Inference on Large-scale Generalized Functional Linear Model

The purpose of this work was to develop and evaluate the accuracy of several predictive models of variation in tumor volume throughout the course of radiation therapy. Nineteen patients with oropharyngeal cancers were imaged daily with CT-on-rails for image-guided alignment per an institutional protocol. The daily volumes of 35 tumors in these 19 patients were determined and used to generate (1) a linear model in which tumor volume changed at a constant rate, (2) a general linear model that utilized the power fit relationship between the daily and initial tumor volumes, and (3) a functional general linear model that identified and exploited the primary modes of variation between time series describing the changing tumor volumes. Primary and nodal tumor volumes were examined separately. The accuracy of these models in predicting daily tumor volumes were compared with those of static and linear reference models using leave-one-out cross-validation. In predicting the daily volume of primary tumors, the general linear model and the functional general linear model were more accurate than the static reference model by 9.9% (range: -11.6%-23.8%) and 14.6% (range: -7.3%-27.5%), respectively, and were more accurate than the linear reference model by 14.2% (range: -6.8%-40.3%) and 13.1% (range: -1.5%-52.5%), respectively. In predicting the daily volume of nodal tumors, only the 14.4% (range: -11.1%-20.5%) improvement in accuracy of the functional general linear model compared to the static reference model was statistically significant. A general linear model and a functional general linear model trained on data from a small population of patients can predict the primary tumor volume throughout the course of radiation therapy with greater accuracy than standard reference models. These more accurate models may increase the prognostic value of information about the tumor garnered from pretreatment computed tomography images and facilitate improved treatment management.

There are two measurement error models in linear regression, the structural and the functional. Theoretical investigations and applications are concentrated on the structural model with jointly normally and identically distributed observations because there is no test for the slope in the functional model so far. This gap will be closed here for the model with one independent variable. Furthermore it is stated that the functional model is a natural extension of the classical linear regression model with one independent variable if there are errors of measurement in both variables. Moreover it is not postulated in the functional model that the expectations are equal. So the functional model is more realistic than the structural.

Checking the adequacy of functional linear quantile regression model

Hydrologic metrics have been used widely to quantify flow-ecology relationships; however, there are several challenges associated with their use, including the selection from a large number of available metrics and the limitation that metrics are a synthetic measure of a multi-dimensional flow regime. Using two case studies of fish species density and community composition, we illustrate the use of functional linear models to provide new insights into flow–ecology relationships and predict the expected impact of environmental flow scenarios, without relying on hydrologic metrics. The models identified statistically significant relationships to river flow over the 12 months prior to sampling (r2 range 36–67%) and an environmental flow scenario that may enhance native species’ densities while controlling a non-native species. Hydrologic metrics continue to play an important role in ecohydrology and environmental flow management; however, functional linear models provide an approach that overcomes some of the limitations associated with their use.Editor Z.W. Kundzewicz; Guest editor M. AcremanCitation Stewart-Koster, B., Olden, J.D., and Gido, K.B., 2014. Quantifying flow–ecology relationships with functional linear models. Hydrological Sciences Journal, 59 (3–4), 629–644.

This study examines the optimal selections of bandwidth and semi-metric for a functional partial linear model. Our proposed method begins by estimating the unknown error density using a kernel density estimator of residuals, where the regression function, consisting of parametric and nonparametric components, can be estimated by functional principal component and functional Nadayara-Watson estimators. The estimation accuracy of the regression function and error density crucially depends on the optimal estimations of bandwidth and semi-metric. A Bayesian method is utilized to simultaneously estimate the bandwidths in the regression function and kernel error density by minimizing the Kullback-Leibler divergence. For estimating the regression function and error density, a series of simulation studies demonstrate that the functional partial linear model gives improved estimation and forecast accuracies compared with the functional principal component regression and functional nonparametric regression. Using a spectroscopy dataset, the functional partial linear model yields better forecast accuracy than some commonly used functional regression models. As a by-product of the Bayesian method, a pointwise prediction interval can be obtained, and marginal likelihood can be used to select the optimal semi-metric.

