Artificial intelligence utilising corneal confocal microscopy for the diagnosis of peripheral neuropathy in diabetes mellitus and prediabetes
Open accessAbstract
Aims/hypothesis: We aimed to develop an artificial intelligence (AI)-based deep learning algorithm (DLA) applying attribution methods without image segmentation to corneal confocal microscopy images and to accurately classify peripheral neuropathy (or lack of). Methods: The AI-based DLA utilised convolutional neural networks with data augmentation to increase the algorithm’s generalisability. The algorithm was trained using a high-end graphics processor for 300 epochs on 329 corneal nerve images and tested on 40 images (1 image/participant). Participants consisted of healthy volunteer (HV) participants (n = 90) and participants with type 1 diabetes (n = 88), type 2 diabetes (n = 141) and prediabetes (n = 50) (defined as impaired fasting glucose, impaired glucose tolerance or a combination of both), and were classified into HV, those without neuropathy (PN−) (n = 149) and those with neuropathy (PN+) (n = 130). For the AI-based DLA, a modified residual neural network called ResNet-50 was developed and used to extract features from images and perform classification. The algorithm was tested on 40 participants (15 HV, 13 PN−, 12 PN+). Attribution methods gradient-weighted class activation mapping (Grad-CAM), Guided Grad-CAM and occlusion sensitivity displayed the areas within the image that had the greatest impact on the decision of the algorithm. Results: The results were as follows: HV: recall of 1.0 (95% CI 1.0, 1.0), precision of 0.83 (95% CI 0.65, 1.0), F1-score of 0.91 (95% CI 0.79, 1.0); PN−: recall of 0.85 (95% CI 0.62, 1.0), precision of 0.92 (95% CI 0.73, 1.0), F1-score of 0.88 (95% CI 0.71, 1.0); PN+: recall of 0.83 (95% CI 0.58, 1.0), precision of 1.0 (95% CI 1.0, 1.0), F1-score of 0.91 (95% CI 0.74, 1.0). The features displayed by the attribution methods demonstrated more corneal nerves in HV, a reduction in corneal nerves for PN− and an absence of corneal nerves for PN+ images. Conclusions/interpretation: We demonstrate promising results in the rapid classification of peripheral neuropathy using a single corneal image. A large-scale multicentre validation study is required to assess the utility of AI-based DLA in screening and diagnostic programmes for diabetic neuropathy. Graphical abstract:
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Preston et al. reported that a CNN using corneal confocal microscopy images to identify diabetic peripheral neuropathy achieved recall of 0.83, precision of 1.0, and F1 score of 0.91.
“the system could achieve recall of 0.83, precision of 1.0, and F1 score of 0.91”
From Artificial intelligence in diabetes management: Advancements, opportunities, and challenges (2023) · cites this paper as Preston et al.119
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Cites
Deep Residual Learning for Image Recognition
He, K., Zhang, X., Ren, S., & Sun, J. (2016) · 2016 IEEE Conference on Computer Vision and Pattern Recognition (CVPR) · doi:10.1109/cvpr.2016.90 · Cited by 235,474 · see citing works
U-Net: Convolutional Networks for Biomedical Image Segmentation
Ronneberger, O., Fischer, P., & Brox, T. (2015) · Lecture notes in computer science · doi:10.1007/978-3-319-24574-4_28 · Cited by 99,404 · see citing works
IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045
Cho, N. H., Shaw, J. E., Karuranga, S., Huang, Y., da Rocha Fernandes, J. D., Ohlrogge, A. W., & Malanda, B. (2018) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2018.02.023 · Cited by 7,283 · see citing works
Tesfaye, S., Boulton, A. J. M., Dyck, P. J., Freeman, R., Horowitz, M., Kempler, P., Lauria, G., Malik, R. A., Spallone, V., Vinik, A., et al. (2010) · Diabetes Care · doi:10.2337/dc10-1303 · Cited by 2,690 · see citing works
Self-citationDiabetic Peripheral Neuropathy: Epidemiology, Diagnosis, and Pharmacotherapy
Iqbal, Z., Azmi, S., Yadav, R., Ferdousi, M., Kumar, M., Cuthbertson, D. J., Lim, J., Malik, R. A., & Alam, U. (2018) · Clinical Therapeutics · doi:10.1016/j.clinthera.2018.04.001 · Cited by 487 · see citing works
Self-citationArtificial intelligence for diabetic retinopathy screening: a review
Grzybowski, A., Brona, P., Lim, G., Ruamviboonsuk, P., Tan, G. S. W., Abramoff, M., & Ting, D. S. W. (2020) · Eye · doi:10.1038/s41433-019-0566-0 · Cited by 376 · cited 1× · see citing works
“However, the development of such AIbased systems requires the acquisition of large image/datasets with human-graded (ground truth) annotations as a reference standard to train the algorithm [44].”
