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.     

Bootstrapping an inhomogeneous point process

In this paper, we focus on resampling non-stationary weakly dependent point processes in two dimensions to make inference on the inhomogeneous K function ( Baddeley et al., 2000). We provide theoretical results that show a consistency result of the bootstrap estimates of the variance as the observation region and resampling blocks increase in size. We present results of a simulation study that examines the performance of nominal 95% confidence intervals for the inhomogeneous K function obtained via our bootstrap procedure. The procedure is also applied to a rainforest dataset.     

Analytical approximations for iterated bootstrap confidence intervals

Standard algorithms for the construction of iterated bootstrap confidence intervals are computationally very demanding, requiring nested levels of bootstrap resampling. We propose an alternative approach to constructing double bootstrap confidence intervals that involves replacing the inner level of resampling by an analytical approximation. This approximation is based on saddlepoint methods and a tail probability approximation of DiCiccio and Martin (1991). Our technique significantly reduces the computational expense of iterated bootstrap calculations. A formal algorithm for the construction of our approximate iterated bootstrap confidence intervals is presented, and some crucial practical issues arising in its implementation are discussed. Our procedure is illustrated in the case of constructing confidence intervals for ratios of means using both real and simulated data. We repeat an experiment of Schenker (1985) involving the construction of bootstrap confidence intervals for a variance and demonstrate that our technique makes feasible the construction of accurate bootstrap confidence intervals in that context. Finally, we investigate the use of our technique in a more complex setting, that of constructing confidence intervals for a correlation coefficient.     

A weighted bootstrap approach to bootstrap iteration

The operation of resampling from a bootstrap resample, encountered in applications of the double bootstrap, maybe viewed as resampling directly from the sample but using probability weights that are proportional to the numbers of times that sample values appear in the resample. This suggests an approximate approach to double-bootstrap Monte Carlo simulation, where weighted bootstrap methods are used to circumvent much of the labour involved in compounded Monte Carlo approximation. In the case of distribution estimation or, equivalently, confidence interval calibration, the new method may be used to reduce the computational labour. Moreover, the method produces the same order of magnitude of coverage error for confidence intervals, or level error for hypothesis tests, as a full application of the double bootstrap.     

Corrected profile likelihood confidence interval for binomial paired incomplete data

Clinical trials often use paired binomial data as their clinical endpoint. The confidence interval is frequently used to estimate the treatment performance. Tang et al. (2009) have proposed exact and approximate unconditional methods for constructing a confidence interval in the presence of incomplete paired binary data. The approach proposed by Tang et al. can be overly conservative with large expected confidence interval width (ECIW) in some situations. We propose a profile likelihood‐based method with a Jeffreys' prior correction to construct the confidence interval. This approach generates confidence interval with a much better coverage probability and shorter ECIWs. The performances of the method along with the corrections are demonstrated through extensive simulation. Finally, three real world data sets are analyzed by all the methods. Statistical Analysis System (SAS) codes to execute the profile likelihood‐based methods are also presented. Copyright © 2013 John Wiley & Sons, Ltd.     

Wild Bootstrapping in Finite Populations with Auxiliary Information

Consider a finite population u , which can be viewed as a realization of a super-population model. A simple ratio model (linear regression, without intercept) with heteroscedastic errors is supposed to have generated u . A random sample is drawn without replacement from u . In this set-up a two-stage wild bootstrap resampling scheme as well as several other useful forms of bootstrapping in finite populations will be considered. Some asymptotic results for various bootstrap approximations for normalized and Studentized versions of the well-known ratio and regression estimator are given. Bootstrap based confidence interval s for the population total and for the regression parameter of the underlying ratio model are also discussed     

Adaptive Nonparametric Comparison of Regression Curves

In this article, we develop a new and novel kernel density estimator for a sum of weighted averages from a single population based on utilizing the well defined kernel density estimator in conjunction with classic inversion theory. This idea is further developed for a kernel density estimator for the difference of weighed averages from two independent populations. The resulting estimator is “bootstrap-like” in terms of its properties with respect to the derivation of approximate confidence intervals via a “plug-in” approach. This new approach is distinct from the bootstrap methodology in that it is analytically and computationally feasible to provide an exact estimate of the distribution function through direct calculation. Thus, our approach eliminates the error due to Monte Carlo resampling that arises within the context of simulation based approaches that are oftentimes necessary in order to derive bootstrap-based confidence intervals for statistics involving weighted averages of i.i.d. random variables. We provide several examples and carry forth a simulation study to show that our kernel density estimator performs better than the standard central limit theorem based approximation in term of coverage probability.     

