Mixtures of Self-Modelling Regressions

A shape invariant model for functions f1,...,fn specifies that each individual function fi can be related to a common shape function g through the relation fi(x) = aig(cix + di) + bi. We consider a flexible mixture model that allows multiple shape functions g1,...,gK, where each fi is a shape invariant transformation of one of those gK. We derive an MCMC algorithm for fitting the model using Bayesian Adaptive Regression Splines (BARS), propose a strategy to improve its mixing properties and utilize existing model selection criteria in semiparametric mixtures to select the number of distinct shape functions. We discuss some of the computational difficulties that arise. The method is illustrated using synaptic transmission data, where the groups of functions may indicate different active zones in a synapse

Semiparametric Mixed Models for Nested Repeated Measures Applied to Ambulatory Blood Pressure Monitoring Data

Semiparametric mixed models are increasingly popular for statistical analysis of medical device studies in which long sequences of repeated measurements are recorded. Monitoring these sequences at different periods over time on the same individual, such as before and after an intervention, results in nested repeated measures (NRM). Covariance models to account for NRM and simultaneously address mean profile estimation with penalized splines via semiparametric regression are considered with application to a prospective study of 24-hour ambulatory blood pressure and the impact of surgical intervention on obstructive sleep apnea

Flexible semiparametric joint modeling: an application to estimate individual lung function decline and risk of pulmonary exacerbations in cystic fibrosis.

BACKGROUND: Epidemiologic surveillance of lung function is key to clinical care of individuals with cystic fibrosis, but lung function decline is nonlinear and often impacted by acute respiratory events known as pulmonary exacerbations. Statistical models are needed to simultaneously estimate lung function decline while providing risk estimates for the onset of pulmonary exacerbations, in order to identify relevant predictors of declining lung function and understand how these associations could be used to predict the onset of pulmonary exacerbations. METHODS: Using longitudinal lung function (FEV1) measurements and time-to-event data on pulmonary exacerbations from individuals in the United States Cystic Fibrosis Registry, we implemented a flexible semiparametric joint model consisting of a mixed-effects submodel with regression splines to fit repeated FEV1 measurements and a time-to-event submodel for possibly censored data on pulmonary exacerbations. We contrasted this approach with methods currently used in epidemiological studies and highlight clinical implications. RESULTS: The semiparametric joint model had the best fit of all models examined based on deviance information criterion. Higher starting FEV1 implied more rapid lung function decline in both separate and joint models; however, individualized risk estimates for pulmonary exacerbation differed depending upon model type. Based on shared parameter estimates from the joint model, which accounts for the nonlinear FEV1 trajectory, patients with more positive rates of change were less likely to experience a pulmonary exacerbation (HR per one standard deviation increase in FEV1 rate of change = 0.566, 95% CI 0.516-0.619), and having higher absolute FEV1 also corresponded to lower risk of having a pulmonary exacerbation (HR per one standard deviation increase in FEV1 = 0.856, 95% CI 0.781-0.937). At the population level, both submodels indicated significant effects of birth cohort, socioeconomic status and respiratory infections on FEV1 decline, as well as significant effects of gender, socioeconomic status and birth cohort on pulmonary exacerbation risk. CONCLUSIONS: Through a flexible joint-modeling approach, we provide a means to simultaneously estimate lung function trajectories and the risk of pulmonary exacerbations for individual patients; we demonstrate how this approach offers additional insights into the clinical course of cystic fibrosis that were not possible using conventional approaches

Integrating latent classes in the Bayesian shared parameter joint model of longitudinal and survival outcomes

