bluuebunny/crossref_metadata_2025 huggingface dataset:
Using provisional diagnoses in monitoring a clinical trial
Authors: Karon John M.
Published: April 2007

In clinical trials there is delay between the occurrence of an event and the recording of that event as an end point in the trial data base. Delays are especially likely if events are reviewed carefully to determine whether diagnostic criteria for end points are satisfied. As a result, the value of a a statistic used to evaluate efficacy during a trial may differ from the value of that statistic based on the true end point status of all events which have already occurred. Simulating the process causing delays can be useful in evaluating interim efficacy data by providing a quantitative estimate of the uncertainty in a monitoring statistic. These ideas are illustrated using data from the Lipid Research Clinics Coronary Primary Prevention Trial.
Crossover trials, degrees of freedom, the carryover problem and its dual
Authors: Senn S. J. , Hildebrand H.
Published: April 2007

The problem of carryover in crossover trials has received a great deal of attention in the statistical literature. Carryover is just one form of period by treatment interaction; yet a parallel problem of patient by treatment interaction, which may be regarded as dual to that of carryover, has received little attention. We suggest that the phenomenon of patient by treatment interaction requires a repeated measures approach to the analysis of crossover trials. A simple solution using predefined contrasts is presented and illustrated by example.
Multivariate probit analysis: A neglected procedure in medical statistics
Authors: Lesaffre E. , Molenberghs G.
Published: April 2007

The multivariate probit model is designed to regress a vector of correlated quantal variables on a mixture of continuous and discrete predictors. Various applications can be found in the biological, economical and psychosociological literature, but the method is not yet widely used in medical applications. We reintroduce this model thereby showing its usefulness in medical problems. Software for this model is, however, not widely available. We have written a PC program to select predictors and estimate parameters in the multivariate probit framework. The performance and characteristics of the program are briefly illustrated.
Pooling controls from different studies
Authors: Raghunathan T. E.
Published: April 2007

This paper develops a method for estimating the odds ratio in a case‐control study that ‘borrows’ strength from the controls in similar previous studies. We assume that the observations within each stratum in the current study are generated from a pair of independent binomial distributions. We assume that the observations on the controls, again within each stratum and from the previous studies, are independent binomial random variables. We use these controls to construct a prior distribution for the stratum specific log‐odds for the controls in the current study which we then combine with the likelihood from the current study to arrive at the posterior distribution of the target quantities of interest, the adjusted or stratum specific log‐odds ratios. We assume a diffuse prior distribution for the stratum specific log‐odds ratio. A simulation study investigates the frequency or repeated sampling properties of the inference based upon the posterior distribution of the log‐odds ratio so constructed.
Modelling hearing thresholds in the elderly
Authors: Morrell Christopher H. , Brant Larry J.
Published: April 2007

This paper concerns a linear mixed‐effects repeated measures model in the analysis of a large data set with over 17,000 observations in a longitudinal study of pure‐tone hearing perception in the elderly. The repeated measurements are described by fixed and random components in the model. The fixed effects include the age at entry, time of follow‐up, a quadratic component in natural logarithm of frequency, a component to allow for participants with hearing impairments, as well as interaction terms between age and frequency and between impairment and frequency. The random factors include a term for subject, a time component and a frequency component. The analysis shows that hearing impaired individuals have similar patterns of hearing loss over time but, on average, have higher hearing thresholds than normal individuals. Estimation of the random effects in the model by restricted maximum likelihood (REML) using the Newton‐Raphson method made possible the analysis of this large data set with speed and efficiency.
Radiation dose and leukaemia risk: General relative risk techniques for dose‐response models in a matched case‐control study
Authors: Blettner Maria , Boice John D.
Published: April 2007

Generalized relative risk functions were used to model radiation dose‐response information from a large matched case‐control study of leukaemia occurring after treatment for cervical cancer. Models suggested by radiobiological theory were investigated and compared to standard analyses of categorical dose‐response to the linear model. Local radiation doses to each of fourteen bone marrow compartements for each patient were incorporated into the models, and the corresponding risks were summed. Conditional maximum likelihood methods were used to estimate risk parameters. Unique features of the analysis include modelling both induction and reduction of risk as a function of radiation dose absorbed by different parts of the body within individuals. Detailed statistical aspects of these analyses are presented and discussed.
AX one degree of freedom nominal association model for testing independence in two‐way contingency tables
Authors: Davis Charles S.
Published: April 2007

In testing the independence of the row and column variables in a two‐way contingency table, the standard Pearson and likelihood ratio chi‐square statistics often have low power, especially as the dimensions of the table increase. In this paper, one degree of freedom tests of independence based on likelihood ratio and score statistics from an association model for tables with nominal row and column classifications are described. The score statistic is especially easy to use, since it can be expressed in closed form, is simple to compute, and has size and power properties which are only slightly inferior to those of the more complicated likelihood ratio statistic.
Estimation of vaccine efficacy in outbreaks of acute infectious diseases
Authors: Haber Michael , Longini Ira M. , Halloran M. Elizabeth
Published: April 2007

