Interval estimation of the 90% effective dose: a comparison of bootstrap resampling methods with some large-sample approaches

A number of recent studies have looked at the coverage probabilities of various common parametric methods of interval estimation of the median effective dose (ED 50 ) for a logistic dose-response curve. There has been comparatively little work done on more extreme effective doses. In this paper, the interval estimation of the 90% effective dose (ED 90 ) will be of principal interest. We provide a comparison of four parametric methods of interval construction with four methods based on bootstrap resampling.     

Selection of number of dose levels and its robustness for binary response data

Müller & Schmitt (1990) have considered the question of how to choose the number of doses for estimating the median effective dose (ED50) when a probit dose-response curve is correctly assumed. However, they restricted their investigation to designs with doses symmetrical about the true ED50. In this paper, we investigate how the conclusions of Müller & Schmitt may change as the dose designs become slightly asymmetric about the true ED50. In addition, we address the question of the robustness of the number of doses chosen for an incorrectly assumed logistic model, when the dose designs are asymmetric about the assumed ED50. The underlying true dose-response curves considered here include the probit, cubic logistic and Aranda- Ordaz asymmetric models. The simulation results show that, for various underlying true dose-response curves and the uniform design density with doses spaced asymmetrically around the assumed ED50, the choice of as many doses as possible is almost optimal. This agrees with the results obtained for a correctly assumed probit or logistic dose-response curve when the dose designs are symmetric or slightly asymmetric about the ED50.     

Improved approaches to interval estimation of effective doses for a logistic dose-response curve

Asymptotic confidence (delta) intervals and intervals based upon the use of Fieller's theorem are alternative methods for constructing intervals for the <$>\gamma<$>% effective doses (ED<$>_\gamma<$>). Sitter and Wu (1993) provided a comparison of the two approaches for the ED<$>_{50}<$>, for the case in which a logistic dose response curve is assumed. They showed that the Fieller intervals are generally superior. In this paper, we introduce two new families of intervals, both of which include the delta and Fieller intervals as special cases. In addition we consider interval estimation of the ED<$>_{90}<$> as well as the ED<$>_{50}<$>. We provide a comparison of the various methods for the problem of constructing a confidence interval for the ED<$>_\gamma<$>.     

Interval estimation of the median effective dose for a logistic dose-response curve

In 1986, Williams showed how, assuming a logistic dose-response curve, one can construct a confidence interval for the median effective dose from the asymptotic likelihood ratio test. He gave reasons for preferring this likelihood ratio interval to the established interval calculated by applying Fieller's theorem to the maximum-likelihood estimates. Here, we assess the impact of applying a Bartlett adjustment to the likelihood ratio statistic and introduce the score test as an alternative approach for constructing a confidence interval for the median effective dose.     

Simultaneous confidence bands for Abbott-adjusted quantal response models in benchmark analysis

We study the use of a Scheffé-style simultaneous confidence band as applied to low-dose risk estimation with quantal response data. We consider two formulations for the dose-response risk function, an Abbott-adjusted Weibull model and an Abbott-adjusted log-logistic model. Using the simultaneous construction, we derive methods for estimating upper confidence limits on predicted extra risk and, by inverting the upper bands on risk, lower bounds on the benchmark dose, or BMD, at a specific level of ‘benchmark risk’. Monte Carlo evaluations explore the operating characteristics of the simultaneous limits.     

A Bayesian approach for generalized linear models with explanatory biomarker measurement variables subject to detection limit: an application to acute lung injury

Biomarkers have the potential to improve our understanding of disease diagnosis and prognosis. Biomarker levels that fall below the assay detection limits (DLs), however, compromise the application of biomarkers in research and practice. Most existing methods to handle non-detects focus on a scenario in which the response variable is subject to the DL; only a few methods consider explanatory variables when dealing with DLs. We propose a Bayesian approach for generalized linear models with explanatory variables subject to lower, upper, or interval DLs. In simulation studies, we compared the proposed Bayesian approach to four commonly used methods in a logistic regression model with explanatory variable measurements subject to the DL. We also applied the Bayesian approach and other four methods in a real study, in which a panel of cytokine biomarkers was studied for their association with acute lung injury (ALI). We found that IL8 was associated with a moderate increase in risk for ALI in the model based on the proposed Bayesian approach.     

A finite sample comparison of nonparametric estimates of the effective dose in quantal bioassay

To estimate the effective dose level ED_α in the common binary response model, several parametric and nonparametric estimators have been proposed in the literature. In the present article, we focus on nonparametric methods and present a detailed numerical comparison of four different approaches to estimate the ED_α nonparametrically. The methods are briefly reviewed and their finite sample properties are studied by means of a detailed simulation study. Moreover, a data example is presented to illustrate the different concepts.     

