bluuebunny/crossref_metadata_2025 huggingface dataset:
Rapid and accurate determination of MYCN copy number and 1p deletion in neuroblastoma by quantitative PCR
Authors: Anderson John , Gibson Sian , Williamson Dan , Rampling Dyanne , Austin Catherine , Shipley Janet , Sebire Neil , Brock Penelope
Published: October 2005

MYCN amplification and 1p36 deletion are adverse prognostic factors in neuroblastoma, and rapid accurate determination of MYCN amplification is essential for risk stratification. MYCN copy number and 1p36 deletion status were determined by fluorescence in situ hybridization (FISH) and real time PCR in a diagnostic pathology laboratory setting on 35 consecutive patients with neuroblastoma. The PCR technique was technically successful in all cases and results were generally available within 24 hr of biospy. There was no discordance between FISH and PCR results. Real time PCR is a reliable, accurate, and simple technique that can be applied to small neuroblastoma biopsies allowing rapid diagnosis. © 2005 Wiley‐Liss, Inc.
Proceedings of the tumor board of St. Jude Children's Research Hospital, Memphis, Tennessee: Gestational choriocarcinoma
Authors: Weiss Aaron , Khoury Joseph D. , Kaste Sue C. , Spunt Sheri L.
Published: October 2005

This paper describes a recent tumor board presentation conducted at our institution involving an adolescent with gestational choriocarcinoma. Despite its rarity in pediatrics, gestational choriocarcinoma offers unique diagnostic, treatment and off‐therapy considerations in adolescent patients who have become pregnant. Key features and findings of the case as well as important management issues will be discussed. Pediatr Blood Cancer 2006; 47:640–646. © 2005 Wiley‐Liss, Inc.
Urinary hepcidin in congenital chronic anemias
Authors: Kearney Susan L. , Nemeth Elizabeta , Neufeld Ellis J. , Thapa Dharma , Ganz Tomas , Weinstein David A. , Cunningham Melody J.
Published: October 2005

Background

Hepcidin, a regulator for iron homeostasis, is induced by inflammation and iron burden and suppressed by anemia and hypoxia. This study was conducted to determine the hepcidin levels in patients with congenital chronic anemias.

Procedure

Forty‐nine subjects with anemia, varying degrees of erythropoiesis and iron burden were recruited. Eight children with immune thrombocytopenia were included as approximate age‐matched controls. Routine hematologic labs and urinary hepcidin (uhepcidin) levels were assessed. For thalassemia major (TM) patients, uhepcidin was obtained pre‐ and post‐transfusion.

Results

In TM, uhepcidin levels increased significantly after transfusion, demonstrated wide variance, and the median did not significantly differ from controls or thalassemia intermedia (TI). In both thalassemia syndromes, the hepcidin to ferritin ratio, a marker of the appropriateness of hepcidin expression relative to the degree of iron burden, was low compared to controls. In TI and sickle cell anemia (SCA), median uhepcidin was low compared to controls, P = 0.013 and <0.001, respectively. In thalassemia subjects, uhepcidin levels were positively associated with ferritin. In subjects with SCA, uhepcidin demonstrated a negative correlation with reticulocyte count.

Conclusions

This study examines hepcidin levels in congenital anemias. In SCA, hepcidin was suppressed and inversely associated with erythropoietic drive. In thalassemic syndromes, hepcidin was suppressed relative to the degree of iron burden. Transfusion led to increased uhepcidin. In thalassemia, the relative influence of known hepcidin modifiers was more difficult to assess. In thalassemic syndromes where iron overload and anemia have opposing effects, the increased erythropoietic drive may positively influence hepcidin production. Pediatr Blood Cancer 2007;48:57–63. © 2005 Wiley‐Liss, Inc.
Synthesis and electrochemical and electroluminescent properties of N‐phenylcarbazole‐substituted poly(p‐phenylenevinylene)
Authors: Liang Fushun , Kurata Takashi , Nishide Hiroyuki , Kido Junji
Published: October 2005

An N‐phenylcarbazole‐containing poly(p‐phenylenevinylene) (PPV), poly[(2‐(4′‐carbazol‐9‐yl‐phenyl)‐5‐octyloxy‐1,4‐phenylenevinylene)‐alt‐(2‐(2′‐ethylhexyloxy)‐5‐methoxy‐1,4‐phenylenevinylene)] (Cz‐PPV), was synthesized, and its optical, electrochemical, and electroluminescent properties were studied. The molecular structures of the key intermediates, the carbazole‐containing boronic ester and the dialdehyde monomer, were crystallographically characterized. The polymer was soluble in common organic solvents and exhibited good thermal stability with a 5% weight loss at temperatures above 420 °C in nitrogen. A cyclic voltammogram showed the oxidation peak potentials of both the pendant carbazole group and the PPV main chain, indicating that the hole‐injection ability of the polymer would be improved by the introduction of the carbazole‐functional group. A single‐layer light‐emitting diode (LED) with a simple configuration of indium tin oxide (ITO)/Cz‐PPV (80 nm)/Ca/Al exhibited a bright yellow emission with a brightness of 1560 cd/m2 at a bias of 11 V and a current density of 565 mA/cm2. A double‐layer LED device with the configuration of ITO/poly(3,4‐ethylenedioxy‐2,5‐thiophene):poly (styrenesulfonic acid) (60 nm)/Cz‐PPV (80 nm)/Ca/Al gave a low turn‐on voltage at 3 V and a maximum brightness of 6600 cd/m2 at a bias of 8 V. The maximum electroluminescent efficiency corresponding to the double‐layer device was 1.15 cd/A, 0.42 lm/W, and 0.5%. The desired electroluminescence results demonstrated that the incorporation of hole‐transporting functional groups into the PPVs was effective for enhancing the electroluminescent performance. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 5765–5773, 2005
Synthesis of core‐shell structured carboxylated microparticles with a straightforward procedure and their evaluation as a polymer support
Authors: Albertsson Ann‐Christine , David Geta , Strandberg Clara , Bilba Doina , Paduraru Carmen
Published: October 2005

