Challenges and developments in tandem mass spectrometry based clinical metabolomics

Ceglarek, Uta; Leichtle, Alexander Benedikt; Brügel, Mathias; Kortz, Linda; Brauer, Romy; Bresler, Kristin; Thiery, Joachim; Fiedler, Georg Martin

doi:10.1016/j.mce.2008.10.013

Cited by 107 publications

(93 citation statements)

References 28 publications

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“…This coupled with the high mass accuracy of many instruments (Ͻ5 ppm) facilitates the initial ('putative') identification of metabolites by searching metabolite databases [13]. This approach has been implemented in a wide range of applications primarily related to functional genomics and clinical studies [4,14].…”

Section: Lc/ms Based Metabolomicsmentioning

confidence: 99%

“…This is due to its ability to effectively ionize a breath of metabolites with minimal fragmentation (versus gas chromatography-mass spectroscopy (GC/MS), robustness, and ability to scale-up to support tandem mass spectrometry based structural studies (versus capillary electrophoresis-mass spectrometry (CE-MS)) [2]. However, known metabolites are typically a small portion of the data obtained in a LC/MS metabolomics experiment (ϳ10%) [3] where the bulk are MS-artifacts and uncharacterized metabolites.Identification of unknown metabolites is cost and effort intensive, often requiring preparative scale isolation for nuclear magnetic resonance (NMR) studies or extensive chemical synthesis to enable structural comparisons using tandem mass spectrometry (MS/MS) [4]. Therefore, it is not surprising that the majority of reports focus on changes in metabolites that have authentic standards or at a minimum are found in metabolite databases.…”

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confidence: 99%

“…Therefore, effective methods for prioritizing, studying, and ultimately identifying uncharacterized metabolites is a critical development for LC/MS based metabolomics [5][6][7][8][9][10]. Here we discuss current LC/MS metabolomic approaches (detailed elsewhere [2,4,11,12]) and their integration into 'Metabolite Atlases' to facilitate annotation and prioritization of uncharacterized metabolites. …”

mentioning

confidence: 99%

“…Identification of unknown metabolites is cost and effort intensive, often requiring preparative scale isolation for nuclear magnetic resonance (NMR) studies or extensive chemical synthesis to enable structural comparisons using tandem mass spectrometry (MS/MS) [4]. Therefore, it is not surprising that the majority of reports focus on changes in metabolites that have authentic standards or at a minimum are found in metabolite databases.…”

mentioning

confidence: 99%

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Dealing with the unknown: Metabolomics and Metabolite Atlases

Bowen

Northen

2010

J. Am. Soc. Mass Spectrom.

178

158

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Metabolomics is the comprehensive profiling of the small molecule composition of a biological sample. Since metabolites are often the indirect products of gene expression, this approach is being used to provide new insights into a variety of biological systems (clinical, bioenergy, etc.). A grand challenge for metabolomics is the complexity of the data, which often include many experimental artifacts. This is compounded by the tremendous chemical diversity of metabolites. Identification of each uncharacterized metabolite is in many ways its own puzzle (compared with proteomics, which is based on predictable fragmentation patterns of polypeptides). Therefore, effective data reduction/prioritization strategies are critical for this rapidly developing field. Here we review liquid chromatography electrospray ionization mass spectrometry (LC/MS)-based metabolomics, methods for feature finding/prioritization, approaches for identifying unknown metabolites, and construction of method specific 'Metabolite Atlases'.(J Am Soc Mass Spectrom 2010, 21, 1471-1476) © 2010 Published by Elsevier Inc. on behalf of American Society for Mass Spectrometry N ature utilizes a tremendous diversity of metabolites, and it is estimated that there are Ͼ200,000 plant metabolites alone [1]. Metabolomics is a rapidly growing field for studying the small molecule composition of a biological system. Liquid chromatography coupled to electrospray ionization mass spectrometry (LC/MS) is becoming a method of choice for profiling metabolites in complex biological samples. This is due to its ability to effectively ionize a breath of metabolites with minimal fragmentation (versus gas chromatography-mass spectroscopy (GC/MS), robustness, and ability to scale-up to support tandem mass spectrometry based structural studies (versus capillary electrophoresis-mass spectrometry (CE-MS)) [2]. However, known metabolites are typically a small portion of the data obtained in a LC/MS metabolomics experiment (ϳ10%) [3] where the bulk are MS-artifacts and uncharacterized metabolites.Identification of unknown metabolites is cost and effort intensive, often requiring preparative scale isolation for nuclear magnetic resonance (NMR) studies or extensive chemical synthesis to enable structural comparisons using tandem mass spectrometry (MS/MS) [4]. Therefore, it is not surprising that the majority of reports focus on changes in metabolites that have authentic standards or at a minimum are found in metabolite databases. Yet, there are only a few thousand commercially available analytical standards due to lack of demand and the inherent instability of many metabolites. These standards and the endogenous metabolites contained in databases represent only a portion of endogenous metabolites. Therefore, effective methods for prioritizing, studying, and ultimately identifying uncharacterized metabolites is a critical development for LC/MS based metabolomics [5][6][7][8][9][10]. Here we discuss current LC/MS metabolomic approaches (detailed elsewhere [2,4,11,12]) and their inte...

