The proportional hazards (PH), proportional odds (PO) and accelerated failure time (AFT) models have been widely used in different applications of survival analysis. Despite their popularity, these models are not suitable to handle lifetime data with crossing survival curves. In 2005, Yang and Prentice proposed a semiparametric two-sample strategy (YP model), including the PH and PO frameworks as particular cases, to deal with this type of data. Assuming a general regression setting, the present paper proposes an unified approach to fit the YP model by employing Bernstein polynomials to manage the baseline hazard and odds under both the frequentist and Bayesian frameworks. The use of the Bernstein polynomials has some advantages: it allows for uniform approximation of the baseline distribution, it leads to closed-form expressions for all baseline functions, it simplifies the inference procedure, and the presence of a continuous survival function allows a more accurate estimation of the crossing survival time. Extensive simulation studies are carried out to evaluate the behavior of the models. The analysis of a clinical trial data set, related to non-small-cell lung cancer, is also developed as an illustration. Our findings indicate that assuming the usual PH model, ignoring the existing crossing survival feature in the real data, is a serious mistake with implications for those patients in the initial stage of treatment.
Palliative medicine is an interdisciplinary specialty focusing on improving quality of life (QOL) for patients with serious illness and their families. Palliative care programs are available or under development at over 80% of large US hospitals (300+ beds). Palliative care clinical trials present unique analytic challenges relative to evaluating the palliative care treatment efficacy which is to improve patients diminishing QOL as disease progresses towards end of life (EOL). A unique feature of palliative care clinical trials is that patients will experience decreasing QOL during the trial d…
Proportional hazards (PH), proportional odds (PO) and accelerated failure time (AFT) models have been widely used to deal with survival data in different fields of knowledge. Despite their popularity, such models are not suitable to handle survival data with crossing survival curves. Yang and Prentice (2005) proposed a semiparametric two-sample approach, denoted here as the YP model, allowing the analysis of crossing survival curves and including the PH and PO configurations as particular cases. In a general regression setting, the present work proposes a fully likelihood-based approach to fit…
In this work we provide a simple estimation procedure for a general frailty model for analysis of prospective correlated failure times. Rigorous large-sample theory for the proposed estimators of both the regression coefficient vector and the dependence parameter is given, including consistent variance estimators. In a simulation study under the widely used gamma frailty model, our proposed approach was found to have essentially the same efficiency as the EM-based estimator considered by other authors, with negligible difference between the standard errors of the two estimators. The proposed a…
In this work we deal with correlated failure time (age at onset) data arising from population-based case-control studies, where case and control probands are selected by population-based sampling and an array of risk factor measures is collected for both cases and controls and their relatives. Parameters of interest are effects of risk factors on the hazard function of failure times and within-family dependencies of failure times after adjusting for the risk factors. Due to the retrospective nature of sampling, a large sample theory for existing methods has not been established. We develop a n…
The present article studies survival analytic aspects of semiparametric copula dependence models with arbitrary univariate marginals. The underlying survival functions admit a representation via exponent measures which have an interpretation within the context of hazard functions. In particular, correlated frailty survival models are linked to copulas. Additionally, the relation to exponent measures of minumum-infinitely divisible distributions as well as to the Lévy measure of the Lévy-Khintchine formula is pointed out. The semiparametric character of the current analyses and the construction…
We propose a general index model for survival data, which generalizes many commonly used semiparametric survival models and belongs to the framework of dimension reduction. Using a combination of geometric approach in semiparametrics and martingale treatment in survival data analysis, we devise estimation procedures that are feasible and do not require covariate-independent censoring as assumed in many dimension reduction methods for censored survival data. We establish the root-$n$ consistency and asymptotic normality of the proposed estimators and derive the most efficient estimator in this …
Nonparametric and semiparametric methods are commonly used in survival analysis to mitigate the bias due to model misspecification. However, such methods often cannot estimate upper-tail survival quantiles when a sizable proportion of the data are censored, in which case parametric likelihood-based estimators present a viable alternative. In this article, we extend a popular family of parametric survival models which make the Accelerated Failure Time (AFT) assumption to account for heteroscedasticity in the survival times. The conditional variances can depend on arbitrary covariates, thus addi…
orthoDr is a package in R that solves dimension reduction problems using orthogonality constrained optimization approach. The package serves as a unified framework for many regression and survival analysis dimension reduction models that utilize semiparametric estimating equations. The main computational machinery of orthoDr is a first-order algorithm developed by \cite{wen2013feasible} for optimization within the Stiefel manifold. We implement the algorithm through Rcpp and OpenMP for fast computation. In addition, we developed a general-purpose solver for such constrained problems with user-…
In comparative research on time-to-event data for two groups, when two survival curves cross each other, it may be difficult to use the log-rank test and hazard ratio (HR) to properly assess the treatment benefit. Our aim was to identify a method for evaluating the treatment benefits for two groups in the above situation. We quantified treatment benefits based on an intuitive measure called the area between two survival curves (ABS), which is a robust measure of treatment benefits in clinical trials regardless of whether the proportional hazards assumption is violated or two survival curves cr…
Crossing survival curves complicate how we interpret results from a clinical trial's primary endpoint. We find the function to determine a crossing point's location depends exponentially on individual survival curves. This exponential relationship between survival curves and the crossing point transforms small survival curve errors into large crossing point errors. In most cases, crossing points are sensitive to individual survival errors and may make accurately locating a crossing point unsuccessful. We argue more complicated analyses for mitigating crossing points should be reserved only aft…
One of Pranab K. Sen's major research areas is sequential nonparametrics and semiparametrics and their applications to clinical trials, to which he has made many important contributions. Herein we review a number of these contributions and related developments. We also describe some recent work on nonparametric and semiparametric inference and the associated computational methods in time-sequential clinical trials with survival endpoints.
