Erythrocyte Deformability As a Potential Biomarker for Chronic Fatigue Syndrome, Davis et al (2018)

I was mulling this over and I think *theoretically* you could get the p values mentioned with an N=18 sample. I agree with the above that sampling hundreds of cells gives you more confidence of the deformability value for a given patient/control but does not provide greater confidence of the differences in average deformability *between* patients and controls. However, if for example all nine patients had deformability lower than all the controls with no overlap between the groups, the chance of getting that result if the null hypothesis was true would imply p = 7.6x10^-6 (based on the heavily oversimplified approach of treating each patient/control sampled as being a 50/50 coin toss between being in the 'high deformability' and 'low deformability' groups). So I could see how one could get a very low p-value if the results were massively clear-cut with no overlap. As you say, we need to see the results.

The wider question is your point around whether the sample is representative of the patient population: the severely ill study as benefits and drawbacks. The benefit is any 'underlying signal' might well be stronger in the severely ill than in mild/moderate ME/CFS patients; the drawback is that severely ill patients are likely to be much more deconditioned and on other medications meaning that any findings may be merely a result of that instead.

ETA: and the real biggie, for all ME/CFS research - we don't even know if severely ill patients have the same disease aetiology as other patients!

 

This may well be a silly question, as I know nothing about the subject. It may be treated as rhetorical if necessary.

If, for the sake of argument, we accept that this is a valid finding and connected in some way with some of the symptoms of some ME patients, how could this fit into a relapsing /remitting condition? Presumably there is a constant production of new RBCs and destruction of old ones. Are the new cells produced already faulty or do they become faulty only when introduced to some other circulating cells? During remission does the proportion of normal cells to faulty cells increase, producing a lessening of symptoms?

 

Or what they might be seeing here is the effect of the unidentified substance in the plasma(?) that causes cells from healthy controls to be affected once exposed to plasma from patients? Though how that fits relapsing/remitting itself I don't know.

 

Nanotracker

This device was in the news recently too.

 

The problem is these estimates are arbitrary, and as you say a measure of likely confidence. However its either right or wrong, statistics usually cannot determine that, no matter the group size. Statistics can only say, at best, that presuming there are no confounds or undetermined biases, and presuming there is a random distribution, an outcome with a very tiny p value is something we can have very great confidence in. Never certainty.

This is a lot like the closed world assumption in computer science. You know that additional factors, not taken into account, can create bugs or errors, but you have to presume that until some other factor is shown to be important enough then the software will do. Other things are outside the specification of the software. Now studies, by their methodology etc., have a defined scope. There can always be confounds, or at least we should presume so.

One thing I like to keep considering is that a statistically significant bias is an estimate of the likelihood a result is due to chance. If its due to high bias or powerful confounds then its not due to chance. So it can be statistically significant, but still wrong.

 

Good point, I had assumed it was from that study due to the number of participants, but that's quite possibly wrong.

 

I know very little about the molecular biology of such things, but I have wondered if the poor RBC deformability could be the product of Naviaux's Cell Danger Response. IIRC, part of the CDR involves a stiffening of the cell membrane. If this is the case, and it could be behind the RBC low deformability, then maybe it is something that is variable with the engagement of the CDR, and therefore could normalize suddenly during remissions.

ETA: Trish's comment reminded me that RBC's dont have mitochondria. I'm not sure if this would preclude them from the affects of CDR in other cells.

 

#MEAction: Study shows red blood cells less deformable in ME patients - possible biomarker
Author: Ron Davis

This paper documents that red blood cells are less deformable in ME/CFS patients compared to healthy controls. It potentially could be a biomarker, and we are proceeding to design new devices that will make a clear distinction between patients and healthy controls. These devices will be hand-held and easy to use by doctors in their offices, or in clinical testing labs.

Past work has looked primarily at the shape of red blood cells, which is difficult to quantitate. Our approach will give a clear quantitative number. It measures the ability of red blood cells to deform while squeezing into a capillary, something that blood cells must do for healthy flow. We measure hundreds of cells from each patient, so, because of this, even though the number of patients is low, we get a very statistically significant distinction between patient and healthy cells’ deformability. We are putting our energy into developing the new devices as soon as possible.

 

I agree, especially with what you say about the sample size, which is, if I recall correctly, 9 patients and 9 controls. Really, all they can be certain of is that they looked at lots of cells from 9 patients, and that they can be pretty certain of the results, in regard to those 9 patients - how many times have we criticised various papers here, both psych and biomedical, for having small sample sizes, this should be no different. For Ron to make such definite statements he really needs to be sampling far far more people.

 

FWIW, it seems that one way RBCs can become more rigid is when small molecules (ligands) bind to a protein in the cell membrane called glycophorin A (GPA), which, in turn, interacts with other proteins in the cell membrane, reducing deformability.

When tracer antibodies to human glycophorin A attach to blood cell GPA the "ligated RBCs travel 33% slower than control RBCs".

Ligation of Glycophorin A Generates Reactive Oxygen Species Leading to Decreased Red Blood Cell Function (2016)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4718526/

 

This may be a very dumb question but could there be a link with livedo reticularis?

Wikipedia says:
Livedo reticularis is a common skin finding consisting of a mottled reticulated vascular pattern that appears as a lace-like purplish discoloration of the skin.[1] The discoloration is caused by swelling of the venules owing to obstruction of capillaries by small blood clots. The blood clots in the small blood vessels can be a secondary effect of a condition that increases a person's risk of forming blood clots, including a wide array of pathological and nonpathological conditions

I have had this since I was a teenager, and of course doctors checked a few things out and labelled it as idiopathic.

 

Lots of confusing statements about that online, but I think Janet Dafoe (Ron Davis' wife) can be trusted to have the correct information

https://twitter.com/user/status/1068089431595204608

 

This is something I've developed over the last 10 years.

 

And @Marco . This is interesting. I thought I was the only one with this. The only factor I found was that it is a possible side effect of Amantadine, which may, or may not have contributed to the severity of my condition. It is mainly apparent on the backs of my hands at certain times. It had to be self diagnosed. I have mentioned it to a GP but it was not thought significant.

 

Hi Chris

The only prescription drug I've been on for any extended period of time has been Tagamet and that was decades ago although I was a heavy smoker until recently which probably didn't help.

It seems to restricted to my arms and upper body but I've a number of other issues which might plausibly be linked to small blood vessels (occasional parathesias; heat intolerance; thinning hair and rapidly deteriorating eyesight).

 

@Marco, @chrisb
Mine is on my legs. In my case it isn't a drug reaction - I wasn't taking any medications when this developed as a teenager. Coincidentally teenage was when my allergy issues started. I have been +'ve ANA for years now, although I don't test positive for antiphospholipid etc so its idiopathic again.

Perhaps I could tell myself a handwavy story about unclassified autoimmune disease which began as a teenager and an increasingly dysregulated immune system producing an ever increasing number of issues such Livedo, ME, migraines, what looks like MCAS. And wait for Prof Edwards to pour cold water on it.

It seems Livedo is not a widespread issue for pwME though, would we expect that if this paper was on the track of a biomarker?