Laplace approximations and Bayesian information criteria in possibly misspecified models

We provide general conditions to ensure the valid Laplace approximations to the marginal likelihoods under model misspecification, and derive the Bayesian information criteria including all terms of order O_p(1). Under conditions in theorem 1 of Lv and Liu [J. R. Statist. Soc. B, 76, (2014), 141–167] and a continuity condition for prior densities, asymptotic expansions with error terms of order o_p(1) are derived for the log-marginal likelihoods of possibly misspecified generalized linear models. We present some numerical examples to illustrate the finite sample performance of the proposed information criteria in misspecified models.     

Hybrid Bayesian inference on HIV viral dynamic models

Modelling of HIV dynamics in AIDS research has greatly improved our understanding of the pathogenesis of HIV-1 infection and guided for the treatment of AIDS patients and evaluation of antiretroviral therapies. Some of the model parameters may have practical meanings with prior knowledge available, but others might not have prior knowledge. Incorporating priors can improve the statistical inference. Although there have been extensive Bayesian and frequentist estimation methods for the viral dynamic models, little work has been done on making simultaneous inference about the Bayesian and frequentist parameters. In this article, we propose a hybrid Bayesian inference approach for viral dynamic nonlinear mixed-effects models using the Bayesian frequentist hybrid theory developed in Yuan [Bayesian frequentist hybrid inference, Ann. Statist. 37 (2009), pp. 2458–2501]. Compared with frequentist inference in a real example and two simulation examples, the hybrid Bayesian approach is able to improve the inference accuracy without compromising the computational load.     

On representing maximin efficient designs by Taylor series

This paper considers exponential and rational regression models that are nonlinear in some parameters. Recently, locally D-optimal designs for such models were investigated in [Melas, V. B., 2005. On the functional approach to optimal designs for nonlinear models. J. Statist. Plann. Inference 132, 93–116] based upon a functional approach. In this article a similar method is applied to construct maximin efficient D-optimal designs. This approach allows one to represent the support points of the designs by Taylor series, which gives us the opportunity to construct the designs by hand using tables of the coefficients of the series. Such tables are provided here for models with two nonlinear parameters. Furthermore, the recurrent formulas for constructing the tables for arbitrary numbers of parameters are introduced.     

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].     

Bayesian inference for a flexible class of bivariate beta distributions

Several bivariate beta distributions have been proposed in the literature. In particular, Olkin and Liu [A bivariate beta distribution. Statist Probab Lett. 2003;62(4):407–412] proposed a 3 parameter bivariate beta model which Arnold and Ng [Flexible bivariate beta distributions. J Multivariate Anal. 2011;102(8):1194–1202] extend to 5 and 8 parameter models. The 3 parameter model allows for only positive correlation, while the latter models can accommodate both positive and negative correlation. However, these come at the expense of a density that is mathematically intractable. The focus of this research is on Bayesian estimation for the 5 and 8 parameter models. Since the likelihood does not exist in closed form, we apply approximate Bayesian computation, a likelihood free approach. Simulation studies have been carried out for the 5 and 8 parameter cases under various priors and tolerance levels. We apply the 5 parameter model to a real data set by allowing the model to serve as a prior to correlated proportions of a bivariate beta binomial model. Results and comparisons are then discussed.     

Minimum Hellinger distance estimation for randomized play the winner design

Response-adaptive designs in clinical trials incorporate information from prior patient responses in order to assign better performing treatments to the future patients of a clinical study. An example of a response adaptive design that has received much attention in recent years is the randomized play the winner design (RPWD). Beran [1977. Minimum Hellinger distance estimates for parametric models. Ann. Statist. 5, 445–463] investigated the problem of minimum Hellinger distance procedure (MHDP) for continuous data and showed that minimum Hellinger distance estimator (MHDE) of a finite dimensional parameter is as efficient as the MLE (maximum likelihood estimator) under a true model assumption. This paper develops minimum Hellinger distance methodology for data generated using RPWD. A new algorithm using the Monte Carlo approximation to the estimating equation is proposed. Consistency and asymptotic normality of the estimators are established and the robustness and small sample performance of the estimators are illustrated using simulations. The methodology when applied to the clinical trial data conducted by Eli-Lilly and Company, brings out the treatment effect in one of the strata using the frequentist techniques compared to the Bayesian argument of Tamura et al [1994. A case study of an adaptive clinical trialin the treatment of out-patients with depressive disorder. J. Amer. Statist. Assoc. 89, 768–776].     

