Quantifying impairment and disease severity using AI models trained on healthy subjects.

Automatic assessment of impairment and disease severity is a key challenge in data-driven medicine. We propose a framework to address this challenge, which leverages AI models trained exclusively on healthy individuals. The COnfidence-Based chaRacterization of Anomalies (COBRA) score exploits the decrease in confidence of these models when presented with impaired or diseased patients to quantify their deviation from the healthy population. We applied the COBRA score to address a key limitation of current clinical evaluation of upper-body impairment in stroke patients. The gold-standard Fugl-Meyer Assessment (FMA) requires in-person administration by a trained assessor for 30-45 minutes, which restricts monitoring frequency and precludes physicians from adapting rehabilitation protocols to the progress of each patient. The COBRA score, computed automatically in under one minute, is shown to be strongly correlated with the FMA on an independent test cohort for two different data modalities: wearable sensors (ρ = 0.814, 95% CI [0.700,0.888]) and video (ρ = 0.736, 95% C.I [0.584, 0.838]). To demonstrate the generalizability of the approach to other conditions, the COBRA score was also applied to quantify severity of knee osteoarthritis from magnetic-resonance imaging scans, again achieving significant correlation with an independent clinical assessment (ρ = 0.644, 95% C.I [0.585,0.696]).

Dictionary learning for integrative, multimodal and scalable single-cell analysis.

Mapping single-cell sequencing profiles to comprehensive reference datasets provides a powerful alternative to unsupervised analysis. However, most reference datasets are constructed from single-cell RNA-sequencing data and cannot be used to annotate datasets that do not measure gene expression. Here we introduce 'bridge integration', a method to integrate single-cell datasets across modalities using a multiomic dataset as a molecular bridge. Each cell in the multiomic dataset constitutes an element in a 'dictionary', which is used to reconstruct unimodal datasets and transform them into a shared space. Our procedure accurately integrates transcriptomic data with independent single-cell measurements of chromatin accessibility, histone modifications, DNA methylation and protein levels. Moreover, we demonstrate how dictionary learning can be combined with sketching techniques to improve computational scalability and harmonize 8.6 million human immune cell profiles from sequencing and mass cytometry experiments. Our approach, implemented in version 5 of our Seurat toolkit ( http://www.satijalab.org/seurat ), broadens the utility of single-cell reference datasets and facilitates comparisons across diverse molecular modalities.

Rapid quantitative magnetization transfer imaging: Utilizing the hybrid state and the generalized Bloch model.

PURPOSE: To explore efficient encoding schemes for quantitative magnetization transfer (qMT) imaging with few constraints on model parameters. THEORY AND METHODS: We combine two recently proposed models in a Bloch-McConnell equation: the dynamics of the free spin pool are confined to the hybrid state, and the dynamics of the semi-solid spin pool are described by the generalized Bloch model. We numerically optimize the flip angles and durations of a train of radio frequency pulses to enhance the encoding of three qMT parameters while accounting for all eight parameters of the two-pool model. We sparsely sample each time frame along this spin dynamics with a three-dimensional radial koosh-ball trajectory, reconstruct the data with subspace modeling, and fit the qMT model with a neural network for computational efficiency. RESULTS: We extracted qMT parameter maps of the whole brain with an effective resolution of 1.24 mm from a 12.6-min scan. In lesions of multiple sclerosis subjects, we observe a decreased size of the semi-solid spin pool and longer relaxation times, consistent with previous reports. CONCLUSION: The encoding power of the hybrid state, combined with regularized image reconstruction, and the accuracy of the generalized Bloch model provide an excellent basis for efficient quantitative magnetization transfer imaging with few constraints on model parameters.

Quantifying Impairment and Disease Severity Using AI Models Trained on Healthy Subjects.

