Using pilot study information to increase efficiency in clinical trials

It is often necessary to conduct a pilot study to determine the sample size required for a clinical trial. Due to differences in sampling environments, the pilot data are usually discarded after sample size calculation. This paper tries to use the pilot information to modify the subsequent testing procedure when a two-sided t$t$-test or a regression model is used to compare two treatments. The new test maintains the required significance level regardless of the dissimilarity between the pilot and the target populations, but increases the power when the two are similar. The test is constructed based on the posterior distribution of the parameters given the pilot study information, but its properties are investigated from a frequentist's viewpoint. Due to the small likelihood of an irrelevant pilot population, the new approach is a viable alternative to the current practice.     

A two-sample test for mean functions with increasing number of projections

We propose a test for equality of two means when data are functions and obtain the asymptotic properties of the test statistic as data dimension increases with the sample size. We also derive the asymptotic power of the test under some local alternatives and show that the test statistic is root-n consistent. A simulation study is conducted to evaluate the performance of the test numerically and to compare the proposed test with other existing four popular tests.     

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.     

On the estimation of homogeneous population size from a complex dual-record system

ABSTRACT

A dual-record system (DRS) (equivalently two sample capture–recapture experiments) model, with time and behavioural response variation, has attracted much attention specifically in the domain of official statistics and epidemiology, as the assumption of list independence often fails. The relevant model suffers from parameter identifiability problem, and suitable Bayesian methodologies could be helpful. In this article, we formulate population size estimation in DRS as a missing data problem and two empirical Bayes approaches are proposed along with the discussion of an existing Bayes treatment. Some features and associated posterior convergence for these methods are mentioned. Investigation through an extensive simulation study finds that our proposed approaches compare favourably with the existing Bayes approach for this complex model depending upon the availability of directional nature of underlying behavioural response effect. A real-data example is given to illustrate these methods.     

A new test for the mean vector in large dimension and small samples

In this article, we consider the problem of testing the mean vector in the multivariate normal distribution, where the dimension p is greater than the sample size N. We propose a new test T_Block and obtain its asymptotic distribution. We also compare the proposed test with other two tests. The simulation results suggest that the performance of the new test is comparable to the existing two tests, and under some circumstances it may have higher power. Therefore, the new statistic can be employed in practice as an alternative choice.     

Comparison of unweighted and weighted rank based tests for an ordered alternative in randomized complete block designs

In randomized complete block designs, a monotonic relationship among treatment groups may already be established from prior information, e.g., a study with different dose levels of a drug. The test statistic developed by Page and another from Jonckheere and Terpstra are two unweighted rank based tests used to detect ordered alternatives when the assumptions in the traditional two-way analysis of variance are not satisfied. We consider a new weighted rank based test by utilizing a weight for each subject based on the sample variance in computing the new test statistic. The new weighted rank based test is compared with the two commonly used unweighted tests with regard to power under various conditions. The weighted test is generally more powerful than the two unweighted tests when the number of treatment groups is small to moderate.     

Study design of single‐arm phase II immunotherapy trials with long‐term survivors and random delayed treatment effect

In the traditional study design of a single‐arm phase II cancer clinical trial, the one‐sample log‐rank test has been frequently used. A common practice in sample size calculation is to assume that the event time in the new treatment follows exponential distribution. Such a study design may not be suitable for immunotherapy cancer trials, when both long‐term survivors (or even cured patients from the disease) and delayed treatment effect are present, because exponential distribution is not appropriate to describe such data and consequently could lead to severely underpowered trial. In this research, we proposed a piecewise proportional hazards cure rate model with random delayed treatment effect to design single‐arm phase II immunotherapy cancer trials. To improve test power, we proposed a new weighted one‐sample log‐rank test and provided a sample size calculation formula for designing trials. Our simulation study showed that the proposed log‐rank test performs well and is robust of misspecified weight and the sample size calculation formula also performs well.     

Monte carlo sampling approach to testing nonnested hypothesis: monte carlo results

Alternative ways of using Monte Carlo methods to implement a Cox-type test for separate families of hypotheses are considered. Monte Carlo experiments are designed to compare the finite sample performances of Pesaran and Pesaran's test, a RESET test, and two Monte Carlo hypothesis test procedures. One of the Monte Carlo tests is based on the distribution of the log-likelihood ratio and the other is based on an asymptotically pivotal statistic. The Monte Carlo results provide strong evidence that the size of the Pesaran and Pesaran test is generally incorrect, except for very large sample sizes. The RESET test has lower power than the other tests. The two Monte Carlo tests perform equally well for all sample sizes and are both clearly preferred to the Pesaran and Pesaran test, even in large samples. Since the Monte Carlo test based on the log-likelihood ratio is the simplest to calculate, we recommend using it.     

