Joint modeling of longitudinal and survival data via a common frailty

We develop a joint model for the analysis of longitudinal and survival data in the presence of data clustering. We use a mixed effects model for the repeated measures that incorporates both subject- and cluster-level random effects, with subjects nested within clusters. A Cox frailty model is used for the survival model in order to accommodate the clustering. We then link the two responses via the common cluster-level random effects, or frailties. This model allows us to simultaneously evaluate the effect of covariates on the two types of responses, while accounting for both the relationship between the responses and data clustering. The model was motivated by a study of end-stage renal disease patients undergoing hemodialysis, where we wished to evaluate the effect of iron treatment on both the patients' hemoglobin levels and survival times, with the patients clustered by enrollment site.     

Score tests of genetic association in the presence of linkage based on the additive genetic gamma frailty model

Nuclear families with multiple affected sibs are often collected for genetic linkage analysis of complex diseases. Once linkage evidence is established, dense markers are often typed in the linked region for genetic association analysis based on linkage disequilibrium (LD). Detection of association in the presence of linkage localizes disease genes more accurately than the methods that rely on linkage alone. However, test of association due to LD in the linked region needs to account for dependency of the allele transmissions to different sibs within a family. In this paper, we define a joint model for genetic linkage and association and derive the corresponding joint survival function of age of onset for the sibs within a sibship. The joint survival function is a function of both the inheritance vector and the genotypes at the candidate marker locus. Based on this joint survival function, we derive score tests for genetic association. The proposed methods utilize the phenotype data of all the sibs and have the advantages of family-based designs which can avoid the potential spurious association caused by population admixture. In addition, the methods can account for variable age of onset or age at censoring and possible covariate effects, and therefore provide important tools for modelling disease heterogeneity. Simulation studies and application to the data sets from the 12th Genetic Analysis Workshop indicate that the proposed methods have correct type 1 error rates and increased power over other existing methods for testing allelic association.     

Frailty modelling of testicular cancer incidence using Scandinavian data

The incidence of testicular cancer is highest among young men, and then decreases sharply with age. This points towards a frailty effect, where some men have a much greater risk of testicular cancer than the majority of the male population. Those with the highest risk get cancer, drain the group of individuals at risk, and leave a healthy male population which has approximately zero risk of testicular cancer. This leads to the observed decrease in incidence. We discuss a frailty model, where the frailty is compound-Poisson-distributed. This allows for a non-susceptible group (of zero frailty). The model is successfully applied to incidence data from the Danish and Norwegian registries. It is indicated that there was a decrease in incidence for males born during World War II in both countries. Bootstrap analysis is used to find the degree of variation in the estimates. In the Armitage-Doll multistage model, the estimated number of transitions needed for a cell to become malignant is close to 3 for non-seminomas and 4 for seminomas in both the Danish and Norwegian data. This paper demonstrates that a model including a frailty effect fits the incidence data well and gives interesting results and interpretations, although this is no proof of the effect's truth.     

Capacidad predictiva de fragilidad basal y fuerza de prensión al ingreso en resultados al alta en una unidad geriátrica de recuperación funcional

ObjectiveTo evaluate the predictive capacity of different frailty scales, as well as the strength of the handgrip, and to determine their relationship with clinical favourable outcomes.Patients and methodProspective study of patients admitted to the Geriatric Functional Recovery Unit (GFRU) of the Hospital Central Cruz Roja. The «FRAIL» scale, «Clinical Frailty Scale» (CFS) and «Fragil-VIG» index, and handgrip strength by hydraulic dynamometer were completed on admission. A functional gain was assumed as 20 or more points in the Barthel Index and return to home, as good outcomes at discharge. The discriminative capacity of favourable outcomes for each frailty scale and handgrip strength was analysed by means of ROC curves, calculating the C statistic (area under the curve = AUC).ResultsThe analysis included 74 patients (median age 82 years; 48.5% women), admitted for stroke recovery (65%), orthopaedic pathology (16%), and other causes (19%). The prevalence of frailty varied between 31% (FRAIL scale), 40% (CFS), and 57.5% («Fragil-VIG»). Median handgrip strength was 15 Kg in males (interquartile range 11-21), and 9 Kg in females (interquartile range 7-12). At discharge, 51.5% of patients had a functional gain of 20 or more points in Barthel index, and 63% returned to their previous home. The discriminating ability to achieve acceptable functional gain at discharge was good for CFS (AUC = 0.72; 95% CI; 0.60-0.84) and «Fragil-VIG» (AUC = 0.72; 95% CI;0.58-0.82), and handgrip strength was the only tool related to return home (AUC = 0.68; 95% CI;0.56-0.81).ConclusionTo evaluate frailty on admission to a GFRU contributes to predicting favourable clinical outcomes, but the discriminating capacity of each scale is variable.     

