BrainGNN: Interpretable Brain Graph Neural Network for fMRI Analysis.

Understanding which brain regions are related to a specific neurological disorder or cognitive stimuli has been an important area of neuroimaging research. We propose BrainGNN, a graph neural network (GNN) framework to analyze functional magnetic resonance images (fMRI) and discover neurological biomarkers. Considering the special property of brain graphs, we design novel ROI-aware graph convolutional (Ra-GConv) layers that leverage the topological and functional information of fMRI. Motivated by the need for transparency in medical image analysis, our BrainGNN contains ROI-selection pooling layers (R-pool) that highlight salient ROIs (nodes in the graph), so that we can infer which ROIs are important for prediction. Furthermore, we propose regularization terms-unit loss, topK pooling (TPK) loss and group-level consistency (GLC) loss-on pooling results to encourage reasonable ROI-selection and provide flexibility to encourage either fully individual- or patterns that agree with group-level data. We apply the BrainGNN framework on two independent fMRI datasets: an Autism Spectrum Disorder (ASD) fMRI dataset and data from the Human Connectome Project (HCP) 900 Subject Release. We investigate different choices of the hyper-parameters and show that BrainGNN outperforms the alternative fMRI image analysis methods in terms of four different evaluation metrics. The obtained community clustering and salient ROI detection results show a high correspondence with the previous neuroimaging-derived evidence of biomarkers for ASD and specific task states decoded for HCP. Our code is available at https://github.com/xxlya/BrainGNN_Pytorch.

Neuropsychiatric disease classification using functional connectomics - results of the connectomics in neuroimaging transfer learning challenge.

Large, open-source datasets, such as the Human Connectome Project and the Autism Brain Imaging Data Exchange, have spurred the development of new and increasingly powerful machine learning approaches for brain connectomics. However, one key question remains: are we capturing biologically relevant and generalizable information about the brain, or are we simply overfitting to the data? To answer this, we organized a scientific challenge, the Connectomics in NeuroImaging Transfer Learning Challenge (CNI-TLC), held in conjunction with MICCAI 2019. CNI-TLC included two classification tasks: (1) diagnosis of Attention-Deficit/Hyperactivity Disorder (ADHD) within a pre-adolescent cohort; and (2) transference of the ADHD model to a related cohort of Autism Spectrum Disorder (ASD) patients with an ADHD comorbidity. In total, 240 resting-state fMRI (rsfMRI) time series averaged according to three standard parcellation atlases, along with clinical diagnosis, were released for training and validation (120 neurotypical controls and 120 ADHD). We also provided Challenge participants with demographic information of age, sex, IQ, and handedness. The second set of 100 subjects (50 neurotypical controls, 25 ADHD, and 25 ASD with ADHD comorbidity) was used for testing. Classification methodologies were submitted in a standardized format as containerized Docker images through ChRIS, an open-source image analysis platform. Utilizing an inclusive approach, we ranked the methods based on 16 metrics: accuracy, area under the curve, F1-score, false discovery rate, false negative rate, false omission rate, false positive rate, geometric mean, informedness, markedness, Matthew's correlation coefficient, negative predictive value, optimized precision, precision, sensitivity, and specificity. The final rank was calculated using the rank product for each participant across all measures. Furthermore, we assessed the calibration curves of each methodology. Five participants submitted their method for evaluation, with one outperforming all other methods in both ADHD and ASD classification. However, further improvements are still needed to reach the clinical translation of functional connectomics. We have kept the CNI-TLC open as a publicly available resource for developing and validating new classification methodologies in the field of connectomics.

Adaptive Checkpoint Adjoint Method for Gradient Estimation in Neural ODE.

Neural ordinary differential equations (NODEs) have recently attracted increasing attention; however, their empirical performance on benchmark tasks (e.g. image classification) are significantly inferior to discrete-layer models. We demonstrate an explanation for their poorer performance is the inaccuracy of existing gradient estimation methods: the adjoint method has numerical errors in reverse-mode integration; the naive method directly back-propagates through ODE solvers, but suffers from a redundantly deep computation graph when searching for the optimal stepsize. We propose the Adaptive Checkpoint Adjoint (ACA) method: in automatic differentiation, ACA applies a trajectory checkpoint strategy which records the forward-mode trajectory as the reverse-mode trajectory to guarantee accuracy; ACA deletes redundant components for shallow computation graphs; and ACA supports adaptive solvers. On image classification tasks, compared with the adjoint and naive method, ACA achieves half the error rate in half the training time; NODE trained with ACA outperforms ResNet in both accuracy and test-retest reliability. On time-series modeling, ACA outperforms competing methods. Finally, in an example of the three-body problem, we show NODE with ACA can incorporate physical knowledge to achieve better accuracy. We provide the PyTorch implementation of ACA: https://github.com/juntang-zhuang/torch-ACA.

