Intermediate clinical events,surrogate markers and survival

This paper investigates one- and two-sample problems comparing survival times when an individual may experience an intermediate event prior to death or reaching some well defined endpoint. The intermediate event may be polychotomous. Patients experiencing the intermediate event may have an altered survival distribution after the intermediate event. Score tests are derived for testing if the occurrence of the intermediate event actually alters survival. These models have implications for evaluating therapies without randomization as well as strengthening the log rank test for comparing two survival distributions. The exact distribution of the score tests can be found by conditioning on both the waiting time and occurrence of the intermedate event.Deceased     

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.     

Nonparametric Two‐Sample Tests of the Marginal Mark Distribution with Censored Marks

Occasionally, investigators collect auxiliary marks at the time of failure in a clinical study. Because the failure event may be censored at the end of the follow‐up period, these marked endpoints are subject to induced censoring. We propose two new families of two‐sample tests for the null hypothesis of no difference in mark‐scale distribution that allows for arbitrary associations between mark and time. One family of proposed tests is a nonparametric extension of an existing semi‐parametric linear test of the same null hypothesis while a second family of tests is based on novel marked rank processes. Simulation studies indicate that the proposed tests have the desired size and possess adequate statistical power to reject the null hypothesis under a simple change of location in the marginal mark distribution. When the marginal mark distribution has heavy tails, the proposed rank‐based tests can be nearly twice as powerful as linear tests.     

Conditional Studentized Survival Tests for Randomly Censored Models

It is shown that in the case of heterogenous censoring distributions Studentized survival tests can be carried out as conditional permutation tests given the order statistics and their censoring status. The result is based on a conditional central limit theorem for permutation statistics. It holds for linear test statistics as well as for sup-statistics. The procedure works under one of the following general circumstances for the two-sample problem: the unbalanced sample size case, highly censored data, certain non-convergent weight functions or under alternatives. For instance, the two-sample log rank test can be carried out asymptotically as a conditional test if the relative amount of uncensored observations vanishes asymptotically as long as the number of uncensored observations becomes infinite. Similar results hold whenever the sample sizes and are unbalanced in the sense that and hold.     

Weighted log‐rank test for time‐to‐event data in immunotherapy trials with random delayed treatment effect and cure rate

A cancer clinical trial with an immunotherapy often has 2 special features, which are patients being potentially cured from the cancer and the immunotherapy starting to take clinical effect after a certain delay time. Existing testing methods may be inadequate for immunotherapy clinical trials, because they do not appropriately take the 2 features into consideration at the same time, hence have low power to detect the true treatment effect. In this paper, we proposed a piece‐wise proportional hazards cure rate model with a random delay time to fit data, and a new weighted log‐rank test to detect the treatment effect of an immunotherapy over a chemotherapy control. We showed that the proposed weight was nearly optimal under mild conditions. Our simulation study showed a substantial gain of power in the proposed test over the existing tests and robustness of the test with misspecified weight. We also introduced a sample size calculation formula to design the immunotherapy clinical trials using the proposed weighted log‐rank test.     

Design considerations in clinical trials with cure rate survival data: A case study in oncology

For clinical trials with time‐to‐event as the primary endpoint, the clinical cutoff is often event‐driven and the log‐rank test is the most commonly used statistical method for evaluating treatment effect. However, this method relies on the proportional hazards assumption in that it has the maximal power in this circumstance. In certain disease areas or populations, some patients can be curable and never experience the events despite a long follow‐up. The event accumulation may dry out after a certain period of follow‐up and the treatment effect could be reflected as the combination of improvement of cure rate and the delay of events for those uncurable patients. Study power depends on both cure rate improvement and hazard reduction. In this paper, we illustrate these practical issues using simulation studies and explore sample size recommendations, alternative ways for clinical cutoffs, and efficient testing methods with the highest study power possible.     

Rank Tests for Clustered Survival Data

In a clinical trial, we may randomize subjects (called clusters) to different treatments (called groups), and make observations from multiple sites (called units) of each subject. In this case, the observations within each subject could be dependent, whereas those from different subjects are independent. If the outcome of interest is the time to an event, we may use the standard rank tests proposed for independent survival data, such as the logrank and Wilcoxon tests, to test the equality of marginal survival distributions, but their standard error should be modified to accommodate the possible intracluster correlation. In this paper we propose a method of calculating the standard error of the rank tests for two-sample clustered survival data. The method is naturally extended to that for K-sample tests under dependence.     

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.     

