bluuebunny/crossref_metadata_2025 huggingface dataset:
The Interaction of Cationic Polymers and Their Bisphosphonate Derivatives with Hydroxyapatite
Authors: Zhang Sufeng , Wright Jennifer E. I. , Özber Natali , Uludağ Hasan
Published: April 2007

Conjugating proteins with bisphosphonates (BPs), a class of molecules with exceptional affinity to hydroxyapatite (HA), is a feasible means to impart bone affinity to protein‐based therapeutic agents. To increase the targeting effectiveness while minimizing protein modification, a polymeric linker containing multiple copies of BPs could be constructed for protein conjugation and targeting to bone. Towards this goal, poly(L‐lysine) (PLL) and poly(ethylenimine) (PEI) were utilized as the polymeric backbones to incorporate a BP, namely 2‐(3‐mercaptopropylsulfanyl)‐ethyl‐1,1‐bisphosphonic acid (thiolBP), by using N‐hydroxysuccinimidyl polyethylene glycol maleimide and succinimidyl‐4‐(N‐maleimidomethyl)‐cyclohexane‐1‐carboxylate, respectively. In vitro and in vivo mineral affinity of the polymer‐BP conjugates were determined in comparison with the unmodified polymers. The in vitro results indicated strong binding of the cationic polymers to HA in their unmodified form. BP conjugation did not enhance the inherent mineral affinity of the polymers; in contrast, certain modifications negatively affected the polymers' binding to the HA. In vivo results from a subcutaneous implant model in rats also showed no significant difference in mineral affinity of the BP modified and unmodified PEI. We conclude that thiolBP conjugation to the cationic polymers PLL and PEI was not beneficial for increasing the mineral affinity of the polymeric molecules. The strong interaction between the cationic polymers and HA may make the polymers suitable for imparting mineral affinity to bone‐acting therapeutics.

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Interface Interactions of Osteoblasts with Structured Titanium and the Correlation between Physicochemical Characteristics and Cell Biological Parameters
Authors: Nebe J. G. Barbara , Luethen Frank , Lange Regina , Beck Ulrich
Published: April 2007

Cellular behavior at the interface of an implant is influenced by the material's topography. However, little is known about the correlation between the biological parameters and the physicochemical characteristics of the biomaterial. We therefore modified pure titanium surfaces by polishing, machining, blasting with glass spheres, blasting with corundum particles, and vacuum plasma spraying to give progressively higher surface roughness. The material surface was characterized by SEM, surface profiling, and electrochemical methods. We revealed a correlation for integrin expression and formation, adhesion, spreading, proliferation, and bone sialo protein expression with the physicochemical parameters of the titanium surfaces.

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Chondroitin‐4‐Sulfate: A Bioactive Macromolecule to Foster Vascular Healing around Stent‐Grafts after Endovascular Aneurysm Repair
Authors: Charbonneau Cindy , Gautrot Julien E. , Hébert Marie‐Josée , Zhu X. X. , Lerouge Sophie
Published: April 2007

Deficient healing after endovascular aneurysm repair with a stent‐graft is thought to be related to pro‐apoptotic environment in abdominal aortic aneurysms and inertness of graft materials. We developed a bioactive coating containing chondroitin‐4‐sulfate and assessed its potential to improve cell adhesion, viability and resistance to apoptosis on PET surfaces. Coatings of collagen type I and CS were prepared and characterized by DMMB, FT‐IR, DSC, SEM and contact angle goniometry. Preliminary cell culture experiments with vascular smooth muscle cells showed increased adhesion and viability in serum‐free medium on CS‐coated surfaces compared to control PET films.

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Pole Approximation and Spectral Concentration
Authors: Demuth M.
Published: April 2007

An asymptotic error estimation of the pole approximation is given by means of spectral concentration in the onedimensional Friedrichs' model.

Übersicht. Mit Hilfe der Spektralkonzentration wird für ein eindimensionales Friedrichs‐Modell die Güte der Polapproximation asymptotisch abgeschätzt.
Des catégories respectivement équivalentes à celles des espaces affines et des modules
Authors: Batbedat André
Published: April 2007

Nous rnontrons que la catégorie des espaces affines (avec anneau variable) est équivalente à une catégorie d'anneaux et plus naturellement à une catégorie de préanneaux. On examine quelques cas particuliers, précise certains applications et présente des généralisations. Ces résultats s'adaptent facilement aux modules.
Diagnose von Schlafstörungen und Tagesschläfrigkeit: Wenn der Schlaf nicht mehr erholsam ist – Ursachen und Folgen
Authors: Popp Roland , Geisler Peter
Published: April 2007

Schlafstörungen haben sowohl eine Störung der physiologischen Erholungsfunktion des Schlafes in der Nacht als auch negative Auswirkungen auf die Befindlichkeit und Leistungsfähigkeit am Tag zur Folge. Ein wesentliches Leitsymptom in der Diagnostik ist die Tagesschläfrigkeit.

