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Improving the diagnostic efficiency of forme fruste keratoconus by a new combined model with Fourier parameters and corneal epithelial aberrations

Eye volume 39, pages 2945–2951 (2025)Cite this article

Subjects

Abstract

Purposes

To explore a new method to improve the diagnostic efficiency of forme fruste keratoconus (FFKC) using the combination of Fourier parameters and corneal epithelial aberrations.

Design

Prospective, case-control analysis.

Methods

This prospective study enrolled 55 FFKC patients and 68 healthy subjects. The same experienced operator performed Casia 2 (Tomey, Nagoya, Japan) and MS-39 (CSO, Florence, Italy) examinations to obtain Fourier parameters and corneal epithelial aberrations within the central 6 mm of the cornea. Independent-samples T tests were applied to compare statistical differences between the two groups. Significant variables were selected through dual logistic regression analysis with a stepwise method. The areas under the receiver operating characteristic curves (AUROC) were calculated to estimate the diagnostic ability for each parameter and the combined model, and the Youden index was used to determine the cut-off value. Delong test was performed to compare the differences among the AUROC in different conditions.

Results

The spherical component in Fourier parameters of the posterior surface of the cornea (P = 0.002), the asymmetry of the posterior surface of the cornea (P < 0.001), the higher-order irregularity in Fourier parameters at the posterior surface of the cornea (P = 0.026), and corneal epithelial Z (3, ±1) coma (P = 0.035) were selected as explanatory variables. The combined model demonstrated significantly improved diagnostic efficiency with the highest AUROC value of 0.95 (sensitivity, 0.855; specificity, 0.897; cut-off, 0.400). And the AUROC of the combined model was significantly different from that of the single parameter (P < 0.05).

Conclusion

The integration of Fourier parameters and corneal epithelial aberrations holds potential in enhancing the diagnostic efficacy of FFKC, thus serving as a valuable reference for future clinical applications.

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Fig. 1: The AUROC graph.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

References

  1. Santodomingo-Rubido J, Carracedo G, Suzaki A, Villa-Collar C, Vincent S, Wolffsohn J. Keratoconus: an updated review. Contact Lens Anterior Eye. 2022;45:101559.

    Article  PubMed  Google Scholar 

  2. Wang YM, Chan TCY, Yu M, Jhanji V. Comparison of corneal dynamic and tomographic analysis in normal, forme fruste keratoconic, and keratoconic eyes. J Refract Surg. 2017;33:632–8.

    Article  PubMed  Google Scholar 

  3. Neuhann L, Vogel D, Hall J, Dreyhaupt J, Werner J, Garip-Kuebler A et al. Keratometry changes between year one to seven after corneal cross-linking in patients with keratoconus. Cornea. 2024;431397–402.

  4. Bevara A, Vaddavalli P. The evolution of diagnostics for keratoconus: from ophthalmometry to biomechanics. Semin Ophthalmol. 2023;38:265–74.

    Article  PubMed  Google Scholar 

  5. Niazi S, Jiménez-García M, Findl O, Gatzioufas Z, Doroodgar F, Shahriari M et al. Keratoconus diagnosis: from fundamentals to artificial intelligence: a systematic narrative review. Diagnostics. 2023;13:2715.

  6. Randleman J, Zhang H, Asroui L, Tarib I, Dupps W, Scarcelli G. Subclinical keratoconus detection and characterization using motion tracking Brillouin microscopy. Ophthalmology. 2024:131:310–21.

  7. Ambrósio R, Machado A, Leão E, Lyra J, Salomão M, Esporcatte L, et al. Optimized artificial intelligence for enhanced ectasia detection using Scheimpflug-based corneal tomography and biomechanical data. Am J Ophthalmol. 2023;251:126–42.

    Article  PubMed  Google Scholar 

  8. Chandapura R, Salomão MQ, Ambrósio R, Swarup R, Shetty R, Sinha Roy A. Bowman’s topography for improved detection of early ectasia. J Biophotonics. 2019;12:e201900126.

