title: Effect of size and heterogeneity of samples on biomarker discovery: synthetic and real data assessment.
abstract: BACKGROUND
  The identification of robust lists of molecular biomarkers related to a disease is a fundamental step for early diagnosis and treatment. However, methodologies for the discovery of biomarkers using microarray data often provide results with limited overlap. These differences are imputable to 1) dataset size (few subjects with respect to the number of features); 2) heterogeneity of the disease; 3) heterogeneity of experimental protocols and computational pipelines employed in the analysis. In this paper, we focus on the first two issues and assess, both on simulated (through an in silico regulation network model) and real clinical datasets, the consistency of candidate biomarkers provided by a number of different methods.
  
  
  METHODS
  We extensively simulated the effect of heterogeneity characteristic of complex diseases on different sets of microarray data. Heterogeneity was reproduced by simulating both intrinsic variability of the population and the alteration of regulatory mechanisms. Population variability was simulated by modeling evolution of a pool of subjects; then, a subset of them underwent alterations in regulatory mechanisms so as to mimic the disease state.
  
  
  RESULTS
  The simulated data allowed us to outline advantages and drawbacks of different methods across multiple studies and varying number of samples and to evaluate precision of feature selection on a benchmark with known biomarkers. Although comparable classification accuracy was reached by different methods, the use of external cross-validation loops is helpful in finding features with a higher degree of precision and stability. Application to real data confirmed these results.
authors.affiliation: Information Engineering Department, University of Padova, Padova, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Di Camillo
authors.forename: Tiziana
authors.initials: T
authors.lastname: Sanavia
authors.forename: Matteo
authors.initials: M
authors.lastname: Martini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Jurman
authors.forename: Francesco
authors.initials: F
authors.lastname: Sambo
authors.forename: Annalisa
authors.initials: A
authors.lastname: Barla
authors.forename: Margherita
authors.initials: M
authors.lastname: Squillario
authors.forename: Cesare
authors.initials: C
authors.lastname: Furlanello
authors.forename: Gianna
authors.initials: G
authors.lastname: Toffolo
authors.forename: Claudio
authors.initials: C
authors.lastname: Cobelli
mesh_terms: D000465:Algorithms; D000704:Analysis of Variance; D015415:Biomarkers / Q000378:metabolism; D019295:Computational Biology / Q000379:methods*; D003627:Data Interpretation, Statistical; D016002:Discriminant Analysis; D004194:Disease / Q000235:genetics; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D012044:Regression Analysis; D018401:Sample Size; D060388:Support Vector Machine
chemical_list: D015415:Biomarkers