MOTIVATION: Imaging genetics integrates imaging and genetic techniques to examine how genetic variations influence the function and structure of organs like the brain or heart, providing insights into their impact on behavior and disease phenotypes. The use of organ-wide imaging endophenotypes has increasingly been used to identify potential genes associated with complex disorders. However, analyzing organ-wide imaging data alongside genetic data presents two significant challenges: high dimensionality and complex relationships. To address these challenges, we propose a novel, nonlinear inference framework designed to partially mitigate these issues. RESULTS: We propose a functional partial least squares through distance covariance (FPLS-DC) framework for efficient genome wide analyses of imaging phenotypes. It consists of two components. The first component utilizes the FPLS-derived base functions to reduce image dimensionality while screening genetic markers. The second component maximizes the distance correlation between genetic markers and projected imaging data, which is a linear combination of the FPLS-basis functions, using simulated annealing algorithm. In addition, we proposed an iterative FPLS-DC method based on FPLS-DC framework, which effectively overcomes the influence of inter-gene correlation on inference analysis. We efficiently approximate the null distribution of test statistics using a gamma approximation. Compared to existing methods, FPLS-DC offers computational and statistical efficiency for handling large-scale imaging genetics. In real-world applications, our method successfully detected genetic variants associated with the hippocampus, demonstrating its value as a statistical toolbox for imaging genetic studies. AVAILABILITY AND IMPLEMENTATION: The FPLS-DC method we propose opens up new research avenues and offers valuable insights for analyzing functional and high-dimensional data. In addition, it serves as a useful tool for scientific analysis in practical applications within the field of imaging genetics research. The R package FPLS-DC is available in Github: https://github.com/BIG-S2/FPLSDC.

We consider the problem of performing an association test between functional data and scalar variables in a varying coefficient model setting. We propose a functional projection regression model and an associated global test statistic to aggregate relatively weak signals across the domain of functional data, while reducing the dimension. An optimal functional projection direction is selected to maximize signal-to-noise ratio with ridge penalty. Theoretically, we systematically study the asymptotic distribution of the global test statistic and provide a strategy to adaptively select the optimal tuning parameter. We use simulations to show that the proposed test outperforms all existing state-of-the-art methods in functional statistical inference. Finally, we apply the proposed testing method to the genome-wide association analysis of imaging genetic data in UK Biobank dataset.

Graph-based semi-supervised learning is a very powerful tool in classification tasks, while in most existing literature the labelled nodes are assumed to be randomly sampled. When the labelling status depends on the unobserved node response, ignoring the missingness can lead to significant estimation bias and handicap the classifiers. This situation is called non-ignorable non-response. To solve the problem, we propose a Graph-based joint model with Non-ignorable Non-response (GNN), followed by a joint inverse weighting estimation procedure incorporated with sampling imputation approach. Our method is proved to outperform some state-of-art models in both regression and classification problems, by simulations and real analysis on the Cora dataset.