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Physical activity is crucial for human health. With the increasing availability of large-scale mobile health data, strong associations have been found between physical activity and various diseases. However, accurately capturing this complex relationship is challenging, possibly because it varies across different subgroups of subjects, especially in large-scale datasets. To fill this gap, we propose a generalized heterogeneous functional method which simultaneously estimates functional effects and identifies subgroups within the generalized functional regression framework. The proposed method captures subgroup-specific functional relationships between physical activity and diseases, providing a more nuanced understanding of these associations. Additionally, we introduce a pre-clustering method that enhances computational efficiency for large-scale data through a finer partition of subjects compared to true subgroups. In the real data application, we examine the impact of physical activity on the risk of mental disorders and Parkinson's disease using the UK Biobank dataset, which includes over 79,000 participants. Our proposed method outperforms existing methods in future-day prediction accuracy, identifying four subgroups for mental disorder outcomes and three subgroups for Parkinson's disease diagnosis, with detailed scientific interpretations for each subgroup. We also demonstrate theoretical consistency of our methods. Supplementary materials are available online. Codes implementing the proposed method are available at: https://github.com/xiaojing777/GHFM.

In many predictive tasks, there are a large number of true predictors with weak signals, leading to substantial uncertainties in prediction outcomes. The polygenic risk score (PRS) is an example of such a scenario, where many genetic variants are used as predictors for complex traits, each contributing only a small amount of information. Although PRS has been a standard tool in genetic predictions, its uncertainty remains largely unexplored. In this paper, we aim to establish the asymptotic normality of PRS in high-dimensional predictions without sparsity constraints. We investigate the popular marginal and ridge-type estimators in PRS applications, developing central limit theorems for both individual-level predicted values (e.g., genetically predicted human height) and cohort-level prediction accuracy measures (e.g., overall predictive $R$-squared in the testing dataset). Our results demonstrate that ignoring the prediction-induced uncertainty can lead to substantial underestimation of the true variance of PRS-based estimators, which in turn may cause overconfidence in the accuracy of confidence intervals and hypothesis testing. These findings provide key insights omitted by existing first-order asymptotic studies of high-dimensional sparsity-free predictions, which often focus solely on the point limits of predictive risks. We develop novel and flexible second-order random matrix theory results to assess the asymptotic normality of functionals with a general covariance matrix, without assuming Gaussian distributions for the data. We evaluate our theoretical results through extensive numerical analyses using real data from the UK Biobank. Our analysis underscores the importance of incorporating uncertainty assessments at both the individual and cohort levels when applying and interpreting PRS.

Reference panel-based estimators have become widely used in genetic prediction of complex traits due to their ability to address data privacy concerns and reduce computational and communication costs. These estimators estimate the covariance matrix of predictors using an external reference panel, instead of relying solely on the original training data. In this paper, we investigate the performance of reference panel-based $L_1$ and $L_2$ regularized estimators within a unified framework based on approximate message passing (AMP). We uncover several key factors that influence the accuracy of reference panel-based estimators, including the sample sizes of the training data and reference panels, the signal-to-noise ratio, the underlying sparsity of the signal, and the covariance matrix among predictors. Our findings reveal that, even when the sample size of the reference panel matches that of the training data, reference panel-based estimators tend to exhibit lower accuracy compared to traditional regularized estimators. Furthermore, we observe that this performance gap widens as the amount of training data increases, highlighting the importance of constructing large-scale reference panels to mitigate this issue. To support our theoretical analysis, we develop a novel non-separable matrix AMP framework capable of handling the complexities introduced by a general covariance matrix and the additional randomness associated with a reference panel. We validate our theoretical results through extensive simulation studies and real data analyses using the UK Biobank database., Comment: 100 pages, 11 figures

This paper studies minimax rates of convergence for nonparametric location-scale models, which include mean, quantile and expectile regression settings. Under Hellinger differentiability on the error distribution and other mild conditions, we show that the minimax rate of convergence for estimating the regression function under the squared $L_2$ loss is determined by the metric entropy of the nonparametric function class. Different error distributions, including asymmetric Laplace distribution, asymmetric connected double truncated gamma distribution, connected normal-Laplace distribution, Cauchy distribution and asymmetric normal distribution are studied as examples. Applications on low order interaction models and multiple index models are also given.

