Time-dependent ROC curve estimation for interval-censored data.

The receiver-operating characteristic (ROC) curve is the most popular graphical method for evaluating the classification accuracy of a diagnostic marker. In time-to-event studies, the subject's event status is time-dependent, and hence, time-dependent extensions of ROC curve have been proposed. However, in practice, the calculation of this curve is not straightforward due to the presence of censoring that may be of different types. Existing methods focus on the more standard and simple case of right-censoring and neglect the general case of mixed interval-censored data that may involve left-, right-, and interval-censored observations. In this context, we propose and study a new time-dependent ROC curve estimator. We also consider some summary measures (area under the ROC curve and Youden index) traditionally associated with ROC as well as the Youden-based cutoff estimation method. The proposed method uses available data very efficiently. To this end, the unknown status (positive or negative) of censored subjects are estimated from the data via the estimation of the conditional survival function given the marker. For that, we investigate both model-based and nonparametric approaches. We also provide variance estimates and confidence intervals using Bootstrap. A simulation study is conducted to investigate the finite sample behavior of the proposed methods and to compare their performance with a competitor. Globally, we observed better finite sample performances for the proposed estimators. Finally, we illustrate the methods using two data sets one from a hypobaric decompression sickness study and the other from an oral health study. The proposed methods are implemented in the R package cenROC.

Smoothed time-dependent receiver operating characteristic curve for right censored survival data.

The prediction reliability is of primary concern in many clinical studies when the objective is to develop new predictive models or improve existing risk scores. In fact, before using a model in any clinical decision making, it is very important to check its ability to discriminate between subjects who are at risk of, for example, developing certain disease in a near future from those who will not. To that end, the time-dependent receiver operating characteristic (ROC) curve is the most commonly used method in practice. Several approaches have been proposed in the literature to estimate the ROC nonparametrically in the context of survival data. But, except one recent approach, all the existing methods provide a nonsmooth ROC estimator whereas, by definition, the ROC curve is smooth. In this article we propose and study a new nonparametric smooth ROC estimator based on a weighted kernel smoother. More precisely, our approach relies on a well-known kernel method used to estimate cumulative distribution functions of random variables with bounded supports. We derived some asymptotic properties for the proposed estimator. As bandwidth is the main parameter to be set, we present and study different methods to appropriately select one. A simulation study is conducted, under different scenarios, to prove the consistency of the proposed method and to compare its finite sample performance with a competitor. The results show that the proposed method performs better and appear to be quite robust to bandwidth choice. As for inference purposes, our results also reveal the good performances of a proposed nonparametric bootstrap procedure. Furthermore, we illustrate the method using a real data example.

On the validity of time-dependent AUC estimation in the presence of cure fraction.

During the last decades, several approaches have been proposed to estimate the time-dependent area under the receiver operating characteristic curve (AUC) of risk tools derived from survival data. The validity of these estimators relies on some regularity assumptions among which a survival function being proper. In practice, this assumption is not always satisfied because a fraction of the population may not be susceptible to experience the event of interest even for long follow-up. Studying the sensitivity of the proposed estimators to the violation of this assumption is of substantial interest. In this paper, we investigate the performance of a nonparametric simple estimator, developed for classical survival data, in the case when the population exhibits a cure fraction. Motivated from the current practice of deriving risk tools in oncology and cardiovascular disease prevention, we also assess the loss, in terms of predictive performance, when deriving risk tools from survival models that do not acknowledge the presence of cure. The simulation results show that the investigated method is valid even under the presence of cure. They also show that risk tools derived from survival models that ignore the presence of cure have smaller AUC compared to those derived from survival models that acknowledge the presence of cure. This was also attested with a real data analysis from a breast cancer study.

Variable selection in a flexible parametric mixture cure model with interval-censored data.

In standard survival analysis, it is generally assumed that every individual will experience someday the event of interest. However, this is not always the case, as some individuals may not be susceptible to this event. Also, in medical studies, it is frequent that patients come to scheduled interviews and that the time to the event is only known to occur between two visits. That is, the data are interval-censored with a cure fraction. Variable selection in such a setting is of outstanding interest. Covariates impacting the survival are not necessarily the same as those impacting the probability to experience the event. The objective of this paper is to develop a parametric but flexible statistical model to analyze data that are interval-censored and include a fraction of cured individuals when the number of potential covariates may be large. We use the parametric mixture cure model with an accelerated failure time regression model for the survival, along with the extended generalized gamma for the error term. To overcome the issue of non-stable and non-continuous variable selection procedures, we extend the adaptive LASSO to our model. By means of simulation studies, we show good performance of our method and discuss the behavior of estimates with varying cure and censoring proportion. Lastly, our proposed method is illustrated with a real dataset studying the time until conversion to mild cognitive impairment, a possible precursor of Alzheimer's disease.

Testing for qualitative heterogeneity: An application to composite endpoints in survival analysis.

Composite endpoints are frequently used in clinical outcome trials to provide more endpoints, thereby increasing statistical power. A key requirement for a composite endpoint to be meaningful is the absence of the so-called qualitative heterogeneity to ensure a valid overall interpretation of any treatment effect identified. Qualitative heterogeneity occurs when individual components of a composite endpoint exhibit differences in the direction of a treatment effect. In this paper, we develop a general statistical method to test for qualitative heterogeneity, that is to test whether a given set of parameters share the same sign. This method is based on the intersection-union principle and, provided that the sample size is large, is valid whatever the model used for parameters estimation. We propose two versions of our testing procedure, one based on a random sampling from a Gaussian distribution and another version based on bootstrapping. Our work covers both the case of completely observed data and the case where some observations are censored which is an important issue in many clinical trials. We evaluated the size and power of our proposed tests by carrying out some extensive Monte Carlo simulations in the case of multivariate time to event data. The simulations were designed under a variety of conditions on dimensionality, censoring rate, sample size and correlation structure. Our testing procedure showed very good performances in terms of statistical power and type I error. The proposed test was applied to a data set from a single-center, randomized, double-blind controlled trial in the area of Alzheimer's disease.

Diagnostic checks in mixture cure models with interval-censoring.

Models for interval-censored survival data presenting a fraction of "cure" or "immune" patients have recently been proposed in the literature, particularly extending the mixture cure model to interval-censored data. However, little is known about the goodness-of-fit of such models. In a mixture cure model, the survival distribution of the entire population is improper and expressed in terms of the survival distribution of uncured individuals, i.e. the latency part of the model, and the probability to experience the event of interest, i.e. the incidence part. To validate a mixture cure model, assumptions made on both parts need to be checked, i.e. the survival distribution of uncured individuals, the link function used in the latency and the linearity of the covariates used in the both parts of the model. In this work, we investigate the Cox-Snell and deviance residuals and show how they can be adapted and used to perform diagnostics checks when all subjects are right- or interval-censored and some subjects are cured with unknown cure status. A large simulation study investigates the ability of these residuals to detect a departure from the assumptions of the mixture model. Developed techniques are applied to a real data set about Alzheimer's disease.