A win ratio approach to comparing continuous non‐normal outcomes in clinical trials

Clinical trials are often designed to compare continuous non‐normal outcomes. The conventional statistical method for such a comparison is a non‐parametric Mann–Whitney test, which provides a P‐value for testing the hypothesis that the distributions of both treatment groups are identical, but does not provide a simple and straightforward estimate of treatment effect. For that, Hodges and Lehmann proposed estimating the shift parameter between two populations and its confidence interval (CI). However, such a shift parameter does not have a straightforward interpretation, and its CI contains zero in some cases when Mann–Whitney test produces a significant result. To overcome the aforementioned problems, we introduce the use of the win ratio for analysing such data. Patients in the new and control treatment are formed into all possible pairs. For each pair, the new treatment patient is labelled a ‘winner’ or a ‘loser’ if it is known who had the more favourable outcome. The win ratio is the total number of winners divided by the total numbers of losers. A 95% CI for the win ratio can be obtained using the bootstrap method. Statistical properties of the win ratio statistic are investigated using two real trial data sets and six simulation studies. Results show that the win ratio method has about the same power as the Mann–Whitney method. We recommend the use of the win ratio method for estimating the treatment effect (and CI) and the Mann–Whitney method for calculating the P‐value for comparing continuous non‐Normal outcomes when the amount of tied pairs is small. Copyright © 2016 John Wiley & Sons, Ltd.     

Distribution of the two‐sample t‐test statistic following blinded sample size re‐estimation

We consider the blinded sample size re‐estimation based on the simple one‐sample variance estimator at an interim analysis. We characterize the exact distribution of the standard two‐sample t‐test statistic at the final analysis. We describe a simulation algorithm for the evaluation of the probability of rejecting the null hypothesis at given treatment effect. We compare the blinded sample size re‐estimation method with two unblinded methods with respect to the empirical type I error, the empirical power, and the empirical distribution of the standard deviation estimator and final sample size. We characterize the type I error inflation across the range of standardized non‐inferiority margin for non‐inferiority trials, and derive the adjusted significance level to ensure type I error control for given sample size of the internal pilot study. We show that the adjusted significance level increases as the sample size of the internal pilot study increases. Copyright © 2016 John Wiley & Sons, Ltd.     

Group sequential monitoring based on the weighted log‐rank test statistic with the Fleming–Harrington class of weights in cancer vaccine studies

In recent years, immunological science has evolved, and cancer vaccines are now approved and available for treating existing cancers. Because cancer vaccines require time to elicit an immune response, a delayed treatment effect is expected and is actually observed in drug approval studies. Accordingly, we propose the evaluation of survival endpoints by weighted log‐rank tests with the Fleming–Harrington class of weights. We consider group sequential monitoring, which allows early efficacy stopping, and determine a semiparametric information fraction for the Fleming–Harrington family of weights, which is necessary for the error spending function. Moreover, we give a flexible survival model in cancer vaccine studies that considers not only the delayed treatment effect but also the long‐term survivors. In a Monte Carlo simulation study, we illustrate that when the primary analysis is a weighted log‐rank test emphasizing the late differences, the proposed information fraction can be a useful alternative to the surrogate information fraction, which is proportional to the number of events. Copyright © 2016 John Wiley & Sons, Ltd.     

A Note on the Large Sample Properties of Estimators Based on Generalized Linear Models for Correlated Pseudo‐observations

Pseudo‐values have proven very useful in censored data analysis in complex settings such as multi‐state models. It was originally suggested by Andersen et al., Biometrika, 90, 2003, 335 who also suggested to estimate standard errors using classical generalized estimating equation results. These results were studied more formally in Graw et al., Lifetime Data Anal., 15, 2009, 241 that derived some key results based on a second‐order von Mises expansion. However, results concerning large sample properties of estimates based on regression models for pseudo‐values still seem unclear. In this paper, we study these large sample properties in the simple setting of survival probabilities and show that the estimating function can be written as a U‐statistic of second order giving rise to an additional term that does not vanish asymptotically. We further show that previously advocated standard error estimates will typically be too large, although in many practical applications the difference will be of minor importance. We show how to estimate correctly the variability of the estimator. This is further studied in some simulation studies.     

Linear Increments with Non‐monotone Missing Data and Measurement Error

Linear increments (LI) are used to analyse repeated outcome data with missing values. Previously, two LI methods have been proposed, one allowing non‐monotone missingness but not independent measurement error and one allowing independent measurement error but only monotone missingness. In both, it was suggested that the expected increment could depend on current outcome. We show that LI can allow non‐monotone missingness and either independent measurement error of unknown variance or dependence of expected increment on current outcome but not both. A popular alternative to LI is a multivariate normal model ignoring the missingness pattern. This gives consistent estimation when data are normally distributed and missing at random (MAR). We clarify the relation between MAR and the assumptions of LI and show that for continuous outcomes multivariate normal estimators are also consistent under (non‐MAR and non‐normal) assumptions not much stronger than those of LI. Moreover, when missingness is non‐monotone, they are typically more efficient.     

Estimating Abundance from Presence–Absence Maps via a Paired Negative‐Binomial Model

The estimation of abundance from presence–absence data is an intriguing problem in applied statistics. The classical Poisson model makes strong independence and homogeneity assumptions and in practice generally underestimates the true abundance. A controversial ad hoc method based on negative‐binomial counts (Am. Nat.) has been empirically successful but lacks theoretical justification. We first present an alternative estimator of abundance based on a paired negative binomial model that is consistent and asymptotically normally distributed. A quadruple negative binomial extension is also developed, which yields the previous ad hoc approach and resolves the controversy in the literature. We examine the performance of the estimators in a simulation study and estimate the abundance of 44 tree species in a permanent forest plot.     

A Necessary Condition for the Strong Oracle Property

A problem of using a non‐convex penalty for sparse regression is that there are multiple local minima of the penalized sum of squared residuals, and it is not known which one is a good estimator. The aim of this paper is to give a guide to design a non‐convex penalty that has the strong oracle property. Here, the strong oracle property means that the oracle estimator is the unique local minimum of the objective function. We summarize three definitions of the oracle property – the global, weak and strong oracle properties. Then, we give sufficient conditions for the weak oracle property, which means that the oracle estimator becomes a local minimum. We give an example of non‐convex penalties that possess the weak oracle property but not the strong oracle property. Finally, we give a necessary condition for the strong oracle property.     

An Automatic Test for the Umbrella Alternatives

The paper proposes a new test for detecting the umbrella pattern under a general non‐parametric scheme. The alternative asserts that the umbrella ordering holds while the hypothesis is its complement. The main focus is put on controlling the power function of the test outside the alternative. As a result, the asymptotic error of the first kind of the constructed solution is smaller than or equal to the fixed significance level α on the whole set where the umbrella ordering does not hold. Also, under finite sample sizes, this error is controlled to a satisfactory extent. A simulation study shows, among other things, that the new test improves upon the solution widely recommended in the literature of the subject. A routine, written in R, is attached as the Supporting Information file.