Sparse Multi-Response Tensor Regression for Alzheimer's Disease Study With Multivariate Clinical Assessments

Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder that has recently seen serious increase in the number of affected subjects. In the last decade, neuroimaging has been shown to be a useful tool to understand AD and its prodromal stage, amnestic mild cognitive impairment (MCI). The majority of AD/MCI studies have focused on disease diagnosis, by formulating the problem as classification with a binary outcome of AD/MCI or healthy controls. There have recently emerged studies that associate image scans with continuous clinical scores that are expected to contain richer information than a binary outcome. However, very few studies aim at modeling multiple clinical scores simultaneously, even though it is commonly conceived that multivariate outcomes provide correlated and complementary information about the disease pathology. In this article, we propose a sparse multi-response tensor regression method to model multiple outcomes jointly as well as to model multiple voxels of an image jointly. The proposed method is particularly useful to both infer clinical scores and thus disease diagnosis, and to identify brain subregions that are highly relevant to the disease outcomes. We conducted experiments on the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset, and showed that the proposed method enhances the performance and clearly outperforms the competing solutions

Predicting Future Clinical Changes of MCI Patients Using Longitudinal and Multimodal Biomarkers

Accurate prediction of clinical changes of mild cognitive impairment (MCI) patients, including both qualitative change (i.e., conversion to Alzheimer's disease (AD)) and quantitative change (i.e., cognitive scores) at future time points, is important for early diagnosis of AD and for monitoring the disease progression. In this paper, we propose to predict future clinical changes of MCI patients by using both baseline and longitudinal multimodality data. To do this, we first develop a longitudinal feature selection method to jointly select brain regions across multiple time points for each modality. Specifically, for each time point, we train a sparse linear regression model by using the imaging data and the corresponding clinical scores, with an extra ‘group regularization’ to group the weights corresponding to the same brain region across multiple time points together and to allow for selection of brain regions based on the strength of multiple time points jointly. Then, to further reflect the longitudinal changes on the selected brain regions, we extract a set of longitudinal features from the original baseline and longitudinal data. Finally, we combine all features on the selected brain regions, from different modalities, for prediction by using our previously proposed multi-kernel SVM. We validate our method on 88 ADNI MCI subjects, with both MRI and FDG-PET data and the corresponding clinical scores (i.e., MMSE and ADAS-Cog) at 5 different time points. We first predict the clinical scores (MMSE and ADAS-Cog) at 24-month by using the multimodality data at previous time points, and then predict the conversion of MCI to AD by using the multimodality data at time points which are at least 6-month ahead of the conversion. The results on both sets of experiments show that our proposed method can achieve better performance in predicting future clinical changes of MCI patients than the conventional methods

Temporally Constrained Group Sparse Learning for Longitudinal Data Analysis in Alzheimer's Disease

Sparse learning has been widely investigated for analysis of brain images to assist the diagnosis of Alzheimer’s disease (AD) and its prodromal stage, i.e., mild cognitive impairment (MCI). However, most existing sparse learning-based studies only adopt cross-sectional analysis methods, where the sparse model is learned using data from a single time-point. Actually, multiple time-points of data are often available in brain imaging applications, which can be used in some longitudinal analysis methods to better uncover the disease progression patterns. Accordingly, in this paper we propose a novel temporally-constrained group sparse learning method aiming for longitudinal analysis with multiple time-points of data. Specifically, we learn a sparse linear regression model by using the imaging data from multiple time-points, where a group regularization term is first employed to group the weights for the same brain region across different time-points together. Furthermore, to reflect the smooth changes between data derived from adjacent time-points, we incorporate two smoothness regularization terms into the objective function, i.e., one fused smoothness term which requires that the differences between two successive weight vectors from adjacent time-points should be small, and another output smoothness term which requires the differences between outputs of two successive models from adjacent time-points should also be small. We develop an efficient optimization algorithm to solve the proposed objective function. Experimental results on ADNI database demonstrate that, compared with conventional sparse learning-based methods, our proposed method can achieve improved regression performance and also help in discovering disease-related biomarkers

Decoding Continuous Variables from Neuroimaging Data: Basic and Clinical Applications

The application of statistical machine learning techniques to neuroimaging data has allowed researchers to decode the cognitive and disease states of participants. The majority of studies using these techniques have focused on pattern classification to decode the type of object a participant is viewing, the type of cognitive task a participant is completing, or the disease state of a participant's brain. However, an emerging body of literature is extending these classification studies to the decoding of values of continuous variables (such as age, cognitive characteristics, or neuropsychological state) using high-dimensional regression methods. This review details the methods used in such analyses and describes recent results. We provide specific examples of studies which have used this approach to answer novel questions about age and cognitive and disease states. We conclude that while there is still much to learn about these methods, they provide useful information about the relationship between neural activity and age, cognitive state, and disease state, which could not have been obtained using traditional univariate analytical methods

Longitudinal clinical score prediction in Alzheimer's disease with soft-split sparse regression based random forest

