bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of triple quadrupole, hybrid linear ion trap triple quadrupole, time‐of‐flight and LTQ‐Orbitrap mass spectrometers in drug discovery phase metabolite screening and identification in vitro – amitriptyline and verapamil as model compounds
Authors: Rousu Timo , Herttuainen Jukka , Tolonen Ari
Published: March 2010

Liquid chromatography in combination with mass spectrometry (LC/MS) is a superior analytical technique for metabolite profiling and identification studies performed in drug discovery and development laboratories. In the early phase of drug discovery the analytical approach should be both time‐ and cost‐effective, thus providing as much data as possible with only one visit to the laboratory, without the need for further experiments. Recent developments in mass spectrometers have created a situation where many different mass spectrometers are available for the task, each with their specific strengths and drawbacks. We compared the metabolite screening properties of four main types of mass spectrometers used in analytical laboratories, considering both the ability to detect the metabolites and provide structural information, as well as the issues related to time consumption in laboratory and thereafter in data processing. Human liver microsomal incubations with amitriptyline and verapamil were used as test samples, and early‐phase ‘one lab visit only’ approaches were used with all instruments. In total, 28 amitriptyline and 69 verapamil metabolites were found and tentatively identified. Time‐of‐flight mass spectrometry (TOFMS) was the only approach detecting all of them, shown to be the most suitable instrument for elucidating as comprehensive metabolite profile as possible leading also to lowest overall time consumption together with the LTQ‐Orbitrap approach. The latter however suffered from lower detection sensitivity and false negatives, and due to slow data acquisition rate required slower chromatography. Approaches with triple quadrupole mass spectrometry (QqQ) and hybrid linear ion trap triple quadrupole mass spectrometry (Q‐Trap) provided the highest amount of fragment ion data for structural elucidation, but, in addition to being unable to produce very high‐important accurate mass data, they suffered from many false negatives, and especially with the QqQ, from very high overall time consumption. Copyright © 2010 John Wiley & Sons, Ltd.
The natural abundance of 15N in plant and soil‐available N indicates a shift of main plant N resources to NO from NH along the N leaching gradient
Authors: Takebayashi Yu , Koba Keisuke , Sasaki Yuji , Fang Yunting , Yoh Muneoki
Published: March 2010

To investigate which of ammonium (NH) or nitrate (NO) is used by plants at gradient sites with different nitrogen (N) availability, we measured the natural abundance of 15N in foliage and soil extractable N. Hinoki cypress (Chamaecyparis obtusa Endlicher) planted broadly in Japan was selected for use in this study. We estimated the source proportion of foliar N (NH vs. NO) quantitatively using mass balance equations. The results showed that C. obtusa used mainly NH in N‐limited forests, although the dependence of C. obtusa on NO was greater in other NO‐rich forests. We regarded dissolved organic N (DON) as a potential N source because a previous study demonstrated that C. obtusa can take up glycine. Thus we added DON to our mass balance equations and calculated the source proportion using an isotope‐mixing model (IsoSource model). The results still showed a positive correlation between the calculated plant N proportion of NO and the NO pool size in the soil, indicating that high NO availability increases the reliance of C. obtusa on NO. Our data suggest the shift of the N source for C. obtusa from NH to NO according to the relative availability of NO. They also show the potential of the foliar δ15N of C. obtusa as an indicator of the N status in forest ecosystems with the help of the δ15N values of soil inorganic and organic N. Copyright © 2010 John Wiley & Sons, Ltd.
Mapping site‐specific protein N‐glycosylations through liquid chromatography/mass spectrometry and targeted tandem mass spectrometry
Authors: Wu Yin , Mechref Yehia , Klouckova Iveta , Mayampurath Anoop , Novotny Milos V. , Tang Haixu
Published: March 2010

Glycosylation is one of the most common posttranslational modifications (PTMs) of proteins, the characterization of which is commonly achieved through proteomic protocol, involving trypsin digestion followed by liquid chromatography/tandem mass spectrometry (LC/MS/MS). However, it is often not possible to characterize all glycopeptides in a complex sample because of the high complexity of glycoproteomic samples, and the relative lower abundances of glycopeptides in comparison to the unmodified peptides. We present here a targeted MS/MS analysis approach, which utilizes a previously developed computational tool, GlyPID, to guide multiple experiments, thus permitting a complete characterization of all N‐glycosylation sites of glycoproteins present in a complex sample. We have tested our approach using model glycoproteins analyzed by high‐resolution LTQ‐FT MS. The results demonstrate a potential use of our method for a high‐throughput characterization of complex mixtures of glycosylated proteins. Copyright © 2010 John Wiley & Sons, Ltd.
Formation of unexpected ions from a first‐generation polyamidoamine dendrimer by use of methanol: an artefact due to electrospray emitter corrosion?
Authors: Maire Florian , Lange Catherine M.
Published: March 2010

