Zhiyun Xue

Sivaramakrishnan Rajaraman, Ghada Zamzmi, Feng Yang et al.

Deep learning (DL) has demonstrated its innate capacity to independently learn hierarchical features from complex and multi-dimensional data. A common understanding is that its performance scales up with the amount of training data. Another data attribute is the inherent variety. It follows, therefore, that semantic redundancy, which is the presence of similar or repetitive information, would tend to lower performance and limit generalizability to unseen data. In medical imaging data, semantic redundancy can occur due to the presence of multiple images that have highly similar presentations for the disease of interest. Further, the common use of augmentation methods to generate variety in DL training may be limiting performance when applied to semantically redundant data. We propose an entropy-based sample scoring approach to identify and remove semantically redundant training data. We demonstrate using the publicly available NIH chest X-ray dataset that the model trained on the resulting informative subset of training data significantly outperforms the model trained on the full training set, during both internal (recall: 0.7164 vs 0.6597, p<0.05) and external testing (recall: 0.3185 vs 0.2589, p<0.05). Our findings emphasize the importance of information-oriented training sample selection as opposed to the conventional practice of using all available training data.

Sivaramakrishnan Rajaraman, Ghada Zamzmi, Feng Yang et al.

Model initialization techniques are vital for improving the performance and reliability of deep learning models in medical computer vision applications. While much literature exists on non-medical images, the impacts on medical images, particularly chest X-rays (CXRs) are less understood. Addressing this gap, our study explores three deep model initialization techniques: Cold-start, Warm-start, and Shrink and Perturb start, focusing on adult and pediatric populations. We specifically focus on scenarios with periodically arriving data for training, thereby embracing the real-world scenarios of ongoing data influx and the need for model updates. We evaluate these models for generalizability against external adult and pediatric CXR datasets. We also propose novel ensemble methods: F-score-weighted Sequential Least-Squares Quadratic Programming (F-SLSQP) and Attention-Guided Ensembles with Learnable Fuzzy Softmax to aggregate weight parameters from multiple models to capitalize on their collective knowledge and complementary representations. We perform statistical significance tests with 95% confidence intervals and p-values to analyze model performance. Our evaluations indicate models initialized with ImageNet-pre-trained weights demonstrate superior generalizability over randomly initialized counterparts, contradicting some findings for non-medical images. Notably, ImageNet-pretrained models exhibit consistent performance during internal and external testing across different training scenarios. Weight-level ensembles of these models show significantly higher recall (p<0.05) during testing compared to individual models. Thus, our study accentuates the benefits of ImageNet-pretrained weight initialization, especially when used with weight-level ensembles, for creating robust and generalizable deep learning solutions.

Sivaramakrishnan Rajaraman, Feng Yang, Ghada Zamzmi et al.

Automated segmentation of tuberculosis (TB)-consistent lesions in chest X-rays (CXRs) using deep learning (DL) methods can help reduce radiologist effort, supplement clinical decision-making, and potentially result in improved patient treatment. The majority of works in the literature discuss training automatic segmentation models using coarse bounding box annotations. However, the granularity of the bounding box annotation could result in the inclusion of a considerable fraction of false positives and negatives at the pixel level that may adversely impact overall semantic segmentation performance. This study (i) evaluates the benefits of using fine-grained annotations of TB-consistent lesions and (ii) trains and constructs ensembles of the variants of U-Net models for semantically segmenting TB-consistent lesions in both original and bone-suppressed frontal CXRs. We evaluated segmentation performance using several ensemble methods such as bitwise AND, bitwise-OR, bitwise-MAX, and stacking. We observed that the stacking ensemble demonstrated superior segmentation performance (Dice score: 0.5743, 95% confidence interval: (0.4055,0.7431)) compared to the individual constituent models and other ensemble methods. To the best of our knowledge, this is the first study to apply ensemble learning to improve fine-grained TB-consistent lesion segmentation performance.

Sivaramakrishnan Rajaraman, Feng Yang, Ghada Zamzmi et al.

