Exhaustive Investigation of CBC-Derived Biomarker Ratios for Clinical Outcome Prediction: The RDW-to-MCHC Ratio as a Novel Mortality Predictor in Critical Care

Abstract

Ratios of common biomarkers and blood analytes are well established for early detection and predictive purposes. Early risk stratification in critical care is often limited by the delayed availability of complex severity scores. Complete blood count (CBC) parameters, available within hours of admission, may enable rapid prognostication. We conducted an exhaustive and systematic evaluation of CBC-derived ratios for mortality prediction to identify robust, accessible, and generalizable biomarkers. We generated all feasible two-parameter CBC ratios with unit checks and plausibility filters on more than 90,000 ICU admissions (MIMIC-IV). Discrimination was assessed via cross-validated and external AUC, calibration via isotonic regression, and clinical utility with decision-curve analysis. Retrospective validation was performed on eICU-CRD (n = 156530) participants. The ratio of Red Cell Distribution Width (RDW) to Mean Corpuscular Hemoglobin Concentration (MCHC), denoted RDW:MCHC, emerged as the top biomarker (AUC = 0.699 discovery; 0.662 validation), outperforming RDW and NLR. It achieved near-universal availability (99.9\% vs.\ 35.0\% for NLR), excellent calibration (Hosmer--Lemeshow $p = 1.0$; $\mathrm{ECE} < 0.001$), and preserved performance across diagnostic groups, with only modest attenuation in respiratory cases. Expressed as a logistic odds ratio, each one standard deviation increase in RDW:MCHC nearly quadrupled 30-day mortality odds (OR = 3.81, 95\% CI [3.70, 3.95]). Decision-curve analysis showed positive net benefit at high-risk triage thresholds. A simple, widely available CBC-derived feature (RDW:MCHC) provides consistent, externally validated signal for early mortality risk. While not a substitute for multivariable scores, it offers a pragmatic adjunct for rapid triage when full scoring is impractical.