Automatic assessment of impairment and disease severity is a key challenge in data-driven medicine. We propose a novel framework to address this challenge, which leverages AI models trained exclusively on healthy individuals. The COnfidence-Based chaRacterization of Anomalies (COBRA) score exploits the decrease in confidence of these models when presented with impaired or diseased patients to quantify their deviation from the healthy population. We applied the COBRA score to address a key limitation of current clinical evaluation of upper-body impairment in stroke patients. The gold-standard Fugl-Meyer Assessment (FMA) requires in-person administration by a trained assessor for 30-45 minutes, which restricts monitoring frequency and precludes physicians from adapting rehabilitation protocols to the progress of each patient. The COBRA score, computed automatically in under one minute, is shown to be strongly correlated with the FMA on an independent test cohort for two different data modalities: wearable sensors ($\rho = 0.845$, 95% CI [0.743,0.908]) and video ($\rho = 0.746$, 95% C.I [0.594, 0.847]). To demonstrate the generalizability of the approach to other conditions, the COBRA score was also applied to quantify severity of knee osteoarthritis from magnetic-resonance imaging scans, again achieving significant correlation with an independent clinical assessment ($\rho = 0.644$, 95% C.I [0.585,0.696]).

Data-Driven Quantitation of Movement Abnormality after Stroke.

Stroke commonly affects the ability of the upper extremities (UEs) to move normally. In clinical settings, identifying and measuring movement abnormality is challenging due to the imprecision and impracticality of available assessments. These challenges interfere with therapeutic tracking, communication, and treatment. We thus sought to develop an approach that blends precision and pragmatism, combining high-dimensional motion capture with out-of-distribution (OOD) detection. We used an array of wearable inertial measurement units to capture upper body motion in healthy and chronic stroke subjects performing a semi-structured, unconstrained 3D tabletop task. After data were labeled by human coders, we trained two deep learning models exclusively on healthy subject data to classify elemental movements (functional primitives). We tested these healthy subject-trained models on previously unseen healthy and stroke motion data. We found that model confidence, indexed by prediction probabilities, was generally high for healthy test data but significantly dropped when encountering OOD stroke data. Prediction probabilities worsened with more severe motor impairment categories and were directly correlated with individual impairment scores. Data inputs from the paretic UE, rather than trunk, most strongly influenced model confidence. We demonstrate for the first time that using OOD detection with high-dimensional motion data can reveal clinically meaningful movement abnormality in subjects with chronic stroke.

PrimSeq: A deep learning-based pipeline to quantitate rehabilitation training.

Stroke rehabilitation seeks to accelerate motor recovery by training functional activities, but may have minimal impact because of insufficient training doses. In animals, training hundreds of functional motions in the first weeks after stroke can substantially boost upper extremity recovery. The optimal quantity of functional motions to boost recovery in humans is currently unknown, however, because no practical tools exist to measure them during rehabilitation training. Here, we present PrimSeq, a pipeline to classify and count functional motions trained in stroke rehabilitation. Our approach integrates wearable sensors to capture upper-body motion, a deep learning model to predict motion sequences, and an algorithm to tally motions. The trained model accurately decomposes rehabilitation activities into elemental functional motions, outperforming competitive machine learning methods. PrimSeq furthermore quantifies these motions at a fraction of the time and labor costs of human experts. We demonstrate the capabilities of PrimSeq in previously unseen stroke patients with a range of upper extremity motor impairment. We expect that our methodological advances will support the rigorous measurement required for quantitative dosing trials in stroke rehabilitation.

Generalizable deep learning model for early Alzheimer's disease detection from structural MRIs.

Early diagnosis of Alzheimer's disease plays a pivotal role in patient care and clinical trials. In this study, we have developed a new approach based on 3D deep convolutional neural networks to accurately differentiate mild Alzheimer's disease dementia from mild cognitive impairment and cognitively normal individuals using structural MRIs. For comparison, we have built a reference model based on the volumes and thickness of previously reported brain regions that are known to be implicated in disease progression. We validate both models on an internal held-out cohort from The Alzheimer's Disease Neuroimaging Initiative (ADNI) and on an external independent cohort from The National Alzheimer's Coordinating Center (NACC). The deep-learning model is accurate, achieved an area-under-the-curve (AUC) of 85.12 when distinguishing between cognitive normal subjects and subjects with either MCI or mild Alzheimer's dementia. In the more challenging task of detecting MCI, it achieves an AUC of 62.45. It is also significantly faster than the volume/thickness model in which the volumes and thickness need to be extracted beforehand. The model can also be used to forecast progression: subjects with mild cognitive impairment misclassified as having mild Alzheimer's disease dementia by the model were faster to progress to dementia over time. An analysis of the features learned by the proposed model shows that it relies on a wide range of regions associated with Alzheimer's disease. These findings suggest that deep neural networks can automatically learn to identify imaging biomarkers that are predictive of Alzheimer's disease, and leverage them to achieve accurate early detection of the disease.

