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Fibrosis blood tests are usually developed using significant fibrosis, which is a unique diagnostic target; however, these tests are employed for other diagnostic targets, such as cirrhosis. We aimed to improve fibrosis staging accuracy by simultaneously targeting biomarkers for several diagnostic targets. A total of 3,809 patients were included, comprising 1,012 individuals with chronic hepatitis C (CHC) into a derivation population and 2,797 individuals into validation populations of different etiologies (CHC, chronic hepatitis B, human immunodeficiency virus/CHC, nonalcoholic fatty liver disease, alcohol) using Metavir fibrosis stages as reference. FibroMeter biomarkers were targeted for different fibrosis‐stage combinations into classical scores by logistic regression. Independent scores were combined into a single score reflecting Metavir stages by linear regression and called Multi‐FibroMeter Version Second Generation (V2G). The primary objective was to combine the advantages of a test targeted for significant fibrosis (FibroMeter V2G ) with those of a test targeted for cirrhosis (CirrhoMeter V2G ). In the derivation CHC population, we first compared Multi‐FibroMeter V2G  to FibroMeter V2G  and observed significant increases in the cirrhosis area under the receiver operating characteristic curve (AUROC), Obuchowski index (reflecting all fibrosis‐stage AUROCs), and classification metric (six classes expressed as a correctly classified percentage) and a nonsignificant increase in significant fibrosis AUROC. Thereafter, we compared it to CirroMeter V2G  and observed a nonsignificant increase in the cirrhosis AUROC. In all 3,809 patients, respective accuracies for Multi‐FibroMeter V2G  and FibroMeter V2G  were the following: cirrhosis AUROC, 0.906 versus 0.878 ( P <  0.001; versus CirroMeter V2G , 0.897,  P =  0.014); Obuchowski index, 0.795 versus 0.791 ( P =  0.059); classification, 86.0% versus 82.1% ( P <  0.001); significant fibrosis AUROC, 0.833 versus 0.832 ( P =  0.366). Multi‐FibroMeter V2G  had the highest correlation with the area of portoseptal fibrosis and the highest reproducibility over time. Correct classification rates of Multi‐FibroMeter with hyaluronate (V2G, 86.0%) or without (V3G, 86.1%) did not differ ( P =  0.938).  Conclusion:  Multitargeting biomarkers significantly improves fibrosis staging and especially cirrhosis diagnosis compared to classical single‐targeted blood tests. ( Hepatology Communications  2018;2:455‐466)

A single blood test adjusted for different liver fibrosis targets improves fibrosis staging and especially cirrhosis diagnosis