On the Choice of a Prior for Bayesian D-Optimal Designs for the Logistic Regression Model with a Single Predictor

The Bayesian design approach accounts for uncertainty of the parameter values on which optimal design depends, but Bayesian designs themselves depend on the choice of a prior distribution for the parameter values. This article investigates Bayesian D-optimal designs for two-parameter logistic models, using numerical search. We show three things: (1) a prior with large variance leads to a design that remains highly efficient under other priors, (2) uniform and normal priors lead to equally efficient designs, and (3) designs with four or five equidistant equally weighted design points are highly efficient relative to the Bayesian D-optimal designs.     

Optimal and efficient designs for 2-parameter nonlinear models

By Carathéodory's theorem, for a k-parameter nonlinear model, the minimum number of support points for any D-optimal design is between k and k(k+1)/2. Characterizing classes of models for which a D-optimal design sits on exactly k support points is of great theoretical interest. By utilizing the equivalence theorem, we identify classes of 2-parameter nonlinear models for which a D-optimal design is precisely supported on 2 points. We also introduce the theory of maximum principle from differential equations into the design area and obtain some results on characterizing the minimally supported nonlinear designs. Examples are given to demonstrate our results. Designs with minimum number of support points may not always be suitable in practice. To alleviate this problem, we utilize some geometric and analytical methods to obtain some efficient designs which provide more opportunity for the model checking and prevent biases due to mis-specified initial parameters.     

Optimal Bayesian sampling plans for exponential distributions based on hybrid censored samples

We study variable sampling plans for exponential distributions based on type-I hybrid censored samples. For this problem, two sampling plans based on the non-failure sample proportion and the conditional maximum likelihood estimator are proposed by Chen et al. [J. Chen, W. Chou, H. Wu, and H. Zhou, Designing acceptance sampling schemes for life testing with mixed censoring, Naval Res. Logist. 51 (2004), pp. 597–612] and Lin et al. [C.-T. Lin, Y.-L. Huang, and N. Balakrishnan, Exact Bayesian variable sampling plans for the exponential distribution based on type-I and type-II censored samples, Commun. Statist. Simul. Comput. 37 (2008), pp. 1101–1116], respectively. From the theoretic decision point of view, the preceding two sampling plans are not optimal due to their decision functions not being the Bayes decision functions. In this article, we consider the decision theoretic approach, and the optimal Bayesian sampling plan based on sufficient statistics is derived under a general loss function. Furthermore, for the conjugate prior distribution, the closed-form formula of the Bayes decision rule can be obtained under either the linear or quadratic decision loss. The resulting Bayesian sampling plan has the minimum Bayes risk, and hence it is better than the sampling plans proposed by Chen et al. (2004) and Lin et al. (2008). Numerical comparisons are given and demonstrate that the performance of the proposed Bayesian sampling plan is superior to that of Chen et al. (2004) and Lin et al. (2008).     

Optimal designs for discriminating between some extensions of the Michaelis–Menten model

In this paper some results on the computation of optimal designs for discriminating between nonlinear models are provided. In particular, some typical deviations of the Michaelis–Menten model are considered. A common deviation of this pharmacokinetic model consists on adding a linear term. If two linear models differ in one parameter the T-optimal design for discriminating between them is c-optimal for estimating the added linear term. This is not the case for nonlinear models.     

