Metin N. Gürcan

Ziyu Su, Mostafa Rezapour, Usama Sajjad et al.

Multiple instance learning (MIL) models have achieved remarkable success in analyzing whole slide images (WSIs) for disease classification problems. However, with regard to gigapixel WSI classification problems, current MIL models are often incapable of differentiating a WSI with extremely small tumor lesions. This minute tumor-to-normal area ratio in a MIL bag inhibits the attention mechanism from properly weighting the areas corresponding to minor tumor lesions. To overcome this challenge, we propose salient instance inference MIL (SiiMIL), a weakly-supervised MIL model for WSI classification. Our method initially learns representations of normal WSIs, and it then compares the normal WSIs representations with all the input patches to infer the salient instances of the input WSI. Finally, it employs attention-based MIL to perform the slide-level classification based on the selected patches of the WSI. Our experiments imply that SiiMIL can accurately identify tumor instances, which could only take up less than 1% of a WSI, so that the ratio of tumor to normal instances within a bag can increase by two to four times. It is worth mentioning that it performs equally well for large tumor lesions. As a result, SiiMIL achieves a significant improvement in performance over the state-of-the-art MIL methods.

Ziyu Su, Yongxin Guo, Robert Wesolowski et al.

Accurate recurrence risk stratification is crucial for optimizing treatment plans for breast cancer patients. Current prognostic tools like Oncotype DX (ODX) offer valuable genomic insights for HR+/HER2- patients but are limited by cost and accessibility, particularly in underserved populations. In this study, we present Deep-BCR-Auto, a deep learning-based computational pathology approach that predicts breast cancer recurrence risk from routine H&E-stained whole slide images (WSIs). Our methodology was validated on two independent cohorts: the TCGA-BRCA dataset and an in-house dataset from The Ohio State University (OSU). Deep-BCR-Auto demonstrated robust performance in stratifying patients into low- and high-recurrence risk categories. On the TCGA-BRCA dataset, the model achieved an area under the receiver operating characteristic curve (AUROC) of 0.827, significantly outperforming existing weakly supervised models (p=0.041). In the independent OSU dataset, Deep-BCR-Auto maintained strong generalizability, achieving an AUROC of 0.832, along with 82.0% accuracy, 85.0% specificity, and 67.7% sensitivity. These findings highlight the potential of computational pathology as a cost-effective alternative for recurrence risk assessment, broadening access to personalized treatment strategies. This study underscores the clinical utility of integrating deep learning-based computational pathology into routine pathological assessment for breast cancer prognosis across diverse clinical settings.

Mostafa Rezapour, Rachel B. Seymour, Stephen H. Sims et al.

This study explored the potential of gait analysis as a tool for assessing post-injury complications, e.g., infection, malunion, or hardware irritation, in patients with lower extremity fractures. The research focused on the proficiency of supervised machine learning models predicting complications using consecutive gait datasets. We identified patients with lower extremity fractures at an academic center. Patients underwent gait analysis with a chest-mounted IMU device. Using software, raw gait data was preprocessed, emphasizing 12 essential gait variables. Machine learning models including XGBoost, Logistic Regression, SVM, LightGBM, and Random Forest were trained, tested, and evaluated. Attention was given to class imbalance, addressed using SMOTE. We introduced a methodology to compute the Rate of Change (ROC) for gait variables, independent of the time difference between gait analyses. XGBoost was the optimal model both before and after applying SMOTE. Prior to SMOTE, the model achieved an average test AUC of 0.90 (95% CI: [0.79, 1.00]) and test accuracy of 86% (95% CI: [75%, 97%]). Feature importance analysis attributed importance to the duration between injury and gait analysis. Data patterns showed early physiological compensations, followed by stabilization phases, emphasizing prompt gait analysis. This study underscores the potential of machine learning, particularly XGBoost, in gait analysis for orthopedic care. Predicting post-injury complications, early gait assessment becomes vital, revealing intervention points. The findings support a shift in orthopedics towards a data-informed approach, enhancing patient outcomes.

