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Background: Diabetic retinopathy (DR) is a complication of diabetes mellitus, which if left untreated may lead to complete vision loss. Early diagnosis and treatment is the key to prevent further complications of DR. Computer-aided diagnosis is a very effective method to support ophthalmologists, as manual inspection of pathological changes in retina images are time consuming and expensive. In recent times, Machine Learning and Deep Learning techniques have subsided conventional rule based approaches for detection, segmentation and classification of DR stages and lesions in fundus images. Method: In this paper, we present a comparative study of the different state-of-the-art preprocessing methods that have been used in deep learning based DR classification tasks in recent times and also propose a new unsupervised learning based retinal region extraction technique and new combinations of preprocessing pipelines designed on top of it. Efficacy of different existing and new combinations of the preprocessing methods are analyzed using two publicly available retinal datasets (EyePACS and APTOS) for different DR stage classification tasks, such as referable DR, DR screening, and five-class DR grading, using a benchmark deep learning model (ResNet-50). Results: It has been observed that the proposed preprocessing strategy composed of region of interest extraction through K-means clustering followed by contrast and edge enhancement using Graham’s method and z-score intensity normalization achieved the highest accuracy of 98.5%, 96.51% and 90.59% in DR-screening, referable-DR, and DR gradation tasks respectively and also achieved the best quadratic weighted kappa score of 0.945 in DR grading task. It achieved best AUC-ROC of 0.98 and 0.9981 in DR grading and DR screening tasks respectively. Conclusion: It is evident from the results that the proposed preprocessing pipeline composed of the proposed ROI extraction through K-means clustering, followed by edge and contrast enhancement using Graham’s method and then z-score intensity normalization outperforms all other existing preprocessing pipelines and has proven to be the most effective preprocessing strategy in helping the baseline CNN model to extract meaningful deep features.

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