Mit der kardiorespiratorischen Polysomnographie kann der Schlafablauf objektiviert werden. Zugleich können die häufigsten Ursachen für einen nicht erholsamen Schlaf erkannt werden. Mit unterschiedlichen Verfahren kann Schläfrigkeit auf subjektiver, physiologischer und verhaltensbasierter Ebene identifiziert und quantifiziert werden.

Schlafstörungen werden üblicherweise unterschieden nach Dyssomnien (zirkadiane Rhythmusstörungen, Insomnien und Hypersomnien), Parasomnien und Schlafstörungen bei körperlich/psychiatrischen Erkrankungen.
Pharmakologie der Benzodiazepine: Allosterische Aktivatoren an GABAA‐Rezeptoren
Authors: Bönisch Heinz
Published: April 2007

Benzodiazepine und die chemisch nicht verwandten Benzodiazepin‐Analoga wie Zolpidem sind alle Agonisten an der allosterischen Bindungsstelle des GABAA‐Rezeptors. Ihre durch Flumazenil antagonisierbaren Effekte beruhen auf einer Verstärkung der Wirkung von GABA im ZNS, die über den GABAA‐Chloridkanalrezeptor vermittelt wird. Die Benzodiazepin‐Analoga binden, im Unterschied zu den klassischen Benzodiazepinen, nicht an die α2‐Untereinheit des Rezeptors; sie wirken daher praktisch nicht anxiolytisch und muskelrelaxierend. Sie sollen auch ein geringeres Abhängigkeitspotential als Benzodiazepine besitzen. Neben kurz wirksamen Benzodiazepinen sind sie Mittel der Wahl bei der Behandlung von Schlafstörungen.
Melatonin, Melatonin‐Rezeptor‐Agonisten und Tryptophan als Schlafmittel. Natürlicher Schlaf?
Authors: Steinhilber Dieter
Published: April 2007

Melatonin und Melatoninrezeptor‐Agonisten stellen ein interessantes Konzept zur Behandlung von Schlafstörungen dar. Melatoninrezeptor‐Agonisten verkürzen die Einschlafzeit und können die Gesamtschlafzeit verlängern. Die Schlafarchitektur wird durch Melatoningabe offensichtlich nicht verändert. Melatonin übt keinen klassischen hypnotischen Effekt wie Benzodiazepine oder H1‐Antihistaminika aus, sondern fungiert als Hormon, welches die zirkadiane Phase je nach Einnahmezeitpunkt verschiebt. Ob Melatonin direkte hypnotische Effekte besitzt, ist umstritten, es scheint jedoch die Einschlafbereitschaft zu erhöhen. Bisher ergaben sich weder im Tierversuch noch in klinischen Studien Hinweise auf ein Abhängigkeits‐ oder Missbrauchspotenzial. Melatonin ist in Europa nicht als Arzneimittel zugelassen. In den USA wird Melatonin als Nahrungsergänzungsmittel vertrieben. Der MT‐Rezeptoragonist Ramelteon ist den USA bereits zugelassen, in Europa befindet er sich in Phase III der klinischen Prüfung.
Die Früchte der Postgenom‐Analyse: Identifizierung von Risikogenen für Morbus Crohn und Typ‐2‐Diabetes
Authors: Winckler Thomas
Published: April 2007

In zwei großen Genomstudien wurden Mutationen in Genen entdeckt, die an der Prädisposition bzw. Pathogenese von Morbus Crohn und Typ‐2‐Diabetes beteiligt sind.
The number of partners and the probability of HIV infection
Authors: Eisenberg Bennett
Published: April 2007

This paper analyses the probability of contracting the AIDS virus in relation to the number of sexual contacts and the number of different partners. It is shown that in the case of a fixed number n of sexual contacts there is the following ranking from least risk to greatest risk: 1. a monogamous relationship with a non‐infected partner; 2. a monogamous relationship with a randomly selected partner; 3. a relationship with more than one randomly selected partners; 4. n randomly selected partners; 5. a monogamous relationship with an infected partner.
Policy implications of modelling of the AIDS epidemic
Authors: Brandt Edward N.
Published: April 2007

Health policy issues associated with AIDS are complex and controversial, including health care, research priorities, education, testing and confidentiality. Modelling may provide information relevant to their solution. Estimates of the future numbers of symptomatic persons and of the mix of severity are necessary for developing the capability to provide and fund health care services. Models may suggest other data needs and research directions. An important policy role of models is to permit evaluation of potential intervention steps and especially to project negative consequences. The critical contribution of models will be improved understanding of the dynamics of the AIDS epidemic.
A comparison of statistical methods for combining event rates from clinical trials
Authors: Berlin Jesse A. , Laird Nan M. , Sacks Henry S. , Chalmers Thomas C.
Published: April 2007

