Methods for analysing cardiovascular studies with repeated measures.

Background. Repeated measurements in a single subject are generally more similar than unrepeated measurements in different subjects. Unrepeated analyses of repeated data cause underestimation of the treatment effects.

Meta-analyses of diagnostic studies.

Background: Diagnostic reviews often include the sensitivity/specificity results of individual studies. A problem occurs when these data are pooled because the correlation between sensitivity and specificity is generally strongly negative, causing overestimation of the pooled results. The diagnostic odds ratio (DOR), defined as the odds of true positives vs.

Cardiovascular drug trials: how to examine interaction, and why so.

Background: In practice the benefit of cardiovascular medicines is less consistent than it is in clinical trials. This is due to multiple uncontrolled factors that co-determine the efficacy of the new treatment. In statistical terms, they interact with the new treatment.

Variability in clinical data is often more useful than the mean: illustration of concept and simple methods of assessment.

Background: Clinical investigators, although they are generally familiar with testing differences between averages, have difficulty testing differences between variabilities.

Objective: To give examples of situations where variability is more relevant than averages and to describe simple methods for testing such data.

Results: Examples include: (1) testing drugs with small therapeutic indices, (2) testing variability in drug response, (3) assessing pill diameters or pill weights, (4) comparing patient groups for variability in patient characteristics, (5) assessing the variability in duration of clinical treatment, (6) finding the best method for patient assessment.

Problems in regression modeling of randomized clinical trials.

Background: Data modeling can be applied to improving the precision of clinical studies and multiple regression modeling is increasingly used for this purpose.

Objective: To assess the uncertainties and risks of misinterpretations commonly encountered in regression analyses and rarely communicated in research papers.

Results: Regression analyses add uncertainties to the data in the form of subjective judgments and uncertainty about the appropriate transformation of the data.

Clinical trials: Renewed attention to the interpretation of the P values--review.

The P values tell us the chance of making a type I error of finding a difference where there is none. In the 1970s, exact P values were laborious to calculate and were generally approximated from statistical tables, in the form of P < 0.01 or 0.

Limitations of randomized clinical trials. Proposed alternative designs.

Background: The classical two-period crossover and two-parallel-groups designs for clinical drug trials are unable to answer many current scientific questions, and are sometimes ethically or financially difficult. For example, the classical designs do not allow the study of the effects of combined treatments and their interactions. Also, the generation of parallel data that are no more than a repetition of previous research is ethically debatable and in a sense a waste of money.

Relevance of correlation between treatment responses in clinical trials.

Background: We recently demonstrated that in self-controlled clinical trials using t-statistic the correlation level between treatment responses is an important determinant of the sensitivity of testing.

Methods: The current study uses hypothetical examples and real data to study whether this phenomenon also affects other parametric statistical procedures.

Results: With negative correlations between treatment responses, not only paired t-test, but also repeated measures analysis of variance (ANOVA), Bonferroni adjustments for ANOVA, and therapeutic equivalence testing, lack sensitivity to demonstrate significant results.

Isosorbide mononitrate 30% immediate-release 70% sustained-release formulation: a review. DUMQOL (DUtch Mononitrate Quality of Life) Study Group.

Since the first publication of isosorbide mononitrate 30% immediate-release 70% sustained-release (IR-SR) formulation in 1985, a considerable body of literature concerning its clinical efficacy and safety has become available. Theoretically, the formulation has the advantage over conventional isosorbide mononitrate or dinitrate (ISMN/ISDN) that it has a simpler and more predictable pharmacokinetic profile. The objectives of this paper are to review published data so far and to see whether the theoretical advantages translate into better clinical effectiveness.

Methods for improving clinical trials.

Over the past decades, the randomized controlled trial has entered an era of continuous improvement and has gradually become accepted as the most effective way of determining the relative efficacy and toxicity of new therapies because it controls for placebo and time effects. However, even sensitive and properly designed and executed trials do not always confirm hypotheses to be tested, and conclusions are not always confirmed by subsequent trials. Although the former may be due to wrong hypotheses, the latter is likely to be due to the presence of certain imperfections within the design and execution of the trial itself.