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Missing covariate values is a common problem in survival analysis. In this paper we propose a novel method for the Cox regression model that is close to maximum likelihood but avoids the use of the EM-algorithm. It exploits that the observed hazard function is multiplicative in the baseline hazard function with the idea being to profile out this function before carrying out the estimation of the parameter of interest. In this step one uses a Breslow type estimator to estimate the cumulative baseline hazard function. We focus on the situation where the observed covariates are categorical which allows us to calculate estimators without having to assume anything about the distribution of the covariates. We show that the proposed estimator is consistent and asymptotically normal, and derive a consistent estimator of the variance-covariance matrix that does not involve any choice of a perturbation parameter. Moderate sample size performance of the estimators is investigated via simulation and by application to a real data example.

We consider data from the Danish twin registry and aim to study in detail how lifetimes for twin-pairs are correlated. We consider models where we specify the marginals using a regression structure, here Cox's regression model or the additive hazards model. The best known such model is the Clayton-Oakes model. This model can be extended in several directions. One extension is to allow the dependence parameter to depend on covariates. Another extension is to model dependence via piecewise constant cross-hazard ratio models. We show how both these models can be implemented for large sample data, and suggest a computational solution for obtaining standard errors for such models for large registry data. In addition we consider alternative models that have some computational advantages and with different dependence parameters based on odds ratios of the survival function using the Plackett distribution. We also suggest a way of assessing how and if the dependence is changing over time, by considering either truncated or right-censored versions of the data to measure late or early dependence. This can be used for formally testing if the dependence is constant, or decreasing/increasing. The proposed procedures are applied to Danish twin data to describe dependence in the lifetimes of the twins. Here we show that the early deaths are more correlated than the later deaths, and by comparing MZ and DZ associations we suggest that early deaths might be more driven by genetic factors. This conclusion requires models that are able to look at more local dependence measures. We further show that the dependence differs for MZ and DZ twins and appears to be the same for males and females, and that there are indications that the dependence increases over calendar time.

Recently, Fine and Gray (J Am Stat Assoc 94:496-509, 1999) proposed a semi-parametric proportional regression model for the subdistribution hazard function which has been used extensively for analyzing competing risks data. However, failure of model adequacy could lead to severe bias in parameter estimation, and only a limited contribution has been made to check the model assumptions. In this paper, we present a class of analytical methods and graphical approaches for checking the assumptions of Fine and Gray's model. The proposed goodness-of-fit test procedures are based on the cumulative sums of residuals, which validate the model in three aspects: (1) proportionality of hazard ratio, (2) the linear functional form and (3) the link function. For each assumption testing, we provide a p-values and a visualized plot against the null hypothesis using a simulation-based approach. We also consider an omnibus test for overall evaluation against any model misspecification. The proposed tests perform well in simulation studies and are illustrated with two real data examples.

There has been considerable interest in studying the magnitude and type of inheritance of specific diseases. This is typically derived from family or twin studies, where the basic idea is to compare the correlation for different pairs that share different amount of genes. We here consider data from the Danish twin registry and discuss how to define heritability for cancer occurrence. The key point is that this should be done taking censoring as well as competing risks due to e.g.  death into account. We describe the dependence between twins on the probability scale and show that various models can be used to achieve sensible estimates of the dependence within monozygotic and dizygotic twin pairs that may vary over time. These dependence measures can subsequently be decomposed into a genetic and environmental component using random effects models. We here present several novel models that in essence describe the association in terms of the concordance probability, i.e., the probability that both twins experience the event, in the competing risks setting. We also discuss how to deal with the left truncation present in the Nordic twin registries, due to sampling only of twin pairs where both twins are alive at the initiation of the registries.

In this paper we consider a problem from hematopoietic cell transplant (HCT) studies where there is interest on assessing the effect of haplotype match for donor and patient on the cumulative incidence function for a right censored competing risks data. For the HCT study, donor's and patient's genotype are fully observed and matched but their haplotypes are missing. In this paper we describe how to deal with missing covariates of each individual for competing risks data. We suggest a procedure for estimating the cumulative incidence functions for a flexible class of regression models when there are missing data, and establish the large sample properties. Small sample properties are investigated using simulations in a setting that mimics the motivating haplotype matching problem. The proposed approach is then applied to the HCT study.

