Varying Coefficient Tensor Models for Brain Imaging

We revisit a multidimensional varying-coefficient model (VCM), by allowing regressor coefficients to vary smoothly in more than one dimension, thereby extending the VCM of Hastie and Tibshirani. The motivating example is 3-dimensional, involving a special type of nuclear magnetic resonance measurement technique that is being used to estimate the diffusion tensor at each point in the human brain. We aim to improve the current state of the art, which is to apply a multiple regression model for each voxel separately using information from six or more volume images. We present a model, based on P-spline tensor products, to introduce spatial smoothness of the estimated diffusion tensor. Since the regression design matrix is space-invariant, a 4-dimensional tensor product model results, allowing more efficient computation with penalized array regression

Space-Varying Coefficient Models for Brain Imaging

The methodological development and the application in this paper originate from diffusion tensor imaging (DTI), a powerful nuclear magnetic resonance technique enabling diagnosis and monitoring of several diseases as well as reconstruction of neural pathways. We reformulate the current analysis framework of separate voxelwise regressions as a 3d space-varying coefficient model (VCM) for the entire set of DTI images recorded on a 3d grid of voxels. Hence by allowing to borrow strength from spatially adjacent voxels, to smooth noisy observations, and to estimate diffusion tensors at any location within the brain, the three-step cascade of standard data processing is overcome simultaneously. We conceptualize two VCM variants based on B-spline basis functions: a full tensor product approach and a sequential approximation, rendering the VCM numerically and computationally feasible even for the huge dimension of the joint model in a realistic setup. A simulation study shows that both approaches outperform the standard method of voxelwise regressions with subsequent regularization. Due to major efficacy, we apply the sequential method to a clinical DTI data set and demonstrate the inherent ability of increasing the rigid grid resolution by evaluating the incorporated basis functions at intermediate points. In conclusion, the suggested fitting methods clearly improve the current state-of-the-art, but ameloriation of local adaptivity remains desirable

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

Bilinear modulation models for seasonal tables of counts

We propose generalized linear models for time or age-time tables of seasonal counts, with the goal of better understanding seasonal patterns in the data. The linear predictor contains a smooth component for the trend and the product of a smooth component (the modulation) and a periodic time series of arbitrary shape (the carrier wave). To model rates, a population offset is added. Two-dimensional trends and modulation are estimated using a tensor product B-spline basis of moderate dimension. Further smoothness is ensured using difference penalties on the rows and columns of the tensor product coefficients. The optimal penalty tuning parameters are chosen based on minimization of a quasi-information criterion. Computationally efficient estimation is achieved using array regression techniques, avoiding excessively large matrices. The model is applied to female death rate in the US due to cerebrovascular diseases and respiratory diseases

Multidimensional Adaptive Penalised Splines with Application to Neurons' Activity Studies

P-spline models have achieved great popularity both in statistical and in applied research. A possible drawback of P-spline is that they assume a smooth transition of the covariate effect across its whole domain. In some practical applications, however, it is desirable and needed to adapt smoothness locally to the data, and adaptive P-splines have been suggested. Yet, the extra flexibility afforded by adaptive P-spline models is obtained at the cost of a high computational burden, especially in a multidimensional setting. Furthermore, to the best of our knowledge, the literature lacks proposals for adaptive P-splines in more than two dimensions. Motivated by the need for analysing data derived from experiments conducted to study neurons' activity in the visual cortex, this work presents a novel locally adaptive anisotropic P-spline model in two (e.g., space) and three (space and time) dimensions. Estimation is based on the recently proposed SOP (Separation of Overlapping Precision matrices) method, which provides the speed we look for. The practical performance of the proposal is evaluated through simulations, and comparisons with alternative methods are reported. In addition to the spatio-temporal analysis of the data that motivated this work, we also discuss an application in two dimensions on the absenteeism of workers

On the estimation of variance parameters in non-standard generalised linear mixed models: application to penalised smoothing

We present a novel method for the estimation of variance parameters in generalised linear mixed models. The method has its roots in Harville (J Am Stat Assoc 72(358):320-338, 1977)'s work, but it is able to deal with models that have a precision matrix for the random effect vector that is linear in the inverse of the variance parameters (i.e., the precision parameters). We call the method SOP (separation of overlapping precision matrices). SOP is based on applying the method of successive approximations to easy-to-compute estimate updates of the variance parameters. These estimate updates have an appealing form: they are the ratio of a (weighted) sum of squares to a quantity related to effective degrees of freedom. We provide the sufficient and necessary conditions for these estimates to be strictly positive. An important application field of SOP is penalised regression estimation of models where multiple quadratic penalties act on the same regression coefficients. We discuss in detail two of those models: penalised splines for locally adaptive smoothness and for hierarchical curve data. Several data examples in these settings are presented.This research was supported by the Basque Government through the BERC 2018-2021 program and by Spanish Ministry of Economy and Competitiveness MINECO through BCAM Severo Ochoa excellence accreditation SEV-2013-0323 and through projects MTM2017-82379-R funded by (AEI/FEDER, UE) and acronym “AFTERAM”, MTM2014-52184-P and MTM2014-55966-P. The MRI/DTI data were collected at Johns Hopkins University and the Kennedy-Krieger Institute. We are grateful to Pedro Caro and Iain Currie for useful discussions, to Martin Boer and Cajo ter Braak for the detailed reading of the paper and their many suggestions, and to Bas Engel for sharing with us his knowledge. We are also grateful to the two peer referees for their constructive comments of the paper

Visualization of Genomic Changes by Segmented Smoothing Using an L0 Penalty

Copy number variations (CNV) and allelic imbalance in tumor tissue can show strong segmentation. Their graphical presentation can be enhanced by appropriate smoothing. Existing signal and scatterplot smoothers do not respect segmentation well. We present novel algorithms that use a penalty on the norm of differences of neighboring values. Visualization is our main goal, but we compare classification performance to that of VEGA

Dynamics of senescence-related QTLs in potato

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Methylation of Migraine-Related Genes in Different Tissues of the Rat

Abstract 17ß-Estradiol, an epigenetic modulator, is involved in the increased prevalence of migraine in women. Together with the prophylactic efficacy of valproate, which influences DNA methylation and histone modification, this points to the involvement of epigenetic mechanisms. Epigenetic studies are often performed on leukocytes, but it is unclear to what extent methylation is similar in other tissues. Therefore, we investigated methylation of migraine-related genes that might be epigenetically regulated (CGRP-ergic pathway, estrogen receptors, endothelial NOS, as well as MTHFR) in different migraine-related tissues and compared this to methylation in rat as well as human leukocytes. Further, we studied whether 17ß-estradiol has a prominent role in methylation of these genes. Female rats (n = 35) were ovariectomized or shamoperated and treated with 17b-estradiol or placebo. DNA was isolated and methylation was assessed through bisulphite treatment and mass spectrometry. Human methylation data were obtained using the Illumina 450k genome-wide methylation array in 395 female subjects from a population-based cohort study. We showed that methylation of the Crcp, Calcrl, Esr1 and Nos3 genes is tissue-specific and that methylation in leukocytes was not correlated to that in other tissues. Interestingly, the interindividual variation in methylation differed considerably between genes and tissues. Furthermore we showed that methylation in human leukocytes was similar to that in rat leukocytes in our genes of interest, suggesting that rat may be a good model to study human DNA methylation in tissues that are difficult to obtain. In none of the genes a significant effect of estradiol treatment was observed