False discovery rate (FDR) control methods are essential for voxel-wise multiple testing in neuroimaging data analysis, where hundreds of thousands or even millions of tests are conducted to detect brain regions associated with disease-related changes. Classical FDR control methods (e.g., BH, q-value, and LocalFDR) assume independence among tests and often lead to high false non-discovery rates (FNR). Although various spatial FDR control methods have been developed to improve power, they still fall short of jointly addressing three major challenges in neuroimaging applications: capturing complex spatial dependencies, maintaining low variability in both false discovery proportion (FDP) and false non-discovery proportion (FNP) across replications, and achieving computational scalability for high-resolution data. To address these challenges, we propose fcHMRF-LIS, a powerful, stable, and scalable spatial FDR control method for voxel-wise multiple testing. It integrates the local index of significance (LIS)-based testing procedure with a novel fully connected hidden Markov random field (fcHMRF) designed to model complex spatial structures using a parsimonious parameterization. We develop an efficient expectation-maximization algorithm incorporating mean-field approximation, the Conditional Random Fields as Recurrent Neural Networks (CRF-RNN) technique, and permutohedral lattice filtering, reducing the time complexity from quadratic to linear in the number of tests. Extensive simulations demonstrate that fcHMRF-LIS achieves accurate FDR control, lower FNR, reduced variability in FDP and FNP, and a higher number of true positives compared to existing methods. Applied to an FDG-PET dataset from the Alzheimer's Disease Neuroimaging Initiative, fcHMRF-LIS identifies neurobiologically relevant brain regions and offers notable advantages in computational efficiency.

Conditional independence (CI) testing is a fundamental task in modern statistics and machine learning. The conditional randomization test (CRT) was recently introduced to test whether two random variables, X and Y, are conditionally independent given a potentially high-dimensional set of random variables, Z. The CRT operates exceptionally well under the assumption that the conditional distribution X|Z is known. However, since this distribution is typically unknown in practice, accurately approximating it becomes crucial. In this paper, we propose using conditional diffusion models (CDMs) to learn the distribution of X|Z. Theoretically and empirically, it is shown that CDMs closely approximate the true conditional distribution. Furthermore, CDMs offer a more accurate approximation of X|Z compared to GANs, potentially leading to a CRT that performs better than those based on GANs. To accommodate complex dependency structures, we utilize a computationally efficient classifier-based conditional mutual information (CMI) estimator as our test statistic. The proposed testing procedure performs effectively without requiring assumptions about specific distribution forms or feature dependencies, and is capable of handling mixed-type conditioning sets that include both continuous and discrete variables. Theoretical analysis shows that our proposed test achieves a valid control of the type I error. A series of experiments on synthetic data demonstrates that our new test effectively controls both type-I and type-II errors, even in high dimensional scenarios.

Voxel-based multiple testing is widely used in neuroimaging data analysis. Traditional false discovery rate (FDR) control methods often ignore the spatial dependence among the voxel-based tests and thus suffer from substantial loss of testing power. While recent spatial FDR control methods have emerged, their validity and optimality remain questionable when handling the complex spatial dependencies of the brain. Concurrently, deep learning methods have revolutionized image segmentation, a task closely related to voxel-based multiple testing. In this paper, we propose DeepFDR, a novel spatial FDR control method that leverages unsupervised deep learning-based image segmentation to address the voxel-based multiple testing problem. Numerical studies, including comprehensive simulations and Alzheimer’s disease FDG-PET image analysis, demonstrate DeepFDR’s superiority over existing methods. DeepFDR not only excels in FDR control and effectively diminishes the false nondiscovery rate, but also boasts exceptional computational efficiency highly suited for tackling large-scale neuroimaging data.

The superiority of magnetic resonance (MR)-only radiotherapy treatment planning (RTP) has been well demonstrated, benefiting from the synthesis of computed tomography (CT) images which supplements electron density and eliminates the errors of multi-modal images registration. An increasing number of methods has been proposed for MR-to-CT synthesis. However, synthesizing CT images of different anatomical regions from MR images with different sequences using a single model is challenging due to the large differences between these regions and the limitations of convolutional neural networks in capturing global context information. In this paper, we propose a multi-scale tokens-aware Transformer network (MTT-Net) for multi-region and multi-sequence MR-to-CT synthesis in a single model. Specifically, we develop a multi-scale image tokens Transformer to capture multi-scale global spatial information between different anatomical structures in different regions. Besides, to address the limited attention areas of tokens in Transformer, we introduce a multi-shape window self-attention into Transformer to enlarge the receptive fields for learning the multi-directional spatial representations. Moreover, we adopt a domain classifier in generator to introduce the domain knowledge for distinguishing the MR images of different regions and sequences. The proposed MTT-Net is evaluated on a multi-center dataset and an unseen region, and remarkable performance was achieved with MAE of 69.33 ± 10.39 HU, SSIM of 0.778 ± 0.028, and PSNR of 29.04 ± 1.32 dB in head & neck region, and MAE of 62.80 ± 7.65 HU, SSIM of 0.617 ± 0.058 and PSNR of 25.94 ± 1.02 dB in abdomen region. The proposed MTT-Net outperforms state-of-the-art methods in both accuracy and visual quality.