Demographic-Guided Attention in Recurrent Neural Networks for Modeling Neuropathophysiological Heterogeneity.

Heterogeneous presentation of a neurological disorder suggests potential differences in the underlying pathophysiological changes that occur in the brain. We propose to model heterogeneous patterns of functional network differences using a demographic-guided attention (DGA) mechanism for recurrent neural network models for prediction from functional magnetic resonance imaging (fMRI) time-series data. The context computed from the DGA head is used to help focus on the appropriate functional networks based on individual demographic information. We demonstrate improved classification on 3 subsets of the ABIDE I dataset used in published studies that have previously produced state-of-the-art results, evaluating performance under a leave-one-site-out cross-validation framework for better generalizeability to new data. Finally, we provide examples of interpreting functional network differences based on individual demographic variables.

Graph Embedding Using Infomax for ASD Classification and Brain Functional Difference Detection.

Significant progress has been made using fMRI to characterize the brain changes that occur in ASD, a complex neuro-developmental disorder. However, due to the high dimensionality and low signal-to-noise ratio of fMRI, embedding informative and robust brain regional fMRI representations for both graph-level classification and region-level functional difference detection tasks between ASD and healthy control (HC) groups is difficult. Here, we model the whole brain fMRI as a graph, which preserves geometrical and temporal information and use a Graph Neural Network (GNN) to learn from the graph-structured fMRI data. We investigate the potential of including mutual information (MI) loss (Infomax), which is an unsupervised term encouraging large MI of each nodal representation and its corresponding graph-level summarized representation to learn a better graph embedding. Specifically, this work developed a pipeline including a GNN encoder, a classifier and a discriminator, which forces the encoded nodal representations to both benefit classification and reveal the common nodal patterns in a graph. We simultaneously optimize graph-level classification loss and Infomax. We demonstrated that Infomax graph embedding improves classification performance as a regularization term. Furthermore, we found separable nodal representations of ASD and HC groups in prefrontal cortex, cingulate cortex, visual regions, and other social, emotional and execution related brain regions. In contrast with GNN with classification loss only, the proposed pipeline can facilitate training more robust ASD classification models. Moreover, the separable nodal representations can detect the functional differences between the two groups and contribute to revealing new ASD biomarkers.

Pooling Regularized Graph Neural Network for fMRI Biomarker Analysis.

Understanding how certain brain regions relate to a specific neurological disorder has been an important area of neuroimaging research. A promising approach to identify the salient regions is using Graph Neural Networks (GNNs), which can be used to analyze graph structured data, e.g. brain networks constructed by functional magnetic resonance imaging (fMRI). We propose an interpretable GNN framework with a novel salient region selection mechanism to determine neurological brain biomarkers associated with disorders. Specifically, we design novel regularized pooling layers that highlight salient regions of interests (ROIs) so that we can infer which ROIs are important to identify a certain disease based on the node pooling scores calculated by the pooling layers. Our proposed framework, Pooling Regularized-GNN (PR-GNN), encourages reasonable ROI-selection and provides flexibility to preserve either individual- or group-level patterns. We apply the PR-GNN framework on a Biopoint Autism Spectral Disorder (ASD) fMRI dataset. We investigate different choices of the hyperparameters and show that PR-GNN outperforms baseline methods in terms of classification accuracy. The salient ROI detection results show high correspondence with the previous neuroimaging-derived biomarkers for ASD.

Jointly Discriminative and Generative Recurrent Neural Networks for Learning from fMRI.