    Article  PubMed  Google Scholar 

  9. Reinstein DZ, Gobbe M, Archer TJ, Silverman RH, Coleman DJ. Epithelial, stromal, and total corneal thickness in keratoconus: three-dimensional display with artemis very-high frequency digital ultrasound. J Refract Surg. 2010;26:259–71.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Salomão MQ, Hofling-Lima AL, Gomes Esporcatte LP, Correa FF, Meneses EF, Li Y, et al. Corneal ectasia detection by epithelial pattern standard deviation from OCT. J Cataract Refract Surg. 2023;49:190–4.

    Article  PubMed  Google Scholar 

  11. Sherwin T, Brookes NH, Loh IP, Poole CA, Clover GM. Cellular incursion into Bowman’s membrane in the peripheral cone of the keratoconic cornea. Exp Eye Res. 2002;74:473–82.

    Article  CAS  PubMed  Google Scholar 

  12. Nan-Ji L, Robert H, Lin W, Ioannis MA, Jia-Qi A, Qin-Mei W, et al. Depicting the epithelium and stroma profiles of post-laser vision correction ectasia by optical coherence tomography. J Cataract Refract Surg. 2025. https://doi.org/10.1097/j.jcrs.0000000000001684. Online ahead of print.

  13. Mocan MC, Yilmaz PT, Irkec M, Orhan M. In vivo confocal microscopy for the evaluation of corneal microstructure in keratoconus. Curr Eye Res. 2008;33:933–9.

    Article  PubMed  Google Scholar 

  14. Ozgurhan EB, Kara N, Yildirim A, Bozkurt E, Uslu H, Demirok A. Evaluation of corneal microstructure in keratoconus: a confocal microscopy study. Am J Ophthalmol. 2013;156:885–893.e882.

    Article  PubMed  Google Scholar 

  15. Matalia H, Francis M, Gangil T, Chandapura R, Kurian M, Shetty R, et al. Noncontact quantification of topography of anterior corneal surface and Bowman’s layer with high-speed OCT. J Refract Surg. 2017;33:330–6.

    Article  PubMed  Google Scholar 

  16. Khamar P, Shetty R, Ahuja P, Chandapura R, Narasimhan R, Nuijts R, et al. Accuracy of OCT curvature and aberrations of Bowman’s layer: a prospective comparison with physical removal of epithelium. J Refract Surg. 2020;36:193–8.

    Article  PubMed  Google Scholar 

  17. Oie Y, Yasukura Y, Nishida N, Koh S, Kawasaki R, Maeda N, et al. Fourier analysis on regular and irregular astigmatism of anterior and posterior corneal surfaces in fuchs endothelial corneal dystrophy. Am J Ophthalmol. 2021;223:33–41.

    Article  PubMed  Google Scholar 

  18. Yamamoto R, Ono T, Toyono T, Shirakawa R, Noda M, Yoshida J, et al. Assessment of long-term anterior and posterior topographic changes in the cornea after ptosis surgery using fourier harmonic analysis. Cornea. 2021;40:440–4.

    Article  PubMed  Google Scholar 

  19. Maeno S, Koh S, Inoue R, Oie Y, Maeda N, Jhanji V, et al. Fourier analysis on irregular corneal astigmatism using optical coherence tomography in various severity stages of keratoconus. Am J Ophthalmol. 2022;243:55–65.

    Article  PubMed  Google Scholar 

  20. Zhang M, Ji S, Huo Y, Bai S, Tao Z, Zhang J et al. Analyzing the effect of surgical and corneal parameters on the postoperative refractive outcomes of SMILE in myopic eyes based on machine learning. Am J Ophthalmol. 2025;271:455–65.

  21. Rabinowitz YS, Rasheed K. KISA% index: a quantitative videokeratography algorithm embodying minimal topographic criteria for diagnosing keratoconus. J Cataract Refract Surg. 1999;25:1327–35.

    Article  CAS  PubMed  Google Scholar 

  22. Almeida GC Jr, Guido RC, Balarin Silva HM, Brandao CC, de Mattos LC, Lopes BT, et al. New artificial intelligence index based on Scheimpflug corneal tomography to distinguish subclinical keratoconus from healthy corneas. J Cataract Refract Surg. 2022;48:1168–74.