Poly(trimethylolpropane trimethacrylate) microspheres with a narrow size distribution were obtained by precipitation polymerization. They were subsequently modified by surface grafting with acrylic acid in a polar ethanol–water reaction medium, without stabilizer, yielding core‐shell particles with diameters in the micrometer range. The resulting polymeric material was characterized by SEM and potentiometric titration, FTIR spectroscopy, and thermal analysis. It was shown that the particle characteristics (size, size distribution, and functionality) obtained by this straightforward procedure can be controlled by modifying the synthesis parameters (monomer concentration, agitation rate, and temperature). The high functionality, the chemical and physico‐mechanical stability, as well as the possibility to control the performances of the resulting polymeric materials by synthesis allow its applications in various areas. Envisaging separation and catalysis domains, Cu(II), Cd(II), and Cr(III) uptake capacity from aqueous solutions was investigated under noncompetitive conditions as a function of synthesized particle functionality, time, and pH range. It was also found that the addition of the carboxylated microparticles to polyethylene stabilized with α‐tocopherol improved the thermo‐oxidative behaviour of the polymeric material. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 5889–5898, 2005
Radical polymeric photoinitiators bearing side‐chain camphorquinone moieties linked to the main chain through a flexible spacer
Authors: Angiolini Luigi , Caretti Daniele , Rossetti Stefano , Salatelli Elisabetta , Scoponi Marco
Published: October 2005

New polymeric photoinitiators bearing the side‐chain camphorquinone moiety spaced from the backbone by a long and flexible connection have been prepared and tested in the photocuring of acrylic monomers upon irradation with visible light in the presence of tertiary amine coinitiator. The results indicate that the photoinitiating activity of the polymeric initiators may be comparable to the related combination of low molecular weight derivatives when the camphorquinone component has a polymeric structure, and depends on the chemical structure of both the components of the initiator/coinitiator pair. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 5879–5888, 2005
Preparation and properties of high performance epoxy–silsesquioxane hybrid resins prepared using a maleimide–alkoxysilane compound as a modifier
Authors: Liu Ying‐Ling , Chang Gung‐Pei , Wu Chuan‐Shao , Chiu Yie‐Shun
Published: October 2005

An alkoxysilane compound possessing maleimide moiety (MSM) was prepared from N‐(4‐hydroxyphenyl)maleimide and 3‐glycidoxypropyltrimethoxysilane and was used as a modifier of epoxy resins. In situ curing epoxy resins with MSM resulted in epoxy resins with good homogeneity. Just 5–10 wt % of MSM is sufficient to yield high glass transition temperature (165 °C), good thermal stability above 360 °C, and high flame retardancy (LOI = 30) to bisphenol‐A‐based epoxy resins. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 5787–5798, 2005
Genesis of the CSIRO polymer group and the discovery and significance of nitroxide‐mediated living radical polymerization
Authors: Solomon David H.
Published: October 2005

The background to the formation of the Commonwealth Scientific and Industrial Research Organization (CSIRO) polymer group is discussed. In particular, the challenges of working with high‐conversion polymerization, as found in commercial systems, and the need to explain variations in polymer properties led to important advances in the theory of radical polymerization and control over both the initiation and termination steps. Studies on the fate of the macromonomer, formed in termination by disproportionation, led to an early form of addition/fragmentation now known as reversible addition–fragmentation chain transfer, whereas detailed studies on initiation pathways using nitroxide trapping led to nitroxide‐mediated living radical polymerization. These studies contributed to the renaissance in free‐radical polymerization studies. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 5748–5764, 2005
Thermally responsive complex polymer networks containing Fe3O4 nanoparticles: Composition/morphology/property relationship
Authors: Lin Chia‐Lung , Chiu Wen‐Yen
Published: October 2005

