For precision medicine and personalized treatment, we need to identify predictive markers of disease. We focus on Alzheimer's disease (AD), where magnetic resonance imaging scans provide information about the disease status. By combining imaging with genome sequencing, we aim at identifying rare genetic markers associated with quantitative traits predicted from convolutional neural networks (CNNs), which traditionally have been derived manually by experts. Kernel-based tests are a powerful tool for associating sets of genetic variants, but how to optimally model rare genetic variants is still an open research question. We propose a generalized set of kernels that incorporate prior information from various annotations and multi-omics data. In the analysis of data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we evaluate whether (i) CNNs yield precise and reliable brain traits, and (ii) the novel kernel-based tests can help to identify loci associated with AD. The results indicate that CNNs provide a fast, scalable and precise tool to derive quantitative AD traits and that new kernels integrating domain knowledge can yield higher power in association tests of very rare variants.
Inter-subject registration of cortical areas is necessary in functional imaging (fMRI) studies for making inferences about equivalent brain function across a population. However, many high-level visual brain areas are defined as peaks of functional contrasts whose cortical position is highly variable. As such, most alignment methods fail to accurately map functional regions of interest (ROIs) across participants. To address this problem, we propose a locally optimized registration method that directly predicts the location of a seed ROI on a separate target cortical sheet by maximizing the functional correlation between their time courses, while simultaneously allowing for non-smooth local deformations in region topology. Our method outperforms the two most commonly used alternatives (anatomical landmark-based AFNI alignment and cortical convexity-based FreeSurfer alignment) in overlap between predicted region and functionally-defined LOC. Furthermore, the maps obtained using our method are more consistent across subjects than both baseline measures. Critically, our method represents an important step forward towards predicting brain regions without explicit localizer scans and deciphering the poorly understood relationship between the location of functional regions, their anatomical extent, and the consistency of computations those regions perform across people.
We introduce a wide and deep neural network for prediction of progression from patients with mild cognitive impairment to Alzheimer's disease. Information from anatomical shape and tabular clinical data (demographics, biomarkers) are fused in a single neural network. The network is invariant to shape transformations and avoids the need to identify point correspondences between shapes. To account for right censored time-to-event data, i.e., when it is only known that a patient did not develop Alzheimer's disease up to a particular time point, we employ a loss commonly used in survival analysis. Our network is trained end-to-end to combine information from a patient's hippocampus shape and clinical biomarkers. Our experiments on data from the Alzheimer's Disease Neuroimaging Initiative demonstrate that our proposed model is able to learn a shape descriptor that augments clinical biomarkers and outperforms a deep neural network on shape alone and a linear model on common clinical biomarkers.
Dai, Peng (University of Western Ontario) | Gwadry-Sridhar, Femida (University of Western Ontario) | Bauer, Michael (University of Western Ontario) | Borrie, Michael ( University of Western Ontario ) | Teng, Xue (Pulse Infoframe Inc.)
Alzheimer's disease (AD) is a genetically complex neurodegenerative disease, which leads to irreversible brain damage, severe cognitive problems and ultimately death. A number of clinical trials and study initiatives have been set up to investigate AD pathology, leading to large amounts of high dimensional heterogeneous data (biomarkers) for analysis. This paper focuses on combining clinical features from different modalities, including medical imaging, cerebrospinal fluid (CSF), etc., to diagnose AD and predict potential progression. Due to privacy and legal issues involved with clinical research, the study cohort (number of patients) is relatively small, compared to thousands of available biomarkers (predictors). We propose a hybrid pathological analysis model, which integrates manifold learning and Random Vector functional-link network (RVFL) so as to achieve better ability to extract discriminant information with limited training materials. Furthermore, we model (current and future) cognitive healthiness as a regression problem about age. By comparing the difference between predicted age and actual age, we manage to show statistical differences between different pathological stages. Verification tests are conducted based on the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Extensive comparison is made against different machine learning algorithms, i.e. Support Vector Machine (SVM), Random Forest (RF), Decision Tree and Multilayer Perceptron (MLP). Experimental results show that our proposed algorithm achieves better results than the comparison targets, which indicates promising robustness for practical clinical implementation.
Multiple modalities of biomarkers have been proved to be very sensitive in assessing the progression of Alzheimer's disease (AD), and using these modalities and machine learning algorithms, several approaches have been proposed to assist in the early diagnosis of AD. Among the recent investigated state-of-the-art approaches, Gaussian discriminant analysis (GDA)-based approaches have been demonstrated to be more effective and accurate in the classification of AD, especially for delineating its prodromal stage of mild cognitive impairment (MCI). Moreover, among those binary classification investigations, the local feature extraction methods were mostly used, which made them hardly be applied to a practical computer aided diagnosis system. Therefore, this study presents a novel global feature extraction model taking advantage of the recent proposed GDA-based dual high-dimensional decision spaces, which can significantly improve the early diagnosis performance comparing to those local feature extraction methods. In the true test using 20% held-out data, for discriminating the most challenging MCI group from the cognitively normal control (CN) group, an F1 score of 91.06%, an accuracy of 88.78%, a sensitivity of 91.80%, and a specificity of 83.78% were achieved that can be considered as the best performance obtained so far.