Survival Analysis Commons^™

The Two-Sample Problem For Failure Rates Depending On A Continuous Mark: An Application To Vaccine Efficacy, Peter B. Gilbert, Ian W. Mckeague, Yanqing Sun

UW Biostatistics Working Paper Series

The efficacy of an HIV vaccine to prevent infection is likely to depend on the genetic variation of the exposing virus. This paper addresses the problem of using data on the HIV sequences that infect vaccine efficacy trial participants to 1) test for vaccine efficacy more powerfully than procedures that ignore the sequence data; and 2) evaluate the dependence of vaccine efficacy on the divergence of infecting HIV strains from the HIV strain that is contained in the vaccine. Because hundreds of amino acid sites in each HIV genome are sequenced, it is natural to treat the divergence (defined in …

Evaluating Prediction Rules For T-Year Survivors With Censored Regression Models, Hajime Uno, Tianxi Cai, Lu Tian, L.J. Wei

Harvard University Biostatistics Working Paper Series

Suppose that we are interested in establishing simple, but reliable rules for predicting future t-year survivors via censored regression models. In this article, we present inference procedures for evaluating such binary classification rules based on various prediction precision measures quantified by the overall misclassification rate, sensitivity and specificity, and positive and negative predictive values. Specifically, under various working models we derive consistent estimators for the above measures via substitution and cross validation estimation procedures. Furthermore, we provide large sample approximations to the distributions of these nonsmooth estimators without assuming that the working model is correctly specified. Confidence intervals, for example, …

Survival Analysis Methods In Genetic Epidemiology, Hongzhe Li

UPenn Biostatistics Working Papers

Mapping genes for complex human diseases is a challenging problem due to the fact that many such diseases are due to both genetic and enviromental risk factors and many also exhibit phenotypic heterogeneity, such as variable age of onset. Information on variable age of disease onset is often a good indicator for disease heterogeneity and incorporation of such information together with enviromental risk factors into genetic analysis should lead to more powerful tests for genetic analysis. Due to the problem of censoring, survival analysis methods have proved to be very useful for genetic analysis. In this paper, I review some …

Case-Cohort Methods For Survival Data On Families From Routine Registers, Tron Anders Moger, Yudi Pawitan, Ørnulf Borgan

UW Biostatistics Working Paper Series

In the Nordic countries, there exist several registers containing information on diseases and risk factors for millions of individuals. This information can be linked into families by use of personal identification numbers, and represent a great opportunity for studying diseases that show familial aggregation. Due to the size of the registers, it is difficult to analyze the data by using traditional methods for multivariate survival analysis, such as frailty or copula models. Since the size of the cohort is known, case-cohort methods based on pseudo-likelihoods are suitable for analyzing the data. We present methods for sampling control families both with …

Semiparametric Approaches For Joint Modeling Of Longitudinal And Survival Data With Time Varying Coefficients, Xiao Song, C.Y. Wang

UW Biostatistics Working Paper Series

We study joint modeling of survival and longitudinal data. There are two regression models of interest. The primary model is for survival outcomes, which are assumed to follow a time varying coefficient proportional hazards model. The second model is for longitudinal data, which are assumed to follow a random effects model. Based on the trajectory of a subject's longitudinal data, some covariates in the survival model are functions of the unobserved random effects. Estimated random effects are generally different from the unobserved random effects and hence this leads to covariate measurement error. To deal with covariate measurement error, we propose …

Nonparametric Estimation Of Bivariate Failure Time Associations In The Presence Of A Competing Risk, Karen Bandeen-Roche, Jing Ning

Johns Hopkins University, Dept. of Biostatistics Working Papers

There has been much research on the study of associations among paired failure times. Most has either assumed time invariance of association or been based on complex measures or estimators. Little has accommodated failures arising amid competing risks. This paper targets the conditional cause specific hazard ratio, a recent modification of the conditional hazard ratio to accommodate competing risks data. Estimation is accomplished by an intuitive, nonparametric method that localizes Kendall’s tau. Time variance is accommodated through a partitioning of space into “bins” between which the strength of association may differ. Inferential procedures are researched, small sample performance evaluated, and …

