bluuebunny/crossref_metadata_2025 huggingface dataset:
Synthesis and morphological characterization of poly(ϵ‐caprolactone) and poly(2‐methyloxazoline) substituted phenyl rings and phenylene oligomers
Authors: Levent Demirel A. , Yurteri Seda , Cianga Ioan , Yagci Yusuf
Published: April 2007

Poly(ϵ‐caprolactone) (PCL) and poly(2‐methyloxazoline) (POx) substituted phenyl rings (macromonomers) and the corresponding substituted polyphenylene oligomers have been synthesized in various chemical structures. Macromonomers were synthesized by ring opening polymerization. Poly(phenylene) oligomers were then synthesized by cross‐coupling of the macromonomers in Ni‐catalyzed polycondensation reactions. The macromonomers and oligomers have been characterized by 1H‐NMR, IR, GPC, and DSC. The effect of side chain chemistry and architecture on the resulting morphology in thin films has been investigated by atomic force micro‐scopy and wide angle X‐ray scattering. Polyphenylene oligomers showed layered morphologies in thin films. The orientation of the layers depended on the chemistry of the side chains and the backbone architecture. Linear oligomers containing statistically distributed segments having POx or PCL side chains showed layers perpendicular to the underlying substrate. Attachment of polystyrene end block to PCL chain together with the meta‐connectivity of the backbone resulted in layers parallel to the substrate. Our results also indicate that substitution of polymeric chains to phenyl rings can induce ordered structures of macromonomers. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 2091–2104, 2007
Mechanical Properties of Thin Films and Nanometric Multilayers Using Tensile Testing and Synchrotron X‐Ray Diffraction
Authors: Le Bourhis Eric , Faurie Damien , Girault Baptiste , Goudeau Philippe , Renault Pierre‐Olivier , Villain Pascale , Badawi Frédéric
Published: April 2007

X‐Ray diffraction (XRD) in combination with tensile testing is a very attractive tool for investigating the elastic behavior and further fracture or plasticity of metallic thin films and multilayers. Such studies are carried out with synchrotron X‐ray sources allowing for several diffraction and loading conditions to be investigated and hence for great precision to be achieved. XRD is phase selective and allows for the study of individual layers or phase contributions. The method is based on a length scale change to relate in‐grain elastic strains to tensile macro‐stresses. Hence, it requires the modeling of the grain interactions in view of the structure of the films (morphology, texture). The paper is illustrated with studies carried out on elastically isotropic tungsten (W) films, elastically anisotropic gold (Au) textured films, and nanometric tungsten/copper (W/Cu) multilayers.

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Nitriding of Stainless Steel: PIII or Low Energy Nitriding?
Authors: Mändl Stephan
Published: April 2007

Both plasma immersion ion implantation (PIII) and low energy implantation (LEI) of nitrogen into austenitic stainless steel lead to the formation of a very hard and wear resistant surface layer, expanded austenite. Heat balance and particle flux measurements were performed and compared with simulations to obtain the global and local temperature variations as a function of the particle and heat flux. Comparing PIII and LEI within the same UHV vacuum system, and on the same substrate holder shows that similar diffusion, hardness and wear are observed; only the lattice expansion is larger for the case of PIII than for LEI.

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Recent Advances in the Research on Non‐Equilibrium Atmospheric Pressure Plasma Jets
Authors: Laimer Johann , Störi Herbert
Published: April 2007

Recently, there has been increased interest in using atmospheric pressure plasmas for materials processing, since these plasmas do not require expensive vacuum systems. However, APGDs face instabilities. Therefore, special plasma sources have been developed to overcome this obstacle, which make use of DC, pulsed DC and AC ranging from mains frequency to RF. Recently, the APPJ was introduced, which features an α‐mode of an RF discharge between two bare metallic electrodes. Basically, three different geometric configurations have been developed. A characterization of the APPJs and their applications is presented.

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Surface Technology with Cold Microplasmas
Authors: Klages Claus‐Peter , Hinze Alena , Lachmann Kristina , Berger Claudia , Borris Jochen , Eichler Marko , von Hausen Margret , Zänker Antje , Thomas Michael
Published: April 2007

Various new plasma‐based surface technological processes are made feasible by localizing atmospheric‐pressure discharges to predefined volumes with sub‐millimeter linear dimensions. So‐called Plasma Printing processes use cold discharges in microcavities formed temporarily by contacting a substrate with a suitably designed kind of plasma stamp. Aside from dielectric barrier discharges driven by mid‐frequency (MF) AC voltages, cold microplasmas can also be sustained in arrangements without a dielectric barrier, if RF excitation is used. The modification or coating of internal surfaces in already sealed microfluidic systems promises the achievement of a wide range of physico‐chemical surface properties which are difficult to attain by wet‐chemical or low‐pressure plasma processes. Using a proper electrode arrangement, the coating or modification can be localized to a selected segment of a microfluidic system.

