Power and sample size determination for a stepwise test procedure for finding the maximum safe dose

This paper addresses the problem of power and sample size calculation for a stepwise multiple test procedure (SD2PC) proposed in Tamhane et al. [2001. Multiple test procedures for identifying the maximum safe dose. J. Amer. Statist. Assoc. 96, 835–843] to identify the maximum safe dose of a compound. A general expression for the power of this procedure is derived. It is used to find the minimum overall power and minimum power under the constraint that the dose response function is bounded from below by a linear response function. It is shown that the two minima are attained under step and linear response functions, respectively. The sample sizes necessary on the zero dose control and each of the positive doses to guarantee a specified power requirement are calculated under these two least favorable configurations. A technique involving a continuous approximation to the sample sizes is used to reduce the number of quantities that need to be tabled, and to derive the asymptotically optimal allocation of the total sample size between the zero dose and the positive doses. An example is given to illustrate use of the tables. Extensions of the basic formulation are noted.     

Impact of surviving time on tests for carcinogenicity

In tumorigenicity experiments, each animal begins in a tumor-free state and then either develops a tumor or dies before developing a tumor. Animals that develop a tumor either die from the tumor or from other competing causes. All surviving animals are sacrificed at the end of the experiment, normally two years. The two most commonly used statistical tests are the logrank test for comparing hazards of death from rapidly lethal tumors and the Hoel-Walburg test for comparing prevalences of nonlethal tumors. However, the data obtained from a carcinogenicity experiment generally contains a mixture of fatal and incidental tumors. Peto et al.(1980)suggested combining the fatal and incidental tests for a comparison of tumor onset distributions.

Extensive simulations show that the trend test for tumor onset using the Peto procedure has the proper size, under the simulation constraints, when each group has identical mortality patterns, and the test with continuity correction tends to be conservative. When the animals n the dosed groups have reduced survival rates, the type I error rate is likely to exceed the nominal level. The continuity correction is recommended for a small reduction in survival time among the dosed groups to ensure the proper size. However, when there is a large reduction in survival times in the dosed groups, the onset test does not have the proper size.     

Sample sizes for the transmission disequilibrium tests: tdt,s-tdt and 1-tdt

The transmission/disequilibrium test (TDT) is widely used to detect the linkage disequilibrium between a candidate locus (a marker) and a disease locus. The TDT is a family-based design and has the advantage that it is a valid test when population stratification exist. The TDT requires the marker genotypes of affected individuals and their parents. For diseases with late age of onset, it is difficult or impossible to obtain the marker genotype of the parents. Therefore, when both parents marker genotypes are unavailable, Ewex and Spielman extended the TDT to the S-TDT for use in sibships with at least one affected individual and one unaffected individual. When only one of the parents' genotype is available. Sun et al. proposed a test the 1-TDT, for use with niarker genotypes of affected individuals and only one available parent. Here, we study the saniple sizes of TDT, S-TDT, and 1-TDT. We show that the sample size needed for the 1-TDT is rogghly the same as the sample size needed for the S-TDT with two sibs and is about twice the sample size for the TDT.     

A comparison of two approaches for power and sample size calculations in logistic regression models

Whittemore (1981) proposed an approach for calculating the sample size needed to test hypotheses with specified significance and power against a given alternative for logistic regression with small response probability. Based on the distribution of covariate, which could be either discrete or continuous, this approach first provides a simple closed-form approximation to the asymptotic covariance matrix of the maximum likelihood estimates, and then uses it to calculate the sample size needed to test a hypothesis about the parameter. Self et al. (1992) described a general approach for power and sample size calculations within the framework of generalized linear models, which include logistic regression as a special case. Their approach is based on an approximation to the distribution of the likelihood ratio statistic. Unlike the Whittemore approach, their approach is not limited to situations of small response probability. However, it is restricted to models with a finite number of covariate configurations. This study compares these two approaches to see how accurate they would be for the calculations of power and sample size in logistic regression models with various response probabilities and covariate distributions. The results indicate that the Whittemore approach has a slight advantage in achieving the nominal power only for one case with small response probability. It is outperformed for all other cases with larger response probabilities. In general, the approach proposed in Self et al. (1992) is recommended for all values of the response probability. However, its extension for logistic regression models with an infinite number of covariate configurations involves an arbitrary decision for categorization and leads to a discrete approximation. As shown in this paper, the examined discrete approximations appear to be sufficiently accurate for practical purpose.     