A novel test to compare two treatments based on endpoints involving both nonfatal and fatal events

In a clinical trial comparing two treatment groups, one commonly‐used endpoint is time to death. Another is time until the first nonfatal event (if there is one) or until death (if not). Both endpoints have drawbacks. The wrong choice may adversely affect the value of the study by impairing power if deaths are too few (with the first endpoint) or by lessening the role of mortality if not (with the second endpoint). We propose a compromise that provides a simple test based on the time to death if the patient has died or time since randomization augmented by an increment otherwise. The test applies the ordinary two‐sample Wilcoxon statistic to these values. The formula for the increment (the same for experimental and control patients) must be specified before the trial starts. In the simplest (and perhaps most useful) case, the increment assumes only two values, according to whether or not the (surviving) patient had a nonfatal event. More generally, the increment depends on the time of the first nonfatal event, if any, and the time since randomization. The test has correct Type I error even though it does not handle censoring in a customary way. For conditions where investigators would face no easy (advance) choice between the two older tests, simulation results favor the new test. An example using a renal‐cancer trial is presented. Copyright © 2015 John Wiley & Sons, Ltd.     

On bootstrap testing inference in cure rate models

Survival models deal with the time until the occurrence of an event of interest. However, in some situations the event may not occur in part of the studied population. The fraction of the population that will never experience the event of interest is generally called cure rate. Models that consider this fact (cure rate models) have been extensively studied in the literature. Hypothesis testing on the parameters of these models can be performed based on likelihood ratio, gradient, score or Wald statistics. Critical values of these tests are obtained through approximations that are valid in large samples and may result in size distortion in small or moderate sample sizes. In this sense, this paper proposes bootstrap corrections to the four mentioned tests and bootstrap Bartlett correction for the likelihood ratio statistic in the Weibull promotion time model. Besides, we present an algorithm for bootstrap resampling when the data presents cure fraction and right censoring time (random and non-informative). Simulation studies are conducted to compare the finite sample performances of the corrected tests. The numerical evidence favours the corrected tests we propose. We also present an application in an actual data set.     

Comparison of the restricted mean survival time with the hazard ratio in superiority trials with a time‐to‐event end point

With the emergence of novel therapies exhibiting distinct mechanisms of action compared to traditional treatments, departure from the proportional hazard (PH) assumption in clinical trials with a time‐to‐event end point is increasingly common. In these situations, the hazard ratio may not be a valid statistical measurement of treatment effect, and the log‐rank test may no longer be the most powerful statistical test. The restricted mean survival time (RMST) is an alternative robust and clinically interpretable summary measure that does not rely on the PH assumption. We conduct extensive simulations to evaluate the performance and operating characteristics of the RMST‐based inference and against the hazard ratio–based inference, under various scenarios and design parameter setups. The log‐rank test is generally a powerful test when there is evident separation favoring 1 treatment arm at most of the time points across the Kaplan‐Meier survival curves, but the performance of the RMST test is similar. Under non‐PH scenarios where late separation of survival curves is observed, the RMST‐based test has better performance than the log‐rank test when the truncation time is reasonably close to the tail of the observed curves. Furthermore, when flat survival tail (or low event rate) in the experimental arm is expected, selecting the minimum of the maximum observed event time as the truncation timepoint for the RMST is not recommended. In addition, we recommend the inclusion of analysis based on the RMST curve over the truncation time in clinical settings where there is suspicion of substantial departure from the PH assumption.     

A new method for the comparison of survival distributions

The assessment of overall homogeneity of time‐to‐event curves is a key element in survival analysis in biomedical research. The currently commonly used testing methods, e.g. log‐rank test, Wilcoxon test, and Kolmogorov–Smirnov test, may have a significant loss of statistical testing power under certain circumstances. In this paper we propose a new testing method that is robust for the comparison of the overall homogeneity of survival curves based on the absolute difference of the area under the survival curves using normal approximation by Greenwood's formula. Monte Carlo simulations are conducted to investigate the performance of the new testing method compared against the log‐rank, Wilcoxon, and Kolmogorov–Smirnov tests under a variety of circumstances. The proposed new method has robust performance with greater power to detect the overall differences than the log‐rank, Wilcoxon, and Kolmogorov–Smirnov tests in many scenarios in the simulations. Furthermore, the applicability of the new testing approach is illustrated in a real data example from a kidney dialysis trial. Copyright © 2009 John Wiley & Sons, Ltd.     

Non-parametric Tests for Recurrent Events under Competing Risks

Abstract.  We consider a data set on nosocomial infections of patients hospitalized in a French intensive care facility. Patients may suffer from recurrent infections of different types and they also have a high risk of death. To deal with such situations, a model of recurrent events with competing risks and a terminal event is introduced. Our aim was to compare the occurrence rates of two types of events. For this purpose, we propose two tests: one to detect if the occurrence rate of a given type of event increases with time; a second to detect if the instantaneous probability of experiencing an event of a given type is always greater than the one of another type. The asymptotic properties of the test statistics are derived and Monte Carlo methods are used to study the power of the tests. Finally, the procedures developed are applied to the French nosocomial infections data set.     