We report the formation of unexpected ions during the analyses of a first‐generation polyamidoamine dendrimer in negative ion mode using an ion trap equipped with an electrospray ionisation source. These surprising ions corresponded to an increase of 12 m/z units over those expected. The formation of the unexpected ions was dependent on the tuning of the solution flow rate and the capillary high voltage. In addition, measurements of unusual value of the current suggested that a reaction was occurring in the corona plasma. The influence of methanol in this phenomenon was demonstrated by using CD3OH in the sample preparation. We propose two structures to explain the observed adduct based on the results of MS2 experiments and by referring to previous work dealing with 12 m/z units addition. We showed that a corona discharge caused by alterations taking place to the electrospray capillary emitter was the origin of these unexpected ions. Finally, we discuss the mechanism involved in the formation of the ions and we propose means to control such artefacts. Copyright © 2010 John Wiley & Sons, Ltd.
Data‐independent liquid chromatography/mass spectrometry (LC/MSE) detection and quantification of the secreted Apium graveolens pathogen defense protein mannitol dehydrogenase
Authors: Blackburn Kevin , Cheng Fang‐yi , Williamson John D. , Goshe Michael B.
Published: March 2010

Plant cells secrete a wide variety of defense‐related proteins into the extracellular space or apoplast in response to pathogen attack. One of these, mannitol dehydrogenase (MTD), is normally a cytoplasmic enzyme whose primary role is the regulation of intracellular levels of the sugar alcohol mannitol in plants. Recent immunological and biochemical evidence, however, suggests that MTD is also secreted into the apoplast in response to pathogen attack, despite lacking a known peptide signal sequence for Golgi‐mediated secretion. Because many plant pathogenic fungi secrete mannitol to overcome pathogen‐induced generation of reactive oxygen species (ROS) by the plant, extracellular localization of MTD is hypothesized to have a defensive role of catabolizing pathogen‐secreted mannitol. In the current study, LC/MSE was used to analyze proteins in the secretome of Apium graveolens (celery) following treatment with salicylic acid (SA), an endogenous elicitor of defense responses in plants. Levels of MTD in the secretome of SA‐treated celery cell cultures were found to be induced at least 18‐fold over secretome samples from cell cultures not exposed to SA. This value is in close agreement with published immunological and biochemical observations. Overall, this report provides the first mass spectrometry identification and quantification measurements supporting the hypothesis that MTD is secreted in response to simulated pathogen attack via a non‐classical secretion mechanism. As demonstrated with MTD secretion, LC/MSE can be implemented as a discovery‐driven MRM‐based quantitative approach which can be used to reveal potential post‐translational modifications, thus providing a new method in the area of gel‐free and label‐free proteomic analysis. Copyright © 2010 John Wiley & Sons, Ltd.
Elucidation of the dissociation pathways of electro‐ionized estrone
Authors: Bouchonnet Stéphane , Genty Christophe , Bourcier Sophie , Sablier Michel
Published: March 2010

With the future aim of using gas chromatography coupled with mass spectrometry to characterize the transformation products of estrone submitted to UV‐photolysis or to waste water treatment plants, an interpretation of the electron impact mass spectrum of estrone is presented. Fragmentation mechanisms are proposed on the basis of high‐resolution measurements performed with a magnetic sector analyzer. Multiple‐stage mass spectrometry experiments were carried out using an ion trap mass spectrometer. The structures proposed for product ions were confirmed by the m/z shifts observed in the estrone‐d4 and estrone methyl ether electron ionization mass spectra. If the formation of some of the most abundant ions may easily be explained by α‐cleavages and retro‐Diels‐Alder type rearrangements, complex mechanisms need to be considered to rationalize the formation of others. Isotope labelling allows discrimination of isobaric ions. Copyright © 2010 John Wiley & Sons, Ltd.
Application of thin‐layer chromatography/infrared matrix‐assisted laser desorption/ionization orthogonal time‐of‐flight mass spectrometry to structural analysis of bacteria‐binding glycosphingolipids selected by affinity detection
Authors: Müsken Anne , Souady Jamal , Dreisewerd Klaus , Zhang Wenlan , Distler Ute , Peter‐Katalinić Jasna , Miller‐Podraza Halina , Karch Helge , Müthing Johannes
Published: March 2010

Glycosphingolipids (GSLs) play key roles in the manifestation of infectious diseases as attachment sites for pathogens. The thin‐layer chromatography (TLC) overlay assay represents one of the most powerful approaches for the detection of GSL receptors of microorganisms. Here we report on the direct structural characterization of microbial GSL receptors by employment of the TLC overlay assay combined with infrared matrix‐assisted laser desorption/ionization orthogonal time‐of‐flight mass spectrometry (IR‐MALDI‐o‐TOF‐MS). The procedure includes TLC separation of GSL mixtures, overlay of the chromatogram with GSL‐specific bacteria, detection of bound microbes with primary antibodies against bacterial surface proteins and appropriate alkaline phosphatase labeled secondary antibodies, and in situ MS analysis of bacteria‐specific GSL receptors. The combined method works on microgram scale of GSL mixtures and is advantageous in that it omits laborious and time‐consuming GSL extraction from the silica gel layer. This technique was successfully applied to the compositional analysis of globo‐series neutral GSLs recognized by P‐fimbriated Escherichia coli bacteria, which were used as model microorganisms for infection of the human urinary tract. Thus, direct TLC/IR‐MALDI‐o‐TOF‐MS adds a novel facet to this fast and sensitive method offering a wide range of applications for the investigation of carbohydrate‐specific pathogens involved in human infectious diseases. Copyright © 2010 John Wiley & Sons, Ltd.
Simultaneous determination of δ15N and δ18O of N2O and δ13C of CH4 in nanomolar quantities from a single water sample
Authors: Hirota A. , Tsunogai U. , Komatsu D. D. , Nakagawa F.
Published: March 2010