Cramér-Rao bound-informed training of neural networks for quantitative MRI.

PURPOSE: To improve the performance of neural networks for parameter estimation in quantitative MRI, in particular when the noise propagation varies throughout the space of biophysical parameters. THEORY AND METHODS: A theoretically well-founded loss function is proposed that normalizes the squared error of each estimate with respective Cramér-Rao bound (CRB)-a theoretical lower bound for the variance of an unbiased estimator. This avoids a dominance of hard-to-estimate parameters and areas in parameter space, which are often of little interest. The normalization with corresponding CRB balances the large errors of fundamentally more noisy estimates and the small errors of fundamentally less noisy estimates, allowing the network to better learn to estimate the latter. Further, proposed loss function provides an absolute evaluation metric for performance: A network has an average loss of 1 if it is a maximally efficient unbiased estimator, which can be considered the ideal performance. The performance gain with proposed loss function is demonstrated at the example of an eight-parameter magnetization transfer model that is fitted to phantom and in vivo data. RESULTS: Networks trained with proposed loss function perform close to optimal, that is, their loss converges to approximately 1, and their performance is superior to networks trained with the standard mean-squared error (MSE). The proposed loss function reduces the bias of the estimates compared to the MSE loss, and improves the match of the noise variance to the CRB. This performance gain translates to in vivo maps that align better with the literature. CONCLUSION: Normalizing the squared error with the CRB during the training of neural networks improves their performance in estimating biophysical parameters.

ANALYSIS OF TRANSFER LEARNING FOR SELECT RETINAL DISEASE CLASSIFICATION.

PURPOSE: To analyze the effect of transfer learning for classification of diabetic retinopathy (DR) by fundus photography and select retinal diseases by spectral domain optical coherence tomography (SD-OCT). METHODS: Five widely used open-source deep neural networks and four customized simpler and smaller networks, termed the CBR family, were trained and evaluated on two tasks: 1) classification of DR using fundus photography and 2) classification of drusen, choroidal neovascularization, and diabetic macular edema using SD-OCT. For DR classification, the quadratic weighted Kappa coefficient was used to measure the level of agreement between each network and ground truth-labeled test cases. For SD-OCT-based classification, accuracy was calculated for each network. Kappa and accuracy were compared between iterations with and without use of transfer learning for each network to assess for its effect. RESULTS: For DR classification, Kappa increased with transfer learning for all networks (range of increase 0.152-0.556). For SD-OCT-based classification, accuracy increased for four of five open-source deep neural networks (range of increase 1.8%-3.5%), slightly decreased for the remaining deep neural network (-0.6%), decreased slightly for three of four CBR networks (range of decrease 0.9%-1.8%), and decreased by 9.6% for the remaining CBR network. CONCLUSION: Transfer learning improved performance, as measured by Kappa, for DR classification for all networks, although the effect ranged from small to substantial. Transfer learning had minimal effect on accuracy for SD-OCT-based classification for eight of the nine networks analyzed. These results imply that transfer learning may substantially increase performance for DR classification but may have minimal effect for SD-OCT-based classification.

StrokeRehab: A Benchmark Dataset for Sub-second Action Identification.