Recurrent neural networks (RNNs) were designed for dealing with time-series data and have recently been used for creating predictive models from functional magnetic resonance imaging (fMRI) data. However, gathering large fMRI datasets for learning is a difficult task. Furthermore, network interpretability is unclear. To address these issues, we utilize multitask learning and design a novel RNN-based model that learns to discriminate between classes while simultaneously learning to generate the fMRI time-series data. Employing the long short-term memory (LSTM) structure, we develop a discriminative model based on the hidden state and a generative model based on the cell state. The addition of the generative model constrains the network to learn functional communities represented by the LSTM nodes that are both consistent with the data generation as well as useful for the classification task. We apply our approach to the classification of subjects with autism vs. healthy controls using several datasets from the Autism Brain Imaging Data Exchange. Experiments show that our jointly discriminative and generative model improves classification learning while also producing robust and meaningful functional communities for better model understanding.

Efficient Interpretation of Deep Learning Models Using Graph Structure and Cooperative Game Theory: Application to ASD Biomarker Discovery.

Discovering imaging biomarkers for autism spectrum disorder (ASD) is critical to help explain ASD and predict or monitor treatment outcomes. Toward this end, deep learning classifiers have recently been used for identifying ASD from functional magnetic resonance imaging (fMRI) with higher accuracy than traditional learning strategies. However, a key challenge with deep learning models is understanding just what image features the network is using, which can in turn be used to define the biomarkers. Current methods extract biomarkers, i.e., important features, by looking at how the prediction changes if "ignoring" one feature at a time. However, this can lead to serious errors if the features are conditionally dependent. In this work, we go beyond looking at only individual features by using Shapley value explanation (SVE) from cooperative game theory. Cooperative game theory is advantageous here because it directly considers the interaction between features and can be applied to any machine learning method, making it a novel, more accurate way of determining instance-wise biomarker importance from deep learning models. A barrier to using SVE is its computational complexity: 2 N given N features. We explicitly reduce the complexity of SVE computation by two approaches based on the underlying graph structure of the input data: 1) only consider the centralized coalition of each feature; 2) a hierarchical pipeline which first clusters features into small communities, then applies SVE in each community. Monte Carlo approximation can be used for large permutation sets. We first validate our methods on the MNIST dataset and compare to human perception. Next, to insure plausibility of our biomarker results, we train a Random Forest (RF) to classify ASD/control subjects from fMRI and compare SVE results to standard RF-based feature importance. Finally, we show initial results on ranked fMRI biomarkers using SVE on a deep learning classifier for the ASD/control dataset.

Graph Neural Network for Interpreting Task-fMRI Biomarkers.

Finding the biomarkers associated with ASD is helpful for understanding the underlying roots of the disorder and can lead to earlier diagnosis and more targeted treatment. A promising approach to identify biomarkers is using Graph Neural Networks (GNNs), which can be used to analyze graph structured data, i.e. brain networks constructed by fMRI. One way to interpret important features is through looking at how the classification probability changes if the features are occluded or replaced. The major limitation of this approach is that replacing values may change the distribution of the data and lead to serious errors. Therefore, we develop a 2-stage pipeline to eliminate the need to replace features for reliable biomarker interpretation. Specifically, we propose an inductive GNN to embed the graphs containing different properties of task-fMRI for identifying ASD and then discover the brain regions/sub-graphs used as evidence for the GNN classifier. We first show GNN can achieve high accuracy in identifying ASD. Next, we calculate the feature importance scores using GNN and compare the interpretation ability with Random Forest. Finally, we run with different atlases and parameters, proving the robustness of the proposed method. The detected biomarkers reveal their association with social behaviors and are consistent with those reported in the literature. We also show the potential of discovering new informative biomarkers. Our pipeline can be generalized to other graph feature importance interpretation problems.

Decision Explanation and Feature Importance for Invertible Networks.

Deep neural networks are vulnerable to adversarial attacks and hard to interpret because of their black-box nature. The recently proposed invertible network is able to accurately reconstruct the inputs to a layer from its outputs, thus has the potential to unravel the black-box model. An invertible network classifier can be viewed as a two-stage model: (1) invertible transformation from input space to the feature space; (2) a linear classifier in the feature space. We can determine the decision boundary of a linear classifier in the feature space; since the transform is invertible, we can invert the decision boundary from the feature space to the input space. Furthermore, we propose to determine the projection of a data point onto the decision boundary, and define explanation as the difference between data and its projection. Finally, we propose to locally approximate a neural network with its first-order Taylor expansion, and define feature importance using a local linear model. We provide the implementation of our method: https://github.com/juntang-zhuang/explain_invertible.

