Supplementary file 1_Association of early chloride-bicarbonate joint phenotypes with in-hospital mortality among intensive care unit patients with sepsis: a dual-database study.docx

In complete-case Model 3b, the phenotype was globally associated with mortality in both cohorts; the low-low contrast was individually significant in eICU but not MIMIC-IV. The low-low association was supported in multiple-imputation analyses (MIMIC-IV OR 1.276, 95% CI 1.066–1.527; eICU OR 1.507, 95% CI 1.277–1.779) and in strict pre-exposure analyses (OR 1.700 and 1.787, respectively). Formal 4-df categorical interaction tests were not significant (P = 0.095 and P = 0.109).

MIMIC-IV-derived data-driven cut points did not significantly outperform the clinical 3 × 3 phenotype in eICU (CART vs. clinical ΔAUROC 0.0009, 95% CI −0.0010 to 0.0029). In the main MIMIC-IV-to-eICU validation, adding the clinical phenotype left discrimination essentially unchanged (ΔAUROC 0.0010, 95% CI −0.0013 to 0.0031), although the Brier score improved modestly (ΔBrier −0.0011, 95% CI −0.0016 to −0.0006); NRI and IDI did not support improved discrimination or reclassification.

Incident and persistent low-low states were both associated with higher subsequent mortality in 24 h landmark analyses in both cohorts.</p>Conclusions<p>Prespecified chloride-bicarbonate phenotypes were associated with mortality in both databases, and persistence or incident development of the low-low state during the first ICU day was associated with higher subsequent mortality. The 3 × 3 framework should therefore be interpreted primarily as a transparent, direction-preserving approach to descriptive risk characterization within a broader clinical assessment, rather than as a stand-alone prediction instrument, therapeutic threshold, or treatment guide.</p>