Permutation-Based Analysis of Clinical Variables in Necrotizing Fasciitis Using NPC and Bootstrap

Necrotizing fasciitis (NF) is a rare but aggressive soft tissue infection with high rates of mortality and amputation, making early identification of key prognostic biomarkers essential for clinical management. However, the rarity and heterogeneity of NF mean clinical datasets are often small and non-normally distributed, limiting the effectiveness of standard parametric statistical approaches. To address this, we retrospectively analyzed 66 NF patients using a robust, distribution-free framework that combines the Nonparametric Combination (NPC) methodology and bootstrap resampling. We specifically assessed glycated hemoglobin (HBA1C) and serum albumin (ALBUMINA) as potential predictors of two outcomes: mortality (MORTO) and major amputation (AMPUTAZIONE). NPC enabled exact multivariate hypothesis testing while rigorously controlling the family-wise error rate (FWER), and bootstrap resampling generated 95% confidence intervals (CI) for critical biomarkers. HBA1C was an exceptionally significant predictor compared to the 7.0% clinical threshold (p = 1.04 × 10−154, CI: 0.0830–0.0957), while ALBUMINA showed greater biological variability but no significant association with outcomes (2.8 g/dL; p = 0.267, CI: 2.551–2.866). We also developed a global severity ranking, integrating multiple variables to improve clinical risk stratification. Our results demonstrate that permutation-based and resampling methods provide reliable, actionable insights from challenging small-sample clinical datasets. Based on a small-sample dataset from necrotizing fasciitis patients, this framework provides a replicable model for robust, nonparametric statistical analysis in similarly rare and high-risk medical conditions. This study introduces a Nonparametric Combination (NPC) framework for risk scoring in necrotizing fasciitis using bootstrap resampling and permutation tests. Key predictors like HBA1C and Albumin were assessed, achieving an AUC of 0.89 and a Youden Index of 0.71. The model offers a robust, interpretable tool for clinical risk stratification in small-sample rare disease settings.