DeepDynaForecast: Phylogenetic-informed graph deep learning for epidemic transmission dynamic prediction.

In the midst of an outbreak or sustained epidemic, reliable prediction of transmission risks and patterns of spread is critical to inform public health programs. Projections of transmission growth or decline among specific risk groups can aid in optimizing interventions, particularly when resources are limited. Phylogenetic trees have been widely used in the detection of transmission chains and high-risk populations. Moreover, tree topology and the incorporation of population parameters (phylodynamics) can be useful in reconstructing the evolutionary dynamics of an epidemic across space and time among individuals. We now demonstrate the utility of phylodynamic trees for transmission modeling and forecasting, developing a phylogeny-based deep learning system, referred to as DeepDynaForecast. Our approach leverages a primal-dual graph learning structure with shortcut multi-layer aggregation, which is suited for the early identification and prediction of transmission dynamics in emerging high-risk groups. We demonstrate the accuracy of DeepDynaForecast using simulated outbreak data and the utility of the learned model using empirical, large-scale data from the human immunodeficiency virus epidemic in Florida between 2012 and 2020. Our framework is available as open-source software (MIT license) at github.com/lab-smile/DeepDynaForcast.

Analysis and Visualization of Single-Cell Sequencing Data with Scanpy and MetaCell: A Tutorial.

The emergence and development of single-cell RNA sequencing (scRNA-seq) techniques enable researchers to perform large-scale analysis of the transcriptomic profiling at cell-specific resolution. Unsupervised clustering of scRNA-seq data is central for most studies, which is essential to identify novel cell types and their gene expression logics. Although an increasing number of algorithms and tools are available for scRNA-seq analysis, a practical guide for users to navigate the landscape remains underrepresented. This chapter presents an overview of the scRNA-seq data analysis pipeline, quality control, batch effect correction, data standardization, cell clustering and visualization, cluster correlation analysis, and marker gene identification. Taking the two broadly used analysis packages, i.e., Scanpy and MetaCell, as examples, we provide a hands-on guideline and comparison regarding the best practices for the above essential analysis steps and data visualization. Additionally, we compare both packages and algorithms using a scRNA-seq dataset of the ctenophore Mnemiopsis leidyi, which is representative of one of the earliest animal lineages, critical to understanding the origin and evolution of animal novelties. This pipeline can also be helpful for analyses of other taxa, especially prebilaterian animals, where these tools are under development (e.g., placozoan and Porifera).

Neuron-level explainable AI for Alzheimer's Disease assessment from fundus images.

Alzheimer's Disease (AD) is a progressive neurodegenerative disease and the leading cause of dementia. Early diagnosis is critical for patients to benefit from potential intervention and treatment. The retina has emerged as a plausible diagnostic site for AD detection owing to its anatomical connection with the brain. However, existing AI models for this purpose have yet to provide a rational explanation behind their decisions and have not been able to infer the stage of the disease's progression. Along this direction, we propose a novel model-agnostic explainable-AI framework, called Granu la ̲ r Neuron-le v ̲ el Expl a ̲ iner (LAVA), an interpretation prototype that probes into intermediate layers of the Convolutional Neural Network (CNN) models to directly assess the continuum of AD from the retinal imaging without the need for longitudinal or clinical evaluations. This innovative approach aims to validate retinal vasculature as a biomarker and diagnostic modality for evaluating Alzheimer's Disease. Leveraged UK Biobank cognitive tests and vascular morphological features demonstrate significant promise and effectiveness of LAVA in identifying AD stages across the progression continuum.

Precise and Rapid Whole-Head Segmentation from Magnetic Resonance Images of Older Adults using Deep Learning.