We have developed a rapid, sensitive, and automated analytical system to simultaneously determine the concentrations and stable isotopic compositions (δ15N, δ18O, and δ13C) of nanomolar quantities of nitrous oxide (N2O) and methane (CH4) in water, by combining continuous‐flow isotope‐ratio mass spectrometry and a helium‐sparging system to extract and purify the dissolved gases. Our system, which is composed of cold traps and a capillary gas chromatograph that use ultra‐pure helium as the carrier gas, achieves complete extraction of N2O and CH4 in a water sample and separation among N2O, CH4, and the other component gases. The flow path following exit from the gas chromatograph was periodically changed to pass the gases through the combustion furnace to convert CH4 and the other hydrocarbons into CO2, or to bypass the combustion furnace for the direct introduction of eluted N2O into the mass spectrometer, for determining the stable isotopic compositions through monitoring the ions of m/z 44, 45, and 46 of CO and N2O+. The analytical system can be operated automatically with sequential software programmed on a personal computer. Analytical precisions better than 0.2‰ and 0.3‰ and better than 1.4‰ and 2.6‰ were obtained for the δ15N and δ18O of N2O, respectively, when more than 6.7 nmol and 0.2 nmol of N2O, respectively, were injected. Simultaneously, analytical precisions better than 0.07‰ and 2.1‰ were obtained for the δ13C of CH4 when more than 5.5 nmol and 0.02 nmol of CH4, respectively, were injected. In this manner, we can simultaneously determine stable isotopic compositions of a 120 mL water sample with concentrations as low as 1.7 nmol/kg for N2O and 0.2 nmol/kg for CH4. Copyright © 2010 John Wiley & Sons, Ltd.
Technology emergence through entrepreneurship across multiple industries
Authors: Woolley Jennifer
Published: March 2010

Radical process discontinuities provide opportunities for the founding of new firms across multiple industries; however, little is known about such emergence activity. This article examines nascent technology emergence by studying patterns of related entrepreneurial activity across multiple industries based on a radical process discontinuity. Using historical and statistical methods to examine all nanotechnology firms founded before 2005, I find that during technology emergence, entrepreneurship occurs first in upstream industries. These upstream entrepreneurs provide the technological foundations that enable the founding of firms in other industries developing the technology. The results show the role of industry interaction in the development of both upstream and downstream industries. Implications for entrepreneurs and technology emergence are discussed. Copyright © 2010 Strategic Management Society.
How alliance formation shapes corporate venture capital investment in the software industry: a resource‐based perspective
Authors: Dushnitsky Gary , Lavie Dovev
Published: March 2010

Corporate venture capital (CVC) investments serve as interfirm relationships that enable established firms to tap into emerging technology markets. Nevertheless, firms may also leverage their strategic alliances to this end. Does alliance formation reinforce or attenuate a firm's tendency to invest in entrepreneurial ventures? We introduce a resource‐based perspective whereby resource complementarity and network resource visibility prompt a reinforcing association between CVC investment and alliance formation. In turn, external resource redundancy and internal resource allocation constraints yield an attenuating effect of alliance formation on CVC investment. Analyzing the alliances and CVC investments of 372 software firms during the 1990s, we reconcile these opposing arguments by revealing an inverted U‐shaped association between CVC investment and alliance formation. Accordingly, the number of CVC investments first increases, but then decreases, with the number of alliances formed. Moreover, the positive association between CVC investment and alliance formation diminishes as firms invest in their internal resource stocks, mature, and accumulate experience with prior CVC investments. We advance strategic entrepreneurship research by elucidating the tendency of established firms to engage in CVC investment and by unpacking the complex association between different types of interfirm relationships that these firms leverage. Copyright © 2010 Strategic Management Society.
How entrepreneurs acquire the capacity to excel: insights from research on expert performance
Authors: Baron Robert A. , Henry Rebecca A.
Published: March 2010

Most new ventures fail, but a few prosper and attain rapid growth. Many factors contribute to such outcomes, but we propose that among these are mechanisms identified by cognitive science research on the origins of expert performance. Literature on this topic indicates that across many fields (e.g., medicine, science, sports, music), outstanding performance derives largely from participation in intense, prolonged, and highly focused efforts to improve current performance—a process known as deliberate practice. By comparison, mere experience in a field and individual talent play smaller roles in generating expert performance. Additional evidence indicates that participation in deliberate practice does not simply expand domain‐specific knowledge and skills; it also generates actual enhancements to basic cognitive resources (e.g., memory, perception, metacognition). We suggest that to the extent entrepreneurs acquire enhanced cognitive resources through current or past deliberate practice, their capacity to perform tasks related to new venture success (e.g., accurate identification and evaluation of business opportunities) is enhanced and, hence, the performance of their new ventures, too, is augmented. Specific ways in which entrepreneurs can gain enhanced cognitive resources are described, and implications for entrepreneurship theory and practice are considered. Copyright © 2010 Strategic Management Society.
Foreign entry and survival in a knowledge‐intensive market: emerging economy countries' international linkages, technology competences, and firm experience
Authors: Giarratana Marco S. , Torrisi Salvatore
Published: March 2010