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Section: Lc/ms Based Metabolomicsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Dealing with the unknown: Metabolomics and Metabolite Atlases

Bowen

Northen

2010

J. Am. Soc. Mass Spectrom.

178

158

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“…Physiological variability has been recognized for millennia and summarized in the modern pre-genomic era by Williams in a 1956 book entitled Biochemical Individuality [46]. The ability to account for and measure individual phenotypic variation, however, has only become possible over the past two decades: high throughput tools and methods such as mass spectroscopy are now available to quantitatively measure human physiology, including in response to food (e. g., [5,47]). A major challenge remains assessing environmental, cultural, and psycho-social variation but modern technology in the form of smart phones and tablets is increasingly used to measure an individual's activities, although linking these data to a common research database remains a challenge [42].…”

Section: The Design Of Experimentsmentioning

confidence: 99%

Discovery-Based Nutritional Systems Biology: Developing N-of-1 Nutrigenomic Research

Kaput

Morine

2012

International Journal for Vitamin and Nutrition Research

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Biological and biomedical research, like many established human activities, is based on conventions and practices that become standardized over time. Many of these conventions are decades old and do not account for the great advances in knowledge resulting from modern research. Some of the main practices of biomedical research are discussed herein, in an attempt to initiate a dialogue in the nutrition community about new concepts for personalized nutrition and health. The Design of ExperimentsThe design of biomedical research experiments rests on standards developed almost 100 years ago. The methodology was codifi ed in RA Fisher's The Design of Experiments [12] a 1935 treatise that described the key elements of good research protocols. These benchmarks are a valued requisite for determining the quality of experimental results and Fisher's experimental design is now considered the gold standard for human Abstract: The progress in and success of biomedical research over the past century was built on the foundation outlined in R.A. Fisher's The Design of Experiments (1935), which described the theory and methodological approach to designing research studies. A key tenet of Fisher's treatise, widely adopted by the research community, is randomization, the process of assigning individuals to random groups or treatments. Comparing outcomes or responses between these groups yields "risk factors" called population attributable risks (PAR), which are statistical estimates of the percentage reduction in disease if the risk were avoided or in the case of genetic associations, if the gene variant were not present in the population . High throughput metabolomics, proteomic and genomic technologies provide 21 st century data that humans cannot be randomized into groups: individuals are genetically and biochemically distinct. Gene -environment interactions caused by unique dietary and lifestyle factors contribute to heterogeneity in physiologies observed in human studies. The risk factors determined for populations (i.e., PAR) cannot be applied to the individual. Developing individual risk or benefi t factors in light of the genetic diversity of human populations, the complexity of foods, culture and lifestyle, and the variety of metabolic processes that lead to health or disease are signifi cant challenges for personalizing dietary advice for healthy or medical treatments for individuals with chronic disease. Table I), when applied to the appropriate scientifi c question, produce reliable evidence for improving public and personal health. More humans survive childbirth, infancy, childhood, and through advanced age than any time in our species history [44].One of the key tenets of designing experiments is the requirement for randomization of subjects or other outbred animals to case and control groups. Randomization distributes unknown or unmeasurable characteristics between groups in an attempt to isolate and identify measurable variables that differ between or distinguish those groups. While this step was necessary in the ...

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