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IntroductionIdentification of Alzheimer's Disease (AD)-related transcriptomic signatures from blood is important for early diagnosis of the disease. Deep learning techniques are potent classifiers for AD diagnosis, but most have been unable to identify biomarkers because of their lack of interpretability.MethodsTo address these challenges, we propose a pathway information-based neural network (PINNet) to predict AD patients and analyze blood and brain transcriptomic signatures using an interpretable deep learning model. PINNet is a deep neural network (DNN) model with pathway prior knowledge from either the Gene Ontology or Kyoto Encyclopedia of Genes and Genomes databases. Then, a backpropagation-based model interpretation method was applied to reveal essential pathways and genes for predicting AD.ResultsThe performance of PINNet was compared with a DNN model without a pathway. Performances of PINNet outperformed or were similar to those of DNN without a pathway using blood and brain gene expressions, respectively. Moreover, PINNet considers more AD-related genes as essential features than DNN without a pathway in the learning process. Pathway analysis of protein-protein interaction modules of highly contributed genes showed that AD-related genes in blood were enriched with cell migration, PI3K-Akt, MAPK signaling, and apoptosis in blood. The pathways enriched in the brain module included cell migration, PI3K-Akt, MAPK signaling, apoptosis, protein ubiquitination, and t-cell activation.DiscussionBy integrating prior knowledge about pathways, PINNet can reveal essential pathways related to AD. The source codes are available at https://github.com/DMCB-GIST/PINNet.

Recent advances in MRI have led to the creation of large datasets. With the increase in data volume, it has become difficult to locate previous scans of the same patient within these datasets (a process known as re-identification). To address this issue, we propose an AI-powered medical imaging retrieval framework called DeepBrainPrint, which is designed to retrieve brain MRI scans of the same patient. Our framework is a semi-self-supervised contrastive deep learning approach with three main innovations. First, we use a combination of self-supervised and supervised paradigms to create an effective brain fingerprint from MRI scans that can be used for real-time image retrieval. Second, we use a special weighting function to guide the training and improve model convergence. Third, we introduce new imaging transformations to improve retrieval robustness in the presence of intensity variations (i.e. different scan contrasts), and to account for age and disease progression in patients. We tested DeepBrainPrint on a large dataset of T1-weighted brain MRIs from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and on a synthetic dataset designed to evaluate retrieval performance with different image modalities. Our results show that DeepBrainPrint outperforms previous methods, including simple similarity metrics and more advanced contrastive deep learning frameworks.

The brain-age gap is one of the most investigated risk markers for brain changes across disorders. While the field is progressing towards large-scale models, recently incorporating uncertainty estimates, no model to date provides the single-subject risk assessment capability essential for clinical application. In order to enable the clinical use of brain-age as a biomarker, we here combine uncertainty-aware deep Neural Networks with conformal prediction theory. This approach provides statistical guarantees with respect to single-subject uncertainty estimates and allows for the calculation of an individual's probability for accelerated brain-aging. Building on this, we show empirically in a sample of N=16,794 participants that 1. a lower or comparable error as state-of-the-art, large-scale brain-age models, 2. the statistical guarantees regarding single-subject uncertainty estimation indeed hold for every participant, and 3. that the higher individual probabilities of accelerated brain-aging derived from our model are associated with Alzheimer's Disease, Bipolar Disorder and Major Depressive Disorder. Comment: arXiv admin note: text overlap with arXiv:2107.07977