This article examines the entry into and survival in the U.S. software market by a sample of firms based in India, Ireland, and Israel, with a focus on the pre‐entry technological capabilities, international linkages, and home‐based experience of these firms as determinants. Using a novel measure of foreign activity, namely, the registration of software trademarks in the United States, this study applies the date of the first trademark application filed with the U.S. Patent and Trademark Office as a proxy for a firm's U.S. entry. Trademark renewals and new trademark applications trace the sample firms' survival. The analysis shows that international linkages have a positive relationship with entry and survival, whereas firm technological capabilities and age are not associated with entry, though technological capabilities affect the likelihood of survival. Copyright © 2010 Strategic Management Society.
A shared frailty model for case‐cohort samples: Parent and offspring relations in an adoption study
Authors: Petersen Liselotte , Sørensen Thorkild I. A. , Andersen Per Kragh
Published: March 2010

The Danish adoption register contains data on the 12 301 Danish nonfamilial adoptions during 1924–1947. From that register a case‐cohort sample was selected consisting of all case adoptees, that is those adoptees dying before age 70 years, and a random sample of 1683 adoptees. The survival data of their biological and adoptive parents were collected with the purpose of studying the association of survival between the adoptee and his/her biological or adoptive parents. Motivated by this study, we explored how to make inference in a shared frailty model for case‐cohort data. Our approach was to use inverse probability weighting to account for the sampling in a conditional, shared frailty Poisson model and to use the robust variance estimator proposed by Moger et al. (Statist. Med. 2008; 27:1062–1074).

To explore the performance of the estimation procedure, a simulation study was conducted. We studied situations with three types of covariates: one with equal values between families (e.g. generation in parent–offspring pairs), an individual covariate, and one with equal values within each family (e.g. family size).

The estimation of the frailty parameter tended to be unbiased; however, a small bias was seen for rare causes of death. The estimation of variance was unbiased when covariates were individual or equal within families, but some overestimation was seen when the covariate was equal between families. As in the earlier analyses, we found that there was a moderate genetic influence on the mortality rate, especially from all causes of death and vascular causes, and we found no effect of familial environment. Copyright © 2010 John Wiley & Sons, Ltd.
Establishing the relationship between nurse staffing and hospital mortality using a clustered discrete‐time logistic model
Authors: Diya L. , Lesaffre E. , Van den Heede K. , Sermeus W. , Vleugels A.
Published: March 2010

Studies based on aggregated hospital outcome data have established that there is a relationship between nurse staffing and adverse events. However, this result could not be confirmed in Belgium where 96 per cent of the variability of nurse staffing levels over nursing units (belonging to different hospitals) is explained by within‐hospital variability. To better appreciate the possible impact of nurse staffing levels on adverse events, we propose a multilevel approach reflecting the complex nature of the data. In particular we suggest a clustered discrete‐time logistic model that captures the risks associated with a given unit in the patient's trajectory through the hospital. The model also allows for nurse staffing levels to affect the current and subsequent nursing unit (carry‐over effect). In the model ‘time’ is represented by the sequential number of the nursing unit that the patient is passing through. The model incorporates hospital and nursing unit random effects to express that patients treated in the same hospital and taken care of by nurses of the same unit share a common environment. In this study we used Belgian national administrative databases for the year 2003 to assess the relationship between nurse staffing levels and nurse education variables with in‐hospital mortality. The analysis was restricted to elective cardiac surgery patients. Lower nursing unit staffing levels in the general nursing units were associated with high in‐hospital mortality in units past the traditional cardiac surgery nursing units. Copyright © 2010 John Wiley & Sons, Ltd.
Comparisons of minimization and Atkinson's algorithm
Authors: Senn Stephen , Anisimov Vladimir V. , Fedorov Valerii V.
Published: March 2010

Some general points regarding efficiency in clinical trials are made. Reasons as to why fitting many covariates to adjust the estimate of the treatment effect may be less problematic than commonly supposed are given. Two methods of dynamic allocation of patients based on covariates, minimization and Atkinson's approach, are compared and contrasted for the particular case where all covariates are binary. The results of Monte Carlo simulations are also presented. It is concluded that in the cases considered, Atkinson's approach is slightly more efficient than minimization although the difference is unlikely to be very important in practice. Both are more efficient than simple randomization, although it is concluded that fitting covariates may make a more valuable and instructive contribution to inferences about treatment effects than only balancing them. Copyright © 2010 John Wiley & Sons, Ltd.
A general, prediction error‐based criterion for selecting model complexity for high‐dimensional survival models
Authors: Porzelius Christine , Schumacher Martin , Binder Harald
Published: March 2010

