Meta-Analysis of COVID-19 Metabolomics Identifies Variations in Robustness of Biomarkers

Abstract

The global COVID-19 pandemic resulted in widespread harms but also rapid advances in vaccine development, diagnostic testing, and treatment. As the disease moves to endemic status, the need to identify characteristic biomarkers of the disease for diagnostics or therapeutics has lessened, but lessons can still be learned to inform biomarker research in dealing with future pathogens. In this work, we test five sets of research-derived biomarkers against an independent targeted and quantitative Liquid Chromatography–Mass Spectrometry metabolomics dataset to evaluate how robustly these proposed panels would distinguish between COVID-19-positive and negative patients in a hospital setting. We further evaluate a crowdsourced panel comprising the COVID-19 metabolomics biomarkers most commonly mentioned in the literature between 2020 and 2023. The best-performing panel in the independent dataset—measured by F1 score (0.76) and AUROC (0.77)—included nine biomarkers: lactic acid, glutamate, aspartate, phenylalanine, β-alanine, ornithine, arachidonic acid, choline, and hypoxanthine. Panels comprising fewer metabolites performed less well, showing weaker statistical significance in the independent cohort than originally reported in their respective discovery studies. Whilst the studies reviewed here were small and may be subject to confounders, it is desirable that biomarker panels be resilient across cohorts if they are to find use in the clinic, highlighting the importance of assessing the robustness and reproducibility of metabolomics analyses in independent populations.

Hemoglobin and Its Relationship with Fatigue in Long-COVID Patients Three to Six Months after SARS-CoV-2 Infection

“…The fact that we could not validate the same link between inflammation and Hb that was reported by Hanson et al emphasizes the need to further test the robustness of biomarker analyses [ 51 ]. Furthermore, a meta-analysis reviewing the studies evaluating the COVID-19 biomarkers revealed a number of findings, including different results per population, which highlights the significance of validation studies [ 53 ]. Especially, since long COVID is a relatively young disease correlations with biomarkers in one population should be validated in other populations.…”

Targeted metabolomics identifies accurate CSF metabolite biomarkers for the differentiation between COVID-19 with neurological involvement and CNS infections with neurotropic viral pathogens

“…Internal cross-validation by the jackknife method showed that the likelihood of false positive findings was very low, but future studies should be directed at validating the current findings in independently recruited cohorts. In this regard, it should be noted that metabolite biomarkers that were discovered in small cohorts, including those analyzed with Biocrates kits, may show lower accuracy when measured in an independent cohort [ 36 ]. Furthermore, the pathophysiological significance of the low levels of (TG[20:1_32:3] in the neuro-COVID samples remains uncertain due to two factors: (i) the absence of healthy controls for comparison, and (ii) the uncertainty surrounding the exact molecular identity of TG(20:1_32:3) (Table S2), as the Biocrates platform lacks specificity on double bond position, acyl length, and exact fatty acid makeup.…”

Post-Acute Sequelae And Mitochondrial Aberration In SARS-CoV-2 Infection

“…Metabolomic studies have focused on acute COVID-19 biomarkers, the most successful including lactic acid, glutamate, aspartate, phenylalanine, β-alanine, ornithine, arachidonic acid, choline and hypoxanthine [106]. A key feature of acute infection by SARS-CoV-2 is dysregulation of hepatic carbon metabolism [107].…”

“…A key feature of acute infection by SARS-CoV-2 is dysregulation of hepatic carbon metabolism [107]. Using gas chromatography and mass spectrometry, metabolomic profiles of patients with mild and severe acute infection reveal dysregulation of energy production and amino acid catabolism strongly correlated with the degree of hypoxia suffered by the patient [106]. In mild cases, tricarboxylic acid cycle metabolites succinate, citrate, pyruvate and glutamate accumulate in the serum in increased quantities, indicating reduced acetyl-CoA oxidation and the removal of oxaloacetate from the mitochondria on failure to condense with acetyl-CoA.…”