Literatur-Rundschau

Gebhard Fürst / David Hober / Jürgen Holtkamp (Hg.): Katholisches Medienhandbuch (Christina Enders)Nicolai Hannig: Die Religion der Öffentlichkeit (Michael Schmolke)Michael Jäckel: Zeitzeichen (Walter Hömberg)Axel Heinrich: Politische Medienethik (Claudia Paganini)Klaus Meier / Christoph Neuberger (Hg.): Journalismusforschung (Alexander Godulla)Anton Hunger: Blattkritik (Petra Hemmelmann)

Comparison of collapsing methods for the statistical analysis of rare variants

Novel technologies allow sequencing of whole genomes and are considered as an emerging approach for the identification of rare disease-associated variants. Recent studies have shown that multiple rare variants can explain a particular proportion of the genetic basis for disease. Following this assumption, we compare five collapsing approaches to test for groupwise association with disease status, using simulated data provided by Genetic Analysis Workshop 17 (GAW17). Variants are collapsed in different scenarios per gene according to different minor allele frequency (MAF) thresholds and their functionality. For comparing the different approaches, we consider the family-wise error rate and the power. Most of the methods could maintain the nominal type I error levels well for small MAF thresholds, but the power was generally low. Although the methods considered in this report are common approaches for analyzing rare variants, they performed poorly with respect to the simulated disease phenotype in the GAW17 data set

Mutant Parkin Impairs Mitochondrial Function and Morphology in Human Fibroblasts

Background: Mutations in Parkin are the most common cause of autosomal recessive Parkinson disease (PD). The mitochondrially localized E3 ubiquitin-protein ligase Parkin has been reported to be involved in respiratory chain function and mitochondrial dynamics. More recent publications also described a link between Parkin and mitophagy.Methodology/Principal Findings: In this study, we investigated the impact of Parkin mutations on mitochondrial function and morphology in a human cellular model. Fibroblasts were obtained from three members of an Italian PD family with two mutations in Parkin (homozygous c.1072delT, homozygous delEx7, compound-heterozygous c.1072delT/delEx7), as well as from two relatives without mutations. Furthermore, three unrelated compound-heterozygous patients (delEx3-4/duplEx7-12, delEx4/c.924C>T and delEx1/c.924C>T) and three unrelated age-matched controls were included. Fibroblasts were cultured under basal or paraquat-induced oxidative stress conditions. ATP synthesis rates and cellular levels were detected luminometrically. Activities of complexes I-IV and citrate synthase were measured spectrophotometrically in mitochondrial preparations or cell lysates. The mitochondrial membrane potential was measured with 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine iodide. Oxidative stress levels were investigated with the OxyBlot technique. The mitochondrial network was investigated immunocytochemically and the degree of branching was determined with image processing methods. We observed a decrease in the production and overall concentration of ATP coinciding with increased mitochondrial mass in Parkin-mutant fibroblasts. After an oxidative insult, the membrane potential decreased in patient cells but not in controls. We further determined higher levels of oxidized proteins in the mutants both under basal and stress conditions. The degree of mitochondrial network branching was comparable in mutants and controls under basal conditions and decreased to a similar extent under paraquat-induced stress.Conclusions: Our results indicate that Parkin mutations cause abnormal mitochondrial function and morphology in non-neuronal human cells

Treosulfan–fludarabine–thiotepa-based conditioning treatment before allogeneic hematopoietic stem cell transplantation for pediatric patients with hematological malignancies

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Epidemic Microclusters of Blood-Culture Proven Sepsis in Very-Low-Birth Weight Infants: Experience of the German Neonatal Network

