Development of predictive signatures for treatment selection in precision medicine with survival outcomes

For survival endpoints in subgroup selection, a score conversion model is often used to convert the set of biomarkers for each patient into a univariate score and using the median of the univariate scores to divide the patients into biomarker‐positive and biomarker‐negative subgroups. However, this may lead to bias in patient subgroup identification regarding the 2 issues: (1) treatment is equally effective for all patients and/or there is no subgroup difference; (2) the median value of the univariate scores as a cutoff may be inappropriate if the sizes of the 2 subgroups are differ substantially. We utilize a univariate composite score method to convert the set of patient's candidate biomarkers to a univariate response score. We propose applying the likelihood ratio test (LRT) to assess homogeneity of the sampled patients to address the first issue. In the context of identification of the subgroup of responders in adaptive design to demonstrate improvement of treatment efficacy (adaptive power), we suggest that subgroup selection is carried out if the LRT is significant. For the second issue, we utilize a likelihood‐based change‐point algorithm to find an optimal cutoff. Our simulation study shows that type I error generally is controlled, while the overall adaptive power to detect treatment effects sacrifices approximately 4.5% for the simulation designs considered by performing the LRT; furthermore, the change‐point algorithm outperforms the median cutoff considerably when the subgroup sizes differ substantially.     

Response‐adaptive designs for binary responses: How to offer patient benefit while being robust to time trends?

Response‐adaptive randomisation (RAR) can considerably improve the chances of a successful treatment outcome for patients in a clinical trial by skewing the allocation probability towards better performing treatments as data accumulates. There is considerable interest in using RAR designs in drug development for rare diseases, where traditional designs are not either feasible or ethically questionable. In this paper, we discuss and address a major criticism levelled at RAR: namely, type I error inflation due to an unknown time trend over the course of the trial. The most common cause of this phenomenon is changes in the characteristics of recruited patients—referred to as patient drift. This is a realistic concern for clinical trials in rare diseases due to their lengthly accrual rate. We compute the type I error inflation as a function of the time trend magnitude to determine in which contexts the problem is most exacerbated. We then assess the ability of different correction methods to preserve type I error in these contexts and their performance in terms of other operating characteristics, including patient benefit and power. We make recommendations as to which correction methods are most suitable in the rare disease context for several RAR rules, differentiating between the 2‐armed and the multi‐armed case. We further propose a RAR design for multi‐armed clinical trials, which is computationally efficient and robust to several time trends considered.     

Financial liberalization and long-run stability of money demand in Nigeria

A stable money demand function is essential when using monetary aggregate as a monetary policy. Thus, there is need to examine the stability of the money demand function in Nigeria after the deregulation of the financial sector. To achieve this, the study employed CUSUM (cumulative sum) and CUSUMSQ (CUSUM of square) tests after using autoregressive distributive lag bounds test to determine the existence of a long run relationship between monetary aggregates and their determinants. Results of the study show that a long-run relationship holds and that the demand for money is stable in Nigeria. In addition, the inflation rate is found to be a better proxy for an opportunity variable when compared to interest rate. The main implication of the study is that interest rate is ineffective as a monetary policy instrument in Nigeria.     

Estimation and simulation of conditional hazard function in the quasi-associated framework when the observations are linked via a functional single-index structure

We consider the estimation of the conditional hazard function of a scalar response variable Y given a Hilbertian random variable X when the observations are linked via a single-index structure in the quasi-associated framework. We establish the pointwise almost complete convergence and the uniform almost complete convergence (with the rate) of the estimate of this model. A simulation is given to illustrate the good behavior in the practice of our methodology.     

Likelihood ratio tests for multivariate normality

This paper presents some powerful omnibus tests for multivariate normality based on the likelihood ratio and the characterizations of the multivariate normal distribution. The power of the proposed tests is studied against various alternatives via Monte Carlo simulations. Simulation studies show our tests compare well with other powerful tests including multivariate versions of the Shapiro–Wilk test and the Anderson–Darling test.     