    Article  PubMed  Google Scholar 

  23. Henriquez MA, Hadid M, Izquierdo L Jr. A systematic review of subclinical keratoconus and forme fruste keratoconus. J Refract Surg. 2020;36:270–9.

    Article  PubMed  Google Scholar 

  24. Toprak I, Gunes CE. Increased epithelial backscatter: a novel finding in subclinical and clinical keratoconus. Clin Exp Ophthalmol. 2021;49:1000–8.

    Article  PubMed  Google Scholar 

  25. Oshika T, Tanabe T, Tomidokoro A, Amano S. Progression of keratoconus assessed by fourier analysis of videokeratography data. Ophthalmology. 2002;109:339–42.

    Article  PubMed  Google Scholar 

  26. Oshika T, Tomidokoro A, Maruo K, Tokunaga T, Miyata N. Quantitative evaluation of irregular astigmatism by fourier series harmonic analysis of videokeratography data. Invest Ophthalmol Vis Sci. 1998;39:705–9.

    CAS  PubMed  Google Scholar 

  27. Shetty R, Narasimhan R, Dadachanji Z, Patel P, Maheshwari S, Chabra A, et al. Early corneal and epithelial remodeling differences identified by OCT imaging and artificial intelligence between two transepithelial PRK platforms. J Refract. 2020;36:678–86.

    Article  Google Scholar 

  28. Elkitkat R, Rifay Y, Gharieb H, Ziada H. Accuracy of the indices of MS-39 anterior segment optical coherence tomography in the diagnosis of keratoconic corneas. Eur J Ophthalmol. 2022;32:2116–24.

    Article  PubMed  Google Scholar 

  29. Shiga S, Kojima T, Nishida T, Nakamura T, Ichikawa K. Evaluation of CorvisST biomechanical parameters and anterior segment optical coherence tomography for diagnosing forme fruste keratoconus. Acta Ophthalmol. 2021;99:644–51.

    Article  PubMed  Google Scholar 

  30. DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics. 1988;44:837–45.

    Article  CAS  PubMed  Google Scholar 

  31. Ferdi AC, Nguyen V, Gore DM, Allan BD, Rozema JJ, Watson SL. Keratoconus natural progression: a systematic review and meta-analysis of 11 529 eyes. Ophthalmology. 2019;126:935–45.

    Article  PubMed  Google Scholar 

  32. Ferrari G, Rama P. The keratoconus enigma: a review with emphasis on pathogenesis. Ocul Surf. 2020;18:363–73.

    Article  PubMed  Google Scholar 

  33. Zhao X, Yuan Y, Sun T, Zhang Y, Chen Y. Associations between keratoconus and the level of sex hormones: a cross-sectional study. Front Med. 2022;9:828233.

    Article  Google Scholar 

  34. Salman A, Kailani O, Marshall J, Ghabra M, Balamoun A, Darwish T, et al. Evaluation of anterior and posterior corneal higher order aberrations for the detection of keratoconus and suspect keratoconus. Tomography. 2022;8:2864–73.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Koh S, Inoue R, Maeno S, Mihashi T, Maeda N, Jhanji V, et al. Characteristics of higher-order aberrations in different stages of keratoconus. Eye Contact Lens. 2022;48:256–60.

    Article  PubMed  Google Scholar 

  36. Hashemi H, Beiranvand A, Yekta A, Maleki A, Yazdani N, Khabazkhoob M. Pentacam top indices for diagnosing subclinical and definite keratoconus. J Curr Ophthalmol. 2016;28:21–26.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Xu Z, Li W, Jiang J, Zhuang X, Chen W, Peng M, et al. Characteristic of entire corneal topography and tomography for the detection of sub-clinical keratoconus with Zernike polynomials using Pentacam. Sci Rep. 2017;7:16486.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Heidari Z, Mohammadpour M, Hashemi H, Jafarzadehpur E, Moghaddasi A, Yaseri M, et al. Early diagnosis of subclinical keratoconus by wavefront parameters using Scheimpflug, Placido and Hartmann-Shack based devices. Int Ophthalmol. 2020;40:1659–71.

