‘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. This research entails, 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. Method: ‘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 diametricmore »
- Authors:
-
- Univ. of Arizona, Tucson, AZ (United States); Univ. of Illinois at Chicago, Chicago, IL (United States); EISTI (Ecole Internationale des Sciences du Traitement de l'Information), Cergy-Pontoise (France)
- Univ. of Arizona, Tucson, AZ (United States); Univ. of Illinois at Chicago, Chicago, IL (United States)
- Univ. of Illinois at Chicago, Chicago, IL (United States)
- Argonne National Lab. (ANL), Argonne, IL (United States); Univ. of Chicago, Chicago, IL (United States)
- Univ. of Illinois at Chicago, Chicago, IL (United States); Univ. of Illinois Cancer Center, Chicago, IL (United States)
- Univ. of Arizona, Tucson, AZ (United States)
- Univ. of Arizona, Tucson, AZ (United States); Univ. of Illinois at Chicago, Chicago, IL (United States); Argonne National Lab. (ANL), Argonne, IL (United States)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- USDOE
- OSTI Identifier:
- 1225365
- Grant/Contract Number:
- AC02-06CH11357
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Journal of the American Medical Informatics Association
- Additional Journal Information:
- Journal Volume: 21; Journal Issue: 6; Journal ID: ISSN 1067-5027
- Publisher:
- Oxford University Press
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; N-of-1; single subject design; precision medicine; personalized medicine; personal transcriptome; geneset
Citation Formats
Gardeux, Vincent, Achour, Ikbel, Li, Jianrong, Maienschein-Cline, Mark, Li, Haiquan, Pesce, Lorenzo, Parinandi, Gurunadh, Bahroos, Neil, Winn, Robert, Garcia, Joe G. N., Foster, Ian, and Lussier, Yves A. ‘N-of-1- pathways ’ unveils personal deregulated mechanisms from a single pair of RNA-Seq samples: Towards precision medicine. United States: N. p., 2014.
Web. doi:10.1136/amiajnl-2013-002519.
Gardeux, Vincent, Achour, Ikbel, Li, Jianrong, Maienschein-Cline, Mark, Li, Haiquan, Pesce, Lorenzo, Parinandi, Gurunadh, Bahroos, Neil, Winn, Robert, Garcia, Joe G. N., Foster, Ian, & Lussier, Yves A. ‘N-of-1- pathways ’ unveils personal deregulated mechanisms from a single pair of RNA-Seq samples: Towards precision medicine. United States. https://doi.org/10.1136/amiajnl-2013-002519
Gardeux, Vincent, Achour, Ikbel, Li, Jianrong, Maienschein-Cline, Mark, Li, Haiquan, Pesce, Lorenzo, Parinandi, Gurunadh, Bahroos, Neil, Winn, Robert, Garcia, Joe G. N., Foster, Ian, and Lussier, Yves A. Sat .
"‘N-of-1- pathways ’ unveils personal deregulated mechanisms from a single pair of RNA-Seq samples: Towards precision medicine". United States. https://doi.org/10.1136/amiajnl-2013-002519. https://www.osti.gov/servlets/purl/1225365.
@article{osti_1225365,
title = {‘N-of-1- pathways ’ unveils personal deregulated mechanisms from a single pair of RNA-Seq samples: Towards precision medicine},
author = {Gardeux, Vincent and Achour, Ikbel and Li, Jianrong and Maienschein-Cline, Mark and Li, Haiquan and Pesce, Lorenzo and Parinandi, Gurunadh and Bahroos, Neil and Winn, Robert and Garcia, Joe G. N. and Foster, Ian and Lussier, Yves A.},
abstractNote = {Background: The emergence of precision medicine allowed the incorporation of individual molecular data into patient care. This research entails, 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. Method: ‘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.},
doi = {10.1136/amiajnl-2013-002519},
journal = {Journal of the American Medical Informatics Association},
number = 6,
volume = 21,
place = {United States},
year = {Sat Nov 01 00:00:00 EDT 2014},
month = {Sat Nov 01 00:00:00 EDT 2014}
}
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Works referenced in this record:
Potential etiologic and functional implications of genome-wide association loci for human diseases and traits
journal, May 2009
- Hindorff, L. A.; Sethupathy, P.; Junkins, H. A.
