Flexible Bayesian estimation of incubation times.

The incubation period is of paramount importance in infectious disease epidemiology as it informs about the transmission potential of a pathogenic organism and helps to plan public health strategies to keep an epidemic outbreak under control. Estimation of the incubation period distribution from reported exposure times and symptom onset times is challenging as the underlying data is coarse. We develop a new Bayesian methodology using Laplacian-P-splines that provides a semi-parametric estimation of the incubation density based on a Langevinized Gibbs sampler. A finite mixture density smoother informs a set of parametric distributions via moment matching and an information criterion arbitrates between competing candidates. Algorithms underlying our method find a natural nest within the EpiLPS package, which has been extended to cover estimation of incubation times. Various simulation scenarios accounting for different levels of data coarseness are considered with encouraging results. Applications to real data on COVID-19, MERS and Mpox reveal results that are in alignment with what has been obtained in recent studies. The proposed flexible approach is an interesting alternative to classic Bayesian parametric methods for estimation of the incubation distribution.

Classification of longitudinal profiles using semi-parametric nonlinear mixed models with P-Splines and the SAEM algorithm.

In this work, we propose an extension of a semiparametric nonlinear mixed-effects model for longitudinal data that incorporates more flexibility with penalized splines (P-splines) as smooth terms. The novelty of the proposed approach consists of the formulation of the model within the stochastic approximation version of the EM algorithm for maximum likelihood, the so-called SAEM algorithm. The proposed approach takes advantage of the formulation of a P-spline as a mixed-effects model and the use of the computational advantages of the existing software for the SAEM algorithm for the estimation of the random effects and the variance components. Additionally, we developed a supervised classification method for these non-linear mixed models using an adaptive importance sampling scheme. To illustrate our proposal, we consider two studies on pregnant women where two biomarkers are used as indicators of changes during pregnancy. In both studies, information about the women's pregnancy outcomes is known. Our proposal provides a unified framework for the classification of longitudinal profiles that may have important implications for the early detection and monitoring of pregnancy-related changes and contribute to improved maternal and fetal health outcomes. We show that the proposed models improve the analysis of this type of data compared to previous studies. These improvements are reflected both in the fit of the models and in the classification of the groups.

An approximate Bayesian approach for estimation of the instantaneous reproduction number under misreported epidemic data.

In epidemic models, the effective reproduction number is of central importance to assess the transmission dynamics of an infectious disease and to orient health intervention strategies. Publicly shared data during an outbreak often suffers from two sources of misreporting (underreporting and delay in reporting) that should not be overlooked when estimating epidemiological parameters. The main statistical challenge in models that intrinsically account for a misreporting process lies in the joint estimation of the time-varying reproduction number and the delay/underreporting parameters. Existing Bayesian approaches typically rely on Markov chain Monte Carlo algorithms that are extremely costly from a computational perspective. We propose a much faster alternative based on Laplacian-P-splines (LPS) that combines Bayesian penalized B-splines for flexible and smooth estimation of the instantaneous reproduction number and Laplace approximations to selected posterior distributions for fast computation. Assuming a known generation interval distribution, the incidence at a given calendar time is governed by the epidemic renewal equation and the delay structure is specified through a composite link framework. Laplace approximations to the conditional posterior of the spline vector are obtained from analytical versions of the gradient and Hessian of the log-likelihood, implying a drastic speed-up in the computation of posterior estimates. Furthermore, the proposed LPS approach can be used to obtain point estimates and approximate credible intervals for the delay and reporting probabilities. Simulation of epidemics with different combinations for the underreporting rate and delay structure (one-day, two-day, and weekend delays) show that the proposed LPS methodology delivers fast and accurate estimates outperforming existing methods that do not take into account underreporting and delay patterns. Finally, LPS is illustrated in two real case studies of epidemic outbreaks.

Laplacian-P-splines for Bayesian inference in the mixture cure model.

