Redefining reference materials for the evolving metabolomics landscape

The evolution of metabolomics, a field aimed at comprehensively measuring the small organic molecule composition of a biological matrix, fundamentally reshaped the landscape of analytical measurement reliability. The 2011 release of Standard Reference Material (SRM) 1950 Metabolites in Frozen Human Plasma by the National Institute of Standards and Technology (NIST) marked the first reference material providing certification for 45 analytes to address the measurement precision of complex biological matrices. Assigning high-order values to many compounds is highly resource-intensive for a National Metrology Institute. Furthermore, certified values for individual metabolites cannot resolve the broad challenges associated with sample processing, analytical measurement, and data processing in untargeted workflows. The metabolomics community recognized the potential for SRM 1950 to serve as a benchmark material for method development and technical quality control (QC) rather than strictly for quantification. Recognizing this consumer-driven shift, NIST launched a novel reference material (RM) development strategy to provide accessible, fit-for-purpose materials evaluated by a new statistical framework for production homogeneity, the Coefficient of Disagreement. Here, we introduce the transition toward matrix-specific QC Suites featuring phenotypically distinct metabolite profiles, the first generation of which includes a human plasma suite, urine suite, liver suite, and fecal material. By prioritizing efficient production and embracing a community engagement model for consensus-based deep characterization, these suites offer a reliable tool for laboratory comparisons, instrument assessment, software development, and training. This new class of RMs underpins the next phase of measurement reliability, complementing traditional measurand certification while supporting the diverse needs of comprehensive metabolic profiling.