Fitting models for the joint action of two drugs using SAS

Combinations of drugs are increasingly being used for a wide variety of diseases and conditions. A pre-clinical study may allow the investigation of the response at a large number of dose combinations. In determining the response to a drug combination, interest may lie in seeking evidence of 'synergism', in which the joint action is greater than the actions of the individual drugs, or of 'antagonism', in which it is less. Two well-known response surface models representing no interaction are Loewe additivity and Bliss independence, and Loewe or Bliss synergism or antagonism is defined relative to these. We illustrate an approach to fitting these models for the case in which the marginal single drug dose-response relationships are represented by four-parameter logistic curves with common upper and lower limits, and where the response variable is normally distributed with a common variance about the dose-response curve. When the dose-response curves are not parallel, the relative potency of the two drugs varies according to the magnitude of the desired effect and the models for Loewe additivity and synergism/antagonism cannot be explicitly expressed. We present an iterative approach to fitting these models without the assumption of parallel dose-response curves. A goodness-of-fit test based on residuals is also described. Implementation using the SAS NLIN procedure is illustrated using data from a pre-clinical study.     

A note on confidence bounds after fixed-sequence multiple tests

We are concerned with the problem of estimating the treatment effects at the effective doses in a dose-finding study. Under monotone dose-response, the effective doses can be identified through the estimation of the minimum effective dose, for which there is an extensive set of statistical tools. In particular, when a fixed-sequence multiple testing procedure is used to estimate the minimum effective dose, Hsu and Berger (1999) show that the confidence lower bounds for the treatment effects can be constructed without the need to adjust for multiplicity. Their method, called the dose-response method, is simple to use, but does not account for the magnitude of the observed treatment effects. As a result, the dose-response method will estimate the treatment effects at effective doses with confidence bounds invariably identical to the hypothesized value. In this paper, we propose an error-splitting method as a variant of the dose-response method to construct confidence bounds at the identified effective doses after a fixed-sequence multiple testing procedure. Our proposed method has the virtue of simplicity as in the dose-response method, preserves the nominal coverage probability, and provides sharper bounds than the dose-response method in most cases.     

On estimating a transformation correlation coefficient

We consider a semiparametric and a parametric transformation-to-normality model for bivariate data. After an unstructured or structured monotone transformation of the measurement scales, the measurements are assumed to have a bivariate normal distribution with correlation coefficient ρ, here termed the 'transformation correlation coefficient'. Under the semiparametric model with unstructured transformation, the principle of invariance leads to basing inference on the marginal ranks. The resulting rank-based likelihood function of ρis maximized via a Monte Carlo procedure. Under the parametric model, we consider Box-Cox type transformations and maximize the likelihood of ρalong with the nuisance parameters. Efficiencies of competing methods are reported, both theoretically and by simulations. The methods are illustrated on a real-data example.     

Bayesian fitting of a logistic dose-response curve with numerically derived priors

In this report we describe the Bayesian analysis of a logistic dose-response curve in a Phase I study, and we present two simple and intuitive numerical approaches to construction of prior probability distributions for the model parameters. We combine these priors with the expert prior opinion and compare the results of the analyses with those obtained from the use of alternative prior formulations.     

The application of stochastic approximation methods to the bio-assay problem

A new general model for the bio-assay problem is introduced. It is shown that when the slope of the dose-response curve and the median effective dose is known, the Robbins-Monro method yields an asymptotically optimal estimation procedure. Adaptive procedures are discussed for the case of unknown slope. Results of Monte Carlo studies are given.     

Nondifferentiable errors in beta-compliance integrated logistic models: numerical results

In dose-response models, there are cases where only a portion of the administered dose may have an effect. This results in a stochastic compliance of the administered dose. In a previous paper (Chen-Mok and Sen, 1999), we developed suitable adjustments for compliance in the logistic model under the assumption of nondifferential measurement error. These compliance-adjusted models were categorized into three types: (i) Low (or near zero) dose levels, (ii) moderate dose levels, and (iii) high dose levels. In this paper, we analyze a set of data on the atomic bomb survivors of Japan to illustrate the use of the proposed methods. In addition, we examine the performance of these methods under different conditions based on a simulation study. Among all three cases, the adjustments proposed for the moderate dose case do not seem to work adequately. Both bias and variance are larger when using the adjusted model in comparison with the unadjusted model. The adjustments for the low dose case seem to work in reducing the bias in the estimation of the parameters under all types of compliance distributions. The MSEs, however, are larger under some of the compliance distribution considered. Finally, the results of this simulation study show that the adjustments for the high dose case are successful in achieving both a reduction in bias as well as a reduction in MSE, hence the overall efficiency of the estimation is improved.     

Optimal design for discrete choice experiments

In this paper we derive locally optimal designs for discrete choice experiments. As in Kanninen (2002) we consider a multinomial logistic model, which contains various qualitative attributes as well as a quantitative one, which may range over a sufficiently large interval. The derived optimal designs improve upon those given in the literature, but have the feature that every choice set contains alternatives, which coincide in all but the quantitative attributes. The multinomial logistic model will then lead to a response behavior, which is apparently unrealistic.     

Bioassay case study applying the maximin D‐optimal design algorithm to the four‐parameter logistic model

Cell‐based potency assays play an important role in the characterization of biopharmaceuticals but they can be challenging to develop in part because of greater inherent variability than other analytical methods. Our objective is to select concentrations on a dose–response curve that will enhance assay robustness. We apply the maximin D‐optimal design concept to the four‐parameter logistic (4PL) model and then derive and compute the maximin D‐optimal design for a challenging bioassay using curves representative of assay variation. The selected concentration points from this ‘best worst case’ design adequately fit a variety of 4PL shapes and demonstrate improved robustness. Copyright © 2015 John Wiley & Sons, Ltd.     

