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Recurrent event data frequently occur in longitudinal studies when subjects experience more than one event during the observation period. Often, the occurrence of subsequent events is associated with the experience of previous events. Such dependence is commonly ignored in the application of standard recurrent event methodology. In this paper, we utilize a Cox-type regression model with time-varying triggering effect depending on the number and timing of previous events to enhance both model fit and prediction. Parameter estimation and statistical inference is achieved via the partial likelihood. A statistical test procedure is provided to assess the existence of the triggering effects. We demonstrate our approach via comprehensive simulation studies and a real data analysis on chronic pseudomonas infections in young cystic fibrosis patients. Our model provides significantly better predictions than standard recurrent event models., (© 2019 John Wiley & Sons, Ltd.)

Objectives: To examine the effect of the number of events per variable (EPV) on the accuracy of estimated regression coefficients, standard errors, empirical coverage rates of estimated confidence intervals, and empirical estimates of statistical power when using the Fine-Gray subdistribution hazard regression model to assess the effect of covariates on the incidence of events that occur over time in the presence of competing risks., Study Design and Setting: Monte Carlo simulations were used. We considered two different definitions of the number of EPV. One included events of any type that occurred (both primary events and competing events), whereas the other included only the number of primary events that occurred., Results: The definition of EPV that included only the number of primary events was preferable to the alternative definition, as the number of competing events had minimal impact on estimation. In general, 40-50 EPV were necessary to ensure accurate estimation of regression coefficients and associated quantities. However, if all of the covariates are continuous or are binary with moderate prevalence, then 10 EPV are sufficient to ensure accurate estimation., Conclusion: Analysts must base the number of EPV on the number of primary events that occurred., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)

In the standard analysis of competing risks data, proportional hazards models are fit to the cause-specific hazard functions for all causes on the same time scale. These regression analyses are the foundation for predictions of cause-specific cumulative incidence functions based on combining the estimated cause-specific hazard functions. However, in predictions arising from disease registries, where only subjects with disease enter the database, disease-related mortality may be more naturally modeled on the time since diagnosis time scale while death from other causes may be more naturally modeled on the age time scale. The single time scale methodology may be biased if an incorrect time scale is employed for one of the causes and an alternative methodology is not available. We propose inferences for the cumulative incidence function in which regression models for the cause-specific hazard functions may be specified on different time scales. Using the disease registry data, the analysis of other cause mortality on the age scale requires left truncating the event time at the age of disease diagnosis, complicating the analysis. In addition, standard Martingale theory is not applicable when combining regression models on different time scales. We establish that the covariate conditional predictions are consistent and asymptotically normal using empirical process techniques and propose consistent variance estimators for constructing confidence intervals. Simulation studies show that the proposed two time scales method performs well, outperforming the single time-scale predictions when the time scale is misspecified. The methods are illustrated with stage III colon cancer data obtained from the Surveillance, Epidemiology, and End Results program of National Cancer Institute., (© The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Instrumental variable (IV) methods are popular in non-experimental studies to estimate the causal effects of medical interventions. These approaches allow for the consistent estimation of treatment effects even if important confounding factors are unobserved. Despite the increasing use of these methods, there have been few extensions of IV methods to censored data problems. In this article, we discuss challenges in applying IV techniques to the proportional hazards model and demonstrate the utility of the additive hazards formulation for IV analyses with censored data. Assuming linear structural equation models for the hazard function, we develop a closed-form, two-stage estimator for the causal effect in the additive hazard model. The methods permit both continuous and discrete exposures, and enable the estimation of causal relative survival measures. The asymptotic properties of the estimators are derived and the resulting inferences are shown to perform well in simulation studies and in an application to a data set on the effectiveness of a novel chemotherapeutic agent for colon cancer., (© 2014, The International Biometric Society.)

This paper concerns using modified weighted Schoenfeld residuals to test the proportionality of subdistribution hazards for the Fine-Gray model, similar to the tests proposed by Grambsch and Therneau for independently censored data. We develop a score test for the time-varying coefficients based on the modified Schoenfeld residuals derived assuming a certain form of non-proportionality. The methods perform well in simulations and a real data analysis of breast cancer data, where the treatment effect exhibits non-proportional hazards., (Copyright © 2013 John Wiley & Sons, Ltd.)

