Estimating Multiple Tumor Transition Rates Based on Data from Survival/Sacrifice Experiments

In this paper, we focus on the model for two types of tumors. Tumor development can be described by four types of death rates and four tumor transition rates. We present a general semi-parametric model to estimate the tumor transition rates based on data from survival/sacrifice experiments. In the model, we make a proportional assumption of tumor transition rates on a common parametric function but no assumption of the death rates from any states. We derived the likelihood function of the data observed in such an experiment, and an EM algorithm that simplified estimating procedures. This article extends work on semi-parametric models for one type of tumor (see Portier and Dinse and Dinse) to two types of tumors.

The discovery of new 11beta-hydroxysteroid dehydrogenase type 1 inhibitors by common feature pharmacophore modeling and virtual screening

11beta-Hydroxysteroid dehydrogenase (11beta-HSD) enzymes catalyze the conversion of biologically inactive 11-ketosteroids into their active 11beta-hydroxy derivatives and vice versa. Inhibition of 11beta-HSD1 has considerable therapeutic potential for glucocorticoid-associated diseases including obesity, diabetes, wound healing, and muscle atrophy. Because inhibition of related enzymes such as 11beta-HSD2 and 17beta-HSDs causes sodium retention and hypertension or interferes with sex steroid hormone metabolism, respectively, highly selective 11beta-HSD1 inhibitors are required for successful therapy. Here, we employed the software package Catalyst to develop ligand-based multifeature pharmacophore models for 11beta-HSD1 inhibitors. Virtual screening experiments and subsequent in vitro evaluation of promising hits revealed several selective inhibitors. Efficient inhibition of recombinant human 11beta-HSD1 in intact transfected cells as well as endogenous enzyme in mouse 3T3-L1 adipocytes and C2C12 myotubes was demonstrated for compound 27, which was able to block subsequent cortisol-dependent activation of glucocorticoid receptors with only minor direct effects on the receptor itself. Our results suggest that inhibitor-based pharmacophore models for 11beta-HSD1 in combination with suitable cell-based activity assays, including such for related enzymes, can be used for the identification of selective and potent inhibitors.

Semiparametric Methods for Semi-competing Risks Problem with Censoring and Truncation

Studies of chronic life-threatening diseases often involve both mortality and morbidity. In observational studies, the data may also be subject to administrative left truncation and right censoring. Since mortality and morbidity may be correlated and mortality may censor morbidity, the Lynden-Bell estimator for left truncated and right censored data may be biased for estimating the marginal survival function of the non-terminal event. We propose a semiparametric estimator for this survival function based on a joint model for the two time-to-event variables, which utilizes the gamma frailty specification in the region of the observable data. Firstly, we develop a novel estimator for the gamma frailty parameter under left truncation. Using this estimator, we then derive a closed form estimator for the marginal distribution of the non-terminal event. The large sample properties of the estimators are established via asymptotic theory. The methodology performs well with moderate sample sizes, both in simulations and in an analysis of data from a diabetes registry.

Model Evaluation Based on the Distribution of Estimated Absolute Prediction Error

The construction of a reliable, practically useful prediction rule for future response is heavily dependent on the "adequacy" of the fitted regression model. In this article, we consider the absolute prediction error, the expected value of the absolute difference between the future and predicted responses, as the model evaluation criterion. This prediction error is easier to interpret than the average squared error and is equivalent to the mis-classification error for the binary outcome. We show that the distributions of the apparent error and its cross-validation counterparts are approximately normal even under a misspecified fitted model. When the prediction rule is "unsmooth", the variance of the above normal distribution can be estimated well via a perturbation-resampling method. We also show how to approximate the distribution of the difference of the estimated prediction errors from two competing models. With two real examples, we demonstrate that the resulting interval estimates for prediction errors provide much more information about model adequacy than the point estimates alone.

A unified approach to modeling multivariate binary data using copulas over partitions

Many seemingly disparate approaches for marginal modeling have been developed in recent years. We demonstrate that many current approaches for marginal modeling of correlated binary outcomes produce likelihoods that are equivalent to the proposed copula-based models herein. These general copula models of underlying latent threshold random variables yield likelihood based models for marginal fixed effects estimation and interpretation in the analysis of correlated binary data. Moreover, we propose a nomenclature and set of model relationships that substantially elucidates the complex area of marginalized models for binary data. A diverse collection of didactic mathematical and numerical examples are given to illustrate concepts.