In this research, the synthesis and properties of thermally responsive complex polymer networks containing Fe3O4 nanoparticles were studied. First, a stable ferrofluid containing Fe3O4 nanoparticles was synthesized via a coprecipitation method in the presence of a poly(acrylic acid) oligomer. This stable ferrofluid could mix well with water‐soluble monomers by the adjustment of its pH value. Second, a thermally responsive copolymer was synthesized in the presence of the ferrofluid containing Fe3O4 nanoparticles to obtain the complex polymer networks. By the adjustment of the pH value, the ferrofluid could remain stable in the polymerization system, in which N‐isopropylacrylamide (NIPAAm) and methacrylic acid (MAA) were used as comonomers to provide thermoresponsive properties and acid groups and ammonium persulfate and sodium metabisulfite were used as the redox initiator system. Several variables, such as the molar ratio of MAA to NIPAAm, the concentrations of the monomers and crosslinking agent, the addition of an ammonium solution, and the content of the ferrofluid, were studied in this polymerization. Their effects on the morphology, structure, polymerization rate, and thermal properties of the complex polymer networks were discussed. The swelling and thermoresponsive behaviors of the complex polymer networks containing Fe3O4 nanoparticles were also studied, and the composition–morphology–property relationship was established. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 5923–5934, 2005
Flux compactification of M‐theory on compact manifolds with Spin(7) holonomy
Authors: Constantin D.
Published: October 2005

At the leading order, M‐theory admits minimal supersymmetric compactifications if the internal manifold has exceptional holonomy. The inclusion of non‐vanishing fluxes in M‐theory and string theory compactifications induce a superpotential in the lower dimensional theory, which depends on the fluxes. In this work, we check the conjectured form of this superpotential in the case of warped M‐theory compactifications on Spin(7) holonomy manifolds. We perform a Kaluza‐Klein reduction of the eleven‐dimensional supersymmetry transformation for the gravitino and we find by direct comparison the superpotential expression. We check the conjecture for the heterotic string compactified on a Calabi‐Yau three‐fold as well. The conjecture can be checked indirectly by inspecting the scalar potential obtained after the compactification of M‐theory on Spin(7) holonomy manifolds with non‐vanishing fluxes. The scalar potential can be written in terms of the superpotential and we show that this potential stabilizes all the moduli fields describing deformations of the metric except for the radial modulus.

All the above analyses require the knowledge of the minimal supergravity action in three dimensions. Therefore we calculate the most general causal 𝒩 =1 three‐dimensional, gauge invariant action coupled to matter in superspace and derive its component form using Ectoplasmic integration theory. We also show that the three‐dimensional theory which results from the compactification is in agreement with the more general supergravity construction.

The compactification procedure takes into account higher order quantum correction terms in the low energy effective action. We analyze the properties of these terms on a Spin(7) background. We derive a perturbative set of solutions which emerges from a warped compactification on a Spin(7) holonomy manifold with non‐vanishing flux for the M‐theory field strength and we show that in general the Ricci flatness of the internal manifold is lost, which means that the supergravity vacua are deformed away from the exceptional holonomy. Using the superpotential form we identify the supersymmetric vacua out of this general set of solutions.
Group functions approach based on the combination of strictly local geminals and molecular orbitals
Authors: Tokmachev A. M. , Tchougréeff A. L.
Published: October 2005

Thegroup functions technique is a natural way to introduce local description into quantum chemistry. It can also be a basis for construction of numerically effective computational schemes having almost linear growth of computational costs with that of the size of the system. Previously, we constructed a family of computationally efficient semiempirical methods based on the variationally determined strictly local geminals (SLGs). It was implemented with four popular parameterization schemes (MINDO/3, MNDO, AM1, and PM3). Because of construction details, its applicability was restricted only to compounds with well‐defined two‐electron two‐center chemical bonds and lone pairs. We generalize the previous treatment to make the electronic structure calculations possible for a wider class of compounds without loss of computational efficiency. The proposed scheme (SLG/SCF) is based on the general group function approach combining different descriptions for different electron groups: essentially local two‐electron ones are described by geminals, while those with other numbers of electrons are described in the one‐electron approximation. We implement the RHF, UHF, and ROHF approaches for the groups with delocalized electrons. This approach is tested for a series of radicals and molecules with extended π‐electron systems. It is shown that the SLG/SCF‐based methods describe the experimental data not worse than the corresponding SCF procedures and provide a good starting point for calculations of polyatomic molecular systems. © 2005 Wiley Periodicals, Inc. Int J Quantum Chem, 2006
Dynamics of meso and thermo citrate synthases with implicit solvation
Authors: Cordeiro J. M. M.
Published: October 2005

The dynamics of hydration of meso and thermo citrate synthases has been investigated using the EEF1 methodology implemented with the CHARMM program. The native enzymes are composed of two identical subunits, each divided into a small and large domain. The dynamics behavior of both enzymes at 30°C and 60°C has been compared. The results of simulations show that during the hydration process, each subunit follows a different pathway of hydration, in spite of the identical sequence. The hydrated structures were compared with the crystalline structure, and the root mean square deviation (RMSD) of each residue along the trajectory was calculated. The regions with larger and smaller mobility were identified. In particular, helices belonging to the small domain are more mobile than those of the large domain. In contrast, the residues that constitute the active site show a much lower displacement compared with the crystalline structure. Hydration free energy calculations point out that Thermoplasma acidophilum citrate synthase (TCS) is more stable than chicken citrate synthase (CCS), at high temperatures. Such result has been ascribed to the higher number of superficial charges in the thermophilic homologue, which stabilizes the enzyme, while the mesophilic homologue denatures. These results are in accord with the experimental found that TCS keeps activity at temperatures farther apart from the catalysis regular temperature than the CCS. © 2005 Wiley Periodicals, Inc. Int J Quantum Chem, 2006
Analysis of the bonding in XH3Cu+(XB, Al, Ga) complexes
Authors: Corral Inés , Mó Otilia , Yáñez Manuel
Published: October 2005

