title: A statistical framework to model the meeting-in-the-middle principle using metabolomic data: application to hepatocellular carcinoma in the EPIC study.
abstract: Metabolomics is a potentially powerful tool for identification of biomarkers associated with lifestyle exposures and risk of various diseases. This is the rationale of the 'meeting-in-the-middle' concept, for which an analytical framework was developed in this study. In a nested case-control study on hepatocellular carcinoma (HCC) within the European Prospective Investigation into Cancer and nutrition (EPIC), serum (1)H nuclear magnetic resonance (NMR) spectra (800 MHz) were acquired for 114 cases and 222 matched controls. Through partial least square (PLS) analysis, 21 lifestyle variables (the 'predictors', including information on diet, anthropometry and clinical characteristics) were linked to a set of 285 metabolic variables (the 'responses'). The three resulting scores were related to HCC risk by means of conditional logistic regressions. The first PLS factor was not associated with HCC risk. The second PLS metabolomic factor was positively associated with tyrosine and glucose, and was related to a significantly increased HCC risk with OR = 1.11 (95% CI: 1.02, 1.22, P = 0.02) for a 1SD change in the responses score, and a similar association was found for the corresponding lifestyle component of the factor. The third PLS lifestyle factor was associated with lifetime alcohol consumption, hepatitis and smoking, and had negative loadings on vegetables intake. Its metabolomic counterpart displayed positive loadings on ethanol, glutamate and phenylalanine. These factors were positively and statistically significantly associated with HCC risk, with 1.37 (1.05, 1.79, P = 0.02) and 1.22 (1.04, 1.44, P = 0.01), respectively. Evidence of mediation was found in both the second and third PLS factors, where the metabolomic signals mediated the relation between the lifestyle component and HCC outcome. This study devised a way to bridge lifestyle variables to HCC risk through NMR metabolomics data. This implementation of the 'meeting-in-the-middle' approach finds natural applications in settings characterised by high-dimensional data, increasingly frequent in the omics generation.
authors.affiliation: International Agency for Research in Cancer (IARC-WHO), 150 Cours Albert Thomas, 69372 Lyon Cedex 08, France.
authors.forename: Nada
authors.initials: N
authors.lastname: Assi
authors.affiliation: Centre de RMN à Très Hauts Champs, Institut des Sciences Analytiques (CNRS/ENS Lyon/UCB Lyon 1), Université de Lyon, 69100 Villeurbanne, France, Present address: Chemical Physics Department, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Anne
authors.initials: A
authors.lastname: Fages
authors.affiliation: Department of Epidemiology and Biostatistics, MRC-HPA Centre for Environment and Health, School of Public Health, Imperial College London, Norfolk Place, London, W2 1PG, UK.
authors.forename: Paolo
authors.initials: P
authors.lastname: Vineis
authors.affiliation: Department of Epidemiology and Biostatistics, MRC-HPA Centre for Environment and Health, School of Public Health, Imperial College London, Norfolk Place, London, W2 1PG, UK.
authors.forename: Marc
authors.initials: M
authors.lastname: Chadeau-Hyam
authors.affiliation: International Agency for Research in Cancer (IARC-WHO), 150 Cours Albert Thomas, 69372 Lyon Cedex 08, France.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Stepien
authors.affiliation: International Agency for Research in Cancer (IARC-WHO), 150 Cours Albert Thomas, 69372 Lyon Cedex 08, France.
authors.forename: Talita
authors.initials: T
authors.lastname: Duarte-Salles
authors.affiliation: International Agency for Research in Cancer (IARC-WHO), 150 Cours Albert Thomas, 69372 Lyon Cedex 08, France.
authors.forename: Graham
authors.initials: G
authors.lastname: Byrnes
authors.affiliation: Centre de RMN à Très Hauts Champs, Institut des Sciences Analytiques (CNRS/ENS Lyon/UCB Lyon 1), Université de Lyon, 69100 Villeurbanne, France.