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Materials Science and Technological Aspects of Electrospark Deposition of Nanostructured WC‐Co Coatings onto Titanium Substrates
Authors: Levashov Evgeny A. , Zamulaeva Evgenia I. , Kudryashov Alexander E. , Vakaev Peter V. , Petrzhik Mikhail I. , Sanz Alejandro
Published: April 2007

The composition and structure of coatings deposited with nano‐ and microstructured electrodes WC‐8% Co onto Ti substrates were characterized by XRD, XPS, EPMA, SEM, and SIM. Physical and chemical processes taking place at the contact surface of electrode and substrate during electrospark deposition are considered. Under optimized conditions (E = 0.13 J), deposition with a nanostructured electrodes provides fine‐grained coatings exhibiting higher hardness, improved wear resistance, and a lower friction coefficient (compared to VK8‐based coatings).

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Similarities and Particularities of Low‐ and High‐Temperature Plasma Technologies
Authors: Schumacher Uwe
Published: April 2007

Although plasmas cover an enormously wide range of parameters, and although the technologies and their applications differ strongly, several general mechanisms and technological processes, such as dimensionless parameters, generation and controlling of plasmas by particle wave interactions, plasma‐wall‐interactions, surface engineering and diagnostics are quite similar. Microwave technology offers both low temperature plasma applications and plasma heating for the fusion reactors. The interaction of plasmas with the nearby surfaces and the resulting material changes follow the same general mechanisms in low, as well as in high temperature plasmas, and their diagnostics are similar.

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Macroscopic Description of Plasma Polymerization
Authors: Hegemann Dirk , Hossain Mohammad Mokbul , Körner Enrico , Balazs Dawn J.
Published: April 2007

Industrial applications based on plasma polymerization require reliable processes that can be transferred to production‐scale reactors. To enable an inexpensive access to control plasma deposition processes, macroscopic kinetics were investigated to describe plasma polymerization, which is based on the concept of chemical quasi‐equilibrium. The evaluation of deposition rates was carried out in order to obtain the apparent activation energy for a specific process. Influencing factors, such as substrate temperature, energetic particles, reactor geometry, plasma expansion, pressure, monomer, carrier/reactive gas, power modulation, and plasma source were thoroughly examined. The obtained activation energy was correlated to the plasma‐chemical processes, such as dissociation and radical formation, which are taking place within the active plasma zone. Since these processes are also contributing to the film growth, the activation energy was used for the scale‐up of plasma polymerization processes.

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Regression analysis of censored survival data with the generalized F family—an alternative to the proportional hazards model
Authors: Ciampi Antonio , Hogg Sheilah A. , Kates Louis
Published: April 2007

We show that the generalized F family is a useful tool for regression analysis with censored survival data. We discuss maximum likelihood estimation and give asymptotic procedures for calculating confidence intervals, tests of significance for the parameters, life expectancy, quantiles and survival rates. Survival data on 704 ovarian carcinoma patients serve to demonstrate the utility of the model.
The use of logit models to investigate social and biological factors in infant mortality. IV: Post‐neonatal mortality
Authors: Machin D. , Murrells T. J. , Catford J. C. , Smith T. M. F.
Published: April 2007

Infant mortality data for England and Wales, cross‐classified by mother's age, parity and social class have been published on two occasions, the first giving the relevant data for 1949/50, the second for 1975, some 25 years later. Published analyses of these separate data sets have been based on graphical and tabular analysis. This paper describes the application of logit models using the methodology presented by Murrells et al.1 to investigate post‐neonatal deaths.
Algorithm for the grouping of contiguous geographical zones
Authors: Huel Guy , Petiot Jean‐Francois , Lazar Philippe
Published: April 2007

In geographical epidemiology, the correlation between two variables is often studied, using as basic units those zones for which these variables are available. However, because of their geographical contiguity, it could be misleading to consider each of these zones as independent statistical units. Moreover, spatial distributions (either of the factor or of the disease) are often distributed in relatively simple patterns; these patterns may induce strong correlations. Thus, the general pattern of the spatial distribution of the variables should be investigated before any attempt to infer epidemiological interpretation of a relationship. This paper presents an algorithm to construct contiguous groupings which are similar enough with regard to one of the two variables considered and to thus divide the original set of geographical areas into contrasting zones. The algorithm is easy to compute and allows mapping of the geographical distribution of the variable studied. It also lessens the risk of duplication of basic information by reducing the autocorrelation of one of the variables.
Dose‐interpolation of immunoassay data: Uncertainties associated with curve‐fitting
Authors: Kay C. , Nix A. B. J. , Kemp K. W. , Rowlands R. J. , Richards G. , Groom G. V. , Griffiths K. , Wilson D. W.
Published: April 2007

