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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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N-of-1-pathways representation (star plot) of individual Gene Ontology annotations of Biological Process (GO-BPs) of diametric extreme patients. Most significantly deregulated GO-BP terms were identified (Wilcoxon test, p<0.05; fold change >4) between the two groups of patients with diametric extreme phenotypes (death of disease in less than 1 year and at least 5 years of disease-free survival (red and blue dots in figure 4C); n=8 patients; figure 5B). The top 15 deregulated mechanisms between these groups were calculated using the N-of-1-pathways statistical analysis component in the exploration dataset. (A) Hierarchical clustering of the 15 GO terms using the GO-information theoretic similarity (GO-ITS) metric (see the Methods section). (B) Legend of the star plots, each edge corresponding to one GO-BP term. Each star reflects a single patient's deregulation of GO-BP terms (see the end of the first paragraph of the ‘N-of-1-pathways framework’ section in Methods). (C) Each extreme patient's own star plot representation of the 15 GO-BP terms. The green zone represents up-regulated pathways (given the N-of-1-pathways direction of deregulation), while the gray zone indicates down-regulation. The non-deregulated zone (z score=0) is represented by a dotted line dividing the two colored zones. We also applied the same representation framework to the GO-BP terms whose FAIME scores were significantly deregulated (online supplementary figure S3).
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AMIAJNL2013002519F6: N-of-1-pathways representation (star plot) of individual Gene Ontology annotations of Biological Process (GO-BPs) of diametric extreme patients. Most significantly deregulated GO-BP terms were identified (Wilcoxon test, p<0.05; fold change >4) between the two groups of patients with diametric extreme phenotypes (death of disease in less than 1 year and at least 5 years of disease-free survival (red and blue dots in figure 4C); n=8 patients; figure 5B). The top 15 deregulated mechanisms between these groups were calculated using the N-of-1-pathways statistical analysis component in the exploration dataset. (A) Hierarchical clustering of the 15 GO terms using the GO-information theoretic similarity (GO-ITS) metric (see the Methods section). (B) Legend of the star plots, each edge corresponding to one GO-BP term. Each star reflects a single patient's deregulation of GO-BP terms (see the end of the first paragraph of the ‘N-of-1-pathways framework’ section in Methods). (C) Each extreme patient's own star plot representation of the 15 GO-BP terms. The green zone represents up-regulated pathways (given the N-of-1-pathways direction of deregulation), while the gray zone indicates down-regulation. The non-deregulated zone (z score=0) is represented by a dotted line dividing the two colored zones. We also applied the same representation framework to the GO-BP terms whose FAIME scores were significantly deregulated (online supplementary figure S3).

Mentions: Comparison of the Gene Ontology annotations of Biological Process (GO-BP) terms predicted by N-of-1-pathways in the exploration dataset and their similarity to those of the external gold standard (combination of three validation studies). (A) Global comparison of the 55 patients’ results taken together. Overall, 92% of GO-BP terms of the external gold standard (GS) are found to be predicted by the N-of-1-pathways (0.7<ITS<1 and ITS=1). Conversely, 61% of the predicted and related GO-information theoretic similarity (GO-ITS) overlap with the GS (0.7<ITS<1 and ITS=1) and 10% of GO-BP terms remain unrelated (0.3<ITS) (see online supplementary tables S1 and S2 which provide a subset of results). (B) The level of similarity of individual deregulated mechanisms with the external GS (as a ratio) for each patient. The two diametric extreme prognosis phenotypes show significant differences in their shared GO-BP terms with the GS (in bold) (Wilcoxon test, p=0.03). The two diametric extreme survival phenotypes are annotated: ‘disease-free survival >5 years’ (blue) and ‘death of disease <1 yr’ (red) (figures 4C and 6C).


'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)

N-of-1-pathways representation (star plot) of individual Gene Ontology annotations of Biological Process (GO-BPs) of diametric extreme patients. Most significantly deregulated GO-BP terms were identified (Wilcoxon test, p<0.05; fold change >4) between the two groups of patients with diametric extreme phenotypes (death of disease in less than 1 year and at least 5 years of disease-free survival (red and blue dots in figure 4C); n=8 patients; figure 5B). The top 15 deregulated mechanisms between these groups were calculated using the N-of-1-pathways statistical analysis component in the exploration dataset. (A) Hierarchical clustering of the 15 GO terms using the GO-information theoretic similarity (GO-ITS) metric (see the Methods section). (B) Legend of the star plots, each edge corresponding to one GO-BP term. Each star reflects a single patient's deregulation of GO-BP terms (see the end of the first paragraph of the ‘N-of-1-pathways framework’ section in Methods). (C) Each extreme patient's own star plot representation of the 15 GO-BP terms. The green zone represents up-regulated pathways (given the N-of-1-pathways direction of deregulation), while the gray zone indicates down-regulation. The non-deregulated zone (z score=0) is represented by a dotted line dividing the two colored zones. We also applied the same representation framework to the GO-BP terms whose FAIME scores were significantly deregulated (online supplementary figure S3).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

AMIAJNL2013002519F6: N-of-1-pathways representation (star plot) of individual Gene Ontology annotations of Biological Process (GO-BPs) of diametric extreme patients. Most significantly deregulated GO-BP terms were identified (Wilcoxon test, p<0.05; fold change >4) between the two groups of patients with diametric extreme phenotypes (death of disease in less than 1 year and at least 5 years of disease-free survival (red and blue dots in figure 4C); n=8 patients; figure 5B). The top 15 deregulated mechanisms between these groups were calculated using the N-of-1-pathways statistical analysis component in the exploration dataset. (A) Hierarchical clustering of the 15 GO terms using the GO-information theoretic similarity (GO-ITS) metric (see the Methods section). (B) Legend of the star plots, each edge corresponding to one GO-BP term. Each star reflects a single patient's deregulation of GO-BP terms (see the end of the first paragraph of the ‘N-of-1-pathways framework’ section in Methods). (C) Each extreme patient's own star plot representation of the 15 GO-BP terms. The green zone represents up-regulated pathways (given the N-of-1-pathways direction of deregulation), while the gray zone indicates down-regulation. The non-deregulated zone (z score=0) is represented by a dotted line dividing the two colored zones. We also applied the same representation framework to the GO-BP terms whose FAIME scores were significantly deregulated (online supplementary figure S3).
Mentions: Comparison of the Gene Ontology annotations of Biological Process (GO-BP) terms predicted by N-of-1-pathways in the exploration dataset and their similarity to those of the external gold standard (combination of three validation studies). (A) Global comparison of the 55 patients’ results taken together. Overall, 92% of GO-BP terms of the external gold standard (GS) are found to be predicted by the N-of-1-pathways (0.7<ITS<1 and ITS=1). Conversely, 61% of the predicted and related GO-information theoretic similarity (GO-ITS) overlap with the GS (0.7<ITS<1 and ITS=1) and 10% of GO-BP terms remain unrelated (0.3<ITS) (see online supplementary tables S1 and S2 which provide a subset of results). (B) The level of similarity of individual deregulated mechanisms with the external GS (as a ratio) for each patient. The two diametric extreme prognosis phenotypes show significant differences in their shared GO-BP terms with the GS (in bold) (Wilcoxon test, p=0.03). The two diametric extreme survival phenotypes are annotated: ‘disease-free survival >5 years’ (blue) and ‘death of disease <1 yr’ (red) (figures 4C and 6C).

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