Correspondences Between Regression Models For Complex Binary Outcomes And Those For Structured Multivariate Survival Analyses, Nicholas P. Jewell

U.C. Berkeley Division of Biostatistics Working Paper Series

Doksum and Gasko [5] described a one-to-one correspondence between regression models for binary outcomes and those for continuous time survival analyses. This correspondence has been exploited heavily in the analysis of current status data (Jewell and van der Laan [11], Shiboski [18]). Here, we explore similar correspondences for complex survival models and categorical regression models for polytomous data. We include discussion of competing risks and progressive multi-state survival random variables.

Analyzing Panel Count Data With Informative Observation Times, Chiung-Yu Huang, Mei-Cheng Wang, Ying Zhang

Johns Hopkins University, Dept. of Biostatistics Working Papers

In this paper, we study panel count data with informative observation times. We assume nonparametric and semiparametric proportional rate models for the underlying recurrent event process, where the form of the baseline rate function is left unspecified and a subject-specific frailty variable inflates or deflates the rate function multiplicatively. The proposed models allow the recurrent event processes and observation times to be correlated through their connections with the unobserved frailty; moreover, the distributions of both the frailty variable and observation times are considered as nuisance parameters. The baseline rate function and the regression parameters are estimated by maximizing a conditional …

Designed Extension Of Survival Studies: Application To Clinical Trials With Unrecognized Heterogeneity, Yi Li, Mei-Chiung Shih, Rebecca A. Betensky

Harvard University Biostatistics Working Paper Series

It is well known that unrecognized heterogeneity among patients, such as is conferred by genetic subtype, can undermine the power of randomized trial, designed under the assumption of homogeneity, to detect a truly beneficial treatment. We consider the conditional power approach to allow for recovery of power under unexplained heterogeneity. While Proschan and Hunsberger (1995) confined the application of conditional power design to normally distributed observations, we consider more general and difficult settings in which the data are in the framework of continuous time and are subject to censoring. In particular, we derive a procedure appropriate for the analysis of …

Cross-Validated Bagged Prediction Of Survival, Sandra E. Sinisi, Romain Neugebauer, Mark J. Van Der Laan

U.C. Berkeley Division of Biostatistics Working Paper Series

In this article, we show how to apply our previously proposed Deletion/Substitution/Addition algorithm in the context of right-censoring for the prediction of survival. Furthermore, we introduce how to incorporate bagging into the algorithm to obtain a cross-validated bagged estimator. The method is used for predicting the survival time of patients with diffuse large B-cell lymphoma based on gene expression variables.

Mixture Cure Survival Models With Dependent Censoring, Yi Li, Ram C. Tiwari, Subharup Guha

Harvard University Biostatistics Working Paper Series

A number of authors have studies the mixture survival model to analyze survival data with nonnegligible cure fractions. A key assumption made by these authors is the independence between the survival time and the censoring time. To our knowledge, no one has studies the mixture cure model in the presence of dependent censoring. To account for such dependence, we propose a more general cure model which allows for dependent censoring. In particular, we derive the cure models from the perspective of competing risks and model the dependence between the censoring time and the survival time using a class of Archimedean …

Semiparametric Normal Transformation Models For Spatially Correlated Survival Data, Yi Li, Xihong Lin

Harvard University Biostatistics Working Paper Series

There is an emerging interest in modeling spatially correlated survival data in biomedical and epidemiological studies. In this paper, we propose a new class of semiparametric normal transformation models for right censored spatially correlated survival data. This class of models assumes that survival outcomes marginally follow a Cox proportional hazard model with unspecified baseline hazard, and their joint distribution is obtained by transforming survival outcomes to normal random variables, whose joint distribution is assumed to be multivariate normal with a spatial correlation structure. A key feature of the class of semiparametric normal transformation models is that it provides a rich …

Inference On Survival Data With Covariate Measurement Error - An Imputation-Based Approach, Yi Li, Louise Ryan

