title: Towards mechanism classifiers: expression-anchored Gene Ontology signature predicts clinical outcome in lung adenocarcinoma patients.
abstract: We aim to provide clinically applicable, reproducible, mechanistic interpretations of gene expression changes that lack in gene overlap among predictive gene-signatures. Using a method we recently developed, Functional Analysis of Individual Microarray Expression (FAIME), we provide evidence that Gene Ontology-anchored signatures (GO-signatures) show reliable prognosis in lung cancer. In order to demonstrate the biological congruence and reproducibility of FAIME-derived mechanism classifiers, we chose a disease where gene expression classifiers signatures alone had failed to significantly stratify a larger collection of samples and that exhibited poor or no genetic overlap. For each patient in the two lung adenocarcinoma studies, personalized FAIME-profiles of GO biological processes are generated from genome-wide expression profiles. For both training studies, GO-signatures significantly associated to patient mortality were identified (Prediction Analysis for Microarrays; three-fold cross-validation). These two GO-signatures could effectively stratify patients from an independent validation cohort into sub-groups that show significant differences in disease-free survival (log-rank test P=0.019; P=0.001). Importantly, significant mechanism overlaps assessed by information-theory similarity were detected between the two GO-signatures (Fischer Exact Test p=0.001). Hence, together with machine learning technologies, FAIME could be utilized to develop an ontology-driven and expression-anchored prognostic signature that is personalized for an individual patient.
authors.affiliation: Center for Biomedical Informatics, Dept. of Medicine, Section of Hematology/Oncology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Xinan
authors.initials: X
authors.lastname: Yang
authors.forename: Haiquan
authors.initials: H
authors.lastname: Li
authors.forename: Kelly
authors.initials: K
authors.lastname: Regan
authors.forename: Jianrong
authors.initials: J
authors.lastname: Li
authors.forename: Yong
authors.initials: Y
authors.lastname: Huang
authors.forename: Yves A
authors.initials: YA
authors.lastname: Lussier
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000077192:Adenocarcinoma of Lung; D018572:Disease-Free Survival; D020869:Gene Expression Profiling; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D059467:Transcriptome