Estimates of analyte concentrations, obtained by immunoassay, have error distributions which are generally underestimated. Better estimates, which take into account the distribution of the response metameter of the calibration curve and uncertainties associated with the location of the fitted curve, have been obtained by computer simulation using practical immunoassay data. The increased use of curve‐fitting software in automated immunoassay equipment has prompted the investigation of reported analyte concentration distributions for three commonly used functions, namely the logit‐log, the 4‐parameter logistic and the fourparameter Amersham models. The simulation model is of potential value for a variety of situations.
Computer simulation of a clinical trial as an aid to teaching the concept of statistical significance
Authors: Bland J. M.
Published: April 2007

The advent of cheap and powerful microcomputers provides opportunities for improving the teaching of statistics in medicine. This paper describes a practical exercise in which students study the concept of statistical significance using a simple computer program which simulates a clinical trial. The students are required to make decisions about patients with incomplete data and form contingency tables for analysis. This includes analysing contingency tables with several cells having small expected frequencies. The results from 25 groups of students are collected together and presented to the class. Two null hypotheses are tested, one of which is true. For the true null hypothesis the group is likely to produce, by chance, at least one significant result at the 0.05 level. For the false null hypothesis only a minority of results will be significant, because the sample size is small. This leads to a discussion of the concept of statistical significance. The simulation model is described and the advantages and potential of this type of teaching are discussed.
GENETIC epidemiology: A review of the statistical basis
Authors: Thompson E. A.
Published: April 2007

Genetic epidemiology is the analysis of the familial distributions of traits, with a view to understanding any possible genetic basis; the fundamentals of this area are reviewed. The terminology of genetic models is fully described, since it is this wealth of terminology which can make it difficult for a statistician to enter the area. The statistical approaches to the analysis of data on sets of interrelated individuals are then discussed, and resulting problems of sampling design and analysis are considered.
Calculating expected mortality
Authors: Keiding Niels , Væth Michael
Published: April 2007

The widely used ‘person‐years method’ of calculating expected mortality has been discussed recently by several authors. In studies where mortality is either lower or higher than the standard mortality of some reference population, the use of exposure to death as an estimator of the expected number of deaths will generally lead to bias, always exaggerating the difference between study and standard mortality. This bias is examined in a proportional hazards model. The recent suggestion by Hartzet al.1of calculating the mortalities of individuals during their ‘potential follow‐up time’ is claimed to be only rarely feasible in practice.
The use of the binomial distribution in establishing an association between high‐risk donors and transfusion‐associated aids
Authors: Kaplan Jonathan E. , Schonberger Lawrence B. , Lui Kung‐Jong
Published: April 2007

In the first seven cases of transfusion‐associated acquired immunodeficiency syndrome (TA‐AIDS) with completion of blood donor investigations, there was identification of at least one person (a high‐risk donor‐ HRD) in each donor set who might have transmitted the disease. Using three definitions of an HRD, we estimated the prevalence of HRDs in the overall donor population and used the binomial distribution to calculate the probabilities of finding at least the observed numbers of donor sets with one or more HRDs. These probabilities‐0.028, 0.007 and 0.014, respectively‐allowed us to reject the null hypothesis that the number of cases of TA‐AIDS exposed to an HRD was not greater than that expected by chance, based on the total number of donors to which each case was exposed and the estimated proportion of HRDs in the overall donor population. We concluded that there was a statistically significant association between HRDs and TA‐AIDS.
Probabilistic prediction in patient management and clinical trials
Authors: Spiegelhalter D. J.
Published: April 2007

It is argued that the provision of accurate and useful probabilistic assessments of future events should be a fundamental task for biostatisticians collaborating in clinical or experimental medicine, and we explore two aspects of obtaining and evaluating such predictions. When covariate information on patients is available, logistic regression and other multivariate techniques are often used to select prognostic factors and create predictive models. An example shows how the explicit aim of prediction needs to be taken into account in such modelling, and how predictive performance may be assessed by decomposition of a scoring rule. Secondly, results from a program that provides pretrial and interim predictions in clinical trials are displayed, bringing together the use of subjective opinion, Bayesian methodology and techniques for evaluating and criticizing predictions.
Clinical trials of cancer prevention agents: True versus observed prevention effect
Authors: Moon Thomas E.
Published: April 2007

Important considerations in the design and conduct of cancer and other long‐term prevention trials include intervention compliance and frequency of events during follow‐up. Each of these can produce observed proportions of events for control and test groups that differ less than anticipated. Methods and approximate ‘rules of thumb’ are presented that relate power and sample size to the impact of compliance and latent intervention effect. Results are based upon specific modifications in well‐known formulae that reflect long‐term prevention trials. Data from an ongoing cancer prevention trial illustrate the methods. Compliance was estimated accurately using the low cost capsule count method.
The determination of practically useful doses of new drugs: Some methodological considerations
Authors: Turri M. , Stein G.
Published: April 2007

An important aim of Phase 2 clinical trials is the firm determination of the doses and the dose regimes to be used both in later clinical trials and in clinical practice. Comparisons of findings made during clinical development and recommendations contained in the package leaflets of marketed preparations indicate that this objective is rarely achieved.