In Survival Analysis, the observed lifetimes often correspond to individuals for which the event occurs within a specific calendar time interval. With such interval sampling, the lifetimes are doubly truncated at values determined by the birth dates and the sampling interval. This double truncation may induce a systematic bias in estimation, so specific corrections are needed. A relevant target in Survival Analysis is the hazard rate function, which represents the instantaneous probability for the event of interest. In this work we introduce a flexible estimation approach for the hazard rate u…
Semiparametric joint models of longitudinal and competing risks data are computationally costly and their current implementations do not scale well to massive biobank data. This paper identifies and addresses some key computational barriers in a semiparametric joint model for longitudinal and competing risks survival data. By developing and implementing customized linear scan algorithms, we reduce the computational complexities from $O(n^2)$ or $O(n^3)$ to $O(n)$ in various components including numerical integration, risk set calculation, and standard error estimation, where $n$ is the number …
The infinite-dimensional information operator for the nuisance parameter plays a key role in semiparametric inference, as it is closely related to the regular estimability of the target parameter. Calculation of information operators has traditionally proceeded in a case-by-case manner and has easily entailed lengthy derivations with complicated arguments. We develop a unified framework for this task by exploiting commonality in the form of semiparametric likelihoods. The general formula allows one to derive information operators with simple calculus and, if necessary at all, a minimal amount …
We consider a log-linear model for survival data, where both the location and scale parameters depend on covariates and the baseline hazard function is completely unspecified. This model provides the flexibility needed to capture many interesting features of survival data at a relatively low cost in model complexity. Estimation procedures are developed and asymptotic properties of the resulting estimators are derived using empirical process theory. Finally, a resampling procedure is developed to estimate the limiting variances of the estimators. The finite sample properties of the estimators a…
We consider estimation in a class of semiparametric transformation models for right--censored data. These models gained much attention in survival analysis; however, most authors consider only regression models derived from frailty distributions whose hazards are decreasing. This paper considers estimation in a more flexible class of models and proposes conditional rank M-estimators for estimation of the Euclidean component of the model.
Survival models incorporating random effects to account for unmeasured heterogeneity are being increasingly used in biostatistical and applied research. Specifically, unmeasured covariates whose lack of inclusion in the model would lead to biased, inefficient results are commonly modelled by including a subject-specific (or cluster-specific) frailty term that follows a given distribution (e.g. Gamma or log-Normal). Despite that, in the context of parametric frailty models little is known about the impact of misspecifying the baseline hazard, the frailty distribution, or both. Therefore, our ai…
Hazard ratios are ubiquitously used in time to event analysis to quantify treatment effects. Although hazard ratios are invaluable for hypothesis testing, other measures of association, both relative and absolute, may be used to fully elucidate study results. Restricted mean survival time differences between groups have been advocated as useful measures of association. Recent work focused on model-free estimates of the difference in restricted mean survival for all follow-up times instead of focusing on a single time horizon. In this work a model-based alternative is proposed with estimation u…
We consider the efficient estimation of the semiparametric additive transformation model with current status data. A wide range of survival models and econometric models can be incorporated into this general transformation framework. We apply the B-spline approach to simultaneously estimate the linear regression vector, the nondecreasing transformation function, and a set of nonparametric regression functions. We show that the parametric estimate is semiparametric efficient in the presence of multiple nonparametric nuisance functions. An explicit consistent B-spline estimate of the asymptotic …
Based on a data set obtained in a dental longitudinal study, conducted in Flanders (Belgium), the joint time to caries distribution of permanent first molars was modeled as a function of covariates. This involves an analysis of multivariate continuous doubly-interval-censored data since: (i) the emergence time of a tooth and the time it experiences caries were recorded yearly, and (ii) events on teeth of the same child are dependent. To model the joint distribution of the emergence times and the times to caries, we propose a dependent Bayesian semiparametric model. A major feature of the propo…
We propose a new class of multivariate survival models based on archimedean copulas with margins modeled by the Yang and Prentice (YP) model. The Ali-Mikhail-Haq (AMH), Clayton, Frank, Gumbel-Hougaard (GH), and Joe copulas are employed to accommodate the dependency among marginal distributions. Baseline distributions are modeled semiparametrically by the piecewise exponential (PE) distribution and the Bernstein polynomials. The new class of models possesses some attractive features: i) the ability to take into account survival data with crossing survival curves; ii) the inclusion of the well-k…