authors.forename: Houda
authors.initials: H
authors.lastname: Boumaza
authors.affiliation: Department of Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbruecke, 14558 Nuthetal, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Knüppel
authors.affiliation: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Tilman
authors.initials: T
authors.lastname: Kühn
authors.affiliation: Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute - ISPO, Florence, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Palli
authors.affiliation: Department of Hygiene, Epidemiology and Medical Statistics, WHO Collaborating Center for Food and Nutrition Policies, University of Athens Medical School, Athens, Greece.
authors.forename: Christina
authors.initials: C
authors.lastname: Bamia
authors.affiliation: National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
authors.forename: Hendriek
authors.initials: H
authors.lastname: Boshuizen
authors.affiliation: Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Institut Català d'Oncologia, L'Hospitalet de Llobregat, Spain.
authors.forename: Catalina
authors.initials: C
authors.lastname: Bonet
authors.affiliation: The Department of Epidemiology, School of Public Health, Aarhus University, Aarhus, Denmark.
authors.forename: Kim
authors.initials: K
authors.lastname: Overvad
authors.affiliation: International Agency for Research in Cancer (IARC-WHO), 150 Cours Albert Thomas, 69372 Lyon Cedex 08, France, The Department for Biobank Research, Umeå University, Umeå, Sweden.
authors.forename: Mattias
authors.initials: M
authors.lastname: Johansson
authors.affiliation: Cancer Epidemiology Unit, Nuffield Department of Population Health University of Oxford, Oxford, UK.
authors.forename: Ruth
authors.initials: R
authors.lastname: Travis
authors.affiliation: Department of Epidemiology and Biostatistics, MRC-HPA Centre for Environment and Health, School of Public Health, Imperial College London, Norfolk Place, London, W2 1PG, UK.
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Gunter
authors.affiliation: The Institute of Community Medicine, University of Tromsø, Tromsø, Norway.
authors.forename: Eiliv
authors.initials: E
authors.lastname: Lund
authors.affiliation: Inserm, Centre for research in Epidemiology and Population Health (CESP), U1018, Lifestyle, Genes and Health: Integrative Trans-generational Epidemiology Team, Villejuif, France, Université Paris Sud, Villejuif, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Dossus
authors.affiliation: Centre de RMN à Très Hauts Champs, Institut des Sciences Analytiques (CNRS/ENS Lyon/UCB Lyon 1), Université de Lyon, 69100 Villeurbanne, France.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Elena-Herrmann
authors.affiliation: Department of Epidemiology and Biostatistics, MRC-HPA Centre for Environment and Health, School of Public Health, Imperial College London, Norfolk Place, London, W2 1PG, UK.
authors.forename: Elio
authors.initials: E
authors.lastname: Riboli
authors.affiliation: International Agency for Research in Cancer (IARC-WHO), 150 Cours Albert Thomas, 69372 Lyon Cedex 08, France.
authors.forename: Mazda
authors.initials: M
authors.lastname: Jenab
authors.forename: Vivian
authors.initials: V
authors.lastname: Viallon
authors.affiliation: International Agency for Research in Cancer (IARC-WHO), 150 Cours Albert Thomas, 69372 Lyon Cedex 08, France, ferrarip@iarc.fr.
authors.forename: Pietro
authors.initials: P
authors.lastname: Ferrari
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D005060:Europe; D006801:Humans; D008019:Life Style; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism*; D055442:Metabolome; D055432:Metabolomics / Q000379:methods; D008875:Middle Aged; D015233:Models, Statistical; D019906:Nuclear Magnetic Resonance, Biomolecular; D054647:Nutrigenomics / Q000379:methods; D016017:Odds Ratio; D012372:ROC Curve; D015203:Reproducibility of Results; D012307:Risk Factors; D055815:Young Adult
chemical_list: D015415:Biomarkers