Simultaneous confidence interval for assessing non‐inferiority with assay sensitivity in a three‐arm trial with binary endpoints

A three‐arm trial including an experimental treatment, an active reference treatment and a placebo is often used to assess the non‐inferiority (NI) with assay sensitivity of an experimental treatment. Various hypothesis‐test‐based approaches via a fraction or pre‐specified margin have been proposed to assess the NI with assay sensitivity in a three‐arm trial. There is little work done on confidence interval in a three‐arm trial. This paper develops a hybrid approach to construct simultaneous confidence interval for assessing NI and assay sensitivity in a three‐arm trial. For comparison, we present normal‐approximation‐based and bootstrap‐resampling‐based simultaneous confidence intervals. Simulation studies evidence that the hybrid approach with the Wilson score statistic performs better than other approaches in terms of empirical coverage probability and mesial‐non‐coverage probability. An example is used to illustrate the proposed approaches.     

Hybrid regions for post-change mean in a sequence of normal variables

The hybrid bootstrap uses resampling ideas to extend the duality approach to the interval estimation for a parameter of interest when there are nuisance parameters. The confidence region constructed by the hybrid bootstrap may perform much better than the ordinary bootstrap region in a situation where the data provide substantial information about the nuisance parameter, but limited information about the parameter of interest. We apply this method to estimate the post-change mean after a change is detected by a stopping procedure in a sequence of independent normal variables. Since distribution theory in change point problems is generally a challenge, we use bootstrap simulation to find empirical distributions of test statistics and calculate critical thresholds. Both likelihood ratio and Bayesian test statistics are considered to set confidence regions for post-change means in the normal model. In the simulation studies, the performance of hybrid regions are compared with that of ordinary bootstrap regions in terms of the widths and coverage probabilities of confidence intervals.     

IMPORTANCE BOOTSTRAP RESAMPLING FOR PROPORTIONAL HAZARDS REGRESSION

Importance resampling is an approach that uses exponential tilting to reduce the resampling necessary for the construction of nonparametric bootstrap confidence intervals. The properties of bootstrap importance confidence intervals are well established when the data is a smooth function of means and when there is no censoring. However, in the framework of survival or time-to-event data, the asymptotic properties of importance resampling have not been rigorously studied, mainly because of the unduly complicated theory incurred when data is censored. This paper uses extensive simulation to show that, for parameter estimates arising from fitting Cox proportional hazards models, importance bootstrap confidence intervals can be constructed if the importance resampling probabilities of the records for the n individuals in the study are determined by the empirical influence function for the parameter of interest. Our results show that, compared to uniform resampling, importance resampling improves the relative mean-squared-error (MSE) efficiency by a factor of nine (for n = 200). The efficiency increases significantly with sample size, is mildly associated with the amount of censoring, but decreases slightly as the number of bootstrap resamples increases. The extra CPU time requirement for calculating importance resamples is negligible when compared to the large improvement in MSE efficiency. The method is illustrated through an application to data on chronic lymphocytic leukemia, which highlights that the bootstrap confidence interval is the preferred alternative to large sample inferences when the distribution of a specific covariate deviates from normality. Our results imply that, because of its computational efficiency, importance resampling is recommended whenever bootstrap methodology is implemented in a survival framework. Its use is particularly important when complex covariates are involved or the survival problem to be solved is part of a larger problem; for instance, when determining confidence bounds for models linking survival time with clusters identified in gene expression microarray data.     

