Comparison of diagnostic accuracy and utility of non-invasive tests for clinically significant liver disease in a general population with metabolic dysfunction

_{Background and Aims:} 

_{Screening for liver disease in the general population requires accurate non-invasive tests (NITs). A head-to-head comparison of NITs for early detection of clinically relevant liver disease among the target population for screening is lacking.}

_{Aproach and Results:} 

_{Among the meta-cohort (Rotterdam Study and National Health and Nutrition Examination Survey) with metabolic dysfunction aged 18–80 years, 10 NITs were investigated. The diagnostic accuracy for clinically relevant conditions [increased liver stiffness measurement (LSM), at-risk metabolic dysfunction–associated steatohepatitis, advanced fibrosis, or cirrhosis) was assessed. Subgroup analysis included stratification by age group and diabetes/obesity status.}

_{We analysed 11,404 participants. Metabolic dysfunction–associated fibrosis 5 (MAF-5) obtained the highest AUC for increased LSM (≥8 kPa: 0.80; ≥12 kPa: 0.87) and advanced fibrosis (AUC: 0.90). Fibrotic NASH index and MAF-5 performed best for detecting metabolic dysfunction–associated steatohepatitis (AUC: 0.93 and AUC: 0.92, p=ns) and SAFE for cirrhosis (AUC: 0.92). To obtain 80% sensitivity for LSM ≥8 kPa, the corresponding MAF-5 cut-off resulted in fewer referrals (42%) compared to fibrosis-4 index (77%) and higher specificity (62% vs. 24%); MAF-5 was also superior for detection of LSM ≥12 kPa and advanced fibrosis. Age-dependent scores yielded lower sensitivity among younger individuals, for example, by referring 20% of the population with the highest NIT scores, the fibrosis-4 index, steatosis-associated fibrosis estimator, NAFLD fibrosis score, FORNS, and Hepamet fibrosis score yielded <10% sensitivity for LSM ≥8 kPa among individuals aged 18–35 years, while fibrotic NASH index and MAF-5 obtained 40% and 71%.}

_Conclusions: 

_{Of the 10 investigated NITs, MAF-5 discriminated best between all conditions except cirrhosis, for which the steatosis-associated fibrosis estimator yielded the highest accuracy. The performance of the fibrosis-4 index was poor, implying that referral pathways for significant liver disease in low-prevalence populations can be improved when more accurate NITs such as MAF-5 are employed.}