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While sample sizes in randomized clinical trials are large enough to estimate the average treatment effect well, they are often insufficient for estimation of treatment-covariate interactions critical to studying data-driven precision medicine. Observational data from real world practice may play an important role in alleviating this problem. One common approach in trials is to predict the outcome of interest with separate regression models in each treatment arm, and estimate the treatment effect based on the contrast of the predictions. Unfortunately, this simple approach may induce spurious treatment-covariate interaction in observational studies when the regression model is misspecified. Motivated by the need of modeling the number of relapses in multiple sclerosis (MS) patients, where the ratio of relapse rates is a natural choice of the treatment effect, we propose to estimate the conditional average treatment effect (CATE) as the ratio of expected potential outcomes, and derive a doubly robust estimator of this CATE in a semiparametric model of treatment-covariate interactions. We also provide a validation procedure to check the quality of the estimator on an independent sample. We conduct simulations to demonstrate the finite sample performance of the proposed methods, and illustrate their advantages on real data by examining the treatment effect of dimethyl fumarate compared to teriflunomide in MS patients. for this article are available online. [ABSTRACT FROM AUTHOR]

In comparing two treatments via a randomized clinical trial, the analysis of covariance (ANCOVA) technique is often utilized to estimate an overall treatment effect. The ANCOVA is generally perceived as a more efficient procedure than its simple two sample estimation counterpart. Unfortunately, when the ANCOVA model is nonlinear, the resulting estimator is generally not consistent. Recently, various nonparametric alternatives to the ANCOVA, such as the augmentation methods, have been proposed to estimate the treatment effect by adjusting the covariates. However, the properties of these alternatives have not been studied in the presence of treatment allocation imbalance. In this article, we take a different approach to explore how to improve the precision of the naive two-sample estimate even when the observed distributions of baseline covariates between two groups are dissimilar. Specifically, we derive a bias-adjusted estimation procedure constructed from a conditional inference principle via relevant ancillary statistics from the observed covariates. This estimator is shown to be asymptotically equivalent to an augmentation estimator under the unconditional setting. We utilize the data from a clinical trial for evaluating a combination treatment of cardiovascular diseases to illustrate our findings. [ABSTRACT FROM AUTHOR]

Health sciences research often involves both right- and interval-censored events because the occurrence of a symptomatic disease can only be observed up to the end of follow-up, while the occurrence of an asymptomatic disease can only be detected through periodic examinations. We formulate the effects of potentially time-dependent covariates on the joint distribution of multiple right- and interval-censored events through semiparametric proportional hazards models with random effects that capture the dependence both within and between the two types of events. We consider nonparametric maximum likelihood estimation and develop a simple and stable EM algorithm for computation. We show that the resulting estimators are consistent and the parametric components are asymptotically normal and efficient with a covariance matrix that can be consistently estimated by profile likelihood or nonparametric bootstrap. In addition, we leverage the joint modelling to provide dynamic prediction of disease incidence based on the evolving event history. Furthermore, we assess the performance of the proposed methods through extensive simulation studies. Finally, we provide an application to a major epidemiological cohort study. Supplementary materials for this article are available online. [ABSTRACT FROM AUTHOR]

Benefit–risk assessment is a crucial step in medical decision process. In many biomedical studies, both longitudinal marker measurements and time to a terminal event serve as important endpoints for benefit–risk assessment. The effect of an intervention or a treatment on the longitudinal marker process, however, can be in conflict with its effect on the time to the terminal event. Thus, questions arise on how to evaluate treatment effects based on the two endpoints, for the purpose of deciding on which treatment is most likely to benefit the patients. In this article, we present a unified framework for benefit–risk assessment using the observed longitudinal markers and time to event data. We propose a cumulative weighted marker process to synthesize information from the two endpoints, and use its mean function at a prespecified time point as a benefit–risk summary measure. We consider nonparametric estimation of the summary measure under two scenarios: (i) the longitudinal marker is measured intermittently during the study period, and (ii) the value of the longitudinal marker is observed throughout the entire follow-up period. The large-sample properties of the estimators are derived and compared. Simulation studies and data examples exhibit that the proposed methods are easy to implement and reliable for practical use. Supplemental materials for this article are available online. [ABSTRACT FROM PUBLISHER]