We compare two statistical methods for combining event rates from several studies. Both methods treat each study as a separate stratum. The Peto‐modified Mantel—Haenszel (Peto) method estimates a combined odds ratio assuming homogeneity across strata and provides a test for heterogeneity. The DerSimonian and Laird modified Cochran method (D&L) produces a weighted average of rate differences, where the weights allow for among‐study variability. We analyse 22 meta‐analyses from ten reports by both methods. The pooled estimates are divided by their standard errors to produce a Z‐statistic. A t‐test comparing Z‐statistics from all 22 studies suggests that the D&L method tends to be more conservative [d(Peto—D&L) = 0.29, t = 2.53, p = 0.02]. For a subset of 14 non‐heterogeneous studies, the difference is smaller and non‐significant (d = 0.09, t = 0.72, p = 0.49). The results from the methods correlate well (r = 0.66 for all 22 studies, r = 0.95 for 14 non‐heterogeneous studies). Thus, the presence of heterogeneity influences our conclusion. We discuss the statistical and scientific implications of these findings.
Factorial designs in clinical trials: The effects of non‐compliance and subadditivity
Authors: Brittain Erica , Wittes Janet
Published: April 2007

Factorial designs in clinical trials allow for the study of several medical treatments simultaneously. This paper distinguishes among different types of settings in which factorial designs are useful. For the experiment that involves investigation of several new or untested therapies, we introduce a model that incorporates rates of non‐compliance to therapy as well as various degrees of subadditivity of treatment effects. We compare the operating characteristics of the factorial under this model with those of competing designs and show that a modest negative interaction can considerably diminish the power to detect treatment effects in the factorial even in cases that have little power to detect this interaction. We urge, therefore, that designers of clinical trials with factorial layouts posit realistic estimates of interactions among treatments in order to assure adequate power to detect beneficial effects of treatment.
Issues in analysing the effects of occupational exposure to low levels of radiation
Authors: Gilbert E. S.
Published: April 2007

A major objective of studying populations exposed to low levels of radiation is provision of direct assessment of the adequacy of estimates of health risks obtained by extrapolation of data on populations exposed at high levels. Meeting this objective requires the use of statistical methods that fully utilize available exposure measurements, and that consider the extensive body of prior knowledge regarding radiation‐induced health effects. This paper describes various methods of analysis and illustrates the methods with data on workers at the Hanford Site. Special problems are discussed, with attention to comparability of estimates and confidence limits with those obtained from extrapolation.
Variance estimation for medical decision analysis
Authors: Katz Barry P. , Hui Siu L.
Published: April 2007

We have derived the variance of an expected utility for a probability tree in medical decision analysis based on a Taylor series approximation of the expected utility as a function of the probability and utility values used in the decision tree. The resulting variance estimate is an algebraic expression of the variances associated with the probability and utility estimates used. We also derive expressions for the case where the input parameter estimates are not independent. We discuss the choice of input parameters and their variance estimates and give an example that compares two protocols for the treatment of chlamydial infection.
An application of a mathematical model to adjust for time lag in case reporting
Authors: Lui Kung‐Jong , Rudy Richard K.
Published: April 2007

In a dynamic, fluctuating surveillance system, the time lag of case reporting often causes an artificial plateau in an epidemic curve. Arbitrarily ignoring data reported in the most recent period to avoid this bias causes the loss of valuable information. In this report, we propose an application of a mathematical model to adjust for the underreporting bias owing to the time lag of the reporting process. We present an example using the acquired immunodeficiency syndrome incidence data for the homosexual group in the San Francisco surveillance system to illustrate and evaluate prospectively this proposed technique. The results show that the adjusted incidence obtained with the model agrees reasonably well with the true incidence, except for the last month of the period under consideration.
Monitoring data quality through comparisons between data systems
Authors: Massey James T. , Hoffman Keith L.
Published: April 2007

Since its creation in 1960, the National Center for Health Statistics (NCHS) has placed a high value on the quality of the information and statistics collected and published by its data systems. An important component of a comprehensive data quality monitoring system for a statistical agency such as NCHS is the comparison of statistics between data systems. Between‐data‐systems comparisons are used to monitor the consistency and comparability of statistics across data systems and between NCHS data systems and outside sources of data. This paper focuses on between‐data‐systems comparisons and describes a number of methodological analyses that can be used to evaluate data quality. The methodological analyses presented include the evaluation of time trends, the estimation of survey method effects, the evaluation of response error, the measurement of definitional and concept effects, and the detection of inconsistencies between data systems. The paper concludes with a discussion of the complexities of the between‐data‐systems comparisons and an assessment of the net benefits from such comparisons.
Estimating trends in the effectiveness of seat belts in saving lives, 1975–1985
Authors: McGee Daniel L. , Rhodes Phil
Published: April 2007

We examine the effectiveness of seat‐belt systems for preventing mortality in automobile crashes. In particular, we examine whether seat‐belt effectiveness has been constant over this period and conclude that there has been a trend toward an increased effectiveness of seat‐belt systems. The relative odds of death associated with wearing seat belts dropped from 0.80 in 1975 to 0.34 in 1985. This trend results from improvements in both the type and design of seat belts and from additional design changes, such as padded dashboards and collapsible steering columns, that protect occupants at the time of collision.
Flexible regression models with cubic splines
Authors: Durrleman Sylvain , Simon Richard
Published: April 2007

