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Deep Learning-Fuzzy Inference (DeLFI): an interpretable model for detecting indirect immunofluorescence patterns associated with nasopharyngeal cancer

      Abstract

      The detection of serum antibodies to Epstein-Barr Virus proteins by immunofluorescence assay (IFA) is considered the gold standard for nasopharyngeal cancer (NPC) screening in high-risk populations. Given the high survival rates of early asymptomatic patients compared to the poor prognosis for late-stage NPC, IFA has tremendous life-saving potential for general population screening. However, IFA requires visual interpretation of cellular staining patterns by trained pathology staff, making it labor-intensive and hence unscalable. This study demonstrates that an automated Fuzzy Inference (FI) system achieved high agreement (κ=0.82) with a human IFA expert in identifying cellular patterns associated with NPC. Integrating a deep learning module into FI further improved FI’s performance (κ=0.90) and reduced the number of uncertain cases which required manual evaluation. The resulting hybrid model, termed deep learning-fuzzy inference (DeLFI), was then evaluated with a separate testing set of clinical samples. In this clinical validation, DeLFI outperformed human evaluation on the Area Under the Curve (0.926 vs 0.821) and closely matched human performance on Youden’s J index (0.81 vs 0.80). We conclude that DeLFI’s combination of deep learning with fuzzy inference has the potential to improve the scalability and accuracy of NPC detection.
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      References

      1. Screening Test Review Committee: Report of the Screening Test Review Committee. Academy of Medicine, Singapore, 2019 Mar.

      2. Chan SH, Goh CHK, Wee JTS, Tam CH, Tan LKS, Heng D, Lee MT: MOH Clinical Practice Guidelines 1/2010. Ministry of Health, Singapore, 2010 Feb.

        • Middeldorp J.M.
        Epstein-Barr Virus-Specific Humoral Immune Responses in Health and Disease.
        Curr Top Microbiol Immunol. 2015; 391: 289-323
        • Tay J.K.
        • Chan S.H.
        • Lim C.M.
        • Siow C.H.
        • Goh H.L.
        • Loh K.S.
        The Role of Epstein-Barr Virus DNA Load and Serology as Screening Tools for Nasopharyngeal Carcinoma.
        Otolaryngol Head Neck Surg. 2016; 155: 274-280
        • Tay J.K.
        • Siow C.H.
        • Goh H.L.
        • Lim C.M.
        • Hsu P.P.
        • Chan S.H.
        • Loh K.S.
        A comparison of EBV serology and serum cell-free DNA as screening tools for nasopharyngeal cancer: Results of the Singapore NPC screening cohort.
        Int J Cancer. 2020; 146: 2923-2931
        • Chan S.H.
        • Soo M.Y.
        • Gan Y.Y.
        • Fones-Tan A.
        • Sim P.S.
        • Kaur A.
        • Chew C.T.
        Epstein Barr virus (EBV) antibodies in the diagnosis of NPC–comparison between IFA and two commercial ELISA kits.
        Singapore Med J. 1998; 39: 263-265
      3. Coghill AE, Hsu W-L, Pfeiffer RM, Juwana H, Yu KJ, Lou P-J, Wang C-P, Chen J-Y, Chen C-J, Middeldorp JM, Hildesheim A: Epstein-Barr virus serology as a potential screening marker for nasopharyngeal carcinoma among high-risk individuals from multiplex families in Taiwan. Cancer Epidemiol Biomarkers Prev 2014, 23:1213–1219.Pubmed Partial Author

        • Hutajulu S.H.
        • Fachiroh J.
        • Argy G.
        • Indrasari S.R.
        • Indrawati L.P.L.
        • Paramita D.K.
        • Jati T.B.R.
        • Middeldorp J.M.
        Seroprevalence of IgA anti Epstein-Barr virus is high among family members of nasopharyngeal cancer patients and individuals presenting with chronic complaints in head and neck area.
        PLoS One. 2017; 12: e0180683
        • Paramita D.K.
        • Fachiroh J.
        • Haryana S.M.
        • Middeldorp J.M.
        Evaluation of commercial EBV RecombLine assay for diagnosis of nasopharyngeal carcinoma.
        J Clin Virol. 2008; 42: 343-352
        • Chan K.C.A.
        • Woo J.K.S.
        • King A.
        • Zee B.C.Y.
        • Lam W.K.J.
        • Chan S.L.
        • Chu S.W.I.
        • Mak C.
        • Tse I.O.L.
        • Leung S.Y.M.
        • Chan G.
        • Hui E.P.
        • Ma B.B.Y.
        • Chiu R.W.K.
        • Leung S.-F.
        • van Hasselt A.C.
        • Chan A.T.C.
        • Lo Y.M.D.
        Analysis of Plasma Epstein-Barr Virus DNA to Screen for Nasopharyngeal Cancer. N Engl J Med.
        Massachusetts Medical Society. 2017; 377: 513-522
        • Nicholls J.M.
        • Lee V.H.-F.
        • Chan S.-K.
        • Tsang K.-C.
        • Choi C.-W.
        • Kwong D.L.-W.
        • Lam K.-O.
        • Chan S.-Y.
        • Tong C.-C.
        • So T.-H.
        • Leung T.-W.
        • Luk M.-Y.
        • Khong P.-L.
        • Lee A.W.-M.
        Negative plasma Epstein-Barr virus DNA nasopharyngeal carcinoma in an endemic region and its influence on liquid biopsy screening programmes.
        Br J Cancer. 2019; 121: 690-698
        • Ricchiuti V.
        • Adams J.
        • Hardy D.J.
        • Katayev A.
        • Fleming J.K.
        Automated Processing and Evaluation of Anti-Nuclear Antibody Indirect Immunofluorescence Testing.
        Front Immunol. 2018; 9: 927
        • Horsfall A.C.
        • Venables P.J.
        • Mumford P.A.
        • Maini R.N.
        Interpretation of the Raji cell assay in sera containing anti-nuclear antibodies and immune complexes.
        Clin Exp Immunol. 1981; 44: 405-415
        • Goh S.M.P.
        • Swaminathan M.
        • Lai J.U.-M.
        • Anwar A.
        • Chan S.H.
        • Cheong I.
        Increasing the accuracy and scalability of the Immunofluorescence Assay for Epstein Barr Virus by inferring continuous titers from a single sample dilution.
        J Immunol Methods. 2017; 440: 35-40
        • Landis J.R.
        • Koch G.G.
        The measurement of observer agreement for categorical data.
        Biometrics. 1977; 33: 159-174
      4. Bonanno D, Nock K, Smith L, Elmore P, Petry F: An approach to explainable deep learning using fuzzy inference. Next-Generation Analyst V, International Society for Optics and Photonics, 2017, p. 102070D.