The local fractional bootstrap

We introduce a bootstrap procedure for high‐frequency statistics of Brownian semistationary processes. More specifically, we focus on a hypothesis test on the roughness of sample paths of Brownian semistationary processes, which uses an estimator based on a ratio of realized power variations. Our new resampling method, the local fractional bootstrap, relies on simulating an auxiliary fractional Brownian motion that mimics the fine properties of high‐frequency differences of the Brownian semistationary process under the null hypothesis. We prove the first‐order validity of the bootstrap method, and in simulations, we observe that the bootstrap‐based hypothesis test provides considerable finite‐sample improvements over an existing test that is based on a central limit theorem. This is important when studying the roughness properties of time series data. We illustrate this by applying the bootstrap method to two empirical data sets: We assess the roughness of a time series of high‐frequency asset prices and we test the validity of Kolmogorov's scaling law in atmospheric turbulence data.     

Kernel Smoothing to Improve Bootstrap Confidence Intervals

Some studies of the bootstrap have assessed the effect of smoothing the estimated distribution that is resampled, a process usually known as the smoothed bootstrap. Generally, the smoothed distribution for resampling is a kernel estimate and is often rescaled to retain certain characteristics of the empirical distribution. Typically the effect of such smoothing has been measured in terms of the mean-squared error of bootstrap point estimates. The reports of these previous investigations have not been encouraging about the efficacy of smoothing. In this paper the effect of resampling a kernel-smoothed distribution is evaluated through expansions for the coverage of bootstrap percentile confidence intervals. It is shown that, under the smooth function model, proper bandwidth selection can accomplish a first-order correction for the one-sided percentile method. With the objective of reducing the coverage error the appropriate bandwidth for one-sided intervals converges at a rate of n ^−1/4, rather than the familiar n ^−1/5 for kernel density estimation. Applications of this same approach to bootstrap t and two-sided intervals yield optimal bandwidths of order n ^−1/2. These bandwidths depend on moments of the smooth function model and not on derivatives of the underlying density of the data. The relationship of this smoothing method to both the accelerated bias correction and the bootstrap t methods provides some insight into the connections between three quite distinct approximate confidence intervals.     

Direct estimation of the percentile 'p-value' for the one-sample median test

In this paper we outline and illustrate an easy-to-use inference procedure for directly calculating the approximate bootstrap percentile-type p-value for the one-sample median test, i.e. we calculate the bootstrap p -value without resampling, by using a fractional order statistics based approach. The method parallels earlier work on fractionalorder-statistics-based non-parametric bootstrap percentile-type confidence intervals for quantiles. Monte Carlo simulation studies are performed, which illustrate that the fractional-order-statistics-based approach to the one-sample median test has accurate type I error control for small samples over a wide range of distributions; is easy to calculate; and is preferable to the sign test in terms of type I error control and power. Furthermore, the fractional-order-statistics-based median test is easily generalized to testing that any quantile has some hypothesized value; for example, tests for the upper or lower quartile may be performed using the same framework.     

A Smooth Bootstrap Procedure towards Deriving Confidence Intervals for the Relative Risk

Given a pair of sample estimators of two independent proportions, bootstrap methods are a common strategy towards deriving the associated confidence interval for the relative risk. We develop a new smooth bootstrap procedure, which generates pseudo-samples from a continuous quantile function. Under a variety of settings, our simulation studies show that our method possesses a better or equal performance in comparison with asymptotic theory based and existing bootstrap methods, particularly for heavily unbalanced data in terms of coverage probability and power. We illustrate our procedure as applied to several published data sets.     

Edgeworth Corrections for Realized Volatility

The quality of the asymptotic normality of realized volatility can be poor if sampling does not occur at very high frequencies. In this article we consider an alternative approximation to the finite sample distribution of realized volatility based on Edgeworth expansions. In particular, we show how confidence intervals for integrated volatility can be constructed using these Edgeworth expansions. The Monte Carlo study we conduct shows that the intervals based on the Edgeworth corrections have improved properties relatively to the conventional intervals based on the normal approximation. Contrary to the bootstrap, the Edgeworth approach is an analytical approach that is easily implemented, without requiring any resampling of one's data. A comparison between the bootstrap and the Edgeworth expansion shows that the bootstrap outperforms the Edgeworth corrected intervals. Thus, if we are willing to incur in the additional computational cost involved in computing bootstrap intervals, these are preferred over the Edgeworth intervals. Nevertheless, if we are not willing to incur in this additional cost, our results suggest that Edgeworth corrected intervals should replace the conventional intervals based on the first order normal approximation.     

