Exploratory assessment of dose proportionality: review of current approaches and proposal for a practical criterion

This article reviews currently used approaches for establishing dose proportionality in Phase I dose escalation studies. A review of relevant literature between 2002 and 2006 found that the power model was the preferred choice for assessing dose proportionality in about one-third of the articles. This article promotes the use of the power model and a conceptually appealing extension, i.e. a criterion based on comparing the 90% confidence interval for the ratio of predicted mean values from the extremes of the dose range (R(dnm)) to pre-defined equivalence criterion (theta(L),theta(U)). The choice of bioequivalence default values of theta(L)=0.8 and theta(U)=1.25 seems reasonable for dose levels only a doubling apart but are impractically strict when applied over the complete dose range. Power calculations are used to show that this prescribed criterion lacks power to conclude dose proportionality in typical Phase I dose-escalation studies. A more lenient criterion with values theta(L)=0.5 and theta(U)=2 is proposed for exploratory dose proportionality assessments across the complete dose range.     

Tests for the Proportional Intensity Assumption Based on the Score Process

Proportional intensity models are widely used for describing the relationship between the intensity of a counting process and associated covariates. A basic assumption in this model is the proportionality, that each covariate has a multiplicative effect on the intensity. We present and study tests for this assumption based on a score process which is equivalent to cumulative sums of the Schoenfeld residuals. Tests within principle power against any type of departure from proportionality can be constructed based on this score process. Among the tests studied, in particular an Anderson-Darling type test turns out to be very useful by having good power properties against general alternatives. A simulation study comparing various tests for proportionality indicates that this test seems to be a good choice for an omnibus test for proportionality.     

Sample size calculation for the Power Model for dose proportionality studies

There are several approaches to assess or demonstrate pharmacokinetic dose proportionality. One statistical method is the traditional ANOVA model, where dose proportionality is evaluated using the bioequivalence limits. A more informative method is the mixed effects Power Model, where dose proportionality is assessed using a decision rule for the estimated slope. Here we propose analytical derivations of sample sizes for various designs (including crossover, incomplete block and parallel group designs) to be analysed according to the Power Model.     

Power-divergence-type measure of departure from symmetry for square contingency tables that have nominal categories

For square contingency tables that have nominal categories, Tomizawa considered two kinds of measure to represent the degree of departure from symmetry. This paper proposes a generalization of those measures. The proposed measure is expressed by using the average of the power divergence of Cressie and Read, or the average of the diversity index of Patil and Taillie. Special cases of the proposed measure include Tomizawa's measures. The proposed measure would be useful for comparing the degree of departure from symmetry in several tables.     

Efficient Estimation of the Seemingly Unrelated Regression Cointegration Model and Testing for Purchasing Power Parity

This paper studies the efficient estimation of seemingly unrelated linear models with integrated regressors and stationary errors. We consider two cases. The first one has no common regressor among the equations. In this case, we show that by adding leads and lags of the first differences of the regressors and estimating this augmented dynamic regression model by generalized least squares using the long-run covariance matrix, we obtain an efficient estimator of the cointegrating vector that has a limiting mixed normal distribution. In the second case we consider, there is a common regressor to all equations, and we discuss efficient minimum distance estimation in this context. Simulation results suggests that our new estimator compares favorably with others already proposed in the literature. We apply these new estimators to the testing of the proportionality and symmetry conditions implied by purchasing power parity (PPP) among the G-7 countries. The tests based on the efficient estimates easily reject the joint hypotheses of proportionality and symmetry for all countries with either the United States or Germany as numeraire. Based on individual tests, our results suggest that Canada and Germany are the most likely countries for which the proportionality condition holds, and that Italy and Japan for the symmetry condition relative to the United States.     

Estimation of the Parameters of the Birnbaum–Saunders Distribution

Some alternative estimators to the maximum likelihood estimators of the two parameters of the Birnbaum–Saunders distribution are proposed. Most have high efficiencies as measured by root mean square error and are robust to departure from the model as well as to outliers. In addition, the proposed estimators are easy to compute. Both complete and right-censored data are discussed. Simulation studies are provided to compare the performance of the estimators.     

An efficient analysis of covariance model for crossover thorough QT studies with period‐specific pre‐dose baselines

Baseline adjustment is an important consideration in thorough QT studies for non‐antiarrhythmic drugs. For crossover studies with period‐specific pre‐dose baselines, we propose a by‐time‐point analysis of covariance model with change from pre‐dose baseline as response, treatment as a fixed effect, pre‐dose baseline for current treatment and pre‐dose baseline averaged across treatments as covariates, and subject as a random effect. Additional factors such as period and sex should be included in the model as appropriate. Multiple pre‐dose measurements can be averaged to obtain a pre‐dose‐averaged baseline and used in the model. We provide conditions under which the proposed model is more efficient than other models. We demonstrate the efficiency and robustness of the proposed model both analytically and through simulation studies. The advantage of the proposed model is also illustrated using the data from a real clinical trial. Copyright © 2014 John Wiley & Sons, Ltd.     

