title: Metabolomics in nutritional epidemiology: identifying metabolites associated with diet and quantifying their potential to uncover diet-disease relations in populations.
abstract: BACKGROUND
  Metabolomics is an emerging field with the potential to advance nutritional epidemiology; however, it has not yet been applied to large cohort studies.
  
  
  OBJECTIVE
  Our first aim was to identify metabolites that are biomarkers of usual dietary intake. Second, among serum metabolites correlated with diet, we evaluated metabolite reproducibility and required sample sizes to determine the potential for metabolomics in epidemiologic studies.
  
  
  METHODS
  Baseline serum from 502 participants in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial was analyzed by using ultra-high-performance liquid-phase chromatography with tandem mass spectrometry and gas chromatography-mass spectrometry. Usual intakes of 36 dietary groups were estimated by using a food-frequency questionnaire. Dietary biomarkers were identified by using partial Pearson's correlations with Bonferroni correction for multiple comparisons. Intraclass correlation coefficients (ICCs) between samples collected 1 y apart in a subset of 30 individuals were calculated to evaluate intraindividual metabolite variability.
  
  
  RESULTS
  We detected 412 known metabolites. Citrus, green vegetables, red meat, shellfish, fish, peanuts, rice, butter, coffee, beer, liquor, total alcohol, and multivitamins were each correlated with at least one metabolite (P < 1.093 × 10(-6); r = -0.312 to 0.398); in total, 39 dietary biomarkers were identified. Some correlations (citrus intake with stachydrine) replicated previous studies; others, such as peanuts and tryptophan betaine, were novel findings. Other strong associations included coffee (with trigonelline-N-methylnicotinate and quinate) and alcohol (with ethyl glucuronide). Intraindividual variability in metabolite levels (1-y ICCs) ranged from 0.27 to 0.89. Large, but attainable, sample sizes are required to detect associations between metabolites and disease in epidemiologic studies, further emphasizing the usefulness of metabolomics in nutritional epidemiology.
  