In a previous paper we defined the efficacy of a vaccine as 1 ‐ β1/β1, where β0 is the instantaneous probability of transmission of infection to an unvaccinated person exposed to a single infectious person, and β1 is similarly defined for a vaccinated person. We showed that under the conditions of an outbreak of an acute, directly transmitted infectious disease in a homogeneous and randomly mixing population, an estimate of this measure of vaccine efficacy is 1 ‐ [ln(1 ‐ A1)/ln(1 ‐ A0)], where A0 and A1 are the observed final attack rates among unvaccinated and vaccinated persons, respectively. In the present work we present an approximation for the standard error of this estimator, accounting for both the sampling and process variation. We extend the results of our previous paper to a stratified population, where the strata correspond to different levels of susceptibility and may have different vaccination coverages. We also consider populations that consist of small units (for example, households) where individuals mix primarily in these units. In this case, definition of vaccine efficacy is in terms of the within‐unit transmission probabilities and is estimable by using transmission models for infectious diseases. We apply the estimation methods described above to data from influenza and measles outbreaks. We also examine, via a stochastic simulation study, the robustness of the vaccine efficacy estimators under various population structures and mixing patterns.
Estimating the effect of the run‐in on the power of the physicians' health study
Authors: Lang Janet M. , Buring Julie E. , Rosner Bernard , Cook Nancy , Hennekens Charles H.
Published: April 2007

In the Physicians' Health Study, a randomized, placebo‐controlled, double‐blind trial of aspirin in the reduction of cardiovascular mortality and beta‐carotene in decreasing cancer incidence, 33,223 subjects were eligible and willing to enter the trial. Instead of randomizing this group immediately, all participants received identical calendar packs that contained active aspirin and beta‐carotene placebo. Following an 18‐week run‐in, only 22,071 subjects who remained eligible and willing and had taken at least 2/3 of their pills were randomized. We estimated the effect of the run‐in as follows: pill taking compliance increased 20‐41 per cent; sample size decreased 34 per cent; duration of follow‐up decreased 7 per cent which resulted in a 7 per cent decrease in the expected event rate for the placebo group. To estimate these changes, we made assumptions about compliance and outcome risk for those excluded by the run‐in. Our conclusion, however, about the net effect of the run‐in on the power of the study remains constant across variations in a number of those assumptions. The power with the run‐in, with 22,071 good compliers was typically higher, and never more than negligibly lower, than the power without the run‐in, with 33,223 good and poor compliers. In addition, savings from enrolling 11,152 fewer subjects in the trial resulted from the use of the run‐in.
Methods for dose finding studies in cancer clinical trials: A review and results of a monte carlo study
Authors: O'Quigley John , Chevret Sylvie
Published: April 2007

We discuss some of the statistical approaches to the design and analysis of phase I clinical trials in cancer. An attempt is made to identify the issues, particular to this type of trial, that should be addressed by an appropriate methodology. A brief review of schemes currently in use is provided together with our views of the extent to which any particular scheme addresses the main issues. Some simulations are provided together with graphical illustration of the operating characteristics of the particular methods. It appears that the continual reassessment method is preferable to other contending schemes.
A general parametric approach to the meta‐analysis of randomized clinical trials
Authors: Whitehead Anne , Whitehead John
Published: April 2007

Meta‐analysis provides a systematic and quantitative approach to the summary of results from randomized studies. Whilst many authors have published actual meta‐analyses concerning specific therapeutic questions, less has been published about comprehensive methodology. This article presents a general parametric approach, which utilizes efficient score statistics and Fisher's information, and relates this to different methods suggested by previous authors. Normally distributed, binary, ordinal and survival data are considered. Both the fixed effects and random effects model for treatments are described.
Multivariate analysis of spect images with illustrations in Alzheimer's disease
Authors: McCrory S. J. , Ford I.
Published: April 2007

Modern neuroimaging techniques such as positron emission tomography and single photon emission computed tomography (SPECT) often generate datasets consisting of a large number of variables measured on a small number of subjects. In addition, the data contain large ‘subject effects’ which must be adjusted for in any statistical analysis. This paper illustrates the dangers inherent in naive univariate analysis and proceeds to demonstrate the application of multivariate methods such as HotellingsT2‐test, canonical correlation analysis and discriminant analysis. The issues and statistical methods are illustrated using a dataset from a SPECT study of groups of normal control subjects and subjects with a clinical diagnosis of Alzheimer's disease.
Methods of adjustment for estimating the attributable risk in case‐control studies: A review
Authors: Benichou Jacques
Published: April 2007