Whole-head segmentation from Magnetic Resonance Images (MRI) establishes the foundation for individualized computational models using finite element method (FEM). This foundation paves the path for computer-aided solutions in fields, particularly in non-invasive brain stimulation. Most current automatic head segmentation tools are developed using healthy young adults. Thus, they may neglect the older population that is more prone to age-related structural decline such as brain atrophy. In this work, we present a new deep learning method called GRACE, which stands for General, Rapid, And Comprehensive whole-hEad tissue segmentation. GRACE is trained and validated on a novel dataset that consists of 177 manually corrected MR-derived reference segmentations that have undergone meticulous manual review. Each T1-weighted MRI volume is segmented into 11 tissue types, including white matter, grey matter, eyes, cerebrospinal fluid, air, blood vessel, cancellous bone, cortical bone, skin, fat, and muscle. To the best of our knowledge, this work contains the largest manually corrected dataset to date in terms of number of MRIs and segmented tissues. GRACE outperforms five freely available software tools and a traditional 3D U-Net on a five-tissue segmentation task. On this task, GRACE achieves an average Hausdorff Distance of 0.21, which exceeds the runner-up at an average Hausdorff Distance of 0.36. GRACE can segment a whole-head MRI in about 3 seconds, while the fastest software tool takes about 3 minutes. In summary, GRACE segments a spectrum of tissue types from older adults T1-MRI scans at favorable accuracy and speed. The trained GRACE model is optimized on older adult heads to enable high-precision modeling in age-related brain disorders. To support open science, the GRACE code and trained weights are made available online and open to the research community at https://github.com/lab-smile/GRACE.

Emergence of Emotion Selectivity in Deep Neural Networks Trained to Recognize Visual Objects.

Recent neuroimaging studies have shown that the visual cortex plays an important role in representing the affective significance of visual input. The origin of these affect-specific visual representations is debated: they are intrinsic to the visual system versus they arise through reentry from frontal emotion processing structures such as the amygdala. We examined this problem by combining convolutional neural network (CNN) models of the human ventral visual cortex pre-trained on ImageNet with two datasets of affective images. Our results show that in all layers of the CNN models, there were artificial neurons that responded consistently and selectively to neutral, pleasant, or unpleasant images and lesioning these neurons by setting their output to zero or enhancing these neurons by increasing their gain led to decreased or increased emotion recognition performance respectively. These results support the idea that the visual system may have the intrinsic ability to represent the affective significance of visual input and suggest that CNNs offer a fruitful platform for testing neuroscientific theories.

Deep learning predicts prevalent and incident Parkinson's disease from UK Biobank fundus imaging.

Parkinson's disease is the world's fastest-growing neurological disorder. Research to elucidate the mechanisms of Parkinson's disease and automate diagnostics would greatly improve the treatment of patients with Parkinson's disease. Current diagnostic methods are expensive and have limited availability. Considering the insidious and preclinical onset and progression of the disease, a desirable screening should be diagnostically accurate even before the onset of symptoms to allow medical interventions. We highlight retinal fundus imaging, often termed a window to the brain, as a diagnostic screening modality for Parkinson's disease. We conducted a systematic evaluation of conventional machine learning and deep learning techniques to classify Parkinson's disease from UK Biobank fundus imaging. Our results suggest Parkinson's disease individuals can be differentiated from age and gender-matched healthy subjects with 68% accuracy. This accuracy is maintained when predicting either prevalent or incident Parkinson's disease. Explainability and trustworthiness are enhanced by visual attribution maps of localized biomarkers and quantified metrics of model robustness to data perturbations.

Morphological Profiling for Drug Discovery in the Era of Deep Learning.

Morphological profiling is a valuable tool in phenotypic drug discovery. The advent of high-throughput automated imaging has enabled the capturing of a wide range of morphological features of cells or organisms in response to perturbations at the single-cell resolution. Concurrently, significant advances in machine learning and deep learning, especially in computer vision, have led to substantial improvements in analyzing large-scale high-content images at high-throughput. These efforts have facilitated understanding of compound mechanism-of-action (MOA), drug repurposing, characterization of cell morphodynamics under perturbation, and ultimately contributing to the development of novel therapeutics. In this review, we provide a comprehensive overview of the recent advances in the field of morphological profiling. We summarize the image profiling analysis workflow, survey a broad spectrum of analysis strategies encompassing feature engineering- and deep learning-based approaches, and introduce publicly available benchmark datasets. We place a particular emphasis on the application of deep learning in this pipeline, covering cell segmentation, image representation learning, and multimodal learning. Additionally, we illuminate the application of morphological profiling in phenotypic drug discovery and highlight potential challenges and opportunities in this field.