Automatic action identification from video and kinematic data is an important machine learning problem with applications ranging from robotics to smart health. Most existing works focus on identifying coarse actions such as running, climbing, or cutting vegetables, which have relatively long durations and a complex series of motions. This is an important limitation for applications that require identification of more elemental motions at high temporal resolution. For example, in the rehabilitation of arm impairment after stroke, quantifying the training dose (number of repetitions) requires differentiating motions with sub-second durations. Our goal is to bridge this gap. To this end, we introduce a large-scale, multimodal dataset, StrokeRehab, as a new action-recognition benchmark that includes elemental short-duration actions labeled at a high temporal resolution. StrokeRehab consists of high-quality inertial measurement unit sensor and video data of 51 stroke-impaired patients and 20 healthy subjects performing activities of daily living like feeding, brushing teeth, etc. Because it contains data from both healthy and impaired individuals, StrokeRehab can be used to study the influence of distribution shift in action-recognition tasks. When evaluated on StrokeRehab, current state-of-the-art models for action segmentation produce noisy predictions, which reduces their accuracy in identifying the corresponding sequence of actions. To address this, we propose a novel approach for high-resolution action identification, inspired by speech-recognition techniques, which is based on a sequence-to-sequence model that directly predicts the sequence of actions. This approach outperforms current state-of-the-art methods on StrokeRehab, as well as on the standard benchmark datasets 50Salads, Breakfast, and Jigsaws.

An artificial intelligence system for predicting the deterioration of COVID-19 patients in the emergency department.

During the coronavirus disease 2019 (COVID-19) pandemic, rapid and accurate triage of patients at the emergency department is critical to inform decision-making. We propose a data-driven approach for automatic prediction of deterioration risk using a deep neural network that learns from chest X-ray images and a gradient boosting model that learns from routine clinical variables. Our AI prognosis system, trained using data from 3661 patients, achieves an area under the receiver operating characteristic curve (AUC) of 0.786 (95% CI: 0.745-0.830) when predicting deterioration within 96 hours. The deep neural network extracts informative areas of chest X-ray images to assist clinicians in interpreting the predictions and performs comparably to two radiologists in a reader study. In order to verify performance in a real clinical setting, we silently deployed a preliminary version of the deep neural network at New York University Langone Health during the first wave of the pandemic, which produced accurate predictions in real-time. In summary, our findings demonstrate the potential of the proposed system for assisting front-line physicians in the triage of COVID-19 patients.

Weakly-supervised High-resolution Segmentation of Mammography Images for Breast Cancer Diagnosis.

In the last few years, deep learning classifiers have shown promising results in image-based medical diagnosis. However, interpreting the outputs of these models remains a challenge. In cancer diagnosis, interpretability can be achieved by localizing the region of the input image responsible for the output, i.e. the location of a lesion. Alternatively, segmentation or detection models can be trained with pixel-wise annotations indicating the locations of malignant lesions. Unfortunately, acquiring such labels is labor-intensive and requires medical expertise. To overcome this difficulty, weakly-supervised localization can be utilized. These methods allow neural network classifiers to output saliency maps highlighting the regions of the input most relevant to the classification task (e.g. malignant lesions in mammograms) using only image-level labels (e.g. whether the patient has cancer or not) during training. When applied to high-resolution images, existing methods produce low-resolution saliency maps. This is problematic in applications in which suspicious lesions are small in relation to the image size. In this work, we introduce a novel neural network architecture to perform weakly-supervised segmentation of high-resolution images. The proposed model selects regions of interest via coarse-level localization, and then performs fine-grained segmentation of those regions. We apply this model to breast cancer diagnosis with screening mammography, and validate it on a large clinically-realistic dataset. Measured by Dice similarity score, our approach outperforms existing methods by a large margin in terms of localization performance of benign and malignant lesions, relatively improving the performance by 39.6% and 20.0%, respectively. Code and the weights of some of the models are available at https://github.com/nyukat/GLAM.

Sparse Recovery Beyond Compressed Sensing: Separable Nonlinear Inverse Problems.

