Performance Assessment Techniques of Liver Fibrosis Non-invasive Diagnostic Methods in an Approach without a “Gold” Standard: Saying Goodbye to Liver Biopsy?

Aims: 1. To evaluate the applicability of The Expert Assessment (EA) based on the algorithm developed by the authors in performance assessment of transient elastography by M-probe (TE-M) and XL-probe (TE-XL), Fibrotest® (FT), shear wave elastography (SWE) and liver biopsy (LB) in fibrosis staging in chronic hepatitis C (CHC) patients in an approach without a «gold» standard; 2. To evaluate the quality of the proposed model (EA efficacy) in comparison with the results of the Rasch Model (MR) being an extension of the Latent Variable Analysis.

Material and methods. Using the five studied diagnostic methods liver fibrosis staging was performed in chronic hepatitis C patients. Based on the algorithm developed EA was applied to each patient of the cohort and as a result fibrosis stage was established. That fibrosis stage considered a virtual reference. Sensitivity and specificity estimation as well as AUC calculation for studied methods was performed against the reference standard. The quality of the model (EA efficacy) estimated in the Rasch Model (MR) being an extension of the Latent Variable Analysis.

Results. 99 patients with reliable results of each of the five diagnostic methods were included into the study. The main characteristics of the cohort were: 59.6% individuals of male gender, average age of 37 years (21–63), median BMI of 25.8 kg / m2. As per the results of the EA in detecting of mild fibrosis (F1), the values of AUC, sensitivity and specificity were, respectively: 0,972; 94,3; 91,3 for TE-M; 0,964; 90,6; 91,3 for TE-XL; 0,806; 81,1; 73,9 for FT; 0,907; 88,7; 71,7 for SWE; 0,832; 92,5; 37,0 for LB. In detecting of moderate fibrosis (F2), the appropriate values were: 0,981; 93,8; 94,0 for TE-M; 0,967; 90,6; 97,0 for TE-XL; 0,873; 75,0; 80,6 for FT; 0,957; 84,4; 91,0 for SWE; 0,937; 90,6; 94,0 for LB. In detecting of significant fibrosis (F3), the corresponding values were: 0,994; 95,5; 96,1 for TE-M; 0,987; 90,9; 97,4 for TE-XL; 0,870; 63,6; 84,4 for FT; 0,961; 86,4; 97,4 for SWE; 0,990; 90,9; 98,7 for LB. In detecting cirrhosis (F4), the appropriate values were: 0,995; 92,3; 97,7 for TE-M; 0,994; 100,0; 98,8 for TE-XL; 0,874; 38,5; 93,0 for FT; 0,996; 92,3; 100,0 for SWE; 0,964; 69,2; 100,0 for LB. The EA was shown to have high degree of consistency (correlation coefficient = 0,923; p <0,05) when compared to the MR.

Conclusion. The EA was shown as a highly informative approach, applicable for performance assessment of the diagnostic methods for liver fibrosis staging without using LB as the “gold” standard. Non-invasive methods have demonstrated higher diagnostic characteristics with changing the standard from the traditional (LB) to virtual (EA). The high degree of consistency of the results of EA and MR confirm the high quality of the algorithm developed by the authors.

1. Абдурахманов Д.Т., Морозов В. Г., Никитин И. Г. и др. Безопасность и эффективность телапревира в лечении хронического гепатита С у больных российской популяции, включенных в исследование по программе раннего доступа // Рос. журн. гастроэнтерол., гепатол., колопроктол. – 2014. – Т. 24, № 1. – С. 39–46. Abdurahmanov D. T., Morozov V. G., Nikitin I. G. et al. Safety and efficacy of telaprevir in the treatment of chronic hepatitis C in patients of the Russian population included in the study on the early access program. Rossijskij zhurnal gastrojenterologii, gepatologii, koloproktologii – Russian Journal of Gastroenterology, Hepatology, Coloproctology, 2014, Vol.24, no. 1, pp. 39–46. (In Russian)

