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.

DOMINO++: Domain-aware Loss Regularization for Deep Learning Generalizability

Out-of-distribution (OOD) generalization poses a serious challenge for modern deep learning (DL). OOD data consists of test data that is significantly different from the model's training data. DL models that perform well on in-domain test data could struggle on OOD data. Overcoming this discrepancy is essential to the reliable deployment of DL. Proper model calibration decreases the number of spurious connections that are made between model features and class outputs. Hence, calibrated DL can improve OOD generalization by only learning features that are truly indicative of the respective classes. Previous work proposed domain-aware model calibration (DOMINO) to improve DL calibration, but it lacks designs for model generalizability to OOD data. In this work, we propose DOMINO++, a dual-guidance and dynamic domain-aware loss regularization focused on OOD generalizability. DOMINO++ integrates expert-guided and data-guided knowledge in its regularization. Unlike DOMINO which imposed a fixed scaling and regularization rate, DOMINO++ designs a dynamic scaling factor and an adaptive regularization rate. Comprehensive evaluations compare DOMINO++ with DOMINO and the baseline model for head tissue segmentation from magnetic resonance images (MRIs) on OOD data. The OOD data consists of synthetic noisy and rotated datasets, as well as real data using a different MRI scanner from a separate site. DOMINO++'s superior performance demonstrates its potential to improve the trustworthy deployment of DL on real clinical data.

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 with limited availability. Considering the long progression time of Parkinson's disease, a desirable screening should be diagnostically accurate even before the onset of symptoms to allow medical intervention. We promote attention for retinal fundus imaging, often termed a window to the brain, as a diagnostic screening modality for Parkinson's disease. We conduct 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 71% accuracy. This accuracy is maintained when predicting either prevalent or incident Parkinson's disease. Explainability and trustworthiness is enhanced by visual attribution maps of localized biomarkers and quantified metrics of model robustness to data perturbations.

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.

LAVA: Granular 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 been hypothesized as a diagnostic site for AD detection owing to its anatomical connection with the brain. Developed AI models for this purpose have yet to provide a rational explanation about the decision and neither infer the stage of disease's progression. Along this direction, we propose a novel model-agnostic explainable-AI framework, called Granular Neuron-level Explainer (LAVA), an interpretation prototype that probes into intermediate layers of the Convolutional Neural Network (CNN) models to assess the AD continuum directly from the retinal imaging without longitudinal or clinical evaluation. This method is applied to validate the retinal vasculature as a biomarker and diagnostic modality for Alzheimer's Disease (AD) evaluation. UK Biobank cognitive tests and vascular morphological features suggest LAVA shows strong promise and effectiveness in identifying AD stages across the progression continuum.

FedTiny: Pruned Federated Learning Towards Specialized Tiny Models

Neural network pruning has been a well-established compression technique to enable deep learning models on resource-constrained devices. The pruned model is usually specialized to meet specific hardware platforms and training tasks (defined as deployment scenarios). However, existing pruning approaches rely heavily on training data to trade off model size, efficiency, and accuracy, which becomes ineffective for federated learning (FL) over distributed and confidential datasets. Moreover, the memory- and compute-intensive pruning process of most existing approaches cannot be handled by most FL devices with resource limitations. In this paper, we develop FedTiny, a novel distributed pruning framework for FL, to obtain specialized tiny models for memory- and computing-constrained participating devices with confidential local data. To alleviate biased pruning due to unseen heterogeneous data over devices, FedTiny introduces an adaptive batch normalization (BN) selection module to adaptively obtain an initially pruned model to fit deployment scenarios. Besides, to further improve the initial pruning, FedTiny develops a lightweight progressive pruning module for local finer pruning under tight memory and computational budgets, where the pruning policy for each layer is gradually determined rather than evaluating the overall deep model structure. Extensive experimental results demonstrate the effectiveness of FedTiny, which outperforms state-of-the-art baseline approaches, especially when compressing deep models to extremely sparse tiny models.

DOMINO: Domain-aware Model Calibration in Medical Image Segmentation

Model calibration measures the agreement between the predicted probability estimates and the true correctness likelihood. Proper model calibration is vital for high-risk applications. Unfortunately, modern deep neural networks are poorly calibrated, compromising trustworthiness and reliability. Medical image segmentation particularly suffers from this due to the natural uncertainty of tissue boundaries. This is exasperated by their loss functions, which favor overconfidence in the majority classes. We address these challenges with DOMINO, a domain-aware model calibration method that leverages the semantic confusability and hierarchical similarity between class labels. Our experiments demonstrate that our DOMINO-calibrated deep neural networks outperform non-calibrated models and state-of-the-art morphometric methods in head image segmentation. Our results show that our method can consistently achieve better calibration, higher accuracy, and faster inference times than these methods, especially on rarer classes. This performance is attributed to our domain-aware regularization to inform semantic model calibration. These findings show the importance of semantic ties between class labels in building confidence in deep learning models. The framework has the potential to improve the trustworthiness and reliability of generic medical image segmentation models. The code for this article is available at: https://github.com/lab-smile/DOMINO.

CADA: Multi-scale Collaborative Adversarial Domain Adaptation for Unsupervised Optic Disc and Cup Segmentation

The diversity of retinal imaging devices poses a significant challenge: domain shift, which leads to performance degradation when applying the deep learning models trained on one domain to new testing domains. In this paper, we propose a multi-scale input along with multiple domain adaptors applied hierarchically in both feature and output spaces. The proposed training strategy and novel unsupervised domain adaptation framework, called Collaborative Adversarial Domain Adaptation (CADA), can effectively overcome the challenge. Multi-scale inputs can reduce the information loss due to the pooling layers used in the network for feature extraction, while our proposed CADA is an interactive paradigm that presents an exquisite collaborative adaptation through both adversarial learning and ensembling weights at different network layers. In particular, to produce a better prediction for the unlabeled target domain data, we simultaneously achieve domain invariance and model generalizability via adversarial learning at multi-scale outputs from different levels of network layers and maintaining an exponential moving average (EMA) of the historical weights during training. Without annotating any sample from the target domain, multiple adversarial losses in encoder and decoder layers guide the extraction of domain-invariant features to confuse the domain classifier. Meanwhile, the ensembling of weights via EMA reduces the uncertainty of adapting multiple discriminator learning. Comprehensive experimental results demonstrate that our CADA model incorporating multi-scale input training can overcome performance degradation and outperform state-of-the-art domain adaptation methods in segmenting retinal optic disc and cup from fundus images stemming from the REFUGE, Drishti-GS, and Rim-One-r3 datasets.

Regression and Learning with Pixel-wise Attention for Retinal Fundus Glaucoma Segmentation and Detection

Observing retinal fundus images by an ophthalmologist is a major diagnosis approach for glaucoma. However, it is still difficult to distinguish the features of the lesion solely through manual observations, especially, in glaucoma early phase. In this paper, we present two deep learning-based automated algorithms for glaucoma detection and optic disc and cup segmentation. We utilize the attention mechanism to learn pixel-wise features for accurate prediction. In particular, we present two convolutional neural networks that can focus on learning various pixel-wise level features. In addition, we develop several attention strategies to guide the networks to learn the important features that have a major impact on prediction accuracy. We evaluate our methods on the validation dataset and The proposed both tasks' solutions can achieve impressive results and outperform current state-of-the-art methods. \textit{The code is available at \url{https://github.com/cswin/RLPA}}.