T2-MAP outperforms native T1-MAP for staging liver fibrosis independent of steatosis and iron overload: A dual-cohort causal validation study.

BACKGROUND & AIMS: Native T1 mapping (T1-MAP) is a promising MRI biomarker for fibrosis but suffers critical confounding from steatosis and iron overload, leading to paradoxical negative correlations. We aimed to compare the fibrosis-specific diagnostic performance of T2-MAP and T1-MAP and evaluate their robustness against these metabolic confounders using a rigorous causal inference framework.

METHODS

In a dual-cohort study (exploratory n = 174; validation n = 198), we employed confounder-stratified subgroup analyses, hierarchical multivariable regression (quantifying ΔR2), causal mediation analysis, net gain metrics (ΔΔAUC, ΔIDI), and Decision Curve Analysis (DCA).

RESULTS

(1) Paradoxical Phenomenon:With advancing fibrosis, T1-MAP paradoxically shortened while T2-MAP increased consistently.(2) Correlation Vanishes:In the non-confounded subgroup (FF ≤ 5 % & R2* ≤70 s⁻1), the apparent correlation between T1-MAP and fibrosis vanished (validation: ρ = -0.038, p = 0.681), while T2-MAP maintained a robust positive association.(3) Causal Deconstruction:Mediation analysis confirmed T1-MAP's total effect was primarily mediated by FF (∼49.9 %), with anon-significant direct effectof fibrosis.(4) Key Evidence (Variance Decomposition):Hierarchical regression revealed that T1-MAP contributedzeroindependent variance (ΔR2 = 0.000, p > 0.8) in the non-confounded subgroup, whereas T2-MAP explained highly significant variance (ΔR2 = +0.092, p < 0.001). Clinically, replacing T1-MAP with T2-MAP yielded a positive net diagnostic gain (ΔΔAUC) and net reclassification improvement (ΔIDI) in non-confounded settings. Crucially,DCA uniquely demonstrated that T2-MAP provided consistent net clinical benefit across all subgroups, while T1-MAP risked clinical harm in confounded patients.

CONCLUSION

This study provides a causal deconstruction of the T1-MAP paradox. T1-MAP functions as a non-specific 'metabolic sensor' with no intrinsic signal for fibrosis. T2-MAP is a robust, fibrosis-specific biomarker that penetrates metabolic noise, offering superior net clinical benefit and safety, as proven by DCA.