The goals in clinical and cohort studies often include evaluation of the association of a time-dependent binary treatment or exposure with a survival outcome. Recently, several impactful studies targeted the association between aspirin-taking and survival following colorectal cancer diagnosis. Due to surgery, aspirin-taking value is zero at baseline and may change its value to one at some time point. Estimating this association is complicated by having only intermittent measurements on aspirin-taking. Naive, commonly-used, methods can lead to substantial bias. We present a class of calibration…
We propose a novel personalized concept for the optimal treatment selection for a situation where the response is a multivariate vector, that could contain right-censored variables such as survival time. The proposed method can be applied with any number of treatments and outcome variables, under a broad set of models. Following a working semiparametric Single Index Model that relates covariates and responses, we first define a patient-specific composite score, constructed from individual covariates. We then estimate conditional means of each response, given the patient score, correspond to ea…
One goal in survival analysis of right-censored data is to estimate the marginal survival function in the presence of dependent censoring. When many auxiliary covariates are sufficient to explain the dependent censoring, estimation based on either a semiparametric model or a nonparametric model of the conditional survival function can be problematic due to the high dimensionality of the auxiliary information. In this paper, we use two working models to condense these high-dimensional covariates in dimension reduction; then an estimate of the marginal survival function can be derived nonparamet…
In this paper we introduce a mixture cure model with a linear hazard rate regression model for the event times. Cure models are statistical models for event times that take into account that a fraction of the population might never experience the event of interest, this fraction is said to be {`}cured{'}. The population survival function in a mixture cure model takes the form $S(t) = 1 - π+ π\exp(-\int_0^tα(s)\,d s)$, where $π$ is the probability of being susceptible to the event under study, and $α(s)$ is the hazard rate of the susceptible fraction. We let both $π$ and $α(s)$ depend on possib…
In this paper, we propose a semiparametric, tree based joint latent class modeling approach (JLCT) to model the joint behavior of longitudinal and time-to-event data. Existing joint latent class modeling approaches are parametric and can suffer from high computational cost. The most common parametric approach, the joint latent class model (JLCM), further restricts analysis to using time-invariant covariates in modeling survival risks and latent class memberships. Instead, the proposed JLCT is fast to fit, and can use time-varying covariates in all of its modeling components. We demonstrate the…
Cure models have been developed as an alternative modelling approach to conventional survival analysis in order to account for the presence of cured subjects that will never experience the event of interest. Mixture cure models, which model separately the cure probability and the survival of uncured subjects depending on a set of covariates, are particularly useful for distinguishing curative from life-prolonging effects. In practice, it is common to assume a parametric model for the cure probability and a semiparametric model for the survival of the susceptibles. Because of the latent cure st…
A comprehensive, unified approach to modeling arbitrarily censored spatial survival data is presented for the three most commonly-used semiparametric models: proportional hazards, proportional odds, and accelerated failure time. Unlike many other approaches, all manner of censored survival times are simultaneously accommodated including uncensored, interval censored, current-status, left and right censored, and mixtures of these. Left-truncated data are also accommodated leading to models for time-dependent covariates. Both georeferenced (location exactly observed) and areally observed (locati…
We propose inference procedures for general nonparametric factorial survival designs with possibly right-censored data. Similar to additive Aalen models, null hypotheses are formulated in terms of cumulative hazards. Thereby, deviations are measured in terms of quadratic forms in Nelson-Aalen-type integrals. Different to existing approaches this allows to work without restrictive model assumptions as proportional hazards. In particular, crossing survival or hazard curves can be detected without a significant loss of power. For a distribution-free application of the method, a permutation strate…
Estimating individualized treatment rules is a central task for personalized medicine. [zhao2012estimating] and [zhang2012robust] proposed outcome weighted learning to estimate individualized treatment rules directly through maximizing the expected outcome without modeling the response directly. In this paper, we extend the outcome weighted learning to right censored survival data without requiring either an inverse probability of censoring weighting or a semiparametric modeling of the censoring and failure times as done in [zhao2015doubly]. To accomplish this, we take advantage of the tree ba…
Rank-Based Estimation of U-Shaped Biomarker Risk Curves and Critical Points for Time-to-Event Outcomes
Emory University Rollins School of Public Health（埃默里大学罗林斯公共卫生学院）；Department of Biostatistics Johns Hopkins Bloomberg School of Public Health（约翰霍普金斯大学彭博公共卫生学院生物统计系）；Eli Lilly and Company（礼来公司）；Department of Neurology Johns Hopkins School of Medicine（约翰霍普金斯大学医学院神经病学系）
Spatial survival analysis has received a great deal of attention over the last 20 years due to the important role that geographical information can play in predicting survival. This paper provides an introduction to a set of programs for implementing some Bayesian spatial survival models in R using the package spBayesSurv. The function survregbayes includes the three most commonly-used semiparametric models: proportional hazards, proportional odds, and accelerated failure time. All manner of censored survival times are simultaneously accommodated including uncensored, interval censored, curren…
