Human experts demonstrate proficiency not only in disentangling anatomical structures from disease conditions but also in intertwining anatomical and disease information to accurately diagnose a variety of disorders. However, deep learning models, despite their prowess in acquiring intricate representation, often struggle to learn representation where distinct semantic aspects of the data (both anatomy and pathology) are entangled, particularly in medical images, which present a rich array of anatomical structures and potential pathological conditions. We envision that a deep model, when trained to comprehend medical images akin to human perception, would offer powerful representation with higher generalizability, robustness, and interpretability. To realize this vision, we have developed LeADER, a framework for learning anatomy-disease entangled representation from medical images. As a proof of concept, we have trained LeADER on ≈IM chest radiographs gatheredfrom 10 public datasets. Experimental results across 11 medical tasks, compared to 8 baselines in zero-shot, linear probing, limited data regimes, and full fine-tuning settings, demonstrate LeADER's superior performance over the Google CXR Foundation Model, large-scale medical models, and fully/self-supervised baselines across diverse downstream tasks. This enhanced performance is attributed to the significance of entangling anatomy-specific and disease-specific representations via our framework, which enables the simultaneous acquisition of both anatomical and disease knowledge, yet overlooked in existing supervised/self-supervised learning methods. All code and models are available at GitHub.com/JLiangLab/LeADER.

Developing robust and versatile deep-learning models is essential for enhancing diagnostic accuracy and guiding clinical interventions in medical imaging, but it requires a large amount of annotated data. The advancement of deep learning has facilitated the creation of numerous medical datasets with diverse expert-level annotations. Aggregating these datasets can maximize data utilization and address the inadequacy of labeled data. However, the heterogeneity of expert-level annotations across tasks such as classification, localization, and segmentation presents a significant challenge for learning from these datasets. To this end, we introduce Foundation X, an end-to-end framework that utilizes diverse expert-level annotations from numerous public datasets to train a foundation model capable of multiple tasks including classification, localization, and segmentation. To address the challenges of annotation and task heterogeneity, we propose a Lock-Release pretraining strategy to enhance the cyclic learning from multiple datasets, combined with the student-teacher learning paradigm, ensuring the model retains general knowledge for all tasks while preventing overfitting to any single task. To demonstrate the effectiveness of Foundation X, we trained a model using 11 chest X-ray datasets, covering annotations for classification, localization, and segmentation tasks. Our experimental results show that Foundation X achieves notable performance gains through extensive annotation utilization, excels in cross-dataset and cross-task learning, and further enhances performance in organ localization and segmentation tasks. All code and pretrained models are publicly accessible at GitHub.com/JLiangLab/Foundation_X.

Medical images acquired from standardized protocols show consistent macroscopic or microscopic anatomical structures, and these structures consist of composable/decomposable organs and tissues, but existing self-supervised learning (SSL) methods do not appreciate such composable/decomposable structure attributes inherent to medical images. To overcome this limitation, this paper introduces a novel SSL approach called ACE to learn anatomically consistent embedding via composition and decomposition with two key branches: (1) global consistency, capturing discriminative macro-structures via extracting global features; (2) local consistency, learning fine-grained anatomical details from composable/decomposable patch features via corresponding matrix matching. Experimental results across 6 datasets 2 backbones, evaluated in few-shot learning, fine-tuning, and property analysis, show ACE's superior robustness, transferability, and clinical potential. The innovations of our ACE lie in grid-wise image cropping, leveraging the intrinsic properties of compositionality and decompositionality of medical images, bridging the semantic gap from high-level pathologies to low-level tissue anomalies, and providing a new SSL method for medical imaging. All code and pretrained models are available at GitHub.com/JLiangLab/ACE.

Humans effortlessly interpret images by parsing them into part-whole hierarchies; deep learning excels in learning multi-level feature spaces, but they often lack explicit coding of part-whole relations, a prominent property of medical imaging. To overcome this limitation, we introduce Adam-v2, a new self-supervised learning framework extending Adam [79] by explicitly incorporating part-whole hierarchies into its learning objectives through three key branches: (1) Localizability, acquiring discriminative representations to distinguish different anatomical patterns; (2) Composability, learning each anatomical structure in a parts-to-whole manner; and (3) Decomposability, comprehending each anatomical structure in a whole-to-parts manner. Experimental results across 10 tasks, compared to 11 baselines in zero-shot, few-shot transfer, and full fine-tuning settings, showcase Adam-v2's superior performance over large-scale medical models and existing SSL methods across diverse downstream tasks. The higher generality and robustness of Adam-v2's representations originate from its explicit construction of hierarchies for distinct anatomical structures from unlabeled medical images. Adam-v2 preserves a semantic balance of anatomical diversity and harmony in its embedding, yielding representations that are both generic and semantically meaningful, yet overlooked in existing SSL methods. All code and pretrained models are available at GitHub.com/JLiangLab/Eden.

Discriminative learning, restorative learning, and adversarial learning have proven beneficial for self-supervised learning schemes in computer vision and medical imaging. Existing efforts, however, omit their synergistic effects on each other in a ternary setup, which, we envision, can sig-nificantly benefit deep semantic representation learning. To realize this vision, we have developed DiRA, thefirstframework that unites discriminative, restorative, and adversarial learning in a unified manner to collaboratively glean complementary visual information from unlabeled medical images for fine-grained semantic representation learning. Our extensive experiments demonstrate that DiRA (1) encourages collaborative learning among three learning ingredients, resulting in more generalizable representation across organs, diseases, and modalities; (2) outperforms fully supervised ImageNet models and increases robustness in small data regimes, reducing annotation cost across multiple medical imaging applications; (3) learns fine-grained semantic representation, facilitating accurate lesion localization with only image-level annotation; and (4) enhances state-of-the-art restorative approaches, revealing that DiRA is a general mechanism for united representation learning. All code and pretrained models are available at https://github.com/JLiangLab/DiRA.