Alzheimer’s disease (AD) is an irreversible neurodegenerative disease and affects a large population in the world. Cognitive scores at multiple time points can be reliably used to evaluate the progression of the disease clinically. In recent studies, machine learning techniques have shown promising results on the prediction of AD clinical scores. However, there are multiple limitations in the current models such as linearity assumption and missing data exclusion. Here, we present a nonlinear supervised sparse regression–based random forest (RF) framework to predict a variety of longitudinal AD clinical scores. Furthermore, we propose a soft-split technique to assign probabilistic paths to a test sample in RF for more accurate predictions. In order to benefit from the longitudinal scores in the study, unlike the previous studies that often removed the subjects with missing scores, we first estimate those missing scores with our proposed soft-split sparse regression–based RF and then utilize those estimated longitudinal scores at all the previous time points to predict the scores at the next time point. The experiment results demonstrate that our proposed method is superior to the traditional RF and outperforms other state-of-art regression models. Our method can also be extended to be a general regression framework to predict other disease scores

A novel matrix-similarity based loss function for joint regression and classification in AD diagnosis

Recent studies on AD/MCI diagnosis have shown that the tasks of identifying brain disease and predicting clinical scores are highly related to each other. Furthermore, it has been shown that feature selection with a manifold learning or a sparse model can handle the problems of high feature dimensionality and small sample size. However, the tasks of clinical score regression and clinical label classification were often conducted separately in the previous studies. Regarding the feature selection, to our best knowledge, most of the previous work considered a loss function defined as an element-wise difference between the target values and the predicted ones. In this paper, we consider the problems of joint regression and classification for AD/MCI diagnosis and propose a novel matrix-similarity based loss function that uses high-level information inherent in the target response matrix and imposes the information to be preserved in the predicted response matrix. The newly devised loss function is combined with a group lasso method for joint feature selection across tasks, i.e., predictions of clinical scores and a class label. In order to validate the effectiveness of the proposed method, we conducted experiments on the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset, and showed that the newly devised loss function helped enhance the performances of both clinical score prediction and disease status identification, outperforming the state-of-the-art methods

Relating one-year cognitive change in mild cognitive impairment to baseline MRI features

Background: We propose a completely automated methodology to investigate the relationship between magnetic resonance image (MRI) features and changes in cognitive estimates, applied to the study of MiniMental State Examination (MMSE) changes in mild cognitive impairment (MCI). Subjects: A reference group composed of 75 patients with clinically probable Alzheimer's Disease (AD) and 75 age-matched controls; and a study group composed of 49 MCI, 20 having progressed to clinically probable AD and 29 having remained stable after a 48 month follow-up. Methods: We created a pathology-specific reference space using principal component analysis of MRI-based features (intensity, local volume changes) within the medial temporal lobe of T1-weighted baseline images for the reference group. We projected similar data from the study group and identified a restricted set of image features highly correlated with one-year change in MMSE, using a bootstrap sampling estimation. We used robust linear regression models to predict one-year MMSE changes from baseline MRI, baseline MMSE, age, gender, and years of education. Results: All experiments were performed using a leave-one-out paradigm. We found multiple image-based features highly correlated with one-year MMSE changes (|r|N0.425). The model for all N= 49 MCI subjects had a correlation of r= 0.31 between actual and predicted one-year MMSE change values. A second model only for MCI subjects with MMSE loss larger than 1 U had a pairwise correlation r= 0.80 with an adjusted coefficient of determination r 2= 0.61. Findings: Our automated MRI-based technique revealed a strong relationship between baseline MRI features and one-year cognitive changes in a sub-group of MCI subjects. This technique should be generalized to other aspects of cognitive evaluation and to a wider scope of dementias

Quantifying anatomical shape variations in neurological disorders

We develop a multivariate analysis of brain anatomy to identify the relevant shape deformation patterns and quantify the shape changes that explain corresponding variations in clinical neuropsychological measures. We use kernel Partial Least Squares (PLS) and formulate a regression model in the tangent space of the manifold of diffeomorphisms characterized by deformation momenta. The scalar deformation momenta completely encode the diffeomorphic changes in anatomical shape. In this model, the clinical measures are the response variables, while the anatomical variability is treated as the independent variable. To better understand the “shape—clinical response” relationship, we also control for demographic confounders, such as age, gender, and years of education in our regression model. We evaluate the proposed methodology on the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database using baseline structural MR imaging data and neuropsychological evaluation test scores. We demonstrate the ability of our model to quantify the anatomical deformations in units of clinical response. Our results also demonstrate that the proposed method is generic and generates reliable shape deformations both in terms of the extracted patterns and the amount of shape changes. We found that while the hippocampus and amygdala emerge as mainly responsible for changes in test scores for global measures of dementia and memory function, they are not a determinant factor for executive function. Another critical finding was the appearance of thalamus and putamen as most important regions that relate to executive function. These resulting anatomical regions were consistent with very high confidence irrespective of the size of the population used in the study. This data-driven global analysis of brain anatomy was able to reach similar conclusions as other studies in Alzheimer’s Disease based on predefined ROIs, together with the identification of other new patterns of deformation. The proposed methodology thus holds promise for discovering new patterns of shape changes in the human brain that could add to our understanding of disease progression in neurological disorders