Emergence of Emotion Selectivity in A Deep Neural Network Trained to Recognize Visual Objects.

Recent neuroimaging studies have shown that the visual cortex plays an important role in representing the affective significance of visual input. The origin of these affect-specific visual representations is debated: they are intrinsic to the visual system versus they arise through reentry from frontal emotion processing structures such as the amygdala. We examined this problem by combining convolutional neural network (CNN) models of the human ventral visual cortex pre-trained on ImageNet with two datasets of affective images. Our results show that (1) in all layers of the CNN models, there were artificial neurons that responded consistently and selectively to neutral, pleasant, or unpleasant images and (2) lesioning these neurons by setting their output to 0 or enhancing these neurons by increasing their gain led to decreased or increased emotion recognition performance respectively. These results support the idea that the visual system may have the intrinsic ability to represent the affective significance of visual input and suggest that CNNs offer a fruitful platform for testing neuroscientific theories.

Ethnic disparity in diagnosing asymptomatic bacterial vaginosis using machine learning.

While machine learning (ML) has shown great promise in medical diagnostics, a major challenge is that ML models do not always perform equally well among ethnic groups. This is alarming for women's health, as there are already existing health disparities that vary by ethnicity. Bacterial Vaginosis (BV) is a common vaginal syndrome among women of reproductive age and has clear diagnostic differences among ethnic groups. Here, we investigate the ability of four ML algorithms to diagnose BV. We determine the fairness in the prediction of asymptomatic BV using 16S rRNA sequencing data from Asian, Black, Hispanic, and white women. General purpose ML model performances vary based on ethnicity. When evaluating the metric of false positive or false negative rate, we find that models perform least effectively for Hispanic and Asian women. Models generally have the highest performance for white women and the lowest for Asian women. These findings demonstrate a need for improved methodologies to increase model fairness for predicting BV.

Machine-learning defined precision tDCS for improving cognitive function.

BACKGROUND: Transcranial direct current stimulation (tDCS) paired with cognitive training (CT) is widely investigated as a therapeutic tool to enhance cognitive function in older adults with and without neurodegenerative disease. Prior research demonstrates that the level of benefit from tDCS paired with CT varies from person to person, likely due to individual differences in neuroanatomical structure. OBJECTIVE: The current study aims to develop a method to objectively optimize and personalize current dosage to maximize the functional gains of non-invasive brain stimulation. METHODS: A support vector machine (SVM) model was trained to predict treatment response based on computational models of current density in a sample dataset (n = 14). Feature weights of the deployed SVM were used in a weighted Gaussian Mixture Model (GMM) to maximize the likelihood of converting tDCS non-responders to responders by finding the most optimum electrode montage and applied current intensity (optimized models). RESULTS: Current distributions optimized by the proposed SVM-GMM model demonstrated 93% voxel-wise coherence within target brain regions between the originally non-responders and responders. The optimized current distribution in original non-responders was 3.38 standard deviations closer to the current dose of responders compared to the pre-optimized models. Optimized models also achieved an average treatment response likelihood and normalized mutual information of 99.993% and 91.21%, respectively. Following tDCS dose optimization, the SVM model successfully predicted all tDCS non-responders with optimized doses as responders. CONCLUSIONS: The results of this study serve as a foundation for a custom dose optimization strategy towards precision medicine in tDCS to improve outcomes in cognitive decline remediation for older adults.

DOMINO: Domain-aware loss for deep learning calibration.

