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The 'gold standard' design for three-arm trials refers to trials with an active control and a placebo control in addition to the experimental treatment group. This trial design is recommended when being ethically justifiable and it allows the simultaneous comparison of experimental treatment, active control, and placebo. Parametric testing methods have been studied plentifully over the past years. However, these methods often tend to be liberal or conservative when distributional assumptions are not met particularly with small sample sizes. In this article, we introduce a studentized permutation test for testing non-inferiority and superiority of the experimental treatment compared with the active control in three-arm trials in the 'gold standard' design. The performance of the studentized permutation test for finite sample sizes is assessed in a Monte Carlo simulation study under various parameter constellations. Emphasis is put on whether the studentized permutation test meets the target significance level. For comparison purposes, commonly used Wald-type tests, which do not make any distributional assumptions, are included in the simulation study. The simulation study shows that the presented studentized permutation test for assessing non-inferiority in three-arm trials in the 'gold standard' design outperforms its competitors, for instance the test based on a quasi-Poisson model, for count data. The methods discussed in this paper are implemented in the R package ThreeArmedTrials which is available on the comprehensive R archive network (CRAN). Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

We investigate rank-based studentized permutation methods for the nonparametric Behrens-Fisher problem, that is, inference methods for the area under the ROC curve. We hereby prove that the studentized permutation distribution of the Brunner-Munzel rank statistic is asymptotically standard normal, even under the alternative. Thus, incidentally providing the hitherto missing theoretical foundation for the Neubert and Brunner studentized permutation test. In particular, we do not only show its consistency, but also that confidence intervals for the underlying treatment effects can be computed by inverting this permutation test. In addition, we derive permutation-based range-preserving confidence intervals. Extensive simulation studies show that the permutation-based confidence intervals appear to maintain the preassigned coverage probability quite accurately (even for rather small sample sizes). For a convenient application of the proposed methods, a freely available software package for the statistical software R has been developed. A real data example illustrates the application., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: In early diagnostic trials, particularly in biomarker studies, the aim is often to select diagnostic tests among several methods. In case of metric, discrete, or even ordered categorical data, the area under the receiver operating characteristic (ROC) curve (denoted by AUC) is an appropriate overall accuracy measure for the selection, because the AUC is independent of cut-off points., Methods: For selection of biomarkers the individual AUC's are compared with a pre-defined threshold. To keep the overall coverage probability or the multiple type-I error rate, simultaneous confidence intervals and multiple contrast tests are considered. We propose a purely nonparametric approach for the estimation of the AUC's with the corresponding confidence intervals and statistical tests. This approach uses the correlation among the statistics to account for multiplicity. For small sample sizes, a Wild-Bootstrap approach is presented. It is shown that the corresponding intervals and tests are asymptotically exact., Results: Extensive simulation studies indicate that the derived Wild-Bootstrap approach keeps and exploits the nominal type-I error at best, even for high accuracies and in case of small samples sizes. The strength of the correlation, the type of covariance structure, a skewed distribution, and also a moderate imbalanced case-control ratio do not have any impact on the behavior of the approach. A real data set illustrates the application of the proposed methods., Conclusion: We recommend the new Wild Bootstrap approach for the selection of biomarkers in early diagnostic trials, especially for high accuracies and small samples sizes.

Multiple contrast tests can be used to test arbitrary linear hypotheses by providing local and global test decisions as well as simultaneous confidence intervals. The ANOVA-F-test on the contrary can be used to test the global null hypothesis of no treatment effect. Thus, multiple contrast tests provide more information than the analysis of variance (ANOVA) by offering which levels cause the significance. We compare the exact powers of the ANOVA-F-test and multiple contrast tests to reject the global null hypothesis. Hereby, we compute their least favorable configurations (LFCs). It turns out that both procedures have the same LFCs under certain conditions. Exact power investigations show that their powers are equal to detect their LFCs.

