Three Neglected STARD Criteria Reduce the Uncertainty of the Liver Fibrosis Biomarker FibroTest-T2D in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

Background and aims: Bariatric surgery (BS), drugs approved for type-2-diabetes (T2D), obesity, and liver fibrosis (resmetirom) announce the widespread use of fibrosis-tests in patients with metabolic liver disease (MASLD). An unmet need is to reduce the uncertainty of biomarkers for the diagnosis of the early stage of clinically significant fibrosis (eF). This can be achieved if three essential but neglected STARD methods (3M) are used—a more sensitive histological score than the standard comparator (five-tiers), the weighted area under the characteristic-curve (wAUROC) instead of the binary-AUROC, and biopsy length. We applied 3M to FibroTest-T2D to demonstrate this reduction of uncertainty, and constructed proxies predicting eF in large populations. Methods: For uncertainty, seven subsets were analyzed, four included biopsies (n=1,903), and to assess eF incidence, three MASLD-populations (n=299,098). FibroTest-T2D classification-rates after BS and in out-patients-T2D (n=402) were compared with and without 3M. In MASLD, trajectories of proxies and incidence against confounding-factors used hazard-ratios.Results: After BS (110 biopsies), reversal of eF was observed in 16/29 patients (84%) using seven-tier scores vs. 3/20 patients (47%) using five-tier scores (P=.005). When biopsy length was above the median, FibroTest-T2D wAUROC was .90 (SD=.01), and the wAUROC was .88 (SD=.1) when the length was below the median (P<.001). For the first time, obesity was associated with eF, before T2D (P<.001), and perimenopausal age with apoA1 and haptoglobin increases (P<.0001).Conclusion: Validations of circulating biomarkers need to assess their uncertainty. FibroTest-T2D predicts fibrosis regression after BS. Applying 3M and adjustments could avoid misinterpretations in MASLD surveillance.