This paper considers estimation and prediction in the Aalen additive hazards model in the case where the covariate vector is high-dimensional such as gene expression measurements. Some form of dimension reduction of the covariate space is needed to obtain useful statistical analyses. We study the partial least squares regression method. It turns out that it is naturally adapted to this setting via the so-called Krylov sequence. The resulting PLS estimator is shown to be consistent provided that the number of terms included is taken to be equal to the number of relevant components in the regression model. A standard PLS algorithm can also be constructed, but it turns out that the resulting predictor can only be related to the original covariates via time-dependent coefficients. The methods are applied to a breast cancer data set with gene expression recordings and to the well known primary biliary cirrhosis clinical data.

In this paper we consider different approaches for estimation and assessment of covariate effects for the cumulative incidence curve in the competing risks model. The classic approach is to model all cause-specific hazards and then estimate the cumulative incidence curve based on these cause-specific hazards. Another recent approach is to directly model the cumulative incidence by a proportional model (Fine and Gray, J Am Stat Assoc 94:496-509, 1999), and then obtain direct estimates of how covariates influences the cumulative incidence curve. We consider a simple and flexible class of regression models that is easy to fit and contains the Fine-Gray model as a special case. One advantage of this approach is that our regression modeling allows for non-proportional hazards. This leads to a new simple goodness-of-fit procedure for the proportional subdistribution hazards assumption that is very easy to use. The test is constructive in the sense that it shows exactly where non-proportionality is present. We illustrate our methods to a bone marrow transplant data from the Center for International Blood and Marrow Transplant Research (CIBMTR). Through this data example we demonstrate the use of the flexible regression models to analyze competing risks data when non-proportionality is present in the data.

We consider tied survival data based on Cox proportional regression model. The standard approaches are the Breslow and Efron approximations and various so called exact methods. All these methods lead to biased estimates when the true underlying model is in fact a Cox model. In this paper we review the methods and suggest a new method based on the missing-data principle using EM-algorithm that leads to a score equation that can be solved directly. This score has mean zero. We also show that all the considered methods have the same asymptotic properties and that there is no loss of asymptotic efficiency when the tie sizes are bounded or even converge to infinity at a given rate. A simulation study is conducted to compare the finite sample properties of the methods.

I suggest an extension of the semiparametric transformation model that specifies a time-varying regression structure for the transformation, and thus allows time-varying structure in the data. Special cases include a stratified version of the usual semiparametric transformation model. The model can be thought of as specifying a first order Taylor expansion of a completely flexible baseline. Large sample properties are derived and estimators of the asymptotic variances of the regression coefficients are given. The method is illustrated by a worked example and a small simulation study. A goodness of fit procedure for testing if the regression effects lead to a satisfactory fit is also suggested.

We use the additive risk model of Aalen (Aalen, 1980) as a model for the rate of a counting process. Rather than specifying the intensity, that is the instantaneous probability of an event conditional on the entire history of the relevant covariates and counting processes, we present a model for the rate function, i.e., the instantaneous probability of an event conditional on only a selected set of covariates. When the rate function for the counting process is of Aalen form we show that the usual Aalen estimator can be used and gives almost unbiased estimates. The usual martingale based variance estimator is incorrect and an alternative estimator should be used. We also consider the semi-parametric version of the Aalen model as a rate model (McKeague and Sasieni, 1994) and show that the standard errors that are computed based on an assumption of intensities are incorrect and give a different estimator. Finally, we introduce and implement a test-statistic for the hypothesis of a time-constant effect in both the non-parametric and semi-parametric model. A small simulation study was performed to evaluate the performance of the new estimator of the standard error.

The nonparametric maximum likelihood estimator for current-status data has been known for at least 40 years, but only recently have the mathematical-statistical properties been clarified. This note provides a case study in the important and often studied context of estimating age-specific immunization intensities from a seroprevalence survey. Fully parametric and spline-based alternatives (also based on continuous-time models) are given. The basic reproduction number R0 exemplifies estimation of a functional. The limitations implied by the necessarily rather restrictive epidemiological assumptions are briefly discussed.