Bayesian Regularisation in Structured Additive Regression Models for Survival Data

During recent years, penalized likelihood approaches have attracted a lot of interest both in the area of semiparametric regression and for the regularization of high-dimensional regression models. In this paper, we introduce a Bayesian formulation that allows to combine both aspects into a joint regression model with a focus on hazard regression for survival times. While Bayesian penalized splines form the basis for estimating nonparametric and flexible time-varying effects, regularization of high-dimensional covariate vectors is based on scale mixture of normals priors. This class of priors allows to keep a (conditional) Gaussian prior for regression coefficients on the predictor stage of the model but introduces suitable mixture distributions for the Gaussian variance to achieve regularization. This scale mixture property allows to device general and adaptive Markov chain Monte Carlo simulation algorithms for fitting a variety of hazard regression models. In particular, unifying algorithms based on iteratively weighted least squares proposals can be employed both for regularization and penalized semiparametric function estimation. Since sampling based estimates do no longer have the variable selection property well-known for the Lasso in frequentist analyses, we additionally consider spike and slab priors that introduce a further mixing stage that allows to separate between influential and redundant parameters. We demonstrate the different shrinkage properties with three simulation settings and apply the methods to the PBC Liver dataset

High-dimensional Structured Additive Regression Models: Bayesian Regularisation, Smoothing and Predictive Performance

Data structures in modern applications frequently combine the necessity of flexible regression techniques such as nonlinear and spatial effects with high-dimensional covariate vectors. While estimation of the former is typically achieved by supplementing the likelihood with a suitable smoothness penalty, the latter are usually assigned shrinkage penalties that enforce sparse models. In this paper, we consider a Bayesian unifying perspective, where conditionally Gaussian priors can be assigned to all types of regression effects. Suitable hyperprior assumptions on the variances of the Gaussian distributions then induce the desired smoothness or sparseness properties. As a major advantage, general Markov chain Monte Carlo simulation algorithms can be developed that allow for the joint estimation of smooth and spatial effects and regularised coefficient vectors. Two applications demonstrate the usefulness of the proposed procedure: A geoadditive regression model for data from the Munich rental guide and an additive probit model for the prediction of consumer credit defaults. In both cases, high-dimensional vectors of categorical covariates will be included in the regression models. The predictive ability of the resulting high-dimensional structure additive regression models compared to expert models will be of particular relevance and will be evaluated on cross-validation test data

Bayesian regularization in regression models for survival data

This thesis is concerned with the development of flexible continuous-time survival models based on the accelerated failure time (AFT) model for the survival time and the Cox relative risk (CRR) model for the hazard rate. The flexibility concerns on the one hand the extension of the predictor to take into account simultaneously for a variety of different forms of covariate effects. On the other hand, the often too restrictive parametric assumptions about the survival distribution are replaced by semiparametric approaches that allow very flexible shapes of survival distribution. We use the Bayesian methodology for inference. The arising problems, like e. g. the penalization of high-dimensional linear covariate effects, the smoothing of nonlinear effects as well as the smoothing of the baseline survival distribution, are solved with the application of regularization priors tailored for the respective demand. The considered expansion of the two survival model classes enables to deal with various challenges arising in practical analysis of survival data. For example the models can deal with high-dimensional feature spaces (e. g. gene expression data), they facilitate feature selection from the whole set or a subset of the available covariates and enable the simultaneous modeling of any type of nonlinear covariate effects for covariates that should always be included in the model. The option of the nonlinear modeling of covariate effects as well as the semiparametric modeling of the survival time distribution enables furthermore also a visual inspection of the linearity assumptions about the covariate effects or accordingly parametric assumptions about the survival time distribution. In this thesis it is shown, how the p>n paradigm, feature relevance, semiparametric inference for functional effect forms and the semiparametric inference for the survival distribution can be treated within a unified Bayesian framework. Due the option to control the amount of regularization of the considered priors for the linear regression coefficients, there is no need to distinguish conceptionally between the cases pn. To accomplish the desired regularization, the regression coefficients are associated with shrinkage, selection or smoothing priors. Since the utilized regularization priors all facilitate a hierarchical representation, the resulting modular prior structure, in combination with adequate independence assumptions for the prior parameters, enables to establish a unified framework and the possibility to construct efficient MCMC sampling schemes for joint shrinkage, selection and smoothing in flexible classes of survival models. The Bayesian formulation enables therefore the simultaneous estimation of all parameters involved in the models as well as prediction and uncertainty statements about model specification. The presented methods are inspired from the flexible and general approach for structured additive regression (STAR) for responses from an exponential family and CRR-type survival models. Such systematic and flexible extensions are in general not available for AFT models. An aim of this work is to extend the class of AFT models in order to provide such a rich class of models as resulting from the STAR approach, where the main focus relies on the shrinkage of linear effects, the selection of covariates with linear effects together with the smoothing of nonlinear effects of continuous covariates as representative of a nonlinear modeling. Combined are in particular the Bayesian lasso, the Bayesian ridge and the Bayesian NMIG (a kind of spike-and-slab prior) approach to regularize the linear effects and the P-spline approach to regularize the smoothness of the nonlinear effects and the baseline survival time distribution. To model a flexible error distribution for the AFT model, the parametric assumption for the baseline error distribution is replaced by the assumption of a finite Gaussian mixture distribution. For the special case of specifying one basis mixture component the estimation problem essentially boils down to estimation of log-normal AFT model with STAR predictor. In addition, the existing class of CRR survival models with STAR predictor, where also baseline hazard rate is approximated by a P-spline, is expanded to enable the regularization of the linear effects with the mentioned priors, which broadens further the area of application of this rich class of CRR models. Finally, the combined shrinkage, selection and smoothing approach is also introduced to the semiparametric version of the CRR model, where the baseline hazard is unspecified and inference is based on the partial likelihood. Besides the extension of the two survival model classes the different regularization properties of the considered shrinkage and selection priors are examined. The developed methods and algorithms are implemented in the public available software BayesX and in R-functions and the performance of the methods and algorithms is extensively tested by simulation studies and illustrated through three real world data sets

Nucleic acid delivery of immune-focused SARS-CoV-2 nanoparticles drives rapid and potent immunogenicity capable of single-dose protection

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines may target epitopes that reduce durability or increase the potential for escape from vaccine-induced immunity. Using synthetic vaccinology, we have developed rationally immune-focused SARS-CoV-2 Spike-based vaccines. Glycans can be employed to alter antibody responses to infection and vaccines. Utilizing computational modeling and in vitro screening, we have incorporated glycans into the receptor-binding domain (RBD) and assessed antigenic profiles. We demonstrate that glycan-coated RBD immunogens elicit stronger neutralizing antibodies and have engineered seven multivalent configurations. Advanced DNA delivery of engineered nanoparticle vaccines rapidly elicits potent neutralizing antibodies in guinea pigs, hamsters, and multiple mouse models, including human ACE2 and human antibody repertoire transgenics. RBD nanoparticles induce high levels of cross-neutralizing antibodies against variants of concern with durable titers beyond 6 months. Single, low-dose immunization protects against a lethal SARS-CoV-2 challenge. Single-dose coronavirus vaccines via DNA-launched nanoparticles provide a platform for rapid clinical translation of potent and durable coronavirus vaccines.</p