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Flagged first, then by citations
Research works printed but not linked: 41
- [3]Kirthi V Perumbalath A Brown E Prevalence of peripheral neuropathy in pre-diabetes: a systematic review BMJ Open Diabetes Res Care 2021 9 1 e002040 10.1136/bmjdrc-2020-002040 34006607 PMC8137250 · DOI
- [4]Alam U Jeziorska M Petropoulos IN Diagnostic utility of corneal confocal microscopy and intra-epidermal nerve fibre density in diabetic neuropathy PLoS One 2017 12 7 e0180175 10.1371/journal.pone.0180175 28719619 PMC5515394 · DOI
- [5]Petropoulos IN Ponirakis G Khan A Almuhannadi H Gad H Malik RA Diagnosing diabetic neuropathy: something old, something new Diabetes Metab J 2018 42 4 255 269 10.4093/dmj.2018.0056 30136449 PMC6107364 · DOI
- [6]Tavakoli M Quattrini C Abbott C Corneal confocal microscopy: a novel noninvasive test to diagnose and stratify the severity of human diabetic neuropathy Diabetes Care 2010 33 8 1792 1797 10.2337/dc10-0253 20435796 PMC2909064 · DOI
- [7]Petropoulos IN Alam U Fadavi H Corneal nerve loss detected with corneal confocal microscopy is symmetrical and related to the severity of diabetic polyneuropathy Diabetes Care 2013 36 11 3646 3651 10.2337/dc13-0193 23877983 PMC3816900 · DOI
- [8]Lewis EJH Lovblom LE Ferdousi M Rapid corneal nerve Fiber loss: a marker of diabetic neuropathy onset and progression Diabetes Care 2020 43 8 1829 1835 10.2337/dc19-0951 32139385 PMC7372054 · DOI
- [9]Petropoulos IN Manzoor T Morgan P Repeatability of in vivo corneal confocal microscopy to quantify corneal nerve morphology Cornea 2013 32 5 e83 e89 10.1097/ICO.0b013e3182749419 23172119 · DOI
- [10]Tavakoli M Mitu-Pretorian M Petropoulos IN Corneal confocal microscopy detects early nerve regeneration in diabetic neuropathy after simultaneous pancreas and kidney transplantation Diabetes 2013 62 1 254 260 10.2337/db12-0574 23002037 PMC3526062 · DOI
- [11]Azmi S Jeziorska M Ferdousi M Early nerve fibre regeneration in individuals with type 1 diabetes after simultaneous pancreas and kidney transplantation Diabetologia 2019 62 8 1478 1487 10.1007/s00125-019-4897-y 31175373 PMC6647173 · DOI
- [12]Tavakoli M Ferdousi M Petropoulos IN Normative values for corneal nerve morphology assessed using corneal confocal microscopy: a multinational normative data set Diabetes Care 2015 38 5 838 843 10.2337/dc14-2311 25633665 PMC4407754 · DOI · Paper page
- [13]Dehghani C Pritchard N Edwards K Morphometric stability of the corneal subbasal nerve plexus in healthy individuals: a 3-year longitudinal study using corneal confocal microscopy Invest Ophthalmol Vis Sci 2014 55 5 3195 3199 10.1167/iovs.14-13959 24764058 · DOI
- [14]Dabbah MA Graham J Petropoulos IN Tavakoli M Malik RA Automatic analysis of diabetic peripheral neuropathy using multi-scale quantitative morphology of nerve fibres in corneal confocal microscopy imaging Med Image Anal 2011 15 5 738 747 10.1016/j.media.2011.05.016 21719344 · DOI
- [15]Ahmed A Bril V Orszag A Detection of diabetic sensorimotor polyneuropathy by corneal confocal microscopy in type 1 diabetes: a concurrent validity study Diabetes Care 2012 35 4 821 828 10.2337/dc11-1396 22323412 PMC3308301 · DOI
- [16]Kalteniece A Ferdousi M Adam S Corneal confocal microscopy is a rapid reproducible ophthalmic technique for quantifying corneal nerve abnormalities PLoS One 2017 12 8 e0183040 10.1371/journal.pone.0183040 28817609 PMC5560560 · DOI
- [17]Petropoulos IN Alam U Fadavi H Rapid automated diagnosis of diabetic peripheral neuropathy with in vivo corneal confocal microscopy Invest Ophthalmol Vis Sci 2014 55 4 2071 2078 10.1167/iovs.13-13787 24569580 PMC3979234 · DOI
- [18]Chen X Graham J Dabbah MA Petropoulos IN Tavakoli M Malik RA An automatic tool for quantification of nerve fibers in corneal confocal microscopy images IEEE Trans Biomed Eng 2017 64 4 786 794 10.1109/tbme.2016.2573642 27295646 PMC5512547 · DOI