Harvard University Biostatistics Working Paper Series

We propose a new method for fitting proportional hazards models with error-prone covariates. Regression coefficients are estimated by solving an estimating equation that is the average of the partial likelihood scores based on imputed true covariates. For the purpose of imputation, a linear spline model is assumed on the baseline hazard. We discuss consistency and asymptotic normality of the resulting estimators, and propose a stochastic approximation scheme to obtain the estimates. The algorithm is easy to implement, and reduces to the ordinary Cox partial likelihood approach when the measurement error has a degenerative distribution. Simulations indicate high efficiency and robustness. …

Survival Point Estimate Prediction In Matched And Non-Matched Case-Control Subsample Designed Studies, Annette M. Molinaro, Mark J. Van Der Laan, Dan H. Moore, Karla Kerlikowske

U.C. Berkeley Division of Biostatistics Working Paper Series

Providing information about the risk of disease and clinical factors that may increase or decrease a patient's risk of disease is standard medical practice. Although case-control studies can provide evidence of strong associations between diseases and risk factors, clinicians need to be able to communicate to patients the age-specific risks of disease over a defined time interval for a set of risk factors.

An estimate of absolute risk cannot be determined from case-control studies because cases are generally chosen from a population whose size is not known (necessary for calculation of absolute risk) and where duration of follow-up is not …

Linear Regression Of Censored Length-Biased Lifetimes, Ying Qing Chen, Yan Wang

UW Biostatistics Working Paper Series

Length-biased lifetimes may be collected in observational studies or sample surveys due to biased sampling scheme. In this article, we use a linear regression model, namely, the accelerated failure time model, for the population lifetime distributions in regression analysis of the length-biased lifetimes. It is discovered that the associated regression parameters are invariant under the length-biased sampling scheme. According to this discovery, we propose the quasi partial score estimating equations to estimate the population regression parameters. The proposed methodologies are evaluated and demonstrated by simulation studies and an application to actual data set.

Attributable Risk Function In The Proportional Hazards Model, Ying Qing Chen, Chengcheng Hu, Yan Wang

UW Biostatistics Working Paper Series

As an epidemiological parameter, the population attributable fraction is an important measure to quantify the public health attributable risk of an exposure to morbidity and mortality. In this article, we extend this parameter to the attributable fraction function in survival analysis of time-to-event outcomes, and further establish its estimation and inference procedures based on the widely used proportional hazards models. Numerical examples and simulations studies are presented to validate and demonstrate the proposed methods.

New Statistical Paradigms Leading To Web-Based Tools For Clinical/Translational Science, Knut M. Wittkowski

COBRA Preprint Series

As the field of functional genetics and genomics is beginning to mature, we become confronted with new challenges. The constant drop in price for sequencing and gene expression profiling as well as the increasing number of genetic and genomic variables that can be measured makes it feasible to address more complex questions. The success with rare diseases caused by single loci or genes has provided us with a proof-of-concept that new therapies can be developed based on functional genomics and genetics.

Common diseases, however, typically involve genetic epistasis, genomic pathways, and proteomic pattern. Moreover, to better understand the underlying biologi-cal …

Application Of The Time-Dependent Roc Curves For Prognostic Accuracy With Multiple Biomarkers, Yingye Zheng, Tianxi Cai, Ziding Feng

UW Biostatistics Working Paper Series

The rapid advancement in molecule technology has lead to the discovery of many markers that have potential applications in disease diagnosis and prognosis. In a prospective cohort study, information on a panel of biomarkers as well as the disease status for a patient are routinely collected over time. Such information is useful to predict patients' prognosis and select patients for targeted therapy. In this paper, we develop procedures for constructing a composite test with optimal discrimination power when there are multiple markers available to assist in prediction and characterize the accuracy of the resulting test by extending the time-dependent receiver …

Survival Ensembles, Torsten Hothorn, Peter Buhlmann, Sandrine Dudoit, Annette M. Molinaro, Mark J. Van Der Laan

U.C. Berkeley Division of Biostatistics Working Paper Series

We propose a unified and flexible framework for ensemble learning in the presence of censoring. For right-censored data, we introduce a random forest algorithm and a generic gradient boosting algorithm for the construction of prognostic models. The methodology is utilized for predicting the survival time of patients suffering from acute myeloid leukemia based on clinical and genetic covariates. Furthermore, we compare the diagnostic capabilities of the proposed censored data random forest and boosting methods applied to the recurrence free survival time of node positive breast cancer patients with previously published findings.