Shear band evolution in Zr/Hf-based bulk metallic glasses under static and dynamic indentations

Bulk metallic glasses (BMGs) exhibit superior mechanical properties as compared with other conventional materials and have been proposed for numerous engineering and technological applications. Zr/Hf-based BMGs or tungsten reinforced BMG composites are considered as a potential replacement for depleted uranium armor-piercing projectiles because of their ability to form localized shear bands during impact, which has been known to be the dominant plastic deformation mechanism in BMGs. However, in conventional tensile, compressive and bending tests, limited ductility has been observed because of fracture initiation immediately following the shear band formation. To fully investigate shear band characteristics, indentation tests that can confine the deformation in a limited region have been pursued. In this thesis, a detailed investigation of thermal stability and mechanical deformation behavior of Zr/Hf-based BMGs is conducted. First, systematic studies had been implemented to understand the influence of relative compositions of Zr and Hf on thermal stability and mechanical property evolution. Second, shear band evolution under indentations were investigated experimentally and theoretically. Three kinds of indentation studies were conducted on BMGs in the current study. (a) Nano-indentation to determine the mechanical properties as a function of Hf/Zr content. (b) Static Vickers indentation on bonded split specimens to investigate the shear band evolution characteristics beneath the indention. (c) Dynamic Vickers indentation on bonded split specimens to investigate the influence of strain rate. It was found in the present work that gradually replacing Zr by Hf remarkably increases the density and improves the mechanical properties. However, a slight decrease in glass forming ability with increasing Hf content has also been identified through thermodynamic analysis although all the materials in the current study were still found to be amorphous. Many indentation studies have revealed only a few shear bands surrounding the indent on the top surface of the specimen. This small number of shear bands cannot account for the large plastic deformation beneath the indentations. Therefore, a bonded interface technique has been used to observe the slip-steps due to shear band evolution. Vickers indentations were performed along the interface of the bonded split specimen at increasing loads. At small indentation loads, the plastic deformation was primarily accommodated by semi-circular primary shear bands surrounding the indentation. At higher loads, secondary and tertiary shear bands were formed inside this plastic zone. A modified expanding cavity model was then used to predict the plastic zone size characterized by the shear bands and to identify the stress components responsible for the evolution of the various types of shear bands. The applicability of various hardness—yield-strength ( H −σγ ) relationships currently available in the literature for bulk metallic glasses (BMGs) is also investigated. Experimental data generated on ZrHf-based BMGs in the current study and those available elsewhere on other BMG compositions were used to validate the models. A modified expanding-cavity model, employed in earlier work, was extended to propose a new H −σγ relationship. Unlike previous models, the proposed model takes into account not only the indenter geometry and the material properties, but also the pressure sensitivity index of the BMGs. The influence of various model parameters is systematically analyzed. It is shown that there is a good correlation between the model predictions and the experimental data for a wide range of BMG compositions. Under dynamic Vickers indentation, a decrease in indentation hardness at high loading rate was observed compared to static indentation hardness. It was observed that at equivalent loads, dynamic indentations produced more severe deformation features on the loading surface than static indentations. Different from static indentation, two sets of widely spaced semi-circular shear bands with two different curvatures were observed. The observed shear band pattern and the strain rate softening in indentation hardness were rationalized based on the variations in the normal stress on the slip plane, the strain rate of shear and the temperature rise associated with the indentation deformation. Finally, a coupled thermo-mechanical model is proposed that utilizes a momentum diffusion mechanism for the growth and evolution of the final spacing of shear bands. The influence of strain rate, confinement pressure and critical shear displacement on the shear band spacing, temperature rise within the shear band, and the associated variation in flow stress have been captured and analyzed. Consistent with the known pressure sensitive behavior of BMGs, the current model clearly captures the influence of the normal stress in the formation of shear bands. The normal stress not only reduces the time to reach critical shear displacement but also causes a significant temperature rise during the shear band formation. Based on this observation, the variation of shear band spacing in a typical dynamic indentation test has been rationalized. The temperature rise within a shear band can be in excess of 2000K at high strain rate and high confinement pressure conditions. The associated drop in viscosity and flow stress may explain the observed decrease in fracture strength and indentation hardness. The above investigations provide valuable insight into the deformation behavior of BMGs under static and dynamic loading conditions. The shear band patterns observed in the above indentation studies can be helpful to understand and model the deformation features under complex loading scenarios such as the interaction of a penetrator with armor. Future work encompasses (1) extending and modifying the coupled thermo-mechanical model to account for the temperature rise in quasistatic deformation; and (2) expanding this model to account for the microstructural variation-crystallization and free volume migration associated with the deformation.

