title: Data-driven analysis approach for biomarker discovery using molecular-profiling technologies.
abstract: High-throughput molecular-profiling technologies provide rapid, efficient and systematic approaches to search for biomarkers. Supervised learning algorithms are naturally suited to analyse a large amount of data generated using these technologies in biomarker discovery efforts. The study demonstrates with two examples a data-driven analysis approach to analysis of large complicated datasets collected in high-throughput technologies in the context of biomarker discovery. The approach consists of two analytic steps: an initial unsupervised analysis to obtain accurate knowledge about sample clustering, followed by a second supervised analysis to identify a small set of putative biomarkers for further experimental characterization. By comparing the most widely applied clustering algorithms using a leukaemia DNA microarray dataset, it was established that principal component analysis-assisted projections of samples from a high-dimensional molecular feature space into a few low dimensional subspaces provides a more effective and accurate way to explore visually and identify data structures that confirm intended experimental effects based on expected group membership. A supervised analysis method, shrunken centroid algorithm, was chosen to take knowledge of sample clustering gained or confirmed by the first step of the analysis to identify a small set of molecules as candidate biomarkers for further experimentation. The approach was applied to two molecular-profiling studies. In the first study, PCA-assisted analysis of DNA microarray data revealed that discrete data structures exist in rat liver gene expression and correlated with blood clinical chemistry and liver pathological damage in response to a chemical toxicant diethylhexylphthalate, a peroxisome-proliferator-activator receptor agonist. Sixteen genes were then identified by shrunken centroid algorithm as the best candidate biomarkers for liver damage. Functional annotations of these genes revealed roles in acute phase response, lipid and fatty acid metabolism and they are functionally relevant to the observed toxicities. In the second study, 26 urine ions identified from a GC/MS spectrum, two of which were glucose fragment ions included as positive controls, showed robust changes with the development of diabetes in Zucker diabetic fatty rats. Further experiments are needed to define their chemical identities and establish functional relevancy to disease development.
authors.affiliation: Integrative Biology, Lilly Research Laboratories, Greenfield, IN 46140, USA.
authors.forename: T
authors.initials: T
authors.lastname: Wei
authors.forename: B
authors.initials: B
authors.lastname: Liao
authors.forename: B L
authors.initials: BL
authors.lastname: Ackermann
authors.forename: R A
authors.initials: RA
authors.lastname: Jolly
authors.forename: J A
authors.initials: JA
authors.lastname: Eckstein
authors.forename: N H
authors.initials: NH
authors.lastname: Kulkarni
authors.forename: L M
authors.initials: LM
authors.lastname: Helvering
authors.forename: K M
authors.initials: KM
authors.lastname: Goldstein
authors.forename: J
authors.initials: J
authors.lastname: Shou
authors.forename: S T
authors.initials: ST
authors.lastname: Estrem
authors.forename: T P
authors.initials: TP
authors.lastname: Ryan
authors.forename: J-M
authors.initials: JM
authors.lastname: Colet
authors.forename: C E
authors.initials: CE
authors.lastname: Thomas
authors.forename: J L
authors.initials: JL
authors.lastname: Stevens
authors.forename: J E
authors.initials: JE
authors.lastname: Onyia
mesh_terms: D000465:Algorithms; D000818:Animals; D015415:Biomarkers / Q000032:analysis*; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism; D016000:Cluster Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D003627:Data Interpretation, Statistical; D003920:Diabetes Mellitus / Q000378:metabolism; D004051:Diethylhexyl Phthalate / Q000633:toxicity; D005234:Fatty Liver / Q000139:chemically induced / Q000378:metabolism; D008401:Gas Chromatography-Mass Spectrometry; D020869:Gene Expression Profiling; D007938:Leukemia / Q000235:genetics; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D025341:Principal Component Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker
chemical_list: D015415:Biomarkers; D004273:DNA, Neoplasm; D004051:Diethylhexyl Phthalate