In patients with myelodysplastic syndromes (MDS) iron overload caused by long-term red blood cell transfusions is an important factor for comorbidity especially in low-risk MDS. In this report we present the results of a comparative study based on colony formation assays of hematopoietic cells in MDS patients with and without iron overload. We demonstrate that iron overload suppresses the proliferation of erythroid progenitors cells (BFU-E), while the myeloid compartment (CFU-GM) was not found to be affected. Even patients with slightly elevated ferritin values show an impaired proliferation capacity in comparison to patients with normal ferritin levels. Furthermore, we show that this negative impact is reversible by sufficient iron chelation therapy., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Statistical association between a single nucleotide polymorphism (SNP) genotype and a quantitative trait in genome-wide association studies is usually assessed using a linear regression model, or, in the case of non-normally distributed trait values, using the Kruskal-Wallis test. While linear regression models assume an additive mode of inheritance via equi-distant genotype scores, Kruskal-Wallis test merely tests global differences in trait values associated with the three genotype groups. Both approaches thus exhibit suboptimal power when the underlying inheritance mode is dominant or recessive. Furthermore, these tests do not perform well in the common situations when only a few trait values are available in a rare genotype category (disbalance), or when the values associated with the three genotype categories exhibit unequal variance (variance heterogeneity). We propose a maximum test based on Marcus-type multiple contrast test for relative effect sizes. This test allows model-specific testing of either dominant, additive or recessive mode of inheritance, and it is robust against variance heterogeneity. We show how to obtain mode-specific simultaneous confidence intervals for the relative effect sizes to aid in interpreting the biological relevance of the results. Further, we discuss the use of a related all-pairwise comparisons contrast test with range preserving confidence intervals as an alternative to Kruskal-Wallis heterogeneity test. We applied the proposed maximum test to the Bogalusa Heart Study dataset, and gained a remarkable increase in the power to detect association, particularly for rare genotypes. Our simulation study also demonstrated that the proposed non-parametric tests control family-wise error rate in the presence of non-normality and variance heterogeneity contrary to the standard parametric approaches. We provide a publicly available R library nparcomp that can be used to estimate simultaneous confidence intervals or compatible multiplicity-adjusted p-values associated with the proposed maximum test.