When fitting predictive survival models to high‐dimensional data, an adequate criterion for selecting model complexity is needed to avoid overfitting. The complexity parameter is typically selected by the predictive partial log‐likelihood (PLL) estimated via cross‐validation. As an alternative criterion, we propose a relative version of the integrated prediction error curve (IPEC), which can be stably estimated via bootstrap resampling. The IPEC has the advantage of being applicable for models and fitting techniques where the PLL is not available. To investigate the performance of this new criterion, a simulation study is carried out, mimicking microarray survival data. Additionally, model selection by predictive PLL, estimated via bootstrap resampling instead of cross‐validation, is examined. It is seen that this mostly results in similar prediction performance of the selected models, compared to estimates based on cross‐validation. Model selection by bootstrap estimates of the IPEC performs about as well as selection by cross‐validation estimates of the PLL. Therefore, it is expected to be a reasonable alternative in cases where there is no PLL. Similar results are seen in the analysis of a microarray survival data set from patients with diffuse large‐B‐cell lymphoma. Copyright © 2010 John Wiley & Sons, Ltd.
Proportional subdistribution hazards modeling offers a summary analysis, even if misspecified
Authors: Grambauer Nadine , Schumacher Martin , Beyersmann Jan
Published: March 2010

Competing risks model time‐to‐first‐event and the event type. Our motivating data example is the ONKO‐KISS study on the occurrence of infections in neutropenic patients after stem‐cell transplantation with first‐event‐types ‘infection’ and ‘end of neutropenia’. The standard approach to study the effects of covariates in competing risks is to assume each event‐specific hazard (ESH) to follow a proportional hazards model. However, a summarizing probability interpretation of the different event‐specific effects of one covariate can be challenging. This difficulty has led to the development of the proportional subdistribution hazards model of a competing event of interest. However, one model specification usually precludes the other. Assuming proportional ESHs, we find that the subdistribution log‐hazard ratio may show a pronounced time‐dependency, even changing sign. Still, the subdistribution analysis is useful by estimating the least false parameter (LFP), a time‐averaged effect on the cumulative event probabilities. In examples, we find that the LFP offers a robust summary of the effects on the ESHs for different observation periods, ranging from heavy censoring to no censoring at all. In particular, if there is no effect on the competing ESH, the subdistribution log‐hazard ratio is close to the event‐specific log‐hazard ratio of interest. We reanalyze an interpretationally challenging example from the ONKO‐KISS study and conduct a simulation study, where we find that the LFP is reliably estimated by the subdistribution analysis even for moderate sample sizes. Copyright © 2010 John Wiley & Sons, Ltd.
Estimating adjusted risk difference (RD) and number needed to treat (NNT) measures in the Cox regression model
Authors: Laubender R. P. , Bender R.
Published: March 2010

In medical research, risk difference (RD) and number needed to treat (NNT) measures for survival times have been mainly proposed without consideration of covariates. In this paper, we develop adjusted RD and NNT measures for use in observational studies with survival time outcomes within the framework of the Cox proportional hazards regression model taking the distribution of confounders into account. We consider the typical situation of a cohort study in which the effect of an exposure on a survival time outcome is investigated and important covariates have to be taken into account. The exposure effect described by means of the RD and NNT measures in dependence on whether the effect of allocating an exposure to unexposed persons (number needed to be exposed) or that of removing an exposure from exposed persons (exposure impact number) is considered. Estimation of these adjusted RD and NNT measures is performed by using the average RD approach recently developed for logistic regression. To determine standard errors and confidence intervals for these estimators we use two approaches, the delta method with respect to the regression coefficients of the Cox model and bootstrapping and compare each other. The performance of these estimators is assessed by performing Monte Carlo simulations demonstrating clear advantages of the bootstrap method. The proposed method for point and interval estimation of adjusted RD and NNT measures in the Cox model is illustrated by means of data of the Düsseldorf Obesity Mortality Study (DOMS). Copyright © 2010 John Wiley & Sons, Ltd.
Bias‐reduced and separation‐proof conditional logistic regression with small or sparse data sets
Authors: Heinze Georg , Puhr Rainer
Published: March 2010

Conditional logistic regression is used for the analysis of binary outcomes when subjects are stratified into several subsets, e.g. matched pairs or blocks. Log odds ratio estimates are usually found by maximizing the conditional likelihood. This approach eliminates all strata‐specific parameters by conditioning on the number of events within each stratum. However, in the analyses of both an animal experiment and a lung cancer case–control study, conditional maximum likelihood (CML) resulted in infinite odds ratio estimates and monotone likelihood. Estimation can be improved by using Cytel Inc.'s well‐known LogXact software, which provides a median unbiased estimate and exact or mid‐pconfidence intervals. Here, we suggest and outline point and interval estimation based on maximization of a penalized conditional likelihood in the spirit of Firth's (Biometrika1993; 80:27–38) bias correction method (CFL). We present comparative analyses of both studies, demonstrating some advantages of CFL over competitors. We report on a small‐sample simulation study where CFL log odds ratio estimates were almost unbiased, whereas LogXact estimates showed some bias and CML estimates exhibited serious bias. Confidence intervals and tests based on the penalized conditional likelihood had close‐to‐nominal coverage rates and yielded highest power among all methods compared, respectively. Therefore, we propose CFL as an attractive solution to the stratified analysis of binary data, irrespective of the occurrence of monotone likelihood. A SAS program implementing CFL is available at:http://www.muw.ac.at/msi/biometrie/programs. Copyright © 2010 John Wiley & Sons, Ltd.
Practical considerations for optimal designs in clinical dose finding studies
Authors: Bretz Frank , Dette Holger , Pinheiro Jose C.
Published: March 2010