The mixture cure model for analyzing survival data is characterized by the assumption that the population under study is divided into a group of subjects who will experience the event of interest over some finite time horizon and another group of cured subjects who will never experience the event irrespective of the duration of follow-up. When using the Bayesian paradigm for inference in survival models with a cure fraction, it is common practice to rely on Markov chain Monte Carlo (MCMC) methods to sample from posterior distributions. Although computationally feasible, the iterative nature of MCMC often implies long sampling times to explore the target space with chains that may suffer from slow convergence and poor mixing. Furthermore, extra efforts have to be invested in diagnostic checks to monitor the reliability of the generated posterior samples. A sampling-free strategy for fast and flexible Bayesian inference in the mixture cure model is suggested in this article by combining Laplace approximations and penalized B-splines. A logistic regression model is assumed for the cure proportion and a Cox proportional hazards model with a P-spline approximated baseline hazard is used to specify the conditional survival function of susceptible subjects. Laplace approximations to the posterior conditional latent vector are based on analytical formulas for the gradient and Hessian of the log-likelihood, resulting in a substantial speed-up in approximating posterior distributions. The spline specification yields smooth estimates of survival curves and functions of latent variables together with their associated credible interval are estimated in seconds. A fully stochastic algorithm based on a Metropolis-Langevin-within-Gibbs sampler is also suggested as an alternative to the proposed Laplacian-P-splines mixture cure (LPSMC) methodology. The statistical performance and computational efficiency of LPSMC is assessed in a simulation study. Results show that LPSMC is an appealing alternative to MCMC for approximate Bayesian inference in standard mixture cure models. Finally, the novel LPSMC approach is illustrated on three applications involving real survival data.

A Fast Weighted Fuzzy C-Medoids Clustering for Time Series Data Based on P-Splines.

The rapid growth of digital information has produced massive amounts of time series data on rich features and most time series data are noisy and contain some outlier samples, which leads to a decline in the clustering effect. To efficiently discover the hidden statistical information about the data, a fast weighted fuzzy C-medoids clustering algorithm based on P-splines (PS-WFCMdd) is proposed for time series datasets in this study. Specifically, the P-spline method is used to fit the functional data related to the original time series data, and the obtained smooth-fitting data is used as the input of the clustering algorithm to enhance the ability to process the data set during the clustering process. Then, we define a new weighted method to further avoid the influence of outlier sample points in the weighted fuzzy C-medoids clustering process, to improve the robustness of our algorithm. We propose using the third version of mueen's algorithm for similarity search (MASS 3) to measure the similarity between time series quickly and accurately, to further improve the clustering efficiency. Our new algorithm is compared with several other time series clustering algorithms, and the performance of the algorithm is evaluated experimentally on different types of time series examples. The experimental results show that our new method can speed up data processing and the comprehensive performance of each clustering evaluation index are relatively good.

Weighted expectile regression for right-censored data.

Expectile regression can be used to analyze the entire conditional distribution of a response, omitting all distributional assumptions. Among its benefits are computational simplicity, efficiency, and the possibility to incorporate a semiparametric predictor. Due to its advantages in full data settings, we propose an extension to right-censored data situations, where conventional methods typically focus only on mean effects. We propose to extend expectile regression with inverse probability weights. Estimates are easy to implement and computationally simple. Expectiles can be converted to more easily interpreted tail expectations, that is, the expected residual life. It provides a meaningful effect measure, similar to the hazard rate. The results from an extensive simulation study are presented, evaluating consistency and sensitivity to violations of assumptions. We use the proposed method to analyze survival times of colorectal cancer patients from a regional certified high volume cancer center.

"Childhood Anemia in India: an application of a Bayesian geo-additive model".

BACKGROUND: The geographical differences that cause anaemia can be partially explained by the variability in environmental factors, particularly nutrition and infections. The studies failed to explain the non-linear effect of the continuous covariates on childhood anaemia. The present paper aims to investigate the risk factors of childhood anaemia in India with focus on geographical spatial effect. METHODS: Geo-additive logistic regression models were fitted to the data to understand fixed as well as spatial effects of childhood anaemia. Logistic regression was fitted for the categorical variable with outcomes (anaemia (Hb < 11) and no anaemia (Hb ≥ 11)). Continuous covariates were modelled by the penalized spline and spatial effects were smoothed by the two-dimensional spline. RESULTS: At 95% posterior credible interval, the influence of unobserved factors on childhood anaemia is very strong in the Northern and Central part of India. However, most of the states in North Eastern part of India showed negative spatial effects. A U-shape non-linear relationship was observed between childhood anaemia and mother's age. This indicates that mothers of young and old ages are more likely to have anaemic children; in particular mothers aged 15 years to about 25 years. Then the risk of childhood anaemia starts declining after the age of 25 years and it continues till the age of around 37 years, thereafter again starts increasing. Further, the non-linear effects of duration of breastfeeding on childhood anaemia show that the risk of childhood anaemia decreases till 29 months thereafter increases. CONCLUSION: Strong evidence of residual spatial effect to childhood anaemia in India is observed. Government child health programme should gear up in treating childhood anaemia by focusing on known measurable factors such as mother's education, mother's anaemia status, family wealth status, child health (fever), stunting, underweight, and wasting which have been found to be significant in this study. Attention should also be given to effects of unknown or unmeasured factors to childhood anaemia at the community level. Special attention to unmeasurable factors should be focused in the states of central and northern India which have shown significant positive spatial effects.

