Estimating disease incidence rates and transition probabilities in elderly patients using multi-state models: a case study in fragility fracture using a Bayesian approach.

BACKGROUND: Multi-state models are complex stochastic models which focus on pathways defined by the temporal and sequential occurrence of numerous events of interest. In particular, the so-called illness-death models are especially useful for studying probabilities associated to diseases whose occurrence competes with other possible diseases, health conditions or death. They can be seen as a generalization of the competing risks models, which are widely used to estimate disease-incidences among populations with a high risk of death, such as elderly or cancer patients. The main advantage of the aforementioned illness-death models is that they allow the treatment of scenarios with non-terminal competing events that may occur sequentially, which competing risks models fail to do. METHODS: We propose an illness-death model using Cox proportional hazards models with Weibull baseline hazard functions, and applied the model to a study of recurrent hip fracture. Data came from the PREV2FO cohort and included 34491 patients aged 65 years and older who were discharged alive after a hospitalization due to an osteoporotic hip fracture between 2008-2015. We used a Bayesian approach to approximate the posterior distribution of each parameter of the model, and thus cumulative incidences and transition probabilities. We also compared these results with a competing risks specification. RESULTS: Posterior transition probabilities showed higher probabilities of death for men and increasing with age. Women were more likely to refracture as well as less likely to die after it. Free-event time was shown to reduce the probability of death. Estimations from the illness-death and the competing risks models were identical for those common transitions although the illness-death model provided additional information from the transition from refracture to death. CONCLUSIONS: We illustrated how multi-state models, in particular illness-death models, may be especially useful when dealing with survival scenarios which include multiple events, with competing diseases or when death is an unavoidable event to consider. Illness-death models via transition probabilities provide additional information of transitions from non-terminal health conditions to absorbing states such as death, what implies a deeper understanding of the real-world problem involved compared to competing risks models.

Accelerated failure time models for semi-competing risks data in the presence of complex censoring.

Statistical analyses that investigate risk factors for Alzheimer's disease (AD) are often subject to a number of challenges. Some of these challenges arise due to practical considerations regarding data collection such that the observation of AD events is subject to complex censoring including left-truncation and either interval or right-censoring. Additional challenges arise due to the fact that study participants under investigation are often subject to competing forces, most notably death, that may not be independent of AD. Towards resolving the latter, researchers may choose to embed the study of AD within the "semi-competing risks" framework for which the recent statistical literature has seen a number of advances including for the so-called illness-death model. To the best of our knowledge, however, the semi-competing risks literature has not fully considered analyses in contexts with complex censoring, as in studies of AD. This is particularly the case when interest lies with the accelerated failure time (AFT) model, an alternative to the traditional multiplicative Cox model that places emphasis away from the hazard function. In this article, we outline a new Bayesian framework for estimation/inference of an AFT illness-death model for semi-competing risks data subject to complex censoring. An efficient computational algorithm that gives researchers the flexibility to adopt either a fully parametric or a semi-parametric model specification is developed and implemented. The proposed methods are motivated by and illustrated with an analysis of data from the Adult Changes in Thought study, an on-going community-based prospective study of incident AD in western Washington State.

Hierarchical models for semi-competing risks data with application to quality of end-of-life care for pancreatic cancer.

Readmission following discharge from an initial hospitalization is a key marker of quality of health care 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 (Normand et al., 1997). 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 semi-competing risks framework. To our knowledge, however, no comprehensive statistical methods have been developed for cluster-correlated semi-competing risks data. To resolve this gap in the literature we propose a novel hierarchical modeling framework for the analysis of cluster-correlated semi-competing risks data that permits parametric or non-parametric 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 SemiCompRisks R package. 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 on-going study of the risk of readmission among Medicare beneficiaries diagnosed with pancreatic cancer. Using data on n=5,298 patients at J=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.

Bayesian Semi-parametric Analysis of Semi-competing Risks Data: Investigating Hospital Readmission after a Pancreatic Cancer Diagnosis.

In the U.S., the Centers for Medicare and Medicaid Services uses 30-day readmission, following hospitalization, as a proxy outcome to monitor quality of care. These efforts generally focus on treatable health conditions, such as pneumonia and heart failure. Expanding quality of care systems to monitor conditions for which treatment options are limited or non-existent, such as pancreatic cancer, is challenging because of the non-trivial force of mortality; 30-day mortality for pancreatic cancer is approximately 30%. In the statistical literature, data that arise when the observation of the time to some non-terminal event is subject to some terminal event are referred to as 'semi-competing risks data'. Given such data, scientific interest may lie in at least one of three areas: (i) estimation/inference for regression parameters, (ii) characterization of dependence between the two events, and (iii) prediction given a covariate profile. Existing statistical methods focus almost exclusively on the first of these; methods are sparse or non-existent, however, when interest lies with understanding dependence and performing prediction. In this paper we propose a Bayesian semi-parametric regression framework for analyzing semi-competing risks data that permits the simultaneous investigation of all three of the aforementioned scientific goals. Characterization of the induced posterior and posterior predictive distributions is achieved via an efficient Metropolis-Hastings-Green algorithm, which has been implemented in an R package. The proposed framework is applied to data on 16,051 individuals diagnosed with pancreatic cancer between 2005-2008, obtained from Medicare Part A. We found that increased risk for readmission is associated with a high comorbidity index, a long hospital stay at initial hospitalization, non-white race, male, and discharge to home care.

Missing information caused by death leads to bias in relative risk estimates.

OBJECTIVES: In most clinical and epidemiologic studies, information on disease status is usually collected at regular follow-up visits. Often, this information can only be retrieved in individuals who are alive at follow-up, and studies frequently right censor individuals with missing information because of death in the analysis. Such ad hoc analyses can lead to seriously biased hazard ratio estimates of potential risk factors. We systematically investigate this bias. STUDY DESIGN AND SETTING: We illustrate under which conditions the bias can occur. Considering three numerical studies, we characterize the bias, its magnitude, and direction as well as its real-world relevance. RESULTS: Depending on the situation studied, the bias can be substantial and in both directions. It is mainly caused by differential mortality: if deaths without occurrence of the disease are more pronounced, the risk factor effect is overestimated. However, if the risk for dying after being diseased is prevailing, the effect is mostly underestimated and might even change signs. CONCLUSION: The bias is a result of both, a too coarse follow-up and an ad hoc Cox analysis in which the data sample is restricted to the observed and known event history. This is especially relevant for studies in which a considerable number of death cases are expected.