Estimation of conditional cumulative incidence functions under generalized semiparametric regression models with missing covariates, with application to analysis of biomarker correlates in vaccine trials.

This article studies generalized semiparametric regression models for conditional cumulative incidence functions with competing risks data when covariates are missing by sampling design or happenstance. A doubly-robust augmented inverse probability weighted complete-case (AIPW) approach to estimation and inference is investigated. This approach modifies IPW complete-case estimating equations by exploiting the key features in the relationship between the missing covariates and the phase-one data to improve efficiency. An iterative numerical procedure is derived to solve the nonlinear estimating equations. The asymptotic properties of the proposed estimators are established. A simulation study examining the finite-sample performances of the proposed estimators shows that the AIPW estimators are more efficient than the IPW estimators. The developed method is applied to the RV144 HIV-1 vaccine efficacy trial to investigate vaccine-induced IgG binding antibodies to HIV-1 as correlates of acquisition of HIV-1 infection while taking account of whether the HIV-1 sequences are near or far from the HIV-1 sequences represented in the vaccine construct.

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Estimating disease onset from change points of markers measured with error.

Huntington disease is an autosomal dominant, neurodegenerative disease without clearly identified biomarkers for when motor-onset occurs. Current standards to determine motor-onset rely on a clinician's subjective judgment that a patient's extrapyramidal signs are unequivocally associated with Huntington disease. This subjectivity can lead to error which could be overcome using an objective, data-driven metric that determines motor-onset. Recent studies of motor-sign decline-the longitudinal degeneration of motor-ability in patients-have revealed that motor-onset is closely related to an inflection point in its longitudinal trajectory. We propose a nonlinear location-shift marker model that captures this motor-sign decline and assesses how its inflection point is linked to other markers of Huntington disease progression. We propose two estimating procedures to estimate this model and its inflection point: one is a parametric method using nonlinear mixed effects model and the other one is a multi-stage nonparametric approach, which we developed. In an empirical study, the parametric approach was sensitive to correct specification of the mean structure of the longitudinal data. In contrast, our multi-stage nonparametric procedure consistently produced unbiased estimates regardless of the true mean structure. Applying our multi-stage nonparametric estimator to Neurobiological Predictors of Huntington Disease, a large observational study of Huntington disease, leads to earlier prediction of motor-onset compared to the clinician's subjective judgment.

Analysis of repeated measures data in nutrition research.

Amino acid nutrition studies often involve repeated measures data. An example is that the concentrations of plasma citrulline in steers are repeatedly measured from the same animals. The standard repeated measures ANOVA method does not detect significant time changes in the concentrations of plasma citrulline within 6 hours after steers consumed rumen-protected citrulline, while a graphical analysis indicates that there exists a time effect. Here we describe three mixed model analyses that capture the time effect in a statistically significant way, while accounting for the correlations of measurements over time from the same steers. First, we allow flexible variance-covariance structures on our model. Second, we use baseline measurements as a covariate in our model. Third, we use percent-change from baseline as a data normalization method. In our data analysis, all these three approaches can lead to meaningful statistical results that oral administration of rumen-protected citrulline enhances the concentrations of plasma citrulline over time in ruminants. This supports the notion that rumen-protected citrulline can bypass the rumen to effectively enter the blood circulation.

Analysis of Generalized Semiparametric Regression Models for Cumulative Incidence Functions with Missing Covariates.

The cumulative incidence function quantifies the probability of failure over time due to a specific cause for competing risks data. The generalized semiparametric regression models for the cumulative incidence functions with missing covariates are investigated. The effects of some covariates are modeled as non-parametric functions of time while others are modeled as parametric functions of time. Different link functions can be selected to add flexibility in modeling the cumulative incidence functions. The estimation procedures based on the direct binomial regression and the inverse probability weighting of complete cases are developed. This approach modifies the full data weighted least squares equations by weighting the contributions of observed members through the inverses of estimated sampling probabilities which depend on the censoring status and the event types among other subject characteristics. The asymptotic properties of the proposed estimators are established. The finite-sample performances of the proposed estimators and their relative efficiencies under different two-phase sampling designs are examined in simulations. The methods are applied to analyze data from the RV144 vaccine efficacy trial to investigate the associations of immune response biomarkers with the cumulative incidence of HIV-1 infection.