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 possibly different covariate vectors $X$ and $Z$. The probability $π$ is taken to be the logistic function $π(X^{\prime}γ) = 1/\{1+\exp(-X^{\prime}γ)\}$, while we model $α(s)$ by Aalen's linear hazard rate regression model. This model postulates that a susceptible individual has hazard rate function $α(t;Z) = β_0(t) + β_1(t)Z_1 + \cdots + Z_{q-1}β_{q-1}(t)$ in terms of her covariate values $Z_1,\ldots,Z_{q-1}$. The large-sample properties of our estimators are studied by way of parametric models that tend to a semiparametric model as a parameter $K \to \infty$. For each model in the sequence of parametric models, we assume that the data generating mechanism is parametric, thus simplifying the derivation of the estimators, as well as the proofs of consistency and limiting normality. Finally, we use contiguity techniques to switch back to assuming that the data stem from the semiparametric model. This technique for deriving and studying estimators in non- and semiparametric settings has previously been studied and employed in the high-frequency data literature, but seems to be novel in survival analysis.
While analysing time-to-event data, it is possible that a certain fraction of subjects will never experience the event of interest and they are said to be cured. When this feature of survival models is taken into account, the models are commonly referred to as cure models. In the presence of covariates, the conditional survival function of the population can be modelled by using cure model which depends on the probability of being uncured (incidence) and the conditional survival function of the uncured subjects (latency), and a combination of logistic regression and Cox proportional hazards (P…
We develop a functional proportional hazards mixture cure (FPHMC) model with scalar and functional covariates measured at the baseline. The mixture cure model, useful in studying populations with a cure fraction of a particular event of interest is extended to functional data. We employ the EM algorithm and develop a semiparametric penalized spline-based approach to estimate the dynamic functional coefficients of the incidence and the latency part. The proposed method is computationally efficient and simultaneously incorporates smoothness in the estimated functional coefficients via roughness …
In the analysis of survival data, it is usually assumed that any unit will experience the event of interest if it is observed for a sufficient long time. However, one can explicitly assume that an unknown proportion of the population under study will never experience the monitored event. The promotion time model, which has a biological motivation, is one of the survival models taking this feature into account. The promotion time model assumes that the failure time of each subject is generated by the minimum of N latent event times which are independent with a common distribution independent of…
Extended cure survival models enable to separate covariates that affect the probability of an event (or `long-term' survival) from those only affecting the event timing (or `short-term' survival). We propose to generalize the bounded cumulative hazard model to handle additive terms for time-varying (exogenous) covariates jointly impacting long- and short-term survival. The selection of the penalty parameters is a challenge in that framework. A fast algorithm based on Laplace approximations in Bayesian P-spline models is proposed. The methodology is motivated by fertility studies where women's …
The mixture cure rate model is the most commonly used cure rate model in the literature. In the context of mixture cure rate model, the standard approach to model the effect of covariates on the cured or uncured probability is to use a logistic function. This readily implies that the boundary classifying the cured and uncured subjects is linear. In this paper, we propose a new mixture cure rate model based on interval censored data that uses the support vector machine (SVM) to model the effect of covariates on the uncured or the cured probability (i.e., on the incidence part of the model). Our…
A new method for the analysis of time to ankylosis complication on a dataset of replanted teeth is proposed. In this context of left-censored, interval-censored and right-censored data, a Cox model with piecewise constant baseline hazard is introduced. Estimation is carried out with the EM algorithm by treating the true event times as unobserved variables. This estimation procedure is shown to produce a block diagonal Hessian matrix of the baseline parameters. Taking advantage of this interesting feature of the estimation method a L0 penalised likelihood method is implemented in order to autom…
Integrating Phase 2 into Phase 3 based on an Intermediate Endpoint While Accounting for a Cure Proportion -- with an Application to the Design of a Clinical Trial in Acute Myeloid Leukemia
We consider kernel smoothed Grenander-type estimators for a monotone hazard rate and a monotone density in the presence of randomly right censored data. We show that they converge at rate $n^{2/5}$ and that the limit distribution at a fixed point is Gaussian with explicitly given mean and variance. It is well-known that standard kernel smoothing leads to inconsistency problems at the boundary points. It turns out that, also by using a boundary correction, we can only establish uniform consistency on intervals that stay away from the end point of the support (though we can go arbitrarily close …