In dose-finding clinical trials, it is becoming increasingly important to account for individual-level heterogeneity while searching for optimal doses to ensure an optimal individualized dose rule (IDR) maximizes the expected beneficial clinical outcome for each individual. In this article, we advocate a randomized trial design where candidate dose levels assigned to study subjects are randomly chosen from a continuous distribution within a safe range. To estimate the optimal IDR using such data, we propose an outcome weighted learning method based on a nonconvex loss function, which can be solved efficiently using a difference of convex functions algorithm. The consistency and convergence rate for the estimated IDR are derived, and its small-sample performance is evaluated via simulation studies. We demonstrate that the proposed method outperforms competing approaches. Finally, we illustrate this method using data from a cohort study for warfarin (an anti-thrombotic drug) dosing. Supplementary materials for this article are available online. [ABSTRACT FROM AUTHOR]

Readmission following discharge from an initial hospitalization is a key marker of quality of healthcare in the United States. For the most part, readmission has been studied among patients with “acute” health conditions, such as pneumonia and heart failure, with analyses based on a logistic-Normal generalized linear mixed model. Naïve application of this model to the study of readmission among patients with “advanced” health conditions such as pancreatic cancer, however, is problematic because it ignores death as a competing risk. A more appropriate analysis is to imbed such a study within the semicompeting risks framework. To our knowledge, however, no comprehensive statistical methods have been developed for cluster-correlated semicompeting risks data. To resolve this gap in the literature we propose a novel hierarchical modeling framework for the analysis of cluster-correlated semicompeting risks data that permits parametric or nonparametric specifications for a range of components giving analysts substantial flexibility as they consider their own analyses. Estimation and inference is performed within the Bayesian paradigm since it facilitates the straightforward characterization of (posterior) uncertainty for all model parameters, including hospital-specific random effects. Model comparison and choice is performed via the deviance information criterion and the log-pseudo marginal likelihood statistic, both of which are based on a partially marginalized likelihood. An efficient computational scheme, based on the Metropolis-Hastings-Green algorithm, is developed and had been implemented in the R package SemiCompRisks. A comprehensive simulation study shows that the proposed framework performs very well in a range of data scenarios, and outperforms competitor analysis strategies. The proposed framework is motivated by and illustrated with an ongoing study of the risk of readmission among Medicare beneficiaries diagnosed with pancreatic cancer. Using data onn= 5298 patients atJ=112 hospitals in the six New England states between 2000–2009, key scientific questions we consider include the role of patient-level risk factors on the risk of readmission and the extent of variation in risk across hospitals not explained by differences in patient case-mix. Supplementary materials for this article are available online. [ABSTRACT FROM AUTHOR]

In many studies with a survival outcome, it is often not feasible to fully observe the primary event of interest. This often leads to heavy censoring and thus, difficulty in efficiently estimating survival or comparing survival rates between two groups. In certain diseases, baseline covariates and the event time of nonfatal intermediate events may be associated with overall survival. In these settings, incorporating such additional information may lead to gains in efficiency in estimation of survival and testing for a difference in survival between two treatment groups. If gains in efficiency can be achieved, it may then be possible to decrease the sample size of patients required for a study to achieve a particular power level or decrease the duration of the study. Most existing methods for incorporating intermediate events and covariates to predict survival focus on estimation of relative risk parameters and/or the joint distribution of events under semiparametric models. However, in practice, these model assumptions may not hold and hence may lead to biased estimates of the marginal survival. In this article, we propose a seminonparametric two-stage procedure to estimate and comparet-year survival rates by incorporating intermediate event information observed before some landmark time, which serves as a useful approach to overcome semicompeting risk issues. In a randomized clinical trial setting, we further improve efficiency through an additional calibration step. Simulation studies demonstrate substantial potential gains in efficiency in terms of estimation and power. We illustrate our proposed procedures using an AIDS Clinical Trial Protocol 175 dataset by estimating survival and examining the difference in survival between two treatment groups: zidovudine and zidovudine plus zalcitabine. Supplementary materials for this article are available online. [ABSTRACT FROM AUTHOR]