High‐level density functional theory (DFT) calculations on XH3Cu+(XB, Al, Ga) complexes show that the attachment of the metal cation to the base takes place through agostic‐type interactions. These interactions that can be viewed as dative bonds from the σXHbonding orbitals of the base toward low‐lying empty 4sorbitals of the metal cation, and back‐donations from the lone pairs of the metal into the σantibonding orbitals of the neutral, are particularly favored when the XH bonds have a high X+δH−δpolarity. Accordingly, the AlH3and GaH3Cu+binding energies are very similar, but much larger than that of BH3. Depopulation of the σXHbonding orbital and the concomitant population of the σantibonding orbital involved in the agostic interaction result in a significant weakening of the corresponding XH linkages, whose bond length increases and whose stretching frequency appears red‐shifted. © 2005 Wiley Periodicals, Inc. Int J Quantum Chem, 2006
Stable isotope analysis of safety matches using isotope ratio mass spectrometry–a forensic case study
Authors: Farmer N. L. , Meier‐Augenstein W. , Kalin R. M.
Published: October 2005

Isotope ratio mass spectrometry (IRMS) was used to assess what contribution the technique could make towards the comparative analysis of matchstick samples within the ‘normal’ framework of a forensic investigation. A method was developed to allow the comparison of samples submitted as a result of an investigation, with the added advantage of rapid sample turn‐around expected within this field. To the best of our knowledge this is the first time that wooden safety matches have been analysed using IRMS. In this particular case, bulk stable isotope analysis carrried out on a ‘like‐for‐like’ basis could demonstrate conclusively that matches seized from a suspect were different from those collected at the scene of crime. The maximum δ13C variability observed within one box was 2.5‰, which, in conjunction with the error of measurement, was regarded to yield too wide an error margin as to permit differentiation of matchsticks based on 13C isotopic composition alone given that the ‘natural’ 13C abundance in wood ranges from −20 to −30‰. However, from the δ2H values obtained for crime scene matches and seized matches of −114.5‰ and −65‰, respectively, it was concluded that the matches seized were distinctly different from those collected at the crime scene. Copyright © 2005 John Wiley & Sons, Ltd.
Carbon isotope analysis of bulk keratin and single amino acids from British and North American hair
Authors: McCullagh James S. O. , Tripp Jennifer A. , Hedges Robert E. M.
Published: October 2005

The reconstruction of ancient diets using isotopic measurements of bone collagen, and other tissues, which survive in archaeological contexts, relies on known isotopic relationships between diet and body tissues. Examination of these relationships often requires the study of modern human and animal subjects. While hair keratin can act as a useful proxy for bone collagen in isotopic studies on living humans, where it is inappropriate to sample tissues such as collagen, it can, in addition, act as a chronological indicator of dietary change. This study investigates hair keratin δ13C values from current residents of the UK and the USA. Residents in the USA showed a clear bulk hair δ13C enrichment of approximately 3‰ over UK individuals, attributed to an elevated C4 dietary input from maize fed to livestock in North America. The keratin δ13C of subjects who moved between the UK and USA showed a pronounced change after relocation, taking approximately 4 months to reach isotopic equilibrium. To investigate these differences further, we measured δ13C values of dispensable and indispensable amino acids as a group, and selected individual amino acids. As a group, enrichment of dispensable amino acids compared with indispensable amino acids occurred in samples from both continents, averaging 7.2‰ in the UK and 7.9‰ in the USA. Dispensable and indispensable amino acids, as well as all individual amino acids measured, were enriched in samples from the USA compared with those from the UK. Copyright © 2005 John Wiley & Sons, Ltd.
Advances in coupling a commercial total organic carbon analyser with an isotope ratio mass spectrometer to determine the isotopic signal of the total dissolved nitrogen pool
Authors: Huygens D. , Boeckx P. , Vermeulen J. , Paepe X. De , Park A. , Barker S. , Pullan C. , Cleemput O. Van
Published: October 2005

A new method has been developed to analyse15N of the total dissolved nitrogen (TDN) pool. The method operates on a commercial total organic carbon (TOC) analyser coupled to an elemental analyser/isotope ratio mass spectrometer (EA‐IRMS). Nitrogen compounds are combusted to nitric oxide (NO) and nitrogen dioxide (NO2) by high‐temperature catalytic oxidation (HTCO), after which the NOxgas is transferred to an EA‐IRMS for isotopic nitrogen analysis. The system is described, including five modifications of the system in order to overcome analytical problems. First, flow paths were modified to run both systems on helium as carrier gas, while complete sample oxidation was maintained. Secondly, the catalyst structure was adapted to allow high injection volumes at the given backpressures delivered by the EA system. Thirdly, we installed a Permapure® dehumidification system as the standard Peltier element did not satisfy dehumidification requirements. Finally, we prevented the inflow of atmospheric nitrogen into the system. In a final stage, we are planning to automate the coupled system in order to run a continuous batch of up to 60 samples. We have obtained satisfactory results on the accuracy and precision of 180 ± 1‰ potassium nitrate samples (IAEA, USGS‐32). Running a batch of five samples resulted in a mean isotopic value of 178.8‰ with a standard deviation of 2.8‰. Some important issues could not yet be addressed here, and will have to be evaluated once the system is running on a continuous base. However, the results appear promising and this system has the potential to become a method for TD15N analysis. An appropriate TD15N analysis method might open new challenges in aquatic and terrestrial ecosystem nitrogen studies, including a more comprehensive study of the dissolved organic nitrogen pool. Copyright © 2005 John Wiley & Sons, Ltd.
Porous polymer monolith assisted electrospray from a glass microdevice
Authors: Koerner Terry , Oleschuk Richard D.
Published: October 2005