The possible reasons for this difficulty are investigated by reviewing the methodology used in the so‐called dose‐finding trials performed during drug development. Since the terminology used in this context is frequently misleading, definitions are given and alternative approaches, referring to the direct and indirect methods of bioassay, are suggested. The practical use of these models depends on a number of medical and ethical considerations, on the indications for treatment and on the characteristics of the drug under investigation.

Some examples are given, indicating that dose‐response relationships can be determined more easily for efficacy, where endpoints more reliably fit commoner distributions, than for tolerability, where the responses frequently follow irregular patterns. This area deserves further investigation to improve the criteria for assessment and to develop adequate statistical methods.
Patient accrual and interim statistical analysis in long‐term randomized clinical trials: The French chronic lymphocytic leukemia CLL 80 protocol as a case study
Authors: Chastang Claude , Travade Philippe , Benichou Jacques , Dighiero Guillaume , Binet Jacques‐Louis
Published: April 2007

The CLL 80 clinical trial of treatment for chronic lymphocytic leukemia was designed using a three‐stage prognostic classification. Within each stage patients received one of two treatments allocated by randomization, two adjacent stages having a common treatment. The fixed‐sample design required 850 patients entered over a period of 8.5 years.

Active patient recruitment led to 741 patients being randomized in four years. The first interim analysis, carried out at this point, showed a treatment difference in one stage which was statistically significant (p = 0.001) and justified an early termination of the protocol. This paper discusses practical aspects of patient accrual and interim analysis in this study.
The changing face of cancer epidemiology
Authors: Wahrendorf Jürgen
Published: April 2007

This paper is concerned with discussing various methodological components of cancer epidemiology. Developments in measuring disease frequency are acknowledged as well as the high level of sophistication of statistical methodology. Several examples are given to illustrate that methods for measuring exposure to factors which cause or protect against cancer have developed considerably over the last few years and allow new approaches in cancer epidemiology. The potential links with clinical research are highlighted.
On the role of ‘habitual aborters’ in the analysis of spontaneous abortion
Authors: Gladen Beth C.
Published: April 2007

Analyses of spontaneous abortion rates often include special provisions to account for the presumed distorting effects that arise because of the presence of habitual aborters. In this paper, I establish a framework for investigating the effects of the presence in study groups of such women. I then examine the strengths and weaknesses of some of the analysis strategies in current use, both in situations where the study group is homogeneous and where there are high‐risk women present. I show that the concept of habitual aborter is not useful and can be misleading, and I suggest that one take a broader view of heterogeneity.
On surveillance methods for congenital malformations
Authors: Gallus G. , Mandelli C. , Marchi M. , Radaelli G.
Published: April 2007

This paper presents an ‘optimal’ procedure for the use of the ‘sets’ method, a system proposed for surveillance of congenital malformations.1 Comparisons over a number of examples shows that the given procedure represents a clear improvement over the one originally proposed, and, in some conditions, is more efficient than the cusum scheme.
Estimating incidence from age‐specific prevalence for irreversible diseases with differential mortality
Authors: Podgor Marvin J. , Leske M. Cristina
Published: April 2007

We present a method for estimating incidence from age‐specific prevalence data for an irreversible disease where the mortality risks may differ for persons with and without the disease. This method is an extension of previously presented methodology1 for estimating incidence from prevalence for a disease that does not entail differential mortality. An application to senile cataract illustrates the method.
Sensitivity, specificity and predictive values: A graphical approach
Authors: Taube Adam
Published: April 2007

The relation between sensitivity, specificity and prevalence is illustrated by means of a graphical device, applied to two diagnostic questions on gastroenteritis in children. The relation between the predictive values and the prevalence is also illustrated graphically.
A model for variability in arteriographic reading
Authors: Hertzberg Vicki Stover , Fisher Lloyd D.
Published: April 2007

We propose a class of models for the joint cumulative distribution function (c.d.f.) of the values of two independent readings of percentage stenosis from a coronary arteriography. We show that these models are identifiable and that a certain subclass has unique consistent estimators for the parameters in question. We obtain these estimates for a data set from a substudy of the Coronary Artery Surgery Study (CASS).
Simultaneous non‐parametric confidence intervals for survival probabilities from censored data
Authors: Afifi A. A. , Elashoff R. M. , Lee J. J.
Published: April 2007

In medical studies with censored data Kaplan and Meier's product limit estimator has frequent use as the estimate of the survival function. Simultaneous confidence intervals for the survival function at various time points constitute a useful addition to the analysis. This study compares several such methods. We consider in a simulation investigation two whole curve confidence bands and four methods based on the Bonferroni inequality. The results show that three Bonferroni‐type methods are essentially equivalent, all being better than the other methods when the number of time points is small (3 or 5).
Sample size requirements and the cost of a randomized clinical trial with repeated measurements
Authors: Bloch Daniel A.
Published: April 2007