Cystic fibrosis is a chronic lung disease requiring frequent lung-function monitoring to track acute respiratory events (pulmonary exacerbations). The association between lung-function trajectory and time-to-first exacerbation can be characterized using joint longitudinal-survival modeling. Joint models specified through the shared parameter framework quantify the strength of association between such outcomes but do not incorporate latent sub-populations reflective of heterogeneous disease progression. Conversely, latent class joint models explicitly postulate the existence of sub-populations but do not directly quantify the strength of association. Furthermore, choosing the optimal number of classes using established metrics like deviance information criterion is computationally intensive in complex models. To overcome these limitations, we integrate latent classes in the shared parameter joint model through a fully Bayesian approach. To choose the optimal number of classes, we construct a mixture model assuming more latent classes than present in the data, thereby asymptotically “emptying” superfluous latent classes, provided the Dirichlet prior on class proportions is sufficiently uninformative. Model properties are evaluated in simulation studies. Application to data from the US Cystic Fibrosis Registry supports the existence of three sub-populations corresponding to lung-function trajectories with high initial forced expiratory volume in 1 s (FEV1), rapid FEV1 decline, and low but steady FEV1 progression. The association between FEV1 and hazard of exacerbation was negative in each class, but magnitude varied

Dynamic predictive probabilities to monitor rapid cystic fibrosis disease progression.

Cystic fibrosis (CF) is a progressive, genetic disease characterized by frequent, prolonged drops in lung function. Accurately predicting rapid underlying lung-function decline is essential for clinical decision support and timely intervention. Determining whether an individual is experiencing a period of rapid decline is complicated due to its heterogeneous timing and extent, and error component of the measured lung function. We construct individualized predictive probabilities for "nowcasting" rapid decline. We assume each patient's true longitudinal lung function, S(t), follows a nonlinear, nonstationary stochastic process, and accommodate between-patient heterogeneity through random effects. Corresponding lung-function decline at time t is defined as the rate of change, S'(t). We predict S'(t) conditional on observed covariate and measurement history by modeling a measured lung function as a noisy version of S(t). The method is applied to data on 30 879 US CF Registry patients. Results are contrasted with a currently employed decision rule using single-center data on 212 individuals. Rapid decline is identified earlier using predictive probabilities than the center's currently employed decision rule (mean difference: 0.65 years; 95% confidence interval (CI): 0.41, 0.89). We constructed a bootstrapping algorithm to obtain CIs for predictive probabilities. We illustrate real-time implementation with R Shiny. Predictive accuracy is investigated using empirical simulations, which suggest this approach more accurately detects peak decline, compared with a uniform threshold of rapid decline. Median area under the ROC curve estimates (Q1-Q3) were 0.817 (0.814-0.822) and 0.745 (0.741-0.747), respectively, implying reasonable accuracy for both. This article demonstrates how individualized rate of change estimates can be coupled with probabilistic predictive inference and implementation for a useful medical-monitoring approach

Measurement of Muscular Activity Associated With Peristalsis in the Human Gut Using Fiber Bragg Grating Arrays

Author version made available under Publisher copyright policy.Diagnostic catheters based on fibre Bragg gratings (FBG’s) are proving to be highly effective for measurement of the muscular activity associated with peristalsis in the human gut. The primary muscular contractions that generate peristalsis are circumferential in nature; however, it has long been known that there is also a component of longitudinal contractility present, acting in harmony with the circumferential component to improve the overall efficiency of material movement. We report on the development of, and latest results from, catheter based sensors capable of detecting both forms of muscular activity. While detection of the circumferential contractions has been possible using solid state, hydraulic, and pneumatic sensor arrays in the oesophagus and anorectum, FBG based devices allow access into the complex and convoluted regions of the gut below the stomach. We report early results from FBG catheters used during trials of novel therapies in patients with both slow transit constipation and faecal incontinence. In addition, there have been relatively few reports on the measurement or inference of longitudinal contractions in humans. This is due to the lack of a viable recording technique suitable for real-time in-vivo measurement of this type of activity over extended lengths of the gut. We report preliminary data on the detection of longitudinal motion in lengths of excised mammalian colon using an FBG technique that should be viable for similar detection in humans. The longitudinal sensors have been combined with pressure sensing elements to form a composite catheter that allows the relative phase between the two components to be detected. The output of both types of catheter has been validated using digital video mapping in an ex-vivo animal preparation using lengths of rabbit ileum