Identifying the most successful dose (MSD) in dose-finding studies in cancer

For a dose finding study in cancer, the most successful dose (MSD), among a group of available doses, is that dose at which the overall success rate is the highest. This rate is the product of the rate of seeing non-toxicities together with the rate of tumor response. A successful dose finding trial in this context is one where we manage to identify the MSD in an efficient manner. In practice we may also need to consider algorithms for identifying the MSD which can incorporate certain restrictions, the most common restriction maintaining the estimated toxicity rate alone below some maximum rate. In this case the MSD may correspond to a different level than that for the unconstrained MSD and, in providing a final recommendation, it is important to underline that it is subject to the given constraint. We work with the approach described in O'Quigley et al. [Biometrics 2001; 57(4):1018-1029]. The focus of that work was dose finding in HIV where both information on toxicity and efficacy were almost immediately available. Recent cancer studies are beginning to fall under this same heading where, as before, toxicity can be quickly evaluated and, in addition, we can rely on biological markers or other measures of tumor response. Mindful of the particular context of cancer, our purpose here is to consider the methodology developed by O'Quigley et al. and its practical implementation. We also carry out a study on the doubly under-parameterized model, developed by O'Quigley et al. but not     

A BAYESIAN INTERPRETATION OF MULTIPLE POINT ESTIMATES

Consider a large number of econometric investigations using different estimation techniques and/or different subsets of all available data to estimate a fixed set of parameters. The resulting empirical distribution of point estimates can be shown - under suitable conditions - to coincide with a Bayesian posterior measure on the parameter space induced by a minimum information procedure. This Bayesian interpretation makes it easier to combine the results of various empirical exercises for statistical decision making. The collection of estimators may be generated by one investigator to ensure the satisfaction of our conditions, or they may be collected from published works, where behavioral assumptions need to be made regarding the dependence structure of econometric studies.     

Order statistics from non-identical right-truncated Lomax random variables with applications

In this paper, we derive some recurrence relations for the single and the product moments of order statistics from n independent and non-identically distributed Lomax and right-truncated Lomax random variables. These recurrence relations are simple in nature and could be used systematically in order to compute all the single and product moments of all order statistics in a simple recursive manner. The results for order statistics from the multiple-outlier model (with a slippage of p observations) are deduced as special cases. We then apply these results by examining the robustness of censored BLUE's to the presence of multiple outliers. Received: November 30, 1998; revised version: March 8, 2000     

Csiszar’s ϕ-divergences for testing the order in a Markov chain

x ₁, ..., x _n+r can be treated as the sample values of a Markov chain of order r or less (chain in which the dependence extends over r+1 consecutive variables only), and consider the problem of testing the hypothesis H ₀ that a chain of order r− 1 will be sufficient on the basis of the tools given by the Statistical Information Theory: _ϕ-Divergences. More precisely, if p _{a 1 ....., a r}: _{a r +1} denotes the transition probability for a r ^th order Markov chain, the hypothesis to be tested is H ₀:p _{a 1 ....., a r}: _{a r +1} = p _{a 2 ....., a r}: _{a r +1}, a _i ∈{1, ..., s}, i = 1, ..., r + 1 The tests given in this paper, for the first time, will have as a particular case the likelihood ratio test and the test based on the chi-squared statistic. Received: August 3, 1998; revised version: November 25, 1999     

Bayesian inference for generalized additive mixed models based on Markov random field priors

Most regression problems in practice require flexible semiparametric forms of the predictor for modelling the dependence of responses on covariates. Moreover, it is often necessary to add random effects accounting for overdispersion caused by unobserved heterogeneity or for correlation in longitudinal or spatial data. We present a unified approach for Bayesian inference via Markov chain Monte Carlo simulation in generalized additive and semiparametric mixed models. Different types of covariates, such as the usual covariates with fixed effects, metrical covariates with non-linear effects, unstructured random effects, trend and seasonal components in longitudinal data and spatial covariates, are all treated within the same general framework by assigning appropriate Markov random field priors with different forms and degrees of smoothness. We applied the approach in several case-studies and consulting cases, showing that the methods are also computationally feasible in problems with many covariates and large data sets. In this paper, we choose two typical applications.     

