Diagnostic accuracy of FibroScan and comparison to liver fibrosis biomarkers in chronic viral hepatitis: A multicenter prospective study (the FIBROSTIC study)
Authors: Françoise Degos, Paul Perez, Julien Asselineau, Pierre Bedossa
Journal: Journal of Hepatology (2011)

FibroStic: A large confirmatory study for non-invasive biomarkers accuracy, if correctly interpretedJournal of HepatologyVol. 55Issue 1PreviewThe article by Degos et al. assessing the diagnostic accuracy of Fibroscan compared to liver fibrosis biomarkers in chronic viral hepatitis is an interesting multicenter study, but several major flaws rendered the conclusions hazardous [1]. Full-Text PDF Open Access Munteanu et al. have commented on our paper [[1]Degos F. Perez P. Roche B. Mahmoudi A. Asselineau J. Voitot H. et al.Diagnostic accuracy of FibroScan and comparison to liver fibrosis biomarkers in chronic viral hepatitis: A multicenter prospective study (the FIBROSTIC study).J Hepatol. 2010; 53: 1013-1021Abstract Full Text Full Text PDF PubMed Scopus (333) Google Scholar] and claim that our conclusions were “hazardous”. We beg to disagree for the following reasons. (a) According to Munteanu et al., there was a high risk of selection bias in the FIBROSTIC study because we included patients who had a liver biopsy either (1) on clinical grounds only, without considering the results of previous non-invasive tests or (2) because previous non-invasive tests were abnormal and/or discordant (see Patients and methods section). However, the inclusion criteria of our study closely reflect the real-life situation in France where non-invasive tests were widely promoted and disseminated before being assessed. The French Health Authorities were calling for an independent, comparative assessment, and this is a reason why they supported our study. In the prevailing context, it was appropriate to assess the diagnostic performance of transient elastography (TE) both as a primary evaluation of liver fibrosis and in a sample of patients with abnormal results in non-invasive tests. Diagnostic accuracy results were provided for both groups of patients (see Supplemental material, Appendix 5.4., page 7). It was the same in both groups for significant fibrosis (AUROC 0.766 vs. 0.760, p = 0.83) and slightly better for the diagnosis of cirrhosis in the patients not selected on the basis of abnormal non-invasive test results (AUROC 0.914 vs. 0.864, p = 0.10). Our results thus provided no evidence of a selection bias. (b) Citing a method they have developed, Munteanu et al. state that an AUROC of 0.78 for significant fibrosis is “mathematically equivalent” to an AUROC of 0.90 for cirrhosis. There is to date no evidence for this mathematical equivalence. All one can say is that the higher AUROC for cirrhosis reflects a well known feature of diagnostic tests, i.e. their better performance for diagnosing more severe conditions [[2]2. Knottnerus JA, ed. The Evidence Base of Clinical Diagnosis. London: BMJ Books 2002.Google Scholar]. Munteanu et al. also affirm that we should have used the Obuchowski method [[3]Lambert J. Halfon P. Penaranda G. Bedossa P. Cacoub P. Carrat F. How to measure the diagnostic accuracy of noninvasive liver fibrosis indices: the area under the ROC curve revisited.Clin Chem. 2008; 54: 1372-1378Crossref PubMed Scopus (109) Google Scholar] to standardize AUROC measures and prevent a spectrum effect. But standardization is required only when “the distribution of fibrosis stages in the study sample do not fit the reference distribution in the population to which the indices are applied” (citation from abstract of Ref. [[3]Lambert J. Halfon P. Penaranda G. Bedossa P. Cacoub P. Carrat F. How to measure the diagnostic accuracy of noninvasive liver fibrosis indices: the area under the ROC curve revisited.Clin Chem. 2008; 54: 1372-1378Crossref PubMed Scopus (109) Google Scholar]). The problem is that the reference distribution of fibrosis stages in chronic hepatitis patients in France is not well known. We had no need to standardize AUROCs because our study sample was representative due to our choice of inclusion criteria; the sample was large; the distribution by fibrosis stage was close to the “reference” distribution used by Poynard et al. [[4]Poynard T. Halfon P. Castera L. Munteanu M. Imbert-Bismut F. Ratziu V. et al.FibroPaca Group. Standardization of ROC curve areas for diagnostic evaluation of liver fibrosis markers based on prevalences of fibrosis stages.Clin Chem. 2007; 53: 1615-1622Crossref PubMed Scopus (208) Google Scholar]; we compared non-invasive test accuracies in the same study population. (c) We acknowledged in the discussion that liver biopsy is an imperfect reference standard for evaluating fibrosis stage. Munteanu et al. claim that the “authors underestimated the risk of false positives/negatives of a 20 mm biopsy” and support this claim, rather misleadingly, by citing our work (“the risk of error of a 20 mm liver biopsy is 30% for false negatives/positives using large surgical samples [[5]Bedossa P. Dargère D. Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C.Hepatology. 2003; 38: 1449-1457Crossref PubMed Scopus (1941) Google Scholar]”). The 30% error rate we give in Ref. [[5]Bedossa P. Dargère D. Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C.Hepatology. 2003; 38: 1449-1457Crossref PubMed Scopus (1941) Google Scholar] is the error rate in fibrosis evaluation when using morphometric analysis and not when using histological scoring (e.g. the METAVIR system) on a 20 mm liver biopsy. To our knowledge, no known histological semi-quantitative score of fibrosis takes account of fibrosis evaluated by morphometry. Liver biopsy clearly has limitations such as errors related to sampling variation but it should not be forgotten that the algorithm applied in the Fibrotest® calculation ironically uses “histological staging of a set of biopsies as the gold standard”. (d) We did not state that the diagnostic accuracy of biomarkers and TE in detecting cirrhosis were similar but that the AUROCs of Fibrotest®, Apri and Hepascore were significantly lower (p <10−4, p <10−4, p = 0.07, respectively) than the AUROC for Fibroscan® (see Table 2). (e) We agree with Munteanu et al. that the prediction of clinical endpoints may be a better objective than the estimation of diagnostic accuracy, even when a satisfying reference standard is available. However, which endpoints we wish to predict using non-invasive tests merits discussion. Predicting treatment response may also be a good idea as they suggest in a recently published paper. (f) The 2006 guidelines of the French National Authority for Health (HAS) stated that there was no study available comparing the efficacy of different approaches of evaluating liver fibrosis and that the “STIC” study (renamed FIBROSTIC study), ongoing in 2006, might provide some answers [[6]Haute Autorité de Santé on site: evaluation des technologies: Méthodes d’évaluation de la fibrose hépatique au cours des hépatopathies chroniques; Dec 2006. p. 147–148.Google Scholar]. The FIBROSTIC study is the largest independent study (none of the authors have any financial conflicts of interest) comparing the diagnostic accuracy of biomarkers, in one and the same population of patients, to that of Fibroscan®. It is not just confirmatory but provides novel information, for instance, on the probability of the occurrence of significant fibrosis and cirrhosis according to different classes of value of non-invasive tests results (see Table 3 and Supplementary data, Appendix 7). Its purpose was to help decision-makers correctly position these tests within the decision-tree describing the treatment decision and care of patients with viral chronic hepatitis. The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.