Ziyu Su, Mostafa Rezapour, Usama Sajjad et al.

Although multiple instance learning (MIL) methods are widely used for automatic tumor detection on whole slide images (WSI), they suffer from the extreme class imbalance within the small tumor WSIs. This occurs when the tumor comprises only a few isolated cells. For early detection, it is of utmost importance that MIL algorithms can identify small tumors, even when they are less than 1% of the size of the WSI. Existing studies have attempted to address this issue using attention-based architectures and instance selection-based methodologies, but have not yielded significant improvements. This paper proposes cross-attention-based salient instance inference MIL (CASiiMIL), which involves a novel saliency-informed attention mechanism, to identify breast cancer lymph node micro-metastasis on WSIs without the need for any annotations. Apart from this new attention mechanism, we introduce a negative representation learning algorithm to facilitate the learning of saliency-informed attention weights for improved sensitivity on tumor WSIs. The proposed model outperforms the state-of-the-art MIL methods on two popular tumor metastasis detection datasets, and demonstrates great cross-center generalizability. In addition, it exhibits excellent accuracy in classifying WSIs with small tumor lesions. Moreover, we show that the proposed model has excellent interpretability attributed to the saliency-informed attention weights. We strongly believe that the proposed method will pave the way for training algorithms for early tumor detection on large datasets where acquiring fine-grained annotations is practically impossible.

Yongxin Guo, Hao Lu, Onur C. Koyun et al.

Multimodal learning that integrates genomics and histopathology has shown strong potential in cancer diagnosis, yet its clinical translation is hindered by the limited availability of paired histology-genomics data. Knowledge distillation (KD) offers a practical solution by transferring genomic supervision into histopathology models, enabling accurate inference using histology alone. However, existing KD methods rely on batch-local alignment, which introduces instability due to limited within-batch comparisons and ultimately degrades performance. To address these limitations, we propose Momentum Memory Knowledge Distillation (MoMKD), a cross-modal distillation framework driven by a momentum-updated memory. This memory aggregates genomic and histopathology information across batches, effectively enlarging the supervisory context available to each mini-batch. Furthermore, we decouple the gradients of the genomics and histology branches, preventing genomic signals from dominating histology feature learning during training and eliminating the modality-gap issue at inference time. Extensive experiments on the TCGA-BRCA benchmark (HER2, PR, and ODX classification tasks) and an independent in-house testing dataset demonstrate that MoMKD consistently outperforms state-of-the-art MIL and multimodal KD baselines, delivering strong performance and generalization under histology-only inference. Overall, MoMKD establishes a robust and generalizable knowledge distillation paradigm for computational pathology.

Hao Lu, Onur C. Koyun, Yongxin Guo et al.

Vector Quantization (VQ) underpins many modern generative frameworks such as VQ-VAE, VQ-GAN, and latent diffusion models. Yet, it suffers from the persistent problem of codebook collapse, where a large fraction of code vectors remains unused during training. This work provides a new theoretical explanation by identifying the nonstationary nature of encoder updates as the fundamental cause of this phenomenon. We show that as the encoder drifts, unselected code vectors fail to receive updates and gradually become inactive. To address this, we propose two new methods: Non-Stationary Vector Quantization (NSVQ), which propagates encoder drift to non-selected codes through a kernel-based rule, and Transformer-based Vector Quantization (TransVQ), which employs a lightweight mapping to adaptively transform the entire codebook while preserving convergence to the k-means solution. Experiments on the CelebA-HQ dataset demonstrate that both methods achieve near-complete codebook utilization and superior reconstruction quality compared to baseline VQ variants, providing a principled and scalable foundation for future VQ-based generative models. The code is available at: https://github.com/CAIR- LAB- WFUSM/NSVQ-TransVQ.git

Hao Lu, Onur C. Koyun, Yongxin Guo et al.