Joint modeling and analysis of longitudinal data with informative observation times

Summary .  In analysis of longitudinal data, it is often assumed that observation times are predetermined and are the same across study subjects. Such an assumption, however, is often violated in practice. As a result, the observation times may be highly irregular. It is well known that if the sampling scheme is correlated with the outcome values, the usual statistical analysis may yield bias. In this article, we propose joint modeling and analysis of longitudinal data with possibly informative observation times via latent variables. A two-step estimation procedure is developed for parameter estimation. We show that the resulting estimators are consistent and asymptotically normal, and that the asymptotic variance can be consistently estimated using the bootstrap method. Simulation studies and a real data analysis demonstrate that our method performs well with realistic sample sizes and is appropriate for practical use.     

From heterochromatin islands to the NAD World: A hierarchical view of aging through the functions of mammalian Sirt1 and systemic NAD biosynthesis

For the past couple of decades, aging science has been rapidly evolving, and powerful genetic tools have identified a variety of evolutionarily conserved regulators and signaling pathways for the control of aging and longevity in model organisms. Nonetheless, a big challenge still remains to construct a comprehensive concept that could integrate many distinct layers of biological events into a systemic, hierarchical view of aging. The “heterochromatin island” hypothesis was originally proposed 10 years ago to explain deterministic and stochastic aspects of cellular and organismal aging, which drove the author to the study of evolutionarily conserved Sir2 proteins. Since a surprising discovery of their NAD-dependent deacetylase activity, Sir2 proteins, now called “sirtuins,” have been emerging as a critical epigenetic regulator for aging. In this review, I will follow the process of conceptual development from the heterochromatin island hypothesis to a novel, comprehensive concept of a systemic regulatory network for mammalian aging, named “NAD World,” summarizing recent studies on the mammalian NAD-dependent deacetylase Sirt1 and nicotinamide phosphoribosyltransferase (Nampt)-mediated systemic NAD biosynthesis. This new concept of the NAD World provides critical insights into a systemic regulatory mechanism that fundamentally connects metabolism and aging and also conveys the ideas of functional hierarchy and frailty for the regulation of aging in mammals.     

Analysis of multivariate recurrent event data with time‐dependent covariates and informative censoring

Multivariate recurrent event data are usually encountered in many clinical and longitudinal studies in which each study subject may experience multiple recurrent events. For the analysis of such data, most existing approaches have been proposed under the assumption that the censoring times are noninformative, which may not be true especially when the observation of recurrent events is terminated by a failure event. In this article, we consider regression analysis of multivariate recurrent event data with both time‐dependent and time‐independent covariates where the censoring times and the recurrent event process are allowed to be correlated via a frailty. The proposed joint model is flexible where both the distributions of censoring and frailty variables are left unspecified. We propose a pairwise pseudolikelihood approach and an estimating equation‐based approach for estimating coefficients of time‐dependent and time‐independent covariates, respectively. The large sample properties of the proposed estimates are established, while the finite‐sample properties are demonstrated by simulation studies. The proposed methods are applied to the analysis of a set of bivariate recurrent event data from a study of platelet transfusion reactions.     

Las 3D/3D+ como herramienta de valoración geriátrica rápida y de adecuación del recurso asistencial al alta de los Servicios de Urgencias

ObjectiveAssess the 3D/3D+ rapid geriatric assessment tool for the early detection of frailty, its usefulness to identify the effects of the acute process on the functional, physical, cognitive and socioenvironmental dimensions, as well as the medications that may have triggered the patient's reason for visit. Finally, assess the usefulness of 3D/3D+ together with the clinical diagnosis to adequate care resource at discharge from the emergency department (ED).MethodRetrospective observational cohort study. Patients ≥75 years old, with clinical complexity visited at the ED were included. Basal frailty status was assessed using 3D (basal component), and the multidimensional impact of the acute process using 3D+ (current component). The main dependent variable was adequacy of the care resource at ED discharge.Results278 patients were included, mean age 86 years (interquartile range: 83–90), 59.7% were women. According to the basal component (3D), 83.1% (95%CI: 78.2–87.3) presented some degree of frailty. The current component (3D+) was altered in 60.1% (95%CI: 54.1–65.9). The adequacy of ED discharge was correct in 96.4% (95%CI: 93.0–98.0). One out of 4 patients was admitted to a medicine ward.Conclusions3D/3D+ facilitates an optimal model of emergency care adapted to patients ≥ 75 years old treated in EDs. It stratifies the level of frailty (3D), detects the severity of patients’ acute problems (3D+) and contributes to decision-making regarding the most appropriate care resource at ED discharge.