kMEn: Analyzing noisy and bidirectional transcriptional pathway responses in single subjects
Schissler, A. Grant
Zhang, Hao Helen
Lussier, Yves A.
AffiliationUniv Arizona, Ctr Biomed Informat & Biostat
Univ Arizona, Inst Bio5
Univ Arizona, Dept Med
Univ Arizona, Grad Interdisciplinary Program Stat
Univ Arizona, Dept Math
Univ Arizona, Canc Ctr
KeywordsHIV treatment response
Single subject analysis
MetadataShow full item record
PublisherACADEMIC PRESS INC ELSEVIER SCIENCE
CitationLi, Q., Schissler, A. G., Gardeux, V., Berghout, J., Achour, I., Kenost, C., ... & Lussier, Y. A. (2017). kMEn: Analyzing noisy and bidirectional transcriptional pathway responses in single subjects. Journal of biomedical informatics, 66, 32-41.
Rights© 2016 Published by Elsevier Inc.
Collection InformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at email@example.com.
AbstractMotivation: 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-l-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-l-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 similar to 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. (C) 2016 Published by Elsevier Inc.
Note12 month embargo; available online 19 December 2016.
VersionFinal accepted manuscript
SponsorsNIH [K22LM008308]; NSF [DMS-1309507, DMS-1418172]; NCI of the University of Arizona Cancer Center [P30CA023074]