A key objective in the clinical development of a medicinal drug is the determination of an adequate dose level and, more broadly, the characterization of its dose response relationship. If the dose is set too high, safety and tolerability problems are likely to result, while selecting too low a dose makes it difficult to establish adequate efficacy in the confirmatory phase, possibly leading to a failed program. Hence, dose finding studies are of critical importance in drug development and need to be planned carefully. In this paper, we focus on practical considerations for establishing efficient study designs to estimate relevant target doses. We consider optimal designs for estimating both the minimum effective dose and the dose achieving a certain percentage of the maximum treatment effect. These designs are compared with D‐optimal designs for a given dose response model. Extensions to robust designs accounting for model uncertainty are also discussed. A case study is used to motivate and illustrate the methods from this paper. Copyright © 2010 John Wiley & Sons, Ltd.
Bootstrap‐based methods for estimating standard errors in Cox's regression analyses of clustered event times
Authors: Xiao Yongling , Abrahamowicz Michal
Published: March 2010

We propose two bootstrap‐based methods to correct the standard errors (SEs) from Cox's model for within‐cluster correlation of right‐censored event times. The cluster‐bootstrap method resamples, with replacement, only the clusters, whereas the two‐step bootstrap method resamples (i) the clusters, and (ii) individuals within each selected cluster, with replacement. In simulations, we evaluate both methods and compare them with the existing robust variance estimator and the shared gamma frailty model, which are available in statistical software packages. We simulate clustered event time data, with latent cluster‐level random effects, which are ignored in the conventional Cox's model. For cluster‐level covariates, both proposed bootstrap methods yield accurate SEs, and type I error rates, and acceptable coverage rates, regardless of the true random effects distribution, and avoid serious variance under‐estimation by conventional Cox‐based standard errors. However, the two‐step bootstrap method over‐estimates the variance for individual‐level covariates. We also apply the proposed bootstrap methods to obtain confidence bands around flexible estimates of time‐dependent effects in a real‐life analysis of cluster event times. Copyright © 2010 John Wiley & Sons, Ltd.
Estimators and confidence intervals for the marginal odds ratio using logistic regression and propensity score stratification
Authors: Stampf Susanne , Graf Erika , Schmoor Claudia , Schumacher Martin
Published: March 2010

Propensity score methods are widely used to estimate treatment or exposure effects in observational studies. In studies with binary response the effect can be described as an odds ratio, and the Mantel–Haenszel estimator is traditionally used for stratified data. Although propensity score methods are designed for marginal treatment effects, it has been shown that the Mantel–Haenszel estimator stratified for propensity score is a questionable estimator for the marginal odds ratio, which describes the change in odds of response if everybody versus nobody were treated.

We studied recently proposed alternative estimators for the marginal odds ratio, one stratified for propensity score, the other derived from logistic regression. Additionally, we adapted the methodology of the logistic regression based estimator for the derivation of a marginal odds ratio estimator to covariate adjustment by the propensity score. We also derived corresponding variance estimators using the Delta‐method.

The estimators were illustrated and compared to the inverse probability weighted estimator and the stratified Mantel–Haenszel estimator in a study dealing with respiratory tract infections in children in Germany. Furthermore, simulation studies that were carried out to investigate relative bias, variance and coverage probability showed reasonable performance of marginal odds ratio estimators if response rates or regression based approaches were used. Their variances were accurately estimated. In contrast, the stratified Mantel–Haenszel estimator was substantially biased in some situations due to problems of non‐collapsibility and thus it is generally inappropriate for a reliable estimation of the marginal odds ratio. Copyright © 2010 John Wiley & Sons, Ltd.
The hidden costs of outsourcing: evidence from patent data
Authors: Reitzig Markus , Wagner Stefan
Published: March 2010

Drawing on patent data for approximately 500 firms over 20 years, we advance recent theory on firm boundaries and test these propositions for the first time. We first provide evidence for the existence of knowledge complementarities between vertically related activities in a firm's value chain by showing that firms face increasing (decreasing) performance in conducting downstream activities (i.e., patent litigation) the less (more) they outsource related upstream activities (i.e., patent filing). We then propose and empirically demonstrate that vertical integration benefits through learning differ from vertical outsourcing costs through forgetting. We show that firms can partly offset these hidden outsourcing costs by sourcing similar upstream products from internal and external suppliers. Copyright © 2010 John Wiley & Sons, Ltd.
Two steel bridges for the high speed railway line in Spain
Authors: Sobrino Juan A.
Published: March 2010

This article synthesises the design criteria and erection process of two steel bridges designed for the high speed rail line connecting Madrid, Barcelona and the French Border. Both structures cross over existing infrastructures, near Barcelona, with a limited vertical clearance in order to reduce environmental impact. The conceptual design is similar for the two structures: a composite steel‐concrete deck suspended on steel tied curved members. An innovative solution, at least for the Spanish HSR lines, that has been used in the past in concrete road bridges. These bridges are two of the three first steel structures built for the HSR in Spain.