Confidence Intervals on Regression Models with Censored Data

Stute (1993, Consistent estimation under random censorship when covariables are present. Journal of Multivariate Analysis 45, 89–103) proposed a new method to estimate regression models with a censored response variable using least squares and showed the consistency and asymptotic normality for his estimator. This article proposes a new bootstrap-based methodology that improves the performance of the asymptotic interval estimation for the small sample size case. Therefore, we compare the behavior of Stute's asymptotic confidence interval with that of several confidence intervals that are based on resampling bootstrap techniques. In order to build these confidence intervals, we propose a new bootstrap resampling method that has been adapted for the case of censored regression models. We use simulations to study the improvement the performance of the proposed bootstrap-based confidence intervals show when compared to the asymptotic proposal. Simulation results indicate that, for the new proposals, coverage percentages are closer to the nominal values and, in addition, intervals are narrower.     

The win ratio: Impact of censoring and follow‐up time and use with nonproportional hazards

The win ratio has been studied methodologically and applied in data analysis and in designing clinical trials. Researchers have pointed out that the results depend on follow‐up time and censoring time, which are sometimes used interchangeably. In this article, we distinguish between follow‐up time and censoring time, show theoretically the impact of censoring on the win ratio, and illustrate the impact of follow‐up time. We then point out that, if the treatment has long‐term benefit from a more important but less frequent endpoint (eg, death), the win ratio can show that benefit by following patients longer, avoiding masking by more frequent but less important outcomes, which occurs in conventional time‐to‐first‐event analyses. For the situation of nonproportional hazards, we demonstrate that the win ratio can be a good alternative to methods such as landmark survival rate, restricted mean survival time, and weighted log‐rank tests.     

Edgeworth Corrections for Realized Volatility

The quality of the asymptotic normality of realized volatility can be poor if sampling does not occur at very high frequencies. In this article we consider an alternative approximation to the finite sample distribution of realized volatility based on Edgeworth expansions. In particular, we show how confidence intervals for integrated volatility can be constructed using these Edgeworth expansions. The Monte Carlo study we conduct shows that the intervals based on the Edgeworth corrections have improved properties relatively to the conventional intervals based on the normal approximation. Contrary to the bootstrap, the Edgeworth approach is an analytical approach that is easily implemented, without requiring any resampling of one's data. A comparison between the bootstrap and the Edgeworth expansion shows that the bootstrap outperforms the Edgeworth corrected intervals. Thus, if we are willing to incur in the additional computational cost involved in computing bootstrap intervals, these are preferred over the Edgeworth intervals. Nevertheless, if we are not willing to incur in this additional cost, our results suggest that Edgeworth corrected intervals should replace the conventional intervals based on the first order normal approximation.     

Double bootstrap estimation of variance under systematic sampling with probability proportional to size

Variance estimation under systematic sampling with probability proportional to size is known to be a difficult problem. We attempt to tackle this problem by the bootstrap resampling method. It is shown that the usual way to bootstrap fails to give satisfactory variance estimates. As a remedy, we propose a double bootstrap method which is based on certain working models and involves two levels of resampling. Unlike existing methods which deal exclusively with the Horvitz–Thompson estimator, the double bootstrap method can be used to estimate the variance of any statistic. We illustrate this within the context of both mean and median estimation. Empirical results based on five natural populations are encouraging.     

Pivotal Quantities Based on Sequential Data: A Bootstrap Approach

A bootstrap algorithm is provided for obtaining a confidence interval for the mean of a probability distribution when sequential data are considered. For this kind of data the empirical distribution can be biased but its bias is bounded by the coefficient of variation of the stopping rule associated with the sequential procedure. When using this distribution for resampling the validity of the bootstrap approach is established by means of a series expansion of the corresponding pivotal quantity. A simulation study is carried out using Wang and Tsiatis type tests and considering the normal and exponential distributions to generate the data. This study confirms that for moderate coefficients of variation of the stopping rule, the bootstrap method allows adequate confidence intervals for the parameters to be obtained, whichever is the distribution of data.