Adaptive modelling of dose–response relationships using smoothing splines

We consider the use of smoothing splines for the adaptive modelling of dose–response relationships. A smoothing spline is a nonparametric estimator of a function that is a compromise between the fit to the data and the degree of smoothness and thus provides a flexible way of modelling dose–response data. In conjunction with decision rules for which doses to continue with after an interim analysis, it can be used to give an adaptive way of modelling the relationship between dose and response. We fit smoothing splines using the generalized cross‐validation criterion for deciding on the degree of smoothness and we use estimated bootstrap percentiles of the predicted values for each dose to decide upon which doses to continue with after an interim analysis. We compare this approach with a corresponding adaptive analysis of variance approach based upon new simulations of the scenarios previously used by the PhRMA Working Group on Adaptive Dose‐Ranging Studies. The results obtained for the adaptive modelling of dose–response data using smoothing splines are mostly comparable with those previously obtained by the PhRMA Working Group for the Bayesian Normal Dynamic Linear model (GADA) procedure. These methods may be useful for carrying out adaptations, detecting dose–response relationships and identifying clinically relevant doses. Copyright © 2009 John Wiley & Sons, Ltd.     

Data skeletons: simultaneous estimation of multiple quantiles for massive streaming datasets with applications to density estimation

We consider the problem of density estimation when the data is in the form of a continuous stream with no fixed length. In this setting, implementations of the usual methods of density estimation such as kernel density estimation are problematic. We propose a method of density estimation for massive datasets that is based upon taking the derivative of a smooth curve that has been fit through a set of quantile estimates. To achieve this, a low-storage, single-pass, sequential method is proposed for simultaneous estimation of multiple quantiles for massive datasets that form the basis of this method of density estimation. For comparison, we also consider a sequential kernel density estimator. The proposed methods are shown through simulation study to perform well and to have several distinct advantages over existing methods.     

Robust williams trent test

To investigate the biological activities of a new compound or drug, experimenters usually compare a series of increasing doses to a control. Among other objectives, one may try to investigate any possible dose-response trend and to determine the minimum effective dose among all the experimental doses. Williams (1971, 1972) proposed a procedure to test the dose-response trend and also to identify the minimum effective dose based on the normally distributed data. In this paper, we propose a similar test procedure based on the robust estimate'of the average response to perform similar analysis. The proposed method is more resistant to the outliers and more powerful than the Williams procedure when the data distribution deviates from normality. We illustrate the use of this procedure with data arising from a recent study.     

Trajectory Modeling of Longitudinal Binary Data: Application of the EM Algorithm for Mixture Models

A developmental trajectory describes the course of behavior over time. Identifying multiple trajectories within an overall developmental process permits a focus on subgroups of particular interest. We introduce a framework for identifying trajectories by using the Expectation-Maximization (EM) algorithm to fit semiparametric mixtures of logistic distributions to longitudinal binary data. For performance comparison, we consider full maximization algorithms (PROC TRAJ in SAS), standard EM, and two other EM-based algorithms for speeding up convergence. Simulation shows that EM methods produce more accurate parameter estimates. The EM methodology is illustrated with a longitudinal dataset involving adolescents smoking behaviors.     

Order statistics from trivariate normal and -distributions in terms of generalized skew-normal and skew- distributions

We consider here a generalization of the skew-normal distribution, GSN(λ₁,λ₂,ρ), defined through a standard bivariate normal distribution with correlation ρ, which is a special case of the unified multivariate skew-normal distribution studied recently by Arellano-Valle and Azzalini [2006. On the unification of families of skew-normal distributions. Scand. J. Statist. 33, 561–574]. We then present some simple and useful properties of this distribution and also derive its moment generating function in an explicit form. Next, we show that distributions of order statistics from the trivariate normal distribution are mixtures of these generalized skew-normal distributions; thence, using the established properties of the generalized skew-normal distribution, we derive the moment generating functions of order statistics, and also present expressions for means and variances of these order statistics.Next, we introduce a generalized skew-t_ν distribution, which is a special case of the unified multivariate skew-elliptical distribution presented by Arellano-Valle and Azzalini [2006. On the unification of families of skew-normal distributions. Scand. J. Statist. 33, 561–574] and is in fact a three-parameter generalization of Azzalini and Capitanio's [2003. Distributions generated by perturbation of symmetry with emphasis on a multivariate skew t distribution. J. Roy. Statist. Soc. Ser. B 65, 367–389] univariate skew-t_ν form. We then use the relationship between the generalized skew-normal and skew-t_ν distributions to discuss some properties of generalized skew-t_ν as well as distributions of order statistics from bivariate and trivariate t_ν distributions. We show that these distributions of order statistics are indeed mixtures of generalized skew-t_ν distributions, and then use this property to derive explicit expressions for means and variances of these order statistics.