Promises and pitfalls of untargeted metabolomics

Abstract

Metabolomics is one of the newer omics fields, and has enabled researchers to complement genomic and protein level analysis of disease with both semi-quantitative and quantitative metabolite levels, which are the chemical mediators that constitute a given phenotype. Over more than a decade, methodologies have advanced for both targeted (quantification of specific analytes) as well as untargeted metabolomics (biomarker discovery and global metabolite profiling). Untargeted metabolomics is especially useful when there is no a priori metabolic hypothesis. Liquid chromatography coupled to mass spectrometry (LC-MS) has been the preferred choice for untargeted metabolomics, given the versatility in metabolite coverage and sensitivity of these instruments. Resolving and profiling many hundreds to thousands of metabolites with varying chemical properties in a biological sample presents unique challenges, or pitfalls. In this review, we address the various obstacles and corrective measures available in four major aspects associated with an untargeted metabolomics experiment: (1) experimental design, (2) pre-analytical (sample collection and preparation), (3) analytical (chromatography and detection), and (4) post-analytical (data processing).

Metabolomics in the clinic: A review of the shared and unique features of untargeted metabolomics for clinical research and clinical testing

“…For example, chloroform‐based extractions are more efficient at extraction lipid‐containing or lipophilic compounds . Polar solvents will do the same for more polar and charged compounds . Standardizing extractions and outlining protocols specifically are two mechanisms for consistently monitoring biochemical levels between laboratories.…”

“…7,16 Polar solvents will do the same for more polar and charged compounds. 1,3,16 Standardizing extractions and outlining protocols specifically are two mechanisms for consistently monitoring biochemical levels between laboratories. In this review, the focus is on the technology developed within our laboratory which utilizes a methanol-based extraction followed by tandem LC-MS/MS but is comparable to aqueous extractions described by others.…”

“…This is particularly true in non‐acute cases where a patient has undifferentiated symptoms, such as developmental delays or seizures, that can have a myriad of root causes including IEMs . Clinical metabolomics testing is also proving a useful complement to clinical genomic testing . It also has merit in screening for rare diseases not yet described or for which the few number of cases limits the ability to develop targeted diagnostic tests .…”

“…1 Clinical metabolomics testing is also proving a useful complement to clinical genomic testing. [2][3][4] It also has merit in screening for rare diseases not yet described or for which the few number of cases limits the ability to develop targeted diagnostic tests. 2,[5][6][7] Since no roadmap and few guideposts exist, the major goal of this review is to point out the key elements involved in developing, launching, and performing clinical metabolomics testing.…”

Tools and resources for metabolomics research community: A 2017–2018 update

“…For instance, in a recent study, where the authors evaluated five software on a benchmarked standard and common dataset (MS‐Dial, MZmine 2, XCMS, MarkerView, and Compound Discoverer), they reported various advantages and disadvantages of each of these tools in the detection of true features derived from compounds in the mixture . Various obstacles and corrective measures available in four major aspects associated with an untargeted MS‐based metabolomics experiment—(1) experimental design, (2) preanalytical (sample collection and preparation), (3) analytical (chromatography and detection), and (4) postanalytical (data processing)—have been discussed elsewhere . These results and others indicate that, till date, no single tool is perfect or does justice to a given data type.…”