Replicated blood-based biomarkers for myalgic encephalomyelitis not explicable by inactivity

Area of Science:

• Biomedical research
• Genomics and molecular biology
• Epidemiology

Background:

• Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, often female-biased disease.
• Current diagnosis of ME/CFS is challenging due to the lack of validated biomarkers, especially those unaffected by reduced physical activity.

Purpose of the Study:

• To investigate molecular and cellular trait differences between ME/CFS patients and controls.
• To determine if these differences are independent of physical activity levels.
• To explore the potential for developing a blood-based biomarker panel for ME/CFS diagnosis.

Main Methods:

• Utilized semi-parametric efficient estimators and Super Learner methods on UK Biobank data (1455 ME/CFS cases, 131,303 controls).
• Employed natural direct and indirect estimands to analyze the effect of ME/CFS status on molecular and cellular traits, considering physical activity as a mediator.
• Replicated findings in the All-of-Us cohort.

Main Results:

• Hundreds of molecular and cellular traits differed significantly between ME/CFS cases and controls, indicating chronic inflammation, insulin resistance, and liver disease.
• These differences were largely independent of physical activity, with only one trait affected when activity was mediated.
• Individuals experiencing post-exertional malaise exhibited more pronounced biomarker differences.
• Nine of 14 significant traits were replicated in the All-of-Us cohort.

Conclusions:

• ME/CFS is associated with distinct molecular and cellular profiles, suggesting underlying biological mechanisms.
• The identified traits are not primarily explained by reduced physical activity, supporting their potential as diagnostic biomarkers.
• While single traits are insufficient, these findings advance the goal of a future blood-based biomarker panel for accurate ME/CFS diagnosis.