What to Do at Low Doses: A Bounding Approach for Economic Analysis

To quantify the health benefits of environmental policies, economists generally require estimates of the reduced probability of illness or death. For policies that reduce exposure to carcinogenic substances, these estimates traditionally have been obtained through the linear extrapolation of experimental dose-response data to low-exposure scenarios as described in the U.S. Environmental Protection Agency's Guidelines for Carcinogen Risk Assessment (1986). In response to evolving scientific knowledge, EPA proposed revisions to the guidelines in 1996. Under the proposed revisions, dose-response relationships would not be estimated for carcinogens thought to exhibit nonlinear modes of action. Such a change in cancer-risk assessment methods and outputs will likely have serious consequences for how benefit-cost analyses of policies aimed at reducing cancer risks are conducted. Any tendency for reduced quantification of effects in environmental risk assessments, such as those contemplated in the revisions to EPA's cancer-risk assessment guidelines, impedes the ability of economic analysts to respond to increasing calls for benefit-cost analysis. This article examines the implications for benefit-cost analysis of carcinogenic exposures of the proposed changes to the 1986 Guidelines and proposes an approach for bounding dose-response relationships when no biologically based models are available. In spite of the more limited quantitative information provided in a carcinogen risk assessment under the proposed revisions to the guidelines, we argue that reasonable bounds on dose-response relationships can be estimated for low-level exposures to nonlinear carcinogens. This approach yields estimates of reduced illness for use in a benefit-cost analysis while incorporating evidence of nonlinearities in the dose-response relationship. As an illustration, the bounding approach is applied to the case of chloroform exposure.     

Constructing optimal designs for fitting pharmacokinetic models

We consider some computational issues that arise when searching for optimal designs for pharmacokinetic (PK) studies. Special factors that distinguish these are (i) repeated observations are taken from each subject and the observations are usually described by a nonlinear mixed model (NLMM), (ii) design criteria depend on the model fitting procedure, (iii) in addition to providing efficient parameter estimates, the design must also permit model checking, (iv) in practice there are several design constraints, (v) the design criteria are computationally expensive to evaluate and often numerical integration is needed and finally (vi) local optimisation procedures may fail to converge or get trapped at local optima.We review current optimal design algorithms and explore the possibility of using global optimisation procedures. We use these latter procedures to find some optimal designs.For multi-purpose designs we suggest two surrogate design criteria for model checking and illustrate their use.     

Parameter estimation of nonlinear mixed-effects models using first-order conditional linearization and the EM algorithm

Nonlinear mixed-effects (NLME) models are flexible enough to handle repeated-measures data from various disciplines. In this article, we propose both maximum-likelihood and restricted maximum-likelihood estimations of NLME models using first-order conditional expansion (FOCE) and the expectation–maximization (EM) algorithm. The FOCE-EM algorithm implemented in the ForStat procedure SNLME is compared with the Lindstrom and Bates (LB) algorithm implemented in both the SAS macro NLINMIX and the S-Plus/R function nlme in terms of computational efficiency and statistical properties. Two realworld data sets an orange tree data set and a Chinese fir (Cunninghamia lanceolata) data set, and a simulated data set were used for evaluation. FOCE-EM converged for all mixed models derived from the base model in the two realworld cases, while LB did not, especially for the models in which random effects are simultaneously considered in several parameters to account for between-subject variation. However, both algorithms had identical estimated parameters and fit statistics for the converged models. We therefore recommend using FOCE-EM in NLME models, particularly when convergence is a concern in model selection.     

On confidence regions of semiparametric nonlinear reproductive dispersion models

This article investigates the confidence regions for semiparametric nonlinear reproductive dispersion models (SNRDMs), which is an extension of nonlinear regression models. Based on local linear estimate of nonparametric component and generalized profile likelihood estimate of parameter in SNRDMs, a modified geometric framework of Bates and Wattes is proposed. Within this geometric framework, we present three kinds of improved approximate confidence regions for the parameters and parameter subsets in terms of curvatures. The work extends the previous results of Hamilton et al. [in Accounting for intrinsic nonlinearity in nonlinear regression parameter inference regions, Ann. Statist. 10, pp. 386–393, 1982], Hamilton [in Confidence regions for parameter subset in nonlinear regression, Biometrika, 73, pp. 57–64, 1986], Wei [in On confidence regions of embedded models in regular parameter families (a geometric approch), Austral. J. Statist. 36, pp. 327–338, 1994], Tang et al. [in Confidence regions in quasi-likelihood nonlinear models: a geometric approach, J. Biomath. 15, pp. 55–64, 2000b] and Zhu et al. [in On confidence regions of semiparametric nonlinear regression models, Acta. Math. Scient. 20, pp. 68–75, 2000].     