2. Галушко М.Ю., Бакулин И. Г., Тимохина А. И. Сравнительный анализ диагностики фиброза печени методом M–XL-эластометрии у пациентов с хроническим гепатитом С // Фарматека. ‒ S5. ‒ 2016. – С. 40–47. Galushko M. Yu., Bakulin I. G., Timokhina A. I. Comparative analysis of the diagnosis of liver fi brosis by M- and XL-elastometry in patients with chronic hepatitis C. Farmateka = Pharmateca, S5, 2016, pp. 40–47. (In Russian)

3. Galushko M., Bakulin I., Munteanu M., Kushnir V. P1322 Real-time shear-wave elastography (SWE, Aixplorer™) performances in chronic hepatitis C (CHC) patients compared to liver stiff ness measurement (LSM, FibroScan™) and FibroTest™ with liver biopsy (LB) as reference. Journal of Hepatology. 2014. Vol. 60, no.1, 536 P.

4. Галушко М.Ю., Ищенко А. Ю., Бакулин И. Г. и др. Соноэластография сдвиговой волной в оценке фиброза печени // Профилактическая и клиническая медицина. ‒ 2019. ‒ № 2 (71). ‒ С. 35 ‒ 39. Galushko M. Yu., Ishchenko A. Yu., Bakulin I. G. et al. Shear wave elastography in liver fi brosis assessing. Preventive and clinical medicine. 2019. No 2 (71), pp. 35–39. (in Russian)

5. Castera L., Chan H. L. Y., Arrese M. et al. European Association for the Study of the Liver (EASL) – Asociación Latinoamericana para el Estudio del Hígado (ALEH) Clinical Practice Guidelines: Non-invasive tests for evaluation of liver disease severity and prognosis. Journal of hepatology. 2015, Vol. 63, iss. 1, pp. 237–264.

6. Bedossa P., Dargère D., Paradis V. Sampling variability of liver fi brosis in chronic hepatitis C. Hepatology (Baltimore, Md.). 2003, Vol. 38, iss. 6, pp. 1449–1457.

7. Regev A., Berho M., Jeff ers L. J. et al. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. Th e American Journal of Gastroenterology. 2002, Vol. 97, no.10, pp. 2614–2618.

8. Poynard T., Ingiliz P., Elkrief L. et al. Concordance in a world without a gold standard: a new non-invasive methodology for improving accuracy of fi brosis markers. PloS one. 2008, Vol. 3, iss. 12. – e3857.

9. Reitsma J. B., Rutjes A. W. S., Khan K. S. et al. A review of solutions for diagnostic accuracy studies with an imperfect or missing reference standard // Journal of Clinical Epidemiology. 2009. vol. 62, no.8, pp. 797–806.

10. Poynard T., Munteanu M., Luckina E. et al. Liver fi brosis evaluation using real-time shear wave elastography: Applicability and diagnostic performance using methods without a gold standard. Journal of hepatology. 2013, Vol. 58, № 5, pp. 928–935.

11. Poynard T., de Ledinghen V., Zarski J. P. et al. Relative performances of FibroTest, Fibroscan, and biopsy for the assessment of the stage of liver fi brosis in patients with chronic hepatitis C: A step toward the truth in the absence of a gold standard. Journal of hepatology. 2012, Vol. 56, no. 3, pp. 541–548.

12. Fernandes F. F., Perazzo H., Andrade L. E. et al. Latent Class Analysis of Noninvasive Methods and Liver Biopsy in Chronic Hepatitis C: An Approach without a Gold Standard. BioMed Research International. 2017, article ID8252980. – 8 p.

13. Castera L., Foucher J., Bernard P.-H. et al. Pitfalls of liver stiff ness measurement: a 5-year prospective study of 13,369 examinations. Hepatology (Baltimore, Md.). 2010, Vol. 51, iss. 3, pp. 828–835.

14. Ferraioli G., Filice C., Castera L. et al. WFUMB guidelines and recommendations for clinical use of ultrasound elastography: Part 3: liver. Ultrasound in medicine & biology. 2015, Vol. 41, iss. 5, pp. 1161–1179.

15. Rasch G. Probabilistic models for some intelligence and attainment tests (Expanded edition, with foreword and aft erword by Benjamin D. Wright). Chicago: University of Chicago Press, 1980. 199 p.

16. Wright B. D., Masters G. N. Rating Scale Analysis. Chicago: MESA PRESS, 1982. 206 p.