Comparison of high-throughput plasma proteomic platforms in a multi-ethnic Asian cohort

Population-scale proteomics is driving precision medicine by enabling systematic drug target identification and robust biomarker discovery. Comparable, well-powered studies across diverse global populations are essential to elucidate shared and population-specific disease pathways. Mass-spectrometry-based and multiplexed affinity-based assays have emerged as complementary, leading strategies for quantifying proteomic variation in large-scale population-based studies. With the objective of performing a comprehensive comparative evaluation of the latest assays for each of these technologies, we compare three leading affinity-based and mass-spectrometry-based proteomic platforms (SomaScan11K, Olink Explore HT, Orbitrap Astral with Seer Proteograph [MS-Seer]) in a multi-ethnic Asian cohort, to inform biomarker discovery and functional genomic studies of global populations. We find limited overlap of 1,740 proteins out of 12,825 total proteins quantified across the three platforms, with modest correlations (0.34–0.10). SomaScan had lower missingness (< 1%) and CV (< 10%), compared to Olink (51%, 23%) and MS-Seer (12%, 19%). The new assays in Olink Explore HT (absent in Explore3072) primarily drove its higher missingness and CV. The number of phenotypic associations varies by trait, while the number of genetic associations ( cis -pQTLs at P < 5 × 10 –8 ) are similar for Olink and SomaScan. Protein levels differ between ethnicities, with SomaScan identifying more ethnicity-differentiated proteins than Olink. Finally, SomaScan ANML normalization attenuates biologically relevant associations in our study likely reflecting a limitation inherent to sample-level normalization approaches. These findings underscore the importance of proteomic platform evaluation and data normalization strategies for application in large-scale, diverse population cohorts.