The coupling of a lab‐on‐a‐chip microfluidic device to a nanoelectrospray ionization mass spectrometer has the potential to automate many routine analytical procedures and produce a powerful analytical tool. However, past coupling strategies have relied on complex manufacturing steps including drilling and etching the device to attach a capillary or building a nanospray emitter directly into the device. This study shows that a nanospray emitter can be easily fabricated using a porous polymer monolith (PPM) at the end of a glass microdevice. These devices are able to obtain a stable electrospray at a variety of flow rates (50–500 nL/min) but optimal results are obtained at lower flow rates (50–100 nL/min) compatible with electroosmotic flow processes. The PPM is photo‐patterned so that it can be placed in any position within the channel of the device with no dead volume. The porous character and the hydrophobic nature of the PPM both aid in development of a stable electrospray process. Total ion current traces for the constant infusion of leucine‐enkephalin and PPG show relative standard errors as low as 4%, and produce mass spectra with good signal‐to‐noise (S/N 43) from only 2 fmol of material. In addition, multiple experiments in a given day show good repeatability with variability as low as 13%, and the multiple flow paths inherent in the PPM limit sprayer clogging. Copyright © 2005 John Wiley & Sons, Ltd.
Photodissociation of singly protonated peptides at 193 nm investigated with tandem time‐of‐flight mass spectrometry
Authors: Moon Jeong Hee , Yoon So Hee , Kim Myung Soo
Published: October 2005

Photodissociation at 193 nm of some singly protonated peptides generated by matrix‐assisted laser desorption/ionization was investigated using tandem time‐of‐flight mass spectrometry. For peptides with arginine at the C‐terminus, x, υ, and w fragment ions were generated preferentially while a and d fragment ions dominated for peptides with arginine at the N‐terminus. These are the same characteristics as photodissociation at 157 nm reported previously. Overall, the photodissociation spectra obtained at 157 and 193 nm were strikingly similar. Copyright © 2005 John Wiley & Sons, Ltd.
Multiple losses of neutral C14H14 in the tandem mass spectrometry of several perbenzyl ether intermediates in the synthesis of green tea constituents
Authors: Lesimple Alain , Di Falco Marcos , Richard Yannick , Lesimple Souad , Wang Zhigang , Chan Tak Hang , Mamer Orval A.
Published: October 2005

Electrospray and matrix‐assisted laser desorption/ionization (MALDI) tandem mass spectrometry (MS/MS) experiments were used to investigate an unusual fragmentation in collision‐induced dissociation (CID) of sodiated and potassiated perbenzyl ether intermediates obtained in the total synthesis of gallate ester constituents of green tea. Prominent fragments correspond to multiple sequential losses of neutral C14H14 that were not observed in the protonated and ammoniated species, that instead present fragment ion series in which members are separated by C7H6. High‐resolution MALDI quadrupole time‐of‐flight (Q‐TOF) and electrospray‐Fourier transform mass spectrometry (FTMS) were used to confirm elemental compositions of these and related ions. Copyright © 2005 John Wiley & Sons, Ltd.
A novel on‐line solid‐phase extraction approach integrated with a monolithic column and tandem mass spectrometry for direct plasma analysis of multiple drugs and metabolites
Authors: Zang Xu , Luo Rosa , Song Ning , Chen Ta Kung , Bozigian Haig
Published: October 2005

An on‐line solid‐phase extraction liquid chromatography/tandem mass spectrometry (SPE LC/MS/MS) assay using a newly developed SPE column and a monolithic column was developed and validated for direct analysis of plasma samples containing multiple analytes. This assay was developed in an effort to increase bioanalysis throughput and reduce the complexity of on‐line SPE LC/MS/MS systems. A simple column‐switching configuration that requires only one six‐port valve and one HPLC pumping system was employed for on‐line plasma sample preparation and subsequent gradient chromatographic separation. The resulting analytical method couples the desired sensitivity with ease of use. The method was found to perform satisfactorily for direct plasma analysis with respect to assay linearity, specificity, sensitivity, precision, accuracy, carryover, and short‐term stability of an eight‐analyte mixture in plasma. A gradient LC condition was applied to separate the eight analytes that cannot be distinctly differentiated by MS/MS. With a run time for every injection of 2.8 min, a minimum of 300 direct plasma injections were made on one on‐line SPE column without noticeable changes in system performance. Due to the ruggedness and simplicity of this system, generic methods can be easily developed and applied to analyze a wide variety of compounds in a high‐throughput manner without laborious off‐line sample preparation. Copyright © 2005 John Wiley & Sons, Ltd.
Combination of solid‐phase affinity capture on magnetic beads and mass spectrometry to study non‐covalent interactions: example of minor groove binding drugs
Authors: Schlosser Gitta , Vékey Károly , Malorni Antonio , Pocsfalvi Gabriella
Published: October 2005