- Proceedings of the National Academy of Sciences, Vol. 106, Issue 23
Network models of genome-wide association studies uncover the topological centrality of protein interactions in complex diseases
journal, July 2013
- Lee, Younghee; Li, Haiquan; Li, Jianrong
- Journal of the American Medical Informatics Association, Vol. 20, Issue 4
Variants Affecting Exon Skipping Contribute to Complex Traits
journal, October 2012
- Lee, Younghee; Gamazon, Eric R.; Rebman, Ellen
- PLoS Genetics, Vol. 8, Issue 10
Network Modeling Identifies Molecular Functions Targeted by miR-204 to Suppress Head and Neck Tumor Metastasis
journal, April 2010
- Lee, Younghee; Yang, Xinan; Huang, Yong
- PLoS Computational Biology, Vol. 6, Issue 4
Protein-network modeling of prostate cancer gene signatures reveals essential pathways in disease recurrence
journal, July 2011
- Chen, James L.; Li, Jianrong; Stadler, Walter M.
- Journal of the American Medical Informatics Association, Vol. 18, Issue 4
Complex-disease networks of trait-associated single-nucleotide polymorphisms (SNPs) unveiled by information theory
journal, March 2012
- Li, Haiquan; Lee, Younghee; Chen, James L.
- Journal of the American Medical Informatics Association, Vol. 19, Issue 2
Single Subject Designs in Biomedicine
book, January 2009
- Janosky, Janine E.; Leininger, Shelley L.; Hoerger, Michael P.
- Springer LInk
Estimating accuracy of RNA-Seq and microarrays with proteomics
journal, January 2009
- Fu, Xing; Fu, Ning; Guo, Song
- BMC Genomics, Vol. 10, Issue 1
RNA-Seq: a revolutionary tool for transcriptomics
journal, January 2009
- Wang, Zhong; Gerstein, Mark; Snyder, Michael
- Nature Reviews Genetics, Vol. 10, Issue 1
The n-of-1 clinical trial: the ultimate strategy for individualizing medicine?
journal, March 2011
- Lillie, Elizabeth O.; Patay, Bradley; Diamant, Joel
- Personalized Medicine, Vol. 8, Issue 2
Network‐based classification of breast cancer metastasis
journal, January 2007
- Chuang, Han‐Yu; Lee, Eunjung; Liu, Yu‐Tsueng
- Molecular Systems Biology, Vol. 3, Issue 1
Single Sample Expression-Anchored Mechanisms Predict Survival in Head and Neck Cancer
journal, January 2012
- Yang, Xinan; Regan, Kelly; Huang, Yong
- PLoS Computational Biology, Vol. 8, Issue 1
Curation-free biomodules mechanisms in prostate cancer predict recurrent disease
journal, January 2013
- Chen, James L.; Hsu, Alexander; Yang, Xinan
- BMC Medical Genomics, Vol. 6, Issue Suppl 2
Prediction of breast cancer prognosis using gene set statistics provides signature stability and biological context
journal, January 2010
- Abraham, Gad; Kowalczyk, Adam; Loi, Sherene
- BMC Bioinformatics, Vol. 11, Issue 1
An integrative pathway-based clinical–genomic model for cancer survival prediction
journal, September 2010
- Chen, Xi; Wang, Lily; Ishwaran, Hemant
- Statistics & Probability Letters, Vol. 80, Issue 17-18
Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1
journal, October 2009
- Barbie, David A.; Tamayo, Pablo; Boehm, Jesse S.
- Nature, Vol. 462, Issue 7269
Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles
journal, September 2005
- Subramanian, A.; Tamayo, P.; Mootha, V. K.
- Proceedings of the National Academy of Sciences, Vol. 102, Issue 43, p. 15545-15550
Principal component analysis-based filtering improves detection for Affymetrix gene expression arrays
journal, April 2011
- Lu, Jun; Kerns, Robnet T.; Peddada, Shyamal D.
- Nucleic Acids Research, Vol. 39, Issue 13
Conserved transcription factor binding sites of cancer markers derived from primary lung adenocarcinoma microarrays
journal, January 2005
- Yap, Y. L.
