CYCLOPS 2.0: Improving and Applying Circadian Phase Reconstruction in Confounded Datasets

Tuesday, June 3, 2025

11:00 AM-1:00 PM

BIOMED PhD Thesis Defense

Title:
CYCLOPS 2.0: Improving and Applying Circadian Phase Reconstruction in Confounded Datasets

Speaker:
Jan Alexander Hammarlund, PhD Candidate
School of Biomedical Engineering, Science and Health Systems
Drexel University

Advisors:
Ron C. Anafi, MD, PhD
Assistant Professor
Perelman School of Medicine
University of Pennsylvania

Andres Kriete, PhD
Associate Dean for Academic Affairs
Teaching Professor
School of Biomedical Engineering, Science and Health Systems
Drexel University

Details:
Circadian rhythms regulate the timing of thousands of genes across human tissues, aligning physiology with the 24-hour day. However, most transcriptomic datasets lack time-of-day annotations, limiting our ability to study these rhythms and their disruption in disease. We improve CYCLOPS, an unsupervised algorithm for inferring internal circadian time from gene expression data, by introducing CYCLOPS 2.0—a covariate-aware model that adjusts for batch effects and non-circadian confounders. Benchmarking confirms its improved accuracy in recovering latent circadian structure under noisy conditions.

We apply CYCLOPS 2.0 to breast cancer and GTEx datasets to reconstruct circadian transcriptional order. In breast tumors, especially luminal A, we observe persistent but reprogrammed rhythms, with enhanced cycling in EMT and immune pathways. A novel metric, CYCLOPS magnitude (CMag), quantifies global rhythm strength and correlates with reduced five-year survival. Functional assays confirm that circadian disruption reduces invasiveness, linking molecular rhythms to metastatic behavior.

We identify circadian eQTLs (cQTLs)—variants that affect rhythmic parameters of gene expression—in adipose, muscle, and skin. Many cQTLs are not detected by traditional methods and frequently colocalize with GWAS loci and circadian transcription factor motifs. These findings reveal a temporally dynamic layer of gene regulation with clinical and functional relevance.

Contact Information

Natalia Broz
njb33@drexel.edu