We describe the use of cubic splines in regression models to represent the relationship between the response variable and a vector of covariates. This simple method can help prevent the problems that result from inappropriate linearity assumptions. We compare restricted cubic spline regression to non‐parametric procedures for characterizing the relationship between age and survival in the Stanford Heart Transplant data. We also provide an illustrative example in cancer therapeutics.
The analysis of titration studies in phase III clinical trials
Authors: Shih Weichung Joseph , Gould A. Lawrence , Hwang Irving K.
Published: April 2007

Clinical trials commonly employ the titration design for certain drugs such as antihypertensives. In a Phase III trial the design has purposes distinct from those of a Phase I or II trial, as well as from those of a trial with a parallel design. In this paper we compare the titration design with the usual parallel design in their respective purposes for Phase III trials, explore the relevant questions addressed, and examine typical data from such trials. We also discuss work which focuses primarily on the Phase I or II titration trials. We formulate the problem in the framework of a one‐way contingency table augmented with incomplete data and obtain the maximum likelihood estimates of the parameters and their estimated variances/covariances via the EM algorithm. An example of a Phase III study of an antihypertensive agent illustrates the proposed procedure.
Assessing diagnostic tests by a strictly proper scoring rule
Authors: Linnet Kristian
Published: April 2007

Evaluation of univariate quantitative diagnostic tests by strictly proper scoring rules is considered as an alternative to the traditional error rate measures. In principle, the posterior probability of disease as a function of the test value is estimated from training observations, and subsequently the score is assessed on a set of test samples. The same subjects may serve as training and test samples when the bootstrap procedure is applied for estimation of standard errors and correction of bias. The method is demonstrated using serum bile acids and bilirubin in patients with liver disease. The power for comparison of scores from two tests is compared with that from error rate measures for some typical situations.
Sample size tables for logistic regression
Authors: Hsieh F. Y.
Published: April 2007

Sample size tables are presented for epidemiologic studies which extend the use of Whittemore's formula. The tables are easy to use for both simple and multiple logistic regressions. Monte Carlo simulations are performed which show three important results. Firstly, the sample size tables are suitable for studies with either high or low event proportions. Secondly, although the tables can be inaccurate for risk factors having double exponential distributions, they are reasonably adequate for normal distributions and exponential distributions. Finally, the power of a study varies both with the number of events and the number of individuals at risk.
A method for the evaluation of dose‐toxicity relationships in clinical trials
Authors: Mather Frances J. , Simon Richard M. , Clark Gary M. , Von Hoff Daniel D.
Published: April 2007

This paper considers a proportional hazards model that describes the relationship between time‐dependent cumulative dose of drug and development of toxicity. We estimate probabilities of developing toxicity in both the presence and the absence of competing risks and provide variances for the latter case. Mitoxantrone data collected in Southwest Oncology Group studies illustrate the methods.
Estimability and estimation of excess and etiologic fractions
Authors: Robins James M. , Greenland Sander
Published: April 2007

This paper describes conditions under which epidemiologic data can provide estimates of the excess fraction (proportionate increase in caseload due to an exposure) and the etiologic fraction (fraction of cases caused by exposure). The excess fraction can be estimated under essentially the same conditions often cited for general study validity. In contrast, estimation of the etiologic fraction will usually require very specific nonidentifiable assumptions about exposure action and interactions, although one can derive simple lower and upper bounds for the fraction from survival comparisons. Since the etiologic fraction is equivalent to the probability of causation, our results have implications for injury compensation in lawsuits involving the probability of causation.
Statistical comparison of ligand‐binding kinetics
Authors: Cologne John B. , Mendelman Paul M. , Chaffin Donald O.
Published: April 2007

We describe the application of generalized linear model methodology to the problem of testing differences among ligand‐receptor interactions, and show that the method is analogous to weighted least squares regression methodology and F tests familiar to many investigators. The method accommodates incomplete block designs so that one can obtain kinetic parameter estimates directly comparable among samples analysed on incompletely overlapping sets of experimental runs. We demonstrate the method with data that compare saturation kinetics for a single penicillin‐binding protein in isogenic ampicillin susceptible and resistant bacteria.
Effect of unequal censoring on the size and power of the logrank and Wilcoxon types of tests for survival data
Authors: Beltangady Mohan S. , Frankowski Ralph F.
Published: April 2007

This paper examines the effect of random unequal censoring on the size and power of two‐sample logrank and Wilcoxon types of tests for comparing two survival distributions by simulation with small samples from censored exponential distributions. We compared equal‐sized samples of n = 8, 16, and 32 with 1000 (size) and 500 (power) simulation trials for 16 combinations of the censoring proportions of 0, 20, 40, and 60 per cent in each of the two samples. For n = 8, the asymptotic normality (AN), Peto‐Peto, and the two Wilcoxon‐type tests performed at nominal 5 per cent size expectations, but the Mantel test exceeded the 5 per cent size acceptance region in 6 of 16 censoring combinations. For n = 16 and 32, all tests showed proper size, with the Peto‐Peto test being most conservative in the presence of unequal censoring. We compared powers of all tests for exponential hazard ratios of 1·4 and 2·0. The Mantel test showed 90 to 95 per cent power efficiency relative to the parametric AN test. Both Wilcoxon tests performed identically and had the lowest relative power of all tests examined but appeared most robust to the differential censoring patterns studied. A modified version of the Peto‐Peto test showed power comparable to the Mantel test.
A review of methods for misclassified categorical data in epidemiology
Authors: Chen T. Timothy
Published: April 2007

