title: Blood transcriptome based biomarkers for human circadian phase.
abstract: Diagnosis and treatment of circadian rhythm sleep-wake disorders both require assessment of circadian phase of the brain's circadian pacemaker. The gold-standard univariate method is based on collection of a 24-hr time series of plasma melatonin, a suprachiasmatic nucleus-driven pineal hormone. We developed and validated a multivariate whole-blood mRNA-based predictor of melatonin phase which requires few samples. Transcriptome data were collected under normal, sleep-deprivation and abnormal sleep-timing conditions to assess robustness of the predictor. Partial least square regression (PLSR), applied to the transcriptome, identified a set of 100 biomarkers primarily related to glucocorticoid signaling and immune function. Validation showed that PLSR-based predictors outperform published blood-derived circadian phase predictors. When given one sample as input, the R2of predicted vs observed phase was 0.74, whereas for two samples taken 12 hr apart, R2was 0.90. This blood transcriptome-based model enables assessment of circadian phase from a few samples.
authors.affiliation: Department of Microbial Sciences, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom.
authors.forename: Emma E
authors.identifier: 0000-0002-2095-2442
authors.initials: EE
authors.lastname: Laing
authors.affiliation: Bioinformatics Core Facility, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom.
authors.forename: Carla S
authors.initials: CS
authors.lastname: Möller-Levet
authors.affiliation: Department of Computer Science, Faculty of Engineering and Physical Sciences, University of Surrey, Guildford, United Kingdom.
authors.forename: Norman
authors.initials: N
authors.lastname: Poh
authors.affiliation: Surrey Sleep Research Centre, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom.
authors.forename: Nayantara
authors.initials: N
authors.lastname: Santhi
authors.affiliation: Surrey Sleep Research Centre, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom.
authors.forename: Simon N
authors.initials: SN
authors.lastname: Archer
authors.affiliation: Surrey Sleep Research Centre, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom.
authors.forename: Derk-Jan
authors.initials: DJ
authors.lastname: Dijk
mesh_terms: D015415:Biomarkers / Q000097:blood*; D002940:Circadian Rhythm; D020869:Gene Expression Profiling; D006801:Humans; D008550:Melatonin / Q000096:biosynthesis*
chemical_list: D015415:Biomarkers; D008550:Melatonin
keywords: biomarker; chronotherapy; computational biology; human; machine learning; neurodegeneration; neuroscience; sleep disorders; systems biology; transcriptomics