With competing risks failure time data, one often needs to assess the covariate effects on the cumulative incidence probabilities. Fine and Gray proposed a proportional hazards regression model to directly model the subdistribution of a competing risk. They developed the estimating procedure for right-censored competing risks data, based on the inverse probability of censoring weighting. Right-censored and left-truncated competing risks data sometimes occur in biomedical researches. In this paper, we study the proportional hazards regression model for the subdistribution of a competing risk with right-censored and left-truncated data. We adopt a new weighting technique to estimate the parameters in this model. We have derived the large sample properties of the proposed estimators. To illustrate the application of the new method, we analyze the failure time data for children with acute leukemia. In this example, the failure times for children who had bone marrow transplants were left truncated., (Copyright © 2011 John Wiley & Sons, Ltd.)

For competing risks data, the Fine-Gray proportional hazards model for subdistribution has gained popularity for its convenience in directly assessing the effect of covariates on the cumulative incidence function. However, in many important applications, proportional hazards may not be satisfied, including multicenter clinical trials, where the baseline subdistribution hazards may not be common due to varying patient populations. In this article, we consider a stratified competing risks regression, to allow the baseline hazard to vary across levels of the stratification covariate. According to the relative size of the number of strata and strata sizes, two stratification regimes are considered. Using partial likelihood and weighting techniques, we obtain consistent estimators of regression parameters. The corresponding asymptotic properties and resulting inferences are provided for the two regimes separately. Data from a breast cancer clinical trial and from a bone marrow transplantation registry illustrate the potential utility of the stratified Fine-Gray model., (© 2010, The International Biometric Society.)

Bandeen-Roche and Liang (2002, Modelling multivariate failure time associations in the presence of a competing risk. Biometrika 89, 299-314.) tailored Oakes (1989, Bivariate survival models induced by frailties. Journal of the American Statistical Association 84, 487-493.)'s conditional hazard ratio to evaluate cause-specific associations in bivariate competing risks data. In many population-based family studies, one observes complex multivariate competing risks data, where the family sizes may be > 2, certain marginals may be exchangeable, and there may be multiple correlated relative pairs having a given pairwise association. Methods for bivariate competing risks data are inadequate in these settings. We show that the rank correlation estimator of Bandeen-Roche and Liang (2002) extends naturally to general clustered family structures. Consistency, asymptotic normality, and variance estimation are easily obtained with U-statistic theories. A natural by-product is an easily implemented test for constancy of the association over different time regions. In the Cache County Study on Memory in Aging, familial associations in dementia onset are of interest, accounting for death prior to dementia. The proposed methods using all available data suggest attenuation in dementia associations at later ages, which had been somewhat obscured in earlier analyses.

Summary: The work is motivated by the Cache County Study of Aging, a population-based study in Utah, in which sibship associations in dementia onset are of interest. Complications arise because only a fraction of the population ever develops dementia, with the majority dying without dementia. The application of standard dependence analyses for independently right-censored data may not be appropriate with such multivariate competing risks data, where death may violate the independent censoring assumption. Nonparametric estimators of the bivariate cumulative hazard function and the bivariate cumulative incidence function are adapted from the simple nonexchangeable bivariate setup to exchangeable clustered data, as needed with the large sibships in the Cache County Study. Time-dependent association measures are evaluated using these estimators. Large sample inferences are studied rigorously using empirical process techniques. The practical utility of the methodology is demonstrated with realistic samples both via simulations and via an application to the Cache County Study, where dementia onset clustering among siblings varies strongly by age.

The cumulative incidence function is widely reported in competing risks studies, with group differences assessed by an extension of the log-rank test. However, simple, interpretable summaries of group differences are not available. An adaptation of the proportional hazards model to the cumulative incidence function is often employed, but the interpretation of the hazard ratio may be somewhat awkward, unlike the usual survival set-up. We propose nonparametric inferences for general summary measures, which may be time-varying, and for time-averaged versions of the measures. Theoretical justification is provided using counting process techniques. A real data example illustrates the practical utility of the methods., (Copyright 2008 John Wiley & Sons, Ltd.)