PREDICTION OF TREATMENT OUTCOME FOR AUTISM FROM STRUCTURE OF THE BRAIN BASED ON SURE INDEPENDENCE SCREENING.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder, and behavioral treatment interventions have shown promise for young children with ASD. However, there is limited progress in understanding the effect of each type of treatment. In this project, we aim to detect structural changes in the brain after treatment and select structural features associated with treatment outcomes. The difficulty in building large databases of patients who have received specific treatments and the high dimensionality of medical image analysis problems are the challenges in this work. To select predictive features and build accurate models, we use the sure independence screening (SIS) method. SIS is a theoretically and empirically validated method for ultra-high dimensional general linear models, and it achieves both predictive accuracy and correct feature selection by iterative feature selection. Compared with step-wise feature selection methods, SIS removes multiple features in each iteration and is computationally efficient. Compared with other linear models such as elastic-net regression, support vector regression (SVR) and partial least squares regression (PSLR), SIS achieves higher accuracy. We validated the superior performance of SIS in various experiments: First, we extract brain structural features from FreeSurfer, including cortical thickness, surface area, mean curvature and cortical volume. Next, we predict different measures of treatment outcomes based on structural features. We show that SIS achieves the highest correlation between prediction and measurements in all tasks. Furthermore, we report regions selected by SIS as biomarkers for ASD.

Invertible Network for Classification and Biomarker Selection for ASD.

Determining biomarkers for autism spectrum disorder (ASD) is crucial to understanding its mechanisms. Recently deep learning methods have achieved success in the classification task of ASD using fMRI data. However, due to the black-box nature of most deep learning models, it's hard to perform biomarker selection and interpret model decisions. The recently proposed invertible networks can accurately reconstruct the input from its output, and have the potential to unravel the black-box representation. Therefore, we propose a novel method to classify ASD and identify biomarkers for ASD using the connectivity matrix calculated from fMRI as the input. Specifically, with invertible networks, we explicitly determine the decision boundary and the projection of data points onto the boundary. Like linear classifiers, the difference between a point and its projection onto the decision boundary can be viewed as the explanation. We then define the importance as the explanation weighted by the gradient of prediction w.r.t the input, and identify biomarkers based on this importance measure. We perform a regression task to further validate our biomarker selection: compared to using all edges in the connectivity matrix, using the top 10% important edges we generate a lower regression error on 6 different severity scores. Our experiments show that the invertible network is both effective at ASD classification and interpretable, allowing for discovery of reliable biomarkers.

Domain-Agnostic Learning with Anatomy-Consistent Embedding for Cross-Modality Liver Segmentation.

Domain Adaptation (DA) has the potential to greatly help the generalization of deep learning models. However, the current literature usually assumes to transfer the knowledge from the source domain to a specific known target domain. Domain Agnostic Learning (DAL) proposes a new task of transferring knowledge from the source domain to data from multiple heterogeneous target domains. In this work, we propose the Domain-Agnostic Learning framework with Anatomy-Consistent Embedding (DALACE) that works on both domain-transfer and task-transfer to learn a disentangled representation, aiming to not only be invariant to different modalities but also preserve anatomical structures for the DA and DAL tasks in cross-modality liver segmentation. We validated and compared our model with state-of-the-art methods, including CycleGAN, Task Driven Generative Adversarial Network (TD-GAN), and Domain Adaptation via Disentangled Representations (DADR). For the DA task, our DALACE model outperformed CycleGAN, TD-GAN, and DADR with DSC of 0.847 compared to 0.721, 0.793 and 0.806. For the DAL task, our model improved the performance with DSC of 0.794 from 0.522, 0.719 and 0.742 by CycleGAN, TD-GAN, and DADR. Further, we visualized the success of disentanglement, which added human interpretability of the learned meaningful representations. Through ablation analysis, we specifically showed the concrete benefits of disentanglement for downstream tasks and the role of supervision for better disentangled representation with segmentation consistency to be invariant to domains with the proposed Domain-Agnostic Module (DAM) and to preserve anatomical information with the proposed Anatomy-Preserving Module (APM).