In the 1980's, progress was made in adjusting estimates of the attributable risk (AR) for confounding factors and in calculating associated confidence intervals. In this paper, methods of adjustment for estimation of the AR in case‐control studies are reviewed. The limitations and problems associated with two methods based on stratification, the weighted‐sum approach and the Mantel‐Haenszel approach, are discussed. They include small‐sample bias with the weighted‐sum approach and the difficulty of taking interaction into account with the Mantel‐Haenszel approach. A third method based on logistic regression is reviewed. It is argued that this latter method has the greatest generality and flexibility, and includes the two other approaches as special cases. Throughout the paper, an example of a case‐control study of oesophageal cancer illustrates the use of the methods described.
A bibliography and comments on the use of statistical models in epidemiology in the 1980s
Authors: Gail Mitchell H.
Published: April 2007

This paper reviews developments in statistical modelling in epidemiology in the 1980's, with emphasis on cohort and case‐control studies. The central roles of the logistic and proportional hazard models are highlighted, and it is shown how these models lead to a deeper understanding of classical designs and methods of analysis as well as to efficient new designs and analytical procedures. The important area of model misspecification is discussed, including the problems of omitted latent structure, mis‐modelling of available measurements, missing data and errors in measurements. Various designs motivated by the logistic model are illustrated numerically, and designs based on the proportional hazards model are discussed, as are papers on sample size determination. There are brief introductions to the literature on other topics, including attributable risk, disease clustering, family studies and genetics, analysis of disease incidence data, infectious disease, longitudinal data, screening and miscellaneous related topics in statistics. An extensive bibliography is indexed according to the outline of the paper.
Advances in statistical methodology for diagnostic medecine ni the 1980's
Authors: Begg Colini B.
Published: April 2007

Research on diagnostic medicine has been directed at a number of topics in the past decade. Issues which have received a lot of attention are ROC analysis and the identification and correction of various analytic biases. Other topics of widespread interest include the use of expert systems, the relationship of such systems to statistical data‐based systems, and the evaluation of tests using cost‐effectiveness analysis. Increasingly there is a sentiment that well‐designed, prospective trials are required to provide credible information on the accuracy of diagnostic technologies, and so a consensus on methodological standards is needed, paralleling the earlier development of such standards in clinical trials and epidemiology.
Statistics in medical journals: Developments in the 1980s
Authors: Altman Douglas G.
Published: April 2007

This paper reviews changes in the use of statistics in medical journals during the 1980s. Aspects considered are research design, statistical analysis, the presentation of results, medical journal policy (including statistical refereeing), and the misuse of statistics. Despite some notable successes, the misuse of statistics in medical papers remains common.
Assessment of quality of life in clinical trials
Authors: Schumacher Martin , Olschewski Manfred , Schulgen Gabi
Published: April 2007

This paper is intended as an overview of developments in the assessment of quality of life (QOL) in clinical trials over the last decade from the viewpoint of clinical biostatistics. In the first part we deal with aspects of obtaining adequate measurements of quality of life. A literature survey shows that a large number of quite heterogeneous measurement approaches for use in clinical trials exist, a substantial percentage of which cannot be regarded as sufficient for their actual measuring purpose. In the second part we review statistical methods applied to and adapted for the analysis of QOL data. Underlying the analysis should be the assumption of QOL as a stochastic process. Applied analysis procedures are again investigated in a literature survey. Finally, critical conclusions are outlined and suggestions for further research are given.
Comparing in‐patient classification systems: A problem of non‐nested regression models
Authors: Willan Andrew R. , Ross William , Mackenzie Thomas A.
Published: April 2007

Since 1983, hospitals in the United States have been receiving prospective payment for their in‐hospital patient admissions covered under Medicare. Under such schemes each patient is placed in a group by a classification system, known as the Diagnosis Related Groups (DRG), and the hospital is reimbursed by the Health Care Financing Administration according to some predetermined group average, adjusted for hospital level characteristics, such as size, location and teaching activity. Recent interest has focused on refining the DRG system or considering totally different systems of classification. Studies designed to compare the ability of different systems to account for between‐patient variability in resource consumption in the same dataset lead to the problem of model selection between large non‐nested regressions, where resource consumption, measured by length of hospital stay or costs, is regressed on dummy‐indicator variables representing different patient groups. We use a simple measure of fit to develop a symmetric test of the null hypothesis that the two systems account equally well for variability in resource consumption. With this method, unlike methods such as Akaike's AIC criterion, we can quantify the probability of a false positive, and thereby limit the probability of choosing one system over another when it is no better at accounting for variability in resource consumption.
Withdrawal censoring and the sequential logrank procedure
Authors: Richardson De Juran
Published: April 2007

The effects of withdrawal censoring on the power of the group sequential logrank procedure are examined in the context of survival studies. Special attention is given to an assumption that the withdrawal censoring mechanism is only conditionally independent of survival time. Simulation studies of two‐sample, fixed duration trials, under random right censoring, staggered entry and exponential life times, reveal a general decrease in statistical power that is most pronounced when the withdrawals are unbalanced, the majority occurring in the group with the higher hazard rate. Generally, this decrease in power is not of practical concern under typical withdrawal rates except when conditional independence is present in which case large fluctuations in power and type I error rates can occur.
Short and medium term projections of the aids/hiv epidemic by a dynamic model with an application to the risk group of homo/bisexual men in amsterdam
Authors: Heisterkamp S. H. , de Haan B. J. , Jager J. C. , van Druten J. A. M. , Hendriks J. C. M.
Published: April 2007

