bluuebunny/crossref_metadata_2025 huggingface dataset:
In Silico Search for Single Nucleotide Polymorphisms in Genes Important in Vitamin E Homeostasis
Authors: Döring Frank , Rimbach Gerald , Lodge John K.
Published: February 2005

Large inter‐individual variation exists in the response to vitamin E supplementation, and this may influence the outcome of human studies. It is our hypothesis that genetic heterogeneity is an important determinant of vitamin E homeostasis. Therefore we have performed an in silico search for single nucleotide polymorphisms (SNPs) associated with genes involved in vitamin E homeostasis. Based on function, the following genes were considered as candidates for vitamin E heterogeneity: α‐tocopherol transfer protein (TTPA), tocopherol associated protein (TAP), lipoprotein lipase (LPL), multidrug resistance protein 2 (MDR‐2), pregnane X receptor (PXR) and members of the cytochrome P450 family (CYP). Searches for coding SNPs were initiated from web based programs of the National Center for Biotechnology Information (NCBI). SNP frequencies were calculated by dividing the number of annotated coding SNPs by the number of base pairs in the open reading frame. Genes for TTPA, TAP and CYP3A5 had calculated SNP frequencies between 503 and 837 base pairs per coding SNP (bp/cSNP) and so are not highly polymorphic. In contrast, cSNP frequencies in LPL, MRP2, PXR, CYP3A4 and CYP4F2 were in the range of 100 bp/cSNP and so are highly polymorphic. Thus proteins involved in specific vitamin E binding are not highly polymorphic, may not influence inter‐individual variation and so may not be good candidates for population studies. Proteins involved in drug/lipid metabolism which indirectly influence vitamin E status are highly polymorphic, are likely to influence inter‐individual variation and so are good candidates for population studies. We suggest that future studies are aimed at addressing the role of such SNPs in vitamin E homeostasis.
IUBMB Life, 56: 615‐620, 2004
Porphyromonas Gingivalis Lipopolysaccharide‐induced Up‐regulation in Endothelin‐1 Interferes with Salivary Mucin Synthesis via Epidermal Growth Factor Receptor Transactivation
Authors: Slomiany Bronislaw L. , Slomiany Amalia
Published: February 2005

Endothelin‐1 (ET‐1) is a 21 amino acid peptide produced from a biologically inactive big ET‐1 by the action of endothelin‐converting enzyme‐1 (ECE‐1) that acts through G protein‐coupled ETA and ETB receptors. Using mucous cells of sublingual salivary gland, we show that P. gingivalis lipopolysaccharide (LPS) inhibitory effect on salivary mucin synthesis is accompanied by a marked increase in ET‐1 generation and the enhancement in ECE‐1 activity. Inhibition of ECE‐1 with phosphoramidon led to the impedance of the LPS‐induced ET‐1 generation as well as countered the detrimental effect of the LPS on mucin synthesis. Moreover, the LPS inhibitory effect of on mucin synthesis was blocked by ETA receptor antagonist, BQ610, but not by ETB receptor antagonist, BQ788. The LPS‐induced reduction in mucin synthesis, furthermore, was countered by PD153035 (76.8%), a specific inhibitor of EGFR kinase as well as PP2 (54.7%), a selective inhibitor of tyrosine kinase Src responsible for ligand‐independent EGFR transactivation. Our findings are the first to demonstrate that P. gingivalis LPS detrimental effect on salivary mucin synthesis is intimately linked to the events controlled by EGFR transactivation, triggered by upregulation in ECE‐1, enhancement in ET‐1 production, and G protein‐coupled ETA receptor activation.
IUBMB Life, 56: 601‐607, 2004
mRNA Decay in Prokaryotes and Eukaryotes: Different Approaches to a Similar Problem
Authors: Kushner Sidney R.
Published: February 2005

Over the past 15 years considerable progress has been made in understanding the molecular mechanisms of mRNA decay in both prokaryotes and eukaryotes. Interestingly, unlike other important biological reactions such as DNA replication and repair, many features of mRNA decay differ between prokaryotes or eukaryotes. Even when a particular enzyme like poly(A) polymerase has been conserved, polyadenylation of mRNAs in prokaryotes appears to serve a very different function than it does in eukaryotes. Furthermore, while mRNA degrading multiprotein complexes have been identified in both prokaryotes and eukaryotes, their composition and biochemical mechanisms are significantly different. Accordingly, this review seeks to provide a concise comparison of our current knowledge regarding the pathways of mRNA decay in two model organisms, the prokaryote Escherichia coli and the eukaryote Saccharomyces cerevisiae.
IUBMB Life, 56: 585‐594, 2004
PATJ regulates tight junction formation and polarity in mammalian epithelial cells
Authors: Shin Kunyoo , Straight Sam , Margolis Ben
Published: February 2005