Power comparison of data depth-based nonparametric tests for testing equality of locations

In the recent years, the notion of data depth has been used in nonparametric multivariate data analysis since it gives natural ‘centre-outward’ ordering of multivariate data points with respect to the given data cloud. In the literature, various nonparametric tests are developed for testing equality of location of two multivariate distributions based on data depth. Here, we define two nonparametric tests based on two different test statistic for testing equality of locations of two multivariate distributions. In the present work, we compare the performance of these tests with the tests developed by Li and Liu [New nonparametric tests of multivariate locations and scales using data depth. Statist Sci. 2004;(1):686–696] for testing equality of locations of two multivariate distributions. Comparison in terms of power is done for multivariate symmetric and skewed distributions using simulation for three popular depth functions. Application of tests to real life data is provided. Conclusion and recommendations are also provided.     

Comparing mean ranks for repeated measures data

Rank tests are considered that compare t treatments in repeated measures designs. A statistic is given that contains as special cases several that have been proposed for this problem, including one that corresponds to the randomized block ANOVA statistic applied to the rank transformed data. Another statistic is proposed, having a null distribution holding under more general conditions, that is the rank transform of the Hotelling statistic for repeated measures. A statistic of this type is also given for data that are ordered categorical rather than fully rankedo Unlike the Friedman statistic, the statistics discussed in this article utilize a single ranking of the entire sample. Power calculations for an underlying normal distribution indicate that the rank transformed ANOVA test can be substantially more powerful than the Friedman test.     

Sample size calculation for an agreement study

It is often necessary to compare two measurement methods in medicine and other experimental sciences. This problem covers a broad range of data. Many authors have explored ways of assessing the agreement of two sets of measurements. However, there has been relatively little attention to the problem of determining sample size for designing an agreement study. In this paper, a method using the interval approach for concordance is proposed to calculate sample size in conducting an agreement study. The philosophy behind this is that the concordance is satisfied when no more than the pre‐specified k discordances are found for a reasonable large sample size n since it is much easier to define a discordance pair. The goal here is to find such a reasonable large sample size n. The sample size calculation is based on two rates: the discordance rate and tolerance probability, which in turn can be used to quantify an agreement study. The proposed approach is demonstrated through a real data set. Copyright © 2009 John Wiley & Sons, Ltd.     

Sample size calculation for logrank test and prediction of number of events over time

We review and compare existing methods for sample size calculation based on the logrank statistic and recommend the method of Lakatos for its accuracy and flexibility in allowing time-dependent rates of event, loss to follow-up, and noncompliance. We extend the Lakatos method to allow a general follow-up scheme, to handle non-inferiority tests, and to predict the number of events over calendar time. We apply the Lakatos method to the simple nonproportional hazard situation of delayed treatment effect to facilitate the comparison of different weighting methods and to evaluate the performance of the maximum combination tests. We use simulation studies to confirm the validity of the Lakatos method and its extensions.     

Rank tests for the k-sample problem with restricted alternatives

An asymptotically maximin most powerful rank test among somewhere asymptotically most powerful linear rank tests with scores generating function cf> is derived for each of the simple order alternative, the simple loop alternative and the simple tree alternative in the k-sample problem. The comparisons of the tests obtained with the rank analogues of the Bartholomew's xv tests are made in terms of local asymptotic relative efficiency. It is found that our tests are better than the rank analogues of the xk tests. Furthermore, the asymptotic equivalence of the ranking by the pooled sample to the ranking in pairs are discuss¬ed and the tests which are asymptotically equivalent to ours are given.     

Comparing diagnostic tests: test of hypothesis for likelihood ratios

Likelihood ratios (LRs) are used to characterize the efficiency of diagnostic tests. In this paper, we use the classical weighted least squares (CWLS) test procedure, which was originally used for testing the homogeneity of relative risks, for comparing the LRs of two or more binary diagnostic tests. We compare the performance of this method with the relative diagnostic likelihood ratio (rDLR) method and the diagnostic likelihood ratio regression (DLRReg) approach in terms of size and power, and we observe that the performances of CWLS and rDLR are the same when used to compare two diagnostic tests, while DLRReg method has higher type I error rates and powers. We also examine the performances of the CWLS and DLRReg methods for comparing three diagnostic tests in various sample size and prevalence combinations. On the basis of Monte Carlo simulations, we conclude that all of the tests are generally conservative and have low power, especially in settings of small sample size and low prevalence.     

