Confidence intervals for the difference between independent binomial proportions: comparison using a graphical approach and moving averages

This paper uses graphical methods to illustrate and compare the coverage properties of a number of methods for calculating confidence intervals for the difference between two independent binomial proportions. We investigate both small‐sample and large‐sample properties of both two‐sided and one‐sided coverage, with an emphasis on asymptotic methods. In terms of aligning the smoothed coverage probability surface with the nominal confidence level, we find that the score‐based methods on the whole have the best two‐sided coverage, although they have slight deficiencies for confidence levels of 90% or lower. For an easily taught, hand‐calculated method, the Brown‐Li ‘Jeffreys’ method appears to perform reasonably well, and in most situations, it has better one‐sided coverage than the widely recommended alternatives. In general, we find that the one‐sided properties of many of the available methods are surprisingly poor. In fact, almost none of the existing asymptotic methods achieve equal coverage on both sides of the interval, even with large sample sizes, and consequently if used as a non‐inferiority test, the type I error rate (which is equal to the one‐sided non‐coverage probability) can be inflated. The only exception is the Gart‐Nam ‘skewness‐corrected’ method, which we express using modified notation in order to include a bias correction for improved small‐sample performance, and an optional continuity correction for those seeking more conservative coverage. Using a weighted average of two complementary methods, we also define a new hybrid method that almost matches the performance of the Gart‐Nam interval. Copyright © 2014 John Wiley & Sons, Ltd.     

A Comparison of Large-Sample Confidence Interval Methods for the Difference of Two Binomial Probabilities

A simulation study was done to compare seven confidence interval methods, based on the normal approximation, for the difference of two binomial probabilities. Cases considered included minimum expected cell sizes ranging from 2 to 15 and smallest group sizes (NMIN) ranging from 6 to 100. Our recommendation is to use a continuity correction of 1/(2 NMIN) combined with the use of (N ? 1) rather than N in the estimate of the standard error. For all of the cases considered with minimum expected cell size of at least 3, this method gave coverage probabilities close to or greater than the nominal 90% and 95%. The Yates method is also acceptable, but it is slightly more conservative. At the other extreme, the usual method (with no continuity correction) does not provide adequate coverage even at the larger sample sizes. For the 99% intervals, our recommended method and the Yates correction performed equally well and are reasonable for minimum expected cell sizes of at least 5. None of the methods performed consistently well for a minimum expected cell size of 2.     

Testing for noninferiority of binomial distributions referring to a modified equivalence region with piecewise linear boundary

In testing for noninferiority of two binomial distributions, the hypothesis formulation most commonly considered defines equivalence in terms of a constant bound to the difference of the two parameters. In order to avoid some basic logical difficulty entailed in this formulation we use an equivalence region whose boundary has fixed vertical distance from the diagonal for all values of the reference responder rate above some cutoff point and coincides left from this point with the line joining it with the origin. For the corresponding noninferiority hypothesis we derive and compare two different testing procedures. The first one is based on an objective Bayesian decision rule. The other one is obtained through combining the score tests for noninferiority with respect to the difference and the ratio of the two proportions, respectively, by means of the intersection–union principle. Both procedures are extensively studied by means of exact computational methods.     

Exact likelihood ratio and score confidence intervals for the binomial proportion

Many methods are available for computing a confidence interval for the binomial parameter, and these methods differ in their operating characteristics. It has been suggested in the literature that the use of the exact likelihood ratio (LR) confidence interval for the binomial proportion should be considered. This paper provides an evaluation of the operating characteristics of the two‐sided exact LR and exact score confidence intervals for the binomial proportion and compares these results to those for three other methods that also strictly maintain nominal coverage: Clopper‐Pearson, Blaker, and Casella. In addition, the operating characteristics of the two‐sided exact LR method and exact score method are compared with those of the corresponding asymptotic methods to investigate the adequacy of the asymptotic approximation. Copyright © 2013 John Wiley & Sons, Ltd.     