Model based experimental investigation on Powered Gait Orthosis (PGO)

Research on rehabilitation showed that appropriate and repetitive mechanical movements can help spinal cord injured individuals to restore their functional standing and walking. The objective of this paper was to achieve appropriate and repetitive joint movements and approximately normal gait through the PGO by replicating normal walking, and to minimize the energy consumption for both patients and the device. A model based experimental investigative approach is presented in this dissertation. First, a human model was created in Ideas and human walking was simulated in Adams. The main feature of this model was the foot ground contact model, which had distributed contact points along the foot and varied viscoelasticity. The model was validated by comparison of simulated results of normal walking and measured ones from the literature. It was used to simulate current PGO walking to investigate the real causes of poor function of the current PGO, even though it had joint movements close to normal walking. The direct cause was one leg moving at a time, which resulted in short step length and no clearance after toe off. It can not be solved by simply adding power on both hip joints. In order to find a better answer, a PGO mechanism model was used to investigate different walking mechanisms by locking or releasing some joints. A trade-off between energy consumption, control complexity and standing position was found. Finally a foot release PGO virtual model was created and simulated and only foot release mechanism was developed into a prototype. Both the release mechanism and the design of foot release were validated through the experiment by adding the foot release on the current PGO. This demonstrated an advancement in improving functional aspects of the current PGO even without a whole physical model of foot release PGO for comparison.

Prevalence of bone attrition on knee radiographs and MRI in a community-based cohort

OBJECTIVES: Bone attrition probably constitutes remodeling of the bone, resulting in flattening or depression of the articular surfaces. Defining bone attrition is challenging because it is an accentuation of the normal curvature of the tibial plateaus. We aimed to define bone attrition on magnetic resonance imaging (MRI) of the knee using information from both radiographs and MRIs, and to assess whether bone attrition is common prior to end stage disease osteoarthritis (OA) in the tibio-femoral joint. METHODS: All knees of participants in the community-based sample of the Framingham OA Study were evaluated for bone attrition in radiographs and MRIs. Radiographs were scored based on templates designed to outline the normal contours of the tibio-femoral joint. MRIs were analyzed using the semi-quantitative Whole-Organ Magnetic Resonance Imaging Scoring (WORMS) method. The prevalence of bone attrition was calculated using two different thresholds for MRI scores. RESULTS: Inter-observer agreement for identification of bone attrition was substantial for the radiographs (kappa=0.71, 95% CI 0.67-0.81) and moderate for MRI (kappa=0.56, 95% CI 0.40-0.72). Of 964 knees, 5.7% of the radiographs showed bone attrition. Of these, 91% of MRIs were also read as showing bone attrition. We selected a conservative threshold for bone attrition on MRI scoring (> or = 2 on a 0-3 scale) based on agreement with attrition on the radiograph or when bone attrition on MRI co-occurred with cartilage loss on OA. Using this threshold for bone attrition on MRI, bone attrition was common in knees with OA. For example, in knees with mild OA but no joint space narrowing, 13 of 88 MRIs (14.8%) showed bone attrition. CONCLUSIONS: Using MRI we found that many knees with mild OA without joint narrowing on radiographs had bone attrition, even using conservative definitions. The validity of our definition of bone attrition should be evaluated in further studies. Bone attrition may occur in milder OA and at earlier stages of disease than previously thought.

Accelerometer based measurements of combustion in an automotive turbocharged diesel engine

