Durable Engraftment Modeling for Stem-Cell-Derived Islet Replacement in Type 1 Diabetes

Abstract

Type 1 diabetes (T1D) remains a paradigmatic autoimmune disease in which loss of beta-cell function causes dysglycemia, severe hypoglycemia, and lifelong dependence on exogenous insulin. Stem-cell-derived islet replacement delivered by portal-vein infusion with glucocorticoid-free immunosuppression has shown early promise, yet durability and comparative interpretation are unresolved in small, open-label cohorts. We present a joint longitudinal–survival framework that links standardized mixed-meal tolerance test (MMTT) C-peptide trajectories to a regulatory-aligned composite endpoint and benchmarks durability using external standardization against historical donor-islet cohorts. Using synthetic validation experiments consistent with trial endpoints, we report survival probabilities near 0.88 at 12 months and 0.62 at 36 months, standardized survival around 0.59 at 36 months, and a reduction in between-trial variance under endpoint harmonization of approximately 25%. A beta-cell composite index improves AUC from 0.741 to 0.767, while potency-to-durability prediction remains weak (AUC 0.56). These results demonstrate how mechanistic graft function can be translated into clinically interpretable durability claims while revealing where evidence remains limited.