Deep learning (DL) models are state-of-the-art in segmenting anatomical and disease regions of interest (ROIs) in medical images. Particularly, a large number of DL-based techniques have been reported using chest X-rays (CXRs). However, these models are reportedly trained on reduced image resolutions for reasons related to the lack of computational resources. Literature is sparse in discussing the optimal image resolution to train these models for segmenting the Tuberculosis (TB)-consistent lesions in CXRs. In this study, we investigated the performance variations using an Inception-V3 UNet model using various image resolutions with/without lung ROI cropping and aspect ratio adjustments, and (ii) identified the optimal image resolution through extensive empirical evaluations to improve TB-consistent lesion segmentation performance. We used the Shenzhen CXR dataset for the study which includes 326 normal patients and 336 TB patients. We proposed a combinatorial approach consisting of storing model snapshots, optimizing segmentation threshold and test-time augmentation (TTA), and averaging the snapshot predictions, to further improve performance with the optimal resolution. Our experimental results demonstrate that higher image resolutions are not always necessary, however, identifying the optimal image resolution is critical to achieving superior performance.

Sivaramakrishnan Rajaraman, Feng Yang, Ghada Zamzmi et al.

Lung segmentation in chest X-rays (CXRs) is an important prerequisite for improving the specificity of diagnoses of cardiopulmonary diseases in a clinical decision support system. Current deep learning models for lung segmentation are trained and evaluated on CXR datasets in which the radiographic projections are captured predominantly from the adult population. However, the shape of the lungs is reported to be significantly different across the developmental stages from infancy to adulthood. This might result in age-related data domain shifts that would adversely impact lung segmentation performance when the models trained on the adult population are deployed for pediatric lung segmentation. In this work, our goal is to (i) analyze the generalizability of deep adult lung segmentation models to the pediatric population and (ii) improve performance through a stage-wise, systematic approach consisting of CXR modality-specific weight initializations, stacked ensembles, and an ensemble of stacked ensembles. To evaluate segmentation performance and generalizability, novel evaluation metrics consisting of mean lung contour distance (MLCD) and average hash score (AHS) are proposed in addition to the multi-scale structural similarity index measure (MS-SSIM), the intersection of union (IoU), Dice score, 95% Hausdorff distance (HD95), and average symmetric surface distance (ASSD). Our results showed a significant improvement (p < 0.05) in cross-domain generalization through our approach. This study could serve as a paradigm to analyze the cross-domain generalizability of deep segmentation models for other medical imaging modalities and applications.

Zhaohui Liang, Sivaramakrishnan Rajaraman, Niccolo Marini et al.

CLIP and BiomedCLIP are examples of vision-language foundation models and offer strong cross-modal embeddings; however, they are not optimized for fine-grained medical retrieval tasks, such as retrieving clinically relevant radiology reports using chest X-ray (CXR) image queries. To address this shortcoming, we propose a multi-task learning framework to fine-tune BiomedCLIP and evaluate improvements to CXR image-text retrieval. Using BiomedCLIP as the backbone, we incorporate a lightweight MLP projector head trained with a multi-task composite loss function that includes: (1) a binary cross-entropy loss to distinguish normal from abnormal CXR studies, (2) a supervised contrastive loss to reinforce intra-class consistency, and (3) a CLIP loss to maintain cross-modal alignment. Experimental results demonstrate that the fine-tuned model achieves more balanced and clinically meaningful performance across both image-to-text and text-to-image retrieval tasks compared to the pretrained BiomedCLIP and general-purpose CLIP models. Furthermore, t-SNE visualizations reveal clearer semantic clustering of normal and abnormal cases, demonstrating the model's enhanced diagnostic sensitivity. These findings highlight the value of domain-adaptive, multi-task learning for advancing cross-modal retrieval in biomedical applications.

Niccolo Marini, Zhaohui Liang, Sivaramakrishnan Rajaraman et al.

Multimodal (MM) learning is emerging as a promising paradigm in biomedical artificial intelligence (AI) applications, integrating complementary modality, which highlight different aspects of patient health. The scarcity of large heterogeneous biomedical MM data has restrained the development of robust models for medical AI applications. In the dermatology domain, for instance, skin lesion datasets typically include only images linked to minimal metadata describing the condition, thereby limiting the benefits of MM data integration for reliable and generalizable predictions. Recent advances in Large Language Models (LLMs) enable the synthesis of textual description of image findings, potentially allowing the combination of image and text representations. However, LLMs are not specifically trained for use in the medical domain, and their naive inclusion has raised concerns about the risk of hallucinations in clinically relevant contexts. This work investigates strategies for generating synthetic textual clinical notes, in terms of prompt design and medical metadata inclusion, and evaluates their impact on MM architectures toward enhancing performance in classification and cross-modal retrieval tasks. Experiments across several heterogeneous dermatology datasets demonstrate that synthetic clinical notes not only enhance classification performance, particularly under domain shift, but also unlock cross-modal retrieval capabilities, a downstream task that is not explicitly optimized during training.

