Statistical considerations in bioequivalence of two area under the concentration–time curves obtained from serial sampling data

In this paper, we study the bioequivalence (BE) inference problem motivated by pharmacokinetic data that were collected using the serial sampling technique. In serial sampling designs, subjects are independently assigned to one of the two drugs; each subject can be sampled only once, and data are collected at K distinct timepoints from multiple subjects. We consider design and hypothesis testing for the parameter of interest: the area under the concentration–time curve (AUC). Decision rules in demonstrating BE were established using an equivalence test for either the ratio or logarithmic difference of two AUCs. The proposed t-test can deal with cases where two AUCs have unequal variances. To control for the type I error rate, the involved degrees-of-freedom were adjusted using Satterthwaite's approximation. A power formula was derived to allow the determination of necessary sample sizes. Simulation results show that, when the two AUCs have unequal variances, the type I error rate is better controlled by the proposed method compared with a method that only handles equal variances. We also propose an unequal subject allocation method that improves the power relative to that of the equal and symmetric allocation. The methods are illustrated using practical examples.     

Bootstrap test for a structural break under possible heteroscedasticity

In this article, we consider the Wald test statistic for testing equality between the sets of regression coefficients in two linear regression models when the disturbance variances may possibly be unequal. This test can be also used as a test for a structural break. However, it is well known that the test based on the Wald test statistic suffers from severe size distortion in small sample when the disturbance variances of the two regression models are unequal. Our simulation results show that substantial improvements are made when the bootstrap methods are applied.     

The two-sample -test with a known ratio of variances

We consider the two-sample t-test where error variances are unknown but with known relationships between them. This situation arises, for example, when two measuring instruments average different number of replicates to report the response. In particular we compare our procedure with the usual Satterthwaite approximation in the two sample t-test with variances unequal. Our procedure uses the knowledge of a known ratio of variances while the Satterthwaite approximation assumes only that the two variances are unequal. Simulations show that our procedure has both better size and better power than the Satterthwaite approximation. Finally, we consider an extension of our results to the General Linear Model.     

A step-down heteroscedastic multiple comparison procedure

All-pairs power in a one-way ANOVA is the probability of detecting all true differences between pairs of means. Ramsey (1978) found that for normal distributions having equal variances, step-down multiple comparison procedures can have substantially more all-pairs power than single-step procedures, such as Tukey’s HSD, when equal sample sizes are randomly sampled from each group. This paper suggests a step-down procedure for the case of unequal variances and compares it to Dunnett's T3 technique. The new procedure is similar in spirit to one of the heteroscedastic procedures described by Hochberg and Tamhane (1987), but it has certain advantages that are discussed in the paper. Included are results on unequal sample sizes.     

Empirical Bayes confidence intervals shrinking both means and variances

Summary.  We construct empirical Bayes intervals for a large number p of means. The existing intervals in the literature assume that variances     are either equal or unequal but known. When the variances are unequal and unknown, the suggestion is typically to replace them by unbiased estimators     . However, when p is large, there would be advantage in 'borrowing strength' from each other. We derive double-shrinkage intervals for means on the basis of our empirical Bayes estimators that shrink both the means and the variances. Analytical and simulation studies and application to a real data set show that, compared with the t -intervals, our intervals have higher coverage probabilities while yielding shorter lengths on average. The double-shrinkage intervals are on average shorter than the intervals from shrinking the means alone and are always no longer than the intervals from shrinking the variances alone. Also, the intervals are explicitly defined and can be computed immediately.     

A test statistic based on ranked set sampling for two normal means

In this study, we considered a hypothesis test for the difference of two population means using ranked set sampling. We proposed a test statistic for this hypothesis test with more than one cycle under normality. We also investigate the performance of this test statistic, when the assumptions hold and are violated. For this reason, we investigate the type I error and power rates of tests under normality with equal and unequal variances, non-normality with equal and unequal variances. We also examine the performance of this test under imperfect ranking case. The simulation results show that derived test performs quite well.     

Selecting the normal population with the largest mean when the variances are bounded

A multiple decision approach to the problem of selecting the population with the largest mean was formulated by Bechhofer (1954), where a single-sample solution was presented for the case of normal populations with known variances. In this paper the problem of selecting the normal population with the largest mean is considered when the population variances are unequal and unknown but are constrained only to be less than a specified upper bound. It is demonstrated that a slight modification of Bechhofer' s procedure will suffice to ensure the probability requirements under this simple constraint for cases of practical interest.     

