Linking disease symptoms and subtypes with personalized systems-based phenotypes: A proof of concept study

Kirstin Aschbacher*, Emma K. Adam, Leslie J. Crofford, Margaret E. Kemeny, Mark A. Demitrack, Amos Ben-Zvi

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

26 Scopus citations


A dynamic systems model was used to generate parameters describing a phenotype of Hypothalamic-Pituitary-Adrenal (HPA) behavior in a sample of 36 patients with chronic fatigue syndrome (CFS) and/or fibromyalgia (FM) and 36 case-matched healthy controls. Altered neuroendocrine function, particularly in relation to somatic symptoms and poor sleep quality, may contribute to the pathophysiology of these disorders. Blood plasma was assayed for cortisol and ACTH every 10. min for 24. h. The dynamic model was specified with an ordinary differential equation using three parameters: (1) ACTH-adrenal signaling, (2) inhibitory feedback, and (3) non-ACTH influences. The model was " personalized" by estimating an individualized set of parameters from each participant's data. Day and nighttime parameters were assessed separately. Two nocturnal parameters (ACTH-adrenal signaling and inhibitory feedback) significantly differentiated the two patient subgroups (" fatigue-predominant" patients with CFS only versus " pain-predominant" patients with FM and comorbid chronic fatigue) from controls (all p's < .05), whereas daytime parameters and diurnal/nocturnal slopes did not. The same nocturnal parameters were significantly associated with somatic symptoms among patients (p's < .05). There was a significantly different pattern of association between nocturnal non-ACTH influences and sleep quality among patients versus controls (p< .05). Although speculative, the finding that patient somatic symptoms decreased when more cortisol was produced per unit ACTH, is consistent with cortisol's anti-inflammatory and sleep-modulatory effects. Patients' HPA systems may compensate by promoting more rapid or sustained cortisol production. Mapping " behavioral phenotypes" of stress-arousal systems onto symptom clusters may help disentangle the pathophysiology of complex disorders with frequent comorbidity.

Original languageEnglish (US)
Pages (from-to)1047-1056
Number of pages10
JournalBrain, Behavior, and Immunity
Issue number7
StatePublished - Oct 2012


  • Chronic fatigue syndrome
  • Cortisol
  • Dynamical systems
  • Feedback sensitivity
  • Fsbromyalgia
  • Functional somatic disorders
  • Glucocorticoid resistance
  • Personalized medicine
  • Psychoneuroendocrinology
  • Sleep quality
  • Somatic symptoms
  • Stress-arousal
  • Systems medicine

ASJC Scopus subject areas

  • Immunology
  • Endocrine and Autonomic Systems
  • Behavioral Neuroscience


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