In recent years, the rapid development of artificial intelligence has promoted the widespread application of convolutional neural networks (CNNs) in neuroimaging analysis. Although three-dimensional (3D) CNNs can utilize the spatial information in 3D volumes, there are still some challenges related to high-dimensional features and potential overfitting issues. To overcome these problems, patch-based CNNs have been used, which are beneficial for model generalization. However, it is unclear how the choice of a patchwise sampling strategy affects the performance of the Alzheimer’s Disease (AD) classification. To this end, the present work investigates the impact of a patchwise sampling strategy for 3D CNN based AD classification. A 3D framework cascaded by two-stage subnetworks was used for AD classification. The patch-level subnetworks learned feature representations from local image patches, and the subject-level subnetwork combined discriminative feature representations from all patch-level subnetworks to generate a classification score at the subject level. Experiments were conducted to determine the effect of patch partitioning methods, the effect of patch size, and interactions between patch size and training set size for AD classification. With the same data size and identical network structure, the 3D CNN model trained with 48 × 48 × 48 cubic image patches showed the best performance in AD classification (ACC = 89.6%). The model trained with hippocampus-centered, region of interest (ROI)-based image patches showed suboptimal performance. If the pathological features are concentrated only in some regions affected by the disease, the empirically predefined ROI patches might be the right choice. The better performance of cubic image patches compared with cuboidal image patches is likely related to the pathological distribution of AD. The image patch size and training sample size together have a complex influence on the performance of the classification. The size of the image patches should be determined based on the size of the training sample to compensate for noisy labels and the problem of the curse of dimensionality. The conclusions of the present study can serve as a reference for the researchers who wish to develop a superior 3D patch-based CNN model with an appropriate patch sampling strategy.

This paper considers canonical correlation analysis for two longitudinal variables that are possibly sampled at different time resolutions with irregular grids. We modeled trajectories of the multivariate variables using random effects and found the most correlated sets of linear combinations in the latent space. Our numerical simulations showed that the longitudinal canonical correlation analysis effectively recovers underlying correlation patterns between two high-dimensional longitudinal data sets. We applied the proposed LCCA to data from the Alzheimer's Disease Neuroimaging Initiative and identified the longitudinal profiles of morphological brain changes and amyloid cumulation. Comment: 24 pages, 16 figures

The hippocampus is one of the most studied neuroanatomical structures due to its involvement in attention, learning, and memory as well as its atrophy in ageing, neurological, and psychiatric diseases. Hippocampal shape changes, however, are complex and cannot be fully characterized by a single summary metric such as hippocampal volume as determined from MR images. In this work, we propose an automated, geometry-based approach for the unfolding, point-wise correspondence, and local analysis of hippocampal shape features such as thickness and curvature. Starting from an automated segmentation of hippocampal subfields, we create a 3D tetrahedral mesh model as well as a 3D intrinsic coordinate system of the hippocampal body. From this coordinate system, we derive local curvature and thickness estimates as well as a 2D sheet for hippocampal unfolding. We evaluate the performance of our algorithm with a series of experiments to quantify neurodegenerative changes in Mild Cognitive Impairment and Alzheimer's disease dementia. We find that hippocampal thickness estimates detect known differences between clinical groups and can determine the location of these effects on the hippocampal sheet. Further, thickness estimates improve classification of clinical groups and cognitively unimpaired controls when added as an additional predictor. Comparable results are obtained with different datasets and segmentation algorithms. Taken together, we replicate canonical findings on hippocampal volume/shape changes in dementia, extend them by gaining insight into their spatial localization on the hippocampal sheet, and provide additional, complementary information beyond traditional measures. We provide a new set of sensitive processing and analysis tools for the analysis of hippocampal geometry that allows comparisons across studies without relying on image registration or requiring manual intervention. Comment: Updated to journal publication

Abstract Alzheimer's disease (AD) is a progressive neurodegenerative disorder. While resting state fMRI holds great promise in identification of diagnostic markers, how spatio-temporal dynamics of functional networks are reconfigured in AD remains elusive. We employed hidden Markov model to examine the time-resolved information of resting state fMRI data from Alzheimer's Disease Neuroimaging Initiative dataset. Two hundred and ninety-four participants well selected (23 with AD, 54 with mild cognitive impairment and 217 normal controls). We focused on the mean activation map which allows reliable measurement for statistical characteristics of spatial distribution of the latent states. At the time scale of seconds, we detected a 'baseline' state at which all the resting state networks had low activation levels. Moreover, AD patients tended to spend more time on this 'baseline' state and less time on the default mode network states than healthy elderly subjects. The prolonged latent 'baseline' state in AD probably reflects departure of the brain from criticality. Our findings provide important clues that help understand mechanisms underlying the reorganization of large-scale functional networks for AD.