Recent studies have revealed an important role for tight junction protein complexes in epithelial cell polarity. One of these complexes contains the apical transmembrane protein, Crumbs, and two PSD95/discs large/zonula occludens domain proteins, protein associated with Lin seven 1 (PALS1)/Stardust and PALS1-associated tight junction protein (PATJ). Although Crumbs and PALS1/Stardust are known to be important for cell polarization, recent studies have suggested that Drosophila PATJ is not essential and its function is unclear. Here, we find that PATJ is targeted to the apical region and tight junctions once cell polarization is initiated. We show using RNAi techniques that reduction in PATJ expression leads to delayed tight junction formation as well as defects in cell polarization. These effects are reversed by reintroduction of PATJ into these RNAi cells. This study provides new functional information on PATJ as a polarity protein and increases our understanding of the Crumbs–PALS1–PATJ complex function in epithelial polarity.
Dynamic ergosterol- and ceramide-rich domains in the peroxisomal membrane serve as an organizing platform for peroxisome fusion
Authors: Boukh-Viner Tatiana , Guo Tong , Alexandrian Alex , Cerracchio André , Gregg Christopher , Haile Sandra , Kyskan Robert , Milijevic Svetlana , Oren Daniel , Solomon Jonathan , Wong Vivianne , Nicaud Jean-Marc , Rachubinski Richard A. , English Ann M. , Titorenko Vladimir I.
Published: February 2005

We describe unusual ergosterol- and ceramide-rich (ECR) domains in the membrane of yeast peroxisomes. Several key features of these detergent-resistant domains, including the nature of their sphingolipid constituent and its unusual distribution across the membrane bilayer, clearly distinguish them from well characterized detergent-insoluble lipid rafts in the plasma membrane. A distinct set of peroxisomal proteins, including two ATPases, Pex1p and Pex6p, as well as phosphoinositide- and GTP-binding proteins, transiently associates with the cytosolic face of ECR domains. All of these proteins are essential for the fusion of the immature peroxisomal vesicles P1 and P2, the earliest intermediates in a multistep pathway leading to the formation of mature, metabolically active peroxisomes. Peroxisome fusion depends on the lateral movement of Pex1p, Pex6p, and phosphatidylinositol-4,5-bisphosphate–binding proteins from ECR domains to a detergent-soluble portion of the membrane, followed by their release to the cytosol. Our data suggest a model for the multistep reorganization of the multicomponent peroxisome fusion machinery that transiently associates with ECR domains.
Crossing over is coupled to late meiotic prophase bivalent differentiation through asymmetric disassembly of the SC
Authors: Nabeshima Kentaro , Villeneuve Anne M. , Colaiácovo Monica P.
Published: February 2005

Homologous chromosome pairs (bivalents) undergo restructuring during meiotic prophase to convert a configuration that promotes crossover recombination into one that promotes bipolar spindle attachment and localized cohesion loss. We have imaged remodeling of meiotic chromosome structures after pachytene exit in Caenorhabditis elegans. Chromosome shortening during diplonema is accompanied by coiling of chromosome axes and highly asymmetric departure of synaptonemal complex (SC) central region proteins SYP-1 and SYP-2, which diminish over most of the length of each desynapsing bivalent while becoming concentrated on axis segments distal to the single emerging chiasma. This and other manifestations of asymmetry along chromosomes are lost in synapsis-proficient crossover-defective mutants, which often retain SYP-1,2 along the full lengths of coiled diplotene axes. Moreover, a γ-irradiation treatment that restores crossovers in the spo-11 mutant also restores asymmetry of SYP-1 localization. We propose that crossovers or crossover precursors serve as symmetry-breaking events that promote differentiation of subregions of the bivalent by triggering asymmetric disassembly of the SC.
Phosphorylation of Titin Modulates Passive Stiffness of Cardiac Muscle in a Titin Isoform-dependent Manner
Authors: Fukuda Norio , Wu Yiming , Nair Preetha , Granzier Henk L.
Published: February 2005

We investigated the effect of protein kinase A (PKA) on passive force in skinned cardiac tissues that express different isoforms of titin, i.e., stiff (N2B) and more compliant (N2BA) titins, at different levels. We used rat ventricular (RV), bovine left ventricular (BLV), and bovine left atrial (BLA) muscles (passive force: RV > BLV > BLA, with the ratio of N2B to N2BA titin, ∼90:10, ∼40:60, and ∼10:90%, respectively) and found that N2B and N2BA isoforms can both be phosphorylated by PKA. Under the relaxed condition, sarcomere length was increased and then held constant for 30 min and the peak passive force, stress-relaxation, and steady-state passive force were determined. Following PKA treatment, passive force was significantly decreased in all muscle types with the effect greatest in RV, lowest in BLA, and intermediate in BLV. Fitting the stress-relaxation data to the sum of three exponential decay functions revealed that PKA blunts the magnitude of stress-relaxation and accelerates its time constants. To investigate whether or not PKA-induced decreases in passive force result from possible alteration of titin–thin filament interaction (e.g., via troponin I phosphorylation), we conducted the same experiments using RV preparations that had been treated with gelsolin to extract thin filaments. PKA decreased passive force in gelsolin-treated RV preparations with a magnitude similar to that observed in control preparations. PKA was also found to decrease restoring force in skinned ventricular myocytes of the rat that had been shortened to below the slack length. Finally, we investigated the effect of the β-adrenergic receptor agonist isoprenaline on diastolic force in intact rat ventricular trabeculae. We found that isoprenaline phosphorylated titin and that it reduced diastolic force to a degree similar to that found in skinned RV preparations. Taken together, these results suggest that during β-adrenergic stimulation, PKA increases ventricular compliance in a titin isoform-dependent manner.
Photoreceptors ofNrl−/− Mice Coexpress Functional S- and M-cone Opsins Having Distinct Inactivation Mechanisms
Authors: Nikonov Sergei S. , Daniele Lauren L. , Zhu Xuemei , Craft Cheryl M. , Swaroop Anand , Pugh Edward N.
Published: February 2005