Sample Size Requirements and Study Duration for Testing Main Effects and Interactions in Completely Randomized Factorial Designs When Time to Event is the Outcome

In this paper, we develop the methodology for designing clinical trials with any factorial arrangement when the primary outcome is time to event. We provide a matrix formulation for calculating the sample size and study duration necessary to test any effect with a prespecified type I error rate and power. Assuming that a time to event follows an exponential distribution, we describe the relationships between the effect size, the power, and the sample size. We present examples for illustration purposes. We provide a simulation study to verify the numerical calculations of the expected number of events and the duration of the trial. The change in the power produced by a reduced number of observations or by accruing no patients to certain factorial combinations is also described.     

Statistical methods of risk assessment for continuous variables

Adverse health effects for continuous responses are not as easily defined as adverse health effects for binary responses. Kodell and West (1993) developed methods for defining adverse effects for continuous responses and the associated risk. Procedures were developed for finding point estimates and upper confidence limits for additional risk under the assumption of a normal distribution and quadratic mean response curve with equal variances at each dose level. In this paper, methods are developed for point estimates and upper confidence limits for additional risk at experimental doses when the equal variance assumption is relaxed. An interpolation procedure is discussed for obtaining information at doses other than the experimental doses. A small simulation study is presented to test the performance of the methods discussed.     

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.     

A generalized analytic solution to the win ratio to analyze a composite endpoint considering the clinical importance order among components

A composite endpoint consists of multiple endpoints combined in one outcome. It is frequently used as the primary endpoint in randomized clinical trials. There are two main disadvantages associated with the use of composite endpoints: a) in conventional analyses, all components are treated equally important; and b) in time‐to‐event analyses, the first event considered may not be the most important component. Recently Pocock et al. (2012) introduced the win ratio method to address these disadvantages. This method has two alternative approaches: the matched pair approach and the unmatched pair approach. In the unmatched pair approach, the confidence interval is constructed based on bootstrap resampling, and the hypothesis testing is based on the non‐parametric method by Finkelstein and Schoenfeld (1999). Luo et al. (2015) developed a close‐form variance estimator of the win ratio for the unmatched pair approach, based on a composite endpoint with two components and a specific algorithm determining winners, losers and ties. We extend the unmatched pair approach to provide a generalized analytical solution to both hypothesis testing and confidence interval construction for the win ratio, based on its logarithmic asymptotic distribution. This asymptotic distribution is derived via U‐statistics following Wei and Johnson (1985). We perform simulations assessing the confidence intervals constructed based on our approach versus those per the bootstrap resampling and per Luo et al. We have also applied our approach to a liver transplant Phase III study. This application and the simulation studies show that the win ratio can be a better statistical measure than the odds ratio when the importance order among components matters; and the method per our approach and that by Luo et al., although derived based on large sample theory, are not limited to a large sample, but are also good for relatively small sample sizes. Different from Pocock et al. and Luo et al., our approach is a generalized analytical method, which is valid for any algorithm determining winners, losers and ties. Copyright © 2016 John Wiley & Sons, Ltd.     

A Design For Survival Studies: A Multi-regional Trial With Unrecognized Heterogeneity

A bridging study defined by ICH E5 is usually conducted in the new region after the test product has been approved for commercial marketing in the original region due to its proven efficacy and safety. However, extensive duplication of clinical evaluation in the new region not only requires valuable development resources but also delay availability of the test product to the needed patients in the new regions. To shorten the drug lag or the time lag for approval, simultaneous drug development, submission, and approval in the world may be desirable. Recently, multi-regional trials have attracted much attention from sponsors as well as regulatory authorities. Current methods for sample determination are based on the assumption that true treatment effect is uniform across regions. However, unrecognized heterogeneity among patients as ethnic or genetic factor will effect patients’ survival. Using the simple log-rank test for analysis of treatment effect on survival in studies under heterogeneity may be severely underpowered. In this article, we address the issue that the treatment effects are different among regions to design a multi-regional trial. The optimal log-rank test is employed to deal with the heterogeneous effect size among regions. The test statistic for the overall treatment effect is used to determine the total sample size for a multi-regional trial and the consistent trend and the proposed criteria are used to rationalize partition sample size to each region.     

Estimation of the Parameters of a Clumped Binomial Model via the EM Algorithm

Binary-response data arise in teratology and mutagenicity studies in which each treatment is applied to a group of litters. In a large experiment, a contingency table can be constructed to test the treatment X litter size interaction (see Kastenbaum and Lamphiear 1959). In situations in which there is a clumped category, as in the Kastenbaum and Lamphiear mice-depletion data, a clumped binomial model (Koch et al. 1976) or a clumped beta-binomial model (Paul 1979) can be used to analyze these data. When a clumped binomial model is appropriate, the maximum likelihood estimates of the parameters of the model under the hypothesis of no treatment X litter size interaction, as well as under the hypothesis of the said interaction, can be estimated via the EM algorithm for computing maximum likelihood estimates from incomplete data (Dempster et al. 1977). In this article the EM algorithm is described and used to test treatment X litter size interaction for the Kastenbaum and Lamphiear data and for a set of data given in Luning et al. (1966).     