A simple and novel approach was developed to detect non‐covalent interactions. It is based on combination of solid‐phase affinity capture with matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry (MALDI‐TOFMS). One of the interacting molecules is bound to magnetic beads and is incubated with the target molecules in solution. The complex bound on the solid support is removed from the solution and transferred for MALDI analysis. Mass spectrometry is used only to detect the target compound, which is far more straightforward than detecting the intact non‐covalent complex. To demonstrate the applicability of the method, an AT‐rich oligonucleotide (5′‐CCCCCAATTCCCCC‐3′) and its complementary biotinylated sequence (5′‐biotin‐GGGGGAATTGGGGG‐3′) were hybridized and immobilized to paramagnetic particles by streptavidin‐biotin interaction. The immobilized duplex oligonucleotide was reacted with minor groove binding drugs, Netropsin, Distamycin A, Hoechst 33258 and 4′,6‐diamidino‐2‐phenylindole. The resulting DNA‐drug complex bound to the particles was separated and analyzed by linear MALDI‐TOFMS after washing. Drugs were selectively detected in the spectra. Relative binding strengths were also estimated using competitive complexation. Copyright © 2005 John Wiley & Sons, Ltd.
Hydropyrolysis of steroids: a preparative step for compound‐specific carbon isotope ratio analysis
Authors: Sephton Mark A. , Meredith Will , Sun Cheng‐Gong , Snape Colin E.
Published: October 2005

Compound‐specific stable carbon isotope analysis by gas chromatography/combustion/isotope ratio mass spectrometry is an important method for the detection of steroid abuse in athletes. However, steroids in their natural form exhibit poor chromatographic resolution, while derivatization adds carbon thereby corrupting the starting stable isotopic composition. Hydropyrolysis is a new approach, which defunctionalizes steroids but leaves their carbon skeleton intact. The process improves chromatography, allowing the faithful measurement of carbon isotope ratios and enabling a more effective apportionment for the source of steroids and their metabolites. Copyright © 2005 John Wiley & Sons, Ltd.
The reassessment of trial perspectives from interim data—a critical view
Authors: Bauer Peter , Koenig Franz
Published: October 2005

If an interim analysis is performed during a trial it is tempting to determine the conditional power to reach a rejection in the trial given the observed results in the interim analysis. Since the true effect size is unknown the conditional power may be calculated by using the effect size, which the study has been powered for in the planning phase or by using an interim estimate of the true size (or a combination of both). In either case the conditional power is a random variable and its density is investigated depending on the analysis time and the true effect size. Under the null hypothesis, in early interim analyses after a small proportion of sample units, the conditional power typically will be close to the overall power when the effect size from the planning stage is used for calculation. In this case the majority of observations must still be made and the small first‐stage sample in general will be dominated by the hypothetical second‐stage chance based on the wrong parameter value. It is shown that the conditional power in moderately underpowered studies can have a distribution symmetric around 0.5. When using the interim estimate for calculating the conditional power the density in general will be u‐shaped. The impact of using conditional power to reassess the sample size using flexible two‐stage combination tests is shown for a specific example in terms of overall power and average sample size as compared to the corresponding group sequential design. For small true effect sizes mid‐trial sample size recalculation based on an interim estimate may lead to an overly large price to be paid in average sample size in relation to the gain in overall power. Finally, the problem is discussed in terms of estimating the true conditional power. Copyright © 2005 John Wiley & Sons, Ltd.
Efficient group sequential designs when there are several effect sizes under consideration
Authors: Jennison Christopher , Turnbull Bruce W.
Published: October 2005

We consider the construction of efficient group sequential designs where the goal is a low expected sample size not only at the null hypothesis and the alternative (taken to be the minimal clinically meaningful effect size), but also at more optimistic anticipated effect sizes. Pre‐specified Type I error rate and power requirements can be achieved both by standard group sequential tests and by more recently proposed adaptive procedures. We investigate four nested classes of designs: (A) group sequential tests with equal group sizes and stopping boundaries determined by a monomial error spending function (the ‘ρ‐family’); (B) as A but the initial group size is allowed to be different from the others; (C) group sequential tests with arbitrary group sizes and arbitrary boundaries, fixed in advance; (D) adaptive tests—as C but at each analysis, future group sizes and critical values are updated depending on the current value of the test statistic. By examining the performance of optimal procedures within each class, we conclude that class B provides simple and efficient designs with efficiency close to that of the more complex designs of classes C and D. We provide tables and figures illustrating the performances of optimal designs within each class and defining the optimal procedures of classes A and B. Copyright © 2005 John Wiley & Sons, Ltd.
Inference for a family of survival models encompassing the proportional hazards and proportional odds models
Authors: Zucker David M. , Yang Song
Published: October 2005