Llinars Bridge crosses, at a very high skew angle, one of the busiest highways (AP‐7) in Spain. This viaduct has an overall length of 574 m with a maximum span of 75 m. Sant Boi Bridge crosses several existing infrastructures (highway, road and railway). The length of the bridge is 870 m with a maximum span of 63 m.

Zwei Stahlbrücken für die Hochgeschwindigkeitsstrecke der Eisenbahn in Spanien. Dieser Beitrag beschreibt die Entwurfskriterien und den Bauprozess von zwei stählernen Eisenbahnbrücken auf der Hochgeschwindigkeitsstrecke Madrid, Barcelona bis zur französischen Grenze. Beide Bauwerke in der Nähe von Barcelona überspannen bestehende Infrastrukturen mit einer minimalen Bauhöhe, um den Eingriff in die Umgebung so weit wie möglich zu reduzieren. Der konzeptuelle Entwurf ist bei beiden Brücken ähnlich: Eine Stahlverbund‐Fahrbahn wird durch gekrümmte Stahlzugglieder unterstützt. Dies ist für die spanischen Hochgeschwindigkeits‐Eisenbahnbrücken eine innovative Lösung, denn in der Vergangenheit wurden ausschließlich Betonbrücken genutzt. Die Brücken sind zwei der ersten drei stählernen Tragwerke, die für die spanische Hochgeschwindigkeitsbahn gebaut wurden.

Die Llinars‐Brücke überspannt in einem sehr spitzen Winkel eine der meistbefahrenen Autobahnen (AP‐7) von Spanien. Die Brücke hat eine Gesamtlänge von 574 m mit einer maximalen Stützweite von 75 m. Die Sant Boi Brücke kreuzt mehrere bestehende Infrastrukturanlagen (Autobahn, Straße und Eisenbahn). Die Gesamtlänge beträgt 870 m, die maximale Stützweite 63 m.
Lobby Fassade und Vordächer für den Trump Tower, Chicago
Authors: Wellershoff Frank , Utz Sebastian , Balint Ladislaus
Published: March 2010

Der Donald Trump Tower inmitten Chicagos beherbergt in seinen 92 Stockwerken neben 339 5‐Sterne Hotelzimmern 486 Luxusappartements und Wohnungen (Bild 1). Mit seinen 427 m Höhe rangiert das Gebäude derzeit auf Rang 7 der höchsten Gebäude der Welt (Quelle CTBUH). Besonders im Eingangsbereich wurden höchste Ansprüche an die Transparenz der Fassade und die Oberflächenqualität der verwendeten Materialien Glas und Edelstahl gelegt. Nur durch aufwendige Bemessungen, begleitet durch Bauteilversuche und umfangreiche Bemusterungen der Bauteile, konnte das außerordentliche Niveau dieses Gebäudes realisiert werden.

Lobby façade and canopy for the Trump Tower, Chicago. The Trump International Hotel and Tower located in the heart of Downtown Chicago offers 339 five‐star hotel rooms and 486 luxury condominium residences (fig. 1). At 92 stories and a height of 427 m to the top of the spire, The Trump Tower is now the 7th tallest building of the world (CTBUH ranking). Highest quality concerning the façade transparency and the quality of the materials and surfaces was requested especially at the entrance area. Extensive calculations and prototype testing as well as lots of visual samples were required to meet the highest demands for this extraordinary building.
Profilbauglas – Prüfmethodik, Tragverhalten und Produktentwicklung
Authors: Kasper Ruth , Langosch Katharina , Feldmann Markus , Sedlacek Gerhard , Tabone Salvatore
Published: March 2010

Während technisch gekühlte Profilbaugläser bereits seit über 40 Jahren zur Verkleidung von Zweck‐ oder Industriebauten verwendet werden, sind thermisch vorgespannte Profilbaugläser im Glasbau relativ neu und wecken vermehrt das Interesse der Architekten. Das sich durch höhere Festigkeit und feinkrümeliges Bruchbild auszeichnende thermisch vorgespannte Profilbauglas eröffnet Einsatzgebiete, die bisher Einscheibensicherheitsgläsern vorbehalten waren. Der vorliegende Artikel beschreibt die Einbaumöglichkeiten von Profilbauglas, die verwendete Prüfmethodik und das zugehörige Bemessungskonzept.