Several methods exist for short term projection of the numbers of AIDS cases. Some use extrapolation of empirical curves fitted to data up to a given time, whereas others such as the popular method of ‘back projection’ or actuarial methods also use information about the process. In this paper we describe a dynamic model based on a distributed modelling technique allowing for variability both in infectiousness and in age distribution of the population at risk. Some model parameters are taken from the literature, others are estimated from AIDS incidence data from the homo/bisexual population in Amsterdam. The model described here simulates prevalence and incidence of HIV infection. We present prediction intervals for two years from January 1990 onwards. We discuss three scenarios based on the estimated model, two of which consider early treatment with anti‐viral drugs. Given the model and the state of the epidemic in Amsterdam, early treatment intervention must be combined with very drastic measures for reducing infectivity in order to have any serious impact on the course of the epidemic.
Analysis of disease risks using ancillary risk factors, with application to job–exposure matrices
Authors: Gilks Walter R. , Richardson Sylvia
Published: April 2007

Epidemiological studies of disease can make use of ancillary risk‐factors, acquired from individuals outside the disease study. For example, several disease studies might use the same job‐exposure matrix to quantify risks due to occupational exposure to industrial agents. We construct a graphical model to combine a logistic regression disease model with models for the ancillary data and the risk‐factor distribution in the population. We estimate the graphical model using Gibbs sampling, and in simulations compare it with methods of direct substitution into logistic regression.
Methods for comparing cumulative hazard functions in a semi‐proportional hazard model
Authors: Dabrowska Dorota M. , Doksum Kjell A. , Feduska Nicholas J. , Husing Robert , Neville Padraic
Published: April 2007

Graphical methods based on the analysis of differences between log cumulative hazard functions are considered for a two‐group semi‐proportional hazard model which allows for interaction between treatments and covariates. Confidence procedures and test statistics that can be used to test for interaction and for main effects are developed. Their use is illustrated by applying them to the analysis of kidney transplant data from the University of California, San Francisco.
Evaluations of methods for statistical surveillance
Authors: Frisén M.
Published: April 2007

The needs for statistical surveillance in different areas of medicine are described. The predictive value of an alarm and other measures for the evaluation of alarm procedures are suggested. The measures are used to evaluate some common methods of continual surveillance of time series. It is demonstrated that some methods have about the same properties at the start of the surveillance period as later. This is however not the case for all methods. For some methods the consequence of an early alarm should be quite different from that of a late one.
Sensitivity and specificity for correlated observations
Authors: Smith Philip J. , Hadgu Alula
Published: April 2007

A general estimating equation approach is used to obtain estimates of sensitivity and specificity when the data consist of correlated binary outcomes. First order approximations to the variances of estimated sensitivity and specificity for prospective and retrospective studies are given. Data from a dental study are used to motivate and illustrate the methods.
On the sample size for studies based upon mcnemar's test
Authors: Lachenbruch Peter A.
Published: April 2007

When computing the sample size for studies using McNemar's test, one needs to know the probability of discordance and the odds ratio to be detected. In many studies, the investigator is unable to specify the probability of discordance, but can state, at least approximately, the marginal probabilities of each variable. This information leads to restrictions on the possible values of the cell probabilities and provides a range of admissible values for the off‐diagonal cells. We compute the sample size needed in these circumstances and compare them to the results cited by Schlesselman and Connett et al. These sample sizes for the method are quite close to those found in the Monte Carlo study of Connett et al.
Using mark‐recapture methodology to estimate the size of a population at risk for sexually transmitted diseases
Authors: Rubin Gail , Umbach David , Shyu Shwu‐Fang , Castillo‐Chavez Carlos
Published: April 2007

To study the spread of sexually transmitted diseases (STDs) using social/sexual mixing models, one must have quantitative information about sexual mixing. An unavoidable complication in gathering such information by survey is that members of the surveyed population will almost certainly have sexual contacts outside that population. The number of these outsiders may be substantial and, hence, important for the modelling process. In this paper, we develop a mark‐recapture model for estimating the size of the population at risk for contracting a STD due to direct sexual contact with a specified population targeted by a survey. This mark‐recapture methodology provides a reliable method of estimating the number of outsiders. Because not everyone in the targeted population may be sexually active, the size of the sexually active subset, used as the number marked in our tag‐recapture formulation, must be estimated, which introduces extra variability. We derive an estimator of the variance of the estimated total number at risk that accounts for this extra variability and an expression for the bias of that estimator. We extend the methodology to stratified surveys and illustrate its use with data collected from a population of university undergraduates to estimate sexual mixing parameters of a deterministic model of the spread of STDs.
Effects of mid‐point imputation on the analysis of doubly censored data
Authors: Law C. Gordon , Brookmeyer Ron
Published: April 2007

