title: 'N-of-1-pathways' unveils personal deregulated mechanisms from a single pair of RNA-Seq samples: towards precision medicine.
abstract: BACKGROUND
  The emergence of precision medicine allowed the incorporation of individual molecular data into patient care. Indeed, DNA sequencing predicts somatic mutations in individual patients. However, these genetic features overlook dynamic epigenetic and phenotypic response to therapy. Meanwhile, accurate personal transcriptome interpretation remains an unmet challenge. Further, N-of-1 (single-subject) efficacy trials are increasingly pursued, but are underpowered for molecular marker discovery.
  
  
  METHODS
  'N-of-1-pathways' is a global framework relying on three principles: (i) the statistical universe is a single patient; (ii) significance is derived from geneset/biomodules powered by paired samples from the same patient; and (iii) similarity between genesets/biomodules assesses commonality and differences, within-study and cross-studies. Thus, patient gene-level profiles are transformed into deregulated pathways. From RNA-Seq of 55 lung adenocarcinoma patients, N-of-1-pathways predicts the deregulated pathways of each patient.
  
  
  RESULTS
  Cross-patient N-of-1-pathways obtains comparable results with conventional genesets enrichment analysis (GSEA) and differentially expressed gene (DEG) enrichment, validated in three external evaluations. Moreover, heatmap and star plots highlight both individual and shared mechanisms ranging from molecular to organ-systems levels (eg, DNA repair, signaling, immune response). Patients were ranked based on the similarity of their deregulated mechanisms to those of an independent gold standard, generating unsupervised clusters of diametric extreme survival phenotypes (p=0.03).
  
  
  CONCLUSIONS
  The N-of-1-pathways framework provides a robust statistical and relevant biological interpretation of individual disease-free survival that is often overlooked in conventional cross-patient studies. It enables mechanism-level classifiers with smaller cohorts as well as N-of-1 studies.
  http://lussierlab.org/publications/N-of-1-pathways.
authors.affiliation: Department of Medicine, Bio5 Institute, UA Cancer Center, University of Arizona, Tucson, Arizona, USA Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA Department of Informatics, School of Engineering, EISTI (École Internationale des Sciences du Traitement de l'Information), Cergy-Pontoise, France Institute for Translational Health Informatics, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Gardeux
authors.affiliation: Department of Medicine, Bio5 Institute, UA Cancer Center, University of Arizona, Tucson, Arizona, USA Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA Institute for Translational Health Informatics, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Ikbel
authors.initials: I
authors.lastname: Achour
authors.affiliation: Department of Medicine, Bio5 Institute, UA Cancer Center, University of Arizona, Tucson, Arizona, USA Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA Institute for Translational Health Informatics, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Jianrong
authors.initials: J
authors.lastname: Li
authors.affiliation: Institute for Translational Health Informatics, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Maienschein-Cline
authors.affiliation: Department of Medicine, Bio5 Institute, UA Cancer Center, University of Arizona, Tucson, Arizona, USA Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA Institute for Translational Health Informatics, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Haiquan
authors.initials: H
authors.lastname: Li
authors.affiliation: Computation Institute, Argonne National Laboratory & University of Chicago, Chicago, Illinois, USA.
authors.forename: Lorenzo
authors.identifier: http://orcid.org/0000-0002-8015-4653
authors.initials: L
authors.lastname: Pesce
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA Institute for Translational Health Informatics, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Gurunadh
authors.initials: G
authors.lastname: Parinandi
authors.affiliation: Institute for Translational Health Informatics, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Bahroos
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA University of Illinois Cancer Center, Chicago, Illinois, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Winn
authors.affiliation: Computation Institute, Argonne National Laboratory & University of Chicago, Chicago, Illinois, USA Department of Computer Science, University of Chicago, Chicago, Illinois, USA Mathematics and Computer Science Division, Argonne National Laboratory, Chicago, Illinois, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Foster
authors.affiliation: Department of Medicine, Bio5 Institute, UA Cancer Center, University of Arizona, Tucson, Arizona, USA.
authors.forename: Joe G N
authors.initials: JG
authors.lastname: Garcia
authors.affiliation: Department of Medicine, Bio5 Institute, UA Cancer Center, University of Arizona, Tucson, Arizona, USA Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA Institute for Translational Health Informatics, University of Illinois at Chicago, Chicago, Illinois, USA Computation Institute, Argonne National Laboratory & University of Chicago, Chicago, Illinois, USA University of Illinois Cancer Center, Chicago, Illinois, USA Department of Bioengineering, University of Illinois at Chicago, Chicago, Illinois, USA Department of Biopharmaceutical Science, College of Pharmacy, University of Illinois at Chicago, Illinois, USA Institute for Genomics and Systems Biology, University of Chicago, Chicago, Illinois, USA Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Yves A
authors.initials: YA
authors.lastname: Lussier
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D019295:Computational Biology; D018572:Disease-Free Survival; D005260:Female; D020869:Gene Expression Profiling; D005819:Genetic Markers; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D018802:Patient-Centered Care; D012313:RNA / Q000032:analysis; D012334:RNA, Neoplasm; D017423:Sequence Analysis, RNA; D059467:Transcriptome
chemical_list: D014408:Biomarkers, Tumor; D005819:Genetic Markers; D012334:RNA, Neoplasm; D012313:RNA
keywords: Geneset; N-of-1; Personal Transcriptome; Personalized Medicine; Precision Medicine; Single Subject Design