Factor-augmented transformation models for interval-censored failure time data.

Interval-censored failure time data frequently arise in various scientific studies where each subject experiences periodical examinations for the occurrence of the failure event of interest, and the failure time is only known to lie in a specific time interval. In addition, collected data may include multiple observed variables with a certain degree of correlation, leading to severe multicollinearity issues. This work proposes a factor-augmented transformation model to analyze interval-censored failure time data while reducing model dimensionality and avoiding multicollinearity elicited by multiple correlated covariates. We provide a joint modeling framework by comprising a factor analysis model to group multiple observed variables into a few latent factors and a class of semiparametric transformation models with the augmented factors to examine their and other covariate effects on the failure event. Furthermore, we propose a nonparametric maximum likelihood estimation approach and develop a computationally stable and reliable expectation-maximization algorithm for its implementation. We establish the asymptotic properties of the proposed estimators and conduct simulation studies to assess the empirical performance of the proposed method. An application to the Alzheimer's Disease Neuroimaging Initiative (ADNI) study is provided. An R package ICTransCFA is also available for practitioners. Data used in preparation of this article were obtained from the ADNI database.

Testing latent classes in gut microbiome data using generalized Poisson regression models.

Human microbiome research has gained increasing importance due to its critical roles in comprehending human health and disease. Within the realm of microbiome research, the data generated often involves operational taxonomic unit counts, which can frequently present challenges such as over-dispersion and zero-inflation. To address dispersion-related concerns, the generalized Poisson model offers a flexible solution, effectively handling data characterized by over-dispersion, equi-dispersion, and under-dispersion. Furthermore, the realm of zero-inflated generalized Poisson models provides a strategic avenue to simultaneously tackle both over-dispersion and zero-inflation. The phenomenon of zero-inflation frequently stems from the heterogeneous nature of study populations. It emerges when specific microbial taxa fail to thrive in the microbial community of certain subjects, consequently resulting in a consistent count of zeros for these individuals. This subset of subjects represents a latent class, where their zeros originate from the genuine absence of the microbial taxa. In this paper, we introduce a novel testing methodology designed to uncover such latent classes within generalized Poisson regression models. We establish a closed-form test statistic and deduce its asymptotic distribution based on estimating equations. To assess its efficacy, we conduct an extensive array of simulation studies, and further apply the test to detect latent classes in human gut microbiome data from the Bogalusa Heart Study.

Semiparametric probit regression model with misclassified current status data.

Current status data arise when each subject under study is examined only once at an observation time, and one only knows the failure status of the event of interest at the observation time rather than the exact failure time. Moreover, the obtained failure status is frequently subject to misclassification due to imperfect tests, yielding misclassified current status data. This article conducts regression analysis of such data with the semiparametric probit model, which serves as an important alternative to existing semiparametric models and has recently received considerable attention in failure time data analysis. We consider the nonparametric maximum likelihood estimation and develop an expectation-maximization (EM) algorithm by incorporating the generalized pool-adjacent-violators (PAV) algorithm to maximize the intractable likelihood function. The resulting estimators of regression parameters are shown to be consistent, asymptotically normal, and semiparametrically efficient. Furthermore, the numerical results in simulation studies indicate that the proposed method performs satisfactorily in finite samples and outperforms the naive method that ignores misclassification. We then apply the proposed method to a real dataset on chlamydia infection.

Joint modeling of generalized scale-change models for recurrent event and failure time data.

Recurrent event and failure time data arise frequently in many clinical and observational studies. In this article, we propose a joint modeling of generalized scale-change models for the recurrent event process and the failure time, and allow the two processes to be correlated through a shared frailty. The proposed joint model is flexible in that it requires neither the Poisson assumption for the recurrent event process nor a parametric assumption on the frailty distribution. Estimating equation approaches are developed for parameter estimation, and the asymptotic properties of the resulting estimators are established. Simulation studies are conducted to evaluate the finite sample performances of the proposed method. An application to a medical cost study of chronic heart failure patients is provided.

Combined estimating equation approaches for the additive hazards model with left-truncated and interval-censored data.