This paper discusses the advantage of using repeated outcome measurements on subjects in a clinical trial. We choose the number of subjects and the number of repeated outcome measurements to minimize a given cost function so that the clinical trial has power (1 −β) for specified significance level < α. An example illustrates the results and emphasizes the importance of study design and of critical evaluation of how one measures the study endpoint.
What do doctors know about statistics?
Authors: Wulff Henrik R. , Andersen Bjørn , Brandenhoff Preben , Guttler Flemming
Published: April 2007

A multiple choice test with nine statistical questions was sent to a random sample of Danish doctors to assess their knowledge of elementary statistical expressions (SD, SE, p < 0·05, p > 0·05 and r). One hundred and forty eight (59 per cent) of 250 doctors answered the questions. The test was also completed by 97 participants in postgraduate courses in research methods, mainly junior hospital doctors. The median number of correct answers was 2·4 in the random sample and 4·0 in the other sample of doctors. It is concluded that the statistical knowledge of most doctors is so limited that they cannot be expected to draw the right conclusions from those statistical analyses which are found in papers in medical journals. Sixty‐five per cent of the doctors in the random sample stated that it is very important that this problem is raised.
Analysis of data arising from a stratified design with the cluster as unit of randomization
Authors: Donner Allan , Donald Alan
Published: April 2007

This paper discusses statistical techniques for the analysis of dichotomous data arising from a design in which the investigator randomly assigns each of two clusters of possibly varying size to interventions within strata. The problem addressed is that of assessing the statistical significance of the intervention effect over all strata. We propose a weighted paired t‐test based on the empirical logistic transform for designs that randomize large aggregate clusters in each of several strata.
Sample size and power for pair‐matched case‐control studies
Authors: Connett John E. , Smith Judith A. , McHugh Richard B.
Published: April 2007

A new sample size formula is derived herein for matched‐pair case‐control studies. This result is based on an unconditional approach to the use of McNemar's statistic. We contrast this method for determining sample size and power with Schlesselman's conditional approach and compare the results numerically in a Monte Carlo study.
The three‐decision problem in medical decision making
Authors: Emerson John D. , Tritchler David
Published: April 2007

Medical researchers and policy makers face decisions that require a choice from among two or more alternatives. Whereas traditional hypothesis tests cannot always serve the needs of the practitioner who needs to make a decision, a problem formulation that assigns losses to various incorrect decisions offers several advantages. With three possible decisions this approach offers a precise representation of the pragmatic and explanatory views of decision making. It enables the investigator to incorporate in the problem specification his attitudes about the seriousness of various errors by guiding him, before he sees the data, to a choice of asymmetric tail probabilities. It also suggests a reformulation of the P‐value that can accommodate some of the difficulties practitioners face.
Correcting for regression in assessing the response to treatment in a selected population
Authors: Curnow R. N.
Published: April 2007

Previous work on the consequences of regression to the mean for the interpretation of responses to treatment is extended to the situation where the response measured is the proportional change in some variable. Methods for correcting for the bias are discussed.
An approximation for the distribution of the scan statistic
Authors: Wallenstein Sylvan , Neff Norman
Published: April 2007

The scan statistic evaluates whether an apparent cluster of disease in time is due to chance. The statistic employs a ‘moving window’ of lengthwand finds the maximum number of cases revealed through the window as it scans or slides over the entire time periodT. Computation of the probability of observing a certain size cluster, under the hypothesis of a uniform distribution, is infeasible whenN, the total number of events, is large, andwis of moderate or small size relative toT. We give an approximation that is an asymptotic upper bound, easy to compute, and, for the purposes of hypothesis testing, more accurate than other approximations presented in the literature. The approximation applies both whenNis fixed, and whenNhas a Poisson distribution. We illustrate the procedure on a data set of trisomic spontaneous abortions observed in a two year period in New York City.
Avoidance of large biases and large random errors in the assessment of moderate treatment effects: The need for systematic overviews
Authors: Collins Rory , Gray Richard , Godwin Jon , Peto Richard
Published: April 2007

In order to avoid selective biases and to minimize random errors, inference about the effects of treatment on serious endpoints needs to be based not on one, or a few, of the available trial results, but on a systematic overview of the totality of the evidence from all the relevant unconfounded randomized trials. But, only where coverage of all, or nearly all, randomized patients in all relevant trials (or a reasonably unbiased sample of such trials) can be assured, is a systematic overview of trials reasonably trustworthy, for then any selective biases are likely to be small in comparison with any moderate effects of treatment. Checks for the existence of such biases can best be conducted if reasonably detailed data are available from each trial. Future trials should take into account the results of any relevant overviews in their design, and should plan to obtain sufficient numbers of events to contribute substantially to such overviews. In many cases, this implies the need for randomized trials that are much larger than is currently standard.
An overview of six clinical trials of aspirin in coronary heart disease
Authors: Canner Paul L.
Published: April 2007

