Universal method for robust detection of circadian state from gene expression
- PMID: 30201705
- PMCID: PMC6166804
- DOI: 10.1073/pnas.1800314115
Universal method for robust detection of circadian state from gene expression
Abstract
Circadian clocks play a key role in regulating a vast array of biological processes, with significant implications for human health. Accurate assessment of physiological time using transcriptional biomarkers found in human blood can significantly improve diagnosis of circadian disorders and optimize the delivery time of therapeutic treatments. To be useful, such a test must be accurate, minimally burdensome to the patient, and readily generalizable to new data. A major obstacle in development of gene expression biomarker tests is the diversity of measurement platforms and the inherent variability of the data, often resulting in predictors that perform well in the original datasets but cannot be universally applied to new samples collected in other settings. Here, we introduce TimeSignature, an algorithm that robustly infers circadian time from gene expression. We demonstrate its application in data from three independent studies using distinct microarrays and further validate it against a new set of samples profiled by RNA-sequencing. Our results show that TimeSignature is more accurate and efficient than competing methods, estimating circadian time to within 2 h for the majority of samples. Importantly, we demonstrate that once trained on data from a single study, the resulting predictor can be universally applied to yield highly accurate results in new data from other studies independent of differences in study population, patient protocol, or assay platform without renormalizing the data or retraining. This feature is unique among expression-based predictors and addresses a major challenge in the development of generalizable, clinically useful tests.
Keywords: circadian rhythms; cross-platform prediction; gene expression dynamics; machine learning.
Copyright © 2018 the Author(s). Published by PNAS.
Conflict of interest statement
The authors declare no conflict of interest.
Figures
Comment in
-
Universal and robust assessment of circadian time?Proc Natl Acad Sci U S A. 2019 Mar 19;116(12):5205. doi: 10.1073/pnas.1817119116. Epub 2019 Mar 14. Proc Natl Acad Sci U S A. 2019. PMID: 30872467 Free PMC article. No abstract available.
-
Reply to Laing et al.: Accurate prediction of circadian time across platforms.Proc Natl Acad Sci U S A. 2019 Mar 19;116(12):5206-5208. doi: 10.1073/pnas.1819173116. Epub 2019 Mar 14. Proc Natl Acad Sci U S A. 2019. PMID: 30872489 Free PMC article. No abstract available.
Similar articles
-
Platform-independent estimation of human physiological time from single blood samples.Proc Natl Acad Sci U S A. 2024 Jan 16;121(3):e2308114120. doi: 10.1073/pnas.2308114120. Epub 2024 Jan 8. Proc Natl Acad Sci U S A. 2024. PMID: 38190520 Free PMC article.
-
A population-based gene expression signature of molecular clock phase from a single epidermal sample.Genome Med. 2020 Aug 21;12(1):73. doi: 10.1186/s13073-020-00768-9. Genome Med. 2020. PMID: 32825850 Free PMC article.
-
Machine learning identifies a compact gene set for monitoring the circadian clock in human blood.Genome Med. 2017 Feb 28;9(1):19. doi: 10.1186/s13073-017-0406-4. Genome Med. 2017. PMID: 28241858 Free PMC article.
-
Chronopharmacological strategies focused on chrono-drug discovery.Pharmacol Ther. 2019 Oct;202:72-90. doi: 10.1016/j.pharmthera.2019.05.018. Epub 2019 Jun 5. Pharmacol Ther. 2019. PMID: 31173839 Review.
-
Circadian rhythms in gene expression: Relationship to physiology, disease, drug disposition and drug action.Adv Drug Deliv Rev. 2010 Jul 31;62(9-10):904-17. doi: 10.1016/j.addr.2010.05.009. Epub 2010 Jun 11. Adv Drug Deliv Rev. 2010. PMID: 20542067 Free PMC article. Review.
Cited by
-
Variational inference of single cell time series.bioRxiv [Preprint]. 2024 Aug 30:2024.08.29.610389. doi: 10.1101/2024.08.29.610389. bioRxiv. 2024. PMID: 39257806 Free PMC article. Preprint.
-
Quantification of circadian rhythms in mammalian lung tissue snapshot data.Sci Rep. 2024 Jul 14;14(1):16238. doi: 10.1038/s41598-024-66694-7. Sci Rep. 2024. PMID: 39004631 Free PMC article.
-
Why does circadian timing of administration matter for immune checkpoint inhibitors' efficacy?Br J Cancer. 2024 Sep;131(5):783-796. doi: 10.1038/s41416-024-02704-9. Epub 2024 Jun 4. Br J Cancer. 2024. PMID: 38834742 Free PMC article. Review.
-
Propofol enhancement of slow wave sleep to target the nexus of geriatric depression and cognitive dysfunction: protocol for a phase I open label trial.BMJ Open. 2024 May 30;14(5):e087516. doi: 10.1136/bmjopen-2024-087516. BMJ Open. 2024. PMID: 38816055 Free PMC article.
-
Using routinely collected clinical data for circadian medicine: A review of opportunities and challenges.PLOS Digit Health. 2024 May 23;3(5):e0000511. doi: 10.1371/journal.pdig.0000511. eCollection 2024 May. PLOS Digit Health. 2024. PMID: 38781189 Free PMC article. Review.
References
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources