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Batch Normalization (BN) and its variants have delivered tremendous success in combating the covariate shift induced by the training step of deep learning methods. While these techniques normalize feature distributions by standardizing with batch statistics, they do not correct the influence on features from extraneous variables or multiple distributions. Such extra variables, referred to as metadata here, may create bias or confounding effects (e.g., race when classifying gender from face images). We introduce the Metadata Normalization (MDN) layer, a new batch-level operation which can be used end-to-end within the training framework, to correct the influence of metadata on feature distributions. MDN adopts a regression analysis technique traditionally used for preprocessing to remove (regress out) the metadata effects on model features during training. We utilize a metric based on distance correlation to quantify the distribution bias from the metadata and demonstrate that our method successfully removes metadata effects on four diverse settings: one synthetic, one 2D image, one video, and one 3D medical image dataset., Comment: Accepted to CVPR 2021. Project page: https://mml.stanford.edu/MDN/

Longitudinal MRIs are often used to capture the gradual deterioration of brain structure and function caused by aging or neurological diseases. Analyzing this data via machine learning generally requires a large number of ground-truth labels, which are often missing or expensive to obtain. Reducing the need for labels, we propose a self-supervised strategy for representation learning named Longitudinal Neighborhood Embedding (LNE). Motivated by concepts in contrastive learning, LNE explicitly models the similarity between trajectory vectors across different subjects. We do so by building a graph in each training iteration defining neighborhoods in the latent space so that the progression direction of a subject follows the direction of its neighbors. This results in a smooth trajectory field that captures the global morphological change of the brain while maintaining the local continuity. We apply LNE to longitudinal T1w MRIs of two neuroimaging studies: a dataset composed of 274 healthy subjects, and Alzheimer's Disease Neuroimaging Initiative (ADNI, N=632). The visualization of the smooth trajectory vector field and superior performance on downstream tasks demonstrate the strength of the proposed method over existing self-supervised methods in extracting information associated with normal aging and in revealing the impact of neurodegenerative disorders. The code is available at \url{https://github.com/ouyangjiahong/longitudinal-neighbourhood-embedding.git}., Comment: Provisional Accepted by Medical Image Computing and Computer Assisted Intervention (MICCAI) 2021

Multi-modal MRIs are widely used in neuroimaging applications since different MR sequences provide complementary information about brain structures. Recent works have suggested that multi-modal deep learning analysis can benefit from explicitly disentangling anatomical (shape) and modality (appearance) information into separate image presentations. In this work, we challenge mainstream strategies by showing that they do not naturally lead to representation disentanglement both in theory and in practice. To address this issue, we propose a margin loss that regularizes the similarity in relationships of the representations across subjects and modalities. To enable robust training, we further use a conditional convolution to design a single model for encoding images of all modalities. Lastly, we propose a fusion function to combine the disentangled anatomical representations as a set of modality-invariant features for downstream tasks. We evaluate the proposed method on three multi-modal neuroimaging datasets. Experiments show that our proposed method can achieve superior disentangled representations compared to existing disentanglement strategies. Results also indicate that the fused anatomical representation has potential in the downstream task of zero-dose PET reconstruction and brain tumor segmentation. The code is available at \url{https://github.com/ouyangjiahong/representation-disentanglement}., Comment: Accepted by Information Processing in Medical Imaging (IPMI) 2021

Interpretability is a critical factor in applying complex deep learning models to advance the understanding of brain disorders in neuroimaging studies. To interpret the decision process of a trained classifier, existing techniques typically rely on saliency maps to quantify the voxel-wise or feature-level importance for classification through partial derivatives. Despite providing some level of localization, these maps are not human-understandable from the neuroscience perspective as they do not inform the specific meaning of the alteration linked to the brain disorder. Inspired by the image-to-image translation scheme, we propose to train simulator networks that can warp a given image to inject or remove patterns of the disease. These networks are trained such that the classifier produces consistently increased or decreased prediction logits for the simulated images. Moreover, we propose to couple all the simulators into a unified model based on conditional convolution. We applied our approach to interpreting classifiers trained on a synthetic dataset and two neuroimaging datasets to visualize the effect of the Alzheimer's disease and alcohol use disorder. Compared to the saliency maps generated by baseline approaches, our simulations and visualizations based on the Jacobian determinants of the warping field reveal meaningful and understandable patterns related to the diseases.