The retinas of mice null for the neural retina leucine zipper transcription factor (Nrl −/−) contain no rods but are populated instead with photoreceptors that on ultrastructural, histochemical, and molecular criteria appear cone like. To characterize these photoreceptors functionally, responses of single photoreceptors of Nrl −/− mice were recorded with suction pipettes at 35–37°C and compared with the responses of rods of WT mice. Recordings were made either in the conventional manner, with the outer segment (OS) drawn into the pipette (“OS in”), or in a novel configuration with a portion of the inner segment drawn in (“OS out”). Nrl −/− photoreceptor responses recorded in the OS-out configuration were much faster than those of WT rods: for dim-flash responses tpeak = 91 ms vs. 215 ms; for saturating flashes, dominant recovery time constants, τD = 110 ms vs. 240 ms, respectively. Nrl −/− photoreceptors in the OS-in configuration had reduced amplification, sensitivity, and slowed recovery kinetics, but the recording configuration had no effect on rod response properties, suggesting Nrl −/− outer segments to be more susceptible to damage. Functional coexpression of two cone pigments in a single mammalian photoreceptor was established for the first time; the responses of every Nrl −/− cell were driven by both the short-wave (S, λmax ≈ 360 nm) and the mid-wave (M, λmax ≈ 510 nm) mouse cone pigment; the apparent ratio of coexpressed M-pigment varied from 1:1 to 1:3,000 in a manner reflecting a dorso-ventral retinal position gradient. The role of the G-protein receptor kinase Grk1 in cone pigment inactivation was investigated in recordings from Nrl −/−/Grk1−/− photoreceptors. Dim-flash responses of cells driven by either the S- or the M-cone pigment were slowed 2.8-fold and 7.5-fold, respectively, in the absence of Grk1; the inactivation of the M-pigment response was much more seriously retarded. Thus, Grk1 is essential to normal inactivation of both S- and M-mouse cone opsins, but S-opsin has access to a relatively effective, Grk1-independent inactivation pathway.
On degrees of irreducible Brauer characters
Authors: Willems W.
Published: February 2005

Based on a large amount of examples, which we have checked so far, we conjecture that

|

G

|

p
′

≤

∑
φ

φ
(
1

)
2

|G|_{p’}\le \sum _\varphi \varphi (1)^2

where

p
p

is a prime and the sum runs through the set of irreducible Brauer characters in characteristic

p
p

of the finite group

G
G

. We prove the conjecture simultaneously for

p
p

-solvable groups and groups of Lie type in the defining characteristic. In non-defining characteristics we give asymptotically an affirmative answer in many cases.
Characteristic subsurfaces and Dehn filling
Authors: Boyer Steve , Culler Marc , Shalen Peter , Zhang Xingru
Published: February 2005

Let

M
M

be a simple knot manifold. Using the characteristic submanifold theory and the combinatorics of graphs in surfaces, we develop a method for bounding the distance between the boundary slope of an essential surface in

M
M

which is not a fiber or a semi-fiber, and the boundary slope of a certain type of singular surface. Applications include bounds on the distances between exceptional Dehn surgery slopes. It is shown that if the fundamental group of

M
(
α
)

M(\alpha )

has no non-abelian free subgroup, and if

M
(
β
)

M(\beta )

is a reducible manifold which is not homeomorphic to

S
1

×

S
2

S^1 \times S^2

or

P
3

#

P
3

P^3 \# P^3

, then

Δ
(
α
,
β
)
≤
5

\Delta (\alpha , \beta )\le 5

. Under the same condition on

M
(
β
)

M(\beta )

, it is shown that if

M
(
α
)

M(\alpha )

is Seifert fibered, then

Δ
(
α
,
β
)
≤
6

\Delta (\alpha , \beta )\le 6

. Moreover, in the latter situation, character variety techniques are used to characterize the topological types of

M
(
α
)

M(\alpha )

and

M
(
β
)

M(\beta )

in case the bound of

6
6

is attained.
Positivity preserving transformations for 𝑞-binomial coefficients
Authors: Berkovich Alexander , Warnaar S.
Published: February 2005