Nonparametric Estimation Of The Case Fatality Ratio With Competing Risks Data: An Application To Severe Acute Respiratory Syndome (Sars) , Nicholas P. Jewell, Xiudong Lei, A. C. Ghani, C. A. Donnelly, G. M. Leung, L. M. Ho, B. Cowling, A. J. Hedley

U.C. Berkeley Division of Biostatistics Working Paper Series

For diseases with some level of associated mortality, the case fatality ratio measures the proportion of diseased individuals who die from the disease. In principle, it is straightforward to estimate this quantity from individual follow-up data that provides times from onset to death or recovery. In particular, in a competing risks context, the case fatality ratio is defined by the limiting value of the sub-distribution function, associated with death, at infinity. When censoring is present, however, estimation of this quantity is complicated by the possibility of little information in the right tail of of the sub-distribution function, requiring use of …

Robust Inferences For Covariate Effects On Survival Time With Censored Linear Regression Models, Larry Leon, Tianxi Cai, L. J. Wei

Harvard University Biostatistics Working Paper Series

Various inference procedures for linear regression models with censored failure times have been studied extensively. Recent developments on efficient algorithms to implement these procedures enhance the practical usage of such models in survival analysis. In this article, we present robust inferences for certain covariate effects on the failure time in the presence of "nuisance" confounders under a semiparametric, partial linear regression setting. Specifically, the estimation procedures for the regression coefficients of interest are derived from a working linear model and are valid even when the function of the confounders in the model is not correctly specified. The new proposals are …

A Hybrid Newton-Type Method For The Linear Regression In Case-Cohort Studies, Menggang Yu, Bin Nan

The University of Michigan Department of Biostatistics Working Paper Series

Case-cohort designs are increasingly commonly used in large epidemiological cohort studies. Nan, Yu, and Kalbeisch (2004) provided the asymptotic results for censored linear regression models in case-cohort studies. In this article, we consider computational aspects of their proposed rank based estimating methods. We show that the rank based discontinuous estimating functions for case-cohort studies are monotone, a property established for cohort data in the literature, when generalized Gehan type of weights are used. Though the estimating problem can be formulated to a linear programming problem as that for cohort data, due to its easily uncontrollable large scale even for a …

Multiple Testing Procedures: R Multtest Package And Applications To Genomics, Katherine S. Pollard, Sandrine Dudoit, Mark J. Van Der Laan

U.C. Berkeley Division of Biostatistics Working Paper Series

The Bioconductor R package multtest implements widely applicable resampling-based single-step and stepwise multiple testing procedures (MTP) for controlling a broad class of Type I error rates, in testing problems involving general data generating distributions (with arbitrary dependence structures among variables), null hypotheses, and test statistics. The current version of multtest provides MTPs for tests concerning means, differences in means, and regression parameters in linear and Cox proportional hazards models. Procedures are provided to control Type I error rates defined as tail probabilities for arbitrary functions of the numbers of false positives and rejected hypotheses. These error rates include tail probabilities …

Survival Analysis Using Auxiliary Variables Via Nonparametric Multiple Imputation, Chiu-Hsieh Hsu, Jeremy Taylor, Susan Murray, Daniel Commenges

The University of Michigan Department of Biostatistics Working Paper Series

We develop an approach, based on multiple imputation, that estimates the marginal survival distribution in survival analysis using auxiliary variable to recover information for censored observations. To conduct the imputation, we use two working survival model to define the nearest neighbor imputing risk set. One model is for the event times and the other for the censoring times. Based on the imputing risk set, two nonparametric multiple imputation methods are considered: risk set imputation, and Kaplan-Meier estimator. For both methods a future event or censoring time is imputed for each censored observation. With a categorical auxiliary variable, we show that …