ON CONFIDENCE INTERVALS FOR GENERALIZED ADDITIVE MODELS BASED ON PENALIZED REGRESSION SPLINES

Generalized additive models represented using low rank penalized regression splines, estimated by penalized likelihood maximisation and with smoothness selected by generalized cross validation or similar criteria, provide a computationally efficient general framework for practical smooth modelling. Various authors have proposed approximate Bayesian interval estimates for such models, based on extensions of the work of Wahba, G. (1983) [Bayesian confidence intervals for the cross validated smoothing spline. J. R. Statist. Soc. B 45 , 133–150] and Silverman, B.W. (1985) [Some aspects of the spline smoothing approach to nonparametric regression curve fitting. J. R. Statist. Soc. B 47 , 1–52] on smoothing spline models of Gaussian data, but testing of such intervals has been rather limited and there is little supporting theory for the approximations used in the generalized case. This paper aims to improve this situation by providing simulation tests and obtaining asymptotic results supporting the approximations employed for the generalized case. The simulation results suggest that while across‐the‐model performance is good, component‐wise coverage probabilities are not as reliable. Since this is likely to result from the neglect of smoothing parameter variability, a simple and efficient simulation method is proposed to account for smoothing parameter uncertainty: this is demonstrated to substantially improve the performance of component‐wise intervals.     

Statistical diagnostics for nonlinear regression models based on scale mixtures of skew-normal distributions

The purpose of this paper is to develop diagnostics analysis for nonlinear regression models (NLMs) under scale mixtures of skew-normal (SMSN) distributions introduced by Garay et al. [Nonlinear regression models based on SMSN distributions. J. Korean Statist. Soc. 2011;40:115–124]. This novel class of models provides a useful generalization of the symmetrical NLM [Vanegas LH, Cysneiros FJA. Assessment of diagnostic procedures in symmetrical nonlinear regression models. Comput. Statist. Data Anal. 2010;54:1002–1016] since the random terms distributions cover both symmetric as well as asymmetric and heavy-tailed distributions such as the skew-t, skew-slash, skew-contaminated normal distributions, among others. Motivated by the results given in Garay et al. [Nonlinear regression models based on SMSN distributions. J. Korean Statist. Soc. 2011;40:115–124], we presented a score test for testing the homogeneity of the scale parameter and its properties are investigated through Monte Carlo simulations studies. Furthermore, local influence measures and the one-step approximations of the estimates in the case-deletion model are obtained. The newly developed procedures are illustrated considering a real data set.     

A Z-theorem with Estimated Nuisance Parameters and Correction Note for 'Weighted Likelihood for Semiparametric Models and Two-phase Stratified Samples, with Application to Cox Regression'

Abstract.  We state and prove a limit theorem for estimators of a general, possibly infinite dimensional parameter based on unbiased estimating equations containing estimated nuisance parameters. The theorem corrects a gap in the proof of one of the assertions of our paper 'Weighted likelihood for semiparametric models and two-phase stratified samples, with application to Cox regression' [ Scand. J. Statist . 34 (2007) 86–102].     

MAXIMUM LIKELIHOOD ESTIMATION IN LINEAR MODELS WITH EQUI-CORRELATED RANDOM ERRORS

Necessary and sufficient conditions for the existence of maximum likelihood estimators of unknown parameters in linear models with equi‐correlated random errors are presented. The basic technique we use is that these models are, first, orthogonally transformed into linear models with two variances, and then the maximum likelihood estimation problem is solved in the environment of transformed models. Our results generalize a result of Arnold, S. F. (1981) [The theory of linear models and multivariate analysis. Wiley, New York]. In addition, we give necessary and sufficient conditions for the existence of restricted maximum likelihood estimators of the parameters. The results of Birkes, D. & Wulff, S. (2003) [Existence of maximum likelihood estimates in normal variance‐components models. J Statist Plann. Inference. 113 , 35–47] are compared with our results and differences are pointed out.     

Outcome-adaptive allocation with natural lead-in for three-group trials with binary outcomes

ABSTRACT

Just as Bayes extensions of the frequentist optimal allocation design have been developed for the two-group case, we provide a Bayes extension of optimal allocation in the three-group case. We use the optimal allocations derived by Jeon and Hu [Optimal adaptive designs for binary response trials with three treatments. Statist Biopharm Res. 2010;2(3):310–318] and estimate success probabilities for each treatment arm using a Bayes estimator. We also introduce a natural lead-in design that allows adaptation to begin as early in the trial as possible. Simulation studies show that the Bayesian adaptive designs simultaneously increase the power and expected number of successfully treated patients compared to the balanced design. And compared to the standard adaptive design, the natural lead-in design introduced in this study produces a higher expected number of successes whilst preserving power.     