- Nucleic Acids Research, Vol. 33, Issue 1
Whole genome exon arrays identify differential expression of alternatively spliced, cancer-related genes in lung cancer
journal, October 2008
- Xi, Liqiang; Feber, Andrew; Gupta, Vanita
- Nucleic Acids Research, Vol. 36, Issue 20
Rewiring of human lung cell lineage and mitotic networks in lung adenocarcinomas
journal, April 2013
- Kim, Il-Jin; Quigley, David; To, Minh D.
- Nature Communications, Vol. 4, Issue 1
Gene Ontology: tool for the unification of biology
journal, May 2000
- Ashburner, Michael; Ball, Catherine A.; Blake, Judith A.
- Nature Genetics, Vol. 25, Issue 1
The Gene Ontology in 2010: extensions and refinements
journal, January 2010
- Consortium, The Gene Ontology
- Nucleic Acids Research, Vol. 38, Issue suppl_1, p. D331-D335
Multi-word complex concept retrieval via lexical semantic similarity
conference, January 1999
- Jiang, J.; Conrath, D.
- Proceedings 1999 International Conference on Information Intelligence and Systems (Cat. No.PR00446)
Lung Adenocarcinoma: Lessons in Translation from Bench to Bedside
journal, November 2010
- Sangodkar, Jaya; Katz, Suzanna; Melville, Heather
- Mount Sinai Journal of Medicine: A Journal of Translational and Personalized Medicine, Vol. 77, Issue 6
Functional classification analysis of somatically mutated genes in human breast and colorectal cancers
journal, June 2008
- Chittenden, Thomas W.; Howe, Eleanor A.; Culhane, Aedin C.
- Genomics, Vol. 91, Issue 6
Individual (N-of-1) trials can be combined to give population comparative treatment effect estimates: methodologic considerations
journal, December 2010
- Zucker, Deborah R.; Ruthazer, Robin; Schmid, Christopher H.
- Journal of Clinical Epidemiology, Vol. 63, Issue 12
Deep Sequence Analysis of Non-Small Cell Lung Cancer: Integrated Analysis of Gene Expression, Alternative Splicing, and Single Nucleotide Variations in Lung Adenocarcinomas with and without Oncogenic KRAS Mutations
journal, January 2012
- Kalari, Krishna R.; Rossell, David; Necela, Brian M.
- Frontiers in Oncology, Vol. 2
Single Subject Designs in Biomedicine
book, January 2009
- Janosky, Janine E.; Leininger, Shelley L.; Hoerger, Michael P.
- Springer LInk
N-of-1 clinical trials should be incorporated into clinical practice
journal, December 2010
- Berlin, Jesse A.
- Journal of Clinical Epidemiology, Vol. 63, Issue 12
Functional classification analysis of somatically mutated genes in human breast and colorectal cancers
journal, June 2008
- Chittenden, Thomas W.; Howe, Eleanor A.; Culhane, Aedin C.
- Genomics, Vol. 91, Issue 6
Combining single patient (N-of-1) trials to estimate population treatment effects and to evaluate individual patient responses to treatment
journal, April 1997
- Zucker, D. R.; Schmid, C. H.; McIntosh, M. W.
- Journal of Clinical Epidemiology, Vol. 50, Issue 4
Network‐based classification of breast cancer metastasis
journal, January 2007
- Chuang, Han‐Yu; Lee, Eunjung; Liu, Yu‐Tsueng
- Molecular Systems Biology, Vol. 3, Issue 1
Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1
journal, October 2009
- Barbie, David A.; Tamayo, Pablo; Boehm, Jesse S.
- Nature, Vol. 462, Issue 7269
Rewiring of human lung cell lineage and mitotic networks in lung adenocarcinomas
journal, April 2013
- Kim, Il-Jin; Quigley, David; To, Minh D.
- Nature Communications, Vol. 4, Issue 1
RNA-Seq: a revolutionary tool for transcriptomics
journal, January 2009
- Wang, Zhong; Gerstein, Mark; Snyder, Michael
- Nature Reviews Genetics, Vol. 10, Issue 1
Application of
a priori
established gene sets to discover biologically important differential expression in microarray data
journal, October 2005
- Bild, Andrea; Febbo, Phillip George
- Proceedings of the National Academy of Sciences, Vol. 102, Issue 43
Potential etiologic and functional implications of genome-wide association loci for human diseases and traits
journal, May 2009
- Hindorff, L. A.; Sethupathy, P.; Junkins, H. A.