Doubly censored data arise in some cohort studies of the AIDS incubation period because the time of infection may be known only up to an interval defined by two successive screening tests for HIV antibody. A simple analytic approach is to impute the infection time by the mid‐point of the interval and then apply standard survival techniques for right censored data. The objective of this paper is to investigate the statistical properties of such a mid‐point imputation approach. We investigated the asymptotic bias of the Kaplan‐Meier estimate, coverage probabilities of associated confidence intervals, bias in hazard ratio, and the size of the logrank test. We show that the statistical properties of mid‐point imputation depend strongly on the underlying distributions of infection times and the incubation periods, and the width of the interval between screening tests. In the absence of treatment, the median incubation period of HIV infection is approximately 10 years, and we conclude that, for this situation, mid‐point imputation is a reasonable procedure for interval widths of 2 years or less.
Estimation of a common risk ratio in stratified case‐cohort studies
Authors: Sato Tosiya
Published: April 2007

The case‐cohort study design is a useful modification of the case‐control design, which allows direct estimation of the risk ratio without the rare‐disease assumption. While several risk ratio estimation procedures have been proposed under large‐strata settings, only the Mantel‐Haenszel point estimator is available in sparse stratifications. This paper provides simple confidence limits methods, based on the large‐sample distribution of the Mantel‐Haenszel risk ratio, that apply to both large‐strata and sparse‐data situations. For the Tarone risk ratio, I give a new large‐strata variance estimate.
Correlated binomial variates: Properties of estimator of intraclass correlation and its effect on sample size calculation
Authors: Feng Ziding , Grizzle James E.
Published: April 2007

In group randomized studies, the sample size calculations are complicated by within group (worksite, community, etc.) correlation. We compare by simulation the moment method and the more standard ANOVA method of estimating the intraclass correlation. We find the former is less biased for a small to moderate number of clusters but the difference disappears when the appropriate degree of freedom is used for the ANOVA estimator. We propose a simulation approach for sample size determination and illustrate it with an example.
A note on last case influence using the partial likelihood approach under heavy censoring
Authors: Oman Paul
Published: April 2007

The Cox proportional hazards model always treats the last observation in a time ordered data set as an inexact survival time. In certain situations this can lead to this observation always having a low case influence and consequently never being highlighted by a case influence analysis. Thus an influential value can become non‐influential by a miscalculation of survival time and this, in turn, can affect conclusions of an analysis based on statistical significance (P‐values).
Estimating hiv prevalence and projecting aids incidence in the united states: A model that accounts for therapy and changes in the surveillance definition of aids
Authors: Rosenberg P. S. , Gail M. H. , Carroll R. J.
Published: April 2007

The AIDS incubation distribution is changing in calendar time because of treatment and changes in the surveillance definition of AIDS. To obtain reliable estimates of HIV prevalence and projections of AIDS incidence in the 1990s using the method of backcalculation, we constructed an appropriate incubation distribution for each calendar date of infection.

We parameterized the impact of treatment on the incubation distribution by specifying the relative hazard for AIDS in treated versus untreated people as a function of duration of HIV infection. To account for trends in the incubation distribution, we modelled the prevalence of treatment, the distribution of treatment onset times, and the impact of the revision of the AIDS surveillance definition in 1987. We selected and evaluated backcalculation models based on consistency with external information. We defined a ‘plausible range’ of estimates that took into account uncertainty about the natural incubation distribution and treatment efficacy, as well as bootsrap assessment of stochastic error.

Using these methods, we projected that national United States AIDS incidence will plateau during 1991–1994 at over 50,000 caes per year. Projections exhibited substantial systematic uncertainty, and we calculated a plausible range for AIDS incidence in 1994 of 42,300 to 70,700 cases. An estimated 628,000 to 988,000 cumulative HIV infections occurred as of 1 January 1991. After accounting for AIDS mortality, we estimated that 484,000 to 844,000 people were living the HIV infection on 1 January 1991. Favourable trends in HIV incidence appeared in gay men and intravenous drug users. Plausible ranges for our estimates overlapped with those from a ‘stage model’ approach to incorporating treatment effects in backcalculations. Our approach, however, tended to yield smaller estimates of epidemic size, mainly because the parameters used with the stage model implied that more treatment was in use and that treatment was more effective than in our model.
Impact of measurement error and temporal variability on the estimation of event probabilities for risk factor intervention trials
Authors: Neaton James D. , Bartsch Glenn E.
Published: April 2007

The impact of measurement error and temporal variability of risk factors on estimates of disease probabilities based on the logistic function is discussed. Monte Carlo results and empirical findings from the Multiple Risk Factor Intervention Trial indicate that the degree of attenuation of logistic parameter estimates is well approximated by the reliability coefficient when the errors are assumed to be normal random variates and event probabilities are small. In the design of intervention studies, measurement error and temporal variability of risk factors do not usually influence estimates of the probability of developing the disease in the control group, but can result in mis‐estimation of the probability of developing the disease in the experimental group, substantially reducing the statistical power of the clinical trial.
Bioequivalence revisited
Authors: Sheiner Lewis B.
Published: April 2007