Deep learning has achieved the state-of-the-art performance across medical imaging tasks; however, model calibration is often not considered. Uncalibrated models are potentially dangerous in high-risk applications since the user does not know when they will fail. Therefore, this paper proposes a novel domain-aware loss function to calibrate deep learning models. The proposed loss function applies a class-wise penalty based on the similarity between classes within a given target domain. Thus, the approach improves the calibration while also ensuring that the model makes less risky errors even when incorrect. The code for this software is available at https://github.com/lab-smile/DOMINO.

Association of longitudinal cognitive decline with diffusion MRI in Gray Matter, Amyloid, and Tau deposition.

Extracellular amyloid plaques in gray matter are the earliest pathological marker for Alzheimer's disease (AD), followed by abnormal tau protein accumulation. The link between diffusion changes in gray matter, amyloid and tau pathology, and cognitive decline is not well understood. We first performed cross-sectional analyses on T1-weighted imaging, diffusion MRI, and amyloid and tau PETs from the ADNI 2/3 database. We evaluated cortical volume, free-water, fractional anisotropy (FA), and amyloid and tau SUVRs in 171 cognitively normal, 103 MCI, and 44 AD individuals. When the 3 groups were combined, increasing amyloid burden was associated with reduced extracellular free-water in the entorhinal cortex and hippocampus in those with amyloid-negative status whereas increasing tau burden was associated with increased extracellular free-water regardless of amyloid status. Next, we found that for the MCI subjects, diffusion measures (free-water, FA) alone predicted MMSE score 2 years later with a high r-square value (87%), as compared to tau SUVRs (27%), T1 volume (36%), and amyloid SUVRs (75%). Diffusion measures represent a potent non-invasive marker for predicting cognitive decline.

Identify diabetic retinopathy-related clinical concepts and their attributes using transformer-based natural language processing methods.

BACKGROUND: Diabetic retinopathy (DR) is a leading cause of blindness in American adults. If detected, DR can be treated to prevent further damage causing blindness. There is an increasing interest in developing artificial intelligence (AI) technologies to help detect DR using electronic health records. The lesion-related information documented in fundus image reports is a valuable resource that could help diagnoses of DR in clinical decision support systems. However, most studies for AI-based DR diagnoses are mainly based on medical images; there is limited studies to explore the lesion-related information captured in the free text image reports. METHODS: In this study, we examined two state-of-the-art transformer-based natural language processing (NLP) models, including BERT and RoBERTa, compared them with a recurrent neural network implemented using Long short-term memory (LSTM) to extract DR-related concepts from clinical narratives. We identified four different categories of DR-related clinical concepts including lesions, eye parts, laterality, and severity, developed annotation guidelines, annotated a DR-corpus of 536 image reports, and developed transformer-based NLP models for clinical concept extraction and relation extraction. We also examined the relation extraction under two settings including 'gold-standard' setting-where gold-standard concepts were used-and end-to-end setting. RESULTS: For concept extraction, the BERT model pretrained with the MIMIC III dataset achieve the best performance (0.9503 and 0.9645 for strict/lenient evaluation). For relation extraction, BERT model pretrained using general English text achieved the best strict/lenient F1-score of 0.9316. The end-to-end system, BERT_general_e2e, achieved the best strict/lenient F1-score of 0.8578 and 0.8881, respectively. Another end-to-end system based on the RoBERTa architecture, RoBERTa_general_e2e, also achieved the same performance as BERT_general_e2e in strict scores. CONCLUSIONS: This study demonstrated the efficiency of transformer-based NLP models for clinical concept extraction and relation extraction. Our results show that it's necessary to pretrain transformer models using clinical text to optimize the performance for clinical concept extraction. Whereas, for relation extraction, transformers pretrained using general English text perform better.

PIMA-CT: Physical Model-Aware Cyclic Simulation and Denoising for Ultra-Low-Dose CT Restoration.