Linkage disequilibrium score regression (LDSC) has emerged as an essential tool for genetic and genomic analyses of complex traits, utilizing high-dimensional data derived from genome-wide association studies (GWAS). LDSC computes the linkage disequilibrium (LD) scores using an external reference panel, and integrates the LD scores with only summary data from the original GWAS. In this paper, we investigate LDSC within a fixed-effect data integration framework, underscoring its ability to merge multi-source GWAS data and reference panels. In particular, we take account of the genome-wide dependence among the high-dimensional GWAS summary statistics, along with the block-diagonal dependence pattern in estimated LD scores. Our analysis uncovers several key factors of both the original GWAS and reference panel datasets that determine the performance of LDSC. We show that it is relatively feasible for LDSC-based estimators to achieve asymptotic normality when applied to genome-wide genetic variants (e.g., in genetic variance and covariance estimation), whereas it becomes considerably challenging when we focus on a much smaller subset of genetic variants (e.g., in partitioned heritability analysis). Moreover, by modeling the disparities in LD patterns across different populations, we unveil that LDSC can be expanded to conduct cross-ancestry analyses using data from distinct global populations (such as European and Asian). We validate our theoretical findings through extensive numerical evaluations using real genetic data from the UK Biobank study., Comment: 13 figures

The aim of this paper is to provide a comprehensive review of statistical challenges in neuroimaging data analysis from neuroimaging techniques to large-scale neuroimaging studies to statistical learning methods. We briefly review eight popular neuroimaging techniques and their potential applications in neuroscience research and clinical translation. We delineate the four common themes of neuroimaging data and review major image processing analysis methods for processing neuroimaging data at the individual level. We briefly review four large-scale neuroimaging-related studies and a consortium on imaging genomics and discuss four common themes of neuroimaging data analysis at the population level. We review nine major population-based statistical analysis methods and their associated statistical challenges and present recent progress in statistical methodology to address these challenges., Comment: 73 pages, 4 Figures

The aim of this paper is to propose a novel estimation method of using genetic-predicted observations to estimate trans-ancestry genetic correlations, which describes how genetic architecture of complex traits varies among populations, in genome-wide association studies (GWAS). Our new estimator corrects for prediction errors caused by high-dimensional weak GWAS signals, while addressing the heterogeneity of GWAS data across ethnicities, such as linkage disequilibrium (LD) differences, which can lead to biased findings in homogeneity-agnostic analyses. Moreover, our estimator only requires one population to have a large GWAS sample size, and the second population can only have a much smaller number of participants (for example, hundreds). It is designed to specifically address the unbalanced data resources such that the GWAS sample size for European populations is usually larger than that of non-European ancestry groups. Extensive simulations and real data analyses of 30 complex traits in the UK Biobank study show that our method is capable of providing reliable estimates of a wide range of complex traits. Our results provide deep insights into the transferability of population-specific genetic findings., Comment: 25 pages, 4 figures

Genetic prediction of complex traits and diseases has attracted enormous attention in precision medicine, mainly because it has the potential to translate discoveries from genome-wide association studies (GWAS) into medical advances. As the high dimensional covariance matrix (or the linkage disequilibrium (LD) pattern) of genetic variants has a block-diagonal structure, many existing methods attempt to account for the dependence among variants in predetermined local LD blocks/regions. Moreover, due to privacy restrictions and data protection concerns, genetic variant dependence in each LD block is typically estimated from external reference panels rather than the original training dataset. This paper presents a unified analysis of block-wise and reference panel-based estimators in a high-dimensional prediction framework without sparsity restrictions. We find that, surprisingly, even when the covariance matrix has a block-diagonal structure with well-defined boundaries, block-wise estimation methods adjusting for local dependence can be substantially less accurate than methods controlling for the whole covariance matrix. Further, estimation methods built on the original training dataset and external reference panels are likely to have varying performance in high dimensions, which may reflect the cost of having only access to summary level data from the training dataset. This analysis is based on our novel results in random matrix theory for block-diagonal covariance matrix. We numerically evaluate our results using extensive simulations and the large-scale UK Biobank real data analysis of 36 complex traits., Comment: 27 pages, 5 figures

