A statistical framework to model the meeting-in-the-middle principle using metabolomic data: application to hepatocellular carcinoma in the EPIC study

被引：31

作者：

Assi, Nada ^{[1
]}

Fages, Anne ^{[2
]}

Vineis, Paolo ^{[3
]}

Chadeau-Hyam, Marc ^{[3
]}

Stepien, Magdalena ^{[1
]}

Duarte-Salles, Talita ^{[1
,3
]}

Byrnes, Graham ^{[1
]}

Boumaza, Houda ^{[2
]}

Knueppel, Sven ^{[4
]}

Kuehn, Tilman ^{[5
]}

Palli, Domenico ^{[6
]}

Bamia, Christina ^{[7
]}

Boshuizen, Hendriek ^{[8
]}

Bonet, Catalina ^{[9
]}

Overvad, Kim ^{[10
]}

Johansson, Mattias ^{[1
,11
]}

Travis, Ruth ^{[12
]}

Gunter, Marc J. ^{[3
]}

Lund, Eiliv ^{[13
]}

Dossus, Laure ^{[14
,15
]}

Elena-Herrmann, Benedicte ^{[2
]}

Riboli, Elio ^{[3
]}

Jenab, Mazda ^{[1
]}

Viallon, Vivian ^{[16
,17
,18
]}

Ferrari, Pietro ^{[1
]}

机构：

[1] Int Agcy Res Canc IARC WHO, F-69372 Lyon 08, France

[2] Univ Lyon, Inst Sci Analyt CNRS ENS Lyon UCB Lyon 1, Ctr RMN Tres Hauts Champs, Villetaneuse, France

[3] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, MRC HPA Ctr Environm, Dept Epidemiol & Biostat, London W2 1PG, England

[4] German Inst Human Nutr, Dept Epidemiol, D-14558 Nuthetal, Germany

[5] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany

[6] Canc Res & Prevent Inst ISPO, Mol & Nutr Epidemiol Unit, Florence, Italy

[7] Univ Athens, Sch Med, WHO Collaborating Ctr Food & Nutr Policies, Dept Hyg Epidemiol & Med Stat, GR-11527 Athens, Greece

[8] Natl Inst Publ Hlth & Environm RIVM, Bilthoven, Netherlands

[9] Hosp Llobregat, Inst Catala Oncol, Canc Epidemiol Res Program, Unit Nutr & Canc, Barcelona, Spain

[10] Aarhus Univ, Sch Publ Hlth, Dept Epidemiol, Aarhus, Denmark

[11] Umea Univ, Dept Biobank Res, Umea, Sweden

[12] Univ Oxford, Nuffield Dept Populat Hlth, Canc Epidemiol Unit, Oxford, England

[13] Univ Tromso, Inst Community Med, Tromso, Norway

[14] Lifestyle Genes & Hlth Integrat Trans Generat Epi, Inserm, U1018, Ctr Res Epidemiol & Populat Hlth CESP, Villejuif, France

[15] Univ Paris 11, Villejuif, France

[16] Univ Lyon, F-69622 Villeurbanne, France

[17] Univ Lyon, F-69622 Villeurbanne, France

[18] UMRESTTE, IFSTTAR, F-69675 Bron, France

来源：

MUTAGENESIS | 2015年 / 30卷 / 06期

基金：

英国医学研究理事会;

关键词：

RISK-FACTORS; MEDIATION ANALYSIS; CANCER; EPIDEMIOLOGY; BIOMARKERS; REGRESSION; SERUM; SETS;

D O I：

10.1093/mutage/gev045

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

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 H-1 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.

引用

页码：743 / 753

页数：11

共 54 条

[1]

Partial least squares regression and projection on latent structure regression (PLS Regression) [J].