The FDA permits marketing of a generic formulation of a drug G for the same indications as a standard preparation S if one can show that G is bioequivalent to S. Present implementation requires convincing evidence that the population mean difference in bioavailability (drug exposure) between the two preparations lies within specified bounds. The basis for this standard does not appear to involve a comprehensive model for the dose‐response relationship, or consideration of clinical issues, notably (i) whether a patient is to commence on the drug or to switch from an established regimen to a new one; or (ii) that the risk of inequivalence relates to uncertainty of outcome. In this paper, I propose a comprehensive model for dose response and a tentative model for risk that addresses these issues. Specifically, I propose two new measures of bioequivalence which are based on these models, which differ in the two clinical circumstances above, and which respond to both bias and variance of outcome. I present two examples, and some simulations of the application of the new measures.
Molecular Exchange through Membranes of Poly(2‐vinylpyridine‐block‐ethylene oxide) Vesicles
Authors: Leson Alina , Hauschild Stephan , Rank Anja , Neub Andreas , Schubert Rolf , Förster Stephan , Mayer Christian
Published: April 2007

The molecular exchange of tracer molecules through the membranes of dispersed vesicles of the block copolymer poly(2‐vinylpyridine‐block‐ethylene oxide) was studied by using NMR spectroscopy combined with pulsed field gradients. The hydrodynamic radius of the tracer molecules was varied systematically to obtain a permeability profile of the vesicle membrane. In addition, the effect of system parameters, such as temperature, pH value, vesicle size, and thickness of the vesicle membrane, was studied. In the case of rapid exchange with average residence times significantly smaller than 10 s, the permeation is observed under equilibrium conditions and the data are analyzed by using a simple analytical approach. For slow exchange processes with average residence times above 10 s, the permeation is monitored in a time‐resolved measurement under nonequilibrium conditions. Generally, the transmembrane exchange rate of the tracer clearly depends on its hydrodynamic radius. The characteristics of this dependence indicate the presence of two different mechanisms of membrane penetration, one dominating for smaller and one for larger tracer molecules, respectively. The exchange rate also shows a significant dependence on the bilayer thickness and on the vesicle diameter. By contrast, no variation of the membrane permeability with the temperature or the pH value could be detected as long as the vesicles remain stable.
Cover Picture: Highly Ordered Nanostructured Surfaces Obtained with Silica‐Filled Diblock‐Copolymer Micelles as Templates (Small 5/2007)
Authors: Frömsdorf Andreas , Kornowski Andreas , Pütter Sabine , Stillrich Holger , Lee Li‐Ting
Published: April 2007

The cover picture shows the size‐controlled preparation of silica‐filled copolymer micelle cores and their self‐assembly as a function of block length, coating technique, and substrate. The micelles self‐assemble into two‐dimensional hexagonal arrays. These structures are used as templates to create highly ordered inorganic nanostructures, for example, as etching masks for ion sputtering to produce magnetic antidot arrays. For more information, please read the Full Paper “Highly Ordered Nanostructured Surfaces Obtained with Silica‐Filled Diblock‐Copolymer Micelles as Templates” by A. Frömsdorf and co‐workers beginning on page 880.
Seismic analysis, design, and review for tall buildings
Authors: Moehle Jack P.
Published: April 2007

Whereas current building codes legally apply to seismic design of tall buildings, their prescriptive provisions do not adequately address many critical aspects. Performance‐based engineering provides a desirable alternative. Application of performance‐based procedures requires: an understanding of the relation between performance and nonlinear modeling; selection and manipulation of ground motions appropriate to design hazard levels; selection of appropriate nonlinear models and analysis procedures; interpretation of results to determine design quantities based on nonlinear dynamic analysis procedures; careful attention to structural details; and peer review by independent qualified experts to help assure the building official that the proposed materials and system are acceptable. These topics are discussed with an emphasis on tall buildings. Copyright © 2006 John Wiley & Sons, Ltd.
Idealized backbone model for existing reinforced concrete columns and comparisons with FEMA 356 criteria
Authors: Elwood Kenneth J. , Moehle Jack P.
Published: April 2007

An idealized backbone model defining the key damage states of an existing reinforced concrete column (flexural yielding, shear failure, and axial load failure) is developed using drift capacity models. Assumptions and limitations of the drift capacity models are discussed. To demonstrate the application of the idealized backbone model to the evaluation of existing reinforced concrete columns, the model is compared to data from shake table tests and measured drifts from an instrumented building damaged during the Northridge earthquake. The results from the backbone model are also compared with modeling parameters recommended in current seismic rehabilitation guidelines. Copyright © 2006 John Wiley & Sons, Ltd.
Electron‐beam‐pumped light sources using graphite nanoneedle field emitters and Si electron‐transparent films
Authors: Mimura Hidenori , Shiozawa Kazufumi , Neo Yoichiro , Okada Morihiro , Takahasi Masafumi , Hashiguchi Gen
Published: April 2007