This chapter introduces some fundamental results in survival analysis. We first describe what is censored failure time data and how to interpret the failure time distribution. Two nonparametric methods for estimating the survival curve, the life table estimator and the Kaplan-Meier estimator, are demonstrated. We then discuss the two-sample problem and the usage of the log-rank test for comparing survival distributions between groups. Lastly, we discuss in some detail the proportional hazards model, which is a semiparametric regression model specifically developed for censored data. All methods are illustrated with artificial or real data sets.

As a useful alternative to Cox's proportional hazard model, the additive risk model assumes that the hazard function is the sum of the baseline hazard function and the regression function of covariates. This article is concerned with estimation and prediction for the additive risk models with right censored survival data, especially when the dimension of the covariates is comparable to or larger than the sample size. Principal component regression is proposed to give unique and numerically stable estimators. Asymptotic properties of the proposed estimators, component selection based on the weighted bootstrap, and model evaluation techniques are discussed. This approach is illustrated with analysis of the primary biliary cirrhosis clinical data and the diffuse large B-cell lymphoma genomic data. It is shown that this methodology is numerically stable and effective in dimension reduction, while still being able to provide satisfactory prediction and classification results.

We consider estimation of the semiparametric additive hazards model with an unspecified baseline hazard function where the effect of a continuous covariate has a specific shape but otherwise unspecified. Such estimation is particularly useful for a unimodal hazard function, where the hazard is monotone increasing and monotone decreasing with an unknown mode. A popular approach of the proportional hazards model is limited in such setting due to the complicated structure of the partial likelihood. Our model defines a quadratic loss function, and its simple structure allows a global Hessian matrix that does not involve parameters. Thus, once the global Hessian matrix is computed, a standard quadratic programming method can be applicable by profiling all possible locations of the mode. However, the quadratic programming method may be inefficient to handle a large global Hessian matrix in the profiling algorithm due to a large dimensionality, where the dimension of the global Hessian matrix and number of hypothetical modes are the same order as the sample size. We propose the quadratic pool adjacent violators algorithm to reduce computational costs. The proposed algorithm is extended to the model with a time‐dependent covariate with monotone or U‐shape hazard function. In simulation studies, our proposed method improves computational speed compared to the quadratic programming method, with bias and mean square error reductions. We analyze data from a recent cardiovascular study. [ABSTRACT FROM AUTHOR]

In the analysis for competing risks data, regression modeling of the cause‐specific hazard functions has been usually conducted using the same time scale for all event types. However, when the true time scale is different for each event type, it would be appropriate to specify regression models for the cause‐specific hazards on different time scales for different event types. Often, the proportional hazards model has been used for regression modeling of the cause‐specific hazard functions. However, the proportionality assumption may not be appropriate in practice. In this article, we consider the additive risk model as an alternative to the proportional hazards model. We propose predictions of the cumulative incidence functions under the cause‐specific additive risk models employing different time scales for different event types. We establish the consistency and asymptotic normality of the predicted cumulative incidence functions under the cause‐specific additive risk models specified on different time scales using empirical processes and derive consistent variance estimators of the predicted cumulative incidence functions. Through simulation studies, we show that the proposed prediction methods perform well. We illustrate the methods using stage III breast cancer data obtained from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute. [ABSTRACT FROM AUTHOR]

Estimates of treatment effects in non-experimental studies are subject to bias owing to unobserved confounding. It is desirable to assess the sensitivity of an estimated treatment effect to a hypothetical unmeasured confounder, U. A commonly used approach to sensitivity analysis requires two parameters: one parameter relates U to the treatment and the other relates it to the outcome. The method uses a simple algebraic formula with these two parameters to relate the true treatment effect to the apparent treatment effect, obtained from a reduced model without U. This formula approximately holds for logistic and proportional hazards models, which are frequently used to model binary and survival outcomes. This approximation works with an assumption that the absolute regression coefficient for the unmeasured confounder is small. Therefore, when the unmeasured confounding is relatively large, the formula will not perform well. In this article, we propose alternative sensitivity analysis methods for binary and survival outcomes. We develop sensitivity analysis formulas for treatment effect estimates under probit and additive hazard models, which are alternatives to the logistic and proportional hazards models, respectively. The proposed formulae hold without any approximations. We also discuss a method to postulate reasonable values of the sensitivity parameters using the observed covariates. Simulation studies demonstrate that the proposed formulae perform well for moderate and severe unmeasured confounding even when the model used for the sensitivity analysis is moderately mis-specified. The practical utility of the approach is illustrated in two example studies. [ABSTRACT FROM AUTHOR]