Several new transformations forqq-binomial coefficients are found, which have the special feature that the kernel is a polynomial with nonnegative coefficients. By studying the group-like properties of these positivity preserving transformations, as well as their connection with the Bailey lemma, many new summation and transformation formulas for basic hypergeometric series are found. The newqq-binomial transformations are also applied to obtain multisum Rogers–Ramanujan identities, to find new representations for the Rogers–Szegö polynomials, and to make some progress on Bressoud’s generalized Borwein conjecture. For the original Borwein conjecture we formulate a refinement based on new triple sum representations of the Borwein polynomials.
On some constants in the supercuspidal characters of 𝐺𝐿_{𝑙}, 𝑙 a prime ≠𝑝
Authors: Takahashi Tetsuya
Published: February 2005

The article gives explicit values of some constants which appear in the character formula for the irreducible supercuspidal representation of

GL
l

⁡
(
F
)

\operatorname {GL}_l(F)

for

F
F

a local field of the residual characteristic

p
≠
l

p\neq l

.
Duality and uniqueness of convex solutions to stationary Hamilton-Jacobi equations
Authors: Goebel Rafal
Published: February 2005

Value functions for convex optimal control problems on infinite time intervals are studied in the framework of duality. Hamilton-Jacobi characterizations and the conjugacy of primal and dual value functions are of main interest. Close ties between the uniqueness of convex solutions to a Hamilton-Jacobi equation, the uniqueness of such solutions to a dual Hamilton-Jacobi equation, and the conjugacy of primal and dual value functions are displayed. Simultaneous approximation of primal and dual infinite horizon problems with a pair of dual problems on finite horizon, for which the value functions are conjugate, leads to sufficient conditions on the conjugacy of the infinite time horizon value functions. Consequently, uniqueness results for the Hamilton-Jacobi equation are established. Little regularity is assumed on the cost functions in the control problems, correspondingly, the Hamiltonians need not display any strict convexity and may have several saddle points.
Analysis of a coupled system of kinetic equations and conservation laws: Rigorous derivation and existence theory via defect measures
Authors: Tidriri M.
Published: February 2005

In this paper we introduce a coupled system of kinetic equations of B.G.K. type and then study its hydrodynamic limit. We obtain as a consequence the rigorous derivation and existence theory for a coupled system of kinetic equations and their hydrodynamic (conservation laws) limit. The latter is a particular case of the coupled system of Boltzmann and Euler equations. A fundamental element in this study is the rigorous derivation and justification of the interface conditions between the kinetic model and its hydrodynamic conservation laws limit, which is obtained using a new regularity theory introduced herein.
Stable rank and real rank for some classes of group 𝐶*-algebras
Authors: Archbold Robert , Kaniuth Eberhard
Published: February 2005

We investigate the real and stable rank of the

C
∗

C^\ast

-algebras of locally compact groups with relatively compact conjugacy classes or finite-dimensional irreducible representations. Estimates and formulae are given in terms of the group-theoretic rank.
Orbifolds and analytic torsions
Authors: Ma Xiaonan
Published: February 2005

In this paper, we calculate the behavior of the Quillen metric by orbifold immersions. We thus extend a formula of Bismut-Lebeau to the orbifold case.

Résumé. Dans cet article, on calcule le comportement de métrique de Quillen par immersions d’orbifold. On étend ainsi une formule de Bismut-Lebeau au cas d’orbifold.
Two‐Sample Tests for Comparing Intra‐Individual Genetic Sequence Diversity between Populations
Authors: Gilbert Peter B. , Rossini A. J. , Shankarappa Raj
Published: February 2005

Summary Consider a study of two groups of individuals infected with a population of a genetically related heterogeneous mixture of viruses, and multiple viral sequences are sampled from each person. Based on estimates of genetic distances between pairs of aligned viral sequences within individuals, we develop four new tests to compare intra‐individual genetic sequence diversity between the two groups. This problem is complicated by two levels of dependency in the data structure: (i) Within an individual, any pairwise distances that share a common sequence are positively correlated; and (ii) for any two pairings of individuals which share a person, the two differences in intra‐individual distances between the paired individuals are positively correlated. The first proposed test is based on the difference in mean intra‐individual pairwise distances pooled over all individuals in each group, standardized by a variance estimate that corrects for the correlation structure using U‐statistic theory. The second procedure is a nonparametric rank‐based analog of the first test, and the third test contrasts the set of subject‐specific average intra‐individual pairwise distances between the groups. These tests are very easy to use and solve correlation problem (i). The fourth procedure is based on a linear combination of all possible U‐statistics calculated on independent, identically distributed sequence subdatasets, over the two levels (i) and (ii) of dependencies in the data, and is more complicated than the other tests but can be more powerful. Although the proposed methods are empirical and do not fully utilize knowledge from population genetics, the tests reflect biology through the evolutionary models used to derive the pairwise sequence distances. The new tests are evaluated theoretically and in a simulation study, and are applied to a dataset of 200 HIV sequences sampled from 21 children.
Multi‐List Methods Using Incomplete Lists in Closed Populations
Authors: Sutherland Jason , Schwarz Carl James
Published: February 2005

