Background
The application of whole-exome sequencing for the diagnosis of genetic disease has paved the way for systems-based approaches in the clinical laboratory. Here, we describe a clinical metabolomics method for the screening of metabolic diseases through the analysis of a multi-pronged mass spectrometry platform. By simultaneously measuring hundreds of metabolites in a single sample, clinical metabolomics offers a comprehensive approach to identify metabolic perturbations across multiple biochemical pathways.
Methods
We conducted a single- and multi-day precision study on hundreds of metabolites in human plasma on 4, multi-arm, high-throughput metabolomics platforms.
Results
The average laboratory coefficient of variation (CV) on the 4 platforms was between 9.3 and 11.5% (median, 6.5–8.4%), average inter-assay CV on the 4 platforms ranged from 9.9 to 12.6% (median, 7.0–8.3%) and average intra-assay CV on the 4 platforms ranged from 5.7 to 6.9% (median, 3.5–4.4%). In relation to patient sample testing, the precision of multiple biomarkers associated with IEM disorders showed CVs that ranged from 0.2 to 11.0% across 4 analytical batches.
Conclusions
This evaluation describes single and multi-day precision across 4 identical metabolomics platforms, comprised each of 4 independent method arms, and reproducibility of the method for the measurement of key IEM metabolites in patient samples across multiple analytical batches, providing evidence that the method is robust and reproducible for the screening of patients with inborn errors of metabolism.
Multimetabolite panels can enable accurate GFR estimation. Metabolomic equations, preferably excluding creatinine and demographic characteristics, should be tested for robustness and generalizability as a potential confirmatory test when eGFRcr is unreliable.
IntroductionA major bottleneck in metabolomic studies is metabolite identification from accurate mass spectrometric data. Metabolite x17299 was identified in plasma as an unknown in a metabolomic study using a compound-centric approach where the associated ion features of the compound were used to determine the true molecular mass.ObjectivesThe aim of this work is to elucidate the chemical structure of x17299, a new compound by de novo interpretation of mass spectrometric data.MethodsAn Orbitrap Elite mass spectrometer was used for acquisition of mass spectra up to MS4 at high resolution. Synthetic standards of N,N,N-trimethyl-l-alanyl-l-proline betaine (l,l-TMAP), a diastereomer, and an enantiomer were chemically prepared.ResultsThe planar structure of x17299 was successfully proposed by de novo mechanistic interpretation of mass spectrometric data without any laborious purification and nuclear magnetic resonance spectroscopic analysis. The proposed structure was verified by deuterium exchanged mass spectrometric analysis and confirmed by comparison to a synthetic standard. Relative configuration of x17299 was determined by direct chromatographic comparison to a pair of synthetic diastereomers. Absolute configuration was assigned after derivatization of x17299 with a chiral auxiliary group followed by its chromatographic comparison to a pair of synthetic standards.ConclusionThe chemical structure of metabolite x17299 was determined to be l,l-TMAP.Electronic supplementary materialThe online version of this article (doi:10.1007/s11306-017-1231-x) contains supplementary material, which is available to authorized users.
Fifty‐eight patients with 62 pathologic fractures secondary to metastatic disease were admitted to a rehabilitation hospital during a 5‐year period. Thirty‐four patients were discharged home, 7 were transferred to other facilities, and 17 died. The average hospital stay for the patients who went home (37 days) was only 3 days longer than for patients with nonpathologic fractures. No patient could transfer independently or ambulate at the time of admission, but 26 and 23, respectively, could do so by the time of discharge; 27 patients showed significant improvement in their ability to perform activities of daily living as measured by Kenny scores. All 11 patients who had hypercalcemia died. Eleven of 13 patients requiring parenteral narcotics died. Patients with pathologic fractures secondary to metastatic disease are excellent candidates for intensive rehabilitation programs, but hypercalcemia and administration of parenteral narcotics suggest a poor rehabilitation outcome.
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