Instrumental variables (IVs) are useful for estimating causal effects in the presence of unmeasured confounding. IV methods are well developed for uncensored outcomes, particularly for structural linear equation models, where simple two-stage estimation schemes are available. Extending these methods to survival settings is challenging, partly because of the nonlinearity of the popular survival regression models, and partly because of the complexity of right censoring and other survival features. Motivated by the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, we develop a simple causal hazard ratio estimator in a proportional hazards model with right-censored data. The method exploits a special characterization of IVs that enables the use of an intuitive inverse weighting scheme that is generally applicable to more complex survival settings with left truncation, competing risks, or recurrent events. We rigorously establish the asymptotic properties of the estimators, and provide plug-in variance estimators. The proposed method can be implemented in standard software, and is evaluated through extensive simulation studies. We apply the proposed IV method to a data set from the PLCO Cancer Screening Trial to identify the causal effect of flexible sigmoidoscopy screening on colorectal cancer survival, which may be confounded by informative noncompliance with the assigned screening regimen. [ABSTRACT FROM AUTHOR]

This article provides methods of causal inference for competing risks data. The methods are formulated as structural nested mean models of causal effects directly related to the cumulative incidence function or subdistribution hazard, which reflect the survival experience of a subject in the presence of competing risks. The effect measures include causal risk differences, causal risk ratios, causal subdistribution hazard ratios, and causal effects of time-varying exposures. Inference is implemented by g-estimation using pseudo-observations, a technique to handle censoring. The finite-sample performance of the proposed estimators in simulated datasets and application to time-varying exposures in a cohort study of type 2 diabetes are also presented. [ABSTRACT FROM AUTHOR]

We consider scenarios in which the likelihood function for a semiparametric regression model factors into separate components, with an efficient estimator of the regression parameter available for each component. An optimal weighted combination of the component estimators, named an ensemble estimator, may be employed as an overall estimate of the regression parameter, and may be fully efficient under uncorrelatedness conditions. This approach is useful when the full likelihood function may be difficult to maximize, but the components are easy to maximize. It covers settings where the nuisance parameter may be estimated at different rates in the component likelihoods. As a motivating example we consider proportional hazards regression with prospective doubly censored data, in which the likelihood factors into a current status data likelihood and a left-truncated right-censored data likelihood. Variable selection is important in such regression modelling, but the applicability of existing techniques is unclear in the ensemble approach. We propose ensemble variable selection using the least squares approximation technique on the unpenalized ensemble estimator, followed by ensemble re-estimation under the selected model. The resulting estimator has the oracle property such that the set of nonzero parameters is successfully recovered and the semiparametric efficiency bound is achieved for this parameter set. Simulations show that the proposed method performs well relative to alternative approaches. Analysis of an AIDS cohort study illustrates the practical utility of the method. [ABSTRACT FROM AUTHOR]

In survival analysis, time-varying covariates are covariates whose value can change during follow-up. Outcomes in medical research are frequently subject to competing risks (events precluding the occurrence of the primary outcome). We review the types of time-varying covariates and highlight the effect of their inclusion in the subdistribution hazard model. External time-dependent covariates are external to the subject, can effect the failure process, but are not otherwise involved in the failure mechanism. Internal time-varying covariates are measured on the subject, can effect the failure process directly, and may also be impacted by the failure mechanism. In the absence of competing risks, a consequence of including internal time-dependent covariates in the Cox model is that one cannot estimate the survival function or the effect of covariates on the survival function. In the presence of competing risks, the inclusion of internal time-varying covariates in a subdistribution hazard model results in the loss of the ability to estimate the cumulative incidence function (CIF) or the effect of covariates on the CIF. Furthermore, the definition of the risk set for the subdistribution hazard function can make defining internal time-varying covariates difficult or impossible. We conducted a review of the use of time-varying covariates in subdistribution hazard models in articles published in the medical literature in 2015 and in the first 5 months of 2019. Seven percent of articles published included a time-varying covariate. Several inappropriately described a time-varying covariate as having an association with the risk of the outcome. [ABSTRACT FROM AUTHOR]