SummaryMulti‐list methods have become a common application of capture–recapture methodology to estimate the size of human populations, and have been successfully applied to estimating prevalence of diabetes, human immunodeficiency virus (HIV), and drug abuse. A key assumption in multi‐list methods is that individuals have a unique “tag” that allows them to be matched across all lists. This article develops multi‐list methodology that relaxes the assumption of a single tag common to all lists. Estimates are found using estimating functions. An example illustrates its application for estimating the prevalence of diabetes, and a simulation study investigates conditions under which the methodology is robust to different list and population sizes.
A Markov Chain Model for Animal Estrous Cycling Data
Authors: Zhai J. , Morris R. W.
Published: February 2005

SummaryEstrous cycling data contain sequences of characters (e.g., DPEMD). Each sequence represents an animal's estrous cycle, with each character indicating the daily estrous cycle stage. Changes in the estrous cycle pattern, which is determined by estrous stage lengths, can provide information on adverse events. Stage lengths are not directly observable. However interval censored lengths for all but the first and the last stages in a sequence can be extracted from the data. We propose a Markov chain model to approximate the estrous cycling process. The transition probabilities from one stage to another can be derived by conditioning on stage lengths. Assuming Weibull distribution for stage lengths, with the second Weibull parameter depending upon treatment effects and animal‐specific random effects, regression models on censored stage lengths are fitted. A Bayesian approach is used for inference on dose effects. The analysis is implemented with MCMC method inWinBUGS. An estrous cycling data set from a National Toxicology Program study is analyzed as an example.
Robust Estimation of Multivariate Covariance Components
Authors: Dueck Amylou , Lohr Sharon
Published: February 2005

Summary In many settings, such as interlaboratory testing, small area estimation in sample surveys, and heritability studies, investigators are interested in estimating covariance components for multivariate measurements. However, the presence of outliers can seriously distort estimates obtained using standard procedures such as maximum likelihood. We propose a procedure based on M‐estimation for robustly estimating multivariate covariance components in the presence of outliers; the procedure applies to balanced and unbalanced data. We present an algorithm for computing the robust estimates and examine the performance of the estimator through a simulation study. The estimator is used to find covariance components and identify outliers in a study of variability of egg length and breadth measurements of American coots.
Attributable Effects in Case2‐Studies
Authors: Rosenbaum Paul R.
Published: February 2005

Summary In an effort to determine whether a particular treatment causes a particular outcome event, data are obtained from a database system that records events when they occur, and for such events, the system records exposure to the treatment. That is, the system records information about cases. The system provides no information about events that might have occurred but did not, that is, about units which are not cases. Roughly speaking, we know the number of successes for two proportions, treated and control, but not the numbers of trials or units for these proportions; indeed, the concept of a “trial” may be somewhat vague. With no further information, the situation is quite hopeless. However, an interesting strategy that is sometimes used entails identifying two types of cases whose origin is entirely different so that it is known the cases of the second type were definitely not affected by the treatment under study. This strategy—the case–case or case2‐study—seems to have been reinvented independently many times, and has recently been offered as a general strategy for infectious disease epidemiology by McCarthy and Giesecke (1999, International Journal of Epidemiology28, 764–768). Can this strategy permit estimation of the number of cases caused by the treatment? Using attributable effects in a new way, a method of exact inference is proposed, along with a large sample approximation. Two examples are discussed: one concerning the effects of daytime running lights (DRLs) on the risk of multivehicle accidents; the other concerning the origin of a Salmonella infection. A counterexample with superficially similar appearance is also discussed concerning suicide rates following the publication of Final Exit; here, the treatment may alter the outcome, or it may alter the type, and the attributable effect cannot be estimated.
A Flexible B‐Spline Model for Multiple Longitudinal Biomarkers and Survival
Authors: Brown Elizabeth R. , Ibrahim Joseph G. , DeGruttola Victor
Published: February 2005

SummaryOften when jointly modeling longitudinal and survival data, we are interested in a multivariate longitudinal measure that may not fit well by linear models. To overcome this problem, we propose a joint longitudinal and survival model that has a nonparametric model for the longitudinal markers. We use cubic B‐splines to specify the longitudinal model and a proportional hazards model to link the longitudinal measures to the hazard. To fit the model, we use a Markov chain Monte Carlo algorithm. We select the number of knots for the cubic B‐spline model using the Conditional Predictive Ordinate (CPO) and the Deviance Information Criterion (DIC). The method and model selection approach are validated in a simulation. We apply this method to examine the link between viral load, CD4 count, and time to event in data from an AIDS clinical trial. The cubic B‐spline model provides a good fit to the longitudinal data that could not be obtained with simple parametric models.
Bayesian Adaptive Biased‐Coin Designs for Clinical Trials with Normal Responses
Authors: Atkinson Anthony C. , Biswas Atanu
Published: February 2005