    Article  PubMed  Google Scholar 

  39. Li Y, Tan O, Brass R, Weiss J, Huang D. Corneal epithelial thickness mapping by Fourier-domain optical coherence tomography in normal and keratoconic eyes. Ophthalmology. 2012;119:2425–33.

    Article  PubMed  Google Scholar 

  40. Ning R, Wang Y, Xu Z, Gustafsson I, Li J, Savini G, et al. Assessing progression limits in different grades of keratoconus from a novel perspective: precision of measurements of the corneal epithelium. Eye Vis. 2024;11:1.

    Article  Google Scholar 

  41. Temstet C, Sandali O, Bouheraoua N, Hamiche T, Galan A, El Sanharawi M, et al. Corneal epithelial thickness mapping using Fourier-domain optical coherence tomography for detection of form fruste keratoconus. J Cataract Refract Surg. 2015;41:812–20.

    Article  PubMed  Google Scholar 

  42. Koppen C, Jiménez-García M, Kreps E, Ní Dhubhghaill S, Rozema J. Definitions for keratoconus progression and their impact on clinical practice. Eye & Contact Lens. 2024;50:1–9.

  43. Akincioglu D, Ozge G, Ayyildiz O, Gokce G, Karaca U, Mutlu F. Fourier analysis of corneal Scheimpflug imaging: clinical use in keratoconus. Int J Ophthalmol. 2021;14:1963–9.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Vega-Estrada A, Fariselli C, Alio J. Posterior corneal features in patients with Down syndrome and their relation with keratoconus. Brit J Ophthalmol. 2020;104:1683–9.

    Article  Google Scholar 

  45. Gomes JA, Tan D, Rapuano CJ, Belin MW, Ambrosio R Jr, Guell JL, et al. Global consensus on keratoconus and ectatic diseases. Cornea. 2015;34:359–69.

    Article  PubMed  Google Scholar 

  46. Pérez-Rueda A, Jiménez-Rodríguez D, Castro-Luna G. Diagnosis of subclinical keratoconus with a combined model of biomechanical and topographic parameters. J Clin Med. 2021;10:2746.

  47. Zhang M, Zhang F, Li Y, Song Y, Wang Z. Early diagnosis of keratoconus in Chinese myopic eyes by combining Corvis ST with Pentacam. Current eye Res. 2020;45:118–23.

    Article  CAS  Google Scholar 

  48. Luz A, Lopes B, Hallahan KM, Valbon B, Fontes B, Schor P, et al. Discriminant value of custom ocular response analyzer waveform derivatives in forme fruste keratoconus. Am J Ophthalmol. 2016;164:14–21.

    Article  PubMed  Google Scholar 

  49. Kirgiz A, Karaman Erdur S, Atalay K, Gurez C. The role of ocular response analyzer in differentiation of forme fruste keratoconus from corneal astigmatism. Eye Contact Lens. 2019;45:83–87.

    Article  PubMed  Google Scholar 

  50. Gharieb HM, Abdelatif MK, Gharieb HM, Othman IS. Early, forme fruste keratoconus and normal thin cornea, evaluation of sensitive parameters by combined Placido Scheimpflug topography. Eur J Ophthalmol. 2024;34:59–70.

    Article  PubMed  Google Scholar 

  51. Tian L, Zhang D, Guo L, Qin X, Zhang H, Zhang H, et al. Comparisons of corneal biomechanical and tomographic parameters among thin normal cornea, forme fruste keratoconus, and mild keratoconus. Eye Vis. 2021;8:44.

    Article  Google Scholar 

  52. Kozobolis V, Sideroudi H, Giarmoukakis A, Gkika M, Labiris G. Corneal biomechanical properties and anterior segment parameters in forme fruste keratoconus. Eur J Ophthalmol. 2012;22:920–30.

    Article  PubMed  Google Scholar 

  53. Naderan M, Jahanrad A, Farjadnia M. Ocular, corneal, and internal aberrations in eyes with keratoconus, forme fruste keratoconus, and healthy eyes. Int Ophthalmol. 2018;38:1565–73.