A body of studies has proposed to obtain high-quality images from low-dose and noisy Computed Tomography (CT) scans for radiation reduction. However, these studies are designed for population-level data without considering the variation in CT devices and individuals, limiting the current approaches' performance, especially for ultra-low-dose CT imaging. Here, we proposed PIMA-CT, a physical anthropomorphic phantom model integrating an unsupervised learning framework, using a novel deep learning technique called Cyclic Simulation and Denoising (CSD), to address these limitations. We first acquired paired low-dose and standard-dose CT scans of the phantom and then developed two generative neural networks: noise simulator and denoiser. The simulator extracts real low-dose noise and tissue features from two separate image spaces (e.g., low-dose phantom model scans and standard-dose patient scans) into a unified feature space. Meanwhile, the denoiser provides feedback to the simulator on the quality of the generated noise. In this way, the simulator and denoiser cyclically interact to optimize network learning and ease the denoiser to simultaneously remove noise and restore tissue features. We thoroughly evaluate our method for removing both real low-dose noise and Gaussian simulated low-dose noise. The results show that CSD outperforms one of the state-of-the-art denoising algorithms without using any labeled data (actual patients' low-dose CT scans) nor simulated low-dose CT scans. This study may shed light on incorporating physical models in medical imaging, especially for ultra-low level dose CT scans restoration.

Baseline Neuroimaging Predicts Decline to Dementia From Amnestic Mild Cognitive Impairment.

Background and Objectives: Prediction of decline to dementia using objective biomarkers in high-risk patients with amnestic mild cognitive impairment (aMCI) has immense utility. Our objective was to use multimodal MRI to (1) determine whether accurate and precise prediction of dementia conversion could be achieved using baseline data alone, and (2) generate a map of the brain regions implicated in longitudinal decline to dementia. Methods: Participants meeting criteria for aMCI at baseline (N = 55) were classified at follow-up as remaining stable/improved in their diagnosis (N = 41) or declined to dementia (N = 14). Baseline T1 structural MRI and resting-state fMRI (rsfMRI) were combined and a semi-supervised support vector machine (SVM) which separated stable participants from those who decline at follow-up with maximal margin. Cross-validated model performance metrics and MRI feature weights were calculated to include the strength of each brain voxel in its ability to distinguish the two groups. Results: Total model accuracy for predicting diagnostic change at follow-up was 92.7% using baseline T1 imaging alone, 83.5% using rsfMRI alone, and 94.5% when combining T1 and rsfMRI modalities. Feature weights that survived the p < 0.01 threshold for separation of the two groups revealed the strongest margin in the combined structural and functional regions underlying the medial temporal lobes in the limbic system. Discussion: An MRI-driven SVM model demonstrates accurate and precise prediction of later dementia conversion in aMCI patients. The multi-modal regions driving this prediction were the strongest in the medial temporal regions of the limbic system, consistent with literature on the progression of Alzheimer's disease.

Unraveling somatotopic organization in the human brain using machine learning and adaptive supervoxel-based parcellations.

In addition to the well-established somatotopy in the pre- and post-central gyrus, there is now strong evidence that somatotopic organization is evident across other regions in the sensorimotor network. This raises several experimental questions: To what extent is activity in the sensorimotor network effector-dependent and effector-independent? How important is the sensorimotor cortex when predicting the motor effector? Is there redundancy in the distributed somatotopically organized network such that removing one region has little impact on classification accuracy? To answer these questions, we developed a novel experimental approach. fMRI data were collected while human subjects performed a precisely controlled force generation task separately with their hand, foot, and mouth. We used a simple linear iterative clustering (SLIC) algorithm to segment whole-brain beta coefficient maps to build an adaptive brain parcellation and then classified effectors using extreme gradient boosting (XGBoost) based on parcellations at various spatial resolutions. This allowed us to understand how data-driven adaptive brain parcellation granularity altered classification accuracy. Results revealed effector-dependent activity in regions of the post-central gyrus, precentral gyrus, and paracentral lobule. SMA, regions of the inferior and superior parietal lobule, and cerebellum each contained effector-dependent and effector-independent representations. Machine learning analyses showed that increasing the spatial resolution of the data-driven model increased classification accuracy, which reached 94% with 1755 supervoxels. Our SLIC-based supervoxel parcellation outperformed classification analyses using established brain templates and random simulations. Occlusion experiments further demonstrated redundancy across the sensorimotor network when classifying effectors. Our observations extend our understanding of effector-dependent and effector-independent organization within the human brain and provide new insight into the functional neuroanatomy required to predict the motor effector used in a motor control task.