A multi-country comparison of stochastic models of breast cancer mortality with P-splines smoothing approach.

BACKGROUND: Precise predictions of incidence and mortality rates due to breast cancer (BC) are required for planning of public health programs as well as for clinical services. A number of approaches has been established for prediction of mortality using stochastic models. The performance of these models intensely depends on different patterns shown by mortality data in different countries. METHODS: The BC mortality data is retrieved from the Global burden of disease (GBD) study 2017 database. This study include BC mortality rates from 1990 to 2017, with ages 20 to 80+ years old women, for different Asian countries. Our study extend the current literature on Asian BC mortality data, on both the number of considered stochastic mortality models and their rigorous evaluation using multivariate Diebold-Marino test and by range of graphical analysis for multiple countries. RESULTS: Study findings reveal that stochastic smoothed mortality models based on functional data analysis generally outperform on quadratic structure of BC mortality rates than the other lee-carter models, both in term of goodness of fit and on forecast accuracy. Besides, smoothed lee carter (SLC) model outperform the functional demographic model (FDM) in case of symmetric structure of BC mortality rates, and provides almost comparable results to FDM in within and outside data forecast accuracy for heterogeneous set of BC mortality rates. CONCLUSION: Considering the SLC model in comparison to the other can be obliging to forecast BC mortality and life expectancy at birth, since it provides even better results in some cases. In the current situation, we can assume that there is no single model, which can truly outperform all the others on every population. Therefore, we also suggest generating BC mortality forecasts using multiple models rather than relying upon any single model.

Bayesian splines versus fractional polynomials in network meta-analysis.

BACKGROUND: Network meta-analysis (NMA) provides a powerful tool for the simultaneous evaluation of multiple treatments by combining evidence from different studies, allowing for direct and indirect comparisons between treatments. In recent years, NMA is becoming increasingly popular in the medical literature and underlying statistical methodologies are evolving both in the frequentist and Bayesian framework. Traditional NMA models are often based on the comparison of two treatment arms per study. These individual studies may measure outcomes at multiple time points that are not necessarily homogeneous across studies. METHODS: In this article we present a Bayesian model based on B-splines for the simultaneous analysis of outcomes across time points, that allows for indirect comparison of treatments across different longitudinal studies. RESULTS: We illustrate the proposed approach in simulations as well as on real data examples available in the literature and compare it with a model based on P-splines and one based on fractional polynomials, showing that our approach is flexible and overcomes the limitations of the latter. CONCLUSIONS: The proposed approach is computationally efficient and able to accommodate a large class of temporal treatment effect patterns, allowing for direct and indirect comparisons of widely varying shapes of longitudinal profiles.

Variable selection with P-splines in functional linear regression: Application in graft-versus-host disease.

This paper focuses on the problems of estimation and variable selection in the functional linear regression model (FLM) with functional response and scalar covariates. To this end, two different types of regularization (L1 and L2 ) are considered in this paper. On the one hand, a sample approach for functional LASSO in terms of basis representation of the sample values of the response variable is proposed. On the other hand, we propose a penalized version of the FLM by introducing a P-spline penalty in the least squares fitting criterion. But our aim is to propose P-splines as a powerful tool simultaneously for variable selection and functional parameters estimation. In that sense, the importance of smoothing the response variable before fitting the model is also studied. In summary, penalized (L1 and L2 ) and nonpenalized regression are combined with a presmoothing of the response variable sample curves, based on regression splines or P-splines, providing a total of six approaches to be compared in two simulation schemes. Finally, the most competitive approach is applied to a real data set based on the graft-versus-host disease, which is one of the most frequent complications (30% -50%) in allogeneic hematopoietic stem-cell transplantation.

Prediction intervals for penalized longitudinal models with multisource summary measures: An application to childhood malnutrition.