Sputter‐induced carbon nanoneedle field emitters and Si electron‐transparent films have been developed for electron‐beam‐pumped light sources. The sputter‐induced carbon nanoneedle field emitters exhibited a stable electron emission of 0.1 mA at an average field of 13 V/µm. The 1.5‐µm thick Si electron‐transparent films achieved an electron transmittance of about 60% at an acceleration voltage of 27 kV. An electron‐beam‐pumped light source was demonstrated from the excitation of N2 gas, and a N2 gas spectrum was clearly observed. The increase of the beam current is important for increasing the light intensity. Copyright © 2007 Institute of Electrical Engineers of Japan© 2007 Institute of Electrical Engineers of Japan. Published by John Wiley & Sons, Inc.
Basic characteristics of a space charge balance sensor using a MOSFET
Authors: Sakuyama Masafumi , Takeuchi Manabu , Terashige Takashi , Yoshioka Sayuri , Okano Kazuo
Published: April 2007

A new space charge balance sensor was developed in order to control ion generation in an air ionizer. Conventionally, a charged plate monitor is widely used in order to detect the space charge balance of the air ionizer. However, the charged plate monitor is not suitable for the feedback system for several reasons. The proposed sensor, in spite of its very simple structure, can detect the space charge balance instantly with enough sensitivity, with a shorter response time, and has a possibility of higher spatial resolution compared to a charge plate monitor. An air ionizer control system that can generate a specific quantity of ions at desired locations is considered to be easily implemented by using feedback of the sensed signal to the air ionizer. Copyright © 2007 Institute of Electrical Engineers of Japan© 2007 Institute of Electrical Engineers of Japan. Published by John Wiley & Sons, Inc.
In situ visualization of degradation of silicon field emitter tips
Authors: Nozawa Naoyuki , Kakushima Kuniyuki , Hashiguchi Gen , Fujita Hiroyuki
Published: April 2007

This paper deals with the simultaneous observation of both the electron field emission from nanoscopic tips by electrical means and their structural shape change by an ultra‐high resolution transmission electron microscope (TEM). Nanoneedles with sharp tips of radius in the nanometer range were fabricated with semiconductor micromachining technology. A correlation between the electron field emission characteristics and the structural change of the emitter tip was clearly observed. Copyright © 2007 Institute of Electrical Engineers of Japan© 2007 Institute of Electrical Engineers of Japan. Published by John Wiley & Sons, Inc.
Evaluation of ferromagnetic shape‐memory alloys by the extended Hückel method
Authors: Ehara Kei , Tanaka Hirokazu , Kanno Yoshinori
Published: April 2007

Ferromagnetic shape‐memory alloy (SMA) are powerful candidates as actuators, pressure sensors, magnetic sensors, etc. Magnetic‐field‐induced strain has been observed in many ferromagnetic SMA. The magnetic‐field‐induced strain is a reversible transformation in the martensite phase with the magnetic field. We have investigated the property of the ferromagnetic shape‐memory materials by the extended Hückel method, and estimated the ferromagnetic shape‐memory of Fe–Pt and Fe–Pd alloys at high temperatures. We used two physical quantities, i.e. cohesive energy and energy fluctuation, to measure the stability of the materials. On the basis of the cohesive energy and energy fluctuation, we discuss the characteristics of ferromagnetic SMA, in which the energy fluctuation is a measure of thermal stability of the metals and/or alloys. The martensite structure is unstable, which means that the energy fluctuation has to be controlled to a small value to keep the martensite phase. Furthermore, it is estimated that the energy fluctuation is associated with the Curie temperature. The Curie temperature is an essential parameter for ferromagnetic materials. From the discussion presented above, we can propose the following: (i) Alloys possessing a low cohesive energy are associated with a high mobility of atoms and are suitable for ferromagnetic shape‐memory materials; (ii) Alloys showing a low energy fluctuation show ferromagnetic shape‐memory and are favored for use as memory devices. We found that I (iodine) is the best dopant for Fe–Pt ferromagnetic SMA, and Tc (technetium) is the best dopant for Fe–Pd ferromagnetic SMA. Copyright © 2007 Institute of Electrical Engineers of Japan© 2007 Institute of Electrical Engineers of Japan. Published by John Wiley & Sons, Inc.
Development of radio frequency transmitters including on‐chip antenna for intelligent human sensing systems
Authors: Kim Jong‐Wan , Takao Hidekuni , Sawada Kazuaki , Ishida Makoto
Published: April 2007