Collective versus Individual Effects in Survival Analysis of Multiple Failures

In survival analysis, we sometimes encounter data with multiple censored outcomes. Under certain scenarios, partial or even all covariates have ‘similar’ relative risks on the multiple outcomes in the Cox regression analysis. The similarity in covariate effects can be quantified using the proportionality of regression coefficients. Identifying the proportionality structure, or equivalently whether covariates have individual or collective effects, may have important scientific implications. In addition, it can lead to a smaller set of unknown parameters, which in turn results in more accurate estimation. In this article, we develop a novel approach for identifying the proportionality structure. Simulation shows the satisfactory performance of the proposed approach and its advantage over estimation under no assumed structure. We analyse three datasets to demonstrate the practical application of the proposed approach.     

Efficient Estimation of the Seemingly Unrelated Regression Cointegration Model and Testing for Purchasing Power Parity

Abstract

This paper studies the efficient estimation of seemingly unrelated linear models with integrated regressors and stationary errors. We consider two cases. The first one has no common regressor among the equations. In this case, we show that by adding leads and lags of the first differences of the regressors and estimating this augmented dynamic regression model by generalized least squares using the long-run covariance matrix, we obtain an efficient estimator of the cointegrating vector that has a limiting mixed normal distribution. In the second case we consider, there is a common regressor to all equations, and we discuss efficient minimum distance estimation in this context. Simulation results suggests that our new estimator compares favorably with others already proposed in the literature. We apply these new estimators to the testing of the proportionality and symmetry conditions implied by purchasing power parity (PPP) among the G-7 countries. The tests based on the efficient estimates easily reject the joint hypotheses of proportionality and symmetry for all countries with either the United States or Germany as numeraire. Based on individual tests, our results suggest that Canada and Germany are the most likely countries for which the proportionality condition holds, and that Italy and Japan for the symmetry condition relative to the United States.     

Power-divergence-type measure of departure from diagonals-parameter symmetry for square contingency tables with ordered categories

For the analysis of square contingency tables with ordered categories, Goodman considered the diagonals-parameter symmetry (DPS) model. This paper proposes a measure to represent the degree of departure from the DPS model. The proposed measure is expressed by applying Read and Cressie’s power-divergence or Patil and Taillie’s diversity index. The measure would be useful for comparing the degree of departure from the DPS model in several tables. Examples are given.     

A Note on the Estimate of Treatment Effect from a Cox Regression Model When the Proportionality Assumption Is Violated

ABSTRACT

Cox proportional hazards regression model has been widely used to estimate the effect of a prognostic factor on a time-to-event outcome. In a survey of survival analyses in cancer journals, it was found that only 5% of studies using Cox proportional hazards model attempted to verify the underlying assumption. Usually an estimate of the treatment effect from fitting a Cox model was reported without validation of the proportionality assumption. It is not clear how such an estimate should be interpreted if the proportionality assumption is violated. In this article, we show that the estimate of treatment effect from a Cox regression model can be interpreted as a weighted average of the log-scaled hazard ratio over the duration of study. A hypothetic example is used to explain the weights.     

Measure of departure from conditional marginal homogeneity for square contingency tables with ordered categories

For the analysis of square contingency tables with ordered categories, Tomizawa et al. (S. Tomizawa, N. Miyamoto, and N. Ashihara, Measure of departure from marginal homogeneity for square contingency tables having ordered categories, Behaviormetrika 30 (2003), pp. 173–193.) and Tahata et al. (K. Tahata, T. Iwashita, and S. Tomizawa, Measure of departure from symmetry of cumulative marginal probabilities for square contingency tables with ordered categories, SUT J. Math., 42 (2006), pp. 7–29.) considered the measures which represent the degree of departure from the marginal homogeneity (MH) model. The present paper proposes a measure that represents the degree of departure from the conditional MH, given that an observation will fall in one of the off-diagonal cells of the table. The measure proposed is expressed by using the Cressie–Read power-divergence or the Patil–Taillie diversity index, which is applied for the conditional cumulative marginal probabilities given that an observation will fall in one of the off-diagonal cells of the table. When the MH model does not hold, the measure is useful for seeing how far the conditional cumulative marginal probabilities are from those with an MH structure and for comparing the degree of departure from MH in several tables. Examples are given.     

Robust integer-valued designs for linear random intercept models

This article considers the robust design problem for linear random intercept models with both departures from fixed effects and correlated errors on a finite design space. Two strategies are proposed. One is a worst-case method minimizing the maximum value of the MSE of estimates for the fixed effects over the departure. The other is an average-case method minimizing the average value of the MSE with respect to some priors for the class of departure functions and correlation structures of random errors. Two examples are given to show robust designs for two polynomial models.     