In evaluating familial risk for disease we have two main statistical tasks: assessing the probability of carrying an inherited genetic mutation conferring higher risk, and predicting the absolute risk of developing diseases over time for those individuals whose mutation status is known. Despite substantial progress, much remains unknown about the role of genetic and environmental risk factors, about the sources of variation in risk among families that carry high-risk mutations, and about the sources of familial aggregation beyond major Mendelian effects. These sources of heterogeneity contribute substantial variation in risk across families. In this article we present simple and efficient methods for accounting for this variation in familial risk assessment. Our methods are based on frailty models. We implemented them in the context of generalizing Mendelian models of cancer risk, and compared our approaches to others that do not consider heterogeneity across families. Our extensive simulation study demonstrates that when predicting the risk of developing a disease over time conditional on carrier status, accounting for heterogeneity results in a substantial improvement in the area under the curve of the receiver operating characteristic. On the other hand, the improvement for carriership probability estimation is more limited. We illustrate the utility of the proposed approach through the analysis of BRCA1 and BRCA2 mutation carriers in the Washington Ashkenazi Kin-Cohort Study of Breast Cancer. Supplementary materials for this article are available online. [ABSTRACT FROM AUTHOR]

In recent years, a wide range of markers have become available as potential tools to predict risk or progression of disease. In addition to such biological and genetic markers, short-term outcome information may be useful in predicting long-term disease outcomes. When such information is available, it would be desirable to combine this along with predictive markers to improve the prediction of long-term survival. Most existing methods for incorporating censored short-term event information in predicting long-term survival focus on modeling the disease process and are derived under restrictive parametric models in a multistate survival setting. When such model assumptions fail to hold, the resulting prediction of long-term outcomes may be invalid or inaccurate. When there is only a single discrete baseline covariate, a fully nonparametric estimation procedure to incorporate short-term event time information has been previously proposed. However, such an approach is not feasible for settings with one or more continuous covariates due to the curse of dimensionality. In this article, we propose to incorporate short-term event time information along with multiple covariates collected up to a landmark point via a flexible varying-coefficient model. To evaluate and compare the prediction performance of the resulting landmark prediction rule, we use robust nonparametric procedures that do not require the correct specification of the proposed varying-coefficient model. Simulation studies suggest that the proposed procedures perform well in finite samples. We illustrate them here using a dataset of postdialysis patients with end-stage renal disease. [ABSTRACT FROM PUBLISHER]

There is increasing interest in discovering individualized treatment rules (ITRs) for patients who have heterogeneous responses to treatment. In particular, one aims to find an optimal ITR that is a deterministic function of patient-specific characteristics maximizing expected clinical outcome. In this article, we first show that estimating such an optimal treatment rule is equivalent to a classification problem where each subject is weighted proportional to his or her clinical outcome. We then propose an outcome weighted learning approach based on the support vector machine framework. We show that the resulting estimator of the treatment rule is consistent. We further obtain a finite sample bound for the difference between the expected outcome using the estimated ITR and that of the optimal treatment rule. The performance of the proposed approach is demonstrated via simulation studies and an analysis of chronic depression data. [ABSTRACT FROM PUBLISHER]

Corporate bankruptcy prediction plays a central role in academic finance research, business practice, and government regulation. Consequently, accurate default probability prediction is extremely important. We propose to apply a discrete transformation family of survival models to corporate default risk predictions. A class of Box-Cox transformations and logarithmic transformations is naturally adopted. The proposed transformation model family is shown to include the popular Shumway model and the grouped relative risk model. We show that a transformation parameter different from those two models is needed for default prediction using a bankruptcy dataset. In addition, we show using out-of-sample validation statistics that our model improves performance. We use the estimated default probability to examine a popular asset pricing question and determine whether default risk has carried a premium. Due to some distinct features of the bankruptcy application, the proposed class of discrete transformation survival models with time-varying covariates is different from the continuous survival models in the survival analysis literature. Their similarities and differences are discussed. [ABSTRACT FROM PUBLISHER]

We present a unified approach to nonparametric comparisons of receiver operating characteristic (ROC) curves for a paired design with clustered data. Treating empirical ROC curves as stochastic processes, their asymptotic joint distribution is derived in the presence of both between-marker and within-subject correlations. A Monte Carlo method is developed to approximate their joint distribution without involving nonparametric density estimation. The developed theory is applied to derive new inferential procedures for comparing weighted areas under the ROC curves, confidence bands for the difference function of ROC curves, confidence intervals for the set of specificities at which one diagnostic test is more sensitive than the other, and multiple comparison procedures for comparing more than two diagnostic markers. Our methods demonstrate satisfactory small-sample performance in simulations. We illustrate our methods using clustered data from a glaucoma study and repeated-measurement data from a startle response study. [ABSTRACT FROM AUTHOR]