- [19]LeCun Y Bengio Y Hinton G Deep learning Nature 2015 521 7553 436 444 10.1038/nature14539 26017442 · DOI · Paper page
- [20]Salahuddin T, Al-Maadeed SA, Petropoulos IN, Malik RA, Ilyas SK, Qidwai U (2019) Smart neuropathy detection using machine intelligence: Filling the void between clinical practice and early diagnosis. In: 2019 Third World Conference on Smart Trends in Systems Security and Sustainablity (WorldS4). IEEE, New Jersey, United States, pp 141–146
- [21]Scarpa F Colonna A Ruggeri A Multiple-image deep learning analysis for neuropathy detection in corneal nerve images Cornea 2020 39 3 342 347 10.1097/ico.0000000000002181 31658167 · DOI
- [22]Williams BM Borroni D Liu R An artificial intelligence-based deep learning algorithm for the diagnosis of diabetic neuropathy using corneal confocal microscopy: a development and validation study Diabetologia 2020 63 2 419 430 10.1007/s00125-019-05023-4 31720728 PMC6946763 · DOI · Paper page
- [23]Zhou X, Chen X, Feng S, Shi F (2020) An improved U-Net for nerve fibre segmentation in confocal corneal microscopy images. In: Medical Imaging 2020: Image Processing. Vol. 11313. International Society for Optics and Photonics, Washington, United States, p 113131Z
- [24]Singh A Sengupta S Lakshminarayanan V Explainable deep learning models in medical image analysis J Imaging 2020 6 6 52 10.3390/jimaging6060052 34460598 PMC8321083 · DOI · Paper page
- [25]Selvaraju RR, Cogswell M, Das A, Vedantam R, Parikh D, Batra D (2017) Grad-CAM: Visual explanations from deep networks via gradient-based localization. In: Proceedings of the IEEE International Conference on Computer Vision. IEEE, New Jersey, United States, pp 618–626
- [26]Zeiler MD, Fergus R (2014) Visualizing and understanding convolutional networks. In: European Conference on Computer Vision. Springer, Berlin/Heidelberg, Germany, pp 818–833
- [30]Bengio Y Simard P Frasconi P Learning long-term dependencies with gradient descent is difficult IEEE Trans Neural Netw 1994 5 2 157 166 10.1109/72.279181 18267787 · DOI · Paper page
- [32]Deng J, Dong W, Socher R, Li L-J, Li K, Fei-Fei L (2009) Imagenet: A large-scale hierarchical image database. In: 2009 IEEE Conference on Computer Vision and Pattern Recognition. IEEE, New Jersey, United States, pp 248–255
- [33]Sandler M, Howard A, Zhu M, Zhmoginov A, Chen L-C (2018) MobileNetV2: Inverted residuals and linear bottlenecks. In: Proceedings of the IEEE Conference on Computer Vision and Pattern Recognition. IEEE, New Jersey, United States, pp 4510–4520
- [34]Ioffe S, Szegedy C (2015) Batch normalization: Accelerating deep network training by reducing internal covariate shift. In: International Conference on Machine Learning. PMLR, United States, pp 448–456
- [35]Clopper CJ Pearson ES The use of confidence or fiducial limits illustrated in the case of the binomial Biometrika 1934 26 4 404 413 10.1093/biomet/26.4.404 · DOI
- [36]Alam U Maria Jeziorska M Petropoulos IN Diagnostic utility of corneal confocal microscopy and intra-epidermal nerve fibre density in diabetic neuropathy PLoS One 2017 12 7 e0180175 10.1371/journal.pone.0180175 28719619 PMC5515394 · DOI
- [37]Petropoulos IN Ponirakis G Ferdousi M Corneal confocal microscopy: a biomarker for diabetic peripheral neuropathy Clin Ther 2021 S0149-2918 21 00197 00191 10.1016/j.clinthera.2021.04.003 33965237 · DOI
- [38]Colonna A, Scarpa F, Ruggeri A (2018) Segmentation of corneal nerves using a U-Net-based convolutional neural network. In: Computational Pathology and Ophthalmic Medical Image Analysis. Springer, Berlin/Heidelberg, Germany, pp 185–192
- [39]Zhao Y Zhang J Pereira E Automated tortuosity analysis of nerve fibers in corneal confocal microscopy IEEE Trans Med Imaging 2020 39 9 2725 2737 10.1109/tmi.2020.2974499 32078542 · DOI