Independence analysis is an indispensable step before regression analysis to find out essential factors that influence the objects. With many applications in machine Learning, medical Learning and a variety of disciplines, statistical methods of measuring the relationship between random variables have been well studied in vector spaces. However, there are few methods developed to verify the relation between random elements in metric spaces. In this paper, we present a novel index called metric distributional discrepancy (MDD) to measure the dependence between a random element $X$ and a categorical variable $Y$, which is applicable to the medical image and genetic data. The metric distributional discrepancy statistics can be considered as the distance between the conditional distribution of $X$ given each class of $Y$ and the unconditional distribution of $X$. MDD enjoys some significant merits compared to other dependence-measures. For instance, MDD is zero if and only if $X$ and $Y$ are independent. MDD test is a distribution-free test since there is no assumption on the distribution of random elements. Furthermore, MDD test is robust to the data with heavy-tailed distribution and potential outliers. We demonstrate the validity of our theory and the property of the MDD test by several numerical experiments and real data analysis. 14 pages, 2 figures

Covariate adjustment and methods of incorporating historical data in randomized clinical trials (RCTs) each provide opportunities to increase trial power. We unite these approaches for the analysis of RCTs with binary outcomes based on the Cochran-Mantel-Haenszel (CMH) test for marginal risk ratio (RR). In PROCOVA-CMH, subjects are stratified on a single prognostic covariate reflective of their predicted outcome on the control treatment (e.g. placebo). This prognostic score is generated based on baseline covariates through a model trained on historical data. We propose two closed-form prospective estimators for the asymptotic sampling variance of the log RR that rely only on values obtainable from observed historical outcomes and the prognostic model. Importantly, these estimators can be used to inform sample size during trial planning. PROCOVA-CMH demonstrates type I error control and appropriate asymptotic coverage for valid inference. Like other covariate adjustment methods, PROCOVA-CMH can reduce the variance of the treatment effect estimate when compared to an unadjusted (unstratified) CMH analysis. In addition to statistical methods, simulations and a case study in Alzheimer's Disease are given to demonstrate performance. Results show that PROCOVA-CMH can provide a gain in power, which can be used to conduct smaller trials. Comment: 18 pages, 11 tables, appendix

Abstract Introduction: Although machine learning classifiers have been frequently used to detect Alzheimer's disease (AD) based on structural brain MRI data, potential bias with respect to sex and age has not yet been addressed. Here, we examine a state-of-the-art AD classifier for potential sex and age bias even in the case of balanced training data. Methods: Based on an age- and sex-balanced cohort of 432 subjects (306 healthy controls, 126 subjects with AD) extracted from the ADNI data base, we trained a convolutional neural network to detect AD in MRI brain scans and performed ten different random training-validation-test splits to increase robustness of the results. Classifier decisions for single subjects were explained using layer-wise relevance propagation. Results: The classifier performed significantly better for women (balanced accuracy 87.58 ± 1.14%) than for men (79.05 ± 1.27%). No significant differences were found in clinical AD scores, ruling out a disparity in disease severity as a cause for the performance difference. Analysis of the explanations revealed a larger variance in regional brain areas for male subjects compared to female subjects. Discussion: The identified sex differences cannot be attributed to an imbalanced training dataset, and therefore point to the importance of examining and reporting classifier performance across population subgroups to increase transparency and algorithmic fairness. Collecting more data especially among underrepresented subgroups and balancing the dataset are important but do not always guarantee a fair outcome.