For survival data regression, the Cox proportional hazards model is the most popular model, but in certain situations the Cox model is inappropriate. Various authors have proposed the proportional odds model as an alternative. Yang and Prentice recently presented a number of easily implemented estimators for the proportional odds model. Here we show how to extend the methods of Yang and Prentice to a family of survival models that includes the proportional hazards model and proportional odds model as special cases. The model is defined in terms of a Box–Cox transformation of the survival function, indexed by a transformation parameter ρ. This model has been discussed by other authors, and is related to the Harrington–FlemingGρfamily of tests and to frailty models. We discuss inference for the case where ρ is known and the case where ρ must be estimated. We present a simulation study of a pseudo‐likelihood estimator and a martingale residual estimator. We find that the methods perform reasonably. We apply our model to a real data set. Copyright © 2005 John Wiley & Sons, Ltd.
Partial questionnaire designs, questionnaire non‐response, and attributable fraction: applications to adult onset asthma
Authors: Andrés Houseman E. , Milton Donald K.
Published: October 2005

The attributable fraction (AF) is often used to explore the policy implications of an association between a disease and an exposure. To date, there have been no proposed estimators of AF in the context of partial questionnaire designs (PQD). The PQD, first proposed in a public health context by Wacholder is often used to enhance response rates in questionnaires. It involves eliciting responses from each subject on preassigned subsets of questions, thereby reducing the burden of response. We propose a computationally efficient method of estimating logistic (or more generally, binary) regression parameters from a PQD model where there is non‐response to the questionnaire and the rates of non‐response differ between sub‐populations. Assuming a log‐linear model for the distribution of missing covariates, we employ the methods of Wacholder to motivate consistent estimating equations, and weight each subject's contribution to the estimating function by the inverse probability of responding to the questionnaire. We also propose techniques for goodness‐of‐fit to assist in model selection. We then use the PQD regression estimates to derive an estimate of AF similar to that proposed by Bruzzi. Finally, we demonstrate our methods using data obtained from a study on adult occupational asthma, conducted within a Massachusetts HMO. Although we concentrate on a particular type of missing data mechanism, other missing data techniques can be incorporated into AF estimation in a similar manner. Copyright © 2005 John Wiley & Sons, Ltd.
Interval estimation for treatment effects using propensity score matching
Authors: Hill Jennifer , Reiter Jerome P.
Published: October 2005

In causal studies without random assignment of treatment, causal effects can be estimated using matched treated and control samples, where matches are obtained using estimated propensity scores. Propensity score matching can reduce bias in treatment effect estimators in cases where the matched samples have overlapping covariate distributions. Despite its application in many applied problems, there is no universally employed approach to interval estimation when using propensity score matching. In this article, we present and evaluate approaches to interval estimation when using propensity score matching. Copyright © 2005 John Wiley & Sons, Ltd.
Estimation of time‐dependent area under the ROC curve for long‐term risk prediction
Authors: Chambless Lloyd E. , Diao Guoqing
Published: October 2005

Sensitivity, specificity, and area under the ROC curve (AUC) are often used to measure the ability of survival models to predict future risk. Estimation of these parameters is complicated by the fact that these parameters are time‐dependent and by the fact that censoring affects their estimation just as it affects estimation of survival curves or coefficients of survival regression models. The authors present several estimators that overcome these complications. One approach is a recursive calculation over the ordered times of events, analogous to the Kaplan–Meier approach to survival function estimation. Another is to first apply Bayes' theorem to write the parameters of interest in terms of conditional survival functions that are then estimated by survival analysis methods. Simulation studies demonstrate that the proposed estimators perform well in practical situations, when compared with an estimator (c‐statistic, from logistic regression) that ignores time. An illustration with data from a cardiovascular follow‐up study is provided. Copyright © 2005 John Wiley & Sons, Ltd.
Forecasting age‐specific breast cancer mortality using functional data models
Authors: Erbas Bircan , Hyndman Rob J. , Gertig Dorota M.
Published: October 2005

Accurate estimates of future age‐specific incidence and mortality are critical for allocation of resources to breast cancer control programmes and evaluation of screening programmes. The purpose of this study is to apply functional data analysis techniques to model age‐specific breast cancer mortality time trends, and forecast entire age‐specific mortality functions using a state‐space approach.

We use annual unadjusted breast cancer mortality rates in Australia, from 1921 to 2001 in 5 year age groups (45 to 85+). We use functional data analysis techniques where mortality and incidence are modelled as curves with age as a functional covariate varying by time. Data are smoothed using non‐parametric smoothing methods then decomposed (using principal components analysis) to estimate basis functions that represent the functional curve. Period effects from the fitted coefficients are forecast then multiplied by the basis functions, resulting in a forecast mortality curve with prediction intervals. To forecast, we adopt a state‐space approach and an automatic modelling framework for selecting among exponential smoothing methods.

Overall, breast cancer mortality rates in Australia remained relatively stable from 1960 to the late 1990s, but have declined over the last few years. A set of four basis functions minimized the mean integrated squared forecasting error and account for 99.3 per cent of variation around the mean mortality curve. Twenty year forecasts suggest a continuing decline, but at a slower rate, and stabilizing beyond 2010. Forecasts show a decline in all age groups with the greatest decline in older women.