Equal‐tailed confidence intervals for comparison of rates

Several methods are available for generating confidence intervals for rate difference, rate ratio, or odds ratio, when comparing two independent binomial proportions or Poisson (exposure‐adjusted) incidence rates. Most methods have some degree of systematic bias in one‐sided coverage, so that a nominal 95% two‐sided interval cannot be assumed to have tail probabilities of 2.5% at each end, and any associated hypothesis test is at risk of inflated type I error rate. Skewness‐corrected asymptotic score methods have been shown to have superior equal‐tailed coverage properties for the binomial case. This paper completes this class of methods by introducing novel skewness corrections for the Poisson case and for odds ratio, with and without stratification. Graphical methods are used to compare the performance of these intervals against selected alternatives. The skewness‐corrected methods perform favourably in all situations—including those with small sample sizes or rare events—and the skewness correction should be considered essential for analysis of rate ratios. The stratified method is found to have excellent coverage properties for a fixed effects analysis. In addition, another new stratified score method is proposed, based on the t‐distribution, which is suitable for use in either a fixed effects or random effects analysis. By using a novel weighting scheme, this approach improves on conventional and modern meta‐analysis methods with weights that rely on crude estimation of stratum variances. In summary, this paper describes methods that are found to be robust for a wide range of applications in the analysis of rates.     

VARIANCE ESTIMATION IN TWO-PHASE SAMPLING

Two‐phase sampling is often used for estimating a population total or mean when the cost per unit of collecting auxiliary variables, x, is much smaller than the cost per unit of measuring a characteristic of interest, y. In the first phase, a large sample s₁ is drawn according to a specific sampling design p(s₁) , and auxiliary data x are observed for the units i∈s₁ . Given the first‐phase sample s₁ , a second‐phase sample s₂ is selected from s₁ according to a specified sampling design {p(s₂∣s₁) } , and (y, x) is observed for the units i∈s₂ . In some cases, the population totals of some components of x may also be known. Two‐phase sampling is used for stratification at the second phase or both phases and for regression estimation. Horvitz–Thompson‐type variance estimators are used for variance estimation. However, the Horvitz–Thompson ( Horvitz & Thompson, J. Amer. Statist. Assoc. 1952 ) variance estimator in uni‐phase sampling is known to be highly unstable and may take negative values when the units are selected with unequal probabilities. On the other hand, the Sen–Yates–Grundy variance estimator is relatively stable and non‐negative for several unequal probability sampling designs with fixed sample sizes. In this paper, we extend the Sen–Yates–Grundy ( Sen , J. Ind. Soc. Agric. Statist. 1953; Yates & Grundy , J. Roy. Statist. Soc. Ser. B 1953) variance estimator to two‐phase sampling, assuming fixed first‐phase sample size and fixed second‐phase sample size given the first‐phase sample. We apply the new variance estimators to two‐phase sampling designs with stratification at the second phase or both phases. We also develop Sen–Yates–Grundy‐type variance estimators of the two‐phase regression estimators that make use of the first‐phase auxiliary data and known population totals of some of the auxiliary variables.     

Critical review and comparison of continuity correction methods: The normal approximation to the binomial distribution

We provide a comprehensive and critical review of Yates’ continuity correction for the normal approximation to the binomial distribution, in particular emphasizing its poor ability to approximate extreme tail probabilities. As an alternative method, we also review Cressie's finely tuned continuity correction. In addition, we demonstrate how Yates’ continuity correction is used to improve the coverage probability of binomial confidence limits, and propose new confidence limits by applying Cressie's continuity correction. These continuity correction methods are numerically compared and illustrated by data examples arising from industry and medicine.     