Introduction: The aim of this study was to evaluate the cleaning efficacy of different irrigant agitation techniques on debris and smear layer removal in curved root canals., Methods: Mesiobuccal root canals of 108 mandibular molars were shaped with nickel-titanium instruments, and a final rinse of NaOCl and ethylenediaminetetraacetic acid was performed. Specimens were assigned to 4 groups (n = 20) and submitted to the following irrigation agitation techniques: no agitation (control), ultrasonic, EndoActivator, and CanalBrush. Root canals were split longitudinally and subjected to scanning electron microscopy. The presence of debris and smear layer at coronal and apical levels was evaluated by using a 5-grade scoring system with 200× and 1000× magnification, respectively., Results: Concerning debris removal, no significant differences among groups were detected. In the coronal region, agitation of the irrigants resulted in significantly more smear layer removal than the control. EndoActivator was significantly more effective than ultrasonic agitation and CanalBrush., Conclusions: In curved root canals, activation of NaOCl and ethylenediaminetetraacetic acid did not enhance debris removal but resulted in significantly more effective smear layer removal at coronal levels., (Copyright © 2010 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Aim: To assess time expenditure using the influence of computer-assisted detection (CAD) system in the interpretation of the dependence of early research and benign and malignant mammograms on readers' experience., Materials and Methods: CAD (Image Checker V2.3; R2 Technology, Los Altos, CA, USA) was prospectively applied on digital mammograms of 303 patients [early research (n=103), benign (n=102), and malignant group (n=98)]. Mammograms were analyzed by three readers with varying experience in evaluating mammograms (medical student, resident and attending) according to the BI-RADS classification. Time was stopped and recorded. All images were presented randomly with and without the influence of CAD and from the different patient groups. To evaluate the statistical significance, the corresponding P value for time to read the mammograms in addition to different patient groups, application of CAD, readers' experience, and interaction of reader was calculated., Results: The attending needs, independent of CAD application, the least time, followed by the medical assistant and the student. In all three patient groups, CAD adoption elongates reading time of the student and the resident. The medical specialist needs with and without CAD median the same time. In the early research group, no significant differences were registered (P=.1343). Concerning readers' experience, there is an explicit significant difference (P<.0001). The application of CAD correlates with the corresponding readers' experience and also provides a not significant result. In comparison, the P value for the malignant and benign groups shows significant interactions between the readers' experiences as well as CAD application., Conclusion: The future role of CAD application depends on whether sensitivity can be increased and time expenditure caused by false-positive marks can be decreased. In the future, second reading could be substituted by a CAD system if the reader has a wide professional experience., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Introduction: The aim of this study was to compare the efficiency of a sonic device (Vibringe), syringe irrigation, and passive ultrasonic irrigation in the removal of debris from simulated root canal irregularities., Methods: Root canals with 2 standardized grooves in the apical and coronal parts were filled with dentin debris. Three different irrigation procedures were performed with NaOCl (1%) and (1) syringe irrigation, (2) Vibringe, and (3) passive ultrasonic irrigation. The amount of remaining debris was evaluated by using a 4-grade scoring system., Results: Ultrasonic irrigation removed debris significantly better from the artificial canal irregularities than the Vibringe System and syringe irrigation (P < .0001). The Vibringe System demonstrated significantly better results than syringe irrigation in the apical part of the root canal (P = .011)., Conclusions: Passive ultrasonic irrigation is more effective than the Vibringe System or syringe irrigation in removing debris. The sonic device demonstrated significantly better results than syringe irrigation in the apical root canal third., (Copyright 2010 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the bond strength between two fiber posts (FRC Postec and DT Light Post) and different composite resins following different surface treatments of the posts., Materials and Methods: One hundred sixty extracted teeth were divided into sixteen groups (n = 10). After pretreatment of the post surface with (1) no treatment, (2) silanization, (3) sandblasting + silanization or (4) tribochemical coating, the posts were either luted with the resin cements provided by the manufacturers of the post system or with a core buildup material. Push-out tests were performed in a universal testing machine until the post segment was dislodged from the root section. Data were analyzed using ANOVA. Multiple comparisons were performed using Tukey's test., Results: FRC Postec achieved significantly higher bond strengths than DT Light Post (p < 0.0001). Cementation with the core buildup material showed significantly higher bond strengths than the resin cement provided by the post manufacturers (p < 0.0001)., Conclusion: Post type, type of surface treatment and type of resin cement were significant factors for bond strength. Luting with a core buildup material significantly increased the bond strengths.

The different forms of superficial and systemic candidiasis are often associated with biofilm formation on surfaces of host tissues or medical devices. The biofilm formation of Candida spp., in general, necessitates significantly increased amounts of antifungal agents for therapy. Often the therapeutic effect is doubtful. A 5-day biofilm model with oral Candida isolates was established according to Chandra et al. (J Dent Res 80:903-908, 2001) on glass and titanium surfaces and was modified by Sennhenn-Kirchner et al. (Z Zahnärztl Implantol 3:45-51, 2007) to investigate different aspects unanswered in the field of dentistry. In this model, the efficacy of erbium:yttrium-aluminium-garnet (Er:YAG) light (2940 nm, 100 mJ, 10 Hz, 300 micros pulsed mode applied for 80 s) and diode laser light (810 nm, 1 W, continuous wave mode applied for 20 s with four repetitions after 30 s pauses each) was evaluated and compared to untreated controls. The photometric evaluation of the samples was completed by observations on morphological changes of yeast cells grown in the biofilm. Compared to the untreated controls Candida cells grown in mature in vitro biofilms were significantly reduced by both wavelengths investigated. Comparison between the different methods of laser treatment additionally revealed a significantly greater effect of the Er:YAG over the diode laser. Scanning electron microscopy findings proved that the diode laser light was effective in direct contact mode. In contrast, in the areas without direct contact, the fungal cells were left almost unchanged. The Er:YAG laser damaged the fungal cells to a great extent wherever it was applied.