Toward AI-Assisted Sickle Cell Screening: A Controlled Comparison of CNN, Transformer, and Hybrid Architectures Using Public Blood-Smear Images

Background: Sickle cell disease (SCD) is a prevalent hereditary hemoglobinopathy associated with substantial morbidity, particularly in regions with limited access to advanced laboratory diagnostics. Conventional diagnostic workflows, including manual peripheral blood smear examination and biochemical or molecular assays, are resource-intensive, time-consuming, and subject to observer variability. Recent advances in artificial intelligence (AI) enable automated analysis of blood smear images and offer a scalable alternative for SCD screening. Methods: This study presents a controlled benchmark of CNNs, Vision Transformers, hierarchical Transformers, and hybrid CNN–Transformer architectures for image-level SCD classification using a publicly available peripheral blood smear dataset. Eleven ImageNet-pretrained models were fine-tuned under identical conditions using an explicit leakage-safe evaluation protocol, incorporating duplicate-aware, group-based data splitting and repeated splits to assess robustness. Performance was evaluated using accuracy and macro-averaged precision, recall, and F1-score, complemented by bootstrap confidence intervals, paired statistical testing, error-type analysis, and explainable AI (XAI). Results: Across repeated group-aware splits, CNN-based and hybrid architectures demonstrated more stable and consistently higher performance than transformer-only models. MaxViT-Tiny and DenseNet121 ranked highest overall, while pure ViTs showed reduced effectiveness under data-constrained conditions. Error analysis revealed a dominance of false-positive predictions, reflecting intrinsic morphological ambiguity in challenging samples. XAI visualizations suggest that CNNs focus on localized red blood cell morphology, whereas hybrid models integrate both local and contextual cues. Conclusions: Under limited-data conditions, convolutional inductive bias remains critical for robust blood-smear-based SCD classification. CNN and hybrid CNN–Transformer models offer interpretable and reliable performance, supporting their potential role as decision-support tools in screening-oriented research settings.