Conditional independence (CI) testing is a fundamental task in statistics and machine learning, but its effectiveness is hindered by the challenges posed by high-dimensional conditioning variables and limited data samples. This article introduces a novel testing approach to address these challenges and enhance control of the type I error while achieving high power under alternative hypotheses. The proposed approach incorporates a computationally efficient classifier-based conditional mutual information (CMI) estimator, capable of capturing intricate dependence structures among variables. To approximate a distribution encoding the null hypothesis, a $k$-nearest-neighbor local sampling strategy is employed. An important advantage of this approach is its ability to operate without assumptions about distribution forms or feature dependencies. Furthermore, it eliminates the need to derive asymptotic null distributions for the estimated CMI and avoids dataset splitting, making it particularly suitable for small datasets. The method presented in this article demonstrates asymptotic control of the type I error and consistency against all alternative hypotheses. Extensive analyses using both synthetic and real data highlight the computational efficiency of the proposed test. Moreover, it outperforms existing state-of-the-art methods in terms of type I and II errors, even in scenarios with high-dimensional conditioning sets. Additionally, the proposed approach exhibits robustness in the presence of heavy-tailed data.

Deep neural networks (DNNs) have achieved great success in image classification, but can be very vulnerable to adversarial attacks with small perturbations to images. To improve adversarial image generation for DNNs, we develop a novel method, called mFI-PSO, which utilizes a Manifold-based First-order Influence measure for vulnerable image and pixel selection and the Particle Swarm Optimization for various objective functions. Our mFI-PSO can thus effectively design adversarial images with flexible, customized options on the number of perturbed pixels, the misclassification probability, and the targeted incorrect class. Experiments demonstrate the flexibility and effectiveness of our mFI-PSO in adversarial attacks and its appealing advantages over some popular methods.

Modern biomedical studies often collect multi-view data, that is, multiple types of data measured on the same set of objects. A popular model in high-dimensional multi-view data analysis is to decompose each view’s data matrix into a low-rank common-source matrix generated by latent factors common across all data views, a low-rank distinctive-source matrix corresponding to each view, and an additive noise matrix. We propose a novel decomposition method for this model, called decomposition-based generalized canonical correlation analysis (D-GCCA). The D-GCCA rigorously defines the decomposition on the L2 space of random variables in contrast to the Euclidean dot product space used by most existing methods, thereby being able to provide the estimation consistency for the low-rank matrix recovery. Moreover, to well calibrate common latent factors, we impose a desirable orthogonality constraint on distinctive latent factors. Existing methods, however, inadequately consider such orthogonality and may thus suffer from substantial loss of undetected common-source variation. Our D-GCCA takes one step further than generalized canonical correlation analysis by separating common and distinctive components among canonical variables, while enjoying an appealing interpretation from the perspective of principal component analysis. Furthermore, we propose to use the variable-level proportion of signal variance explained by common or distinctive latent factors for selecting the variables most influenced. Consistent estimators of our D-GCCA method are established with good finite-sample numerical performance, and have closed-form expressions leading to efficient computation especially for large-scale data. The superiority of D-GCCA over state-of-the-art methods is also corroborated in simulations and real-world data examples.

Deep neural networks (DNNs) have achieved superior performance in various prediction tasks, but can be very vulnerable to adversarial examples or perturbations. Therefore, it is crucial to measure the sensitivity of DNNs to various forms of perturbations in real applications. We introduce a novel perturbation manifold and its associated influence measure to quantify the effects of various perturbations on DNN classifiers. Such perturbations include various external and internal perturbations to input samples and network parameters. The proposed measure is motivated by information geometry and provides desirable invariance properties. We demonstrate that our influence measure is useful for four model building tasks: detecting potential ‘outliers’, analyzing the sensitivity of model architectures, comparing network sensitivity between training and test sets, and locating vulnerable areas. Experiments show reasonably good performance of the proposed measure for the popular DNN models ResNet50 and DenseNet121 on CIFAR10 and MNIST datasets.