Data from six randomized, placebo‐controlled clinical trials of aspirin, involving a total of 10,703 post‐myocardial infarction patients, have been compared and combined. An apparent heterogeneity of findings among the six trials with respect to all‐cause mortality is noted (P = 0.08). The reasons for this heterogeneity are explored. Two common methods of combining the results of several trials – the logrank and the log odds ratio methods – yield two‐sided P‐values of 0.112 and 0.110, respectively, for the aspirin‐placebo effect on all‐cause mortality. Alternative statistical methods of combining the results of the six trials give two‐sided P‐values ranging from 0.017 to 0.487.
Obtaining medically meaningful answers from an overview of randomized clinical trials
Authors: Yusuf Salim
Published: April 2007

Answers that have medical value can often be obtained from overviews of randomized clinical trials if care is taken in formulating a biologically sensible question and unbiased and careful methods are used in collecting, extracting and analysing the results. This article discusses some of the pitfalls that are encountered during this process, outlines some solutions and emphasizes the need for a conservative interpretation of the results.
Lessons from overviews of cardiovascular trials
Authors: Furberg Curt D. , Morgan Timothy M.
Published: April 2007

Overviews of clinical trials in the cardiovascular field have been critically reviewed. Six reasons for the overviews were identified. An impression, at least from a scientific viewpoint, is that the pooled analyses have been valuable. Six potential problems are discussed and recommendations given based on lessons learned. These include the avoidance of three types of biases – publication bias, overviewer bias and investigator bias. The role of time‐dependent treatment effects, the complex issue of ‘mixing of apples and oranges’ and the problem of errors are also addressed.
Potential pooling opportunities: Cancer
Authors: Friedman Michael A.
Published: April 2007

The pooling of large amounts of clinical data from all available and relevant (diverse) sources in order to achieve greater statistical confidence may be appropriate for most modern and well conducted clinical investigations. However, in order to arrive at specific and meaningful conclusions, such exercises absolutely depend upon the homogeneity (or at least comparability) of the study population and therapy under scrutiny. There are currently many opportunities for pooling studies of cancer treatment. The most attractive disease situations are those with a sufficiently large number of completed randomized studies. Some to be considered are colon cancer, gastric cancer, hepatoma, ovarian cancer and lymphoma.
Inter‐study differences: How should they influence the interpretation and analysis of results?
Authors: Bailey Kent R.
Published: April 2007

In determining the role inter‐study variation should play in an overview analysis, it is important to consider three factors: (1) which question one is trying to answer; (2) the degree of similarity or dissimilarity of design, and (3) the degree to which heterogeneity of outcomes can be explained. Three questions one might be interested in are: (1) whether treatment can be effective in some circumstances; (2) whether treatment is effective on average, and (3) whether treatment was effective on average in the trials at hand. Under the assumption of no qualitative interaction, the answers to these questions coincide. The O – E analysis most directly answers the third question. Other analyses are suggested when the first question is of interest, using the aspirin post‐MI studies as an example.
Internal quality control in clinical chemistry: A teaching review
Authors: Nix A. B. J. , Rowlands R. J. , Kemp K. W. , Wilson D. W. , Griffiths K.
Published: April 2007

This survey introduces the subject of internal quality assessment from a historical point of view, presents a unified approach to notation, concepts and definitions, and describes briefly those quality control procedures that are used most commonly in clinical chemistry. It is not the aim of this report to comment on all the individual contributions made in this field, but rather to concentrate on the principles. Particular emphasis is centred around assessment criteria to compare the efficiencies of selected control procedures for monitoring analyte concentrations in biological fluids. The question of whether to compare control schemes by means of average run lengths, run length distribution functions or average cost functions is considered. A rationalized approach based on the comparison of optimal procedures, using average run length, is adopted.
Adjustments to the Mantel–Haenszel chi‐square statistic and odds ratio variance estimator when the data are clustered
Authors: Donald Alan , Donner Allan
Published: April 2007

Dependence between observations on a dichotomous variable renders invalid the usual chi‐square tests of independence and inflates the variances of parameter estimates. Such a situation occurs, for example, when subjects consist of members of the same family or with repeated observations on the same person. In this paper we describe methods of measuring the extent of correlation (or clustering). We also develop methods of adjusting the Mantel–Haenszel chi‐square test statistic and the variance of the Mantel–Haenszel estimate of a common odds ratio in sets of 2 × 2 contingency tables.
Analysis of total mortality in the rotterdam sample of the Kaunas–Rotterdam intervention study (KRIS)
Authors: Mulder Paul G. H. , Hempenius Anton L.
Published: April 2007

