Chemical space blind spots: how chromatographic selectivity dictates chemical measurability and coverage of LC-HRMS comprehensive analysis.

Liquid chromatography high-resolution mass spectrometry enables broad chemical detection by comprehensive accurate mass to charge ratio measurement of the components in complex samples; yet, analytical design constrains chemical space measurability. A meta-analysis of 236 methods and over 75 000 measured compounds reveals strong convergence toward reversed-phase separations, limiting the coverage of sample chemical diversity. This "measurability trap" narrows the observable chemical space and can lead to the underrepresentation of many environmentally and biologically relevant compounds.