Choice Of Monitoring Mechanism For Optimal Nonparametric Functional Estimation For Binary Data, Nicholas P. Jewell, Mark J. Van Der Laan, Stephen Shiboski

U.C. Berkeley Division of Biostatistics Working Paper Series

Optimal designs of dose levels in order to estimate parameters from a model for binary response data have a long and rich history. These designs are based on parametric models. Here we consider fully nonparametric models with interest focused on estimation of smooth functionals using plug-in estimators based on the nonparametric maximum likelihood estimator. An important application of the results is the derivation of the optimal choice of the monitoring time distribution function for current status observation of a survival distribution. The optimal choice depends in a simple way on the dose response function and the form of the functional. …

Semiparametric Binary Regression Under Monotonicity Constraints, Moulinath Banerjee, Pinaki Biswas, Debashis Ghosh

The University of Michigan Department of Biostatistics Working Paper Series

Summary: We study a binary regression model where the response variable $\Delta$ is the indicator of an event of interest (for example, the incidence of cancer) and the set of covariates can be partitioned as $(X,Z)$ where $Z$ (real valued) is the covariate of primary interest and $X$ (vector valued) denotes a set of control variables. For any fixed $X$, the conditional probability of the event of interest is assumed to be a monotonic function of $Z$. The effect of the control variables is captured by a regression parameter $\beta$. We show that the baseline conditional probability function (corresponding to …

Deletion/Substitution/Addition Algorithm For Partitioning The Covariate Space In Prediction, Annette Molinaro, Mark J. Van Der Laan

U.C. Berkeley Division of Biostatistics Working Paper Series

We propose a new method for predicting censored (and non-censored) clinical outcomes from a highly-complex covariate space. Previously we suggested a unified strategy for predictor construction, selection, and performance assessment. Here we introduce a new algorithm which generates a piecewise constant estimation sieve of candidate predictors based on an intensive and comprehensive search over the entire covariate space. This algorithm allows us to elucidate interactions and correlation patterns in addition to main effects.

Semiparametric Methods For Semi-Competing Risks Problem With Censoring And Truncation, Hongyu Jiang, Jason Fine, Richard J. Chappell

Harvard University Biostatistics Working Paper Series

Studies of chronic life-threatening diseases often involve both mortality and morbidity. In observational studies, the data may also be subject to administrative left truncation and right censoring. Since mortality and morbidity may be correlated and mortality may censor morbidity, the Lynden-Bell estimator for left truncated and right censored data may be biased for estimating the marginal survival function of the non-terminal event. We propose a semiparametric estimator for this survival function based on a joint model for the two time-to-event variables, which utilizes the gamma frailty specification in the region of the observable data. Firstly, we develop a novel estimator …

Censored Linear Regression For Case-Cohort Studies, Bin Nan, Menggang Yu, Jack Kalbfleisch

The University of Michigan Department of Biostatistics Working Paper Series

Right censored data from a classical case-cohort design and a stratified case-cohort design are considered. In the classical case-cohort design, the subcohort is obtained as a simple random sample of the entire cohort, whereas in the stratified design, the subcohort is selected by independent Bernoulli sampling with arbitrary selection probabilities. For each design and under a linear regression model, methods for estimating the regression parameters are proposed and analyzed. These methods are derived by modifying the linear ranks tests and estimating equations that arise from full-cohort data using methods that are similar to the "pseudo-likelihood" estimating equation that has been …

Estimating A Survival Distribution With Current Status Data And High-Dimensional Covariates, Mark J. Van Der Laan, Aad Van Der Vaart

U.C. Berkeley Division of Biostatistics Working Paper Series

We consider the inverse problem of estimating a survival distribution when the survival times are only observed to be in one of the intervals of a random bisection of the time axis. We are particularly interested in the case that high-dimensional and/or time-dependent covariates are available, and/or the survival events and censoring times are only conditionally independent given the covariate process. The method of estimation consists of regularizing the survival distribution by taking the primitive function or smoothing, estimating the regularized parameter by using estimating equations, and finally recovering an estimator for the parameter of interest.