Tests for Comparing Mark-Specific Hazards and Cumulative Incidence Functions

It is of interest in some applications to determine whether there is a relationship between a hazard rate function (or a cumulative incidence function) and a mark variable which is only observed at uncensored failure times. We develop nonparametric tests for this problem when the mark variable is continuous. Tests are developed for the null hypothesis that the mark-specific hazard rate is independent of the mark versus ordered and two-sided alternatives expressed in terms of mark-specific hazard functions and mark-specific cumulative incidence functions. The test statistics are based on functionals of a bivariate test process equal to a weighted average of differences between a Nelson--Aalen-type estimator of the mark-specific cumulative hazard function and a nonparametric estimator of this function under the null hypothesis. The weight function in the test process can be chosen so that the test statistics are asymptotically distribution-free.Asymptotically correct critical values are obtained through a simple simulation procedure. The testing procedures are shown to perform well in numerical studies, and are illustrated with an AIDS clinical trial example. Specifically, the tests are used to assess if the instantaneous or absolute risk of treatment failure depends on the amount of accumulation of drug resistance mutations in a subject's HIV virus. This assessment helps guide development of anti-HIV therapies that surmount the problem of drug resistance.

A Functional-Based Distribution Diagnostic for a Linear Model with Correlated Outcomes: Technical Report

Despite the widespread popularity of linear models for correlated outcomes (e.g. linear mixed modesl and time series models), distribution diagnostic methodology remains relatively underdeveloped in this context. In this paper we present an easy-to-implement approach that lends itself to graphical displays of model fit. Our approach involves multiplying the estimated marginal residual vector by the Cholesky decomposition of the inverse of the estimated marginal variance matrix. Linear functions or the resulting "rotated" residuals are used to construct an empirical cumulative distribution function (ECDF), whose stochastic limit is characterized. We describe a resampling technique that serves as a computationally efficient parametric bootstrap for generating representatives of the stochastic limit of the ECDF. Through functionals, such representatives are used to construct global tests for the hypothesis of normal margional errors. In addition, we demonstrate that the ECDF of the predicted random effects, as described by Lange and Ryan (1989), can be formulated as a special case of our approach. Thus, our method supports both omnibus and directed tests. Our method works well in a variety of circumstances, including models having independent units of sampling (clustered data) and models for which all observations are correlated (e.g., a single time series).

Markers Models in Survival Analysis and Applications to Issues Associated with AIDS

Jewell and Kalbfleisch (1992) consider the use of marker processes for applications related to estimation of the survival distribution of time to failure. Marker processes were assumed to be stochastic processes that, at a given point in time, provide information about the current hazard and consequently on the remaining time to failure. Particular attention was paid to calculations based on a simple additive model for the relationship between the hazard function at time t and the history of the marker process up until time t. Specific applications to the analysis of AIDS data included the use of markers as surrogate responses for onset of AIDS with censored data and as predictors of the time elapsed since infection in prevalent individuals. Here we review recent work on the use of marker data to tackle these kinds of problems with AIDS data. The Poisson marker process with an additive model, introduced in Jewell and Kalbfleisch (1992) may be a useful "test" example for comparison of various procedures.