A new generation of non-invasive tests of liver fibrosis with improved accuracy in MASLD

Background & aims: The accuracy of non-invasive tests (NITs) should be ≥80% (EASL recommendation). We aimed to compare the accuracies of the recommended NITs for advanced fibrosis in MASLD and improve NIT accuracy.

Methods: 1051 MASLD patients were allocated to derivation (n=637) and validation (n=414) sets. The main outcome (Kleiner F3+F4) was primarily evaluated by accuracy. Conventional NITs were FIB-4, Fibrotest, FibroMeter, liver stiffness measurement (LSM by Fibroscan), Elasto-FibroMeter (FibroMeter-LSM combination), and ELF in 396 patients. We used machine-learning-optimized multitargeting to develop new NITs: FIB-9 (including 9 usual biomarkers), FIB-11 (adding 2 specialized blood markers) and FIB-12 (adding LSM).

Results: In the whole population, the accuracies of recommended NITs were insufficient, Fibrotest: 68.0%, FIB-4: 71.2%, FibroMeter: 75.1%, LSM: 75.9%, Elasto-FibroMeter: 78.6%. Therefore, new NITs (FIB-9, FIB-11, FIB-12) were developed in the derivation set. In the validation set, AUROCs were, FIB-4: 0.757, Fibrotest: 0.766, FibroMeter: 0.850, LSM: 0.852, FIB-9: 0.863, FIB-11: 0.880, Elasto-FibroMeter: 0.894, FIB-12: 0.912 (p<0.001). The FIB-12 AUROC was superior to the ELF AUROC (0.906 vs 0.865, p=0.039). Accuracies were, FIB-4: 68.8%, Fibrotest: 68.6%, LSM: 75.4%, FibroMeter: 76.3%, FIB-9: 78.7%, Elasto-FibroMeter: 79.7%, FIB-11: 80.2%, FIB-12: 83.3% (p<0.001 between all NITs). Scores were segmented by ≥90% sensitivity and specificity cut-offs or NIT match, which individualized subgroups with NIT accuracies ≥80%, e.g. for FIB-9: 85.8% in 68.1% of patients using two cut-offs and 83.2% in 71.7% of patients where FIB-9 agreed with FIB-4.

Conclusions: Recommended NITs had accuracies <80% for advanced fibrosis in MASLD. Several NIT segmentations individualized subgroups with accuracies ≥80%. New NITs further improved accuracy. The simple FIB-9 (available via a free calculator) provided accuracy equaling or surpassing recommended NITs. FIB-12 outperformed other NITs.

Impact and implications: Currently recommended non-invasive tests (NITs) have insufficient accuracy (<80%) for the diagnosis of advanced fibrosis in MASLD. Therefore, we developed three new NITs with new statistical techniques. Thus, FIB-9 (available via a free calculator), including nine usual blood markers, equaled the performance of patented NITs. FIB-11, adding two specialized blood markers, and FIB-12, adding liver stiffness, had accuracy >80%. FIB-12, outperformed all other NITs. FIB-9 is suitable for screening and FIB-11 or FIB-12 for diagnosis.