Interval-censored failure time data arise commonly in various scientific studies where the failure time of interest is only known to lie in a certain time interval rather than observed exactly. In addition, left truncation on the failure event may occur and can greatly complicate the statistical analysis. In this paper, we investigate regression analysis of left-truncated and interval-censored data with the commonly used additive hazards model. Specifically, we propose a conditional estimating equation approach for the estimation, and further improve its estimation efficiency by combining the conditional estimating equation and the pairwise pseudo-score-based estimating equation that can eliminate the nuisance functions from the marginal likelihood of the truncation times. Asymptotic properties of the proposed estimators are discussed including the consistency and asymptotic normality. Extensive simulation studies are conducted to evaluate the empirical performance of the proposed methods, and suggest that the combined estimating equation approach is obviously more efficient than the conditional estimating equation approach. We then apply the proposed methods to a set of real data for illustration.

Simultaneous variable selection in regression analysis of multivariate interval-censored data.

Multivariate interval-censored data arise when each subject under study can potentially experience multiple events and the onset time of each event is not observed exactly but is known to lie in a certain time interval formed by adjacent examination times with changed statuses of the event. This type of incomplete and complex data structure poses a substantial challenge in practical data analysis. In addition, many potential risk factors exist in numerous studies. Thus, conducting variable selection for event-specific covariates simultaneously becomes useful in identifying important variables and assessing their effects on the events of interest. In this paper, we develop a variable selection technique for multivariate interval-censored data under a general class of semiparametric transformation frailty models. The minimum information criterion (MIC) method is embedded in the optimization step of the proposed expectation-maximization (EM) algorithm to obtain the parameter estimator. The proposed EM algorithm greatly reduces the computational burden in maximizing the observed likelihood function, and the MIC naturally avoids selecting the optimal tuning parameter as needed in many other popular penalties, making the proposed algorithm promising and reliable. The proposed method is evaluated through extensive simulation studies and illustrated by an analysis of patient data from the Aerobics Center Longitudinal Study.

On estimating optimal regime for treatment initiation time based on restricted mean residual lifetime.

When to initiate treatment on patients is an important problem in many medical studies such as AIDS and cancer. In this article, we formulate the treatment initiation time problem for time-to-event data and propose an optimal individualized regime that determines the best treatment initiation time for individual patients based on their characteristics. Different from existing optimal treatment regimes where treatments are undertaken at a pre-specified time, here new challenges arise from the complicated missing mechanisms in treatment initiation time data and the continuous treatment rule in terms of initiation time. To tackle these challenges, we propose to use restricted mean residual lifetime as a value function to evaluate the performance of different treatment initiation regimes, and develop a nonparametric estimator for the value function, which is consistent even when treatment initiation times are not completely observable and their distribution is unknown. We also establish the asymptotic properties of the resulting estimator in the decision rule and its associated value function estimator. In particular, the asymptotic distribution of the estimated value function is nonstandard, which follows a weighted chi-squared distribution. The finite-sample performance of the proposed method is evaluated by simulation studies and is further illustrated with an application to a breast cancer data.

Dynamic semiparametric transformation models for recurrent event data with a terminal event.

Recurrent event data with a terminal event commonly arise in many longitudinal follow-up studies. This article proposes a class of dynamic semiparametric transformation models for the marginal mean functions of the recurrent events with a terminal event, where some covariate effects may be time-varying. An estimation procedure is developed for the model parameters, and the asymptotic properties of the resulting estimators are established. In addition, relevant significance tests are suggested for examining whether or not covariate effects vary with time, and a model checking procedure is presented for assessing the adequacy of the proposed models. The finite sample performance of the proposed estimators is examined through simulation studies, and an application to a medical cost study of chronic heart failure patients is provided.

Augmented weighting estimators for the additive rates model under multivariate recurrent event data with missing event type.

Multivariate recurrent event data are frequently encountered in biomedical and epidemiological studies when subjects experience multiple types of recurrent events. In practice, the event type information may be missing due to a variety of reasons. In this article, we consider a semiparametric additive rates model for multivariate recurrent event data with missing event types. We develop the augmented inverse probability weighting technique to handle event types that are missing at random. The nonparametric kernel-assisted proposals for the missing mechanisms are studied. The resulting estimator is shown to be consistent and asymptotically normal. Extensive simulation studies and a real data application are provided to illustrate the validity and practical utility of the proposed method.

A joint modeling approach for analyzing marker data in the presence of a terminal event.