Meta-analysis of genetic data must account for differences among studies including study designs, markers genotyped, and covariates. The effects of genetic variants may differ from population to population, i.e., heterogeneity. Thus, meta-analysis of combining data of multiple studies is difficult. Novel statistical methods for meta-analysis are needed. In this article, functional linear models are developed for meta-analyses that connect genetic data to quantitative traits, adjusting for covariates. The models can be used to analyze rare variants, common variants, or a combination of the two. Both likelihood-ratio test (LRT) and F-distributed statistics are introduced to test association between quantitative traits and multiple variants in one genetic region. Extensive simulations are performed to evaluate empirical type I error rates and power performance of the proposed tests. The proposed LRT and F-distributed statistics control the type I error very well and have higher power than the existing methods of the meta-analysis sequence kernel association test (MetaSKAT). We analyze four blood lipid levels in data from a meta-analysis of eight European studies. The proposed methods detect more significant associations than MetaSKAT and the P-values of the proposed LRT and F-distributed statistics are usually much smaller than those of MetaSKAT. The functional linear models and related test statistics can be useful in whole-genome and whole-exome association studies.

Point process data have become increasingly popular these days. For example, many of the data captured in electronic health records (EHR) are in the format of point process data. It is of great interest to study the association between a point process predictor and a scalar response using generalized functional linear regression models. Various generalized functional linear regression models have been developed under different settings in the past decades. However, existing methods can only deal with functional or longitudinal predictors, not point process predictors. In this article, we propose a novel generalized functional linear regression model for a point process predictor. Our proposed model is based on the joint modeling framework, where we adopt a log-Gaussian Cox process model for the point process predictor and a generalized linear regression model for the outcome. We also develop a new algorithm for fast model estimation based on the Gaussian variational approximation method. We conduct extensive simulation studies to evaluate the performance of our proposed method and compare it to competing methods. The performance of our proposed method is further demonstrated on an EHR dataset of patients admitted into the intensive care units of the Beth Israel Deaconess Medical Center between 2001 and 2008.

Our work focuses on the functional linear model given by \(Y=\langle\theta,X\rangle+\epsilon,\) where Y and e are real random variables, X is a zero-mean random variable valued in a Hilbert space \((\mathcal{H},\langle\cdot,\cdot\rangle)\), and \(\theta\in\mathcal{H}\) is the fixed model parameter. Using an initial sample \(\{(X_i,Y_i)\}_{i=1}^n\), a bootstrap resampling \(Y_i^{*}=\langle\hat{\theta},X_i\rangle+\hat{\epsilon}_i^{*}\), \(i=1,\ldots,n\), is proposed, where \(\hat{\theta}\) is a general pilot estimator, and \(\hat{\epsilon}_i^{*}\) is a naive or wild bootstrap error. The obtained consistency of bootstrap allows us to calibrate distributions as \(P_X\{\sqrt{n}(\langle\hat{\theta},x\rangle-\langle\theta,x\rangle)\leq y\}\) for a fixed x, where P X is the probability conditionally on \(\{X_i\}_{i=1}^n\). Different applications illustrate the usefulness of bootstrap for testing different hypotheses related with θ, and a brief simulation study is also presented.

Recent history functional linear models for sparse longitudinal data

This study introduces a partial functional linear spatial autoregressive model which can explore the relationship between a scalar spatially dependent response variable and predictive variables containing both multiple scalar covariates and a functional covariate. With approximating to the functional coefficient by Karhunen–Loève representation, we propose a Bayesian adaptive Lasso method to simultaneously estimate unknown parameters and select important covariates in the model, which can be performed by combining the Gibbs sampler and the Metropolis–Hastings algorithm. Some simulation studies are conducted and the results show that the proposed Bayesian method behaves well.

