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. 2023 Nov 2:10:1283083.
doi: 10.3389/fmolb.2023.1283083. eCollection 2023.

A one-year pilot study comparing direct-infusion high resolution mass spectrometry based untargeted metabolomics to targeted diagnostic screening for inherited metabolic diseases

Anke P Willems  1 , Maria van der Ham  1 , Birgit G M Schiebergen-Bronkhorst  1 , Mirjam van Aalderen  1 , Martina M J de Barse  1 , Fini E De Gruyter  1 , Ilja N van Hoek  1 , Mia L Pras-Raves  1 , Monique G M de Sain-van der Velden  1 , Hubertus C M T Prinsen  1 , Nanda M Verhoeven-Duif  1 , Judith J M Jans  1
Affiliations

A one-year pilot study comparing direct-infusion high resolution mass spectrometry based untargeted metabolomics to targeted diagnostic screening for inherited metabolic diseases

Anke P Willems et al. Front Mol Biosci. .

Abstract

Background: Early diagnosis of inherited metabolic diseases (IMDs) is important because treatment may lead to reduced mortality and improved prognosis. Due to their diversity, it is a challenge to diagnose IMDs in time, effecting an emerging need for a comprehensive test to acquire an overview of metabolite status. Untargeted metabolomics has proven its clinical potential in diagnosing IMDs, but is not yet widely used in genetic metabolic laboratories. Methods: We assessed the potential role of plasma untargeted metabolomics in a clinical diagnostic setting by using direct infusion high resolution mass spectrometry (DI-HRMS) in parallel with traditional targeted metabolite assays. We compared quantitative data and qualitative performance of targeted versus untargeted metabolomics in patients suspected of an IMD (n = 793 samples) referred to our laboratory for 1 year. To compare results of both approaches, the untargeted data was limited to polar metabolites that were analyzed in targeted plasma assays. These include amino acid, (acyl)carnitine and creatine metabolites and are suitable for diagnosing IMDs across many of the disease groups described in the international classification of inherited metabolic disorders (ICIMD). Results: For the majority of metabolites, the concentrations as measured in targeted assays correlated strongly with the semi quantitative Z-scores determined with DI-HRMS. For 64/793 patients, targeted assays showed an abnormal metabolite profile possibly indicative of an IMD. In 55 of these patients, similar aberrations were found with DI-HRMS. The remaining 9 patients showed only marginally increased or decreased metabolite concentrations that, in retrospect, were most likely to be clinically irrelevant. Illustrating its potential, DI-HRMS detected additional patients with aberrant metabolites that were indicative of an IMD not detected by targeted plasma analysis, such as purine and pyrimidine disorders and a carnitine synthesis disorder. Conclusion: This one-year pilot study showed that DI-HRMS untargeted metabolomics can be used as a first-tier approach replacing targeted assays of amino acid, acylcarnitine and creatine metabolites with ample opportunities to expand. Using DI-HRMS untargeted metabolomics as a first-tier will open up possibilities to look for new biomarkers.

Keywords: biomarker; diagnostics; direct-infusion high resolution mass spectrometry; genetic diseases; inherited metabolic diseases; untargeted metabolomics.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

FIGURE 1
FIGURE 1
Overview of pilot study. Schematic view of pilot study comparing DI-HRMS untargeted metabolomics to targeted metabolic assays. The middle part (darker shade) represents assays and yield included in the pilot. The outer part (lighter shade) represents additional assays and yield. The lower part gives an overview of suspected diagnosis based on metabolite analysis, these are not (all) patients with confirmed diagnosis. *CTX is detected by both targeted and untargeted approaches, but based on different metabolites, therefore depicted here twice.
FIGURE 2
FIGURE 2
Description of pilot study. (A) Age and gender of patient population referred for symptomatic diagnostic screening of IMDs. (B) Most observed phenotypes in patient population referred for symptomatic diagnostic screening of IMDs, according to HPO systematic.
FIGURE 3
FIGURE 3
Qualitative performance Number of plasma samples with aberrant (amino acid, acylcarnitine and creatine) metabolites based on reference range for targeted metabolic assays and based on Z-score limits Z = 2 and Z = −1,5 for untargeted metabolomics. Number of plasma samples that showed aberrant (amino acid, acylcarnitine and creatine) metabolites possibly indicative of an IMD.
See this image and copyright information in PMC

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