The proposed methods have the potential to incorporate important covariates such as hormone replacement therapy and interventions to represent mammographic screening. This would be particularly useful for evaluating the impact of screening on mortality and incidence from breast cancer. Copyright © 2005 John Wiley & Sons, Ltd.
Random effects logistic models for analysing efficacy of a longitudinal randomized treatment with non‐adherence
Authors: Small Dylan S. , Ten Have Thomas R. , Joffe Marshall M. , Cheng Jing
Published: October 2005

We present a random effects logistic approach for estimating the efficacy of treatment for compliers in a randomized trial with treatment non‐adherence and longitudinal binary outcomes. We use our approach to analyse a primary care depression intervention trial. The use of a random effects model to estimate efficacy supplements intent‐to‐treat longitudinal analyses based on random effects logistic models that are commonly used in primary care depression research. Our estimation approach is an extension of Nagelkerkeet al.'s instrumental variables approximation for cross‐sectional binary outcomes. Our approach is easily implementable with standard random effects logistic regression software. We show through a simulation study that our approach provides reasonably accurate inferences for the setting of the depression trial under model assumptions. We also evaluate the sensitivity of our approach to model assumptions for the depression trial. Copyright © 2005 John Wiley & Sons, Ltd.
Comparison of case‐deletion diagnostic methods for Cox regression
Authors: Wang Hsiao‐Mei , Jones Michael P. , Storer Barry E.
Published: October 2005

Case‐deletion diagnostics are a routine component of regression analysis since they identify unusual observations that substantially affect parameter estimates. The exact approach is to compute the change in each regression parameter by dropping that individual and refitting the model. Repeating a Cox regression for the removal of each individual is very time consuming and therefore not done in practice. The two methods commonly used to approximate the exact case‐deletion change for Cox regression are the empirical influence function approach and the covariate‐vector augmentation approach. This paper reports the results of a simulation study on how well these methods estimate the exact change in a parameter estimate when deleting a known outlier or a known non‐outlier. Additionally, we investigate how well these methods correctly identify outliers and non‐outliers. The covariate augmentation approach clearly outperformed the influence function approach in these simulations. Copyright © 2005 John Wiley & Sons, Ltd.
A new classification rule for incomplete doubly multivariate data using mixed effects model with performance comparisons on the imputed data
Authors: Roy Anuradha
Published: October 2005

A mixed effects model, enhanced by a Kronecker product structure for the residual variance–covariance matrix, is used in conjunction with a discriminant analysis technique, to devise a new statistical classification method on incomplete doubly multivariate data. The proposed method is efficient in small scale clinical trials that use relatively few patients. The new classification method is also applied to multiply imputed data sets. The misclassification error rates (MERs) are compared in order to investigate the effectiveness of the new classification rule on an incomplete data set. The classification method is applied to a real data set. The error rates on the incomplete data set are found to be much less than the median error rate on the multiply imputed data sets. Non‐parametric methods, such as kernel method and k‐nearest neighbourhood method, are also applied to multiply imputed data sets. Results illustrating the advantages of the new classification method over classic non‐parametric classification methods are presented. Copyright © 2005 John Wiley & Sons, Ltd.
Assessment on homogeneity tests for kappa statistics under equal prevalence across studies in reliability
Authors: Nam Jun‐mo
Published: October 2005

In this paper, we assess the performance of homogeneity tests for two or more kappa statistics when prevalence rates across reliability studies are assumed to be equal. The likelihood score method and the chi‐square goodness‐of‐fit (GOF) test provide type 1 error rates that are satisfactorily close to the nominal level, but a Fleiss‐like test is not satisfactory for small or moderate sample sizes. Simulations show that the score test is more powerful than the chi‐square GOF test and the approximate sample size required for a specific power of the former is substantially smaller than the latter. In addition, the score test is robust to deviations from the equal prevalence assumption, while the GOF test is highly sensitive and it may give a grossly misleading type 1 error rate when the assumption of equal prevalence is violated. We conclude that the homogeneity score test is the preferred method. Published in 2005 by John Wiley & Sons, Ltd.
Decision‐theoretic designs for dose‐finding clinical trials with multiple outcomes
Authors: Fan Shenghua K. , Wang You‐Gan
Published: October 2005

A decision‐theoretic framework is proposed for designing sequential dose‐finding trials with multiple outcomes. The optimal strategy is solvable theoretically via backward induction. However, for dose‐finding studies involvingkdoses, the computational complexity is the same as the bandit problem withk‐dependent arms, which is computationally prohibitive. We therefore provide two computationally compromised strategies, which is of practical interest as the computational complexity is greatly reduced: one is closely related to the continual reassessment method (CRM), and the other improves CRM and approximates to the optimal strategy better. In particular, we present the framework for phase I/II trials with multiple outcomes. Applications to a pediatric HIV trial and a cancer chemotherapy trial are given to illustrate the proposed approach. Simulation results for the two trials show that the computationally compromised strategy can perform well and appear to be ethical for allocating patients. The proposed framework can provide better approximation to the optimal strategy if more extensive computing is available. Copyright © 2005 John Wiley & Sons, Ltd.