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.     

Confidence intervals for secondary parameters following a sequential test

In sequential studies, formal interim analyses are usually restricted to a consideration of a single null hypothesis concerning a single parameter of interest. Valid frequentist methods of hypothesis testing and of point and interval estimation for the primary parameter have already been devised for use at the end of such a study. However, the completed data set may warrant a more detailed analysis, involving the estimation of parameters corresponding to effects that were not used to determine when to stop, and yet correlated with those that were. This paper describes methods for setting confidence intervals for secondary parameters in a way which provides the correct coverage probability in repeated frequentist realizations of the sequential design used. The method assumes that information accumulates on the primary and secondary parameters at proportional rates. This requirement will be valid in many potential applications, but only in limited situations in survival analysis.     

Bayes linear analysis for graphical models: The geometric approach to local computation and interpretive graphics

This paper concerns the geometric treatment of graphical models using Bayes linear methods. We introduce Bayes linear separation as a second order generalised conditional independence relation, and Bayes linear graphical models are constructed using this property. A system of interpretive and diagnostic shadings are given, which summarise the analysis over the associated moral graph. Principles of local computation are outlined for the graphical models, and an algorithm for implementing such computation over the junction tree is described. The approach is illustrated with two examples. The first concerns sales forecasting using a multivariate dynamic linear model. The second concerns inference for the error variance matrices of the model for sales, and illustrates the generality of our geometric approach by treating the matrices directly as random objects. The examples are implemented using a freely available set of object-oriented programming tools for Bayes linear local computation and graphical diagnostic display.     

Designing and integrating composite networks for monitoring multivariate gaussian pollution fields

Networks of ambient monitoring stations are used to monitor environmental pollution fields such as those for acid rain and air pollution. Such stations provide regular measurements of pollutant concentrations. The networks are established for a variety of purposes at various times so often several stations measuring different subsets of pollutant concentrations can be found in compact geographical regions. The problem of statistically combining these disparate information sources into a single 'network' then arises. Capitalizing on the efficiencies so achieved can then lead to the secondary problem of extending this network. The subject of this paper is a set of 31 air pollution monitoring stations in southern Ontario. Each of these regularly measures a particular subset of ionic sulphate, sulphite, nitrite and ozone. However, this subset varies from station to station. For example only two stations measure all four. Some measure just one. We describe a Bayesian framework for integrating the measurements of these stations to yield a spatial predictive distribution for unmonitored sites and unmeasured concentrations at existing stations. Furthermore we show how this network can be extended by using an entropy maximization criterion. The methods assume that the multivariate response field being measured has a joint Gaussian distribution conditional on its mean and covariance function. A conjugate prior is used for these parameters, some of its hyperparameters being fitted empirically.     

Diagnostic checks for discrete data regression models using posterior predictive simulations

Model checking with discrete data regressions can be difficult because the usual methods such as residual plots have complicated reference distributions that depend on the parameters in the model. Posterior predictive checks have been proposed as a Bayesian way to average the results of goodness-of-fit tests in the presence of uncertainty in estimation of the parameters. We try this approach using a variety of discrepancy variables for generalized linear models fitted to a historical data set on behavioural learning. We then discuss the general applicability of our findings in the context of a recent applied example on which we have worked. We find that the following discrepancy variables work well, in the sense of being easy to interpret and sensitive to important model failures: structured displays of the entire data set, general discrepancy variables based on plots of binned or smoothed residuals versus predictors and specific discrepancy variables created on the basis of the particular concerns arising in an application. Plots of binned residuals are especially easy to use because their predictive distributions under the model are sufficiently simple that model checks can often be made implicitly. The following discrepancy variables did not work well: scatterplots of latent residuals defined from an underlying continuous model and quantile–quantile plots of these residuals.     

Factors influencing Soay sheep survival

We present a survival analysis of Soay sheep mark recapture and recovery data. Unlike previous conditional analyses, it is not necessary to assume equality of recovery and recapture probabilities; instead these are estimated by maximum likelihood. Male and female sheep are treated separately, with the higher numbers and survival probabilities of the females resulting in a more complex model than that used for the males. In both cases, however, age and time aspects need to be included and there is a strong indication of a reduction in survival for sheep aged 7 years or more. Time variation in survival is related to the size of the population and selected weather variables, by using logistic regression. The size of the population significantly affects the survival probabilities of male and female lambs, and of female sheep aged 7 or more years. March rainfall and a measure of the North Atlantic oscillation are found to influence survival significantly for all age groups considered, for both males and females. Either of these weather variables can be used in a model. Several phenotypic and genotypic individual covariates are also fitted. The only covariate which is found to influence survival significantly is the type of horn of first-year female sheep. There is a substantial variation in the recovery probabilities over time, reflecting in part the increased effort when a population crash was expected. The goodness of fit of the model is checked by using graphical procedures.     

Binary probability maps using a hidden conditional autoregressive Gaussian process with an application to Finnish common toad data

The Finnish common toad data of Heikkinen and Hogmander are reanalysed using an alternative fully Bayesian model that does not require a pseudolikelihood approximation and an alternative prior distribution for the true presence or absence status of toads in each 10 km×10 km square. Markov chain Monte Carlo methods are used to obtain posterior probability estimates of the square-specific presences of the common toad and these are presented as a map. The results are different from those of Heikkinen and Hogmander and we offer an explanation in terms of the prior used for square-specific presence of the toads. We suggest that our approach is more faithful to the data and avoids unnecessary confounding of effects. We demonstrate how to extend our model efficiently with square-specific covariates and illustrate this by introducing deterministic spatial changes.     

Asymptotic Bias in Parameter Estimation of AR-Processes Using Recursive Least Squares with Exponential Forgetting

The recursive least squares technique is often extended with exponential forgetting as a tool for parameter estimation in time-varying systems. The distribution of the resulting parameter estimates is, however, unknown when the forgetting factor is less than one. In this paper an approximative expression for bias of the recursively obtained parameter estimates in a time-invariant AR( n_a ) process with arbitrary noise is given, showing that the bias is non-zero and giving bounds on the approximation errors. Simulations confirm the approximation expressions.     

Adaptive Estimation of the Integral of Squared Regression Derivatives

A problem of estimating the integral of a squared regression function and of its squared derivatives has been addressed in a number of papers. For the case of a heteroscedastic model where smoothness of the underlying regression function, the design density, and the variance of errors are known, the asymptotically sharp minimax lower bound and a sharp estimator were found in Pastuchova & Khasminski (1989). However, there are apparently no results on the either rate optimal or sharp optimal adaptive, or data-driven, estimation when neither the degree of regression function smoothness nor design density, scale function and distribution of errors are known. After a brief review of main developments in non-parametric estimation of non-linear functionals, we suggest a simple adaptive estimator for the integral of a squared regression function and its derivatives and prove that it is sharp-optimal whenever the estimated derivative is sufficiently smooth.