title: Evaluation of the biomarker candidate MFAP4 for non-invasive assessment of hepatic fibrosis in hepatitis C patients.
abstract: The human microfibrillar-associated protein 4 (MFAP4) is located to extracellular matrix fibers and plays a role in disease-related tissue remodeling. Previously, we identified MFAP4 as a serum biomarker candidate for hepatic fibrosis and cirrhosis in hepatitis C patients. The aim of the present study was to elucidate the potential of MFAP4 as biomarker for hepatic fibrosis with a focus on the differentiation of no to moderate (F0-F2) and severe fibrosis stages and cirrhosis (F3 and F4, Desmet-Scheuer scoring system).
  
  
  
  MFAP4 levels were measured using an AlphaLISA immunoassay in a retrospective study including n = 542 hepatitis C patients. We applied a univariate logistic regression model based on MFAP4 serum levels and furthermore derived a multivariate model including also age and gender. Youden-optimal cutoffs for binary classification were determined for both models without restrictions and considering a lower limit of 80 % sensitivity (correct classification of F3 and F4), respectively. To assess the generalization error, leave-one-out cross validation (LOOCV) was performed.
  
  
  
  MFAP4 levels were shown to differ between no to moderate fibrosis stages F0-F2 and severe stages (F3 and F4) with high statistical significance (t test on log scale, p value <2.2·10(-16)). In the LOOCV, the univariate classification resulted in 85.8 % sensitivity and 54.9 % specificity while the multivariate model yielded 81.3 % sensitivity and 61.5 % specificity (restricted approaches).
  
  
  
  We confirmed the applicability of MFAP4 as a novel serum biomarker for assessment of hepatic fibrosis and identification of high-risk patients with severe fibrosis stages in hepatitis C. The combination of MFAP4 with existing tests might lead to a more accurate non-invasive diagnosis of hepatic fibrosis and allow a cost-effective disease management in the era of new direct acting antivirals.
authors.affiliation: Medizinisches Proteom-Center, Ruhr-Universität Bochum, 44801, Bochum, Germany. thilo.bracht@rub.de.
authors.forename: Thilo
authors.initials: T
authors.lastname: Bracht
authors.affiliation: Department of Gastroenterology and Hepatology, Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil, Bochum, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Mölleken
authors.affiliation: Medizinisches Proteom-Center, Ruhr-Universität Bochum, 44801, Bochum, Germany.
authors.forename: Maike
authors.initials: M
authors.lastname: Ahrens
authors.affiliation: Molecular Proteomics Laboratory (MPL), Biologisch-Medizinisches Forschungszentrum (BMFZ), Heinrich-Heine-Universität, Düsseldorf, Germany.
authors.forename: Gereon
authors.initials: G
authors.lastname: Poschmann
authors.affiliation: Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Schlosser
authors.affiliation: Medizinisches Proteom-Center, Ruhr-Universität Bochum, 44801, Bochum, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Eisenacher
authors.affiliation: Molecular Proteomics Laboratory (MPL), Biologisch-Medizinisches Forschungszentrum (BMFZ), Heinrich-Heine-Universität, Düsseldorf, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Stühler
authors.affiliation: Medizinisches Proteom-Center, Ruhr-Universität Bochum, 44801, Bochum, Germany.
authors.forename: Helmut E
authors.initials: HE
authors.lastname: Meyer
authors.affiliation: Department of Gastroenterology and Hepatology, Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil, Bochum, Germany.
authors.forename: Wolff H
authors.initials: WH
authors.lastname: Schmiegel
authors.affiliation: Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Uffe
authors.initials: U
authors.lastname: Holmskov
authors.affiliation: Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Grith L
authors.initials: GL
authors.lastname: Sorensen
authors.affiliation: Medizinisches Proteom-Center, Ruhr-Universität Bochum, 44801, Bochum, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Sitek
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D015415:Biomarkers / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D015331:Cohort Studies; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005260:Female; D006023:Glycoproteins / Q000378:metabolism*; D006526:Hepatitis C / Q000150:complications* / Q000175:diagnosis / Q000378:metabolism*; D006801:Humans; D008103:Liver Cirrhosis / Q000150:complications* / Q000175:diagnosis / Q000378:metabolism*; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D012372:ROC Curve; D012680:Sensitivity and Specificity
chemical_list: D015415:Biomarkers; D002352:Carrier Proteins; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; C400752:MFAP4 protein, human
keywords: Cirrhosis; Direct acting antivirals; Hepatic fibrosis; Hepatitis C; Microfibrillar-associated protein 4; Serum biomarker