Secondary design considerations for minimum bias estimation

Several authors have suggested the method of minimum bias estimation for estimating response surfaces. The minimum bias estimation procedure achieves minimum average squared bias of the fitted model without depending on the values of the unknown parameters of the true surface. The only requirement is that the design satisfies a simple estimability condition. Subject to providing minimum average squared bias, the minimum bias estimator also provides minimum average variance of ?(x) where ?(x) is the estimate of the response at the point x.

To support the estimation of the parameters in the fitted model, very little has been suggested in the way of experimental designs except to say that a full rank matrix X of independent variables should be used. This paper presents a closer look at the estimability conditions that are required for minimum bias estimation, and from the form of the matrix X, a formula is derived which measures the amount of design flexibility available. The design flexibility is termed “the degrees of freedom” of the X matrix and it is shown how the degrees of freedom can be used to decide if other design optimality criteria might be considered along with minimum bias estimation. Several examples are provided.     

A Stepwise Confidence Interval Procedure Under Unknown Variances Based on an Asymmetric Loss Function for Toxicological Evaluation

One of the most important issues in toxicity studies is the identification of the equivalence of treatments with a placebo. Because it is unacceptable to declare non‐equivalent treatments to be equivalent, it is important to adopt a reliable statistical method to properly control the family‐wise error rate (FWER). In dealing with this issue, it is important to keep in mind that overestimating toxicity equivalence is a more serious error than underestimating toxicity equivalence. Consequently asymmetric loss functions are more appropriate than symmetric loss functions. Recently Tao, Tang & Shi (2010) developed a new procedure based on an asymmetric loss function. However, their procedure is somewhat unsatisfactory because it assumes that the variances of various dose levels are known. This assumption is restrictive for some applications. In this study we propose an improved approach based on asymmetric confidence intervals without the restrictive assumption of known variances. The asymmetry guarantees reliability in the sense that the FWER is well controlled. Although our procedure is developed assuming that the variances of various dose levels are unknown but equal, simulation studies show that our procedure still performs quite well when the variances are unequal.     

Bayesian adaptive linearization method for phase I drug combination trials with dimension reduction

Many phase I drug combination designs have been proposed to find the maximum tolerated combination (MTC). Due to the two‐dimension nature of drug combination trials, these designs typically require complicated statistical modeling and estimation, which limit their use in practice. In this article, we propose an easy‐to‐implement Bayesian phase I combination design, called Bayesian adaptive linearization method (BALM), to simplify the dose finding for drug combination trials. BALM takes the dimension reduction approach. It selects a subset of combinations, through a procedure called linearization, to convert the two‐dimensional dose matrix into a string of combinations that are fully ordered in toxicity. As a result, existing single‐agent dose‐finding methods can be directly used to find the MTC. In case that the selected linear path does not contain the MTC, a dose‐insertion procedure is performed to add new doses whose expected toxicity rate is equal to the target toxicity rate. Our simulation studies show that the proposed BALM design performs better than competing, more complicated combination designs.     

Reducing Bias and Mean Squared Error Associated With Regression-Based Odds Ratio Estimators

Ratio estimators of effect are ordinarily obtained by exponentiating maximum-likelihood estimators (MLEs) of log-linear or logistic regression coefficients. These estimators can display marked positive finite-sample bias, however. We propose a simple correction that removes a substantial portion of the bias due to exponentiation. By combining this correction with bias correction on the log scale, we demonstrate that one achieves complete removal of second-order bias in odds ratio estimators in important special cases. We show how this approach extends to address bias in odds or risk ratio estimators in many common regression settings. We also propose a class of estimators that provide reduced mean bias and squared error, while allowing the investigator to control the risk of underestimating the true ratio parameter. We present simulation studies in which the proposed estimators are shown to exhibit considerable reduction in bias, variance, and mean squared error compared to MLEs. Bootstrapping provides further improvement, including narrower confidence intervals without sacrificing coverage.     

