Semiparametric temporal process regression of survival-out-of-hospital

Lifetime Data Analysis - The recurrent/terminal event data structure has undergone considerable methodological development in the last 10–15 years. An example of the data structure that has...     

Semiparametric regression methods for temporal processes subject to multiple sources of censoring

Process regression methodology is underdeveloped relative to the frequency with which pertinent data arise. In this article, the response-190 is a binary indicator process representing the joint event of being alive and remaining in a specific state. The process is indexed by time (e.g., time since diagnosis) and observed continuously. Data of this sort occur frequently in the study of chronic disease. A general area of application involves a recurrent event with non-negligible duration (e.g., hospitalization and associated length of hospital stay) and subject to a terminating event (e.g., death). We propose a semiparametric multiplicative model for the process version of the probability of being alive and in the (transient) state of interest. Under the proposed methods, the regression parameter is estimated through a procedure that does not require estimating the baseline probability. Unlike the majority of process regression methods, the proposed methods accommodate multiple sources of censoring. In particular, we derive a computationally convenient variant of inverse probability of censoring weighting based on the additive hazards model. We show that the regression parameter estimator is asymptotically normal, and that the baseline probability function estimator converges to a Gaussian process. Simulations demonstrate that our estimators have good finite sample performance. We apply our method to national end-stage liver disease data. The Canadian Journal of Statistics 48: 222–237; 2020 © 2019 Statistical Society of Canada     

Marginal Means/Rates Models for Multiple Type Recurrent Event Data

Recurrent events are frequently observed in biomedical studies, and often more than one type of event is of interest. Follow-up time may be censored due to loss to follow-up or administrative censoring. We propose a class of semi-parametric marginal means/rates models, with a general relative risk form, for assessing the effect of covariates on the censored event processes of interest. We formulate estimating equations for the model parameters, and examine asymptotic properties of the parameter estimators. Finite sample properties of the regression coefficients are examined through simulations. The proposed methods are applied to a retrospective cohort study of risk factors for preschool asthma.     

Estimating treatment effects on the marginal recurrent event mean in the presence of a terminating event

In biomedical studies where the event of interest is recurrent (e.g., hospitalization), it is often the case that the recurrent event sequence is subject to being stopped by a terminating event (e.g., death). In comparing treatment options, the marginal recurrent event mean is frequently of interest. One major complication in the recurrent/terminal event setting is that censoring times are not known for subjects observed to die, which renders standard risk set based methods of estimation inapplicable. We propose two semiparametric methods for estimating the difference or ratio of treatment-specific marginal mean numbers of events. The first method involves imputing unobserved censoring times, while the second methods uses inverse probability of censoring weighting. In each case, imbalances in the treatment-specific covariate distributions are adjusted out through inverse probability of treatment weighting. After the imputation and/or weighting, the treatment-specific means (then their difference or ratio) are estimated nonparametrically. Large-sample properties are derived for each of the proposed estimators, with finite sample properties assessed through simulation. The proposed methods are applied to kidney transplant data.     

Proportional hazards models based on biased samples and estimated selection probabilities

In non‐randomized biomedical studies using the proportional hazards model, the data often constitute an unrepresentative sample of the underlying target population, which results in biased regression coefficients. The bias can be avoided by weighting included subjects by the inverse of their respective selection probabilities, as proposed by Horvitz & Thompson (1952) and extended to the proportional hazards setting for use in surveys by Binder (1992) and Lin (2000). In practice, the weights are often estimated and must be treated as such in order for the resulting inference to be accurate. The authors propose a two‐stage weighted proportional hazards model in which, at the first stage, weights are estimated through a logistic regression model fitted to a representative sample from the target population. At the second stage, a weighted Cox model is fitted to the biased sample. The authors propose estimators for the regression parameter and cumulative baseline hazard. They derive the asymptotic properties of the parameter estimators, accounting for the difference in the variance introduced by the randomness of the weights. They evaluate the accuracy of the asymptotic approximations in finite samples through simulation. They illustrate their approach in an analysis of renal transplant patients using data obtained from the Scientific Registry of Transplant Recipients     