In many global health analyses, it is of interest to examine countries' progress using indicators of socio-economic conditions based on national surveys from varying sources. This results in longitudinal data where heteroscedastic summary measures, rather than individual level data, are available. Administration of national surveys can be sporadic, resulting in sparse data measurements for some countries. Furthermore, the trend of the indicators over time is usually nonlinear and varies by country. It is of interest to track the current level of indicators to determine if countries are meeting certain thresholds, such as those indicated in the United Nations Sustainable Development Goals. In addition, estimation of confidence and prediction intervals are vital to determine true changes in prevalence and where data is low in quantity and/or quality. In this article, we use heteroscedastic penalized longitudinal models with survey summary data to estimate yearly prevalence of malnutrition quantities. We develop and compare methods to estimate confidence and prediction intervals using asymptotic and parametric bootstrap techniques. The intervals can incorporate data from multiple sources or other general data-smoothing steps. The methods are applied to African countries in the UNICEF-WHO-The World Bank joint child malnutrition data set. The properties of the intervals are demonstrated through simulation studies and cross-validation of real data.

Estimation and identification issues in the promotion time cure model when the same covariates influence long- and short-term survival.

The promotion time cure model is a survival model acknowledging that an unidentified proportion of subjects will never experience the event of interest whatever the duration of the follow-up. We focus our interest on the challenges raised by the strong posterior correlation between some of the regression parameters when the same covariates influence long- and short-term survival. Then, the regression parameters of shared covariates are strongly correlated with, in addition, identification issues when the maximum follow-up duration is insufficiently long to identify the cured fraction. We investigate how, despite this, plausible values for these parameters can be obtained in a computationally efficient way. The theoretical properties of our strategy will be investigated by simulation and illustrated on clinical data. Practical recommendations will also be made for the analysis of survival data known to include an unidentified cured fraction.

Improved dynamic predictions from joint models of longitudinal and survival data with time-varying effects using P-splines.

In the field of cardio-thoracic surgery, valve function is monitored over time after surgery. The motivation for our research comes from a study which includes patients who received a human tissue valve in the aortic position. These patients are followed prospectively over time by standardized echocardiographic assessment of valve function. Loss of follow-up could be caused by valve intervention or the death of the patient. One of the main characteristics of the human valve is that its durability is limited. Therefore, it is of interest to obtain a prognostic model in order for the physicians to scan trends in valve function over time and plan their next intervention, accounting for the characteristics of the data. Several authors have focused on deriving predictions under the standard joint modeling of longitudinal and survival data framework that assumes a constant effect for the coefficient that links the longitudinal and survival outcomes. However, in our case, this may be a restrictive assumption. Since the valve degenerates, the association between the biomarker with survival may change over time. To improve dynamic predictions, we propose a Bayesian joint model that allows a time-varying coefficient to link the longitudinal and the survival processes, using P-splines. We evaluate the performance of the model in terms of discrimination and calibration, while accounting for censoring.

Flexible multistate models for interval-censored data: Specification, estimation, and an application to ageing research.

Continuous-time multistate survival models can be used to describe health-related processes over time. In the presence of interval-censored times for transitions between the living states, the likelihood is constructed using transition probabilities. Models can be specified using parametric or semiparametric shapes for the hazards. Semiparametric hazards can be fitted using P-splines and penalised maximum likelihood estimation. This paper presents a method to estimate flexible multistate models that allow for parametric and semiparametric hazard specifications. The estimation is based on a scoring algorithm. The method is illustrated with data from the English Longitudinal Study of Ageing.

Nonlinear association structures in flexible Bayesian additive joint models.

Joint models of longitudinal and survival data have become an important tool for modeling associations between longitudinal biomarkers and event processes. The association between marker and log hazard is assumed to be linear in existing shared random effects models, with this assumption usually remaining unchecked. We present an extended framework of flexible additive joint models that allows the estimation of nonlinear covariate specific associations by making use of Bayesian P-splines. Our joint models are estimated in a Bayesian framework using structured additive predictors for all model components, allowing for great flexibility in the specification of smooth nonlinear, time-varying, and random effects terms for longitudinal submodel, survival submodel, and their association. The ability to capture truly linear and nonlinear associations is assessed in simulations and illustrated on the widely studied biomedical data on the rare fatal liver disease primary biliary cirrhosis. All methods are implemented in the R package bamlss to facilitate the application of this flexible joint model in practice.

Predicting pregnancy outcomes using longitudinal information: a penalized splines mixed-effects model approach.

