An empirical delineation of the heterogeneity of chronic unexplained fatigue in women

Pharmacogenomics. 2006 Apr;7(3):355-64. doi: 10.2217/14622416.7.3.355.


Objectives: To test the hypothesis that medically unexplained chronic fatigue and chronic fatigue syndrome (CFS) are heterogeneous conditions, and to define the different conditions using both symptom and laboratory data.

Methods: We studied 159 women from KS, USA. A total of 51 of these suffered from fatigue consistent with established criteria for CFS, 55 had chronic fatigue of insufficient symptoms/severity for a CFS diagnosis and 53 were healthy controls matched by age and body mass index (BMI) against those with CFS. We used principal components analyses to define factors that best described the variable space and to reduce the number of variables. The 38 most explanatory variables were then used in latent class analyses to define discrete subject groups.

Results: Principal components analyses defined six discrete factors that explained 40% of the variance. Latent class analyses provided several interpretable solutions with four, five and six classes. The four-class solution was statistically most convincing, but the six-class solution was more interpretable. Class 1 defined 41 (26%) subjects with obesity and relative sleep hypnoea. Class 2 were 38 (24%) healthy subjects. Class 3 captured 24 (15%) obese relatively hypnoeic subjects, but with low heart rate variability and cortisol. Class 4 were 23 (14%) sleep-disturbed and myalgic subjects without obesity or significant depression. The two remaining classes with 22 (14%) and 11 (7%) subjects consisted of the most symptomatic and depressed, but without obesity or hypnoea. Class 5 had normal sleep indices. Class 6 was characterized by disturbed sleep, with low sleep heart rate variability, cortisol, and sex hormones.

Conclusion: Chronic medically unexplained fatigue is heterogeneous. The putative syndromes were differentiated by obesity, sleep hypnoea, depression, physiological stress response, sleep disturbance, interoception and menopausal status. If these syndromes are externally validated and replicated, they may prove useful in determining the causes, pathophysiology and treatments of CFS.

MeSH terms

  • Adult
  • Aged
  • Body Mass Index
  • Data Interpretation, Statistical
  • Fatigue Syndrome, Chronic / complications
  • Fatigue Syndrome, Chronic / physiopathology*
  • Fatigue Syndrome, Chronic / psychology
  • Female
  • Genetic Heterogeneity
  • Humans
  • Menopause / physiology
  • Middle Aged
  • Obesity / complications
  • Principal Component Analysis
  • Sleep Wake Disorders / complications
  • Stress, Physiological / physiopathology