Summary Adaptive designs are used in phase III clinical trials for skewing the allocation pattern toward the better treatments. We use optimum design theory to derive a skewed Bayesian biased‐coin procedure for sequential designs with continuous responses. The skewed designs are used to provide adaptive designs, the performance of which is studied numerically and theoretically. Important properties are loss and the proportion of allocation to the better treatment.
Multiple Imputation for Model Checking: Completed‐Data Plots with Missing and Latent Data
Authors: Gelman Andrew , Van Mechelen Iven , Verbeke Geert , Heitjan Daniel F. , Meulders Michel
Published: February 2005

SummaryIn problems with missing or latent data, a standard approach is to first impute the unobserved data, then perform all statistical analyses on thecompleteddataset—corresponding to the observed data and imputed unobserved data—using standard procedures for complete‐data inference. Here, we extend this approach to model checking by demonstrating the advantages of the use of completed‐data model diagnostics on imputed completed datasets. The approach is set in the theoretical framework of Bayesian posterior predictive checks (but, as with missing‐data imputation, our methods of missing‐data model checking can also be interpreted as “predictive inference” in a non‐Bayesian context). We consider the graphical diagnostics within this framework. Advantages of the completed‐data approach include: (1) One can often check model fit in terms of quantities that are of key substantive interest in a natural way, which is not always possible using observed data alone. (2) In problems with missing data, checks may be devised that do not require to model the missingness or inclusion mechanism; the latter is useful for the analysis of ignorable but unknown data collection mechanisms, such as are often assumed in the analysis of sample surveys and observational studies. (3) In many problems with latent data, it is possible to check qualitative features of the model (for example, independence of two variables) that can be naturally formalized with the help of the latent data. We illustrate with several applied examples.
Applying Concepts of Generalizability Theory on Clinical Trial Data to Investigate Sources of Variation and Their Impact on Reliability
Authors: Vangeneugden Tony , Laenen Annouschka , Geys Helena , Renard Didier , Molenberghs Geert
Published: February 2005

SummaryThis work aims at applying concepts of generalizability theory to data resulting from clinical trials. The focus is to study the sources of variance and their impact on the reliability and generalizability of a psychiatric measurement scale. The goal is to identify, measure, and thereby potentially find strategies to reduce the influence of these sources on the measurement in question for future trials. This approach was originally devised by Cronbach and his associates and is known as generalizability theory. This work shows how full modeling power in mixed models can be used to study generalizability using data from five double‐blind randomized clinical trials, comparing the effects of risperidone to conventional antipsychotic agents for the treatment of chronic schizophrenia.
Wavelet Thresholding with Bayesian False Discovery Rate Control
Authors: Tadesse Mahlet G. , Ibrahim Joseph G. , Vannucci Marina , Gentleman Robert
Published: February 2005

Summary The false discovery rate (FDR) procedure has become a popular method for handling multiplicity in high‐dimensional data. The definition of FDR has a natural Bayesian interpretation; it is the expected proportion of null hypotheses mistakenly rejected given a measure of evidence for their truth. In this article, we propose controlling the positive FDR using a Bayesian approach where the rejection rule is based on the posterior probabilities of the null hypotheses. Correspondence between Bayesian and frequentist measures of evidence in hypothesis testing has been studied in several contexts. Here we extend the comparison to multiple testing with control of the FDR and illustrate the procedure with an application to wavelet thresholding. The problem consists of recovering signal from noisy measurements. This involves extracting wavelet coefficients that result from true signal and can be formulated as a multiple hypotheses‐testing problem. We use simulated examples to compare the performance of our approach to the Benjamini and Hochberg (1995, Journal of the Royal Statistical Society, Series B57, 289–300) procedure. We also illustrate the method with nuclear magnetic resonance spectral data from human brain.
Assessing Accuracy of Mammography in the Presence of Verification Bias and Intrareader Correlation
Authors: Zheng Yingye , Barlow William E. , Cutter Gary
Published: February 2005

SummaryThe performance of a medical diagnostic test is often evaluated by comparing the outcome of the test to the patient's true disease state. Receiver operating characteristic analysis may then be used to summarize test accuracy. However, such analysis may encounter several complications in actual practice. One complication is verification bias, i.e., gold standard assessment of disease status may only be partially available and the probability of ascertainment of disease may depend on both the test result and characteristics of the subject. A second issue is that tests interpreted by the same rater may not be independent. Using estimating equations, we generalize previous methods that address these problems. We contrast the performance of alternative estimators of accuracy using robust sandwich variance estimators to permit valid asymptotic inference. We suggest that in the context of an observational cohort study where rich covariate information is available, a weighted estimating equations approach may be preferable for its robustness against model misspecification. We apply the methodology to mammography as performed by community radiologists.
A Stochastic Model to Analyze Clonal Data on Multi‐Type Cell Populations
Authors: Hyrien Ollivier , Mayer‐Pröschel Margot , Noble Mark , Yakovlev Andrei
Published: February 2005