This paper introduces a new concept called "transferable visual words" (TransVW), aiming to achieve annotation efficiency for deep learning in medical image analysis. Medical imaging-focusing on particular parts of the body for defined clinical purposes-generates images of great similarity in anatomy across patients and yields sophisticated anatomical patterns across images, which are associated with rich semantics about human anatomy and which are natural visual words. We show that these visual words can be automatically harvested according to anatomical consistency via self-discovery, and that the self-discovered visual words can serve as strong yet free supervision signals for deep models to learn semantics-enriched generic image representation via self-supervision (self-classification and self-restoration). Our extensive experiments demonstrate the annotation efficiency of TransVW by offering higher performance and faster convergence with reduced annotation cost in several applications. Our TransVW has several important advantages, including (1) TransVW is a fully autodidactic scheme, which exploits the semantics of visual words for self-supervised learning, requiring no expert annotation; (2) visual word learning is an add-on strategy, which complements existing self-supervised methods, boosting their performance; and (3) the learned image representation is semantics-enriched models, which have proven to be more robust and generalizable, saving annotation efforts for a variety of applications through transfer learning. Our code, pre-trained models, and curated visual words are available at https://github.com/JLiangLab/TransVW.

Generative adversarial networks (GANs) have ushered in a revolution in image-to-image translation. The development and proliferation of GANs raises an interesting question: can we train a GAN to remove an object, if present, from an image while otherwise preserving the image? Specifically, can a GAN "virtually heal" anyone by turning his medical image, with an unknown health status (diseased or healthy), into a healthy one, so that diseased regions could be revealed by subtracting those two images? Such a task requires a GAN to identify a minimal subset of target pixels for domain translation, an ability that we call fixed-point translation, which no GAN is equipped with yet. Therefore, we propose a new GAN, called Fixed-Point GAN, trained by (1) supervising same-domain translation through a conditional identity loss, and (2) regularizing cross-domain translation through revised adversarial, domain classification, and cycle consistency loss. Based on fixed-point translation, we further derive a novel framework for disease detection and localization using only image-level annotation. Qualitative and quantitative evaluations demonstrate that the proposed method outperforms the state of the art in multi-domain image-to-image translation and that it surpasses predominant weakly-supervised localization methods in both disease detection and localization. Implementation is available at https://github.com/jlianglab/Fixed-Point-GAN.

Intense interest in applying convolutional neural networks (CNNs) in biomedical image analysis is wide spread, but its success is impeded by the lack of large annotated datasets in biomedical imaging. Annotating biomedical images is not only tedious and time consuming, but also demanding of costly, specialty-oriented knowledge and skills, which are not easily accessible. To dramatically reduce annotation cost, this paper presents a novel method called AIFT (active, incremental fine-tuning) to naturally integrate active learning and transfer learning into a single framework. AIFT starts directly with a pre-trained CNN to seek "worthy" samples from the unannotated for annotation, and the (fine-tuned) CNN is further fine-tuned continuously by incorporating newly annotated samples in each iteration to enhance the CNN's performance incrementally. We have evaluated our method in three different biomedical imaging applications, demonstrating that the cost of annotation can be cut by at least half. This performance is attributed to the several advantages derived from the advanced active and incremental capability of our AIFT method.

Training a deep convolutional neural network (CNN) from scratch is difficult because it requires a large amount of labeled training data and a great deal of expertise to ensure proper convergence. A promising alternative is to fine-tune a CNN that has been pre-trained using, for instance, a large set of labeled natural images. However, the substantial differences between natural and medical images may advise against such knowledge transfer. In this paper, we seek to answer the following central question in the context of medical image analysis: Can the use of pre-trained deep CNNs with sufficient fine-tuning eliminate the need for training a deep CNN from scratch? To address this question, we considered four distinct medical imaging applications in three specialties (radiology, cardiology, and gastroenterology) involving classification, detection, and segmentation from three different imaging modalities, and investigated how the performance of deep CNNs trained from scratch compared with the pre-trained CNNs fine-tuned in a layer-wise manner. Our experiments consistently demonstrated that 1) the use of a pre-trained CNN with adequate fine-tuning outperformed or, in the worst case, performed as well as a CNN trained from scratch; 2) fine-tuned CNNs were more robust to the size of training sets than CNNs trained from scratch; 3) neither shallow tuning nor deep tuning was the optimal choice for a particular application; and 4) our layer-wise fine-tuning scheme could offer a practical way to reach the best performance for the application at hand based on the amount of available data.

MicroRNAs are small non-coding RNAs of 21-25 nucleotides that might impact regulatory mechanisms in cancer. Due to their influence on cell physiology, alteration of miRNA regulation can be implicated in carcinogenesis and disease progression. In general, one miRNA is predicted to regulate several hundred genes, and as a result, miRNA profiling could serve as a better classifier than gene expression profiling.More than 50% of brain metastasis (brain mets) are associated with non-small cell lung cancer (NSCLC). As miRNAs can regulate certain genes, the presence or absence of certain miRNA could lead to oncogene potential for brain mets. In this study, we combine validated miRNA expression values with imaging features to separate NSCLC brain mets from non-brain mets and identify biomarkers that may indicate possibility of brain mets. This research involves comprehensive miRNA expression profiling, validation of miRNA with qRT-PCR, correlation of miRNA with imaging features such as PET/CT and CT scan. Eleven statistically significant miRNA were identified and matched with imaging features to yield a class separation of brain mets and non-brain mets.