An update on ‘a comparative study of tests for homogeneity of variance’

Tests for equality of variances using independent samples are widely used in data analysis. Conover et al. [A comparative study of tests for homogeneity of variance, with applications to the outer continental shelf bidding data. Technometrics. 1981;23:351–361], won the Youden Prize by comparing 56 variations of popular tests for variance on the basis of robustness and power in 60 different scenarios. None of the tests they compared were robust and powerful for the skewed distributions they considered. This study looks at 12 variations they did not consider, and shows that 10 are robust for the skewed distributions they considered plus the lognormal distribution, which they did not study. Three of these 12 have clearly superior power for skewed distributions, and are competitive in terms of robustness and power for all of the distributions considered. They are recommended for general use based on robustness, power, and ease of application.     

Statistical considerations in clinical trial design with event-free survival as the primary efficacy endpoint

In late-phase confirmatory clinical trials in the oncology field, time-to-event (TTE) endpoints are commonly used as primary endpoints for establishing the efficacy of investigational therapies. Among these TTE endpoints, overall survival (OS) is always considered as the gold standard. However, OS data can take years to mature, and its use for measurement of efficacy can be confounded by the use of post-treatment rescue therapies or supportive care. Therefore, to accelerate the development process and better characterize the treatment effect of new investigational therapies, other TTE endpoints such as progression-free survival and event-free survival (EFS) are applied as primary efficacy endpoints in some confirmatory trials, either as a surrogate for OS or as a direct measure of clinical benefits. For evaluating novel treatments for acute myeloid leukemia, EFS has been gradually recognized as a direct measure of clinical benefits. However, the application of an EFS endpoint is still controversial mainly due to the debate surrounding definition of treatment failure (TF) events. In this article, we investigate the EFS endpoint with the most conservative definition for the timing of TF, which is Day 1 since randomization. Specifically, the corresponding non-proportional hazard pattern of the EFS endpoint is investigated with both analytical and numerical approaches.     

Multivariate Approach for Comparative Evaluations of Customer Satisfaction with Application to Transport Services

In problems related to evaluations of products or services (e.g. in customer satisfaction analysis) the main difficulties concern the synthesis of the information, which is necessary for the presence of several evaluators and many response variables (aspects under evaluation). In this article, the problem of determining and comparing the satisfaction of different groups of customers, in the presence of multivariate response variables and using the results of pairwise comparisons is addressed. Within the framework of group ranking methods and multi criteria decision making theory, a new approach, based on nonparametric techniques, for evaluating group satisfaction in a multivariate framework is proposed and the concept of Multivariate Relative Satisfaction is defined. An application to the evaluation of public transport services, like the railway service and the urban bus service, by students of the University of Ferrara (Italy) is also discussed.     

Estimation of error probabilities in stochastic dominance

The process of using data to infer the existence of stochastic dominance is subject to sampling error. Kroll and Levy (1980), among others, have presented simulation results for several normal and lognormal distributions which show high error probabilities for a wide range of parameter values. This paper continues this line of research and uses simulation to estimate error probabilities. Distributions considered are a pair of normals and a pair of lognormals. Analysis of these distributions is made computationally feasible through theoretical results which reduce the number of parameters of the pair of distributions from four to two.     

A robust test for autocorrelation in the presence of a structural break in variance

It has been known that when there is a break in the variance (unconditional heteroskedasticity) of the error term in linear regression models, a routine application of the Lagrange multiplier (LM) test for autocorrelation can cause potentially significant size distortions. We propose a new test for autocorrelation that is robust in the presence of a break in variance. The proposed test is a modified LM test based on a generalized least squares regression. Monte Carlo simulations show that the new test performs well in finite samples and it is especially comparable to other existing heteroskedasticity-robust tests in terms of size, and much better in terms of power.