A semiparametric additive rates model for recurrent event data

Recurrent event data often arise in biomedical studies, with examples including hospitalizations, infections, and treatment failures. In observational studies, it is often of interest to estimate the effects of covariates on the marginal recurrent event rate. The majority of existing rate regression methods assume multiplicative covariate effects. We propose a semiparametric model for the marginal recurrent event rate, wherein the covariates are assumed to add to the unspecified baseline rate. Covariate effects are summarized by rate differences, meaning that the absolute effect on the rate function can be determined from the regression coefficient alone. We describe modifications of the proposed method to accommodate a terminating event (e.g., death). Proposed estimators of the regression parameters and baseline rate are shown to be consistent and asymptotically Gaussian. Simulation studies demonstrate that the asymptotic approximations are accurate in finite samples. The proposed methods are applied to a state-wide kidney transplant data set.     

Tobit regression for modeling mean survival time using data subject to multiple sources of censoring

Mean survival time is often of inherent interest in medical and epidemiologic studies. In the presence of censoring and when covariate effects are of interest, Cox regression is the strong default, but mostly due to convenience and familiarity. When survival times are uncensored, covariate effects can be estimated as differences in mean survival through linear regression. Tobit regression can validly be performed through maximum likelihood when the censoring times are fixed (ie, known for each subject, even in cases where the outcome is observed). However, Tobit regression is generally inapplicable when the response is subject to random right censoring. We propose Tobit regression methods based on weighted maximum likelihood which are applicable to survival times subject to both fixed and random censoring times. Under the proposed approach, known right censoring is handled naturally through the Tobit model, with inverse probability of censoring weighting used to overcome random censoring. Essentially, the re‐weighting data are intended to represent those that would have been observed in the absence of random censoring. We develop methods for estimating the Tobit regression parameter, then the population mean survival time. A closed form large‐sample variance estimator is proposed for the regression parameter estimator, with a semiparametric bootstrap standard error estimator derived for the population mean. The proposed methods are easily implementable using standard software. Finite‐sample properties are assessed through simulation. The methods are applied to a large cohort of patients wait‐listed for kidney transplantation.     

Semiparametric methods for center effect measures based on the ratio of survival functions

The survival function is often of chief interest in epidemiologic studies of time to an event. We develop methods for evaluating center-specific survival outcomes through a ratio of survival functions. The proposed method assumes a center-stratified additive hazards model, which provides a convenient framework for our purposes. Under the proposed methods, the center effects measure is cast as the ratio of subject-specific survival functions under two scenarios: the scenario in which the subject is treated at center \(j\) ; and that wherein the subject is treated at a hypothetical center with survival function equal to the population average. The proposed measure reduces to the ratio of baseline survival functions, but is invariant to the choice of baseline covariate level. We derive the asymptotic properties of the proposed estimators, and assess finite-sample characteristics through simulation. The proposed methods are applied to national kidney transplant data.     

Multiple imputation methods for recurrent event data with missing event category

Frequently in clinical and epidemiologic studies, the event of interest is recurrent (i.e., can occur more than once per subject). When the events are not of the same type, an analysis which accounts for the fact that events fall into different categories will often be more informative. Often, however, although event times may always be known, information through which events are categorized may potentially be missing. Complete‐case methods (whose application may require, for example, that events be censored when their category cannot be determined) are valid only when event categories are missing completely at random. This assumption is rather restrictive. The authors propose two multiple imputation methods for analyzing multiple‐category recurrent event data under the proportional means/rates model. The use of a proper or improper imputation technique distinguishes the two approaches. Both methods lead to consistent estimation of regression parameters even when the missingness of event categories depends on covariates. The authors derive the asymptotic properties of the estimators and examine their behaviour in finite samples through simulation. They illustrate their approach using data from an international study on dialysis.