Estimation of two order restricted normal means with unknown and possibly unequal variances

Estimation of each of and linear functions of two order restricted normal means is considered when variances are unknown and possibly unequal. We replace unknown variances with sample variances and construct isotonic regression estimators, which we call in our paper the plug-in estimators, to estimate ordered normal means. Under squared error loss, a necessary and sufficient condition is given for the plug-in estimators to improve upon the unrestricted maximum likelihood estimators uniformly. As for the estimation of linear functions of ordered normal means, we also show that when variances are known, the restricted maximum likelihood estimator always improves upon the unrestricted maximum likelihood estimator uniformly, but when variances are unknown, the plug-in estimator does not always improve upon the unrestricted maximum likelihood estimator uniformly.     

Multiple comparisons with a control under heteroscedasticity

This article investigates three procedures on the multiple comparisons with a control in the presence of unequal error variances. The advantages of the proposed methods are illustrated through two examples. The performance of the proposed methods and other alternative methods is compared by simulation studies. The results show that the typical methods assuming equal variance will have inflated error rate and may lead to erroneous inference when the equal variance assumption fails. In addition, the simulation study shows that the proposed approaches always control the family-wise error rate at a specified nominal level α, while some established methods are liberal and have inflated error rate in some scenarios.     

New monte carlo results on the robustness of the anova f,w and f statistics

Because the usual F test for equal means is not robust to unequal variances, Brown and Forsythe (1974a) suggest replacing F with the statistics F or W which are based on the Satterthwaite and Welch adjusted degrees of freedom procedures. This paper reports practical situations where both F and W give * unsatisfactory results. In particular, both F and W may not provide adequate control over Type I errors. Moreover, for equal variances, but unequal sample sizes, W should be avoided in favor of F (or F ), but for equal sample sizes, and possibly unequal variances, W was the only satisfactory statistic. New results on power are included as well. The paper also considers the effect of using F or W only after a significant test for equal variances has been obtained, and new results on the robustness of the F test are described. It is found that even for equal sample sizes as large as 50 per treatment group, there are practical situations where the F test does not provide adequately control over the probability of a Type I error.     

Small sample size comparisons of tests for homogeneity of variances by Monte-Carlo

A number of tests are available for testing the equality of several population variances. Some are claimed to be robust. We compared six of those claimed robust procedures by Monte Carlo simulated experiments, particularly for cases of small and unequal sample sizes. Our results show that the jack-knife test compares favorably with the other tests.     

Anova and minque type of estimators for the one-way random effects model

The one-way random effects model with unequal variances and unequal sample sizes is considered. Estimation of the variances, variance of a single observation (total variance), and the standard error of the unweighted mean are considered. Precision of the Analysis of Variance and Unweighted Sums of Squares type of estimators and the Minimum Norm Quadratic Unbiased Estimators with a priori weights are examined.     

Robust analysis of variance

SUMMARY For the c -sample location problem with equal and unequal variances, we compare the classical F -test and its robustified version-the Welch test-with some nonparametric counterparts defined for two-sided and one-sided ordered alternatives, such as trend and umbrella alternatives. A new rank test for long-tailed distributions is proposed. The comparison is referred to level alpha and power beta of the tests, and is carried out via Monte Carlo simulation, assuming short-, medium- and long-tailed as well as asymmetric distributions. It turns out that the Welch test is the best one in the case of unequal variances but in the case of equal variances special non-parametric tests are to prefer.     

Testing for equivalence of variances using Hartley's ratio

Hartley's test for homogeneity of k normal‐distribution variances is based on the ratio between the maximum sample variance and the minimum sample variance. In this paper, the author uses the same statistic to test for equivalence of k variances. Equivalence is defined in terms of the ratio between the maximum and minimum population variances, and one concludes equivalence when Hartley's ratio is small. Exact critical values for this test are obtained by using an integral expression for the power function and some theoretical results about the power function. These exact critical values are available both when sample sizes are equal and when sample sizes are unequal. One related result in the paper is that Hartley's test for homogeneity of variances is no longer unbiased when the sample sizes are unequal. The Canadian Journal of Statistics 38: 647–664; 2010 © 2010 Statistical Society of Canada     