Anabik Pal, Zhiyun Xue, Sameer Antani

Cervical cancer is the fourth most common cancer in women worldwide. The availability of a robust automated cervical image classification system can augment the clinical care provider's limitation in traditional visual inspection with acetic acid (VIA). However, there are a wide variety of cervical inspection objectives which impact the labeling criteria for criteria-specific prediction model development. Moreover, due to the lack of confirmatory test results and inter-rater labeling variation, many images are left unlabeled. Motivated by these challenges, we propose a self-supervised learning (SSL) based approach to produce a pre-trained cervix model from unlabeled cervical images. The developed model is further fine-tuned to produce criteria-specific classification models with the available labeled images. We demonstrate the effectiveness of the proposed approach using two cervical image datasets. Both datasets are partially labeled and labeling criteria are different. The experimental results show that the SSL-based initialization improves classification performance (Accuracy: 2.5% min) and the inclusion of images from both datasets during SSL further improves the performance (Accuracy: 1.5% min). Further, considering data-sharing restrictions, we experimented with the effectiveness of Federated SSL and find that it can improve performance over the SSL model developed with just its images. This justifies the importance of SSL-based cervix model development. We believe that the present research shows a novel direction in developing criteria-specific custom deep models for cervical image classification by combining images from different sources unlabeled and/or labeled with varying criteria, and addressing image access restrictions.

Yuan Xue, Jiarong Ye, Qianying Zhou et al.

Histopathological analysis is the present gold standard for precancerous lesion diagnosis. The goal of automated histopathological classification from digital images requires supervised training, which requires a large number of expert annotations that can be expensive and time-consuming to collect. Meanwhile, accurate classification of image patches cropped from whole-slide images is essential for standard sliding window based histopathology slide classification methods. To mitigate these issues, we propose a carefully designed conditional GAN model, namely HistoGAN, for synthesizing realistic histopathology image patches conditioned on class labels. We also investigate a novel synthetic augmentation framework that selectively adds new synthetic image patches generated by our proposed HistoGAN, rather than expanding directly the training set with synthetic images. By selecting synthetic images based on the confidence of their assigned labels and their feature similarity to real labeled images, our framework provides quality assurance to synthetic augmentation. Our models are evaluated on two datasets: a cervical histopathology image dataset with limited annotations, and another dataset of lymph node histopathology images with metastatic cancer. Here, we show that leveraging HistoGAN generated images with selective augmentation results in significant and consistent improvements of classification performance (6.7% and 2.8% higher accuracy, respectively) for cervical histopathology and metastatic cancer datasets.

Jiarong Ye, Yuan Xue, L. Rodney Long et al.

Synthesizing realistic medical images provides a feasible solution to the shortage of training data in deep learning based medical image recognition systems. However, the quality control of synthetic images for data augmentation purposes is under-investigated, and some of the generated images are not realistic and may contain misleading features that distort data distribution when mixed with real images. Thus, the effectiveness of those synthetic images in medical image recognition systems cannot be guaranteed when they are being added randomly without quality assurance. In this work, we propose a reinforcement learning (RL) based synthetic sample selection method that learns to choose synthetic images containing reliable and informative features. A transformer based controller is trained via proximal policy optimization (PPO) using the validation classification accuracy as the reward. The selected images are mixed with the original training data for improved training of image recognition systems. To validate our method, we take the pathology image recognition as an example and conduct extensive experiments on two histopathology image datasets. In experiments on a cervical dataset and a lymph node dataset, the image classification performance is improved by 8.1% and 2.3%, respectively, when utilizing high-quality synthetic images selected by our RL framework. Our proposed synthetic sample selection method is general and has great potential to boost the performance of various medical image recognition systems given limited annotation.

Sudhir Sornapudi, R. Joe Stanley, William V. Stoecker et al.

