Asymptotic Variance Estimation for the Misclassification SIMEX

Most epidemiological studies suffer from misclassification in the response and/or the covariates. Since ignoring misclassification induces bias on the parameter estimates, correction for such errors is important. For measurement error, the continuous analog to misclassification, a general approach for bias correction is the SIMEX (simulation extrapolation) originally suggested by Cook and Stefanski (1994). This approach has been recently extended to regression models with a possibly misclassified categorical response and/or the covariates by Küchenhoff et al. (2005), and is called the MC-SIMEX approach. To assess the importance of a regressor not only its (corrected) estimate is needed, but also its standard error. For the original SIMEX approach. Carroll et al. (1996) developed a method for estimating the asymptotic variance. Here we derive the asymptotic variance estimators for the MC-SIMEX approach, extending the methodology of Carroll et al. (1996). We also include the case where the misclassification probabilities are estimated by a validation study. An extensive simulation study shows the good performance of our approach. The approach is illustrated using an example in caries research including a logistic regression model, where the response and a binary covariate are possibly misclassified

Konfokalmikroskopie an stabilen und metastabilen kolloidalen Hartkugel-Fluiden : interne Struktur, Kristallnukleation und Kristallwachstum

Die vorliegende Forschungsarbeit behandelt konfokalmikroskopische Untersuchungen zur Strukturbildung in kolloidalen Suspensionen, die als experimentelles Modellsystem für harte Kugeln verwendet werden. Die lokale und globale Struktur wurde im stabilen und metastabilen Fluid bestimmt. Bereits unterhalb des Gefriervolumenbruchs wurden nah-geordnete Cluster vorgefunden, die mit zunehmendem Volumenbruch häufiger und größer werden. Das Kristallwachstum aus der metastabilen kolloidalen Schmelze konnte quantitativ analysiert werden und es zeigt sich eine Übereinstimmung mehrerer Kenngrößen mit Literaturdaten nahe dem Schmelzvolumenbruch. Die Untersuchung demonstrierte die Realisierbarkeit der quantitativen Analyse der Kristallisationskinetik mittels konfokaler Mikroskopie. Es zeigte sich ein mehrstufiges Nukleationsszenario bei dem zuerst nah-geordnete Cluster gebildet werden, die im weiteren Verlauf zu kristall-artigen Clustern transformieren. Die Beobachtungen belegen den Mechanismus der Precursornukleation in Hartkugelsystemen. Die heterogene Nukleation wurde an glatten und an hexagonal strukturierten Substraten untersucht. Anhand der Kristallisationskinetik und der direkten Messung der Benetzungswinkel konnte ein Übergang des Benetzungsverhaltens unter Variation des Substratgitterabstands nachgewiesen werden: An glatten und an kommensurabel strukturierten Substraten zeigten sich eine vollständige Bedeckung des Substrats mit der kristallinen Phase und ein sofortiges unidirektionales Wachstum. Bei inkommensurabel strukturierten Substraten wurde eine unvollständige Bedeckung des strukturierten Substrats mit der kristallinen Phase sowie ein verzögertes isotropes Wachstum bei fortwährender Kristallnukleation beobachtet.This thesis deals with confocal microscopic investigations of the structure formation in colloidal suspensions that can be regarded as an experimental hard sphere model system. The local and global structure were measured in the stable and metastable fluid. Even below freezing volume fraction, near-ordered clusters were found that increase continuously in frequency and size. The crystallization kinetics from the metastable colloidal melt was analyzed in a quantitative way. Several properties coincide with literature data near melting volume fraction. The investigation demonstrated the feasibility of quantitative analysis of the crystallization kinetics by confocal microscopy. A multiple-step nucleation scenario was found, starting with the appearance of near-ordered clusters transforming into crystal-like clusters with time. The investigations support the precursor nucleation mechanism in hard sphere systems. Heterogeneous nucleation was investigated near smooth and near hexagonal structured substrates. The crystallization kinetics and direct observation of the wetting angles showed a wetting transition by varying the substrate’s lattice constant: Near smooth and near commensurate substrates a full wetting by the crystalline phase and an instantaneous and unidirectional growth was observed. At incommensurate substrates incomplete wetting by the crystalline phase and a delayed isotropic growth during ongoing crystal nucleation was found

Revealing Hidden Potentials of the q-Space Signal in Breast Cancer

Mammography screening for early detection of breast lesions currently suffers from high amounts of false positive findings, which result in unnecessary invasive biopsies. Diffusion-weighted MR images (DWI) can help to reduce many of these false-positive findings prior to biopsy. Current approaches estimate tissue properties by means of quantitative parameters taken from generative, biophysical models fit to the q-space encoded signal under certain assumptions regarding noise and spatial homogeneity. This process is prone to fitting instability and partial information loss due to model simplicity. We reveal unexplored potentials of the signal by integrating all data processing components into a convolutional neural network (CNN) architecture that is designed to propagate clinical target information down to the raw input images. This approach enables simultaneous and target-specific optimization of image normalization, signal exploitation, global representation learning and classification. Using a multicentric data set of 222 patients, we demonstrate that our approach significantly improves clinical decision making with respect to the current state of the art.Comment: Accepted conference paper at MICCAI 201

