Danilo Alvares

This paper introduces a random activation framework for cure rate modeling that provides a novel latent mechanistic interpretation of the standard mixture cure model, utilizing a Waring-distributed number of latent causes. The proposed approach represents unobserved heterogeneity through a discrete latent variable interpreted as the number of potential risk factors, providing a flexible and biologically interpretable characterization of individual susceptibility. In contrast to classical competing risks models based on extremal operators or deterministic activation schemes, the event time is assumed to arise from a stochastic selection among latent causes. This random activation mechanism defines a unified probabilistic framework in which the cure fraction emerges naturally as the probability of having zero latent causes. The Waring distribution is adopted to model the latent count structure due to its hierarchical formulation, which accommodates overdispersion and heavy-tailed behavior strictly within the latent parametrization of individual risk factors. Under this framework, while the population survival function mathematically reduces to the classical mixture cure representation, the model provides an alternative structure where covariates directly impact the expected latent burden. Parameter estimation for the identifiable regression structure is performed via maximum likelihood, and the finite-sample performance of the estimators is assessed through Monte Carlo simulations, showing accurate parameter recovery and stable inferential properties. An application to real survival data illustrates the practical relevance and epidemiological interpretability of the proposed framework. Overall, this work extends the understanding of existing cure rate models by integrating latent count structures and stochastic activation within a coherent setting, providing a powerful interpretation tool for heterogeneous survival data with long-term survivors.

Joint models have proven to be an effective approach for uncovering potentially hidden connections between various types of outcomes, mainly continuous, time-to-event, and binary. Typically, longitudinal continuous outcomes are characterized by linear mixed-effects models, survival outcomes are described by proportional hazards models, and the link between outcomes are captured by shared random effects. Other modeling variations include generalized linear mixed-effects models for longitudinal data and logistic regression when a binary outcome is present, rather than time until an event of interest. However, in a clinical research setting, one might be interested in modeling the physician’s chosen treatment based on the patient’s medical history to identify prognostic factors. In this situation there are often multiple treatment options, requiring the use of a multiclass classification approach. Inspired by this context, we develop a Bayesian joint model for longitudinal and categorical data. In particular, our motivation comes from a multiple myeloma study in which biomarkers display nonlinear trajectories that are well captured through biexponential submodels, where patient-level information is shared with the categorical submodel. We also present a variable importance strategy to rank prognostic factors. We apply our proposal and a competing model to the multiple myeloma data, compare the variable importance and inferential results for both models, and illustrate patient-level interpretations using our joint model.

Joint models have proven to be an effective approach for uncovering potentially hidden connections between various types of outcomes, mainly continuous, time-to-event, and binary. Typically, longitudinal continuous outcomes are characterized by linear mixed-effects models, survival outcomes are described by proportional hazards models, and the link between outcomes are captured by shared random effects. Other modeling variations include generalized linear mixed-effects models for longitudinal data and logistic regression when a binary outcome is present, rather than time until an event of interest. However, in a clinical research setting, one might be interested in modeling the physician’s chosen treatment based on the patient’s medical history to identify prognostic factors. In this situation there are often multiple treatment options, requiring the use of a multiclass classification approach. Inspired by this context, we develop a Bayesian joint model for longitudinal and categorical data. In particular, our motivation comes from a multiple myeloma study in which biomarkers display nonlinear trajectories that are well captured through biexponential submodels, where patient-level information is shared with the categorical submodel. We also present a variable importance strategy to rank prognostic factors. We apply our proposal and a competing model to the multiple myeloma data, compare the variable importance and inferential results for both models, and illustrate patient-level interpretations using our joint model.

Joint models have proven to be an effective approach for uncovering potentially hidden connections between various types of outcomes, mainly continuous, time-to-event, and binary. Typically, longitudinal continuous outcomes are characterized by linear mixed-effects models, survival outcomes are described by proportional hazards models, and the link between outcomes are captured by shared random effects. Other modeling variations include generalized linear mixed-effects models for longitudinal data and logistic regression when a binary outcome is present, rather than time until an event of interest. However, in a clinical research setting, one might be interested in modeling the physician’s chosen treatment based on the patient’s medical history to identify prognostic factors. In this situation there are often multiple treatment options, requiring the use of a multiclass classification approach. Inspired by this context, we develop a Bayesian joint model for longitudinal and categorical data. In particular, our motivation comes from a multiple myeloma study in which biomarkers display nonlinear trajectories that are well captured through biexponential submodels, where patient-level information is shared with the categorical submodel. We also present a variable importance strategy to rank prognostic factors. We apply our proposal and a competing model to the multiple myeloma data, compare the variable importance and inferential results for both models, and illustrate patient-level interpretations using our joint model.