- Proceedings of the National Academy of Sciences, Vol. 106, Issue 23
Conserved transcription factor binding sites of cancer markers derived from primary lung adenocarcinoma microarrays
journal, April 2005
- Yap, Y. L.
- Nucleic Acids Research, Vol. 33, Issue 8
Principal component analysis-based filtering improves detection for Affymetrix gene expression arrays
journal, April 2011
- Lu, Jun; Kerns, Robnet T.; Peddada, Shyamal D.
- Nucleic Acids Research, Vol. 39, Issue 13
Protein-network modeling of prostate cancer gene signatures reveals essential pathways in disease recurrence
journal, July 2011
- Chen, James L.; Li, Jianrong; Stadler, Walter M.
- Journal of the American Medical Informatics Association, Vol. 18, Issue 4
Complex-disease networks of trait-associated single-nucleotide polymorphisms (SNPs) unveiled by information theory
journal, March 2012
- Li, Haiquan; Lee, Younghee; Chen, James L.
- Journal of the American Medical Informatics Association, Vol. 19, Issue 2
Network models of genome-wide association studies uncover the topological centrality of protein interactions in complex diseases
journal, July 2013
- Lee, Younghee; Li, Haiquan; Li, Jianrong
- Journal of the American Medical Informatics Association, Vol. 20, Issue 4
Interpreting Personal Transcriptomes: Personalized Mechanism-Scale Profiling of Rna-Seq data
conference, November 2012
- Perez-Rathke, Alan; Li, Haiquan; Lussier, Yves A.
- Biocomputing 2013
Why Your New Cancer Biomarker May Never Work: Recurrent Patterns and Remarkable Diversity in Biomarker Failures
journal, November 2012
- Kern, Scott E.
- Cancer Research, Vol. 72, Issue 23
Prediction of breast cancer prognosis using gene set statistics provides signature stability and biological context
journal, January 2010
- Abraham, Gad; Kowalczyk, Adam; Loi, Sherene
- BMC Bioinformatics, Vol. 11, Issue 1
Concordance of deregulated mechanisms unveiled in underpowered experiments: PTBP1 knockdown case study
journal, January 2014
- Gardeux, Vincent; Arslan, Ahmet D.; Achour, Ikbel
- BMC Medical Genomics, Vol. 7, Issue Suppl 1
New Pathologic Classification of Lung Cancer: Relevance for Clinical Practice and Clinical Trials
journal, March 2013
- Travis, William D.; Brambilla, Elisabeth; Riely, Gregory J.
- Journal of Clinical Oncology, Vol. 31, Issue 8
Network Modeling Identifies Molecular Functions Targeted by miR-204 to Suppress Head and Neck Tumor Metastasis
journal, April 2010
- Lee, Younghee; Yang, Xinan; Huang, Yong
- PLoS Computational Biology, Vol. 6, Issue 4
International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society: International Multidisciplinary Classification of Lung Adenocarcinoma: Executive Summary
journal, September 2011
- Travis, W. D.; Brambilla, E.; Noguchi, M.
- Proceedings of the American Thoracic Society, Vol. 8, Issue 5
Deep Sequence Analysis of Non-Small Cell Lung Cancer: Integrated Analysis of Gene Expression, Alternative Splicing, and Single Nucleotide Variations in Lung Adenocarcinomas with and without Oncogenic KRAS Mutations
journal, January 2012
- Kalari, Krishna R.; Rossell, David; Necela, Brian M.