In 3284 middle‐aged Rotterdam men, the dependency of 9‐year survival on a number of cardiovascular risk factors is analysed. The purpose of this analysis is twofold. First, there is interest in the relationship between total mortality and the continuous variables blood pressure and plasma cholesterol. In accordance with other studies, the results provide further evidence for a U‐shaped relationship. The second purpose is to compare three models theoretically as well as empirically: a piecewise exponential distribution of survival time, Cox's proportional hazards model (both with a log‐linear dependency specification of the mortality rate), and a logistic model. The disadvantage of a logistic model is that it is theoretically not appropriate in longitudinal (prospective) epidemiologic studies. The theoretical advantage of the piecewise exponential distribution to Cox's model is that longitudinal (time) effects on the mortality rate can be specified and estimated directly. Empirically, with 342 deaths all three methods yield quite similar estimates and therefore are almost equally capable of detecting relationships between mortality and the risk factors in the data set at hand.
The probability of inevitability: The inherent impossibility of validating criteria for brain death or ‘irreversibility’ through clinical studies
Authors: Shewmon D. Alan
Published: April 2007

A great need persists for diagnostic criteria for both brain death in young children and irreversible loss of consciousness at all ages. This article examines the inferences derived from a hypothetical confirmatory study in which all of the N patients who fulfilled the criterion did in fact experience brain death (irreversibility). A Bayesian methodology proves that, for N in the range of a large clinical study, estimations of prior probabilities are, for all practical purposes, irrelevant to the calculation of the posterior probabilities. The risk of a false positive diagnosis for the next patient who meets the criterion is approximately 1/(N + 2). The chance of at least one false positive diagnosis among the next (N + 1) patients who meet the criterion is around 50 per cent. Thus, achievement of the requisite moral certainty of a declaration of death (irreversibility) necessitates an impossibly large N for the study. This does not mean that one cannot diagnose death, but rather that the validity of the diagnostic criteria must be self‐evident on a priori grounds, and that confirmatory studies are necessarily either inadequate or superfluous.
Multiple comparisons for relative risk regression: Extension of the k‐ratio method
Authors: Dixon Dennis O. , Divine George W.
Published: April 2007

We propose a k‐ratio method for multiple comparisons among disjoint groups in survival analysis, specifically among relative risk estimates from a proportional hazards regression analysis. The new method relates the magnitude of critical values to an overall measure of group heterogeneity. That is, large critical values result from small values of a chi‐square statistic for testing between‐groups homogeneity. Conversely, large values of the overall statistic lead to small critical values for individual comparisons, even if there are many groups. The adaptivity of the k‐ratio method contrasts sharply with the conservatism of competing methods.
Monitoring distributional assumptions and early stopping for a prospective clinical trial using Monte Carlo simulation
Authors: Gebski Val , McNeil Don , Coates Alan , Forbes John
Published: April 2007

We have applied the technique of Monte Carlo simulation to the determination of sample size for a partially completed clinical trial of chemotherapy for breast cancer. Simulations based on results observed after the entry of 243 patients in 2 years indicated a power greater than that predicted by the calculations made before the protocol was activated, and allowed a recommendation for an eventual trial closure earlier than would have been permitted by traditional methods. Both estimative and predictive approaches to the simulation of expected survival times for censored patients are presented. The use of simulation is recommended as an aid in reassessing the exact nature of the underlying survival distributions (as these affect the sample size calculations) and in optimizing stopping rules relating to patient accrual to a clinical trial in progress.
Variance estimators for attributable fraction estimates consistent in both large strata and sparse data
Authors: Greenland Sander
Published: April 2007

A number of variance formulae for the attributable fraction have been presented, but none is consistent in sparse data, such as found in individually matched case‐control studies. This paper employs Mantel–Haenszel estimation to derive variance estimators for attributable fractions that are dually consistent, that is, consistent in both sparse data and large strata. The method may also be applied using conditional maximum likelihood. Extensions of these estimators to situations involving effect modification and preventive exposures are also derived. Examples of applications to individually matched case‐control studies are given.
Age, period and cohort analysis of trends in mortality from major diseases in Japan, 1955 to 1979: Peculiarity of the cohort born in the early Showa Era
Authors: Tang Toshiro , Kurashina Shiusuke
Published: April 2007

Japanese researchers have reported that recent mortality rates from diabetes mellitus, ischemic heart disease, peptic ulcer, cirrhosis of the liver and suicide for middle‐aged Japanese men have increased by comparison with those for other age groups. There has been some controversy over the etiology of this unusual trend, and in particular whether it is due primarily to recent undesirable socio‐economic factors (period effects) or to factors specific to these cohorts born in the early Showa Era, around 1925 to 1940 (cohort effects). A possible source of this controversy lies in the methods which have been used to describe the trends; these are mostly descriptive and graphical.

