medRxiv [Preprint]. 2026 Feb 24:2026.02.23.26346831. doi: 10.64898/2026.02.23.26346831.
ABSTRACT
The daily cortisol cycle is a critical indicator of hypothalamic-pituitary-adrenal (HPA) axis function. The current analytical approaches produce several outputs difficult to integrate into simple statistical models, clinical workflows, and ML/AI pipelines requiring single-value inputs. We developed the Cortisol Sine Score (CSS), a model-free scalar metric that quantifies daily cortisol exposure by computing a weighted sum of cortisol measurements across the day, using sine-transformed time-of-day weights. The CSS produces positive values for morning-dominant patterns, negative values for evening-shifted profiles, and near-zero values for flattened rhythms characteristic of chronic stress and circadian disruption. We validated the CSS performance in 3,006 samples from 501 pregnant women enrolled in the March of Dimes program, with cortisol values measured at 6 time points per day collected during the second trimester of pregnancy. The CSS showed strong correlations with observed and model-estimated amplitude and acrophase from Cosinor regression and JTK_CYCLE approaches, with excellent classifying performance (AUC=0.89, high versus low). The CSS successfully captured established associations between social disadvantage and cortisol dysregulation, and demonstrated utility in predicting gut microbiome composition in metagenomic analyses. Importantly, the CSS maintains excellent fidelity to the full 6-sample protocol with as few as 3-4 daily measurements. The 4-sample protocol achieves great performance (r = 0.952, MAE = 0.087) while reducing participant burden. The 06:00 time point was identified as essential for accurate CSS quantification. The CSS bridges the gap between circadian analysis and practical implementation by providing a simple, interpretable, and robust assessment of cortisol daily cycle in large-scale epidemiological studies, clinical screening, and biomedical sensors.
HIGHLIGHTS: Current state-of-the-art approaches estimating the daily cortisol exposures produce multi-output information difficult to implement in simple statistical analyses or ML/AI multi-omics approachesCortisol Sine Score is a novel model-free scalar metric expressing cortisol daily exposure and rhythmicity (morning vs evening exposure)Cortisol Sine Score was validated using 3006 salivary samples from clinical data and golden standards in circadian analyses such as Cosinor and JTK_CYCLECortisol Sine Score was the top performer in our benchmarking approach predicting association with social disadvantage and gut microbiome compositionReliable with 3-4 daily samples, reducing participant burdenOpen-source R package CortSineScore democratizes cortisol cycle analysis.
PMID:41810379 | PMC:PMC12970380 | DOI:10.64898/2026.02.23.26346831