Design and analysis of a 3‐arm noninferiority trial with a prespecified margin for the hazard ratio

A 3‐arm trial design that includes an experimental treatment, an active reference treatment, and a placebo is useful for assessing the noninferiority of an experimental treatment. The inclusion of a placebo arm enables the assessment of assay sensitivity and internal validation, in addition to the testing of the noninferiority of the experimental treatment compared with the reference treatment. In 3‐arm noninferiority trials, various statistical test procedures have been considered to evaluate the following 3 hypotheses: (i) superiority of the experimental treatment over the placebo, (ii) superiority of the reference treatment over the placebo, and (iii) noninferiority of the experimental treatment compared with the reference treatment. However, hypothesis (ii) can be insufficient and may not accurately assess the assay sensitivity for the noninferiority of the experimental treatment compared with the reference treatment. Thus, demonstrating that the superiority of the reference treatment over the placebo is greater than the noninferiority margin (the nonsuperiority of the reference treatment compared with the placebo) can be necessary. Here, we propose log‐rank statistical procedures for evaluating data obtained from 3‐arm noninferiority trials to assess assay sensitivity with a prespecified margin Δ. In addition, we derive the approximate sample size and optimal allocation required to minimize the total sample size and that of the placebo treatment sample size, hierarchically.     

A continuously adaptive nonparametric two–sample test

A two–sample test statistic for detecting shifts in location is developed for a broad range of underlying distributions using adaptive techniques. The test statistic is a linear rank statistics which uses a simple modification of the Wilcoxon test; the scores are Winsorized ranks where the upper and lower Winsorinzing proportions are estimated in the first stage of the adaptive procedure using sample the first stage of the adaptive procedure using sample measures of the distribution's skewness and tailweight. An empirical relationship between the Winsorizing proportions and the sample skewness and tailweight allows for a ‘continuous’ adaptation of the test statistic to the data. The test has good asymptotic properties, and the small sample results are compared with other populatr parametric, nonparametric, and two–stage tests using Monte Carlo methods. Based on these results, this proposed test procedure is recommended for moderate and larger sample sizes.     

A nonparametric test for proving noninferiority in clinical trials with ordered categorical data

We consider the problem of proving noninferiority when the comparison is based on ordered categorical data. We apply a rank test based on the Wilcoxon–Mann–Whitney effect where the asymptotic variance is estimated consistently under the alternative and a small‐sample approximation is given. We give the associated 100(1?α)% confidence interval and propose a formula for sample size determination. Finally, we illustrate the procedure and possible choices of the noninferiority margin using data from a clinical trial. Copyright © 2003 John Wiley & Sons, Ltd.     

Additional results for 'Sequential design approaches for bioequivalence studies with crossover designs'

In 2008, this group published a paper on approaches for two‐stage crossover bioequivalence (BE) studies that allowed for the reestimation of the second‐stage sample size based on the variance estimated from the first‐stage results. The sequential methods considered used an assumed GMR of 0.95 as part of the method for determining power and sample size. This note adds results for an assumed GMR = 0.90. Two of the methods recommended for GMR = 0.95 in the earlier paper have some unacceptable increases in Type I error rate when the GMR is changed to 0.90. If a sponsor wants to assume 0.90 for the GMR, Method D is recommended. Copyright © 2011 John Wiley & Sons, Ltd.     

A note on sample size savings with the use of a single well‐controlled clinical trial to support the efficacy of a new drug

In terms of the risk of making a Type I error in evaluating a null hypothesis of equality, requiring two independent confirmatory trials with two‐sided p‐values less than 0.05 is equivalent to requiring one confirmatory trial with two‐sided p‐value less than 0.001 25. Furthermore, the use of a single confirmatory trial is gaining acceptability, with discussion in both ICH E9 and a CPMP Points to Consider document. Given the growing acceptance of this approach, this note provides a formula for the sample size savings that are obtained with the single clinical trial approach depending on the levels of Type I and Type II errors chosen. For two replicate trials each powered at 90%, which corresponds to a single larger trial powered at 81%, an approximate 19% reduction in total sample size is achieved with the single trial approach. Alternatively, a single trial with the same sample size as the total sample size from two smaller trials will have much greater power. For example, in the case where two trials are each powered at 90% for two‐sided α=0.05 yielding an overall power of 81%, a single trial using two‐sided α=0.001 25 would have 91% power. Copyright © 2004 John Wiley & Sons, Ltd.     

