title: Least absolute shrinkage and selection operator type methods for the identification of serum biomarkers of overweight and obesity: simulation and application.
abstract: The study of circulating biomarkers and their association with disease outcomes has become progressively complex due to advances in the measurement of these biomarkers through multiplex technologies. The Least Absolute Shrinkage and Selection Operator (LASSO) is a data analysis method that may be utilized for biomarker selection in these high dimensional data. However, it is unclear which LASSO-type method is preferable when considering data scenarios that may be present in serum biomarker research, such as high correlation between biomarkers, weak associations with the outcome, and sparse number of true signals. The goal of this study was to compare the LASSO to five LASSO-type methods given these scenarios.
  
  
  
  A simulation study was performed to compare the LASSO, Adaptive LASSO, Elastic Net, Iterated LASSO, Bootstrap-Enhanced LASSO, and Weighted Fusion for the binary logistic regression model. The simulation study was designed to reflect the data structure of the population-based Tucson Epidemiological Study of Airway Obstructive Disease (TESAOD), specifically the sample size (N = 1000 for total population, 500 for sub-analyses), correlation of biomarkers (0.20, 0.50, 0.80), prevalence of overweight (40%) and obese (12%) outcomes, and the association of outcomes with standardized serum biomarker concentrations (log-odds ratio = 0.05-1.75). Each LASSO-type method was then applied to the TESAOD data of 306 overweight, 66 obese, and 463 normal-weight subjects with a panel of 86 serum biomarkers.
  
  
  
  Based on the simulation study, no method had an overall superior performance. The Weighted Fusion correctly identified more true signals, but incorrectly included more noise variables. The LASSO and Elastic Net correctly identified many true signals and excluded more noise variables. In the application study, biomarkers of overweight and obesity selected by all methods were Adiponectin, Apolipoprotein H, Calcitonin, CD14, Complement 3, C-reactive protein, Ferritin, Growth Hormone, Immunoglobulin M, Interleukin-18, Leptin, Monocyte Chemotactic Protein-1, Myoglobin, Sex Hormone Binding Globulin, Surfactant Protein D, and YKL-40.
  
  
  
  For the data scenarios examined, choice of optimal LASSO-type method was data structure dependent and should be guided by the research objective. The LASSO-type methods identified biomarkers that have known associations with obesity and obesity related conditions.
authors.affiliation: Mel and Enid Zuckerman College of Public Health, The University of Arizona, 1295 North Martin Avenue, P.O. Box 245211, Tucson, AZ, 85724, USA. mmv@email.arizona.edu.|Asthma and Airway Disease Research Center, The University of Arizona, 1501 North Campbell Avenue, P.O. Box 245030, Tucson, AZ, 85724, USA. mmv@email.arizona.edu.
authors.forename: Monica M
authors.initials: MM
authors.lastname: Vasquez
authors.affiliation: Mel and Enid Zuckerman College of Public Health, The University of Arizona, 1295 North Martin Avenue, P.O. Box 245211, Tucson, AZ, 85724, USA.
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Hu
authors.affiliation: Mel and Enid Zuckerman College of Public Health, The University of Arizona, 1295 North Martin Avenue, P.O. Box 245211, Tucson, AZ, 85724, USA.
authors.forename: Denise J
authors.initials: DJ
authors.lastname: Roe
authors.affiliation: Mel and Enid Zuckerman College of Public Health, The University of Arizona, 1295 North Martin Avenue, P.O. Box 245211, Tucson, AZ, 85724, USA.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Asthma and Airway Disease Research Center, The University of Arizona, 1501 North Campbell Avenue, P.O. Box 245030, Tucson, AZ, 85724, USA.
authors.forename: Marilyn
authors.initials: M
authors.lastname: Halonen
authors.affiliation: Asthma and Airway Disease Research Center, The University of Arizona, 1501 North Campbell Avenue, P.O. Box 245030, Tucson, AZ, 85724, USA.|ISGlobal CREAL Centre, University Pompeu Fabra, Barcelona, Spain.
authors.forename: Stefano
authors.initials: S
authors.lastname: Guerra
mesh_terms: D000465:Algorithms; D019540:Area Under Curve; D015415:Biomarkers / Q000097:blood; D006801:Humans; D016015:Logistic Models; D008954:Models, Biological; D009765:Obesity / Q000097:blood / Q000175:diagnosis*; D050177:Overweight / Q000097:blood / Q000175:diagnosis; D012372:ROC Curve
chemical_list: D015415:Biomarkers
keywords: Biomarkers; High-Dimensional; LASSO; Obesity; Overweight