Parkinson's disease (PD) is a progressive neurological disorder primarily affecting motor function resulting in tremor at rest, rigidity, bradykinesia, and postural instability. The physical severity of PD impairments can be quantified through the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), a widely used clinical rating scale. Accurate and quantitative assessment of disease progression is critical to developing a treatment that slows or stops further advancement of the disease. Prior work has mainly focused on dopamine transport neuroimaging for diagnosis or costly and intrusive wearables evaluating motor impairments. For the first time, we propose a computer vision-based model that observes non-intrusive video recordings of individuals, extracts their 3D body skeletons, tracks them through time, and classifies the movements according to the MDS-UPDRS gait scores. Experimental results show that our proposed method performs significantly better than chance and competing methods with an F1-score of 0.83 and a balanced accuracy of 81%. This is the first benchmark for classifying PD patients based on MDS-UPDRS gait severity and could be an objective biomarker for disease severity. Our work demonstrates how computer-assisted technologies can be used to non-intrusively monitor patients and their motor impairments. The code is available at https://github.com/mlu355/PD-Motor-Severity-Estimation., Comment: Accepted as a conference paper at MICCAI (Medical Image Computing and Computer Assisted Intervention), Lima, Peru, October 2020. 11 pages, LaTeX

Machine learning analysis of longitudinal neuroimaging data is typically based on supervised learning, which requires a large number of ground-truth labels to be informative. As ground-truth labels are often missing or expensive to obtain in neuroscience, we avoid them in our analysis by combing factor disentanglement with self-supervised learning to identify changes and consistencies across the multiple MRIs acquired of each individual over time. Specifically, we propose a new definition of disentanglement by formulating a multivariate mapping between factors (e.g., brain age) associated with an MRI and a latent image representation. Then, factors that evolve across acquisitions of longitudinal sequences are disentangled from that mapping by self-supervised learning in such a way that changes in a single factor induce change along one direction in the representation space. We implement this model, named Longitudinal Self-Supervised Learning (LSSL), via a standard autoencoding structure with a cosine loss to disentangle brain age from the image representation. We apply LSSL to two longitudinal neuroimaging studies to highlight its strength in extracting the brain-age information from MRI and revealing informative characteristics associated with neurodegenerative and neuropsychological disorders. Moreover, the representations learned by LSSL facilitate supervised classification by recording faster convergence and higher (or similar) prediction accuracy compared to several other representation learning techniques.

Many neurological diseases are characterized by gradual deterioration of brain structure and function. Large longitudinal MRI datasets have revealed such deterioration, in part, by applying machine and deep learning to predict diagnosis. A popular approach is to apply Convolutional Neural Networks (CNN) to extract informative features from each visit of the longitudinal MRI and then use those features to classify each visit via Recurrent Neural Networks (RNNs). Such modeling neglects the progressive nature of the disease, which may result in clinically implausible classifications across visits. To avoid this issue, we propose to combine features across visits by coupling feature extraction with a novel longitudinal pooling layer and enforce consistency of the classification across visits in line with disease progression. We evaluate the proposed method on the longitudinal structural MRIs from three neuroimaging datasets: Alzheimer's Disease Neuroimaging Initiative (ADNI, N=404), a dataset composed of 274 normal controls and 329 patients with Alcohol Use Disorder (AUD), and 255 youths from the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA). In all three experiments our method is superior to other widely used approaches for longitudinal classification thus making a unique contribution towards more accurate tracking of the impact of conditions on the brain. The code is available at https://github.com/ouyangjiahong/longitudinal-pooling., Comment: Accepted by Journal of Biomedical and Health Informatics (JBHI)

The Blood-Oxygen-Level-Dependent (BOLD) signal of resting-state fMRI (rs-fMRI) records the temporal dynamics of intrinsic functional networks in the brain. However, existing deep learning methods applied to rs-fMRI either neglect the functional dependency between different brain regions in a network or discard the information in the temporal dynamics of brain activity. To overcome those shortcomings, we propose to formulate functional connectivity networks within the context of spatio-temporal graphs. We train a spatio-temporal graph convolutional network (ST-GCN) on short sub-sequences of the BOLD time series to model the non-stationary nature of functional connectivity. Simultaneously, the model learns the importance of graph edges within ST-GCN to gain insight into the functional connectivities contributing to the prediction. In analyzing the rs-fMRI of the Human Connectome Project (HCP, N=1,091) and the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA, N=773), ST-GCN is significantly more accurate than common approaches in predicting gender and age based on BOLD signals. Furthermore, the brain regions and functional connections significantly contributing to the predictions of our model are important markers according to the neuroscience literature.

