title: Difference detection in LC-MS data for protein biomarker discovery.
abstract: BACKGROUND
  There is a pressing need for improved proteomic screening methods allowing for earlier diagnosis of disease, systematic monitoring of physiological responses and the uncovering of fundamental mechanisms of drug action. The combined platform of LC-MS (Liquid-Chromatography-Mass-Spectrometry) has shown promise in moving toward a solution in these areas. In this paper we present a technique for discovering differences in protein signal between two classes of samples of LC-MS serum proteomic data without use of tandem mass spectrometry, gels or labeling. This method works on data from a lower-precision MS instrument, the type routinely used by and available to the community at large today. We test our technique on a controlled (spike-in) but realistic (serum biomarker discovery) experiment which is therefore verifiable. We also develop a new method for helping to assess the difficulty of a given spike-in problem. Lastly, we show that the problem of class prediction, sometimes mistaken as a solution to biomarker discovery, is actually a much simpler problem.
  
  
  RESULTS
  Using precision-recall curves with experimentally extracted ground truth, we show that (1) our technique has good performance using seven replicates from each class, (2) performance degrades with decreasing number of replicates, (3) the signal that we are teasing out is not trivially available (i.e. the differences are not so large that the task is easy). Lastly, we easily obtain perfect classification results for data in which the problem of extracting differences does not produce absolutely perfect results. This emphasizes the different nature of the two problems and also their relative difficulties.
  
  
  BACKGROUND
  Our data are publicly available as a benchmark for further studies of this nature at http://www.cs.toronto.edu/~jenn/LCMS
authors.affiliation: Department of Computer Science, University of Toronto, Toronto, Ontario M5S 3G4, Canada. jenn@cs.toronto.edu
authors.forename: Jennifer
authors.initials: J
authors.lastname: Listgarten
authors.forename: Radford M
authors.initials: RM
authors.lastname: Neal
authors.forename: Sam T
authors.initials: ST
authors.lastname: Roweis
authors.forename: Peter
authors.initials: P
authors.lastname: Wong
authors.forename: Andrew
authors.initials: A
authors.lastname: Emili
mesh_terms: D000465:Algorithms; D015415:Biomarkers / Q000032:analysis* / Q000737:chemistry*; D001798:Blood Proteins / Q000032:analysis* / Q000737:chemistry*; D002853:Chromatography, Liquid / Q000379:methods*; D013058:Mass Spectrometry / Q000379:methods*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D020539:Sequence Analysis, Protein / Q000379:methods*
chemical_list: D015415:Biomarkers; D001798:Blood Proteins