title: Random Survival Forest in practice: a method for modelling complex metabolomics data in time to event analysis.
abstract: The application of metabolomics in prospective cohort studies is statistically challenging. Given the importance of appropriate statistical methods for selection of disease-associated metabolites in highly correlated complex data, we combined random survival forest (RSF) with an automated backward elimination procedure that addresses such issues.
  
  
  
  Our RSF approach was illustrated with data from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study, with concentrations of 127 serum metabolites as exposure variables and time to development of type 2 diabetes mellitus (T2D) as outcome variable. Out of this data set, Cox regression with a stepwise selection method was recently published. Replication of methodical comparison (RSF and Cox regression) was conducted in two independent cohorts. Finally, the R-code for implementing the metabolite selection procedure into the RSF-syntax is provided.
  
  
  
  The application of the RSF approach in EPIC-Potsdam resulted in the identification of 16 incident T2D-associated metabolites which slightly improved prediction of T2D when used in addition to traditional T2D risk factors and also when used together with classical biomarkers. The identified metabolites partly agreed with previous findings using Cox regression, though RSF selected a higher number of highly correlated metabolites.
  
  
  
  The RSF method appeared to be a promising approach for identification of disease-associated variables in complex data with time to event as outcome. The demonstrated RSF approach provides comparable findings as the generally used Cox regression, but also addresses the problem of multicollinearity and is suitable for high-dimensional data.
authors: Department of Epidemiology, German Institute of Human Nutrition, Nuthetal, Germany stefan.dietrich@dife.de.
authors: Stefan
authors: S
authors: Dietrich
authors: Department of Epidemiology, German Institute of Human Nutrition, Nuthetal, Germany.
authors: Anna
authors: A
authors: Floegel
authors: Research Unit of Molecular Epidemiology.|Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
authors: Martina
authors: M
authors: Troll
authors: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Tilman
authors: T
authors: Kühn
authors: Institute for Biometrics and Epidemiology, Leibniz Center for Diabetes Research at Heinrich Heine University, Germany.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
authors: Wolfgang
authors: W
authors: Rathmann
authors: Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany.|Department of Environmental Health, Harvard School of Public Health, Boston, MA, USA and.
authors: Anette
authors: A
authors: Peters
authors: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Disorn
authors: D
authors: Sookthai
authors: Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research (UFZ), Institute of Biochemistry, Faculty of Biosciences, Pharmacy and Psychology, University of Leipzig, Leipzig, Germany and Department of Chemistry and Bioscience, University of Aalborg, Aalborg East, Denmark.
authors: Martin
authors: M
authors: von Bergen
authors: Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Rudolf
authors: R
authors: Kaaks
authors: German Center for Diabetes Research (DZD), München-Neuherberg, Germany.|Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, German Research Center for Environmental Health, München-Neuherberg, Germany.|Lehrstuhl für Experimentelle Genetik, Technische Universität München, Freising-Weihenstephan, Germany.
authors: Jerzy
authors: J
authors: Adamski
authors: Institute of Experimental Genetics, Genome Analysis Center, Helmholtz Zentrum München, German Research Center for Environmental Health, München-Neuherberg, Germany.
authors: Cornelia
authors: C
authors: Prehn
authors: Department of Epidemiology, German Institute of Human Nutrition, Nuthetal, Germany.
authors: Heiner
authors: H
authors: Boeing
authors: German Center for Diabetes Research (DZD), München-Neuherberg, Germany.|Department of Molecular Epidemiology, German Institute of Human Nutrition, Nuthetal, Germany.
authors: Matthias B
authors: MB
authors: Schulze
authors: Research Unit of Molecular Epidemiology.|Hannover Unified Biobank, and Institute for Human Genetics, Hannover, Germany.
authors: Thomas
authors: T
authors: Illig
authors: Department of Epidemiology, German Institute of Human Nutrition, Nuthetal, Germany.|Molecular Epidemiology Group, Max Delbruck Center for Molecular Medicine (MDC) Berlin-Buch, Berlin, Germany.
authors: Tobias
authors: T
authors: Pischon
authors: Department of Epidemiology, German Institute of Human Nutrition, Nuthetal, Germany.
authors: Sven
authors: S
authors: Knüppel
authors: Research Unit of Molecular Epidemiology.|Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
authors: Rui
authors: R
authors: Wang-Sattler
authors: Department of Epidemiology, German Institute of Human Nutrition, Nuthetal, Germany.
authors: Dagmar
authors: D
authors: Drogan
mesh_terms: D000328:Adult; D000368:Aged; D000465:Algorithms; D015415:Biomarkers / Q000097:blood*; D003627:Data Interpretation, Statistical; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000401:mortality; D005060:Europe; D005260:Female; D006801:Humans; D008297:Male; D055432:Metabolomics / Q000379:methods*; D008875:Middle Aged; D015233:Models, Statistical; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012307:Risk Factors; D016019:Survival Analysis
chemical_list: D015415:Biomarkers
keywords: Cox proportional hazards regression; exploratory survival analysis; metabolomics; multicollinearity; random survival forest; right-censored data; type 2 diabetes mellitus; variable selection