The capability to detect combustion in a diesel engine has the potential of being an important control feature to meet increasingly stringent emission regulations, develop alternative combustion strategies, and use of biofuels. In this dissertation, block mounted accelerometers were investigated as potential feedback sensors for detecting combustion characteristics in a high-speed, high pressure common rail (HPCR), 1.9L diesel engine. Accelerometers were positioned in multiple placements and orientations on the engine, and engine testing was conducted under motored, single and pilot-main injection conditions. Engine tests were conducted at varying injection timings, engine loads, and engine speeds to observe the resulting time and frequency domain changes of the cylinder pressure and accelerometer signals. The frequency content of the cylinder pressure based signals and the accelerometer signals between 0.5 kHz and 6 kHz indicated a strong correlation with coherence values of nearly 1. The accelerometers were used to produce estimated combustion signals using the Frequency Response Functions (FRF) measured from the frequency domain characteristics of the cylinder pressure signals and the response of the accelerometers attached to the engine block. When compared to the actual combustion signals, the estimated combustion signals produced from the accelerometer response had Root Mean Square Errors (RMSE) between 7% and 25% of the actual signals peak value. Weighting the FRF’s from multiple test conditions along their frequency axis with the coherent output power reduced the median RMSE of the estimated combustion signals and the 95th percentile of RMSE produced from each test condition. The RMSE’s of the magnitude based combustion metrics including peak cylinder pressure, MPG, peak ROHR, and work estimated from the combustion signals produced by the accelerometer responses were between 15% and 50% of their actual value. The MPG measured from the estimated pressure gradient shared a direct relationship to the actual MPG. The location based combustion metrics such as the location of peak values and burn durations were capable of RMSE measurements as low as 0.9°. Overall, accelerometer based combustion sensing system was capable of detecting combustion and providing feedback regarding the in cylinder combustion process

Structural model of the CopA copper ATPase of Enterococcus hirae based on chemical cross-linking

The CopA copper ATPase of Enterococcus hirae belongs to the family of heavy metal pumping CPx-type ATPases and shares 43% sequence similarity with the human Menkes and Wilson copper ATPases. Due to a lack of suitable protein crystals, only partial three-dimensional structures have so far been obtained for this family of ion pumps. We present a structural model of CopA derived by combining topological information obtained by intramolecular cross-linking with molecular modeling. Purified CopA was cross-linked with different bivalent reagents, followed by tryptic digestion and identification of cross-linked peptides by mass spectrometry. The structural proximity of tryptic fragments provided information about the structural arrangement of the hydrophilic protein domains, which was integrated into a three-dimensional model of CopA. Comparative modeling of CopA was guided by the sequence similarity to the calcium ATPase of the sarcoplasmic reticulum, Serca1, for which detailed structures are available. In addition, known partial structures of CPx-ATPase homologous to CopA were used as modeling templates. A docking approach was used to predict the orientation of the heavy metal binding domain of CopA relative to the core structure, which was verified by distance constraints derived from cross-links. The overall structural model of CopA resembles the Serca1 structure, but reveals distinctive features of CPx-type ATPases. A prominent feature is the positioning of the heavy metal binding domain. It features an orientation of the Cu binding ligands which is appropriate for the interaction with Cu-loaded metallochaperones in solution. Moreover, a novel model of the architecture of the intramembranous Cu binding sites could be derived.

High-resolution summer temperature reconstruction from Lake Silvaplana based on in-situ reflectance spectroscopy

Annually laminated (varved) sediments of proglacial Lake Silvaplana (46 ̊27’N, 9 ̊48’E, 1791 m a.s.l., Engadine, eastern Swiss Alps) provide an excellent archive for quantitative high-resolution (seasonal – annual) reconstruction of high- and lowfrequency climate signals back to AD 1580. The chronology of the core is based on varve counting, Cs-137, Pb-210 and event stratigraphy. In this study we present a reconstruction based on in-situ reflectance spectroscopy. In situ reflectance spectroscopy is known as a cost- and time-effective non destructtive method for semi-quantitative analysis of pigments (e.g., chlorines and carotenoids) and of lithoclastic sediment fractions. Reflectance-dependent absorption (RDA) was measured with a Gretac Macbeth spectrolino at 2 mm resolution. The spectral coverage ranges from 380 nm to 730 nm at 10 nm band resolution. In proglacial Lake Silvaplana, 99% of the sediment is lithoclastic prior to AD 1950. Therefore, we concentrate on absorption features that are characteristic for lithoclastic sediment fractions. In Lake Silvaplana, two significant correlations that are stable in time were found between RDA typical for lithoclastics and meteorological data: (1) the time series R 570 /R 630 (ratio between RDA at 570 nm and 630 nm) of varves in Lake Silvaplana and May to October temperatures at nearby station of Sils correlate highly significantly (calibration period AD 1864 – 1951, r = 0.74, p < 0.01 for 5ptsmoothed series; RMSE is 0.28 ̊C, RE = 0.41 and CE = 0.38), and (2) the minimum reflectance within the 690nm band (min690) data correlate with May to October (calibration period AD 1864 – 1951, r = 0.68, p < 0.01 for 5pt-smoothed series; RMSE = 0.22 ̊C, RE = 0.5, CE = 0.31). Both proxy series (min690nm and R 570 /R 630 values) are internally highly consistent (r = 0.8, p < 0.001). In proglacial Lake Silvaplana the largest amount of sediment is transported by glacial meltwater. The melting season spans approximately from May to October, which gives us a good understanding of the geophysical processes explaining the correlations between lithoclastic proxies and the meteorological data. The reconstructions were extended back to AD 1580 and show a broad corresponddence with fully independent reconstructions from tree rings and documentary data.