Bayesian analysis of bivariate competing risks models with covariates

Bivariate exponential models have often been used for the analysis of competing risks data involving two correlated risk components. Competing risks data consist only of the time to failure and cause of failure. In situations where there is positive probability of simultaneous failure, possibly the most widely used model is the Marshall–Olkin (J. Amer. Statist. Assoc. 62 (1967) 30) bivariate lifetime model. This distribution is not absolutely continuous as it involves a singularity component. However, the likelihood function based on the competing risks data is then identifiable, and any inference, Bayesian or frequentist, can be carried out in a straightforward manner. For the analysis of absolutely continuous bivariate exponential models, standard approaches often run into difficulty due to the lack of a fully identifiable likelihood (Basu and Ghosh; Commun. Statist. Theory Methods 9 (1980) 1515). To overcome the nonidentifiability, the usual frequentist approach is based on an integrated likelihood. Such an approach is implicit in Wada et al. (Calcutta Statist. Assoc. Bull. 46 (1996) 197) who proved some related asymptotic results. We offer in this paper an alternative Bayesian approach. Since systematic prior elicitation is often difficult, the present study focuses on Bayesian analysis with noninformative priors. It turns out that with an appropriate reparameterization, standard noninformative priors such as Jeffreys’ prior and its variants can be applied directly even though the likelihood is not fully identifiable. Two noninformative priors are developed that consist of Laplace's prior for nonidentifiable parameters and Laplace's and Jeffreys's priors for identifiable parameters. The resulting Bayesian procedures possess some frequentist optimality properties as well. Finally, these Bayesian methods are illustrated with analyses of a data set originating out of a lung cancer clinical trial conducted by the Eastern Cooperative Oncology Group.     

Bayesian D-optimal designs for exponential regression models

We consider the Bayesian D-optimal design problem for exponential growth models with one, two or three parameters. For the one-parameter model conditions on the shape of the density of the prior distribution and on the range of its support are given guaranteeing that a one-point design is also Bayesian D-optimal within the class of all designs. In the case of two parameters the best two-point designs are determined and for special prior distributions it is proved that these designs are Bayesian D-optimal. Finally, the exponential growth model with three parameters is investigated. The best three-point designs are characterized by a nonlinear equation. The global optimality of these designs cannot be proved analytically and it is demonstrated that these designs are also Bayesian D-optimal within the class of all designs if gamma-distributions are used as prior distributions.     