We propose a semiparametric nonlinear mixed-effects model (SNMM) using penalized splines to classify longitudinal data and improve the prediction of a binary outcome. The work is motivated by a study in which different hormone levels were measured during the early stages of pregnancy, and the challenge is using this information to predict normal versus abnormal pregnancy outcomes. The aim of this paper is to compare models and estimation strategies on the basis of alternative formulations of SNMMs depending on the characteristics of the data set under consideration. For our motivating example, we address the classification problem using a particular case of the SNMM in which the parameter space has a finite dimensional component (fixed effects and variance components) and an infinite dimensional component (unknown function) that need to be estimated. The nonparametric component of the model is estimated using penalized splines. For the parametric component, we compare the advantages of using random effects versus direct modeling of the correlation structure of the errors. Numerical studies show that our approach improves over other existing methods for the analysis of this type of data. Furthermore, the results obtained using our method support the idea that explicit modeling of the serial correlation of the error term improves the prediction accuracy with respect to a model with random effects, but independent errors. Copyright © 2017 John Wiley & Sons, Ltd.

Dynamic predictions using flexible joint models of longitudinal and time-to-event data.

Joint models for longitudinal and time-to-event data are particularly relevant to many clinical studies where longitudinal biomarkers could be highly associated with a time-to-event outcome. A cutting-edge research direction in this area is dynamic predictions of patient prognosis (e.g., survival probabilities) given all available biomarker information, recently boosted by the stratified/personalized medicine initiative. As these dynamic predictions are individualized, flexible models are desirable in order to appropriately characterize each individual longitudinal trajectory. In this paper, we propose a new joint model using individual-level penalized splines (P-splines) to flexibly characterize the coevolution of the longitudinal and time-to-event processes. An important feature of our approach is that dynamic predictions of the survival probabilities are straightforward as the posterior distribution of the random P-spline coefficients given the observed data is a multivariate skew-normal distribution. The proposed methods are illustrated with data from the HIV Epidemiology Research Study. Our simulation results demonstrate that our model has better dynamic prediction performance than other existing approaches. © 2017 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

Flexible Bayesian additive joint models with an application to type 1 diabetes research.

The joint modeling of longitudinal and time-to-event data is an important tool of growing popularity to gain insights into the association between a biomarker and an event process. We develop a general framework of flexible additive joint models that allows the specification of a variety of effects, such as smooth nonlinear, time-varying and random effects, in the longitudinal and survival parts of the models. Our extensions are motivated by the investigation of the relationship between fluctuating disease-specific markers, in this case autoantibodies, and the progression to the autoimmune disease type 1 diabetes. Using Bayesian P-splines, we are in particular able to capture highly nonlinear subject-specific marker trajectories as well as a time-varying association between the marker and event process allowing new insights into disease progression. The model is estimated within a Bayesian framework and implemented in the R-package bamlss.

Maximum penalized likelihood estimation in semiparametric mark-recapture-recovery models.

We discuss the semiparametric modeling of mark-recapture-recovery data where the temporal and/or individual variation of model parameters is explained via covariates. Typically, in such analyses a fixed (or mixed) effects parametric model is specified for the relationship between the model parameters and the covariates of interest. In this paper, we discuss the modeling of the relationship via the use of penalized splines, to allow for considerably more flexible functional forms. Corresponding models can be fitted via numerical maximum penalized likelihood estimation, employing cross-validation to choose the smoothing parameters in a data-driven way. Our contribution builds on and extends the existing literature, providing a unified inferential framework for semiparametric mark-recapture-recovery models for open populations, where the interest typically lies in the estimation of survival probabilities. The approach is applied to two real datasets, corresponding to gray herons (Ardea cinerea), where we model the survival probability as a function of environmental condition (a time-varying global covariate), and Soay sheep (Ovis aries), where we model the survival probability as a function of individual weight (a time-varying individual-specific covariate). The proposed semiparametric approach is compared to a standard parametric (logistic) regression and new interesting underlying dynamics are observed in both cases.

Bayesian nonlinear model selection for gene regulatory networks.

Gene regulatory networks represent the regulatory relationships between genes and their products and are important for exploring and defining the underlying biological processes of cellular systems. We develop a novel framework to recover the structure of nonlinear gene regulatory networks using semiparametric spline-based directed acyclic graphical models. Our use of splines allows the model to have both flexibility in capturing nonlinear dependencies as well as control of overfitting via shrinkage, using mixed model representations of penalized splines. We propose a novel discrete mixture prior on the smoothing parameter of the splines that allows for simultaneous selection of both linear and nonlinear functional relationships as well as inducing sparsity in the edge selection. Using simulation studies, we demonstrate the superior performance of our methods in comparison with several existing approaches in terms of network reconstruction and functional selection. We apply our methods to a gene expression dataset in glioblastoma multiforme, which reveals several interesting and biologically relevant nonlinear relationships.