We consider the estimation of the semiparametric proportional hazards model with an unspecified baseline hazard function where the effect of a continuous covariate is assumed to be monotone. Previouswork on nonparametric maximum likelihood estimation for isotonic proportional hazard regression with right-censored data is computationally intensive, lacks theoretical justification, and may be prohibitive in large samples. In this paper, partial likelihood estimation is studied. An iterative quadratic programming method is considered, which has performed well with likelihoods for isotonic parametric regression models. However, the iterative quadratic programming method for the partial likelihood cannot be implemented using standard pool-adjacent-violators techniques, increasing the computational burden and numerical instability. The iterative convex minorant algorithm which uses pool-adjacent-violators techniques has also been shown to perform well in related parametric likelihood set-ups, but evidences computational difficulties under the proportional hazards model.An alternative pseudo-iterative convex minorant algorithm is proposed which exploits the pool-adjacent-violators techniques, is theoretically justified, and exhibits computational stability.Aseparate estimator of the baseline hazard function is provided. The algorithms are extended to models with time-dependent covariates. Simulation studies demonstrate that the pseudo-iterative convex minorant algorithm may yield orders-of-magnitude reduction in computing time relative to the iterative quadratic programming method and the iterative convex minorant algorithm, with moderate reductions in the bias and variance of the estimators. Analysis of data from a recent HIV prevention study illustrates the practical utility of the isotonic methodology in estimating nonlinear, monotonic covariate effects. [ABSTRACT FROM AUTHOR]

In survival analysis, a competing risk is an event whose occurrence precludes the occurrence of the primary event of interest. Outcomes in medical research are frequently subject to competing risks. In survival analysis, there are 2 key questions that can be addressed using competing risk regression models: first, which covariates affect the rate at which events occur, and second, which covariates affect the probability of an event occurring over time. The cause-specific hazard model estimates the effect of covariates on the rate at which events occur in subjects who are currently event-free. Subdistribution hazard ratios obtained from the Fine-Gray model describe the relative effect of covariates on the subdistribution hazard function. Hence, the covariates in this model can also be interpreted as having an effect on the cumulative incidence function or on the probability of events occurring over time. We conducted a review of the use and interpretation of the Fine-Gray subdistribution hazard model in articles published in the medical literature in 2015. We found that many authors provided an unclear or incorrect interpretation of the regression coefficients associated with this model. An incorrect and inconsistent interpretation of regression coefficients may lead to confusion when comparing results across different studies. Furthermore, an incorrect interpretation of estimated regression coefficients can result in an incorrect understanding about the magnitude of the association between exposure and the incidence of the outcome. The objective of this article is to clarify how these regression coefficients should be reported and to propose suggestions for interpreting these coefficients. [ABSTRACT FROM AUTHOR]

In the standard analysis of competing risks data, proportional hazards models are fit to the cause-specific hazard functions for all causes on the same time scale. These regression analyses are the foundation for predictions of cause-specific cumulative incidence functions based on combining the estimated cause-specific hazard functions. However, in predictions arising from disease registries, where only subjects with disease enter the database, disease-related mortality may be more naturally modeled on the time since diagnosis time scale while death from other causes may be more naturally modeled on the age time scale. The single time scale methodology may be biased if an incorrect time scale is employed for one of the causes and an alternative methodology is not available. We propose inferences for the cumulative incidence function in which regression models for the cause-specific hazard functions may be specified on different time scales. Using the disease registry data, the analysis of other cause mortality on the age scale requires left truncating the event time at the age of disease diagnosis, complicating the analysis. In addition, standard Martingale theory is not applicable when combining regression models on different time scales. We establish that the covariate conditional predictions are consistent and asymptotically normal using empirical process techniques and propose consistent variance estimators for constructing confidence intervals. Simulation studies show that the proposed two time scales method performs well, outperforming the single time-scale predictions when the time scale is misspecified. The methods are illustrated with stage III colon cancer data obtained from the Surveillance, Epidemiology, and End Results program of National Cancer Institute. [ABSTRACT FROM AUTHOR]