Differential diagnosis of CT focal liver lesions using texture features, feature selection and ensemble driven classifiers

The aim of the present study is to define an optimally performing computer-aided diagnosis (CAD) architecture for the classification of liver tissue from non-enhanced computed tomography (CT) images into normal liver (C1), hepatic cyst (C2), hemangioma (C3), and hepatocellular carcinoma (C4). To this end, various CAD architectures, based on texture features and ensembles of classifiers (ECs), are comparatively assessed.

Computer-aided diagnosis of carotid atherosclerosis based on ultrasound image statistics, laws' texture and neural networks

Quantitative characterisation of carotid atherosclerosis and classification into symptomatic or asymptomatic is crucial in planning optimal treatment of atheromatous plaque. The computer-aided diagnosis (CAD) system described in this paper can analyse ultrasound (US) images of carotid artery and classify them into symptomatic or asymptomatic based on their echogenicity characteristics. The CAD system consists of three modules: a) the feature extraction module, where first-order statistical (FOS) features and Laws' texture energy can be estimated, b) the dimensionality reduction module, where the number of features can be reduced using analysis of variance (ANOVA), and c) the classifier module consisting of a neural network (NN) trained by a novel hybrid method based on genetic algorithms (GAs) along with the back propagation algorithm. The hybrid method is able to select the most robust features, to adjust automatically the NN architecture and to optimise the classification performance. The performance is measured by the accuracy, sensitivity, specificity and the area under the receiver-operating characteristic (ROC) curve. The CAD design and development is based on images from 54 symptomatic and 54 asymptomatic plaques. This study demonstrates the ability of a CAD system based on US image analysis and a hybrid trained NN to identify atheromatous plaques at high risk of stroke.

How to Improve the Production Process for interactive TV with semi-formal Methods

The central question for this paper is how to improve the production process by closing the gap between industrial designers and software engineers of television(TV)-based User Interfaces (UI) in an industrial environment. Software engineers are highly interested whether one UI design can be converted into several fully functional UIs for TV products with different screen properties. The aim of the software engineers is to apply automatic layout and scaling in order to speed up and improve the production process. However, the question is whether a UI design lends itself for such automatic layout and scaling. This is investigated by analysing a prototype UI design done by industrial designers. In a first requirements study, industrial designers had created meta-annotations on top of their UI design in order to disclose their design rationale for discussions with software engineers. In a second study, five (out of ten) industrial designers assessed the potential of four different meta-annotation approaches. The question was which annotation method industrial designers would prefer and whether it could satisfy the technical requirements of the software engineering process. One main result is that the industrial designers preferred the method they were already familiar with, which therefore seems to be the most effective one although the main objective of automatic layout and scaling could still not be achieved.

Performance Availability and Anticipatory Change Planning of Intralogistics Systems: A Simulation-Based Approach

In recent years, the ability to respond to real time changes in operations and reconfigurability in equipment are likely to become essential characteristics for next generation intralogistics systems as well as the level of automation, cost effectiveness and maximum throughput. In order to cope with turbulences and the increasing level of dynamic conditions, future intralogistics systems have to feature short reaction times, high flexibility in processes and the ability to adapt to frequent changes. The increasing autonomy and complexity in processes of today’s intralogistics systems requires new and innovative management approaches, which allow a fast response to (un)anticipated events and adaptation to changing environment in order to reduce the negative consequences of these events. The ability of a system to respond effectively a disruption depends more on the decisions taken before the event than those taken during or after. In this context, anticipatory change planning can be a usable approach for managers to make contingency plans for intralogistics systems to deal with the rapidly changing marketplace. This paper proposes a simulation-based decision making framework for the anticipatory change planning of intralogistics systems. This approach includes the quantitative assessments based on the simulation in defined scenarios as well as the analysis of performance availability that combines the flexibility corridors of different performance dimensions. The implementation of the approach is illustrated on a new intralogistics technology called the Cellular Transport System.