Fitting of self-exciting threshold autoregressive moving average nonlinear time-series model through genetic algorithm and development of out-of-sample forecasts

Self-exciting threshold autoregressive moving average (SETARMA) nonlinear time-series model is considered here. Sufficient conditions for invertibility and stationarity are derived. Parameter estimation algorithm is developed by employing real-coded genetic algorithm stochastic optimization procedure. A significant feature of the work done is that optimal out-of-sample forecasts up to three-step ahead and their forecast error variances are derived analytically. Relevant computer programs are written in statistical analysis system (SAS) and C. As an illustration, annual mackerel catch time-series data are considered. Forecast performance of the fitted model for hold-out data is evaluated by using Naive and Monte Carlo approaches. It is found that optimal out-of-sample forecast values are quite close to actual values and estimated variances are quite close to theoretical values. Superiority of the SETARMA model over the SETAR model for equal predictive ability through Diebold–Mariano test is also established.     

The collected works of john w. tukey

We describe novel, analytical, data-analysis, and Monte-Carlo-simulation studies of strongly heteroscedastic data of both small and wide range.Many different types of heteroscedasticity and fixed or variable weighting are incorporated through error-variance models.Attention is given to parameter bias determinations, evaluations of their significances, and to new ways to correct for bias.The error-variance models allow for both additive and independent power-law errors, and the power exponent is shown to be able to be well determined for typical physicalsciences data by the rapidly-converging, general-purpose, extended-least-squares program we use.The fitting and error-variance models are applied to both low-and high-heteroscedasticity situations, including single-response data from radioactive decay.Monte-Carlo simulations of data with similar parameters are used to evaluate the analytical models developed and the various minimization methods em-ployed, such as extended and generalized least squares.Logarithmic and inversion transformations are investigated in detail, and it is shown analytically and by simulations that exponential data with constant percentage errors can be logarithmically transformed to allow a simple parameter-bias-removal procedure.A more-general bias-reduction approach combining direct and inversion fitting is also developed.Distributions of fitting-model and error-variance-model parameters are shown to be typically non-normal, thus invalidating the usual estimates of parameter bias and precision.Errors in conventional confidence-interval estimates are quantified by comparison with accurate simulation results.     

Notes on likelihood intervals and profiling

In many applications, decisions are made on the basis of function of parameters g(θ). When the value of g(theta;) is calculated using estimated values for te parameters, its is important to have a measure of the uncertainty associated with that value of g(theta;). Likelihood ratio approaches to finding likelihood intervals for functions of parameters have been shown to be more reliable, in terms of coverage probability, than the linearization approach. Two approaches to the generalization of the profiling algorithm have been proposed in the literature to enable construction of likelihood intervals for a function of parameters (Chen and Jennrich, 1996; Bates and Watts, 1988). In this paper we show the equivalence of these two methods. We also provide and analysis of cases in which neither profiling algorithm is appropriate. For one of these cases an alternate approach is suggested Whereas generalized profiling is based on maximizing the likelihood function given a constraint on the value of g(θ), the alternative algorithm is based on optimizing g(θ) given a constraint on the value of the likelihood function.     

Influence Diagnostics of Semiparametric Nonlinear Reproductive Dispersion Models

This article proposes a semiparametric nonlinear reproductive dispersion model (SNRDM) which is an extension of nonlinear reproductive dispersion model and semiparametric regression model. Maximum penalized likelihood estimators (MPLEs) of unknown parameters and nonparametric functions in SNRDMs are presented. Some novel diagnostic statistics such as Cook distance and difference deviance for parametric and nonparametric parts are developed to identify influence observations in SNRDMs on the basis of case-deletion method, and some formulae readily computed with the MPLEs algorithm for diagnostic measures are given. The equivalency of case-deletion models and mean-shift outlier models in SNRDM is investigated. A simulation study and a real example are used to illustrate the proposed diagnostic measures.     

On concurrence of several linear regressions and applications to problems of enzyme kinetics

In comparing several regressions E(y_ij) =α_i + β_ix_ij i = 1, 2, ..., k, j = 1,2, ..., n_i, researchers are generally interested in the following five problems: whether they have (1) equal slope, (2) equal intercept, (3) coincidence, (4) common intersection on X-axis, and (5) common intersection on (X,Y) - plane. Problems (1) - (3) can be put into the framework of the general linear hypothesis and the F-test can be used. However, problems (4) and (5) cannot be put into the general linear hypothesis because they are ratios of parameters. Hence, in this paper we consider the generalized likelihood ratio test for hypothesis testing. An application to an enzyme kinetics problem in Aniline Metabolism is demonstrated     

Correcting for nonlinear measurement errors in the dependent variable in the general linear model

Linear models are considered in which measurement error is present in the dependent variable. Observed values are related to true values via nonlinear regression models with the parameters in the measurement error models being estimated with the use of independent, external data, collected using standards. Pseudo-maximum likelihood estimators and their asymptotic properties are developed under normality assumptions and the common approach of simply analyzing imputed values obtained from the nestimated calibration curves is assessed. A small simulation evaluates the procedures. An example is presented in which urinary neopterin (measured via radioimmunoassay) is nbeing compared between two groups of individuals.