Misclassification introduces errors in categorical variables. This paper presents a review of methods for misclassified categorical data in epidemiology. Different sampling schemes for a 2 × 2 × 2 table and methods of analyses will be discussed first. A misclassification matrix is defined, and the usual misclassification models will be shown to be a subclass of log‐linear models. Well‐known results on a 2 × 2 table with misclassification and recent results on a 2 × 2 × 2 table are then reviewed. Finally two methods of adjusting for misclassification will be given. The first method assumes a known misclassification matrix, and the second method uses subsampling to estimate the misclassification matrix. The analysis is based on a recursive system of log‐linear models: first determine a misclassification model, then select a model for the correctly classified variables. The methods are illustrated by data from traffic safety research on the effectiveness of seatbelt use in reducing injuries.
Indoor air pollution and pulmonary performance: Investigating errors in exposure assessment
Authors: Hasabelnaby Nancy A. , Ware James H. , Fuller Wayne A.
Published: April 2007

We use pulmonary function measurements on pre‐adolescent children and indoor air pollution measurements in the homes of these children to illustrate estimation techniques for linear regression models containing independent variables measured with error. In our data set, replicate measures of indoor air pollutant concentrations provide one method of estimating measurement error variances. Surrogate information in the form of cigarettes smoked is also available for the pollutant of interest. Several estimation procedures are presented, and we combine two estimators, one based on surrogate information and one based on replication information, using generalized least squares.
Analysis of case‐control data with covariate measurement error: Application to diet and colon cancer
Authors: Armstrong Ben G. , Whittemore Alice S. , Howe Geoff R.
Published: April 2007

We propose a method for estimating odds ratios from case‐control data in which covariates are subject to measurement error. The measurement error may contain both a random component and a systematic difference between cases and controls (recall bias). A multivariate normal discriminant analysis model is assumed. If the distribution of measurement error is known, then a simple correction to naive (biased) estimates of odds ratios from logistic regression of disease on fallible measurements of covariates removes bias. The same correction yields confidence intervals and significance tests. We apply the proposed methods to data from a case‐control study of colon cancer and diet.
The ordered logistic regression model in psychiatry: Rising prevalence of dementia in old people's homes
Authors: Ashby Deborah , West Christopher R. , Ames David
Published: April 2007

Ordered logistic regression is an extension of binary logistic regression, and is particularly well suited to the analysis of many psychiatric scores. Its use is demonstrated in a pair of linked cross‐sectional surveys of dementia in residents of old people's homes, first to model the association of dementia with demographic characteristics, and then to explore possible reasons for a rise in the prevalence of dementia in the homes over a four‐year period.
Estimation of temporal effects in treatment‐induced second cancer
Authors: Kaldor J. M. , Day N. E.
Published: April 2007

Cancer chemotherapy has been remarkably successful in the treatment of several types of malignancies, but has also been demonstrated to cause leukaemia and perhaps other cancer in long‐term survivors. Radiotherapy also carries a carcinogenic risk. A large case‐control study of second cancer has been carried out, with the aim of quantifying the risk due to chemotherapy and radiotherapy. One of the most important goals of this study is the estimation of the temporal pattern of risk following chemotherapy. Methods are presented for modelling risk as a function of type of treatment and the interval since reatment. The methods are applications of generally available linear regression programs for epidemiological data, and could be equally well applied to studies of occupationally induced cancer.
A measure of similarity for response curves based on ranks
Authors: Schulgen Gabi
Published: April 2007

A measure of similarity for response curves is presented and its potential use is discussed. The distribution of a suitable test statistic for testing the independence of the course of two curves is derived. The method proposed is compared with other proposals in the literature for the analysis of paired response curves. A study on the quality of life of patients with acute heart failure is used as an example.
The performance of the two‐stage analysis of two‐treatment, two‐period crossover trials
Authors: Freeman P. R.
Published: April 2007

In the two‐treatment, two‐period crossover trial, patients are randomly allocated either to one group that receives treatment A followed by treatment B, or to another group that receives the treatments in the reverse order. Grizzle first proposed a two‐stage procedure for analysing the data from such a trial. This paper examines the long‐run sampling properties of this procedure, in terms of mean square error of point estimates, coverage probability of confidence intervals and actual significance level of hypothesis tests for the differences between the effects of the two treatments. The advantages of incorporating baseline observations into the analysis are also explored. Because the preliminary test for carryover is highly correlated with the analysis of data from the first period only, actual significance levels are higher than nominal levels even when there is no differential carryover. When carryover is present, the nominal level very seriously understates the actual level, and this becomes even worse when baseline observations are ignored. Increasing sample size only exacerbates the problem since this adverse behaviour then occurs at smaller values of the carryover effect. It is concluded that the two‐stage analysis is too potentially misleading to be of practical use.
Grading of images in a clinical trial
Authors: Seigel Daniel , Milton Roy C.
Published: April 2007

