Bringing Untargeted Metabolomics to the Clinic: Real-World Data and Implementation for Screening of Inherited Metabolic Diseases.

Abstract

Inherited metabolic diseases (IMD) require timely diagnosis since a considerable number of these disorders respond to early treatment. Traditional metabolic screening relies on multiple targeted assays guided by clinical symptoms, making it laborious and potentially increasing the risk of underdiagnosis. Untargeted metabolomics provides broader biochemical coverage, but evidence of its diagnostic performance is limited. In this metabolomics implementation study, we analysed 484 plasma samples submitted for routine metabolic screening using both targeted assays and metabolomics in parallel. The results of these analyses were independently interpreted by two laboratory specialists and results were compared. Overall, 85.5% concordance was achieved between the two approaches. The majority of discrepancies stem from aberrant biomarkers traditionally measured in urine observed in metabolomics but not in the targeted plasma analyses. Importantly, inconclusive results requiring follow up were equally observed among the two methods. Metabolomics screening resulted in the detection of one new and one tentative IMD, which were not detected by targeted tests. Collectively, these results support the application of untargeted metabolomics for IMD screening in clinical practice. In addition to our study results, we share our detailed protocol and workflow towards implementation of untargeted metabolomics in clinical practice to facilitate broader use of diagnostic metabolomics in the IMD community.

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