Effect of design specifications in dose‐finding trials for combination therapies in oncology

Model‐based dose‐finding methods for a combination therapy involving two agents in phase I oncology trials typically include four design aspects namely, size of the patient cohort, three‐parameter dose‐toxicity model, choice of start‐up rule, and whether or not to include a restriction on dose‐level skipping. The effect of each design aspect on the operating characteristics of the dose‐finding method has not been adequately studied. However, some studies compared the performance of rival dose‐finding methods using design aspects outlined by the original studies. In this study, we featured the well‐known four design aspects and evaluated the impact of each independent effect on the operating characteristics of the dose‐finding method including these aspects. We performed simulation studies to examine the effect of these design aspects on the determination of the true maximum tolerated dose combinations as well as exposure to unacceptable toxic dose combinations. The results demonstrated that the selection rates of maximum tolerated dose combinations and UTDCs vary depending on the patient cohort size and restrictions on dose‐level skipping However, the three‐parameter dose‐toxicity models and start‐up rules did not affect these parameters. Copyright © 2016 John Wiley & Sons, Ltd.     

Estimation procedures for grouped data – a comparative study

Interval-censored data are very common in the reliability and lifetime data analysis. This paper investigates the performance of different estimation procedures for a special type of interval-censored data, i.e. grouped data, from three widely used lifetime distributions. The approaches considered here include the maximum likelihood estimation, the minimum distance estimation based on chi-square criterion, the moment estimation based on imputation (IM) method and an ad hoc estimation procedure. Although IM-based techniques are extensively used recently, we show that this method is not always effective. It is found that the ad hoc estimation procedure is equivalent to the minimum distance estimation with another distance metric and more effective in the simulation. The procedures of different approaches are presented and their performances are investigated by Monte Carlo simulation for various combinations of sample sizes and parameter settings. The numerical results provide guidelines to analyse grouped data for practitioners when they need to choose a good estimation approach.     

Estimating Archimedean Copulas in High Dimensions

Abstract. This article presents a novel estimation procedure for high‐dimensional Archimedean copulas. In contrast to maximum likelihood estimation, the method presented here does not require derivatives of the Archimedean generator. This is computationally advantageous for high‐dimensional Archimedean copulas in which higher‐order derivatives are needed but are often difficult to obtain. Our procedure is based on a parameter‐dependent transformation of the underlying random variables to a one‐dimensional distribution where a minimum‐distance method is applied. We show strong consistency of the resulting minimum‐distance estimators to the case of known margins as well as to the case of unknown margins when pseudo‐observations are used. Moreover, we conduct a simulation comparing the performance of the proposed estimation procedure with the well‐known maximum likelihood approach according to bias and standard deviation.     

Bayesian adaptive dose‐escalation designs for simultaneously estimating the optimal and maximum safe dose based on safety and efficacy

The main purpose of dose‐escalation trials is to identify the dose(s) that is/are safe and efficacious for further investigations in later studies. In this paper, we introduce dose‐escalation designs that incorporate both the dose‐limiting events and dose‐limiting toxicities (DLTs) and indicative responses of efficacy into the procedure. A flexible nonparametric model is used for modelling the continuous efficacy responses while a logistic model is used for the binary DLTs. Escalation decisions are based on the combination of the probabilities of DLTs and expected efficacy through a gain function. On the basis of this setup, we then introduce 2 types of Bayesian adaptive dose‐escalation strategies. The first type of procedures, called “single objective,” aims to identify and recommend a single dose, either the maximum tolerated dose, the highest dose that is considered as safe, or the optimal dose, a safe dose that gives optimum benefit risk. The second type, called “dual objective,” aims to jointly estimate both the maximum tolerated dose and the optimal dose accurately. The recommended doses obtained under these dose‐escalation procedures provide information about the safety and efficacy profile of the novel drug to facilitate later studies. We evaluate different strategies via simulations based on an example constructed from a real trial on patients with type 2 diabetes, and the use of stopping rules is assessed. We find that the nonparametric model estimates the efficacy responses well for different underlying true shapes. The dual‐objective designs give better results in terms of identifying the 2 real target doses compared to the single‐objective designs.     

Penalized Composite Quasi-Likelihood for Ultrahigh-Dimensional Variable Selection

In high-dimensional model selection problems, penalized least-square approaches have been extensively used. This paper addresses the question of both robustness and efficiency of penalized model selection methods, and proposes a data-driven weighted linear combination of convex loss functions, together with weighted L(1)-penalty. It is completely data-adaptive and does not require prior knowledge of the error distribution. The weighted L(1)-penalty is used both to ensure the convexity of the penalty term and to ameliorate the bias caused by the L(1)-penalty. In the setting with dimensionality much larger than the sample size, we establish a strong oracle property of the proposed method that possesses both the model selection consistency and estimation efficiency for the true non-zero coefficients. As specific examples, we introduce a robust method of composite L1-L2, and optimal composite quantile method and evaluate their performance in both simulated and real data examples.     

