A theoretical model of inflammation- and mechanotransduction- driven asthmatic airway remodelling

Inflammation, airway hyper-responsiveness and airway remodelling are well-established hallmarks of asthma, but their inter-relationships remain elusive. In order to obtain a better understanding of their inter-dependence, we develop a mechanochemical morphoelastic model of the airway wall accounting for local volume changes in airway smooth muscle (ASM) and extracellular matrix in response to transient inflammatory or contractile agonist challenges. We use constrained mixture theory, together with a multiplicative decomposition of growth from the elastic deformation, to model the airway wall as a nonlinear fibre-reinforced elastic cylinder. Local contractile agonist drives ASM cell contraction, generating mechanical stresses in the tissue that drive further release of mitogenic mediators and contractile agonists via underlying mechanotransductive signalling pathways. Our model predictions are consistent with previously described inflammation-induced remodelling within an axisymmetric airway geometry. Additionally, our simulations reveal novel mechanotransductive feedback by which hyper-responsive airways exhibit increased remodelling, for example, via stress-induced release of pro-mitogenic and procontractile cytokines. Simulation results also reveal emergence of a persistent contractile tone observed in asthmatics, via either a pathological mechanotransductive feedback loop, a failure to clear agonists from the tissue, or a combination of both. Furthermore, we identify various parameter combinations that may contribute to the existence of different asthma phenotypes, and we illustrate a combination of factors which may predispose severe asthmatics to fatal bronchospasms

Selecting principal components in regression

Criteria for the deletion of principal components in regression are usually based on one of two indicators of components effects: (i) the magnitude of the eigenvalues of the predictor-variable correlation matrix or (ii) statistical tests of the significance of the components. Advocates of the first criterion cite guaranteed variance reduction properties as a rational for their proposals whereas proponents of inferential criteria point out that deletion solely on the basis of the magnitude of the eigenvalues ignores the potentials for bias. In this note we discuss the liminations of the second approach.preliminary test estimators biased estimation collinearity

Multicollinear effects of weighted least squares regression

Weighted least squares estimators, such as those arising from certain variance stabilizing transformations and robust regression procedures, alter the multicollinear structure of the original matrix of predictor variables. We investigate the effects of weighted least squares on the eigenvalues and the spectral condition number of the original correlation matrix of predictor variables.Biased estimation robust regression spectral condition number