Presence of bias (in datasets or tasks) is inarguably one of the most critical challenges in machine learning applications that has alluded to pivotal debates in recent years. Such challenges range from spurious associations between variables in medical studies to the bias of race in gender or face recognition systems. Controlling for all types of biases in the dataset curation stage is cumbersome and sometimes impossible. The alternative is to use the available data and build models incorporating fair representation learning. In this paper, we propose such a model based on adversarial training with two competing objectives to learn features that have (1) maximum discriminative power with respect to the task and (2) minimal statistical mean dependence with the protected (bias) variable(s). Our approach does so by incorporating a new adversarial loss function that encourages a vanished correlation between the bias and the learned features. We apply our method to synthetic data, medical images (containing task bias), and a dataset for gender classification (containing dataset bias). Our results show that the learned features by our method not only result in superior prediction performance but also are unbiased. The code is available at https://github.com/QingyuZhao/BR-Net/., Comment: WACV 2021

With recent advances in deep learning, neuroimaging studies increasingly rely on convolutional networks (ConvNets) to predict diagnosis based on MR images. To gain a better understanding of how a disease impacts the brain, the studies visualize the salience maps of the ConvNet highlighting voxels within the brain majorly contributing to the prediction. However, these salience maps are generally confounded, i.e., some salient regions are more predictive of confounding variables (such as age) than the diagnosis. To avoid such misinterpretation, we propose in this paper an approach that aims to visualize confounder-free saliency maps that only highlight voxels predictive of the diagnosis. The approach incorporates univariate statistical tests to identify confounding effects within the intermediate features learned by ConvNet. The influence from the subset of confounded features is then removed by a novel partial back-propagation procedure. We use this two-step approach to visualize confounder-free saliency maps extracted from synthetic and two real datasets. These experiments reveal the potential of our visualization in producing unbiased model-interpretation.

While unsupervised variational autoencoders (VAE) have become a powerful tool in neuroimage analysis, their application to supervised learning is under-explored. We aim to close this gap by proposing a unified probabilistic model for learning the latent space of imaging data and performing supervised regression. Based on recent advances in learning disentangled representations, the novel generative process explicitly models the conditional distribution of latent representations with respect to the regression target variable. Performing a variational inference procedure on this model leads to joint regularization between the VAE and a neural-network regressor. In predicting the age of 245 subjects from their structural Magnetic Resonance (MR) images, our model is more accurate than state-of-the-art methods when applied to either region-of-interest (ROI) measurements or raw 3D volume images. More importantly, unlike simple feed-forward neural-networks, disentanglement of age in latent representations allows for intuitive interpretation of the structural developmental patterns of the human brain.

Variation Autoencoder (VAE) has become a powerful tool in modeling the non-linear generative process of data from a low-dimensional latent space. Recently, several studies have proposed to use VAE for unsupervised clustering by using mixture models to capture the multi-modal structure of latent representations. This strategy, however, is ineffective when there are outlier data samples whose latent representations are meaningless, yet contaminating the estimation of key major clusters in the latent space. This exact problem arises in the context of resting-state fMRI (rs-fMRI) analysis, where clustering major functional connectivity patterns is often hindered by heavy noise of rs-fMRI and many minor clusters (rare connectivity patterns) of no interest to analysis. In this paper we propose a novel generative process, in which we use a Gaussian-mixture to model a few major clusters in the data, and use a non-informative uniform distribution to capture the remaining data. We embed this truncated Gaussian-Mixture model in a Variational AutoEncoder framework to obtain a general joint clustering and outlier detection approach, called tGM-VAE. We demonstrated the applicability of tGM-VAE on the MNIST dataset and further validated it in the context of rs-fMRI connectivity analysis.

As shown in computer vision, the power of deep learning lies in automatically learning relevant and powerful features for any perdition task, which is made possible through end-to-end architectures. However, deep learning approaches applied for classifying medical images do not adhere to this architecture as they rely on several pre- and post-processing steps. This shortcoming can be explained by the relatively small number of available labeled subjects, the high dimensionality of neuroimaging data, and difficulties in interpreting the results of deep learning methods. In this paper, we propose a simple 3D Convolutional Neural Networks and exploit its model parameters to tailor the end-to-end architecture for the diagnosis of Alzheimer's disease (AD). Our model can diagnose AD with an accuracy of 94.1\% on the popular ADNI dataset using only MRI data, which outperforms the previous state-of-the-art. Based on the learned model, we identify the disease biomarkers, the results of which were in accordance with the literature. We further transfer the learned model to diagnose mild cognitive impairment (MCI), the prodromal stage of AD, which yield better results compared to other methods.