Reduction of CPR artifacts in the ventricular fibrillation ECG by coherent line removal

<p>Abstract</p> <p>Background</p> <p>Interruption of cardiopulmonary resuscitation (CPR) impairs the perfusion of the fibrillating heart, worsening the chance for successful defibrillation. Therefore ECG-analysis <it>during ongoing chest compression </it>could provide a considerable progress in comparison with standard analysis techniques working only during "hands-off" intervals.</p> <p>Methods</p> <p>For the reduction of CPR-related artifacts in ventricular fibrillation ECG we use a localized version of the <it>coherent line removal </it>algorithm developed by Sintes and Schutz. This method can be used for removal of periodic signals with sufficiently coupled harmonics, and can be adapted to specific situations by optimal choice of its parameters (e.g., the number of harmonics considered for analysis and reconstruction). Our testing was done with 14 different human ventricular fibrillation (VF) ECGs, whose fibrillation band lies in a frequency range of [1 Hz, 5 Hz]. The VF-ECGs were mixed with 12 different ECG-CPR-artifacts recorded in an animal experiment during asystole. The length of each of the ECG-data was chosen to be 20 sec, and testing was done for all 168 = 14 × 12 pairs of data. VF-to-CPR ratio was chosen as -20 dB, -15 dB, -10 dB, -5 dB, 0 dB, 5 dB and 10 dB. Here -20 dB corresponds to the highest level of CPR-artifacts.</p> <p>Results</p> <p>For non-optimized <it>coherent line removal </it>based on signals with a VF-to-CPR ratio of -20 dB, -15 dB, -10 dB, -5 dB and 0 dB, the signal-to-noise gains (SNR-gains) were 9.3 ± 2.4 dB, 9.4 ± 2.4 dB, 9.5 ± 2.5 dB, 9.3 ± 2.5 dB and 8.0 ± 2.7 (mean ± std, <it>n </it>= 168), respectively. Characteristically, an original VF-to-CPR ratio of -10 dB, corresponds to a variance ratio <it>var</it>(VF):<it>var</it>(CPR) = 1:10. An improvement by 9.5 dB results in a restored VF-to-CPR ratio of -0.5 dB, corresponding to a variance ratio <it>var</it>(VF):<it>var</it>(CPR) = 1:1.1, the variance of the CPR in the signal being reduced by a factor of 8.9.</p> <p>Discussion</p> <p>The <it>localized coherent line removal </it>algorithm uses the information of a single ECG channel. In contrast to multi-channel algorithms, no additional information such as thorax impedance, blood pressure, or pressure exerted on the sternum during CPR is required. Predictors of defibrillation success such as mean and median frequency of VF-ECGs containing CPR-artifacts are prone to being governed by the harmonics of the artifacts. Reduction of CPR-artifacts is therefore necessary for determining reliable values for estimators of defibrillation success.</p> <p>Conclusions</p> <p>The <it>localized coherent line removal </it>algorithm reduces CPR-artifacts in VF-ECG, but does not eliminate them. Our SNR-improvements are in the same range as offered by multichannel methods of Rheinberger et al., Husoy et al. and Aase et al. The latter two authors dealt with different ventricular rhythms (VF and VT), whereas here we dealt with VF, only. Additional developments are necessary before the algorithm can be tested in real CPR situations.</p

Monitoring of selected skin- and breath-borne volatile organic compounds emitted from the human body using gas chromatography ion mobility spectrometry (GC-IMS)

ISSN:1873-376XISSN:1570-0232ISSN:1572-6495ISSN:1387-227

Association between Blood Glucose and cardiac Rhythms during pre-hospital care of Trauma Patients - a retrospective Analysis

Abstract Background Deranged glucose metabolism is frequently observed in trauma patients after moderate to severe traumatic injury, but little data is available about pre-hospital blood glucose and its association with various cardiac rhythms and cardiac arrest following trauma. Methods We retrospectively investigated adult trauma patients treated by a nationwide helicopter emergency medical service (34 bases) between 2005 and 2013. All patients with recorded initial cardiac rhythms and blood glucose levels were enrolled. Blood glucose concentrations were categorised; descriptive and regression analyses were performed. Results In total, 18,879 patients were included, of whom 185 (1.0%) patients died on scene. Patients with tachycardia (≥100/min, 7.0 ± 2.4 mmol/L p  10.0 mmol/L, 70/1271; 5.5%, p  10 mmol/L; 47/69; 68.1%) than in hypoglycaemic (≤4.2 mmol/L; 13/31; 41.9%) trauma patients (p = 0.01). Conclusions In adult trauma patients, pre-hospital higher blood glucose levels were related to tachycardic and shockable rhythms. Cardiac arrest was more frequently observed in hypoglycaemic and hyperglycaemic pre-hospital trauma patients. The rate of ROSC rose significantly with rising blood glucose concentration. Blood glucose measurements in addition to common vital parameters (GCS, heart rate, blood pressure, breathing frequency) may help identify patients at risk for cardiopulmonary arrest and dysrhythmias

