Gene Level Meta-Analysis of Quantitative Traits by Functional Linear Models.

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.

Genome-wide association analysis is an important approach to identify genetic variants associated with complex traits. Complex traits are not only affected by single gene loci, but also by the interaction of multiple gene loci. Studies of association between gene regions and quantitative traits are of great significance in revealing the genetic mechanism of biological development. There have been a lot of studies on single-gene region association analysis, but the application of functional linear models in multi-gene region association analysis is still less. In this paper, a functional multi-gene region association analysis test method is proposed based on the functional linear model. From the three directions of common multi-gene region method, multi-gene region weighted method and multi-gene region loci weighted method, that test method is studied combined with computer simulation. The following conclusions are obtained through computer simulation: (a) The functional multi-gene region association analysis test method has higher power than the functional single gene region association analysis test method; (b) The functional multi-gene region weighted method performs better than the common functional multi-gene region method; (c) the functional multi-gene region loci weighted method is the best method for association analysis on three directions of the common multi-gene region method; (d) the performance of the Step method and Multi-gene region loci weighted Step for multi-gene regions is the best in general. Functional multi-gene region association analysis test method can theoretically provide a feasible method for the study of complex traits affected by multiple genes.

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.

Checking the adequacy of functional linear quantile regression model

The functional linear model with scalar response is a regression model where the predictor is a random function defined on some compact set of ℝ and the response is scalar. The response is modelled as Y=Ψ(X)+ɛ, where Ψ is some linear continuous operator defined on the space of square integrable functions and valued in ℝ. The random input X is independent from the noise ɛ. In this paper, we are interested in testing the null hypothesis of no effect, that is, the nullity of Ψ restricted to the Hilbert space generated by the random variable X. We introduce two test statistics based on the norm of the empirical cross‐covariance operator of (X,Y). The first test statistic relies on a χ2 approximation and we show the asymptotic normality of the second one under appropriate conditions on the covariance operator of X. The test procedures can be applied to check a given relationship between X and Y. The method is illustrated through a simulation study.

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.

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.

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.

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.

Fast and cheaper next-generation sequencing technologies will generate unprecedentedly massive and highly dimensional genetic variation data that allow nearly complete evaluation of genetic variation including both common and rare variants. There are two types of association tests: variant-by-variant test and group test. The variant-by-variant test is designed to test the association of common variants, while the group test is suitable to collectively test the association of multiple rare variants. We propose here a smoothed functional principal component analysis (SFPCA) statistic as a general approach for testing association of the entire allelic spectrum of genetic variation (both common and rare variants), which utilizes the merits of both variant-by-variant analysis and group tests. By intensive simulations, we demonstrate that the SFPCA statistic has the correct type 1 error rates and much higher power than the existing methods to detect association of (1) common variants, (2) rare variants, (3) both common and rare variants and (4) variants with opposite directions of effects. To further evaluate its performance, the SFPCA statistic is applied to ANGPTL4 sequence and six continuous phenotypes data from the Dallas Heart Study as an example for testing association of rare variants and a GWAS of schizophrenia data as an example for testing association of common variants. The results show that the SFPCA statistic has much smaller P-values than many existing statistics in both real data analysis examples.

This paper studies the applications of extreme value theory on analysis for closing price data of the Dow-Jones industrial index and Danish fire insurance claims data. The generalized extreme value (GEV) distribution is considered in analyzing the real data, and the hypothesis testing problem for the shape parameter of GEV distribution is investigated based on a new test statistic—the $$L_q$$ -likelihood ratio ( $$L_q$$ R) statistic. The $$L_q$$ R statistic can be treated as a generalized form of the classical likelihood ratio (LR) statistic. We show that the asymptotic behavior of proposed statistic is characterized by the degree of distortion $$q$$ . For small and modest sample sizes, the $$L_q$$ R statistic is still available when $$q$$ is properly chosen. By simulation studies, the proposed statistic not only performs the asymptotic properties, but also outperforms the classical LR statistic as the sample sizes are modest or even small. Meanwhile, the test power based on the new statistic is also simulated by Monte Carlo methods. At last, the models are diagnosed by graphical methods.

BackgroundIn many medical studies the likelihood ratio test (LRT) has been widely applied to examine whether the random effects variance component is zero within the mixed effects models framework; whereas little work about likelihood-ratio based variance component test has been done in the generalized linear mixed models (GLMM), where the response is discrete and the log-likelihood cannot be computed exactly. Before applying the LRT for variance component in GLMM, several difficulties need to be overcome, including the computation of the log-likelihood, the parameter estimation and the derivation of the null distribution for the LRT statistic.MethodsTo overcome these problems, in this paper we make use of the penalized quasi-likelihood algorithm and calculate the LRT statistic based on the resulting working response and the quasi-likelihood. The permutation procedure is used to obtain the null distribution of the LRT statistic. We evaluate the permutation-based LRT via simulations and compare it with the score-based variance component test and the tests based on the mixture of chi-square distributions. Finally we apply the permutation-based LRT to multilocus association analysis in the case–control study, where the problem can be investigated under the framework of logistic mixed effects model.ResultsThe simulations show that the permutation-based LRT can effectively control the type I error rate, while the score test is sometimes slightly conservative and the tests based on mixtures cannot maintain the type I error rate. Our studies also show that the permutation-based LRT has higher power than these existing tests and still maintains a reasonably high power even when the random effects do not follow a normal distribution. The application to GAW17 data also demonstrates that the proposed LRT has a higher probability to identify the association signals than the score test and the tests based on mixtures.ConclusionsIn the present paper the permutation-based LRT was developed for variance component in GLMM. The LRT outperforms existing tests and has a reasonably higher power under various scenarios; additionally, it is conceptually simple and easy to implement.

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.

Summary The mixed linear model is a popular method for analysing unbalanced repeated measurement data. The classical statistical tests for parameters in this model are based on asymptotic theory that is unreliable in the small samples that are often encountered in practice. For testing a given fixed effect parameter with a small sample, we develop and investigate refined likelihood ratio (LR) tests. The refinements considered are the Bartlett correction and use of the Cox–Reid adjusted likelihood; these are examined separately and in combination. We illustrate the various LR tests on an actual data set and compare them in two simulation studies. The conventional LR test yields type I error rates that are higher than nominal. The adjusted LR test yields rates that are lower than nominal, with absolute accuracy similar to that of the conventional LR test in the first simulation study and better in the second. The Bartlett correction substantially improves the accuracy of the type I error rates with either the conventional or the adjusted LR test. In many cases, error rates that are very close to nominal are achieved with the refined methods.

This paper studies how to identify in uential curves in the functional linear model in which the response is scalar and the predictor is functional and how to measure their e ects on the estimation of the model and on the forecasts, when the model is estimated by the principal components method. For that, we introduce and analyze two statistics that measure the inuence of each curve on the functional slope estimate of the model, which are generalizations of the measures proposed for the standard regression model by Cook (1977) and Pena (2005), respectively.