Vector-quantized autoencoders deliver high-fidelity latents but suffer inherent flaws: the quantizer is non-differentiable, requires straight-through hacks, and is prone to collapse. We address these issues at the root by replacing VQ with a simple, principled, and fully differentiable alternative: an online PCA bottleneck trained via Oja's rule. The resulting model, PCA-VAE, learns an orthogonal, variance-ordered latent basis without codebooks, commitment losses, or lookup noise. Despite its simplicity, PCA-VAE exceeds VQ-GAN and SimVQ in reconstruction quality on CelebAHQ while using 10-100x fewer latent bits. It also produces naturally interpretable dimensions (e.g., pose, lighting, gender cues) without adversarial regularization or disentanglement objectives. These results suggest that PCA is a viable replacement for VQ: mathematically grounded, stable, bit-efficient, and semantically structured, offering a new direction for generative models beyond vector quantization.

Usman Afzaal, Ziyu Su, Usama Sajjad et al.

Reproducibility remains a critical challenge in foundation model training for histopathology, often hindered by software randomness, hardware non-determinism, and inconsistent hyperparameter reporting. To investigate these issues, we trained a CLIP model on the QUILT-1M dataset and systematically evaluated the impact of different hyperparameter settings and augmentation strategies across three downstream histopathology datasets (PatchCamelyon, LC25000-Lung, and LC25000-Colon). Despite variability across runs, we identified clear trends: RandomResizedCrop values of 0.7-0.8 outperformed more aggressive (0.6) or conservative (0.9) settings, distributed training without local loss improved stability, and learning rates below 5.0e-5 consistently degraded performance across all datasets. The LC25000 (Colon) dataset consistently provided the most reproducible benchmark. These findings highlight that reproducibility in computational pathology depends not only on transparent documentation but also on carefully chosen experimental configurations, and we provide practical rules to guide future efforts in developing reproducible foundation models for digital pathology.

Mostafa Rezapour, Aarthi Narayanan, Wyatt H. Mowery et al.

This study evaluates the concordance between RNA sequencing (RNA-Seq) and NanoString technologies for gene expression analysis in non-human primates (NHPs) infected with Ebola virus (EBOV). We performed a detailed comparison of both platforms, demonstrating a strong correlation between them, with Spearman coefficients for 56 out of 62 samples ranging from 0.78 to 0.88, with a mean of 0.83 and a median of 0.85. Bland-Altman analysis further confirmed high consistency, with most measurements falling within 95% confidence limits. A machine learning approach, using the Supervised Magnitude-Altitude Scoring (SMAS) method trained on NanoString data, identified OAS1 as a key marker for distinguishing RT-qPCR positive from negative samples. Remarkably, when applied to RNA-Seq data, OAS1 also achieved 100% accuracy in differentiating infected from uninfected samples using logistic regression, demonstrating its robustness across platforms. Further differential expression analysis identified 12 common genes including ISG15, OAS1, IFI44, IFI27, IFIT2, IFIT3, IFI44L, MX1, MX2, OAS2, RSAD2, and OASL which demonstrated the highest levels of statistical significance and biological relevance across both platforms. Gene Ontology (GO) analysis confirmed that these genes are directly involved in key immune and viral infection pathways, reinforcing their importance in EBOV infection. In addition, RNA-Seq uniquely identified genes such as CASP5, USP18, and DDX60, which play key roles in immune regulation and antiviral defense. This finding highlights the broader detection capabilities of RNA-Seq and underscores the complementary strengths of both platforms in providing a comprehensive and accurate assessment of gene expression changes during Ebola virus infection.

Mostafa Rezapour, Muhammad Khalid Khan Niazi, Hao Lu et al.