The role of tobacco taxes in starting and quitting smoking: Duration analysis of British data

The annual 5% increase in tobacco taxes in real terms proposed in the recent White Paper on smoking has reaffirmed the commitment of successive UK Governments to above-inflation increases in tobacco taxation to encourage people to stop smoking. This paper presents evidence on the determinants of starting and quitting smoking by using data from the British Health and Lifestyle Survey and is the first to identify tax elasticities for starting and quitting smoking using British data. Self-reported individual smoking histories are coupled with a long time series for the tax rate on cigarettes to construct a longitudinal data set. Estimates are obtained for the effect of above-inflation tax rises on the age of starting smoking and the number of years of smoking. The estimates of the tax elasticity of the age of starting smoking are 0.16 for men and 0.08 for women. The estimates of the tax elasticity of quitting are −0.60 for men and −0.46 for women. These are robust to different specifications.     

Pooling multivariate data under W, LR and LM tests

Two independent random samples are drawn from two multivariate normal populations with mean vectors μ1 and μ2 and a common variance-covariance matrix Σ. Ahmed and Saleh (1990) considered preliminary test maximum likelihood estimator (PMLTE) for estimating μ1 based on the Hotelling's T _N ², when it is suspected that μ1=μ2. In this paper, the PTMLE based on the Wald (W), Likelihood Ratio (LR) and Lagrangian Multiplier (LM) tests are considered. Using the quadratic risk function, the conditions of superiority of the proposed estimator for departure parameter are derived. A max-min rule for the size of the preliminary test of significance is presented. It is demonstrated that the PTMLE based on W test produces the highest minimum guaranteed efficiencies compared to UMLE among the three test procedures.     

Approximating probability density functions in hybrid Bayesian networks with mixtures of truncated exponentials

Mixtures of truncated exponentials (MTE) potentials are an alternative to discretization and Monte Carlo methods for solving hybrid Bayesian networks. Any probability density function (PDF) can be approximated by an MTE potential, which can always be marginalized in closed form. This allows propagation to be done exactly using the Shenoy-Shafer architecture for computing marginals, with no restrictions on the construction of a join tree. This paper presents MTE potentials that approximate standard PDF’s and applications of these potentials for solving inference problems in hybrid Bayesian networks. These approximations will extend the types of inference problems that can be modelled with Bayesian networks, as demonstrated using three examples.     

A computationally simple bivariate survival estimator for efficacy and safety

Both treatment efficacy and safety are typically the primary endpoints in Phase II, and even in some Phase III, clinical trials. Efficacy is frequently measured by time to response, death, or some other milestone event and thus is a continuous, possibly censored, outcome. Safety, however, is frequently measured on a discrete scale; in Eastern Cooperative Oncology Group clinical trial E2290, it was measured as the number of weekly rounds of chemotherapy that were tolerable to colorectal cancer patients. For the joint analysis of efficacy and safety, we propose a non-parametric, computationally simple estimator for the bivariate survival function when one time-to-event is continuous, one is discrete, and both are subject to right-censoring. The bivariate censoring times may depend on each other, but they are assumed to be independent of both event times. We derive a closed-form covariance estimator for the survivor function which allows for inference to be based on any of several possible statistics of interest. In addition, we derive its covariance with respect to calendar time of analysis, allowing for its use in sequential studies.     

Adaptive weights smoothing with applications to image restoration

We propose a new method of nonparametric estimation which is based on locally constant smoothing with an adaptive choice of weights for every pair of data points. Some theoretical properties of the procedure are investigated. Then we demonstrate the performance of the method on some simulated univariate and bivariate examples and compare it with other nonparametric methods. Finally we discuss applications of this procedure to magnetic resonance and satellite imaging.