Influence of residual fat signal on diffusion kurtosis MRI of suspicious mammography findings

Abstract Recent studies showed the potential of diffusion kurtosis imaging (DKI) as a tool for improved classification of suspicious breast lesions. However, in diffusion-weighted imaging of the female breast, sufficient fat suppression is one of the main factors determining the success. In this study, the data of 198 patients examined in two study centres was analysed using standard diffusion and kurtosis evaluation methods and three DKI fitting approaches accounting phenomenologically for fat-related signal contamination of the lesions. Receiver operating characteristic curve analysis showed the highest area under the curve (AUC) for the method including fat correction terms (AUC = 0.85, p < 0.015) in comparison to the values obtained with the standard diffusion (AUC = 0.77) and kurtosis approach (AUC = 0.79). Comparing the two study centres, the AUC value improved from 0.77 to 0.86 (p = 0.036) using a fat correction term for the first centre, while no significant difference with no adverse effects was observed for the second centre (AUC 0.89 vs. 0.90, p = 0.95). Contamination of the signal in breast lesions with unsuppressed fat causing a reduction of diagnostic performance of diffusion kurtosis imaging may potentially be counteracted by proposed adapted evaluation methods

A practical and robust zwitterionic cooperative Lewis acid/acetate/benzimidazolium catalyst for direct 1,4‐additions

A catalyst type is disclosed allowing for exceptional efficiency in direct 1,4‐additions. The catalyst is a zwitterionic entity, in which acetate binds to CuII, which is formally negatively charged and serving as counterion for benzimidazolium. All 3 functionalities are involved in the catalytic activation. For maleimides productivity was increased by a factor >300 compared to literature (TONs up to 6700). High stereoselectivity and productivity was attained for a broad range of other Michael acceptors as well. The polyfunctional catalyst is accessible in only 4 steps from N‐Ph‐benzimidazole with an overall yield of 96 % and robust during catalysis. This allowed to reuse the same catalyst multiple times with nearly constant efficiency. Mechanistic studies, in particular by DFT, give a detailed picture how the catalyst operates. The benzimidazolium unit stabilizes the coordinated enolate nucleophile and prevents that acetate/acetic acid dissociate from the catalyst.Deutsche ForschungsgemeinschaftState of Baden WürttembergStudienstiftung des Deutschen VolkesDeutschland StipendiumProjekt DEA

Superconducting undulator activities at the European X-ray Free-Electron Laser Facility

For more than 5 years, superconducting undulators (SCUs) have been successfully delivering X-rays in storage rings. The European X-Ray Free-Electron Laser Facility (XFEL) plans to demonstrate the operation of SCUs in X-ray free-electron lasers (FELs). For the same geometry, SCUs can reach a higher peak field on the axis with respect to all other available technologies, offering a larger photon energy tunability range. The application of short-period SCUs in a high electron beam energy FEL > 11 GeV will enable lasing at very hard X-rays > 40 keV. The large tunability range of SCUs will allow covering the complete photon energy range of the soft X-ray experiments at the European XFEL without changing electron beam energy, as currently needed with the installed permanent magnet undulators. For a possible continuous-wave (CW) upgrade under discussion at the European XFEL with a lower electron beam energy of approximately 7–8 GeV, SCUs can provide the same photon energy range as available at present with the permanent magnet undulators and electron energies. This paper will describe the potential of SCUs for X-ray FELs. In particular, it will focus on the different activities ongoing at the European XFEL and in collaboration with DESY to allow the implementation of SCUs in the European XFEL in the upcoming years

A protein functional leap: how a single mutation reverses the function of the transcription regulator TetR

Today's proteome is the result of innumerous gene duplication, mutagenesis, drift and selection processes. Whereas random mutagenesis introduces predominantly only gradual changes in protein function, a case can be made that an abrupt switch in function caused by single amino acid substitutions will not only considerably further evolution but might constitute a prerequisite for the appearance of novel functionalities for which no promiscuous protein intermediates can be envisaged. Recently, tetracycline repressor (TetR) variants were identified in which binding of tetracycline triggers the repressor to associate with and not to dissociate from the operator DNA as in wild-type TetR. We investigated the origin of this activity reversal by limited proteolysis, CD spectroscopy and X-ray crystallography. We show that the TetR mutant Leu17Gly switches its function via a disorder–order mechanism that differs completely from the allosteric mechanism of wild-type TetR. Our study emphasizes how single point mutations can engender unexpected leaps in protein function thus enabling the appearance of new functionalities in proteins without the need for promiscuous intermediates