Extracting information from nonlinear measurements is a fundamental challenge in data analysis. In this work, we consider separable inverse problems, where the data are modeled as a linear combination of functions that depend nonlinearly on certain parameters of interest. These parameters may represent neuronal activity in a human brain, frequencies of electromagnetic waves, fluorescent probes in a cell, or magnetic relaxation times of biological tissues. Separable nonlinear inverse problems can be reformulated as underdetermined sparse-recovery problems, and solved using convex programming. This approach has had empirical success in a variety of domains, from geophysics to medical imaging, but lacks a theoretical justification. In particular, compressed-sensing theory does not apply, because the measurement operators are deterministic and violate incoherence conditions such as the restricted-isometry property. Our main contribution is a theory for sparse recovery adapted to deterministic settings. We show that convex programming succeeds in recovering the parameters of interest, as long as their values are sufficiently distinct with respect to the correlation structure of the measurement operator. The theoretical results are illustrated through numerical experiments for two applications: heat-source localization and estimation of brain activity from electroencephalography data.

An artificial intelligence system for predicting the deterioration of COVID-19 patients in the emergency department.

During the coronavirus disease 2019 (COVID-19) pandemic, rapid and accurate triage of patients at the emergency department is critical to inform decision-making. We propose a data-driven approach for automatic prediction of deterioration risk using a deep neural network that learns from chest X-ray images and a gradient boosting model that learns from routine clinical variables. Our AI prognosis system, trained using data from 3,661 patients, achieves an area under the receiver operating characteristic curve (AUC) of 0.786 (95% CI: 0.745-0.830) when predicting deterioration within 96 hours. The deep neural network extracts informative areas of chest X-ray images to assist clinicians in interpreting the predictions and performs comparably to two radiologists in a reader study. In order to verify performance in a real clinical setting, we silently deployed a preliminary version of the deep neural network at New York University Langone Health during the first wave of the pandemic, which produced accurate predictions in real-time. In summary, our findings demonstrate the potential of the proposed system for assisting front-line physicians in the triage of COVID-19 patients.

Towards data-driven stroke rehabilitation via wearable sensors and deep learning.

Recovery after stroke is often incomplete, but rehabilitation training may potentiate recovery by engaging endogenous neuroplasticity. In preclinical models of stroke, high doses of rehabilitation training are required to restore functional movement to the affected limbs of animals. In humans, however, the necessary dose of training to potentiate recovery is not known. This ignorance stems from the lack of objective, pragmatic approaches for measuring training doses in rehabilitation activities. Here, to develop a measurement approach, we took the critical first step of automatically identifying functional primitives, the basic building block of activities. Forty-eight individuals with chronic stroke performed a variety of rehabilitation activities while wearing inertial measurement units (IMUs) to capture upper body motion. Primitives were identified by human labelers, who labeled and segmented the associated IMU data. We performed automatic classification of these primitives using machine learning. We designed a convolutional neural network model that outperformed existing methods. The model includes an initial module to compute separate embeddings of different physical quantities in the sensor data. In addition, it replaces batch normalization (which performs normalization based on statistics computed from the training data) with instance normalization (which uses statistics computed from the test data). This increases robustness to possible distributional shifts when applying the method to new patients. With this approach, we attained an average classification accuracy of 70%. Thus, using a combination of IMU-based motion capture and deep learning, we were able to identify primitives automatically. This approach builds towards objectively-measured rehabilitation training, enabling the identification and counting of functional primitives that accrues to a training dose.

Multicompartment Magnetic Resonance Fingerprinting.

Magnetic resonance fingerprinting (MRF) is a technique for quantitative estimation of spin- relaxation parameters from magnetic-resonance data. Most current MRF approaches assume that only one tissue is present in each voxel, which neglects intravoxel structure, and may lead to artifacts in the recovered parameter maps at boundaries between tissues. In this work, we propose a multicompartment MRF model that accounts for the presence of multiple tissues per voxel. The model is fit to the data by iteratively solving a sparse linear inverse problem at each voxel, in order to express the measured magnetization signal as a linear combination of a few elements in a precomputed fingerprint dictionary. Thresholding-based methods commonly used for sparse recovery and compressed sensing do not perform well in this setting due to the high local coherence of the dictionary. Instead, we solve this challenging sparse-recovery problem by applying reweighted-𝓁1-norm regularization, implemented using an efficient interior-point method. The proposed approach is validated with simulated data at different noise levels and undersampling factors, as well as with a controlled phantom-imaging experiment on a clinical magnetic-resonance system.