To elucidate which factors are responsible for these trends, we analysed the mortality data quantitatively applying an age‐period‐cohort model modified so that period effects remain constant within certain age groups but may vary from one age group to the next. Although the identifiability problem still occurs in the modified model, estimable curvature components of time effects may be used to examine these unusual trends. In fact, the peculiarity of the cohort born in the early Showa Era was clearly detected by the curvature components of cohort effects for these major diseases. These findings are consistent with the ‘cohort hypothesis’ for the recent peculiar trend in Japanese male mortality.
Meta‐analysis of clinical trials as a scientific discipline. II: Replicate variability and comparison of studies that agree and disagree
Authors: Chalmers Thomas C. , Berrier Jayne , Sacks Henry S. , Levin Howard , Reitman Dinah , Nagalingam Raguraman
Published: April 2007

The replicate variability of meta‐analyses of controlled clinical trials has been assessed as a measure of scientific precision. 46 of 91 known meta‐analysis papers were divided into 20 cohorts of studies of the same therapies. Ten cohorts contained meta‐analyses with different statistical conclusions; 14 contained differing clinical conclusions with a wider spread than the statistically differing studies. Possible causes of variability, such as different trials included, different policies regarding the inclusion of non‐randomized and unpublished trials, and different statistical methodologies, were not obvious causes of differing conclusions. Further work in this area should include multivariate analyses in order to explore possible interactions in the factors accounting for the variability found in replicate meta‐analyses.
A method of analysis taking into account competing events: Application to the study of digestive complications following irradiation for cervical cancer
Authors: Kramar Andrew , Pejovic Marie‐Hélène , Chassagne Daniel
Published: April 2007

Over the past 20 years, mortality rates from uterine cervix carcinoma have been decreasing owing to earlier diagnosis and improved treatment. The incidence of secondary effects from radiation therapy has spurred some interest and injuries resulting from ‘over’‐treatment have been of some concern. The present study concerns the evaluation of bowel complications following treatment for the 272 stage IIb and III patients treated in our centre between 1967 and 1973. Competing risk methodology is applied and the influence of radiotherapy parameters is evaluated by a log‐linear model of the event‐specific failure rates. A single parameter (NSD) which summarizes total dose, total number of sessions and total treatment time is found to be related to the occurrence of complications.
A probability‐based aid for teaching medical students a logical approach to diagnosis
Authors: Crichton Nicola J. , Emerson Peter A.
Published: April 2007

In this paper we present a method of teaching medical students a logical approach to diagnosis. By using the independent Bayes method, commonly employed in decision aids, students can be made aware of how information on each new symptom affects what is likely in the light of what is known already. This approach is used for the diagnosis of thoracic symptoms in patients with normal chest X‐rays and an example is given. Extensions of the system to incorporate information from investigations and error costs are discussed.
Designing a study for evaluating a protocol for the selective performance of preoperative tests
Authors: Charpak Yves , Bléry Christian , Chastang Claude
Published: April 2007

Some basic concepts concerning classification of studies evaluating diagnostic procedures are given. The specific problem of assessment of routine preoperative tests is discussed: actual knowledge and methodological criticisms of previous studies, hypothesis for further evaluations, difficulties in the choice of a design and realization of a clinical study to assess a protocol for selective ordering of preoperative tests during one year in a teaching hospital. 3866 consecutive patients were included. The protocol led to perform only 33 per cent of all potential tests and did not apparently produce major adverse effects on the quality of care as appreciated by a clinical decision analysis.
Predicting the dynamic effects of rubella vaccination programmes
Authors: De Boo Th. M. , Van Druten J. A. M. , Plantinga A. D.
Published: April 2007

In the Netherlands, prepubertal girls have been vaccinated against rubella since 1974 (the UK strategy). Recently the Dutch Health Council advocated the introduction of an elimination strategy: vaccination of 1‐and 9‐year‐old children. Dynamic effects of both strategies are studied using deterministic and stochastic models. Estimates of several epidemiological parameters are given. All computations and simulations were performed using as much field data as possible. Under the old strategy a new equilibrium is expected around the years 1995 to 2000; the new strategy is estimated to eliminate rubella (CRS) in large parts of the population 3 to 5 years after its initiation. Possible consequences of the new strategy on a cluster of people who refuse vaccination are investigated.
Modelling the effect of intervention on the transmission of malaria in east malaysia
Authors: Collett D. , Lye M. S.
Published: April 2007

To assess the public health importance of malaria on Banggi Island, Sabah, baseline epidemiological and entomological data were obtained in a study of three villages. These data were used to model the transmission of malaria using a non‐seasonal version of the deterministic model of Dietz, Molineaux and Thomas. The model provided a satisfactory description of prevalence rates of Plasmodium falciparum parasitaemia. Modifications to the basic model enable the effects of mass chemotherapy with various combinations of schizonticidal and gametocidal drugs to be simulated. In this way, the relative merits of different procedures of mass drug administration can be compared. The fitted model is also used to examine the relationship between the overall prevalence of infection and the vectorial capacity, and to predict the consequences of a reduction in the size of the vector population.