify Sox14 as a positive regulator of ecdysone-mediated cell death and provide new insights into the molecular mechanisms underlying the ecdysone signaling network governing cell death and cell survival