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'N-of-1-pathways' unveils personal deregulated mechanisms from a single pair of RNA-Seq samples: towards precision medicine.

Gardeux V, Achour I, Li J, Maienschein-Cline M, Li H, Pesce L, Parinandi G, Bahroos N, Winn R, Foster I, Garcia JG, Lussier YA - J Am Med Inform Assoc (2014)

Bottom Line: 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.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).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.

View Article: PubMed Central - PubMed

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.

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Concordant deregulated pathways between exploration and external validation studies. To establish that N-of-1-pathways yielded relevant Gene Ontology (GO) terms associated pathways, we compared the deregulated pathways to two conventional enrichment methods in three independent lung adenocarcinoma studies (see Methods and table 1). In (A), the Venn diagram corresponds to the overlap of deregulated GO annotations of Biological Process (GO-BP) terms associated pathways between the three external validation studies I, II and III (deregulated pathways were directly retrieved from the ones published in study I, while they were enriched using DEG enrichment from the DE genes list published in studies II and III, at FDR≤5%). In (B–F), the unveiled pathways of the exploration set were compared to those discovered in the independent validation studies using either genesets enrichment analysis (GSEA) (C and E), DEG enrichment as a proxy gold standard (D and F), or pathways reported in study I (B). Bonf., Bonferroni; FDR, false discovery rate; PPV, positive predictive value.
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AMIAJNL2013002519F3: Concordant deregulated pathways between exploration and external validation studies. To establish that N-of-1-pathways yielded relevant Gene Ontology (GO) terms associated pathways, we compared the deregulated pathways to two conventional enrichment methods in three independent lung adenocarcinoma studies (see Methods and table 1). In (A), the Venn diagram corresponds to the overlap of deregulated GO annotations of Biological Process (GO-BP) terms associated pathways between the three external validation studies I, II and III (deregulated pathways were directly retrieved from the ones published in study I, while they were enriched using DEG enrichment from the DE genes list published in studies II and III, at FDR≤5%). In (B–F), the unveiled pathways of the exploration set were compared to those discovered in the independent validation studies using either genesets enrichment analysis (GSEA) (C and E), DEG enrichment as a proxy gold standard (D and F), or pathways reported in study I (B). Bonf., Bonferroni; FDR, false discovery rate; PPV, positive predictive value.

Mentions: Since a gold standard (GS) for lung adenocarcinoma does not exist, we generated proxy GSs151718 in order to objectively assess the accuracy of the significantly deregulated mechanisms identified by N-of-1-pathways (see online supplementary methods and figures 2–5).


'N-of-1-pathways' unveils personal deregulated mechanisms from a single pair of RNA-Seq samples: towards precision medicine.

Gardeux V, Achour I, Li J, Maienschein-Cline M, Li H, Pesce L, Parinandi G, Bahroos N, Winn R, Foster I, Garcia JG, Lussier YA - J Am Med Inform Assoc (2014)

Concordant deregulated pathways between exploration and external validation studies. To establish that N-of-1-pathways yielded relevant Gene Ontology (GO) terms associated pathways, we compared the deregulated pathways to two conventional enrichment methods in three independent lung adenocarcinoma studies (see Methods and table 1). In (A), the Venn diagram corresponds to the overlap of deregulated GO annotations of Biological Process (GO-BP) terms associated pathways between the three external validation studies I, II and III (deregulated pathways were directly retrieved from the ones published in study I, while they were enriched using DEG enrichment from the DE genes list published in studies II and III, at FDR≤5%). In (B–F), the unveiled pathways of the exploration set were compared to those discovered in the independent validation studies using either genesets enrichment analysis (GSEA) (C and E), DEG enrichment as a proxy gold standard (D and F), or pathways reported in study I (B). Bonf., Bonferroni; FDR, false discovery rate; PPV, positive predictive value.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4215042&req=5

AMIAJNL2013002519F3: Concordant deregulated pathways between exploration and external validation studies. To establish that N-of-1-pathways yielded relevant Gene Ontology (GO) terms associated pathways, we compared the deregulated pathways to two conventional enrichment methods in three independent lung adenocarcinoma studies (see Methods and table 1). In (A), the Venn diagram corresponds to the overlap of deregulated GO annotations of Biological Process (GO-BP) terms associated pathways between the three external validation studies I, II and III (deregulated pathways were directly retrieved from the ones published in study I, while they were enriched using DEG enrichment from the DE genes list published in studies II and III, at FDR≤5%). In (B–F), the unveiled pathways of the exploration set were compared to those discovered in the independent validation studies using either genesets enrichment analysis (GSEA) (C and E), DEG enrichment as a proxy gold standard (D and F), or pathways reported in study I (B). Bonf., Bonferroni; FDR, false discovery rate; PPV, positive predictive value.
Mentions: Since a gold standard (GS) for lung adenocarcinoma does not exist, we generated proxy GSs151718 in order to objectively assess the accuracy of the significantly deregulated mechanisms identified by N-of-1-pathways (see online supplementary methods and figures 2–5).

Bottom Line: 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.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).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.

View Article: PubMed Central - PubMed

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.

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Related in: MedlinePlus