Measure of departure from symmetry for the analysis of collapsed square contingency tables with ordered categories

For square contingency tables with ordered categories, there may be some cases that one wants to analyze them by considering collapsed tables with some adjacent categories combined in the original table. This paper considers the symmetry model for collapsed square contingency tables and proposes a measure to represent the degree of departure from symmetry. The proposed measure is defined as the arithmetic mean of submeasures each of which represents the degree of departure from symmetry for each collapsed 3×3 table. Each submeasure also represents the mean of power-divergence or diversity index for each collapsed table. Examples are given.     

Incorporating historical information to improve dose optimization design with toxicity and efficacy endpoints: iBOIN-ET

In modern oncology drug development, adaptive designs have been proposed to identify the recommended phase 2 dose. The conventional dose finding designs focus on the identification of maximum tolerated dose (MTD). However, designs ignoring efficacy could put patients under risk by pushing to the MTD. Especially in immuno-oncology and cell therapy, the complex dose-toxicity and dose-efficacy relationships make such MTD driven designs more questionable. Additionally, it is not uncommon to have data available from other studies that target on similar mechanism of action and patient population. Due to the high variability from phase I trial, it is beneficial to borrow historical study information into the design when available. This will help to increase the model efficiency and accuracy and provide dose specific recommendation rules to avoid toxic dose level and increase the chance of patient allocation at potential efficacious dose levels. In this paper, we propose iBOIN-ET design that uses prior distribution extracted from historical studies to minimize the probability of decision error. The proposed design utilizes the concept of skeleton from both toxicity and efficacy data, coupled with prior effective sample size to control the amount of historical information to be incorporated. Extensive simulation studies across a variety of realistic settings are reported including a comparison of iBOIN-ET design to other model based and assisted approaches. The proposed novel design demonstrates the superior performances in percentage of selecting the correct optimal dose (OD), average number of patients allocated to the correct OD, and overdosing control during dose escalation process.     

Testing the equality of two high‐dimensional spatial sign covariance matrices

This paper is concerned with testing the equality of two high‐dimensional spatial sign covariance matrices with applications to testing the proportionality of two high‐dimensional covariance matrices. It is interesting that these two testing problems are completely equivalent for the class of elliptically symmetric distributions. This paper develops a new test for testing the equality of two high‐dimensional spatial sign covariance matrices based on the Frobenius norm of the difference between two spatial sign covariance matrices. The asymptotic normality of the proposed testing statistic is derived under the null and alternative hypotheses when the dimension and sample sizes both tend to infinity. Moreover, the asymptotic power function is also presented. Simulation studies show that the proposed test performs very well in a wide range of settings and can be allowed for the case of large dimensions and small sample sizes.     

Checking the censored two-sample accelerated life model using integrated cumulative hazard difference

In this paper, new statistical tests for the censored two-sample accelerated life model are discussed. From the estimating functions using integrated cumulative hazard difference, stochastic processes are constructed. They can be described by martingale residuals, and, given the data, conditional distributions can be approximated by zero mean Gaussian processes. The new methods, based on these processes, provide asymptotically consistent tests against a general departure from the model. A graphical method is also discussed. In various numerical studies, the new tests performed better than the existing method, especially when the hazard curves cross. The proposed procedures are illustrated with two real data sets.     

Higher order inference for stress–strength reliability with independent Burr-type X distributions

In this paper, a small-sample asymptotic method is proposed for higher order inference in the stress–strength reliability model, R=P(Y<X), where X and Y are distributed independently as Burr-type X distributions. In a departure from the current literature, we allow the scale parameters of the two distributions to differ, and the likelihood-based third-order inference procedure is applied to obtain inference for R. The difficulty of the implementation of the method is in obtaining the the constrained maximum likelihood estimates (MLE). A penalized likelihood method is proposed to handle the numerical complications of maximizing the constrained likelihood model. The proposed procedures are illustrated using a sample of carbon fibre strength data. Our results from simulation studies comparing the coverage probabilities of the proposed small-sample asymptotic method with some existing large-sample asymptotic methods show that the proposed method is very accurate even when the sample sizes are small.     

An extension of the placebo‐based pattern‐mixture model

Pattern‐mixture models provide a general and flexible framework for sensitivity analyses of nonignorable missing data in longitudinal studies. The placebo‐based pattern‐mixture model handles missing data in a transparent and clinically interpretable manner. We extend this model to include a sensitivity parameter that characterizes the gradual departure of the missing data mechanism from being missing at random toward being missing not at random under the standard placebo‐based pattern‐mixture model. We derive the treatment effect implied by the extended model. We propose to utilize the primary analysis based on a mixed‐effects model for repeated measures to draw inference about the treatment effect under the extended placebo‐based pattern‐mixture model. We use simulation studies to confirm the validity of the proposed method. We apply the proposed method to a clinical study of major depressive disorders. Copyright © 2013 John Wiley & Sons, Ltd.     

Alternate test statistics for a functional errors-in-variables model

Some test statistics for the structural coefficients of simultaneous equations model often referred to as the multivariate linear functional relationship model are proposed in this article. The following cases are considered: the covariance matrix of errors is either unknown, known up to a proportionality factor, or completely known. The exact and approximate distributions of the proposed test statistics, as well as those of some that are known, are also given.