Accommodating the Analysis Model in Multiple Imputation for the Weibull Mixture Cure Model:Performance under Penalized Likelihood
University of Toronto（多伦多大学）；Lunenfeld-Tanenbaum Research Institute, Sinai Health（Sinai健康莱嫩费尔德-塔嫩鲍姆研究所）；Temerty Faculty of Medicine, University of Toronto（多伦多大学特默蒂医学院）
Identifying causal relationships for a treatment intervention is a fundamental problem in health sciences. Randomized controlled trials (RCTs) are considered the gold standard for identifying causal relationships. However, recent advancements in the theory of causal inference based on the foundations of structural causal models (SCMs) have allowed the identification of causal relationships from observational data, under certain assumptions. Survival analysis provides standard measures, such as the hazard ratio, to quantify the effects of an intervention. While hazard ratios are widely used in …
Latent class analysis (LCA) is a useful tool to investigate the heterogeneity of a disease population with time-to-event data. We propose a new method based on non-parametric maximum likelihood estimator (NPMLE), which facilitates theoretically validated inference procedure for covariate effects and cumulative hazard functions. We assess the proposed method via extensive simulation studies and demonstrate improved predictive performance over standard Cox regression model. We further illustrate the practical utility of the proposed method through an application to a mild cognitive impairment (M…
In survival analysis, the lifetime under study is not always observed. In certain applications, for some individuals, the value of the lifetime is only known to be smaller or larger than some random duration. This framework represent an extension of standard situations where the lifetime is only left or only right randomly censored. We consider the case where the independent observation units include also some covariates, and we propose two semiparametric regression models. The new models extend the standard Cox proportional hazard model to the situation of a more complex censoring mechanism. …
This work presents novel and powerful tests for comparing non-proportional hazard functions, based on sample-space partitions. Right censoring introduces two major difficulties which make the existing sample-space partition tests for uncensored data non-applicable: (i) the actual event times of censored observations are unknown; and (ii) the standard permutation procedure is invalid in case the censoring distributions of the groups are unequal. We overcome these two obstacles, introduce invariant tests, and prove their consistency. Extensive simulations reveal that under non-proportional alter…
The Cox regression, a semi-parametric method of survival analysis, is extremely popular in biomedical applications. The proportional hazards assumption is a key requirement in the Cox model. To accommodate non-proportional hazards, we propose to parameterise the shape parameter of the baseline hazard function using the additional, separate Cox-regression term which depends on the vector of the covariates. We call this model the double-Cox model. The R programs for fitting the double-Cox model are available on Github. We formally introduce the double-Cox model with shared frailty and investigat…
The Cox model, which remains as the first choice in analyzing time-to-event data even for large datasets, relies on the proportional hazards (PH) assumption. When survival data arrive sequentially in chunks, a fast and minimally storage intensive approach to test the PH assumption is desirable. We propose an online updating approach that updates the standard test statistic as each new block of data becomes available, and greatly lightens the computational burden. Under the null hypothesis of PH, the proposed statistic is shown to have the same asymptotic distribution as the standard version co…
Combining patient-level data from clinical trials can connect rare phenomena with clinical endpoints, but statistical techniques applied to a single trial may become problematical when trials are pooled. Estimating the hazard of a binary variable unevenly distributed across trials showcases a common pooled database issue. We studied how an unevenly distributed binary variable can compromise the integrity of fixed and random effects Cox proportional hazards models. We compared fixed effect and random effects Cox proportional hazards models on a set of simulated datasets inspired by a 17-trial p…
An individualized risk prediction model that dynamically updates the probability of a clinical event from a specific cause is valuable for physicians to be able to optimize personalized treatment strategies in real-time by incorporating all available information collected over the follow-up. However, this is more complex and challenging when competing risks are present, because it requires simultaneously updating the overall survival and the cumulative incidence functions (CIFs) while adjusting for the time-dependent covariates and time-varying covariate effects. In this study, we developed a …
A Novel Stratified Analysis Method for Testing and Estimating Overall Treatment Effects on Time-to-Event Outcomes Using Average Hazard with Survival Weight