Theoretical study of the continual reassessment method

The continual reassessment method (CRM) was first introduced by O’Quigley et al. [1990. Continual reassessment method: a practical design for Phase I clinical trials in cancer. Biometrics 46, 33–48]. Many articles followed adding to the original ideas, among which are articles by Babb et al. [1998. Cancer Phase I clinical trials: efficient dose escalation with overdose control. Statist. Med. 17, 1103–1120], Braun [2002. The bivariate-continual reassessment method. Extending the CRM to phase I trials of two competing outcomes. Controlled Clin. Trials 23, 240–256], Chevret [1993. The continual reassessment method in cancer phase I clinical trials: a simulation study. Statist. Med. 12, 1093–1108], Faries [1994. Practical modifications of the continual reassessment method for phase I cancer clinical trials. J. Biopharm. Statist. 4, 147–164], Goodman et al. [1995. Some practical improvements in the continual reassessment method for phase I studies. Statist. Med. 14, 1149–1161], Ishizuka and Ohashi [2001. The continual reassessment method and its applications: a Bayesian methodology for phase I cancer clinical trials. Statist. Med. 20, 2661–2681], Legedeza and Ibrahim [2002. Longitudinal design for phase I trials using the continual reassessment method. Controlled Clin. Trials 21, 578–588], Mahmood [2001. Application of preclinical data to initiate the modified continual reassessment method for maximum tolerated dose-finding trial. J. Clin. Pharmacol. 41, 19–24], Moller [1995. An extension of the continual reassessment method using a preliminary up and down design in a dose finding study in cancer patients in order to investigate a greater number of dose levels. Statist. Med. 14, 911–922], O’Quigley [1992. Estimating the probability of toxicity at the recommended dose following a Phase I clinical trial in cancer. Biometrics 48, 853–862], O’Quigley and Shen [1996. Continual reassessment method: a likelihood approach. Biometrics 52, 163–174], O’Quigley et al. (1999), O’Quigley et al. [2002. Non-parametric optimal design in dose finding studies. Biostatistics 3, 51–56], O’Quigley and Paoletti [2003. Continual reassessment method for ordered groups. Biometrics 59, 429–439], Piantodosi et al., 1998. [1998 Practical implementation of a modified continual reassessment method for dose-finding trials. Cancer Chemother. Pharmacol. 41, 429–436] and Whitehead and Williamson [1998. Bayesian decision procedures based on logistic regression models for dose-finding studies. J. Biopharm. Statist. 8, 445–467]. The method is broadly described by Storer [1989. Design and analysis of Phase I clinical trials. Biometrics 45, 925–937]. Whether likelihood or Bayesian based, inference poses particular theoretical difficulties in view of working models being under-parameterized. Nonetheless CRM models have proven themselves to be of practical use and, in this work, the aim is to turn the spotlight on the main theoretical ideas underpinning the approach, obtaining results which can provide guidance in practice. Stemming from this theoretical framework are a number of results and some further development, in particular the way to structure a randomized allocation of subjects as well as a more robust approach to the problem of dealing with patient heterogeneity.     

Bayesian optimization design for dose-finding based on toxicity and efficacy outcomes in phase I/II clinical trials

In phase I trials, the main goal is to identify a maximum tolerated dose under an assumption of monotonicity in dose–response relationships. On the other hand, such monotonicity is no longer applied to biologic agents because a different mode of action from that of cytotoxic agents potentially draws unimodal or flat dose–efficacy curves. Therefore, biologic agents require an optimal dose that provides a sufficient efficacy rate under an acceptable toxicity rate instead of a maximum tolerated dose. Many trials incorporate both toxicity and efficacy data, and drugs with a variety of modes of actions are increasingly being developed; thus, optimal dose estimation designs have been receiving increased attention. Although numerous authors have introduced parametric model-based designs, it is not always appropriate to apply strong assumptions in dose–response relationships. We propose a new design based on a Bayesian optimization framework for identifying optimal doses for biologic agents in phase I/II trials. Our proposed design models dose–response relationships via nonparametric models utilizing a Gaussian process prior, and the uncertainty of estimates is considered in the dose selection process. We compared the operating characteristics of our proposed design against those of three other designs through simulation studies. These include an expansion of Bayesian optimal interval design, the parametric model-based EffTox design, and the isotonic design. In simulations, our proposed design performed well and provided results that were more stable than those from the other designs, in terms of the accuracy of optimal dose estimations and the percentage of correct recommendations.     

Bayes sequential estimation for a Poisson process under a LINEX loss function

In this paper, within the framework of a Bayesian model, we consider the problem of sequentially estimating the intensity parameter of a homogeneous Poisson process with a linear exponential (LINEX) loss function and a fixed cost per unit time. An asymptotically pointwise optimal (APO) rule is proposed. It is shown to be asymptotically optimal for the arbitrary priors and asymptotically non-deficient for the conjugate priors in a similar sense of Bickel and Yahav [Asymptotically pointwise optimal procedures in sequential analysis, in Proceedings of the Fifth Berkeley Symposium on Mathematical Statistics and Probability, Vol. 1, University of California Press, Berkeley, CA, 1967, pp. 401–413; Asymptotically optimal Bayes and minimax procedures in sequential estimation, Ann. Math. Statist. 39 (1968), pp. 442–456] and Woodroofe [A.P.O. rules are asymptotically non-deficient for estimation with squared error loss, Z. Wahrsch. verw. Gebiete 58 (1981), pp. 331–341], respectively. The proposed APO rule is illustrated using a real data set.