Adaptive Isotonic Estimation of the Minimum Effective and Peak Doses in the Presence of Covariates

We consider a problem of estimating the minimum effective and peak doses in the presence of covariates. We propose a sequential strategy for subject assignment that includes an adaptive randomization component to balance the allocation to placebo and active doses with respect to covariates. We conclude that either adjusting for covariates in the model or balancing allocation with respect to covariates is required to avoid bias in the target dose estimation. We also compute optimal allocation to estimate the minimum effective and peak doses in discrete dose space using isotonic regression.     

Comparison of estimation methods for the Marshall–Olkin extended Lindley distribution

The aim of this paper is to compare the parameters' estimations of the Marshall–Olkin extended Lindley distribution obtained by six estimation methods: maximum likelihood, ordinary least-squares, weighted least-squares, maximum product of spacings, Cramér–von Mises and Anderson–Darling. The bias, root mean-squared error, average absolute difference between the true and estimate distributions' functions and the maximum absolute difference between the true and estimate distributions' functions are used as comparison criteria. Although the maximum product of spacings method is not widely used, the simulation study concludes that it is highly competitive with the maximum likelihood method.     

Regression‐type models for extremal dependence

We propose a vector generalized additive modeling framework for taking into account the effect of covariates on angular density functions in a multivariate extreme value context. The proposed methods are tailored for settings where the dependence between extreme values may change according to covariates. We devise a maximum penalized log‐likelihood estimator, discuss details of the estimation procedure, and derive its consistency and asymptotic normality. The simulation study suggests that the proposed methods perform well in a wealth of simulation scenarios by accurately recovering the true covariate‐adjusted angular density. Our empirical analysis reveals relevant dynamics of the dependence between extreme air temperatures in two alpine resorts during the winter season.     

Estimating and comparing adverse event probabilities in the presence of varying follow-up times and competing events

Safety analyses of adverse events (AEs) are important in assessing benefit–risk of therapies but are often rather simplistic compared to efficacy analyses. AE probabilities are typically estimated by incidence proportions, sometimes incidence densities or Kaplan–Meier estimation are proposed. These analyses either do not account for censoring, rely on a too restrictive parametric model, or ignore competing events. With the non-parametric Aalen-Johansen estimator as the “gold standard”, that is, reference estimator, potential sources of bias are investigated in an example from oncology and in simulations, for both one-sample and two-sample scenarios. The Aalen-Johansen estimator serves as a reference, because it is the proper non-parametric generalization of the Kaplan–Meier estimator to multiple outcomes. Because of potential large variances at the end of follow-up, comparisons also consider further quantiles of the observed times. To date, consequences for safety comparisons have hardly been investigated, the impact of using different estimators for group comparisons being unclear. For example, the ratio of two both underestimating or overestimating estimators may not be comparable to the ratio of the reference, and our investigation also considers the ratio of AE probabilities. We find that ignoring competing events is more of a problem than falsely assuming constant hazards by the use of the incidence density and that the choice of the AE probability estimator is crucial for group comparisons.     

Specifications of a continual reassessment method design for phase I trials of combined drugs

In studies of combinations of agents in phase I oncology trials, the dose–toxicity relationship may not be monotone for all combinations, in which case the toxicity probabilities follow a partial order. The continual reassessment method for partial orders (PO‐CRM) is a design for phase I trials of combinations that leans upon identifying possible complete orders associated with the partial order. This article addresses some practical design considerations not previously undertaken when describing the PO‐CRM. We describe an approach in choosing a proper subset of possible orderings, formulated according to the known toxicity relationships within a matrix of combination therapies. Other design issues, such as working model selection and stopping rules, are also discussed. We demonstrate the practical ability of PO‐CRM as a phase I design for combinations through its use in a recent trial designed at the University of Virginia Cancer Center. Copyright © 2013 John Wiley & Sons, Ltd.     

