Minimal correlation but complementary diagnostic utility for plasma cell-free RNA and proteins.

BACKGROUND: Proteins and RNA circulate in plasma and can offer insights into human physiology. Yet, despite their clinical importance, direct comparisons between these analytes remain unexplored. METHODS: Here, we measure and compare plasma cell-free RNA (cfRNA) and protein levels for 263 children diagnosed with inflammatory diseases, specifically either Kawasaki disease (KD) or Multisystem Inflammatory Syndrome in Children (MIS-C), by RNA sequencing (n = 108 KD and n = 47 MIS-C, mean age=4.2 years) and SomaScan proteomics (n = 70 KD and n = 101 MIS-C, mean age=6.8 years). RESULTS: Here we show that cell-free RNA and protein levels are largely uncorrelated across samples (feature-by-sample correlation coefficient 0.052; median feature-level correlation coefficient 0.009). Nonetheless, machine learning models based on either modality distinguish KD from MIS-C with similar high accuracy (median area under the curve greater than 0.93). Analysis of KD subtypes reveals distinct cell-free RNA and protein signatures, with one group showing molecular similarity to MIS-C. CONCLUSIONS: These findings underscore the complementary nature of cell-free RNA and protein profiling and highlight the utility of integrating multiple plasma analytes to improve disease classification and deepen our understanding of complex inflammatory conditions.