Revisiting IgG Antibody Reactivity to Epstein-Barr Virus in [ME/CFS] and Its Potential Application to Disease Diagnosis, 2022, Scheibenbogen et al.

Abstract

Infections by the Epstein-Barr virus (EBV) are often at the disease onset of patients suffering from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). However, serological analyses of these infections remain inconclusive when comparing patients with healthy controls (HCs). In particular, it is unclear if certain EBV-derived antigens eliciting antibody responses have a biomarker potential for disease diagnosis.

With this purpose, we re-analyzed a previously published microarray data on the IgG antibody responses against 3,054 EBV-related antigens in 92 patients with ME/CFS and 50 HCs. This re-analysis consisted of constructing different regression models for binary outcomes with the ability to classify patients and HCs.

In these models, we tested for a possible interaction of different antibodies with age and gender. When analyzing the whole data set, there were no antibody responses that could distinguish patients from healthy controls. A similar finding was obtained when comparing patients with non-infectious or unknown disease trigger with healthy controls.

However, when data analysis was restricted to the comparison between HCs and patients with a putative infection at their disease onset, we could identify stronger antibody responses against two candidate antigens (EBNA4_0529 and EBNA6_0070).

Using antibody responses to these two antigens together with age and gender, the final classification model had an estimated sensitivity and specificity of 0.833 and 0.720, respectively. This reliable case-control discrimination suggested the use of the antibody levels related to these candidate viral epitopes as biomarkers for disease diagnosis in this subgroup of patients. To confirm this finding, a follow-up study will be conducted in a separate cohort of patients.


Citation: Sepúlveda N, Malato J, Sotzny F, Grabowska AD, Fonseca A, Cordeiro C, Graça L, Biecek P, Behrends U, Mautner J, Westermeier F, Lacerda EM and Scheibenbogen C (2022) Revisiting IgG Antibody Reactivity to Epstein-Barr Virus in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Its Potential Application to Disease Diagnosis. Front. Med. 9:921101. doi: 10.3389/fmed.2022.921101

https://www.frontiersin.org/articles/10.3389/fmed.2022.921101/full

 

They seem to be theorizing a fair bit about potential autoimmunity through cross-reactivity with these EBV antibodies. But are the differences between controls and the infectious-onset ME group for these antibodies large enough to make this a potentially significant factor in ME? They sure don't look like huge differences, but then I know very little about immunology.

 

OK, they found nothing and went rummaging through the data looking for an interesting finding:

So by selecting two antigens in combination with age and gender they found not very impressive sensitivity and specificity. No doubt they explored many different combinations of antigens and patient features and this was the best result. They did not try to validate the finding.

Any large dataset will have lots of random associations if you look hard enough. They only become interesting and useful if they validate (e.g. by splitting the data into discovery and validation sets at the start of the analysis).

I don't see how this moves us forward.