We developed a computer model to compare the power in clinical trials that use either of two grading schemes for objectively recorded dependent variables. The example we use is an eye lens photo. The first grading system consists of side by side comparison of the before and after treatment photos; the second involves separate grading of the two photos. This modelling experience suggests that separate grading may often yield more power than side by side comparison, and offers other advantages as well. For applications in which grading error is considerably smaller in the side by side method, power may be markedly better. Most importantly, strong prejudice in favour of one or the other approach in all situations seems unwarranted.
A comparison of tests of homogeneity of odds ratios inK2 × 2 tables
Authors: Paul S. R. , Donner A.
Published: April 2007

We conducted a simulation study to determine the performance of nine procedures for testing the homogeneity of odds ratios inK2 × 2 contingency tables. We recommend Tarone's approximate score test, based on the Mantel—Haenszel estimator of the common odds ratio, for use in practice. We also recommend a non‐iterative statistic developed by Gart and based on the modified Woolf estimator of the common odds ratio for very large samples in balanced or mildly unbalanced designs. We base our recommendation of a statistic on its performance in terms of size and power in comparison with the other statistics considered.
On alleged gains in power from lowerP‐values
Authors: Barnard G. A.
Published: April 2007

The various suggestions that have been made to increase the power of Fisher's test for 2 × 2 tables are shown to give no real increases. One‐sided tests are examined in detail but two‐sided test problems are also considered. The need for flexibility in use ofP‐values is stressed.
The case of gissi in changing the attitudes and practice of Italian cardiologists
Authors: Tognoni Gianni , Franzosi Maria Grazia , Garattini Silvio , Maggioni Aldo , Lotto Antonio , Mauri Francesco , Rovelli Fausto
Published: April 2007

This report first describes the efficiency achieved by a large scale clinical trial (GISSI), which is widely recognized as having made an important contribution to the therapy of AMI, and second emphasizes how a comprehensive research project based upon an innovative clinical trial methodology can influence the attitude and the scientific productivity of a professional community operating within a national health system. To understand the methodology of GISSI, one must appreciate both the cultural and institutional setting in which the first GISSI trial took place as well as the strong economic and scientific expectation surrounding the second GISSI trial.
Efficient means of studying ancillary questions in clinical trials
Authors: Davis C. E.
Published: April 2007

Ancillary questions in clinical trials can often be answered by studying subcohorts of the participants. If the question compares responses between treatment groups, a subcohort that preserves the randomization can be used. However, if the question can be answered by analysis within a treatment group or by combining treatment groups, efficient methods developed for observational studies can be used. These methods include case‐control and case‐cohort methods.
How much data should we collect in a randomized clinical trial?
Authors: Verter Joel
Published: April 2007

Multicentre randomized controlled clinical trials are usually designed to answer a specific question. In accomplishing this they often collect a large quantity of data during screening, baseline and follow‐up visits. These data are not all necessarily related to the main study question. This collection impacts on the overall recruitment process and the participants' time. During the planning phase of the trial we need to consider the reasons for collecting data and the use of that data for the current study as well as its potential use in future investigations. We discuss briefly some of the possible reasons that data may be collected: screening or determining eligibility; conducting a run‐in or dose titration phase; assessing group comparability; aiding patient management; evaluating the natural history of the disease; monitoring the study; testing the study hypotheses; evaluating adherence; estimating side effects and the use of other therapies; analysis of other study questions.
A clinic's perspective on screening, recruitment and data collection
Authors: Eaton Terry , Pratt Craig M.
Published: April 2007

This paper summarizes the approach of one university cardiology section with over a decade of experience in conducting National Institutes of Health and pharmaceutical cardiovascular trials. Many of the organizational and personnel issues discussed can be directly applied to most university cardiovascular clinical research settings. Other aspects reflect a very specialized approach but key features can be modified or adapted to smaller individual research clinics. In terms of organizational features, our multi‐hospital recruitment effort is co‐ordinated by a weekly clinical research conference which is attended by all nurse coordinators and cardiology fellows. Centralization of all clinic facilities and non‐invasive laboratories, the central computer facility, and the availability of clinical research inpatient hospital beds facilitate our clinical research effort.

