FibroStic: A large confirmatory study for non-invasive biomarkers accuracy, if correctly interpreted
Authors: Mona Munteanu, Vlad Ratziu, Thierry Poynard
Journal: Journal of Hepatology (2011)

Diagnostic accuracy of FibroScan and comparison to liver fibrosis biomarkers in chronic viral hepatitis: A multicenter prospective study (the FIBROSTIC study)Journal of HepatologyVol. 53Issue 6PreviewThe diagnostic accuracy of non-invasive liver fibrosis tests that may replace liver biopsy in patients with chronic hepatitis remains controversial. We assessed and compared the accuracy of FibroScan® and that of the main biomarkers used for predicting cirrhosis and significant fibrosis (METAVIR ⩾ F2) in patients with chronic viral hepatitis. Full-Text PDF Diagnostic accuracy of FibroScan and comparison to liver fibrosis biomarkers in chronic viral hepatitis: A multicenter prospective study (the FIBROSTIC study)Journal of HepatologyVol. 55Issue 1PreviewMunteanu et al. have commented on our paper [1] and claim that our conclusions were “hazardous”. We beg to disagree for the following reasons. Full-Text PDF Open Access The 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]Degos F. Perez P. Roche B. Mahmoudi A. Asselineau J. Voitot H. et al.FIBROSTIC study group. 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 (365) Google Scholar]. First, the design induced a high risk of selection bias. During the study inclusion period, biomarkers were already being widely used in France with an obvious selection of patients, i.e. all the patients included from our center had biopsy because of a significant discordance between FibroTest and elastography [[2]Castera L. Denis J. Babany G. Roudot-Thoraval F. Evolving practices of non-invasive markers of liver fibrosis in patients with chronic hepatitis C in France: time for new guidelines?.J Hepatol. 2007; 46: 528-529Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar]. This was too late to be representative of näive patients without a selection bias. The authors compared patients with and without prior non-invasive marker use, but this was not the point. They should have identified patients who had discordance between tests or inapplicable tests leading to the indication of biopsy, in the different tertiary centers, in order to prevent the selection bias. Second, the conclusion that “the diagnostic accuracy of non-invasive tests was high for cirrhosis but poor for significant fibrosis” is a caricature of a spectrum effect. An accuracy defined by AUROC of 0.90 for cirrhosis is mathematically equivalent to an AUROC of 0.78 for significant fibrosis [3Poynard 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 (222) Google Scholar, 4Lambert 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 (111) Google Scholar]. The authors should have used the Obuchowski method to assess all pairwise comparisons between fibrosis stages to prevent this spectrum effect, as was already recommended [[4]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 (111) Google Scholar]. Third, the authors underestimated the risk of false positives/negatives of a 20 mm biopsy in chronic hepatitis C. They stated that the performance of biopsy can be improved “by using an appropriate specimen length and number of portal tracts, as we have done in this study”. They forgot to mention that 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 (2054) Google Scholar]. Therefore, they should have used at least one of the appropriate statistical methods they cited and not only those such as multilevel likelihood ratios, which need a perfect reference [[6]Poynard T. Ingiliz P. Elkrief L. Munteanu M. Lebray P. Morra R. et al.Concordance in a world without a gold standard: a new non-invasive methodology for improving accuracy of fibrosis markers.PLoS One. 2008; 3: e3857Crossref PubMed Scopus (79) Google Scholar]. Test validation is probably the way to go in case there is a test that is proclaimed to be ‘better than (or at least similar to) the existing reference standard’ [[7]Rutjes A.W. Reitsma J.B. Coomarasamy A. Khan K.S. Bossuyt P.M. Evaluation of diagnostic tests when there is no gold standard. A review of methods.Health Technol Assess. 2007; 11: 1-51Crossref Scopus (405) Google Scholar]. In these cases also, we have to show that the differences between that test and the reference standard are ‘meaningful’ by demonstrating reliable associations with other findings. Clinical endpoints belong to this “test validation” and the authors should have commented on previously published studies that observed a similar or better prognostic value of biomarkers versus biopsy for the prediction of treatment response [[8]Poynard T. Munteanu M. Colombo M. et al.FibroTest is an independent predictor of virologic response in chronic hepatitis C patients retreated with pegylated interferon alfa-2b and ribavirin in the EPIC (3) program.J Hepatol. 2011; 54: 586-587Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar], and for the prediction of morbidity or mortality in patients with chronic hepatitis C [[9]Ngo Y. Munteanu M. Messous D. Charlotte F. Imbert-Bismut F. Thabut D. et al.A prospective analysis of the prognostic value of biomarkers (FibroTest) in patients with chronic hepatitis C.Clin Chem. 2006; 52: 1887-1896Crossref PubMed Scopus (209) Google Scholar]. Finally, the only scientific result from this study is confirmatory: the accuracy of biomarkers and elastography is similar both for cirrhosis and significant fibrosis when using biopsy as a perfect reference. Furthermore these results, when correctly discussed, fully support the first recommendations from the French National Authority for Health for FibroTest and elastography as first-line estimates of fibrosis in patients with chronic hepatitis C in December 2006 and their use by French hepatologists [[2]Castera L. Denis J. Babany G. Roudot-Thoraval F. Evolving practices of non-invasive markers of liver fibrosis in patients with chronic hepatitis C in France: time for new guidelines?.J Hepatol. 2007; 46: 528-529Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar]. M. Munteanu is full time employee of Biopredictive, the company marketing FibroTest. T. Poynard is the inventor of FibroTest and has a capital interest in Biopredictive. The patent belongs to the public organization Assistance Publique Hôpitaux de Paris.