Iterative Bias Correction of the Cross‐Validation Criterion

Abstract. The cross‐validation (CV) criterion is known to be asecond‐order unbiased estimator of the risk function measuring the discrepancy between the candidate model and the true model, as well as the generalized information criterion (GIC) and the extended information criterion (EIC). In the present article, we show that the 2kth‐order unbiased estimator can be obtained using a linear combination from the leave‐one‐out CV criterion to the leave‐k‐out CV criterion. The proposed scheme is unique in that a bias smaller than that of a jackknife method can be obtained without any analytic calculation, that is, it is not necessary to obtain the explicit form of several terms in an asymptotic expansion of the bias. Furthermore, the proposed criterion can be regarded as a finite correction of a bias‐corrected CV criterion by using scalar coefficients in a bias‐corrected EIC obtained by the bootstrap iteration.     

A comparison of estimation techniques for the three parameter pareto distribution

This paper compares minimum distance estimation with best linear unbiased estimation to determine which technique provides the most accurate estimates for location and scale parameters as applied to the three parameter Pareto distribution. Two minimum distance estimators are developed for each of the three distance measures used (Kolmogorov, Cramer‐von Mises, and Anderson‐Darling) resulting in six new estimators. For a given sample size 6 or 18 and shape parameter 1(1)4, the location and scale parameters are estimated. A Monte Carlo technique is used to generate the sample sets. The best linear unbiased estimator and the six minimum distance estimators provide parameter estimates based on each sample set. These estimates are compared using mean square error as the evaluation tool. Results show that the best linear unbaised estimator provided more accurate estimates of location and scale than did the minimum estimators tested.     

ASYMPTOTIC DISTRIBUTIONS OF SEMIPARAMETRIC MAXIMUM LIKELIHOOD ESTIMATORS WITH ESTIMATING EQUATIONS FOR GROUP-CENSORED DATA

Semiparametric maximum likelihood estimation with estimating equations (SMLE) is more flexible than traditional methods; it has fewer restrictions on distributions and regression models. The required information about distribution and regression structures is incorporated in estimating equations of the SMLE to improve the estimation quality of non‐parametric methods. The likelihood of SMLE for censored data involves complicated implicit functions without closed‐form expressions, and the first derivatives of the log‐profile‐likelihood cannot be expressed as summations of independent and identically distributed random variables; it is challenging to derive asymptotic properties of the SMLE for censored data. For group‐censored data, the paper shows that all the implicit functions are well defined and obtains the asymptotic distributions of the SMLE for model parameters and lifetime distributions. With several examples the paper compares the SMLE, the regular non‐parametric likelihood estimation method and the parametric MLEs in terms of their asymptotic efficiencies, and illustrates application of SMLE. Various asymptotic distributions of the likelihood ratio statistics are derived for testing the adequacy of estimating equations and a partial set of parameters equal to some known values.     

A Comparison of Estimation Methods on the Coverage Probability of Satterthwaite Confidence Intervals for Assay Precision with Unbalanced Data

Construction of closed-form confidence intervals on linear combinations of variance components were developed generically for balanced data and studied mainly for one-way and two-way random effects analysis of variance models. The Satterthwaite approach is easily generalized to unbalanced data and modified to increase its coverage probability. They are applied on measures of assay precision in combination with (restricted) maximum likelihood and Henderson III Type 1 and 3 estimation. Simulations of interlaboratory studies with unbalanced data and with small sample sizes do not show superiority of any of the possible combinations of estimation methods and Satterthwaite approaches on three measures of assay precision. However, the modified Satterthwaite approach with Henderson III Type 3 estimation is often preferred above the other combinations.     

Survivor Function Estimators Under Group Sequential Monitoring Based on the Logrank Statistic

In this paper we investigate a group sequential analysis of censored survival data with staggered entry, in which the trial is monitored using the logrank test while comparisons of treatment and control Kaplan-Meier curves at various time points are performed at the end of the trial. We concentrate on two-sample tests under local alternatives. We describe the relationship of the asymptotic bias of Kaplan-Meier curves between the two groups. We show that even if the asymptotic bias of the Kaplan-Meier curve is negligible relative to the true survival, this is not the case for the difference between the curves of the two arms of the trial. A corrected estimator for the difference between the survival curves is presented and by simulations we show that the corrected estimator reduced the bias dramatically and has a smaller variance. The methods of estimation are applied to the Beta-Blocker Heart Attack Trial (1982), a well-known group sequential trial.