In many medical studies, markers are contingent on recurrent events and the cumulative markers are usually of interest. However, the recurrent event process is often interrupted by a dependent terminal event, such as death. In this article, we propose a joint modeling approach for analyzing marker data with informative recurrent and terminal events. This approach introduces a shared frailty to specify the explicit dependence structure among the markers, the recurrent, and terminal events. Estimation procedures are developed for the model parameters and the degree of dependence, and a prediction of the covariate-specific cumulative markers is provided. The finite sample performance of the proposed estimators is examined through simulation studies. An application to a medical cost study of chronic heart failure patients from the University of Virginia Health System is illustrated.

Mixture proportional hazards cure model with latent variables.

A mixture proportional hazards cure model with latent variables is proposed. The proposed model assesses the effects of the observed and latent risk factors on the hazards of uncured subjects and the cure rate through a proportional hazards model and a logistic model, respectively. Factor analysis is employed to measure the latent variables through correlated multiple indicators. Maximum likelihood estimation is performed through a Gaussian quadratic technique that approximates the integration over the latent variables. A piecewise constant function is used for the unspecified baseline hazard of uncured subjects. The proposed method can be conveniently implemented by using SAS Proc NLMIXED. Simulation studies are conducted to evaluate the performance of the proposed approach. An application to a study concerning the risk factors of chronic kidney disease for type 2 diabetic patients is provided.

k-Resolution sequential randomization procedure to improve covariates balance in a randomized experiment.

Balancing allocation of assigning units to two treatment groups to minimize the allocation differences is important in biomedical research. The complete randomization, rerandomization, and pairwise sequential randomization (PSR) procedures can be employed to balance the allocation. However, the first two do not allow a large number of covariates. In this article, we generalize the PSR procedure and propose a k-resolution sequential randomization (k-RSR) procedure by minimizing the Mahalanobis distance between both groups with equal group size. The proposed method can be used to achieve adequate balance and obtain a reasonable estimate of treatment effect. Compared to PSR, k-RSR is more likely to achieve the optimal value theoretically. Extensive simulation studies are conducted to show the superiorities of k-RSR and applications to the clinical synthetic data and GAW16 data further illustrate the methods.

Testing inflated zeros in binomial regression models.

Binomial regression models are commonly applied to proportion data such as those relating to the mortality and infection rates of diseases. However, it is often the case that the responses may exhibit excessive zeros; in such cases a zero-inflated binomial (ZIB) regression model can be applied instead. In practice, it is essential to test if there are excessive zeros in the outcome to help choose an appropriate model. The binomial models can yield biased inference if there are excessive zeros, while ZIB models may be unnecessarily complex and hard to interpret, and even face convergence issues, if there are no excessive zeros. In this paper, we develop a new test for testing zero inflation in binomial regression models by directly comparing the amount of observed zeros with what would be expected under the binomial regression model. A closed form of the test statistic, as well as the asymptotic properties of the test, is derived based on estimating equations. Our systematic simulation studies show that the new test performs very well in most cases, and outperforms the classical Wald, likelihood ratio, and score tests, especially in controlling type I errors. Two real data examples are also included for illustrative purpose.

Variable selection in joint frailty models of recurrent and terminal events.

Recurrent event data are commonly encountered in biomedical studies. In many situations, they are subject to an informative terminal event, for example, death. Joint modeling of recurrent and terminal events has attracted substantial recent research interests. On the other hand, there may exist a large number of covariates in such data. How to conduct variable selection for joint frailty proportional hazards models has become a challenge in practical data analysis. We tackle this issue on the basis of the "minimum approximated information criterion" method. The proposed method can be conveniently implemented in SAS Proc NLMIXED for commonly used frailty distributions. Its finite-sample behavior is evaluated through simulation studies. We apply the proposed method to model recurrent opportunistic diseases in the presence of death in an AIDS study.

A semiparametric additive rates model for the weighted composite endpoint of recurrent and terminal events.

Recurrent event data with a terminal event commonly arise in longitudinal follow-up studies. We use a weighted composite endpoint of all recurrent and terminal events to assess the overall effects of covariates on the two types of events. A semiparametric additive rates model is proposed to analyze the weighted composite event process and the dependence structure among recurrent and terminal events is left unspecified. An estimating equation approach is developed for inference, and the asymptotic properties of the resulting estimators are established. The finite-sample behavior of the proposed estimators is evaluated through simulation studies, and an application to a bladder cancer study is illustrated.