    Article  PubMed  Google Scholar 

  54. Thulasidas M, Teotia P. Evaluation of corneal topography and tomography in fellow eyes of unilateral keratoconus patients for early detection of subclinical keratoconus. Indian J Ophthalmol. 2020;68:2415–20.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Zhang H, Tian L, Guo L, Qin X, Zhang D, Li L, et al. Comprehensive evaluation of corneas from normal, forme fruste keratoconus and clinical keratoconus patients using morphological and biomechanical properties. Int Ophthalmol. 2021;41:1247–59.

  56. Scarcelli G, Besner S, Pineda R, Kalout P, Yun SH. In vivo biomechanical mapping of normal and keratoconus corneas. JAMA Ophthalmol. 2015;133:480–2.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Hwang E, Perez-Straziota C, Kim S, Santhiago M, Randleman J. Distinguishing highly asymmetric keratoconus eyes using combined scheimpflug and spectral-domain OCT analysis. Ophthalmology. 2018;125:1862–71.

    Article  PubMed  Google Scholar 

  58. Ambrósio R, Lopes B, Faria-Correia F, Salomão M, Bühren J, Roberts C, et al. Integration of Scheimpflug-based corneal tomography and biomechanical assessments for enhancing Ectasia detection. J Refract Surg. 2017;33:434–43.

    Article  PubMed  Google Scholar 

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Funding

This work was supported in part by Science and Technology Commission of Shanghai Municipality (Grant No. 22S11900200, 23XD1420500); EYE & ENT Hospital of Fudan University High-level Talents Program (Grant No. 2021318); Program for Professor of Special Appointment (Eastern Scholar, TP2022046) at Shanghai Institutions of Higher Learning; Medical Engineering fund of Fudan University (yg2023-06, yg2023-26). Shanghai Yangpu District Clinical Special Project for Young Researchers (YPQ202407). The funders had no role in study design, data collection and analysis, decision to publish, or reparation of the manuscript. Shanghai Municipal Health Commission Health Industry General Clinical Research Project (No. 202540083).

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Author notes

  1. These authors contributed equally: Rui Ning, Yue Li.

Authors and Affiliations

  1. Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University; NHC Key laboratory of Myopia and Related Eye Diseases; Key Laboratory of Myopia and Related Eye Diseases, Chinese Academy of Medical Sciences, Shanghai, China

    Rui Ning, Yizhou Yang, Xingtao Zhou, Xiaoying Wang & Jinhai Huang

  2. Shanghai Research Center of Ophthalmology and Optometry, Shanghai, China

    Rui Ning, Yizhou Yang, Xingtao Zhou, Xiaoying Wang & Jinhai Huang

  3. Department of Ophthalmology, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China

    Yue Li

  4. School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China

    Jiawei li

  5. University of Shanghai for science and technology, school of health science and engineering, Shanghai, China

    Xinning Yang

  6. Department of Clinical Sciences, Ophthalmology, Lund University, Skåne University Hospital, Lund, Sweden

    Ingemar Gustafsson

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  1. Rui Ning
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  2. Yue Li
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  3. Jiawei li
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  4. Xinning Yang
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  5. Yizhou Yang
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  6. Ingemar Gustafsson
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Contributions

Patient data was gathered by RN, YL, JWL, and XNY. RN and YL prepared the main manuscript content. YZY, IG, XTZ and XYW have drafted the work or substantively revised it. JHH and XYW reviewed statistical techniques and provided article ideas. The manuscript was reviewed by all authors.

Corresponding authors

Correspondence to Xiaoying Wang or Jinhai Huang.

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Competing interests

The authors declare no competing interests.

Ethics

The authors are accountable for all aspects of the work. This includes ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The trial was conducted in accordance with the Declaration of Helsinki. The study was approved by Ethics Committee of the Eye and ENT Hospital of Fudan University (2021174) and informed consent was obtained from all individual participants.

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Ning, R., Li, Y., li, J. et al. Improving the diagnostic efficiency of forme fruste keratoconus by a new combined model with Fourier parameters and corneal epithelial aberrations. Eye 39, 2945–2951 (2025). https://doi.org/10.1038/s41433-025-03975-z

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