Elsevier

Clinical Biochemistry

Volume 41, Issues 16–17, November 2008, Pages 1368-1376
Clinical Biochemistry

Diagnostic accuracy, reproducibility and robustness of fibrosis blood tests in chronic hepatitis C: A meta-analysis with individual data

https://doi.org/10.1016/j.clinbiochem.2008.06.020Get rights and content

Abstract

Objectives

To evaluate the diagnostic accuracy of liver fibrosis tests and its influencing factors in a meta-analysis with individual data.

Design and methods

Four independent centers provided four blood tests and Metavir staging from 825 patients with chronic hepatitis C.

Results

FibroMeter AUROC (0.840) for significant fibrosis was superior to those of Fibrotest (0.803, p = 0.049), APRI (0.789, p = 0.001) and Hepascore (0.781, p < 0.001). The misclassification rate was lower for FibroMeter (23%) than for Fibrotest and Hepascore (both 28%, p < 0.001). The variation in the diagnostic cut-offs of tests among centers, reflecting the overall reproducibility, was: FibroMeter: 4.2%, APRI: 24.0%, Fibrotest: 24.2%, Hepascore: 35.0%. Accordingly, the proportion of patients diagnosed with significant fibrosis changed: FibroMeter: 0.8%, Hepascore: 2.4% (p = 0.02 vs FibroMeter), Fibrotest: 5.8% (p < 10 3), APRI: 18.2% (p < 10 3).

Conclusions

This study on clinical applicability shows significant differences in diagnostic accuracy, inter-center reproducibility, and robustness of biomarkers to changes in population characteristics between blood tests.

Introduction

Several blood tests have been proposed to evaluate fibrosis in liver diseases [1]. They may have strong clinical applications, such as initial staging of fibrosis, assessment of anti-fibrotic treatments, prognosis indicators and general screening [2], [3], [4]. Blood tests are composed of direct [2] or indirect [3] markers of fibrosis depending on their relationship with the connective tissue. Some tests such as the aspartate aminotransferase (AST) to platelet ratio index (APRI) are simple and easily available in clinical practice [4]. Other tests are more complex and were constructed from multivariate regression analyses. They variably include several indirect markers – Fibrotest – [5], direct markers – European liver fibrosis test – [6] or both direct and indirect markers – FibroMeter, and Hepascore – [7]. Only a minority of tests including APRI, Fibrotest and more recently FibroMeter and Hepascore have so far been evaluated by external and independent analysis and they have rarely been compared to one another [8], [9], [10]. In addition, their diagnostic performance was evaluated using small sample sizes, straightforward and limited statistical tools such as the area under the receiver operating characteristic (AUROC), whereas more accurate and stringent indexes of performance could be useful to precisely define their clinical application [11].

Therefore, we conducted a meta-analysis with individual data aiming primarily at comprehensively characterizing and comparing the diagnostic accuracy of four major blood tests of fibrosis including FibroMeter, Hepascore, APRI and Fibrotest in patients with chronic viral hepatitis C. The secondary aims were to evaluate the factors influencing this diagnostic accuracy, especially the reproducibility (center effect) and robustness (population effect) by the means of new statistical methods.

Section snippets

Data source

We systematically reviewed the literature from 1997 to 2007 for studies comparing FibroMeter and Fibrotest in patients with chronic viral hepatitis C in the Medline data base and by hand searching. Hepascore and APRI, whose markers are included in the two former tests, could thus be calculated. Three independent publications were retrieved. The first study including one center, Angers, was the original publication that described the FibroMeter [7]. The second study included two independent

Characteristics of patients

The main characteristics of the 825 patients are presented in Table 2. Some significant differences were observed between centers. The most important one concerned the prevalence of histological fibrosis stages. The prevalence of severe fibrosis ranged from 9% to 30%, and the prevalence of cirrhosis ranged from 1% to 19%. Biopsy length also was significantly different among centers. Therefore, comparisons between centers were adjusted on these variables.

Overall performance of blood tests

The main indices of diagnostic accuracy

Performance indexes

We focused in this multicenter study on four tests of liver fibrosis, namely FibroMeter, Fibrotest, Hepascore and APRI. Other easily available tests such as Forns' index [22] and Fibroindex [23] were not evaluated. The performance of Forns' index was indeed found to be inferior to Fibrotest or FibroMeter in several studies [7], [10], [23] including 3 centers involved in the present study. The interlaboratory reproducibility of gammaglobulins included in Fibroindex is not optimal in our

Acknowledgments

We thank other investigators from Angers: Frédéric Oberti, Sophie Michalak, Isabelle Hubert-Fouchard, Anselme Konaté, Catherine Ternisien, Alain Chevailler, Françoise Lunel, Dermot O'Toole; PACA: Denis Ouzan, Albert Tran, Danielle Botta, Christophe Renou, Christophe Sattonnet, Marie-Christine Saint-Paul, Thierry Benderitter, Stéphane Garcia, Henri Pierre Bonneau ; Grenoble: Marie-Noelle Hilleret, Jean-Pierre Zarski, Patrice Faure, Jean-Charles Renversez, Francoise Morel; Clichy: Claude Degott,

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