This paper presents the essentials of the development of an integrated smart microsensor system that has been developed to monitor the motion and vital signs of humans in various environments. Integration of RF transmitter technology with complementary metal‐oxide‐semiconductor/micro electro mechanical systems (CMOS/MEMS) microsensors is required to realize wireless smart microsensors for the monitoring system. Sensors for the measurement of body temperature, perspiration, heart rate (pressure sensor), and motion (accelerometers) are candidates for integration on the wireless smart microsensor system. In this paper, the development of radio frequency transmitter (RF) that will be integrated on wireless smart microsensors is presented. A voltage controlled RF‐CMOS oscillator (VCO) has been fabricated for the 300‐MHz frequency band applications. Also, spiral inductors for an LC resonator and an integrated antenna have been realized with a CMOS‐compatible metallization process. The essential RF components have been fabricated and evaluated experimentally. The fabricated CMOS VCO showed a conversion factor from voltage to frequency of about 81 MHz/V. After matching the characteristic impedance (50 Ω) of the on‐chip integrated antenna and the VCO output, more than 5 m signal transmission from the microchip antenna has been observed. The transmitter showed remarkable improvement in transmission power efficiency by correct matching with the microchip antenna. Essential technologies of the RF transmitter for the wireless smart microsensors have been successfully developed. Also, for the 300‐MHz band application, the integrated RF transmitter, with the CMOS oscillator and the on‐chip antenna, has been successfully demonstrated for the first time. Copyright © 2007 Institute of Electrical Engineers of Japan© 2007 Institute of Electrical Engineers of Japan. Published by John Wiley & Sons, Inc.
Transparent biosensor with micro channel array for optical and electrophysiological detection of luciferin–luciferase reaction
Authors: Tonomura Wataru , Okamura Hitoshi , Konishi Satoshi
Published: April 2007

This paper describes a transparent biosensor that was designed to detect both the optical and electrophysiological signals of the luciferin–luciferase reaction. By using microelectromechanical system (MEMS) technologies, we have studied and developed a ‘Micro Channel Array’ (MCA) integrated with suction holes and electrodes as planar patch‐clamp biosensors. A transparent biosensor was developed as an advanced MCA. The developed transparent biosensor employs an SU‐8‐based MCA structure for simultaneous multipoint sensing of optical and electrophysiological signals. In this study, we tested the newly developed biosensor using the mPer1‐luc slice culture, which has circadian rhythms and is a typical example of cells in which a luciferin–luciferase reaction occurs. We could measure the optical and electrophysiological signals of the mPer1‐luc slice culture. Here we describe the experimental results of this study, and describe the design and fabrication of the transparent biosensor with MCA. Copyright © 2007 Institute of Electrical Engineers of Japan© 2007 Institute of Electrical Engineers of Japan. Published by John Wiley & Sons, Inc.
Cell adhesion characteristics of chemically modified silicon nitride surfaces
Authors: Sakata Toshiya , Ueda Aiko , Miyahara Yuji
Published: April 2007

We investigated the fundamental characteristics of cell adhesion during cell culture on the Si3N4 surface for using it as the gate insulator in field‐effect devices. The culture medium and the surface condition of Si3N4 were controlled for cell culture on the Si3N4 substrate. When we measure electrical characteristics of cell adhesion and cell function using field‐effect devices, we require a stable measurement of the electrical signals. The serum in the culture medium includes a number of proteins, which cause instability of the potential behavior. In this paper, we show that the cell‐adhesive molecules on the Si3N4 surface used as a gate insulator should be designed and controlled when cell culture is performed in the culture medium without the serum. Copyright © 2007 Institute of Electrical Engineers of Japan© 2007 Institute of Electrical Engineers of Japan. Published by John Wiley & Sons, Inc.
Towards mechanical characterization of biomolecules by MNEMS tools
Authors: Collard Dominique , Yamahata Christophe , Legrand Bernard , Takekawa Tetsuya , Kumemura Momoko , Sakaki Naoyoshi , Hashiguchi Gen , Fujita Hiroyuki
Published: April 2007

Single‐molecule micromanipulations have provided information that has been awaited for a long time. However, these experiments relying on optical tweezers (OT) or magnetic tweezers (MT) have a low throughput since the molecular preparation is done one at a time. In order to move towards systematic biological or medical analysis, micro‐nano‐electromechanical systems (MNEMS) are the appropriate devices, as they integrate accurate molecular level engineering tools and can be cheaply produced with highly parallel fabrication processes. This paper investigates the ability of MNEMS tweezers to perform molecular manipulations. The mechanical forces relevant in biological interactions are first reviewed and compared to the performances of biophysical instruments. MNEMS tweezers are then presented. The tweezers integrate opposing sharp tips to capture the molecules, an actuator to stretch them and a displacement sensor to measure in real time the produced molecular extension. DNA molecular bundles are readily assembled and manipulated. The sensor provides a 0.3‐nm stretching resolution, equivalent to the interbase pair distance in double‐stranded DNA. Copyright © 2007 Institute of Electrical Engineers of Japan© 2007 Institute of Electrical Engineers of Japan. Published by John Wiley & Sons, Inc.