Cell-Based Blood Biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Missailidis et al Feb 2020

borko2100 said:
I really think they are on to something. Their main idea is that Complex V inefficiency is the root cause of ME/CFS. I don't understand exactly what Complex V is and what it does, however it seems that ME/CFS might be a milder form of a genetic mitochondrial disease called Complex V deficiency.



The bold part describes ME/CFS very well, or at least a subset. Namely, extreme lactic acid build up and muscle fatiguability after trivial / minor activities, such as walking, staying upright, etc. I recall reading several papers confirming this lactic acid issue.

I wonder though if Complex V deficiency also has PEM as a symptom?

PS:

Another mitochondrial disease affecting the complexes, Leigh's disease seems to be triggered in certain cases by a sudden stressor. From wikipedia:



If this mitochondrial disease can be triggered in such a way, then maybe ME/CFS could be triggered in a similar manner? Very interesting.
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There is a high chance that severe me/cfs patients have a mitochondrial disease.
 
In terms of predictive accuracy, the numbers are very good. What worries is me is whether their methods can differentiate between other diseases such as MS or other mitochondrial diseases. Nevertheless, if this test is able to predict Mito diseases (in general) vs other diseases then that is a good start
 
Hutan said:
Yes, but as Simon and others have pointed out, they have essentially only tested their 3 biomarker model on their initial dataset. So, having a model that perfectly predicts diagnosed ME/CFS in that initial dataset is a promising start. It's better than if they combined their 3 best factors and there was only a 70% specificity.

Lymphoctye death rate propensity (after freezing and thawing) does show pretty good separation.
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My comment was intended to indicate that I worry when people start talking of 'nearly 100%' as if 100% were something to aim for. Almost all clinicians make this mistake. Useful biomarkers for ME/CFS are very likely to give much lower rates. I seriously worry that this sort of combined analysis just tends to muddle what might be useful candidate markers with fluff. Why try to run on a tightrope if you are walking comfortably?

I am less impressed by any 'separation' on lymphocytes death rate. There is certainly an obvious difference in distribution but no sign of a cut off. Controls go up into the middle of the ME/CFS range and ME/CFS goes down below the middle of the control range. I think the coloured boxes a confusing because they are just a statistical trick. I prefer scatter plots to be raw.

Although there are conditions where several measures are taken together to make a diagnosis this is usually in a situation where we can perceive an obvious reason why you would need them. For instance if you measure calcium, phosphate and alkaline phosphatase you have eight possible combinations of low and high values. At least four of these (it may be as many as seven) are diagnostic for a particular condition and we can see why - because we understand the actions of things like vitamin D, parathyroid hormone, myeloma and kidney failure on each measure and how they relate.

I agree that looking for anything like this in ME/CFS is worthwhile but so far I cannot see any obvious way to relate the various potential marker findings. Lymphocyte survival seems to me very likely to be susceptible to irrelevant lifestyle factors. Growing lymphoblasts takes you away from the in vivo milieu and selection problems loom large.
 
Jonathan Edwards said:
I agree that looking for anything like this in ME/CFS is worthwhile but so far I cannot see any obvious way to relate the various potential marker findings. Lymphocyte survival seems to me very likely to be susceptible to irrelevant lifestyle factors. Growing lymphoblasts takes you away from the in vivo milieu and selection problems loom large.
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Isn't the point of doing studies using controls is to specifically answer the above question. As the number of controls increase, that will be apparent. To date it seems fine.
 
Pondering said:
Isn't the point of doing studies using controls is to specifically answer the above question. As the number of controls increase, that will be apparent. To date it seems fine.
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The studies so far show an apparent difference but answering the question about how these findings relate to a mechanism that might make them more than just a correlation is a completely different aspect of science.

Doing more controls will not take that any further. Doing another patient cohort with controls is the way to find out whether or not the findings so far are by chance. But we also want to know if the findings are more than an epiphenomenon - may be due to less activity or whatever.

Although there is a difference so far between ME/CFS and controls it is not the sort of difference one would expect to see if measuring something directly involved in the primary mechanism of the illness. For most clinical conditions the tests we use give fairly black and white differences - with perhaps no more than 10% overlap between the two groups.
 
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