  
  CONCLUSIONS
  We identified dietary biomarkers by using metabolomics in an epidemiologic data set. Given the strength of the associations observed, we expect that some of these metabolites will be validated in future studies and later used as biomarkers in large cohorts to study diet-disease associations. The PLCO trial was registered at clinicaltrials.gov as NCT00002540.
authors.affiliation: From the Nutritional Epidemiology Branch (KAG, SCM, QX, RZS-S, RS, and AJC), the Biostatistics Branch (JNS), and the Occupational and Environmental Epidemiology Branch (W-YH), Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda, MD.
authors.forename: Kristin A
authors.initials: KA
authors.lastname: Guertin
authors.affiliation: From the Nutritional Epidemiology Branch (KAG, SCM, QX, RZS-S, RS, and AJC), the Biostatistics Branch (JNS), and the Occupational and Environmental Epidemiology Branch (W-YH), Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda, MD.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Moore
authors.affiliation: From the Nutritional Epidemiology Branch (KAG, SCM, QX, RZS-S, RS, and AJC), the Biostatistics Branch (JNS), and the Occupational and Environmental Epidemiology Branch (W-YH), Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda, MD.
authors.forename: Joshua N
authors.initials: JN
authors.lastname: Sampson
authors.affiliation: From the Nutritional Epidemiology Branch (KAG, SCM, QX, RZS-S, RS, and AJC), the Biostatistics Branch (JNS), and the Occupational and Environmental Epidemiology Branch (W-YH), Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda, MD.
authors.forename: Wen-Yi
authors.initials: WY
authors.lastname: Huang
authors.affiliation: From the Nutritional Epidemiology Branch (KAG, SCM, QX, RZS-S, RS, and AJC), the Biostatistics Branch (JNS), and the Occupational and Environmental Epidemiology Branch (W-YH), Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda, MD.
authors.forename: Qian
authors.initials: Q
authors.lastname: Xiao
authors.affiliation: From the Nutritional Epidemiology Branch (KAG, SCM, QX, RZS-S, RS, and AJC), the Biostatistics Branch (JNS), and the Occupational and Environmental Epidemiology Branch (W-YH), Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda, MD.
authors.forename: Rachael Z
authors.initials: RZ
authors.lastname: Stolzenberg-Solomon
authors.affiliation: From the Nutritional Epidemiology Branch (KAG, SCM, QX, RZS-S, RS, and AJC), the Biostatistics Branch (JNS), and the Occupational and Environmental Epidemiology Branch (W-YH), Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda, MD.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Sinha
authors.affiliation: From the Nutritional Epidemiology Branch (KAG, SCM, QX, RZS-S, RS, and AJC), the Biostatistics Branch (JNS), and the Occupational and Environmental Epidemiology Branch (W-YH), Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda, MD.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Cross
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D004032:Diet; D016021:Epidemiologic Studies; D005247:Feeding Behavior; D005260:Female; D005500:Follow-Up Studies; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008297:Male; D055442:Metabolome / Q000502:physiology; D055432:Metabolomics / Q000379:methods / Q000592:standards*; D008875:Middle Aged; D009369:Neoplasms / Q000175:diagnosis / Q000453:epidemiology; D015596:Nutrition Assessment; D015203:Reproducibility of Results; D011795:Surveys and Questionnaires
chemical_list: D015415:Biomarkers
references.citation: Br J Nutr. 2011 Sep;106(6):812-24
references.pmid: 21736852
references.citation: Am J Clin Nutr. 1997 Apr;65(4 Suppl):1240S-1245S
references.pmid: 9094928
references.citation: J Agric Food Chem. 2010 Aug 11;58(15):8715-21
references.pmid: 20617853
references.citation: Anal Chem. 2009 Aug 15;81(16):6656-67
references.pmid: 19624122
references.citation: J Acad Nutr Diet. 2013 Apr;113(4):569-80
references.pmid: 23415502
references.citation: Nucleic Acids Res. 2007 Jan;35(Database issue):D521-6
references.pmid: 17202168
references.citation: Am J Epidemiol. 1990 Dec;132(6):1185-95
references.pmid: 2135637
references.citation: Nucleic Acids Res. 2013 Jan;41(Database issue):D801-7
references.pmid: 23161693
references.citation: Am J Clin Nutr. 1997 Apr;65(4 Suppl):1232S-1239S
references.pmid: 9094927
references.citation: Am J Clin Nutr. 2011 Feb;93(2):314-21
references.pmid: 21177801
references.citation: Eur J Nutr. 2007 Dec;46(8):446-52
references.pmid: 18060588
references.citation: Nature. 2011 Aug 31;477(7362):54-60
references.pmid: 21886157
references.citation: Environ Mol Mutagen. 2013 Aug;54(7):480-99
references.pmid: 23681765
references.citation: Cancer Epidemiol Biomarkers Prev. 2013 Apr;22(4):631-40
references.pmid: 23396963
references.citation: Nat Rev Microbiol. 2011 Apr;9(4):279-90
references.pmid: 21407244
references.citation: J Agric Food Chem. 2013 Aug 7;61(31):7654-60
references.pmid: 23855762
references.citation: Talanta. 2012 Jan 15;88:420-6
references.pmid: 22265520
references.citation: Food Chem. 2012 Oct 15;134(4):1870-7
references.pmid: 23442632
references.citation: Am J Clin Nutr. 2013 Feb;97(2):377-89
references.pmid: 23269817
references.citation: Nucleic Acids Res. 2009 Jan;37(Database issue):D603-10
references.pmid: 18953024
references.citation: Eur J Clin Nutr. 2013 Oct;67(10):1100-8
references.pmid: 23942179
references.citation: Hum Genet. 2009 Jun;125(5-6):507-25
references.pmid: 19357868
references.citation: J Clin Invest. 1987 Mar;79(3):731-7
references.pmid: 3546377
references.citation: Proc Nutr Soc. 2013 Aug;72(3):352-61
references.pmid: 23632011
references.citation: Annu Rev Nutr. 2012 Aug 21;32:183-202
references.pmid: 22540256
references.citation: Am J Epidemiol. 2001 Dec 15;154(12):1089-99
references.pmid: 11744511
references.citation: Control Clin Trials. 2000 Dec;21(6 Suppl):273S-309S
references.pmid: 11189684
references.citation: Nature. 2011 May 12;473(7346):174-80
references.pmid: 21508958
references.citation: J Proteome Res. 2013 Apr 5;12(4):1645-59
references.pmid: 23425595
references.citation: Transl Psychiatry. 2013 Jul 02;3:e276
references.pmid: 23820610