The age at puberty onset varies greatly between individuals and ethnic populations, with significant health implications. Early menarche increases risk for breast cancer, cardiovascular disease, depression, behavioral disorders, diabetes, and all-cause mortality. While genetic factors and higher body mass index (BMI) have been associated with earlier pubertal timing in girls, the effect of Native American genetic ancestry on menarche timing is virtually unknown. We assessed how individual Mapuche Native American genetic ancestry proportions and BMI changes over time influence age at menarche in a cohort of admixed girls with mainly European and Mapuche ancestries. We developed a novel joint statistical model that captures individual-specific BMI trajectory dynamics through individual random effects, linking longitudinal BMI patterns directly to early menarche risk, incorporating the assessment of genetic ancestry effects as well. Two parameter estimation methods were developed, confirming the robustness of the model fit. We found significant ancestry effects, with girls experiencing early menarche having higher mean Mapuche ancestry proportions (47.5% vs 45.1%, p=0.010). Each 10% increase in Mapuche ancestry substantially increased early menarche risk (gamma_1 = 3.405, p=0.010). Childhood BMI growth patterns strongly predicted early menarche: both BMI change rate (alpha_1 = 1.189, p<0.001) and growth acceleration (alpha_2 = 9.080, p=0.003) were significant predictors, while baseline BMI showed no association (p=0.254). These results demonstrate that higher Mapuche ancestry and accelerating BMI trajectories independently increase early menarche likelihood.

In recent medical studies, the combination of longitudinal measurements with time-to-event data has increased the demand for more sophisticated models without unbiased estimates. Joint models for longitudinal and survival data have been developed to address such problems. One complex issue that may arise in the clinical trials is the presence of individuals who are statistically immune to the event of interest, those who may not experience the event even after extended follow-up periods. So far, the literature has addressed joint modeling with the presence of cured individuals mainly through mixture models for cure fraction and their extensions. In this study, we propose a joint modeling framework that accommodates the existence or absence of a cure fraction in an integrated way, using the defective Gompertz distribution. Our aim is to provide a more parsimonious alternative within an estimation process that involves a parameter vector with multiple components. Parameter estimation is performed using Bayesian inference via the efficient integrated nested Laplace approximation algorithm, by formulating the model as a latent Gaussian model. A simulation study is conducted to evaluate the frequentist properties of the proposed method under low-information prior settings. The model is further illustrated using a publicly available, yet underexplored, dataset on antiepileptic drug failure, where quality-of-life scores serve as longitudinal biomarkers. This application allows us to estimate the proportion of patients achieving seizure control under both traditional and modern antiepileptic therapies, demonstrating the model's ability to assess and compare long-term treatment effectiveness within a clinical trial context.

Joint models (JMs) for longitudinal and time-to-event data are an important class of biostatistical models in health and medical research. When the study population consists of heterogeneous subgroups, standard JMs may be inadequate, leading to misleading results or loss of information. Joint latent class models (JLCMs) and their variants have been proposed to incorporate latent class structures into JMs. JLCMs are useful for identifying latent subgroups, uncovering deeper insights into relationships between the outcomes, and improving prediction performance. We consider the problem of Bayesian inference for the generic form of JLCMs, which poses significant computational challenges due to the complex nature of the posterior distribution. We propose a new Bayesian inference framework to tackle these challenges. Our approach leverages state-of-the-art Markov chain Monte Carlo techniques and parallel computing for parameter estimation and model selection regarding the number of latent classes. Through a simulation study, we demonstrate the feasibility and superiority of our proposed method over the existing approach. Additionally, we provide practical guidance on model and prior specification, which has received little attention, to facilitate the implementation of such complex models. We illustrate our method using data from the PAQUID prospective cohort study, where the outcomes of interest include a longitudinal measurement of cognitive performance and time to dementia diagnosis. Our analysis provides deeper insights into the latent class characteristics underlying the study population.

Motivated by a pregnancy miscarriage study, we propose a Bayesian joint model for longitudinal and time-to-event outcomes that takes into account different complexities of the problem. In particular, the longitudinal process is modeled by means of a nonlinear specification with subject-specific error variance. In addition, the exact time of fetal death is unknown, and a subgroup of women is not susceptible to miscarriage. Hence, we model the survival process via a mixture cure model for interval-censored data. Finally, both processes are linked through the subject-specific longitudinal mean and variance. A simulation study is conducted in order to validate our joint model. In the real application, we use individual weighted and Cox-Snell residuals to assess the goodness-of-fit of our proposal versus a joint model that shares only the subject-specific longitudinal mean (standard approach). In addition, the leave-one-out cross-validation criterion is applied to compare the predictive ability of both models.

Frailty survival models are widely used to capture unobserved heterogeneity among individuals in clinical and epidemiological research. This paper introduces a Bayesian survival model that features discrete frailty induced by the hurdle zero-modified power series (HZMPS) distribution. A key characteristic of HZMPS is the inclusion of a dispersion parameter, enhancing flexibility in capturing diverse heterogeneity patterns. Furthermore, this frailty specification allows the model to distinguish individuals with higher susceptibility to the event of interest from those potentially cured or no longer at risk. We employ a Bayesian framework for parameter estimation, enabling the incorporation of prior information and robust inference, even with limited data. A simulation study is performed to explore the limits of the model. Our proposal is also applied to a lung cancer study, in which patient variability plays a crucial role in disease progression and treatment response. The findings of this study highlight the importance of more flexible frailty models in survival data analysis and emphasize the potential of the Bayesian approach to modeling heterogeneity in biomedical studies.