- [40]Mou L Zhao Y Fu H CS2-net: deep learning segmentation of curvilinear structures in medical imaging Med Image Anal 2021 67 101874 10.1016/j.media.2020.101874 33166771 · DOI
- [41]Oakley JD Russakoff DB McCarron ME Deep learning-based analysis of macaque corneal sub-basal nerve fibers in confocal microscopy images Eye Vis 2020 7 1 27 10.1186/s40662-020-00192-5 PMC7206808 32420401 · DOI
- [42]Dorsey JL Mangus LM Oakley JD Loss of corneal sensory nerve fibers in SIV-infected macaques: an alternate approach to investigate HIV-induced PNS damage Am J Pathol 2014 184 6 1652 1659 10.1016/j.ajpath.2014.02.009 24828391 PMC4044714 · DOI
- [43]Tan B Hosseinaee Z Han L Kralj O Sorbara L Bizheva K 250 kHz, 1.5 μm resolution SD-OCT for in-vivo cellular imaging of the human cornea Biomed Opt Express 2018 9 12 6569 6583 10.1364/boe.9.006569 31065450 PMC6490998 · DOI
- [45]Campanella G Hanna MG Geneslaw L Clinical-grade computational pathology using weakly supervised deep learning on whole slide images Nat Med 2019 25 8 1301 1309 10.1038/s41591-019-0508-1 31308507 PMC7418463 · DOI · Paper page
- [46]Salahouddin T Petropoulos IN Ferdousi M Artificial intelligence-based classification of diabetic peripheral neuropathy from corneal confocal microscopy images Diabetes Care 2021 44 7 e151 e153 10.2337/dc20-2012 34083322 PMC8323170 · DOI · Paper page
- [47]Burgess J Frank B Marshall A Early detection of diabetic peripheral neuropathy: a focus on small nerve fibres Diagnostics 2021 11 2 165 10.3390/diagnostics11020165 33498918 PMC7911433 · DOI
- [49]Heydon P Egan C Bolter L Prospective evaluation of an artificial intelligence-enabled algorithm for automated diabetic retinopathy screening of 30 000 patients Br J Ophthalmol 2021 105 5 723 728 10.1136/bjophthalmol-2020-316594 32606081 PMC8077216 · DOI
Cited by
Sorted by citations
Artificial intelligence in diabetes management: Advancements, opportunities, and challenges
Guan, Z., Li, H., Liu, R., Cai, C., Liu, Y., Li, J., Wang, X., Huang, S., Wu, L., Liu, D., et al. (2023) · Cell Reports Medicine · doi:10.1016/j.xcrm.2023.101213 · Cited by 287 · see citing works
“115 For neuropathy screening, previous studies explored the development of AI systems to identify diabetic neuropathy based on EHRs 116 or corneal confocal microscopy images, 117–119 with AUCs ranging from 0.83 to 0.95.”
BackgroundInfluential
- Authors
- Preston, F. G., Meng, Y., Burgess, J., Ferdousi, M., Azmi, S., Petropoulos, I. N., Kaye, S., Malik, R. A., Zheng, Y., & Alam, U.
- Affiliations
- University of Liverpool (GB)
- University of Manchester (GB)
- Weill Cornell Medical College in Qatar (QA)
- Corresponding author
- Zheng, Yalin
- Alam, Uazman
- ORCID
- Venue
- Diabetologia
- Published
- 2021-11-21
- Volume
- 65
- Issue
- 3
- Pages
- 457-466
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- PMC
- PMC8803718
- OpenAlex
- W3215647506
- Cited by
- 70
- References
- 6
- Citations by year
- 2026: 10 · 2025: 16 · 2024: 16 · 2023: 20 · 2022: 8
- FWCI
- 9.53
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Diabetologia (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Juvenile Diabetes Research Foundation (8-2008-362)
- National Institutes of Health (1DP3DK104386-01)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Ocular Surface and Contact Lens
- Health Sciences › Health Professions › Health Information Management › Artificial Intelligence in Healthcare
- Health Sciences › Medicine › Health Informatics › Artificial Intelligence in Healthcare and Education
- Keywords
- diabetic peripheral neuropathy, corneal confocal microscopy, artificial intelligence, deep learning, corneal nerves, prediabetes, type 1 diabetes, type 2 diabetes, Grad-CAM, occlusion sensitivity, ResNet, neuropathy diagnosis, diabetic neuropathy screening
- MeSH terms
- Artificial Intelligence, Diabetes Mellitus, Type 2, Diabetic Neuropathies, Humans, Prediabetic State, Microscopy, Confocal
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