Modular machine learning for Alzheimer's disease classification from retinal vasculature.

Alzheimer's disease is the leading cause of dementia. The long progression period in Alzheimer's disease provides a possibility for patients to get early treatment by having routine screenings. However, current clinical diagnostic imaging tools do not meet the specific requirements for screening procedures due to high cost and limited availability. In this work, we took the initiative to evaluate the retina, especially the retinal vasculature, as an alternative for conducting screenings for dementia patients caused by Alzheimer's disease. Highly modular machine learning techniques were employed throughout the whole pipeline. Utilizing data from the UK Biobank, the pipeline achieved an average classification accuracy of 82.44%. Besides the high classification accuracy, we also added a saliency analysis to strengthen this pipeline's interpretability. The saliency analysis indicated that within retinal images, small vessels carry more information for diagnosing Alzheimer's diseases, which aligns with related studies.

Machine learning and individual variability in electric field characteristics predict tDCS treatment response.

BACKGROUND: Transcranial direct current stimulation (tDCS) is widely investigated as a therapeutic tool to enhance cognitive function in older adults with and without neurodegenerative disease. Prior research demonstrates that electric current delivery to the brain can vary significantly across individuals. Quantification of this variability could enable person-specific optimization of tDCS outcomes. This pilot study used machine learning and MRI-derived electric field models to predict working memory improvements as a proof of concept for precision cognitive intervention. METHODS: Fourteen healthy older adults received 20 minutes of 2 mA tDCS stimulation (F3/F4) during a two-week cognitive training intervention. Participants performed an N-back working memory task pre-/post-intervention. MRI-derived current models were passed through a linear Support Vector Machine (SVM) learning algorithm to characterize crucial tDCS current components (intensity and direction) that induced working memory improvements in tDCS responders versus non-responders. MAIN RESULTS: SVM models of tDCS current components had 86% overall accuracy in classifying treatment responders vs. non-responders, with current intensity producing the best overall model differentiating changes in working memory performance. Median current intensity and direction in brain regions near the electrodes were positively related to intervention responses (r=0.811,p<0.001 and r=0.774,p=0.001). CONCLUSIONS: This study provides the first evidence that pattern recognition analyses of MRI-derived tDCS current models can provide individual prognostic classification of tDCS treatment response with 86% accuracy. Individual differences in current intensity and direction play important roles in determining treatment response to tDCS. These findings provide important insights into mechanisms of tDCS response as well as proof of concept for future precision dosing models of tDCS intervention.

A survey on medical image analysis in diabetic retinopathy.

Diabetic Retinopathy (DR) represents a highly-prevalent complication of diabetes in which individuals suffer from damage to the blood vessels in the retina. The disease manifests itself through lesion presence, starting with microaneurysms, at the nonproliferative stage before being characterized by neovascularization in the proliferative stage. Retinal specialists strive to detect DR early so that the disease can be treated before substantial, irreversible vision loss occurs. The level of DR severity indicates the extent of treatment necessary - vision loss may be preventable by effective diabetes management in mild (early) stages, rather than subjecting the patient to invasive laser surgery. Using artificial intelligence (AI), highly accurate and efficient systems can be developed to help assist medical professionals in screening and diagnosing DR earlier and without the full resources that are available in specialty clinics. In particular, deep learning facilitates diagnosis earlier and with higher sensitivity and specificity. Such systems make decisions based on minimally handcrafted features and pave the way for personalized therapies. Thus, this survey provides a comprehensive description of the current technology used in each step of DR diagnosis. First, it begins with an introduction to the disease and the current technologies and resources available in this space. It proceeds to discuss the frameworks that different teams have used to detect and classify DR. Ultimately, we conclude that deep learning systems offer revolutionary potential to DR identification and prevention of vision loss.