Inferences from biased samples with a memory effect

Biased sampling occurs often in observational studies. With one biased sample, the problem of nonparametrically estimating both a target density function and a selection bias function is unidentifiable. This paper studies the nonparametric estimation problem when there are two biased samples that have some overlapping observations (i.e. recaptures) from a finite population. Since an intelligent subject sampled previously may experience a memory effect if sampled again, two general 2-stage models that incorporate both a selection bias and a possible memory effect are proposed. Nonparametric estimators of the target density, selection bias, and memory functions, as well as the population size are developed. Asymptotic properties of these estimators are studied and confidence bands for the selection function and memory function are provided. Our procedures are compared with those ignoring the memory effect or the selection bias in finite sample situations. A nonparametric model selection procedure is also given for choosing a model from the two 2-stage models and a mixture of these two models. Our procedures work well with or without a memory effect, and with or without a selection bias. The paper concludes with an application to a real survey data set.     

Some statistical considerations in the clinical development of cancer immunotherapies

Immuno‐oncology has emerged as an exciting new approach to cancer treatment. Common immunotherapy approaches include cancer vaccine, effector cell therapy, and T‐cell–stimulating antibody. Checkpoint inhibitors such as cytotoxic T lymphocyte–associated antigen 4 and programmed death‐1/L1 antagonists have shown promising results in multiple indications in solid tumors and hematology. However, the mechanisms of action of these novel drugs pose unique statistical challenges in the accurate evaluation of clinical safety and efficacy, including late‐onset toxicity, dose optimization, evaluation of combination agents, pseudoprogression, and delayed and lasting clinical activity. Traditional statistical methods may not be the most accurate or efficient. It is highly desirable to develop the most suitable statistical methodologies and tools to efficiently investigate cancer immunotherapies. In this paper, we summarize these issues and discuss alternative methods to meet the challenges in the clinical development of these novel agents. For safety evaluation and dose‐finding trials, we recommend the use of a time‐to‐event model‐based design to handle late toxicities, a simple 3‐step procedure for dose optimization, and flexible rule‐based or model‐based designs for combination agents. For efficacy evaluation, we discuss alternative endpoints/designs/tests including the time‐specific probability endpoint, the restricted mean survival time, the generalized pairwise comparison method, the immune‐related response criteria, and the weighted log‐rank or weighted Kaplan‐Meier test. The benefits and limitations of these methods are discussed, and some recommendations are provided for applied researchers to implement these methods in clinical practice.     

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.     

Subgroup Analysis with Time‐to‐Event Data Under a Logistic‐Cox Mixture Model

Subgroup detection has received increasing attention recently in different fields such as clinical trials, public management and market segmentation analysis. In these fields, people often face time‐to‐event data, which are commonly subject to right censoring. This paper proposes a semiparametric Logistic‐Cox mixture model for subgroup analysis when the interested outcome is event time with right censoring. The proposed method mainly consists of a likelihood ratio‐based testing procedure for testing the existence of subgroups. The expectation–maximization iteration is applied to improve the testing power, and a model‐based bootstrap approach is developed to implement the testing procedure. When there exist subgroups, one can also use the proposed model to estimate the subgroup effect and construct predictive scores for the subgroup membership. The large sample properties of the proposed method are studied. The finite sample performance of the proposed method is assessed by simulation studies. A real data example is also provided for illustration.     

Testing nonparametric statistical functionals with applications to rank tests

The present paper discusses how nonparametric tests can be deduced from statistical functionals. Efficient and asymptotically most powerful maximin tests are derived. Their power function is calculated under implicit alternatives given by the functional for one – and two – sample testing problems. It is shown that the asymptotic power function does not depend on the special implicit direction of the alternatives but only on quantities of the functional. The present approach offers a nonparametric principle how to construct common rank tests as the Wilcoxon test, the log rank test, and the median test from special two-sample functionals. In addition it is shown that studentized permutation tests yield asymptotically valid tests for certain extended null hypotheses given by functionals which are strictly larger than the common i.i.d. null hypothesis. As example tests concerning the von Mises functional and the Wilcoxon two-sample test are treated.     

Asymptotic power efficiency for a location and scale problem

The asymptotic power efficiency of the class of linear rank tests relative to the asymptotically most powerful rank test is derived for a two sample location and scale problem and numerical evaluations are presented for two special tests.