A review and re‐interpretation of a group‐sequential approach to sample size re‐estimation in two‐stage trials

In this paper, we review the adaptive design methodology of Li et al. (Biostatistics 3 :277–287) for two‐stage trials with mid‐trial sample size adjustment. We argue that it is closer in principle to a group sequential design, in spite of its obvious adaptive element. Several extensions are proposed that aim to make it even more attractive and transparent alternative to a standard (fixed sample size) trial for funding bodies to consider. These enable a cap to be put on the maximum sample size and for the trial data to be analysed using standard methods at its conclusion. The regulatory view of trials incorporating unblinded sample size re‐estimation is also discussed. © 2014 The Authors. Pharmaceutical Statistics published by John Wiley & Sons, Ltd.     

Sample Size Determination and Rational Partition for A Multi- Regional Trial for Survival (Time-To-Event) Data with Unrecognized Heterogeneity that Interacts with Treatment

To shorten the drug lag or the time lag for approval, simultaneous drug development, submission, and approval in the world may be desirable. Recently, multi-regional trials have attracted much attention from sponsors as well as regulatory authorities. Current methods for sample determination are based on the assumption that true treatment effect is uniform across regions. However, unrecognized heterogeneity among patients as ethnic or genetic factor will effect patients’ survival. In this article, we address the issue that the treatment effects with unrecognized heterogeneity that interacts with treatment are among regions to design a multi-regional trial. The log-rank test is employed to deal with the heterogeneous effect size among regions. The test statistic for the overall treatment effect is used to determine the total sample size for a multi-regional trial and the consistent trend is used to rationalize partition for sample size to each region.     

Ordered Tests for Right–Censored Survival Data

In comparative clinical trials or animal carcinogenesis studies, the effect of increasing dose levels of an agent or an increasing number of additional modalities are frequently evaluated on the prolonged survival time of patients with a particular disease. It is of particular interest to test the ordered alternative that a treatment level increase leads to better survival. This paper considers an ordered test based on the two–sample weighted Kaplan–Meier statistics (Pepe & Fleming, 1989, 1991). It evaluates asymptotic relative efficiencies of the proposed ordered weighted Kaplan–Meier test, the competing ordered weighted logrank test (Liu et al., 1993) and modified ordered logrank test (Liu & Tsai, 1999) under Lehmann alternatives, for various piecewise exponential survival distributions. Finally, it demonstrates the proposed test on an appropriate dataset.     

Evaluation of Linear Trend Tests Using Resampling Techniques

A number of parametric and non-parametric linear trend tests for time series are evaluated in terms of test size and power, using also resampling techniques to form the empirical distribution of the test statistics under the null hypothesis of no linear trend. For resampling, both bootstrap and surrogate data are considered. Monte Carlo simulations were done for several types of residuals (uncorrelated and correlated with normal and nonnormal distributions) and a range of small magnitudes of the trend coefficient. In particular for AR(1) and ARMA(1, 1) residual processes, we investigate the discrimination of strong autocorrelation from linear trend with respect to the sample size. The correct test size is obtained for larger data sizes as autocorrelation increases and only when a randomization test that accounts for autocorrelation is used. The overall results show that the type I and II errors of the trend tests are reduced with the use of resampled data. Following the guidelines suggested by the simulation results, we could find significant linear trend in the data of land air temperature and sea surface temperature.     

Seme distributions and their implications for an internal pilot study with a univariate linear model

In planning a study, the choice of sample size may depend on a variance value based on speculation or obtained from an earlier study. Scientists may wish to use an internal pilot design to protect themselves against an incorrect choice of variance. Such a design involves collecting a portion of the originally planned sample and using it to produce a new variance estimate. This leads to a new power analysis and increasing or decreasing sample size. For any general linear univariate model, with fixed predictors and Gaussian errors, we prove that the uncorrected fixed sample F-statistic is the likelihood ratio test statistic. However, the statistic does not follow an F distribution. Ignoring the discrepancy may inflate test size. We derive and evaluate properties of the components of the likelihood ratio test statistic in order to characterize and quantify the bias. Most notably, the fixed sample size variance estimate becomes biased downward. The bias may inflate test size for any hypothesis test, even if the parameter being tested was not involved in the sample size re-estimation. Furthermore, using fixed sample size methods may create biased confidence intervals for secondary parameters and the variance estimate.     