Linear rank tests under general alternatives,with application to summary statistics computed from repeated measures data

Linear rank tests are used extensively for comparing two or more groups of continuous outcomes. Tests in this class retain proper test size with minimal assumptions and can have high efficiency towards an alternative of interest. In recent years, these tests have been increasingly used in settings where an individual's observation is itself a scalar summary of several outcome measures. Here, simple distributional structures on the outcome variables can lead to complex differences between the distributions of summary statistics of the comparison groups. The local asymptotic power of linear rank tests when the groups are assumed to differ by a location or scale alternative has been studied in detail. However, not much is known about their behavior for other types of alternatives. To address this, we derive the asymptotic distribution of linear rank tests under a general contiguous alternative and then investigate the implications for location–scale families and more general settings, including an example drawn from an AIDS clinical trial where the continuous outcome is a summary statistic computed from repeated measures of a biological marker.     

Designing cancer immunotherapy trials with delayed treatment effect using maximin efficiency robust statistics

The indirect mechanism of action of immunotherapy causes a delayed treatment effect, producing delayed separation of survival curves between the treatment groups, and violates the proportional hazards assumption. Therefore using the log‐rank test in immunotherapy trial design could result in a severe loss efficiency. Although few statistical methods are available for immunotherapy trial design that incorporates a delayed treatment effect, recently, Ye and Yu proposed the use of a maximin efficiency robust test (MERT) for the trial design. The MERT is a weighted log‐rank test that puts less weight on early events and full weight after the delayed period. However, the weight function of the MERT involves an unknown function that has to be estimated from historical data. Here, for simplicity, we propose the use of an approximated maximin test, the V₀ test, which is the sum of the log‐rank test for the full data set and the log‐rank test for the data beyond the lag time point. The V₀ test fully uses the trial data and is more efficient than the log‐rank test when lag exits with relatively little efficiency loss when no lag exists. The sample size formula for the V₀ test is derived. Simulations are conducted to compare the performance of the V₀ test to the existing tests. A real trial is used to illustrate cancer immunotherapy trial design with delayed treatment effect.     

On power and sample size of the ANOVA-type rank test

When using nonparametric methods to analyze factorial designs with repeated measures, the ANOVA-type rank test has gained popularity due to its robustness and appropriate type I error control. This article proposes power and sample size calculation formulas under two scenarios where the nonparametric regression coefficients are known or they are unknown but a pilot study is available. When a pilot study is available, the formulas do not need any assumption on the underlying population distributions. Simulation results confirm the accuracy of the proposed methods. An STZ rat excisional wound study is used to demonstrate the application of the methods.     

Comparing the Survival of Two Groups with an Intermediate Clinical Event

Consider a subject entered on a clinicaltrial in which the major endpoint is a time metric such as deathor time to reach a well defined event. During the observationalperiod the subject may experience an intermediate clinical event.The intermediate clinical event may induce a change in the survivaldistribution. We consider models for the one and two sample problem.The model for the one sample problem enables one to test if theoccurrence of the intermediate event changed the survival distribution.This models provides a way of carrying out non-randomized clinicaltrial to determine if a therapy has benefit. The two sample problemconsiders testing if the probability distributions, with andwithout an intermediate event, are the same. Statistical testsare derived using a semi-Markov or a time dependent mixture model.Simulation studies are carried out to compare these new procedureswith the log rank, stratified log rank and landmark tests. Thenew tests appear to have uniformly greater power than these competitortests. The methods are applied to a randomized clinical trialcarried out by the Aids Clinical Trial Group (ACTG) which comparedlow versus high doses of zidovudine (AZT).     

Wilcoxon's signed‐rank statistic: what null hypothesis and why it matters

In statistical literature, the term ‘signed‐rank test’ (or ‘Wilcoxon signed‐rank test’) has been used to refer to two distinct tests: a test for symmetry of distribution and a test for the median of a symmetric distribution, sharing a common test statistic. To avoid potential ambiguity, we propose to refer to those two tests by different names, as ‘test for symmetry based on signed‐rank statistic’ and ‘test for median based on signed‐rank statistic’, respectively. The utility of such terminological differentiation should become evident through our discussion of how those tests connect and contrast with sign test and one‐sample t‐test. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.     

Exact tests based on the Baumgartner-Weiß-Schindler statistic—A survey

It is the purpose of this paper to review recently-proposed exact tests based on the Baumgartner-Weiß-Schindler statistic and its modification. Except for the generalized Behrens-Fisher problem, these tests are broadly applicable, and they can be used to compare two groups irrespective of whether or not ties occur. In addition, a nonparametric trend test and a trend test for binomial proportions are possible. These exact tests are preferable to commonly-applied tests, such as the Wilcoxon rank sum test, in terms of both type I error rate and power.