Channel shaped glass – Testing method, structural behaviour and product development. Before, channel shaped glass was used as a cost efficient material for the cladding of industrial buildings. Recently, architecture discovered channel shaped glass as a design element. Newly, the glass industry offers channel shaped glass as thermally toughened glass and the material is able to respect and to fulfil security aspects compared to fully thermally toughened flat glass. The paper describes the application of channel shaped glass, the test procedure und the design concept.
Gekrümmte Glasflächen – Zusammenspiel von Geometrie und Glasdetaillierung
Authors: Laufs Wilfried , Vilkner Gregor
Published: March 2010

Der folgende Aufsatz aus dem Bereich der Fassadenplanung beschreibt, welche Möglichkeiten sich für die Glaseindeckung gekrümmter Gebäudehüllen ergeben. Insbesondere viereckige Isolierglasscheiben bieten dazu Vorteile aus Sicht der Bauphysik und der Baukosten. Für Trockenfugen sollten Flachglaselemente auch nach Einbau vollständig eben gehalten werden, um Gebrauchstauglichkeit der Primärversiegelung sicherzustellen, während für nassversiegelte Glasfugen eine gewisse Glasverwindung durchaus möglich ist, sofern Detaillierung und 3D‐Geometrie sinnvoll zusammenspielen. Wird die Glasverwindung (“twist”) zu groß, kann eine geschuppte Stufenverglasung angestrebt werden. In allen Fällen bieten der Ansatz von Building Information Modeling (BIM) und digitaler Fabrikation wesentliche Vorteile für Planung und Realisierung solcher komplexer verglaster Oberflächen.

Clad curved building surfaces – Interaction of geometry and glass detailing. The following article addresses the field of façade engineering, describing different options how to clad curved building surfaces. Especially insulated glazing unit quadrangles offer advantages related to building physics and cost. For dry joints, flat glazing units should remain flat also after installation, to achieve long‐term serviceability of the primary edge spacer seal, while for wet joints a certain amount of glazing twist is well possible to panelise curved surfaces, given that their detailing and 3D geometry set‐up work well together. If the glazing twist exceeds certain limits, a scaled and stepped glazing facade can be aimed for. In all cases the Building Information Modeling (BIM) and digital fabrication approach offer substantial advantages for the planning and realisation process of such complex curved building skin surfaces.
Using orthogonal pairs of rollers on concave beds (OPRCB) as a base isolation system—part I: analytical, experimental and numerical studies of OPRCB isolators
Authors: Hosseini Mahmood , Soroor Amirhossein
Published: March 2010

A somehow new isolating system is introduced for short‐ to mid‐rise buildings. It does not need high technology for manufacturing and is not costly, contrary to other existing systems like lead‐rubber bearing or friction pendulum bearing systems. Each isolator of the proposed system consists of two Orthogonal Pairs of Rollers on Concave Beds (OPRCB). Rolling rods installed in two orthogonal directions make possible the movement of the superstructure in all horizontal directions. The concave beds, in addition to giving the system both restoring and re‐centring capabilities, make the force–displacement behaviour of the isolators to be of hardening type. The results of the studies on the specifications of the proposed isolating system and its application to buildings can be presented in two parts. Part I relates to the analytical formulations and the results of experimental and numerical studies of the system's mechanical feature, including its dynamical properties, and part II focuses on the effectiveness of the proposed isolation system in seismic response reduction of low‐ to mid‐rise buildings. In part I of the work, presented in this paper, at first general features of the OPRCB isolator are explained and the analytical formulation, governing its dynamic motion, is derived and discussed in detail. Then, the results of experimental and numerical investigations, including the lateral load displacement relationship of the OPRCB isolators under various vertical loads, obtained by both Finite Element Analyses (FEA) and laboratory tests are presented (FEA results have been verified by the laboratory tests). Finally, responses of some Single Degree of Freedom (SDOF) systems, isolated by OPRCB devices, subjected to simultaneous effect of horizontal and vertical ground motions, are presented and compared with responses of their fixed‐base counterparts. Based on the numerical calculations, it is observed that the oscillation period of the isolated SDOF system is independent of its mass, the initial amplitude of its free vibration response and the value of rolling resistance coefficient. With regard to seismic response reduction it is seen that the amount of absolute accelerations in the SDOF systems, isolated by OPRCB devices, can be reduced drastically in comparison with the fixed‐base systems. Results also show that if the rollers and cylindrical beds are made of high‐strength steel materials, the system can be used effectively under the vertical loads of about the axial forces of ground floor columns in ordinary buildings up to 14 storeys. Copyright © 2010 John Wiley & Sons, Ltd.
A method for design of seismic resistant structures with viscoelastic dampers
Authors: Ribakov Y. , Agranovich G.
Published: March 2010

Viscoelastic (VE) dampers are widely used for enhancing structural response to earthquakes, wind and other dynamic loadings. Various methods were proposed for effective design of passive control systems with VE dampers. These methods are based on desired level of additional damping, eigenvalue assignment, modal strain energy, linear quadratic regulator control theories and other approaches. This paper presents an alternative method based on an optimal active control algorithm. At the first stage for design purposes, the structure is assumed to be an active controlled one. The active control is designed, based on a modified LQR optimization method previously developed by the authors. By analyzing the response of the structure to an artificial white noise earthquake, force‐displacement relationship in the active devices is obtained. A structure with VE dampers in an ideal case should have a response that is as close as possible to that of the active controlled structure. The properties of VE dampers are obtained assuming that additional stiffness and energy dissipated in active and VE dampers at the peak inter‐storey displacement are equal. Numerical analysis of an eight‐storey structure was carried out. Natural earthquake records were used to verify the efficiency of the proposed method. It was demonstrated that seismic response in a structure with VE dampers, designed according to the proposed method, is similar to that with active controlled devices. Copyright © 2010 John Wiley & Sons, Ltd.