An expanded role of the nurse co‐ordinator is considered pivotal to trial performance. Suggestions are made as to the identification and recruitment of ideal nurse co‐ordinators, maximizing their productivity, and retaining them. The key feature is the physicians' acceptance of the nurse co‐ordinator as a colleague. The roles of the principal investigator and clinical cardiology fellows are delineated, and suggestions made for data entry and computer technical expertise to optimize nurse co‐ordinator efficiency, allowing total focus on recruitment and follow‐up.
Opportunities for enhancing efficiency and reducing cost in large scale disease prevention trials: A statistical perspective
Authors: Prentice Ross L.
Published: April 2007

Randomized intervention trials play an important role in the identification of practical approaches to reducing major chronic diseases in our society. Very few such trials are likely to be possible, however, in coming years unless we adopt procedures less demanding and less costly than those used in the past. Towards this end some elements of an efficient prevention trial are discussed, including aspects of study design, criteria for eligibility and exclusion, procedures for data collection, follow‐up, endpoint ascertainment, and data analysis, and for ancillary studies. For example, possibilities for enhancing efficiency in the use of endpoint events include the selection of an appropriately weighted test statistic, the use of case‐control or case‐cohort sampling procedures in the processing of covariate data and specimens, and the notion of replacing a disease endpoint by an earlier or less expensive surrogate endpoint. Ideas for enhancing the efficiency of prevention trials will be illustrated in the context of a proposed Dietary Fat Intervention Trial for disease prevention in women.
Survival analysis techniques in angina pectoris trials
Authors: Bristol D. R. , Castellana J. V.
Published: April 2007

The variable ‘walking time to moderate angina’ on an exercise stress test is the primary means to judge the efficacy of new treatments for angina pectoris. Unfortunately, ‘walking time to moderate angina’; is often censored by fatigue or other reasons for premature termination of the exercise stress test. If time to fatigue is not treatment‐dependent, we propose use of survival analysis techniques in such trials. We present an example from a placebo‐controlled multicentre clinical trial and results of simulations that compare various methods of analysis.
Receiver operator characteristic (ROC) curves and non‐normal data: An empirical study
Authors: Goddard M. J. , Hinberg I.
Published: April 2007

This paper evaluates the performance of several diagnostic kits for assessing levels of serum prostatic acid phosphatase on patients at different stages of cancer of the prostate. Each patient was studied with several kits. We compare results obtained for receiver operator characteristic (ROC) curve methodology with data assumed to follow a normal distribution, with log‐transformed data assumed to follow a normal distribution, and when neither of these assumptions holds. There were important differences between the results of the different approaches. For these data, the normal distribution assumption should be used with extreme caution. The log‐transformed based results compared favourably with the non‐parametric, but unconsidered application of the method should be avoided.
On the use of a logistic risk score in predicting risk of coronary heart disease
Authors: Chambless Lloyd E. , Dobson Annette J. , Patterson C. C. , Raines Byron
Published: April 2007

Many studies over the last 20 years have used logistic regression to model the relationship between the risk of developing coronary heart disease (CHD) and the levels of risk factors such as high blood pressure, high serum cholesterol, and cigarette smoking. Subsequently, several investigators have proposed the use of some of the published estimated logistic risk functions to predict risk in new populations. Because of great variation in definition of event, duration of follow‐up, population characteristics, definition of risk variables, and selection of other variables in the logistic functions, direct use of such established functions would generally not have validity for the prediction of absolute risk levels. A review of fifteen of these studies indicates on the one hand generally similar results in direction and order of magnitude of effects of the major risk factors, confirming the importance of these risk factors of CHD. On the other hand the reviews indicate sufficient variation to suggest that extrapolation to new populations even to predict relative risk is not justified.
Application of the theory of finite mixtures for the estimation of ‘cure’ rates of treated cancer patients
Authors: Gordon N. H.
Published: April 2007

I assume the survival function of treated cancer patients to be a mixture of two subpopulations, withcequal to the proportion who will die of other causes, and 1 —cthe proportion who will die of their disease. Using census data, I estimate the parameters of the survival distribution of those patients dying of other causes, and then use follow‐up data to determine the maximum likelihood estimates of the proportion constantcand the parameters of the survival function of those dying of their disease. I illustrate the methodology using data from a prospective clinical trial in breast cancer.
The power to detect differences in average rates of change in longitudinal studies
Authors: Lefante John J.
Published: April 2007

With considerable current interest in longitudinal epidemiologic studies, little is available regarding sample size requirements. This paper considers a method for analysis of longitudinal data, where one compares the mean rates of change for two or more groups, and proposes a statistic for use in determining sample size requirements. One calculates individual rates of change with least squares estimates of slopes of individuals' responses regressed over time. The assumption of linear change over time, while clearly not applicable for some data, applies to many biological measurements, either as recorded or with some transformation. The variances of these estimated slopes have two components: within‐individual variability based on measurement error and length and frequency of follow‐up, and true between‐individual slope variability. It is assumed that measurement error is the same for all subjects, so that the total variances differ due to differences in follow‐up. The question addressed is: when can one use the usual ANOVA F statistic to compare group means of estimated slopes? Expected mean squares demonstrate that this F is appropriate when either each group has the same number of subjects, or when each subject has the same length and frequency of follow‐up. A procedure for computing power and sample size is presented, where one can specify the maximum detectable difference in any two average slopes. Moment estimation and maximum likelihood estimation of variance components from prior data are discussed.
Factorial designs for crossover clinical trials
Authors: Fletcher D. J. , Lewis S. M. , Matthews J. N. S.
Published: April 2007