The estimation of large functional and longitudinal data, which refers to the estimation of mean function, estimation of covariance function, and prediction of individual trajectory, is one of the most challenging problems in the field of high-dimensional statistics. Functional Principal Components Analysis (FPCA) and Functional Linear Mixed Model (FLMM) are two major statistical tools used to address the estimation of large functional and longitudinal data; however, the former suffers from a dramatically increasing computational burden while the latter does not have clear asymptotic properties. In this paper, we propose a computationally effective estimator of large functional and longitudinal data within the framework of FLMM, in which all the parameters can be automatically estimated. Under certain regularity assumptions, we prove that the mean function estimation and individual trajectory prediction reach the minimax lower bounds of all nonparametric estimations. Through numerous simulations and real data analysis, we show that our new estimator outperforms the traditional FPCA in terms of mean function estimation, individual trajectory prediction, variance estimation, covariance function estimation, and computational effectiveness.

Functional linear regression model with randomly censored data: Predicting conversion time to Alzheimer ’s disease

Functional linear regression models have been widely used in the gene association analysis of complex traits. These models retain all the genetic information in the data and take full advantage of spatial information in genetic variation data, which leads to brilliant detection power. However, the significant association signals identified by the high-power methods are not all the real causal SNPs, because it is easy to regard noise information as significant association signals, leading to a false association. In this paper, a method based on the sparse functional data association test (SFDAT) of gene region association analysis is developed based on a functional linear regression model with local sparse estimation. The evaluation indicators CSR and DL are defined to evaluate the feasibility and performance of the proposed method with other indicators. Simulation studies show that: (1) SFDAT performs well under both linkage equilibrium and linkage disequilibrium simulation; (2) SFDAT performs successfully for gene regions (including common variants, low-frequency variants, rare variants and mix variants); (3) With power and type I error rates comparable to OLS and Smooth, SFDAT has a better ability to handle the zero regions. The Oryza sativa data set is analyzed by SFDAT. It is shown that SFDAT can better perform gene association analysis and eliminate the false positive of gene localization. This study showed that SFDAT can lower the interference caused by noise while maintaining high power. SFDAT provides a new method for the association analysis between gene regions and phenotypic quantitative traits.

Genetics plays a role in age-related macular degeneration (AMD), a common cause of blindness in the elderly. There is a need for powerful methods for carrying out region-based association tests between a dichotomous trait like AMD and genetic variants on family data. Here, we apply our new generalized functional linear mixed models (GFLMM) developed to test for gene-based association in a set of AMD families. Using common and rare variants, we observe significant association with two known AMD genes: CFH and ARMS2. Using rare variants, we find suggestive signals in four genes: ASAH1, CLEC6A, TMEM63C, and SGSM1. Intriguingly, ASAH1 is down-regulated in AMD aqueous humor, and ASAH1 deficiency leads to retinal inflammation and increased vulnerability to oxidative stress. These findings were made possible by our GFLMM which model the effect of a major gene as a fixed mean, the polygenic contributions as a random variation, and the correlation of pedigree members by kinship coefficients. Simulations indicate that the GFLMM likelihood ratio tests (LRTs) accurately control the Type I error rates. The LRTs have similar or higher power than existing retrospective kernel and burden statistics. Our GFLMM-based statistics provide a new tool for conducting family-based genetic studies of complex diseases. Supplementary materials for this article, including a standardized description of the materials available for reproducing the work, are available as an online supplement.

In this paper, we consider rank estimation for partial functional linear regression models based on functional principal component analysis. The proposed rank-based method is robust to outliers in the errors and highly efficient under a wide range of error distributions. The asymptotic properties of the resulting estimators are established under some regularity conditions. A simulation study conducted to investigate the finite sample performance of the proposed estimators shows that the proposed rank method performs well. Furthermore, the proposed methodology is illustrated by means of an analysis of the Berkeley growth data.