kMEn: Analyzing noisy and bidirectional transcriptional pathway responses in single subjects

Qike Li, A. Grant Schissler, Vincent Gardeux, Joanne Berghout, Ikbel Achour, Colleen Kenost, Haiquan Li, Hao Zhang, Yves A Lussier

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Motivation Understanding dynamic, patient-level transcriptomic response to therapy is an important step forward for precision medicine. However, conventional transcriptome analysis aims to discover cohort-level change, lacking the capacity to unveil patient-specific response to therapy. To address this gap, we previously developed two N-of-1-pathways methods, Wilcoxon and Mahalanobis distance, to detect unidirectionally responsive transcripts within a pathway using a pair of samples from a single subject. Yet, these methods cannot recognize bidirectionally (up and down) responsive pathways. Further, our previous approaches have not been assessed in presence of background noise and are not designed to identify differentially expressed mRNAs between two samples of a patient taken in different contexts (e.g. cancer vs non cancer), which we termed responsive transcripts (RTs). Methods We propose a new N-of-1-pathways method, k-Means Enrichment (kMEn), that detects bidirectionally responsive pathways, despite background noise, using a pair of transcriptomes from a single patient. kMEn identifies transcripts responsive to the stimulus through k-means clustering and then tests for an over-representation of the responsive genes within each pathway. The pathways identified by kMEn are mechanistically interpretable pathways significantly responding to a stimulus. Results In ∼9000 simulations varying six parameters, superior performance of kMEn over previous single-subject methods is evident by: (i) improved precision-recall at various levels of bidirectional response and (ii) lower rates of false positives (1-specificity) when more than 10% of genes in the genome are differentially expressed (background noise). In a clinical proof-of-concept, personal treatment-specific pathways identified by kMEn correlate with therapeutic response (p-value < 0.01). Conclusion Through improved single-subject transcriptome dynamics of bidirectionally-regulated signals, kMEn provides a novel approach to identify mechanism-level biomarkers.

Original languageEnglish (US)
Pages (from-to)32-41
Number of pages10
JournalJournal of Biomedical Informatics
Volume66
DOIs
StatePublished - Feb 1 2017

Fingerprint

Genes
Noise
Transcriptome
Biomarkers
Medicine
Precision Medicine
Gene Expression Profiling
Therapeutics
Cluster Analysis
Neoplasms
Genome
Messenger RNA

Keywords

  • HIV treatment response
  • k-means clustering
  • N-of-1-pathways
  • Pathway analysis
  • Precision medicine
  • Single subject analysis

ASJC Scopus subject areas

  • Computer Science Applications
  • Health Informatics

Cite this

kMEn : Analyzing noisy and bidirectional transcriptional pathway responses in single subjects. / Li, Qike; Schissler, A. Grant; Gardeux, Vincent; Berghout, Joanne; Achour, Ikbel; Kenost, Colleen; Li, Haiquan; Zhang, Hao; Lussier, Yves A.

In: Journal of Biomedical Informatics, Vol. 66, 01.02.2017, p. 32-41.

Research output: Contribution to journalArticle

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title = "kMEn: Analyzing noisy and bidirectional transcriptional pathway responses in single subjects",
abstract = "Motivation Understanding dynamic, patient-level transcriptomic response to therapy is an important step forward for precision medicine. However, conventional transcriptome analysis aims to discover cohort-level change, lacking the capacity to unveil patient-specific response to therapy. To address this gap, we previously developed two N-of-1-pathways methods, Wilcoxon and Mahalanobis distance, to detect unidirectionally responsive transcripts within a pathway using a pair of samples from a single subject. Yet, these methods cannot recognize bidirectionally (up and down) responsive pathways. Further, our previous approaches have not been assessed in presence of background noise and are not designed to identify differentially expressed mRNAs between two samples of a patient taken in different contexts (e.g. cancer vs non cancer), which we termed responsive transcripts (RTs). Methods We propose a new N-of-1-pathways method, k-Means Enrichment (kMEn), that detects bidirectionally responsive pathways, despite background noise, using a pair of transcriptomes from a single patient. kMEn identifies transcripts responsive to the stimulus through k-means clustering and then tests for an over-representation of the responsive genes within each pathway. The pathways identified by kMEn are mechanistically interpretable pathways significantly responding to a stimulus. Results In ∼9000 simulations varying six parameters, superior performance of kMEn over previous single-subject methods is evident by: (i) improved precision-recall at various levels of bidirectional response and (ii) lower rates of false positives (1-specificity) when more than 10{\%} of genes in the genome are differentially expressed (background noise). In a clinical proof-of-concept, personal treatment-specific pathways identified by kMEn correlate with therapeutic response (p-value < 0.01). Conclusion Through improved single-subject transcriptome dynamics of bidirectionally-regulated signals, kMEn provides a novel approach to identify mechanism-level biomarkers.",
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AU - Li, Qike

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AU - Berghout, Joanne

AU - Achour, Ikbel

AU - Kenost, Colleen

AU - Li, Haiquan

AU - Zhang, Hao

AU - Lussier, Yves A

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