When measuring the joint effect of two factors it is advantageous to use a factorial design. If the application is suitable, efficiency may be further improved by using a crossover design. This paper presents a flexible method for amalgamating these two devices. Designs are constructed from smaller designs, known as bricks, generated cyclically from tabulated initial sequences. The bricks have known efficiencies for estimation of direct treatment main effects and interactions; the efficiencies can be simply combined to approximate the efficiencies of the whole design. This allows the user to build a design that is tailored to the particular objectives of the experiment. Three and four periods, and two factors with up to four levels are considered.
Symmetry and quasi‐symmetry: An example in modelling pairs of sounds from children's early speech
Authors: Stasny Elizabeth A. , Bauer Harold R.
Published: April 2007

The models of symmetry and quasi‐symmetry may have use in the analysis of categorical data in square tables where the row and column classifications are the same. Under the model of symmetry, the probability that an observation falls in, say, the (i, j) cell of a square table is the same as the probability that it falls in the (j, i) cell. The model of symmetry requires that the expected marginal total for any one row of the table be the same as the expected marginal total for the corresponding column. The model of quasi‐symmetry, which is a generalization of the model of symmetry, does not require this equality of expected row and column totals. In this paper, we illustrate the use of the models of symmetry and quasi‐symmetry in the analysis of categorical data that summarize pairs of sounds in infants' and toddlers' early utterances. In the past, the complexity of infants' early vocalizations has been difficult to measure because of a lack of methods to quantify prelinguistic phonetic variables. We use the models of symmetry and quasi‐symmetry as a first attempt to quantify the complexity of infants' early speech. We hope that the discovery of models appropriate for quantification of language development in normal children will have later use in identification of children at risk for communicative disorders.
A comparison of poisson regression models fitted to multiway summary tables and cox's survival model using data from a blood pressure screening in the city of Bergen, Norway
Authors: Selmer Randi
Published: April 2007

Multiplicative models for the association between blood pressure and coronary heart disease mortality in 5201 men aged 40–49 years at time of examination were compared. Piecewise exponential models fitted to summary tables formed by cross‐classification by three systolic and three diastolic blood pressure groups, two age groups and three time intervals gave results close to the Cox model for continuous data. The parametric integrated baseline hazard functions estimated from grouped data were close to Breslow's non‐parametric estimate in the Cox model.
A note on point estimation of the hazard ratio in exponential distributions
Authors: Lui Kung‐Jong , Rhodes Phil
Published: April 2007

The maximum likelihood estimator (MLE) of the ratio of the hazard rates in two exponential distributions is biased. This bias can be important when sample sizes are small or the ratio of these two hazard rates is large. When there is either no censoring or type II censoring, we propose using the uniformly minimum variance unbiased estimator (UMVUE). We show that using the UMVUE instead of the MLE reduces the mean‐squared error (MSE). We have found that the UMVUE always has MSEs smaller than the MLE. We have also found that the UMVUE leads to important reductions in the MSE when the sample size used to calculate the hazard rate in the numerator of the hazard ratio is small (say ⩾ 20) regardless of the sample size in the denominator. In the presence of type I censoring, the proposed estimator and the MLE are both biased. On the basis of a Monte Carlo study, however, we obtain similar reductions in the MSE using the UMVUE, as for no censoring or type II censoring.
Analysing clinical decision analyses
Authors: Habbema J. D. F. , Bossuyt P. M. M. , Dippel D. W. J. , Marshall S. , Hilden J.
Published: April 2007

We present a critical review of aspects of clinical decision analysis which uses an application to screening for familial intracranial aneurysms. The analysis is reported together with methods for assessing decision trees. These methods appear to be powerful checks on the usually rather intuitive way in which decision trees are built. The problem of assessing the uncertainty in the results of a decision analysis is discussed in detail. In practice, sensitivity analysis covers nearly every calculation apart from the standard evaluation of the decision tree. Different forms of sensitivity analysis are distinguished and given appropriate names: influence analysis, threshold analysis, full Bayesian analysis, Bayesian influence analysis, attribute analysis, generalization analysis and scenario analysis. The biostatistical community may well contribute to the much needed methodological improvement in decision analysis and its different forms of sensitivity analysis, especially if prepared to look beyond the standard statistical techniques.
The marriage of clinical trials and clinical decision science
Authors: Hilden Jørgen , Habbema J. Dik F.
Published: April 2007

Clinical decision science is concerned with rational clinical decisions. All branches of medical research contribute here, but controlled clinical trials of the pragmatic variety carry a particular responsibility. Usually, however, they are not conducted and reported so that they can be used directly as input to a decision analysis. We suggest that the forces of the two methodologies should be united, and point out some areas where this ‘marriage’ will have a non‐trivial impact: choice of end points, style of outcome recording, adaptive designs, and style of result presentation. Special attention is given to the decision‐analytic setting of research priorities, the role of utility calculus in quantifying the ethical dilemmas that surround clinical trials, and the use of patient attitude towards outcomes of treatment as a covariate in its own right.