Sample size recalculation for binary data in internal pilot study designs

For binary endpoints, the required sample size depends not only on the known values of significance level, power and clinically relevant difference but also on the overall event rate. However, the overall event rate may vary considerably between studies and, as a consequence, the assumptions made in the planning phase on this nuisance parameter are to a great extent uncertain. The internal pilot study design is an appealing strategy to deal with this problem. Here, the overall event probability is estimated during the ongoing trial based on the pooled data of both treatment groups and, if necessary, the sample size is adjusted accordingly. From a regulatory viewpoint, besides preserving blindness it is required that eventual consequences for the Type I error rate should be explained. We present analytical computations of the actual Type I error rate for the internal pilot study design with binary endpoints and compare them with the actual level of the chi‐square test for the fixed sample size design. A method is given that permits control of the specified significance level for the chi‐square test under blinded sample size recalculation. Furthermore, the properties of the procedure with respect to power and expected sample size are assessed. Throughout the paper, both the situation of equal sample size per group and unequal allocation ratio are considered. The method is illustrated with application to a clinical trial in depression. Copyright © 2004 John Wiley & Sons Ltd.     

A new goodness of fit test for the equality of multinomial cell probabilities versus trend alternatives

In this paper, a new test statistic is presented for testing the null hypothesis of equal multinomial cell probabilities versus various trend alternatives. Exact asymptotic critical values are obtained, The power of the test is compared with several other statistics considered by Choulakian et al (1995), The test is shown to have better power for certain trend alternatives.     

Leveraging historical data into oncology development programs: Two case studies of phase 2 Bayesian augmented control trial designs

Leveraging historical data into the design and analysis of phase 2 randomized controlled trials can improve efficiency of drug development programs. Such approaches can reduce sample size without loss of power. Potential issues arise when the current control arm is inconsistent with historical data, which may lead to biased estimates of treatment efficacy, loss of power, or inflated type 1 error. Consideration as to how to borrow historical information is important, and in particular, adjustment for prognostic factors should be considered. This paper will illustrate two motivating case studies of oncology Bayesian augmented control (BAC) trials. In the first example, a glioblastoma study, an informative prior was used for the control arm hazard rate. Sample size savings were 15% to 20% by using a BAC design. In the second example, a pancreatic cancer study, a hierarchical model borrowing method was used, which enabled the extent of borrowing to be determined by consistency of observed study data with historical studies. Supporting Bayesian analyses also adjusted for prognostic factors. Incorporating historical data via Bayesian trial design can provide sample size savings, reduce study duration, and enable a more scientific approach to development of novel therapies by avoiding excess recruitment to a control arm. Various sensitivity analyses are necessary to interpret results. Current industry efforts for data transparency have meaningful implications for access to patient‐level historical data, which, while not critical, is helpful to adjust for potential imbalances in prognostic factors.     

A gamma goodness-of-fit test based on characteristic independence of the mean and coefficient of variation

Characterization theorems in probability and statistics are widely appreciated for their role in clarifying the structure of the families of probability distributions. Less well known is the role characterization theorems have as a natural, logical and effective starting point for constructing goodness-of-fit tests. The characteristic independence of the mean and variance and of the mean and the third central moment of a normal sample were used, respectively, by Lin and Mudholkar [1980. A simple test for normality against asymmetric alternatives. Biometrika 67, 455–461] and by Mudholkar et al. [2002a. Independence characterizations and testing normality against skewness-kurtosis alternatives. J. Statist. Plann. Inference 104, 485–501] for developing tests of normality. The characteristic independence of the maximum likelihood estimates of the population parameters was similarly used by Mudholkar et al. [2002b. Independence characterization and inverse Gaussian goodness-of-fit. Sankhya A 63, 362–374] to develop a test of the composite inverse Gaussian hypothesis. The gamma models are extensively used for applied research in the areas of econometrics, engineering and biomedical sciences; but there are few goodness-of-fit tests available to test if the data indeed come from a gamma population. In this paper we employ Hwang and Hu's [1999. On a characterization of the gamma distribution: the independence of the sample mean and the sample coefficient of variation. Ann. Inst. Statist. Math. 51, 749–753] characterization of the gamma population in terms of the independence of sample mean and coefficient of variation for developing such a test. The asymptotic null distribution of the proposed test statistic is obtained and empirically refined for use with samples of moderate size.     

Variance reduction for kernel estimators in clustered/longitudinal data analysis

We develop a variance reduction method for the seemingly unrelated (SUR) kernel estimator of Wang (2003). We show that the quadratic interpolation method introduced in Cheng et al. (2007) works for the SUR kernel estimator. For a given point of estimation, Cheng et al. (2007) define a variance reduced local linear estimate as a linear combination of classical estimates at three nearby points. We develop an analogous variance reduction method for SUR kernel estimators in clustered/longitudinal models and perform simulation studies which demonstrate the efficacy of our variance reduction method in finite sample settings.