This study introduces the Supervised Magnitude-Altitude Scoring (SMAS) methodology, a machine learning-based approach, for analyzing gene expression data obtained from nonhuman primates (NHPs) infected with Ebola virus (EBOV). We utilize a comprehensive dataset of NanoString gene expression profiles from Ebola-infected NHPs, deploying the SMAS system for nuanced host-pathogen interaction analysis. SMAS effectively combines gene selection based on statistical significance and expression changes, employing linear classifiers such as logistic regression to accurately differentiate between RT-qPCR positive and negative NHP samples. A key finding of our research is the identification of IFI6 and IFI27 as critical biomarkers, demonstrating exceptional predictive performance with 100% accuracy and Area Under the Curve (AUC) metrics in classifying various stages of Ebola infection. Alongside IFI6 and IFI27, genes, including MX1, OAS1, and ISG15, were significantly upregulated, highlighting their essential roles in the immune response to EBOV. Our results underscore the efficacy of the SMAS method in revealing complex genetic interactions and response mechanisms during EBOV infection. This research provides valuable insights into EBOV pathogenesis and aids in developing more precise diagnostic tools and therapeutic strategies to address EBOV infection in particular and viral infection in general.

Qing Lyu, Sanjeev V. Namjoshi, Emory McTyre et al.

Treatment decisions for brain metastatic disease rely on knowledge of the primary organ site, and currently made with biopsy and histology. Here we develop a novel deep learning approach for accurate non-invasive digital histology with whole-brain MRI data. Our IRB-approved single-site retrospective study was comprised of patients (n=1,399) referred for MRI treatment-planning and gamma knife radiosurgery over 21 years. Contrast-enhanced T1-weighted and T2-weighted Fluid-Attenuated Inversion Recovery brain MRI exams (n=1,582) were preprocessed and input to the proposed deep learning workflow for tumor segmentation, modality transfer, and primary site classification into one of five classes. Ten-fold cross-validation generated overall AUC of 0.878 (95%CI:0.873,0.883), lung class AUC of 0.889 (95%CI:0.883,0.895), breast class AUC of 0.873 (95%CI:0.860,0.886), melanoma class AUC of 0.852 (95%CI:0.842,0.862), renal class AUC of 0.830 (95%CI:0.809,0.851), and other class AUC of 0.822 (95%CI:0.805,0.839). These data establish that whole-brain imaging features are discriminative to allow accurate diagnosis of the primary organ site of malignancy. Our end-to-end deep radiomic approach has great potential for classifying metastatic tumor types from whole-brain MRI images. Further refinement may offer an invaluable clinical tool to expedite primary cancer site identification for precision treatment and improved outcomes.

Saima Rathore, Muhammad A. Iftikhar, Metin N. Gurcan et al.

Both radiographic (Rad) imaging, such as multi-parametric magnetic resonance imaging, and digital pathology (Path) images captured from tissue samples are currently acquired as standard clinical practice for glioblastoma tumors. Both these data streams have been separately used for diagnosis and treatment planning, despite the fact that they provide complementary information. In this research work, we aimed to assess the potential of both Rad and Path images in combination and comparison. An extensive set of engineered features was extracted from delineated tumor regions in Rad images, comprising T1, T1-Gd, T2, T2-FLAIR, and 100 random patches extracted from Path images. Specifically, the features comprised descriptors of intensity, histogram, and texture, mainly quantified via gray-level-co-occurrence matrix and gray-level-run-length matrices. Features extracted from images of 107 glioblastoma patients, downloaded from The Cancer Imaging Archive, were run through support vector machine for classification using leave-one-out cross-validation mechanism, and through support vector regression for prediction of continuous survival outcome. The Pearson correlation coefficient was estimated to be 0.75, 0.74, and 0.78 for Rad, Path and RadPath data. The area-under the receiver operating characteristic curve was estimated to be 0.74, 0.76 and 0.80 for Rad, Path and RadPath data, when patients were discretized into long- and short-survival groups based on average survival cutoff. Our results support the notion that synergistically using Rad and Path images may lead to better prognosis at the initial presentation of the disease, thereby facilitating the targeted enrollment of patients into clinical trials.