Usama Sajjad

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, 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.

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.

Ziyu Su, Abdul Rehman Akbar, Usama Sajjad et al.

Foundation models (FM) have transformed computational pathology but remain computationally prohibitive for clinical deployment due to their massive parameter counts and high-magnification processing requirements. Here, we introduce XMAG, a lightweight FM developed through corss-magnification distillation that transfers knowledge from state-of-the-art 20x magnification teacher to an efficient 5x magnification student architecture. XMAG employs a compact backbone and operates entirely at 5x, requiring 11.3 times fewer patches per whole slide image (WSI) compared to existing approaches. Our Novel distillation framework incorporates dual-level knowledge transfer, aligning both global image representations and local spatial token mapping. We trained XMAG on 3.49 million images curated from publicly available datasets and evaluated performance across six clinically relevant histopathology analysis tasks spanning multiple cancer types. XMAG achieved diagnostic accuracy within 1% of substantially larger foundation models while delivering 30-fold processing acceleration, reaching 8.8 WSIs per minute processing speed. Our cross-institutional validation confirmed robust generalization. Further, we developed an end-to-end training strategy to further boost our model's performance to approach the larger FMs' performance. These results establish cross-magnification distillation as a viable approach for deploying FM capabilities in resource-constrained clinical environments, potentially enabling real-time pathology AI integration.