Notes on interval estimation of the proportion ratio under a three-treatment three-period crossover trial

When comparing two experimental treatments with a placebo, we focus our attention on interval estimation of the proportion ratio (PR) of patient responses under a three-period crossover design. We propose a random effects exponential multiplicative risk model and derive asymptotic interval estimators in closed form for the PR between treatments and placebo. Using Monte Carlo simulations, we compare the performance of these interval estimators in a variety of situations. We use the data comparing two different doses of an analgesic with placebo for the relief of primary dysmenorrhea to illustrate the use of these interval estimators and the difference in estimates of the PR and odds ratio (OR) when the underlying relief rates are not small.     

Notes on estimation of the intraclass correlation under the AB/BA crossover trial

Under the AB/BA crossover trial, we focus our attention on estimation of the intraclass correlation in normal data. We develop both point and interval estimators in closed form for the intraclass correlation. We employ Monte Carlo simulation to study the performance of these estimators in a variety of situations. We note that the estimators developed here for the intraclass correlation remain valid even when there are possibly unexpected carry-over effects.     

Estimation of proportion ratio in non-compliance randomized trials with repeated measurements in binary data

It is not uncommon to encounter a randomized clinical trial (RCT) in which each patient is treated with several courses of therapies and his/her response is taken after treatment with each course because of the nature of a treatment design for a disease. On the basis of a simple multiplicative risk model proposed elsewhere for repeated binary measurements, we derive the maximum likelihood estimator (MLE) for the proportion ratio (PR) of responses between two treatments in closed form without the need of modeling the complicated relationship between patient’s compliance and patient’s response. We further derive the asymptotic variance of the MLE and propose an asymptotic interval estimator for the PR using the logarithmic transformation. We also consider two other asymptotic interval estimators. One is derived from the principle of Fieller’s Theorem and the other is derived by using the randomization-based approach suggested elsewhere. To evaluate and compare the finite-sample performance of these interval estimators, we apply the Monte Carlo simulation. We find that the interval estimator using the logarithmic transformation of the MLE consistently outperforms the other two estimators with respect to efficiency. This gain in efficiency can be substantial especially when there are patients not complying with their assigned treatments. Finally, we employ the data regarding the trial of using macrophage colony stimulating factor (M-CSF) over three courses of intensive chemotherapies to reduce febrile neutropenia incidence for acute myeloid leukemia patients to illustrate the use of these estimators.     

Notes on testing carry-over effects in continuous data under an incomplete block crossover design

We consider hypothesis testing and estimation of carry-over effects in continuous data under an incomplete block crossover design when comparing two experimental treatments with a placebo. We develop procedures for testing differential carry-over effects based on the weighted-least-squares (WLS) method. We apply Monte Carlo simulations to evaluate the performance of these test procedures in a variety of situations. We use the data regarding the forced expiratory volume in one second (FEV₁) readings taken from a double-blind crossover trial comparing two different doses of formoterol with a placebo to illustrate the use of test procedures proposed here.     

Efficient crossover designs in the presence of interactions between direct and carry-over treatment effects

Crossover designs, or repeated measurements designs, are used for experiments in which t treatments are applied to each of n experimental units successively over p time periods. Such experiments are widely used in areas such as clinical trials, experimental psychology and agricultural field trials. In addition to the direct effect on the response of the treatment in the period of application, there is also the possible presence of a residual, or carry-over, effect of a treatment from one or more previous periods. We use a model in which the residual effect from a treatment depends upon the treatment applied in the succeeding period; that is, a model which includes interactions between the treatment direct and residual effects. We assume that residual effects do not persist further than one succeeding period.A particular class of strongly balanced repeated measurements designs with n=t² units and which are uniform on the periods is examined. A lower bound for the A-efficiency of the designs for estimating the direct effects is derived and it is shown that such designs are highly efficient for any number of periods p=2,…,2t.