SummaryThis article presents a stochastic model designed to analyze experimental data on the development of cell clones composed of two (or more) distinct types of cells. The proposed model is an extension of the traditional multi‐type Bellman–Harris branching stochastic process allowing for nonidentical time‐to‐transformation distributions defined for different cell types. A simulated pseudo likelihood method has been developed for the parametric statistical inference from experimental data on cell clones under the proposed model. The method uses simulation‐based approximations of the means and the variance–covariance matrices of cell counts. The proposed estimator for the vector of unknown parameters is strongly consistent and asymptotically normal under mild regularity conditions, while its variance–covariance matrix is estimated by the parametric bootstrap. A Monte Carlo Wald test is proposed for the test of hypotheses. Finite sample properties of the estimator have been studied by computer simulations. The model and associated methods of parametric inference have been applied to the analysis of proliferation and differentiation of cultured O‐2A progenitor cells that play a key role in the development of the central nervous system. It follows from this analysis that the time to division of the progenitor cell and the time to its differentiation (into an oligodendrocyte) are not identically distributed. This biological finding suggests that a molecular event determining the type of cell transformation is more likely to occur at the start rather than at the end of the mitotic cycle.
Multiplicity‐Adjusted Inferences in Risk Assessment: Benchmark Analysis with Quantal Response Data
Authors: Nitcheva Daniela K. , Piegorsch Walter W. , Webster West R. , Kodell Ralph L.
Published: February 2005

Summary A primary objective in quantitative risk or safety assessment is characterization of the severity and likelihood of an adverse effect caused by a chemical toxin or pharmaceutical agent. In many cases data are not available at low doses or low exposures to the agent, and inferences at those doses must be based on the high‐dose data. A modern method for making low‐dose inferences is known as benchmark analysis, where attention centers on the dose at which a fixed benchmark level of risk is achieved. Both upper confidence limits on the risk and lower confidence limits on the “benchmark dose” are of interest. In practice, a number of possible benchmark risks may be under study; if so, corrections must be applied to adjust the limits for multiplicity. In this short note, we discuss approaches for doing so with quantal response data.
Bayesian Inferences on Predictors of Conception Probabilities
Authors: Dunson David B. , Stanford Joseph B.
Published: February 2005

SummaryReproductive scientists and couples attempting pregnancy are interested in identifying predictors of the day‐specific probabilities of conception in relation to the timing of a single intercourse act. Because most menstrual cycles have multiple days of intercourse, the occurrence of conception represents the aggregation across Bernoulli trials for each intercourse day. Because of this data structure and dependency among the multiple cycles from a woman, implementing analyses has proven challenging. This article proposes a Bayesian approach based on a generalization of the Barrett and Marshall model to incorporate a woman‐specific frailty and day‐specific covariates. The model results in a simple closed form expression for the marginal probability of conception, and has an auxiliary variables formulation that facilitates efficient posterior computation. Although motivated by fecundability studies, the approach can be used for efficient variable selection and model averaging in general applications with categorical or discrete event time data.
A Queueing Model for Chronic Recurrent Conditions under Panel Observation
Authors: Crespi Catherine M. , Cumberland William G. , Blower Sally
Published: February 2005

Summary In many chronic conditions, subjects alternate between an active and an inactive state, and sojourns into the active state may involve multiple lesions, infections, or other recurrences with different times of onset and resolution. We present a biologically interpretable model of such chronic recurrent conditions based on a queueing process. The model has a birth–death process describing recurrences and a semi‐Markov process describing the alternation between active and inactive states, and can be fit to panel data that provide only a binary assessment of the active or inactive state at a series of discrete time points using a hidden Markov approach. We accommodate individual heterogeneity and covariates using a random effects model, and simulate the posterior distribution of unknowns using a Markov chain Monte Carlo algorithm. Application to a clinical trial of genital herpes shows how the method can characterize the biology of the disease and estimate treatment efficacy.
Genomic Control for Association Studies under Various Genetic Models
Authors: Zheng Gang , Freidlin Boris , Li Zhaohai , Gastwirth Joseph L.
Published: February 2005

Summary Case–control studies are commonly used to study whether a candidate allele and a disease are associated. However, spurious association can arise due to population substructure or cryptic relatedness, which cause the variance of the trend test to increase. Devlin and Roeder derived the appropriate variance inflation factor (VIF) for the trend test and proposed a novel genomic control (GC) approach to estimate VIF and adjust the test statistic. Their results were derived assuming an additive genetic model and the corresponding VIF is independent of the candidate allele frequency. We determine the appropriate VIFs for recessive and dominant models. Unlike the additive test, the VIFs for the optimal tests for these two models depend on the candidate allele frequency. Simulation results show that, when the null loci used to estimate the VIF have allele frequencies similar to that of the candidate gene, the GC tests derived for recessive and dominant models remain optimal. When the underlying genetic model is unknown or the null loci and candidate gene have quite different allele frequencies, the GC tests derived for the recessive or dominant models cannot be used while the GC test derived for the additive model can be.
Singing as a handicap: the effects of food availability and weather on song output in the Australian reed warbler Acrocephalus australis
Authors: Berg Mathew L. , Beintema Nienke H. , Welbergen Justin A. , Komdeur Jan
Published: February 2005