Exact Confidence Intervals for Proportions Estimated by Group Testing with Different Group Sizes

Group testing is the process of combining individual samples and testing them as a group for the presence of an attribute. The use of such testing to estimate proportions is an important statistical tool in many applications. When samples are collected and tested in groups of different size, complications arise in the construction of exact confidence intervals. In this case, the numbers of positive groups has a multivariate distribution, and the difficulty stems from a lack of a natural ordering of the sample points. Exact two‐sided intervals such as the equal‐tail method based on maximum likelihood estimation, and those based on joint probability or likelihood ratio statistics, have been previously considered. In this paper several new estimators are developed and assessed. We show that the combined tails (or Blaker) method based on a suitable ordering statistic, is the best choice in this setting. The methods are illustrated using a study involving the infection prevalence of Myxobolus cerebralis among free‐ranging fish.     

Exact calculation of power and sample size in bioequivalence studies using two one‐sided tests

The number of subjects in a pharmacokinetic two‐period two‐treatment crossover bioequivalence study is typically small, most often less than 60. The most common approach to testing for bioequivalence is the two one‐sided tests procedure. No explicit mathematical formula for the power function in the context of the two one‐sided tests procedure exists in the statistical literature, although the exact power based on Owen's special case of bivariate noncentral t‐distribution has been tabulated and graphed. Several approximations have previously been published for the probability of rejection in the two one‐sided tests procedure for crossover bioequivalence studies. These approximations and associated sample size formulas are reviewed in this article and compared for various parameter combinations with exact power formulas derived here, which are computed analytically as univariate integrals and which have been validated by Monte Carlo simulations. The exact formulas for power and sample size are shown to improve markedly in realistic parameter settings over the previous approximations. Copyright © 2014 John Wiley & Sons, Ltd.     

Inference for Box–Cox Transformed Threshold GARCH Models with Nuisance Parameters

Abstract. Generalized autoregressive conditional heteroscedastic (GARCH) models have been widely used for analyzing financial time series with time‐varying volatilities. To overcome the defect of the Gaussian quasi‐maximum likelihood estimator (QMLE) when the innovations follow either heavy‐tailed or skewed distributions, Berkes & Horváth (Ann. Statist., 32, 633, 2004) and Lee & Lee (Scand. J. Statist. 36, 157, 2009) considered likelihood methods that use two‐sided exponential, Cauchy and normal mixture distributions. In this paper, we extend their methods for Box–Cox transformed threshold GARCH model by allowing distributions used in the construction of likelihood functions to include parameters and employing the estimated quasi‐likelihood estimators (QELE) to handle those parameters. We also demonstrate that the proposed QMLE and QELE are consistent and asymptotically normal under regularity conditions. Simulation results are provided for illustration.     

Effective directed tests for models with ordered categorical data

This paper offers a new method for testing one‐sided hypotheses in discrete multivariate data models. One‐sided alternatives mean that there are restrictions on the multidimensional parameter space. The focus is on models dealing with ordered categorical data. In particular, applications are concerned with R×C contingency tables. The method has advantages over other general approaches. All tests are exact in the sense that no large sample theory or large sample distribution theory is required. Testing is unconditional although its execution is done conditionally, section by section, where a section is determined by marginal totals. This eliminates any potential nuisance parameter issues. The power of the tests is more robust than the power of the typical linear tests often recommended. Furthermore, computer programs are available to carry out the tests efficiently regardless of the sample sizes or the order of the contingency tables. Both censored data and uncensored data models are discussed.     