Cervical cancer is one of the deadliest cancers affecting women globally. Cervical intraepithelial neoplasia (CIN) assessment using histopathological examination of cervical biopsy slides is subject to interobserver variability. Automated processing of digitized histopathology slides has the potential for more accurate classification for CIN grades from normal to increasing grades of pre-malignancy: CIN1, CIN2 and CIN3. Cervix disease is generally understood to progress from the bottom (basement membrane) to the top of the epithelium. To model this relationship of disease severity to spatial distribution of abnormalities, we propose a network pipeline, DeepCIN, to analyze high-resolution epithelium images (manually extracted from whole-slide images) hierarchically by focusing on localized vertical regions and fusing this local information for determining Normal/CIN classification. The pipeline contains two classifier networks: 1) a cross-sectional, vertical segment-level sequence generator (two-stage encoder model) is trained using weak supervision to generate feature sequences from the vertical segments to preserve the bottom-to-top feature relationships in the epithelium image data; 2) an attention-based fusion network image-level classifier predicting the final CIN grade by merging vertical segment sequences. The model produces the CIN classification results and also determines the vertical segment contributions to CIN grade prediction. Experiments show that DeepCIN achieves pathologist-level CIN classification accuracy.

Yuan Xue, Jiarong Ye, Rodney Long et al.

Supervised training of an automated medical image analysis system often requires a large amount of expert annotations that are hard to collect. Moreover, the proportions of data available across different classes may be highly imbalanced for rare diseases. To mitigate these issues, we investigate a novel data augmentation pipeline that selectively adds new synthetic images generated by conditional Adversarial Networks (cGANs), rather than extending directly the training set with synthetic images. The selection mechanisms that we introduce to the synthetic augmentation pipeline are motivated by the observation that, although cGAN-generated images can be visually appealing, they are not guaranteed to contain essential features for classification performance improvement. By selecting synthetic images based on the confidence of their assigned labels and their feature similarity to real labeled images, our framework provides quality assurance to synthetic augmentation by ensuring that adding the selected synthetic images to the training set will improve performance. We evaluate our model on a medical histopathology dataset, and two natural image classification benchmarks, CIFAR10 and SVHN. Results on these datasets show significant and consistent improvements in classification performance (with 6.8%, 3.9%, 1.6% higher accuracy, respectively) by leveraging cGAN generated images with selective augmentation.

Sudhir Sornapudi, G. T. Brown, Zhiyun Xue et al.

Liquid-based cytology (LBC) is a reliable automated technique for the screening of Papanicolaou (Pap) smear data. It is an effective technique for collecting a majority of the cervical cells and aiding cytopathologists in locating abnormal cells. Most methods published in the research literature rely on accurate cell segmentation as a prior, which remains challenging due to a variety of factors, e.g., stain consistency, presence of clustered cells, etc. We propose a method for automatic classification of cervical slide images through generation of labeled cervical patch data and extracting deep hierarchical features by fine-tuning convolution neural networks, as well as a novel graph-based cell detection approach for cellular level evaluation. The results show that the proposed pipeline can classify images of both single cell and overlapping cells. The VGG-19 model is found to be the best at classifying the cervical cytology patch data with 95 % accuracy under precision-recall curve.

Yuan Xue, Qianying Zhou, Jiarong Ye et al.

Cervical intraepithelial neoplasia (CIN) grade of histopathology images is a crucial indicator in cervical biopsy results. Accurate CIN grading of epithelium regions helps pathologists with precancerous lesion diagnosis and treatment planning. Although an automated CIN grading system has been desired, supervised training of such a system would require a large amount of expert annotations, which are expensive and time-consuming to collect. In this paper, we investigate the CIN grade classification problem on segmented epithelium patches. We propose to use conditional Generative Adversarial Networks (cGANs) to expand the limited training dataset, by synthesizing realistic cervical histopathology images. While the synthetic images are visually appealing, they are not guaranteed to contain meaningful features for data augmentation. To tackle this issue, we propose a synthetic-image filtering mechanism based on the divergence in feature space between generated images and class centroids in order to control the feature quality of selected synthetic images for data augmentation. Our models are evaluated on a cervical histopathology image dataset with a limited number of patch-level CIN grade annotations. Extensive experimental results show a significant improvement of classification accuracy from 66.3% to 71.7% using the same ResNet18 baseline classifier after leveraging our cGAN generated images with feature-based filtering, which demonstrates the effectiveness of our models.