Bird song is generally regarded as a sexually selected trait, and may represent a reliable handicap signal under at least certain conditions. Females may use the degree of male song production as a reliable cue to male condition or territory quality. We investigated the effect of supplementary feeding on song output in the migratory Australian reed warbler Acrocephalus australis. We experimentally increased the food availability on alternate days, and recorded several weather variables. We measured song rate and song length independently. Supplementary fed birds sang more on feeding days than on non‐feeding days, while control birds did not show this effect. Song output was not significantly associated with any of the weather variables examined. Our results indicate that singing has the potential to serve as a reliable handicap signal to territorial food availability irrespective of the prevailing weather conditions. We discuss the role of energetic constraints and behavioural flexibility on the signaling function of song.
Effects of large‐scale climatic fluctuations on survival and production of young in a Neotropical migrant songbird, the yellow warblerDendroica petechia
Authors: Mazerolle Daniel F. , Dufour Kevin W. , Hobson Keith A. , Haan Heidi E. den
Published: February 2005

Migrant songbirds are vulnerable to changes in climatic conditions on both the breeding and wintering grounds. For North American Neotropical migrants, the El Niño/Southern Oscillation (ENSO), via its effects on global precipitation and temperature, modulates the productivity of their temperate and tropical terrestrial ecosystems used during the course of their annual cycle. We evaluated how a densely nesting population of yellow warblersDendroica petechiain a riparian forest in southern Manitoba, Canada, responded to the El Niño/Southern Oscillation (ENSO) between 1992 and 2001. Standardized mist netting was used to estimate apparent annual survival of adults and production of young. Both adult survival and the production of young were positively correlated with the Southern Oscillation Index (SOI). More specifically, values of both these demographic parameters were lowest during El Niño years and highest during La Niña years. These findings demonstrate the influence of climate on populations of Neotropical migrants in North America. The more frequent El Niños predicted to result from future global climate change could negatively affect populations of yellow warblers and other Neotropical migrants breeding in this region.
Dietary calcium limits size and growth of nestling tree swallows Tachycineta bicolor in a non‐acidified landscape
Authors: Dawson Russell D. , Bidwell Mark T.
Published: February 2005

Much previous research has focussed on the role of food supply in determining the growth and the survival of avian offspring. More recently, acid deposition in some ecosystems has demonstrated that in addition to energy, birds also need to acquire sufficient nutrients such as calcium to be successful. Whether procurement of adequate levels of calcium can limit reproductive success in areas that have not been impacted by acid rain remains equivocal. We tested whether calcium affected reproductive success of tree swallows Tachycineta bicolor by feeding extra calcium to nestlings during the brood‐rearing period. Our manipulation did not enhance the survival of offspring, however, provisioning of extra calcium resulted in nestlings showing enhanced rates of growth of mass (all nests) and of ninth primary flight feathers (nests with after‐second year female parents), compared to control nestlings. Calcium supplementation also resulted in nestlings having longer feathers and tarsi at age 16 days, and there was evidence that some nestlings receiving extra calcium were heavier at 16 days old. As offspring that have faster growth, or that are in good condition at fledging, often survive better after leaving the nest, these results suggest that calcium availability can limit fitness. Our results are noteworthy because our experiment was conducted in an area with abundant soil calcium where acid deposition has not occurred. The role of calcium in limiting the reproductive performance of avian species may therefore be more pervasive than previously thought.
3D seismic technology: the geological ‘Hubble’
Authors: Cartwright Joe , Huuse Mads
Published: February 2005

The proliferation of three‐dimensional (3D) seismic technology is one of the most exciting developments in the Earth Sciences over the past century. 3D reflection seismic data provide interpreters with the ability to map structures and stratigraphic features in 3D detail to a resolution of a few tens of metres over thousands of square kilometres. It is a geological ‘Hubble’, whose resolving power has already yielded some fascinating (and surprising) insights and will continue to provide a major stimulus for research into geological processes and products for many decades to come. Academic and other research institutions have a major role to play in the use of this data by exploiting the enormous volume of geological information contained in 3D seismic surveys. This paper reviews some of the recent advances in basin analysis made using the medium of 3D seismic data, focusing on the fields of structural and sedimentary geology, fluid–rock interactions and igneous geology. It is noted that the increased resolution of the 3D seismic method provided the essential catalyst necessary to stimulate novel observations and discover new geological structures such as mud diapir feeders, km‐long gas blow‐out pipes, giant pockmarks and sandstone intrusions, and to capture the spatial variability of diagenetic fronts. The UKs first impact crater was also discovered using 3D seismic data. The potential for future developments in this field of geophysical interpretation is considerable, and we anticipate that new discoveries will be made in many years to come.