Brain Biomarker Interpretation in ASD Using Deep Learning and fMRI.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder. Finding the biomarkers associated with ASD is extremely helpful to understand the underlying roots of the disorder and can lead to earlier diagnosis and more targeted treatment. Although Deep Neural Networks (DNNs) have been applied in functional magnetic resonance imaging (fMRI) to identify ASD, understanding the data driven computational decision making procedure has not been previously explored. Therefore, in this work, we address the problem of interpreting reliable biomarkers associated with identifying ASD; specifically, we propose a 2-stage method that classifies ASD and control subjects using fMRI images and interprets the saliency features activated by the classifier. First, we trained an accurate DNN classifier. Then, for detecting the biomarkers, different from the DNN visualization works in computer vision, we take advantage of the anatomical structure of brain fMRI and develop a frequency-normalized sampling method to corrupt images. Furthermore, in the ASD vs. control subjects classification scenario, we provide a new approach to detect and characterize important brain features into three categories. The biomarkers we found by the proposed method are robust and consistent with previous findings in the literature. We also validate the detected biomarkers by neurological function decoding and comparing with the DNN activation maps.

Prediction of severity and treatment outcome for ASD from fMRI.

Autism spectrum disorder (ASD) is a complex neurodevelop-mental syndrome. Early diagnosis and precise treatment are essential for ASD patients. Although researchers have built many analytical models, there has been limited progress in accurate predictive models for early diagnosis. In this project, we aim to build an accurate model to predict treatment outcome and ASD severity from early stage functional magnetic resonance imaging (fMRI) scans. The difficulty in building large databases of patients who have received specific treatments and the high dimensionality of medical image analysis problems are challenges in this work. We propose a generic and accurate two-level approach for high-dimensional regression problems in medical image analysis. First, we perform region-level feature selection using a predefined brain parcellation. Based on the assumption that voxels within one region in the brain have similar values, for each region we use the bootstrapped mean of voxels within it as a feature. In this way, the dimension of data is reduced from number of voxels to number of regions. Then we detect predictive regions by various feature selection methods. Second, we extract voxels within selected regions, and perform voxel-level feature selection. To use this model in both linear and non-linear cases with limited training examples, we apply two-level elastic net regression and random forest (RF) models respectively. To validate accuracy and robustness of this approach, we perform experiments on both task-fMRI and resting state fMRI datasets. Furthermore, we visualize the influence of each region, and show that the results match well with other findings.

2-CHANNEL CONVOLUTIONAL 3D DEEP NEURAL NETWORK (2CC3D) FOR FMRI ANALYSIS: ASD CLASSIFICATION AND FEATURE LEARNING.

In this paper, we propose a new whole brain fMRI-analysis scheme to identify autism spectrum disorder (ASD) and explore biological markers in ASD classification. To utilize both spatial and temporal information in fMRI, our method investigates the potential benefits of using a sliding window over time to measure temporal statistics (mean and standard deviation) and using 3D convolutional neural networks (CNNs) to capture spatial features. The sliding window created 2-channel images, which were used as inputs to the 3D CNN. From the outputs of the 3D CNN convolutional layers, ASD related fMRI spatial features were directly deciphered. Input formats and sliding window parameters were investigated in our study. The power of aligning 2-channel images was shown in our proposed method. Compared with traditional machine learning classification models, our proposed 2CC3D method increased mean F-scores over 8.5%.

PREDICTION OF PIVOTAL RESPONSE TREATMENT OUTCOME WITH TASK FMRI USING RANDOM FOREST AND VARIABLE SELECTION.

Behavior intervention has shown promise for treatment for young children with autism spectrum disorder (ASD). However, current therapeutic decisions are based on trial and error, often leading to suboptimal outcomes. We propose an approach that employs task-based fMRI for early outcome prediction. Our strategy is based on the general linear model (GLM) and a random forest, combined with feature selection techniques. GLM analysis is performed on each voxel to get t-statistic of contrast between two tasks. Due to the high dimensionality of predictor variables, feature selection is crucial for accurate prediction. Thus we propose a two-step feature selection method: a "shadow" method to select all-relevant variables, followed by a stepwise method to select minimal-optimal set of variables for prediction. A few columns of random noise are generated and added as shadow variables. Regression based on the random forest is performed, and permutation importance of each variable is estimated. Candidate voxels with higher importance than the shadow are kept. Surviving voxels are fed into stepwise variable selection methods. We test both forward and backward stepwise selection. Our method was validated on a dataset of 20 children with ASD using leave-one-out cross-validation, and compared to other standard regression methods. The proposed pipeline generated highest accuracy.