Marginal association summary statistics have attracted great attention in statistical genetics, mainly because the primary results of most genome-wide association studies (GWAS) are produced by marginal screening. In this paper, we study the prediction accuracy of marginal estimator in dense (or sparsity free) high-dimensional settings with $(n,p,m) \to \infty$, $m/n \to \gamma \in (0,\infty)$, and $p/n \to \omega \in (0,\infty)$. We consider a general correlation structure among the $p$ features and allow an unknown subset $m$ of them to be signals. As the marginal estimator can be viewed as a ridge estimator with regularization parameter $\lambda \to \infty$, we further investigate a class of ridge-type estimators in a unifying framework, including the popular best linear unbiased prediction (BLUP) in genetics. We find that the influence of $\lambda$ on out-of-sample prediction accuracy heavily depends on $\omega$. Though selecting an optimal $\lambda$ can be important when $p$ and $n$ are comparable, it turns out that the out-of-sample $R^2$ of ridge-type estimators becomes near-optimal for any $\lambda \in (0,\infty)$ as $\omega$ increases. For example, when features are independent, the out-of-sample $R^2$ is always bounded by $1/\omega$ from above and is largely invariant to $\lambda$ given large $\omega$ (say, $\omega>5$). We also find that in-sample $R^2$ has completely different patterns and depends much more on $\lambda$ than out-of-sample $R^2$. In practice, our analysis delivers useful messages for genome-wide polygenic risk prediction and computation-accuracy trade-off in dense high-dimensions. We numerically illustrate our results in simulation studies and a real data example.

Genome-wide association studies (GWAS) have been widely used to examine the association between single nucleotide polymorphisms (SNPs) and complex traits, where both the sample size n and the number of SNPs p can be very large. Recently, cross-trait polygenic risk score (PRS) method has gained extremely popular for assessing genetic correlation of complex traits based on GWAS summary statistics (e.g., SNP effect size). However, empirical evidence has shown a common bias phenomenon that even highly significant cross-trait PRS can only account for a very small amount of genetic variance (R^2 often <1%). The aim of this paper is to develop a novel and powerful method to address the bias phenomenon of cross-trait PRS. We theoretically show that the estimated genetic correlation is asymptotically biased towards zero when complex traits are highly polygenic/omnigenic. When all p SNPs are used to construct PRS, we show that the asymptotic bias of PRS estimator is independent of the unknown number of causal SNPs m. We propose a consistent PRS estimator to correct such asymptotic bias. We also develop a novel estimator of genetic correlation which is solely based on two sets of GWAS summary statistics. In addition, we investigate whether or not SNP screening by GWAS p-values can lead to improved estimation and show the effect of overlapping samples among GWAS. Our results may help demystify and tackle the puzzling "missing genetic overlap" phenomenon of cross-trait PRS for dissecting the genetic similarity of closely related heritable traits. We illustrate the finite sample performance of our bias-corrected PRS estimator by using both numerical experiments and the UK Biobank data, in which we assess the genetic correlation between brain white matter tracts and neuropsychiatric disorders., Comment: 50 pages

This paper aims to better predict highly skewed auto insurance claims by combining candidate predictions. We analyze a version of the Kangaroo Auto Insurance company data and study the effects of combining different methods using five measures of prediction accuracy. The results show the following. First, when there is an outstanding (in terms of Gini Index) prediction among the candidates, the "forecast combination puzzle" phenomenon disappears. The simple average method performs much worse than the more sophisticated model combination methods, indicating that combining different methods could help us avoid performance degradation. Second, the choice of the prediction accuracy measure is crucial in defining the best candidate prediction for "low frequency and high severity" (LFHS) data. For example, mean square error (MSE) does not distinguish well between model combination methods, as the values are close. Third, the performances of different model combination methods can differ drastically. We propose using a new model combination method, named ARM-Tweedie, for such LFHS data; it benefits from an optimal rate of convergence and exhibits a desirable performance in several measures for the Kangaroo data. Fourth, overall, model combination methods improve the prediction accuracy for auto insurance claim costs. In particular, Adaptive Regression by Mixing (ARM), ARM-Tweedie, and constrained Linear Regression can improve forecast performance when there are only weak learners or when no dominant learner exists.