Variable selection in semiparametric nonmixture cure model with interval-censored failure time data: An application to the prostate cancer screening study.

Censored failure time data with a cured subgroup is frequently encountered in many scientific areas including the cancer screening research, tumorigenicity studies, and sociological surveys. Meanwhile, one may also encounter an extraordinary large number of risk factors in practice, such as patient's demographic characteristics, clinical measurements, and medical history, which makes variable selection an emerging need in the data analysis. Motivated by a medical study on prostate cancer screening, we develop a variable selection method in the semiparametric nonmixture or promotion time cure model when interval-censored data with a cured subgroup are present. Specifically, we propose a penalized likelihood approach with the use of the least absolute shrinkage and selection operator, adaptive least absolute shrinkage and selection operator, or smoothly clipped absolute deviation penalties, which can be easily accomplished via a novel penalized expectation-maximization algorithm. We assess the finite-sample performance of the proposed methodology through extensive simulations and analyze the prostate cancer screening data for illustration.

A semiparametric additive rate model for a modulated renewal process.

Recurrent event data from a long single realization are widely encountered in point process applications. Modeling and analyzing such data are different from those for independent and identical short sequences, and the development of statistical methods requires careful consideration of the underlying dependence structure of the long single sequence. In this paper, we propose a semiparametric additive rate model for a modulated renewal process, and develop an estimating equation approach for the model parameters. The asymptotic properties of the resulting estimators are established by applying the limit theory for stationary mixing sequences. A block-based bootstrap procedure is presented for the variance estimation. Simulation studies are conducted to assess the finite-sample performance of the proposed estimators. An application to a data set from a cardiovascular mortality study is provided.

Analysis of proportional mean residual life model with latent variables.

End-stage renal disease (ESRD) is one of the most serious diabetes complications. Numerous studies have been devoted to revealing the risk factors of the onset time of ESRD. In this article, we propose a proportional mean residual life (MRL) model with latent variables to assess the effects of observed and latent risk factors on the MRL function of ESRD in a cohort of Chinese type 2 diabetic patients. The proposed model generalizes the conventional proportional MRL model to accommodate the latent risk factor that cannot be measured by a single observed variable. We employ a factor analysis model to characterize the latent risk factors via multiple observed variables. We develop a borrow-strength estimation procedure, which incorporates the expectation-maximization algorithm and an extended estimating equation approach. The asymptotic properties of the proposed estimators are established. Simulation shows that the performance of the proposed methodology is satisfactory. The application to the study of type 2 diabetes reveals insights into the prevention of ESRD. Copyright © 2016 John Wiley & Sons, Ltd.

An additive-multiplicative mean residual life model for right-censored data.

Many studies have focused on determining the effect of the body mass index (BMI) on the mortality in different cohorts. In this article, we propose an additive-multiplicative mean residual life (MRL) model to assess the effects of BMI and other risk factors on the MRL function of survival time in a cohort of Chinese type 2 diabetic patients. The proposed model can simultaneously manage additive and multiplicative risk factors and provide a comprehensible interpretation of their effects on the MRL function of interest. We develop an estimation procedure through pseudo partial score equations to obtain parameter estimates. We establish the asymptotic properties of the proposed estimators and conduct simulations to demonstrate the performance of the proposed method. The application of the procedure to a study on the life expectancy of type 2 diabetic patients reveals new insights into the extension of the life expectancy of such patients.

Additive mixed effect model for recurrent gap time data.

Gap times between recurrent events are often of primary interest in medical and observational studies. The additive hazards model, focusing on risk differences rather than risk ratios, has been widely used in practice. However, the marginal additive hazards model does not take the dependence among gap times into account. In this paper, we propose an additive mixed effect model to analyze gap time data, and the proposed model includes a subject-specific random effect to account for the dependence among the gap times. Estimating equation approaches are developed for parameter estimation, and the asymptotic properties of the resulting estimators are established. In addition, some graphical and numerical procedures are presented for model checking. The finite sample behavior of the proposed methods is evaluated through simulation studies, and an application to a data set from a clinic study on chronic granulomatous disease is provided.