Recent research has shown the potential for neural networks to improve upon classical survival models such as the Cox model, which is widely used in clinical practice. Neural networks, however, typically rely on data that are centrally available, whereas healthcare data are frequently held in secure silos. We present a federated Cox model that accommodates this data setting and also relaxes the proportional hazards assumption, allowing time-varying covariate effects. In this latter respect, our model does not require explicit specification of the time-varying effects, reducing upfront organisa…
Studies to compare the survival of two or more groups using time-to-event data are of high importance in medical research. The gold standard is the log-rank test, which is optimal under proportional hazards. As the latter is no simple regularity assumption, we are interested in evaluating the power of various statistical tests under different settings including proportional and non-proportional hazards with a special emphasize on crossing hazards. This challenge has been going on for many years now and multiple methods have already been investigated in extensive simulation studies. However, in…
The cause-specific cumulative incidence function (CIF) quantifies the subject-specific disease risk with competing risk outcome. With longitudinally collected biomarker data, it is of interest to dynamically update the predicted CIF by incorporating the most recent biomarker as well as the cumulating longitudinal history. Motivated by a longitudinal cohort study of chronic kidney disease, we propose a framework for dynamic prediction of end stage renal disease using multivariate longitudinal biomarkers, accounting for the competing risk of death. The proposed framework extends the landmark sur…
We introduce new methods of analysing time to event data via extended versions of the proportional hazards and accelerated failure time (AFT) models. In many time to event studies, the time of first observation is arbitrary, in the sense that no risk modifying event occurs. This is particularly common in epidemiological studies. We show formally that, in these situations, it is not sensible to take the first observation as the time origin, either in AFT or proportional hazards type models. Instead, we advocate using age of the subject as the time scale. We account for the fact that baseline ob…
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…
Predicting patient survival probabilities based on observed covariates is an important assessment in clinical practice. These patient-specific covariates are often measured over multiple follow-up appointments. It is then of interest to predict survival based on the history of these longitudinal measurements, and to update predictions as more observations become available. The standard approaches to these so-called `dynamic prediction' assessments are joint models and landmark analysis. Joint models involve high-dimensional parametrisations, and their computational complexity often prohibits i…
Comparison of the Cox proportional hazards model and Random Survival Forest algorithm for predicting patient-specific survival probabilities in clinical trial data
University of Augsburg（奥格斯堡大学）；University of Reading（雷丁大学）
Medical practitioners use survival models to explore and understand the relationships between patients' covariates (e.g. clinical and genetic features) and the effectiveness of various treatment options. Standard survival models like the linear Cox proportional hazards model require extensive feature engineering or prior medical knowledge to model treatment interaction at an individual level. While nonlinear survival methods, such as neural networks and survival forests, can inherently model these high-level interaction terms, they have yet to be shown as effective treatment recommender system…
In this paper the regression discontinuity design is adapted to the survival analysis setting with right-censored data, studied in an intensity based counting process framework. In particular, a local polynomial regression version of the Aalen additive hazards estimator is introduced as an estimator of the difference between two covariate dependent cumulative hazard rate functions. Large-sample theory for this estimator is developed, including confidence intervals that take into account the uncertainty associated with bias correction. As is standard in the causality literature, the models and …
Statistical estimation and inference for marginal hazard models with varying coefficients for multivariate failure time data are important subjects in survival analysis. A local pseudo-partial likelihood procedure is proposed for estimating the unknown coefficient functions. A weighted average estimator is also proposed in an attempt to improve the efficiency of the estimator. The consistency and asymptotic normality of the proposed estimators are established and standard error formulas for the estimated coefficients are derived and empirically tested. To reduce the computational burden of the…
We consider the Cox regression model and prove some properties of the maximum partial likelihood estimator $\hatβ_n$ and of the the Breslow estimator $Λ_n$. The asymptotic properties of these estimators have been widely studied in the literature but we are not aware of a reference where it is shown that they have uniformly bounded moments. These results are needed, for example, when studying global errors of shape restricted estimators of the baseline hazard function.