A dynamic power prior for borrowing historical data in noninferiority trials with binary endpoint

Traditionally, noninferiority hypotheses have been tested using a frequentist method with a fixed margin. Given that information for the control group is often available from previous studies, it is interesting to consider a Bayesian approach in which information is “borrowed” for the control group to improve efficiency. However, construction of an appropriate informative prior can be challenging. In this paper, we consider a hybrid Bayesian approach for testing noninferiority hypotheses in studies with a binary endpoint. To account for heterogeneity between the historical information and the current trial for the control group, a dynamic P value–based power prior parameter is proposed to adjust the amount of information borrowed from the historical data. This approach extends the simple test‐then‐pool method to allow a continuous discounting power parameter. An adjusted α level is also proposed to better control the type I error. Simulations are conducted to investigate the performance of the proposed method and to make comparisons with other methods including test‐then‐pool and hierarchical modeling. The methods are illustrated with data from vaccine clinical trials.     

Validation of qualitative microbiological test methods

This paper considers a statistical model for the detection mechanism of qualitative microbiological test methods with a parameter for the detection proportion (the probability to detect a single organism) and a parameter for the false positive rate. It is demonstrated that the detection proportion and the bacterial density cannot be estimated separately, not even in a multiple dilution experiment. Only the product can be estimated, changing the interpretation of the most probable number estimator. The asymptotic power of the likelihood ratio statistic for comparing an alternative method with the compendial method, is optimal for a single dilution experiment. The bacterial density should either be close to two CFUs per test unit or equal to zero, depending on differences in the model parameters between the two test methods. The proposed strategy for method validation is to use these two dilutions and test for differences in the two model parameters, addressing the validation parameters specificity and accuracy. Robustness of these two parameters might still be required, but all other validation parameters can be omitted. A confidence interval‐based approach for the ratio of the detection proportions for the two methods is recommended, since it is most informative and close to the power of the likelihood ratio test. Copyright © 2014 John Wiley & Sons, Ltd.     

Increasing the sample size at interim for a two‐sample experiment without Type I error inflation

For the case of a one‐sample experiment with known variance σ²=1, it has been shown that at interim analysis the sample size (SS) may be increased by any arbitrary amount provided: (1) The conditional power (CP) at interim is ?50% and (2) there can be no decision to decrease the SS (stop the trial early). In this paper we verify this result for the case of a two‐sample experiment with proportional SS in the treatment groups and an arbitrary common variance. Numerous authors have presented the formula for the CP at interim for a two‐sample test with equal SS in the treatment groups and an arbitrary common variance, for both the one‐ and two‐sided hypothesis tests. In this paper we derive the corresponding formula for the case of unequal, but proportional SS in the treatment groups for both one‐sided superiority and two‐sided hypothesis tests. Finally, we present an SAS macro for doing this calculation and provide a worked out hypothetical example. In discussion we note that this type of trial design trades the ability to stop early (for lack of efficacy) for the elimination of the Type I error penalty. The loss of early stopping requires that such a design employs a data monitoring committee, blinding of the sponsor to the interim calculations, and pre‐planning of how much and under what conditions to increase the SS and that this all be formally written into an interim analysis plan before the start of the study. Copyright © 2009 John Wiley & Sons, Ltd.     

Blinded sample size re‐estimation in superiority and noninferiority trials: bias versus variance in variance estimation

The internal pilot study design allows for modifying the sample size during an ongoing study based on a blinded estimate of the variance thus maintaining the trial integrity. Various blinded sample size re‐estimation procedures have been proposed in the literature. We compare the blinded sample size re‐estimation procedures based on the one‐sample variance of the pooled data with a blinded procedure using the randomization block information with respect to bias and variance of the variance estimators, and the distribution of the resulting sample sizes, power, and actual type I error rate. For reference, sample size re‐estimation based on the unblinded variance is also included in the comparison. It is shown that using an unbiased variance estimator (such as the one using the randomization block information) for sample size re‐estimation does not guarantee that the desired power is achieved. Moreover, in situations that are common in clinical trials, the variance estimator that employs the randomization block length shows a higher variability than the simple one‐sample estimator and in turn the sample size resulting from the related re‐estimation procedure. This higher variability can lead to a lower power as was demonstrated in the setting of noninferiority trials. In summary, the one‐sample estimator obtained from the pooled data is extremely simple to apply, shows good performance, and is therefore recommended for application. Copyright © 2013 John Wiley & Sons, Ltd.