- Frontiers in Oncology, Vol. 2
Works referencing / citing this record:
Unmet Needs in Systemic Sclerosis Understanding and Treatment: the Knowledge Gaps from a Scientist’s, Clinician’s, and Patient’s Perspective
journal, September 2017
- Cossu, Marta; Beretta, Lorenzo; Mosterman, Petra
- Clinical Reviews in Allergy & Immunology, Vol. 55, Issue 3
The mechanism of cancer drug addiction in ALK-positive T-Cell lymphoma
journal, December 2019
- Rajan, Soumya S.; Amin, Amit Dipak; Li, Lingxiao
- Oncogene, Vol. 39, Issue 10
Interpretation of ‘Omics dynamics in a single subject using local estimates of dispersion between two transcriptomes
posted_content, January 2019
- Li, Qike; Zaim, Samir Rachid; Aberasturi, Dillon
- BioRxiv
Evaluating single-subject study methods for personal transcriptomic interpretations to advance precision medicine
journal, September 2018
- Zaim, Samir Rachid; Kenost, Colleen; Berghout, Joanne
- BMC Medical Genomics
N-of-1-pathways MixEnrich: advancing precision medicine via single-subject analysis in discovering dynamic changes of transcriptomes
journal, May 2017
- Li, Qike; Schissler, A. Grant; Gardeux, Vincent
- BMC Medical Genomics, Vol. 10, Issue S1
Evaluating single-subject study methods for personal transcriptomic interpretations to advance precision medicine
journal, July 2019
- Rachid Zaim, Samir; Kenost, Colleen; Berghout, Joanne
- BMC Medical Genomics, Vol. 12, Issue S5
Detecting gene signature activation in breast cancer in an absolute, single-patient manner
journal, March 2017
- Paquet, E. R.; Lesurf, R.; Tofigh, A.
- Breast Cancer Research, Vol. 19, Issue 1
Exploiting Drug Addiction Mechanisms to Select against MAPKi-Resistant Melanoma
journal, September 2017
- Hong, Aayoung; Moriceau, Gatien; Sun, Lu
- Cancer Discovery, Vol. 8, Issue 1
Unmet Needs in Systemic Sclerosis Understanding and Treatment: the Knowledge Gaps from a Scientist’s, Clinician’s, and Patient’s Perspective
journal, September 2017
- Cossu, Marta; Beretta, Lorenzo; Mosterman, Petra
- Clinical Reviews in Allergy & Immunology, Vol. 55, Issue 3
Potential Diagnostic Power of Blood Circular RNA Expression in Active Pulmonary Tuberculosis
journal, January 2018
- Qian, Zhongqing; Liu, Hui; Li, Musheng
- EBioMedicine, Vol. 27
Developing a ‘personalome’ for precision medicine: emerging methods that compute interpretable effect sizes from single-subject transcriptomes
journal, December 2017
- Vitali, Francesca; Li, Qike; Schissler, A. Grant
- Briefings in Bioinformatics, Vol. 20, Issue 3
Dynamic changes of RNA-sequencing expression for precision medicine: N-of-1-pathways Mahalanobis distance within pathways of single subjects predicts breast cancer survival
journal, June 2015
- Schissler, A. Grant; Gardeux, Vincent; Li, Qike
- Bioinformatics, Vol. 31, Issue 12
Analysis of aggregated cell–cell statistical distances within pathways unveils therapeutic-resistance mechanisms in circulating tumor cells
journal, June 2016
- Schissler, A. Grant; Li, Qike; Chen, James L.
- Bioinformatics, Vol. 32, Issue 12
A genome-by-environment interaction classifier for precision medicine: personal transcriptome response to rhinovirus identifies children prone to asthma exacerbations
journal, July 2017
- Gardeux, Vincent; Berghout, Joanne; Achour, Ikbel
- Journal of the American Medical Informatics Association, Vol. 24, Issue 6
Personalized beyond Precision: Designing Unbiased Gold Standards to Improve Single-Subject Studies of Personal Genome Dynamics from Gene Products
journal, November 2020
- Zaim, Samir Rachid; Kenost, Colleen; Zhang, Hao Helen
- Journal of Personalized Medicine
A Single-Subject Method to Detect Pathways Enriched With Alternatively Spliced Genes
journal, May 2019
- Schissler, Alfred Grant; Aberasturi, Dillon; Kenost, Colleen
- Frontiers in Genetics, Vol. 10
Personalised Interventions—A Precision Approach for the Next Generation of Dietary Intervention Studies
journal, August 2017
- de Roos, Baukje; Brennan, Lorraine
- Nutrients, Vol. 9, Issue 8