Predicting the occurrence of an adverse event over time is an important issue in clinical medicine. Clinical prediction models and associated points-based risk-scoring systems are popular statistical methods for summarizing the relationship between a multivariable set of patient risk factors and the risk of the occurrence of an adverse event. Points-based risk-scoring systems are popular amongst physicians as they permit a rapid assessment of patient risk without the use of computers or other electronic devices. The use of such points-based risk-scoring systems facilitates evidence-based clinical decision making. There is a growing interest in cause-specific mortality and in non-fatal outcomes. However, when considering these types of outcomes, one must account for competing risks whose occurrence precludes the occurrence of the event of interest. We describe how points-based risk-scoring systems can be developed in the presence of competing events. We illustrate the application of these methods by developing risk-scoring systems for predicting cardiovascular mortality in patients hospitalized with acute myocardial infarction. Code in the R statistical programming language is provided for the implementation of the described methods. © 2016 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

The traditional Cox model assumes a log-linear relationship between covariates and the underlying hazard function. However, the linearity may be invalid in real data. We study a Cox model which employs unknown parametric covariate transformations. This model is applicable to observational studies or randomized trials when a treatment effect is investigated after controlling for a confounding variable that may have non-log-linear relationship with the underlying hazard function. While the proposed generalization is simple, the inferential issues are challenging due to the loss of identifiability under no effects of transformed covariates. Optimal tests are derived for certain alternatives. Rigorous parametric inference is established under regularity conditions and non-zero transformed covariate effects. The estimates perform well in simulation studies with realistic sample size, and the proposed tests are more powerful than the usual partial likelihood ratio test, which is no longer optimal. Data from a breast cancer trial are used to illustrate the model building strategy and the better fit of the proposed model, comparing to the traditional Cox model. [ABSTRACT FROM AUTHOR]

For competing risks data, the Fine-Gray proportional hazards model for subdistribution has gained popularity for its convenience in directly assessing the effect of covariates on the cumulative incidence function. However, in many important applications, proportional hazards may not be satisfied, including multicenter clinical trials, where the baseline subdistribution hazards may not be common due to varying patient populations. In this article, we consider a stratified competing risks regression, to allow the baseline hazard to vary across levels of the stratification covariate. According to the relative size of the number of strata and strata sizes, two stratification regimes are considered. Using partial likelihood and weighting techniques, we obtain consistent estimators of regression parameters. The corresponding asymptotic properties and resulting inferences are provided for the two regimes separately. Data from a breast cancer clinical trial and from a bone marrow transplantation registry illustrate the potential utility of the stratified Fine-Gray model. [ABSTRACT FROM AUTHOR]

Competing risks occur frequently in the analysis of survival data. A competing risk is an event whose occurrence precludes the occurrence of the primary event of interest. In a study examining time to death attributable to cardiovascular causes, death attributable to noncardiovascular causes is a competing risk. When estimating the crude incidence of outcomes, analysts should use the cumulative incidence function, rather than the complement of the Kaplan-Meier survival function. The use of the Kaplan-Meier survival function results in estimates of incidence that are biased upward, regardless of whether the competing events are independent of one another. When fitting regression models in the presence of competing risks, researchers can choose from 2 different families of models: modeling the effect of covariates on the cause-specific hazard of the outcome or modeling the effect of covariates on the cumulative incidence function. The former allows one to estimate the effect of the covariates on the rate of occurrence of the outcome in those subjects who are currently event free. The latter allows one to estimate the effect of covariates on the absolute risk of the outcome over time. The former family of models may be better suited for addressing etiologic questions, whereas the latter model may be better suited for estimating a patient's clinical prognosis. We illustrate the application of these methods by examining cause-specific mortality in patients hospitalized with heart failure. Statistical software code in both R and SAS is provided. [ABSTRACT FROM AUTHOR]