INTRODUCTION: We evaluated blood culture-proven sepsis episodes occurring in microclusters in very-low-birth-weight infants born in the German Neonatal Network (GNN) during 2009-2010. METHODS: Thirty-seven centers participated in GNN; 23 centers enrolled ≥50 VLBW infants in the study period. Data quality was approved by on-site monitoring. Microclusters of sepsis were defined as occurrence of at least two blood-culture proven sepsis events in different patients of one center within 3 months with the same bacterial species. For microcluster analysis, we selected sepsis episodes with typically cross-transmitted bacteria of high clinical significance including gram-negative rods and Enterococcus spp. RESULTS: In our cohort, 12/2110 (0.6%) infants were documented with an early-onset sepsis and 235 late-onset sepsis episodes (≥72 h of age) occurred in 203/2110 (9.6%) VLBW infants. In 182/235 (77.4%) late-onset sepsis episodes gram-positive bacteria were documented, while coagulase negative staphylococci were found to be the most predominant pathogens (48.5%, 95%CI: 42.01-55.01). Candida spp. and gram-negative bacilli caused 10/235 (4.3%, 95%CI: 1.68% -6.83%) and 43/235 (18.5%) late-onset sepsis episodes, respectively. Eleven microclusters of blood-culture proven sepsis were detected in 7 hospitals involving a total 26 infants. 16/26 cluster patients suffered from Klebsiella spp. sepsis. The median time interval between the first patient's Klebsiella spp. sepsis and cluster cases was 14.1 days (interquartile range: 1-27 days). First patients in the cluster, their linked cases and sporadic sepsis events did not show significant differences in short term outcome parameters. DISCUSSION: Microclusters of infection are an important phenomenon for late-onset sepsis. Most gram-negative cluster infections occur within 30 days after the first patient was diagnosed and Klebsiella spp. play a major role. It is essential to monitor epidemic microclusters of sepsis in surveillance networks to adapt clinical practice, inform policy and further improve quality of care

Step-Up And Step-Down Procedures Controlling The Number And Proportion Of False Positives

In multiple hypotheses testing, it is important to control the probability of rejecting true null hypotheses. A standard procedure has been to control the family-wise error rate (FWER), the probability of rejecting at least one true null hypothesis. For large numbers of hypotheses, using FWER can result in very low power for testing single hypotheses. Recently, powerful multiple step FDR procedures have been proposed which control the false discovery rate (expected proportion of Type I errors). More recently, van der Laan et al. [Augmentation procedures for control of the generalized family-wise error rate and tail probabilities for the proportion of false positives. Statist. Appl. in Genetics and Molecular Biol. 3, 1-25] proposed controlling a generalized family-wise error rate k-FWER (also called gFWER(k)), defined as the probability of at least (k + 1) Type I errors (k = 0 for the usual FWER). Lehmann and Romano [Generalizations of the familywise error rate. Ann. Statist. 33(3), 1138-1154] suggested both a single-step and a step-down procedure for controlling the generalized FWER. They make no assumptions concerning the p-values of the individual tests. The step-down procedure is simple to apply, and cannot be improved without violation of control of the k-FWER. In this paper, by limiting the number of steps in step-down or step-up procedures, new procedures are developed to control k-FWER (and the proportion of false positives) PFP. Using data from the literature, the procedures are compared with those of Lehmann and Romano [Generalizations of the familywise error rate. Ann. Statist. 33(3), 1138-1154], and, under the assumption of a multivariate normal distribution of the test statistics, show considerable improvement in the reduction of the number and PFP. © 2007 Elsevier B.V. All rights reserved

Multiple test procedures using an upper bound of the number of true hypotheses and their use for evaluating high-dimensional EEG data

Hemmelmann C, Ziegler A, Guiard V, Weiss S, Walther M, Vollandt R. Multiple test procedures using an upper bound of the number of true hypotheses and their use for evaluating high-dimensional EEG data. Journal Of Neuroscience Methods. 2008;170(1):158-164

Multivariate tests for the evaluation of high-dimensional EEG data

Hemmelmann C, Horn M, Reiterer S, Schack B, Süsse T, Weiss S. Multivariate tests for the evaluation of high-dimensional EEG data. Journal of Neuroscience Methods. 2004;139(1):111-120