A Stepwise Confidence Interval Procedure Under Unknown Variances Based on an Asymmetric Loss Function for Toxicological Evaluation

One of the most important issues in toxicity studies is the identification of the equivalence of treatments with a placebo. Because it is unacceptable to declare non‐equivalent treatments to be equivalent, it is important to adopt a reliable statistical method to properly control the family‐wise error rate (FWER). In dealing with this issue, it is important to keep in mind that overestimating toxicity equivalence is a more serious error than underestimating toxicity equivalence. Consequently asymmetric loss functions are more appropriate than symmetric loss functions. Recently Tao, Tang & Shi (2010) developed a new procedure based on an asymmetric loss function. However, their procedure is somewhat unsatisfactory because it assumes that the variances of various dose levels are known. This assumption is restrictive for some applications. In this study we propose an improved approach based on asymmetric confidence intervals without the restrictive assumption of known variances. The asymmetry guarantees reliability in the sense that the FWER is well controlled. Although our procedure is developed assuming that the variances of various dose levels are unknown but equal, simulation studies show that our procedure still performs quite well when the variances are unequal.     

Interval Estimation for the Difference of Two Independent Variances

Analytical methods for interval estimation of differences between variances have not been described. A simple analytical method is given for interval estimation of the difference between variances of two independent samples. It is shown, using simulations, that confidence intervals generated with this method have close to nominal coverage even when sample sizes are small and unequal and observations are highly skewed and leptokurtic, provided the difference in variances is not very large. The method is also adapted for testing the hypothesis of no difference between variances. The test is robust but slightly less powerful than Bonett's test with small samples.     

Selecting the best normal population better than a standard under unequal variances

In this article we consider a problem of selecting the best normal population that is better than a standard when the variances are unequal. Single-stage selection procedures are proposed when the variances are known. Wilcox (1984) and Taneja and Dudewicz (1992) proposed two-stage selection procedures when the variances are unknown. In addition to these procedures, we propose a two-stage selection procedure based on the method of Lam (1988). Comparisons are made between these selection procedures in terms of the sample sizes.     

Simultaneous Confidence Intervals for Monotone Contrasts of Normal Means

The one-way ANOVA model is considered. The variances are assumed to be either equal but unknown or unequal and unknown. Two-stage procedures for generating simultaneous confidence intervals (SCI) for the class of monotone contrasts of the means are presented. The intervals are of fixed length and independent of the unknown variances.     

Two separate effects of variance heterogeneity on the validity and power of significance tests of location

Heterogeneity of variances of treatment groups influences the validity and power of significance tests of location in two distinct ways. First, if sample sizes are unequal, the Type I error rate and power are depressed if a larger variance is associated with a larger sample size, and elevated if a larger variance is associated with a smaller sample size. This well-established effect, which occurs in t and F tests, and to a lesser degree in nonparametric rank tests, results from unequal contributions of pooled estimates of error variance in the computation of test statistics. It is observed in samples from normal distributions, as well as non-normal distributions of various shapes. Second, transformation of scores from skewed distributions with unequal variances to ranks produces differences in the means of the ranks assigned to the respective groups, even if the means of the initial groups are equal, and a subsequent inflation of Type I error rates and power. This effect occurs for all sample sizes, equal and unequal. For the t test, the discrepancy diminishes, and for the Wilcoxon–Mann–Whitney test, it becomes larger, as sample size increases. The Welch separate-variance t test overcomes the first effect but not the second. Because of interaction of these separate effects, the validity and power of both parametric and nonparametric tests performed on samples of any size from unknown distributions with possibly unequal variances can be distorted in unpredictable ways.     

POWER ASPECTS OF ANALYSIS OF VARIANCE IN FIXED EFFECT MODEL ONE-WAY CLASSIFICATION

The sensitivity of the power in analysis of variance to the departure from the in-built assumptions other than the normality of errors is discussed in Kanji (1975). To obtain the power values he considered the general linear hypothesis model.
Kanji (1976a) discussed a particular case of the above situation, that is fixed effect model two-way classification. In this paper another particular case, that of the fixed effect model one-way classification is discussed, the main purpose of which is to investigate whether it could show a different picture to the two-way classification, especially for unequal replication. The results so obtained are presented in Tables 1A, 1B and 1C. They indicate that the power value is greatly affected by the inequality of error variances and unequal group sizes.