A nanoelectronics-blood-based diagnostic biomarker for ME/CFS (2019) Esfandyarpour, Davis et al

It's quite a stark difference between patients and controls, so unless there's been a real screw-up this should lead on to some interesting work. I've got some concerns about the politics of promoting this to the media now, but even if this is something the 'only' provides a useful way of testing for ill-health/fatigue in those suffering from a range of different conditions, that would still be quite a break-through.

Presumably work on this test has been continuing since their paper was submitted, and hopefully they will be getting further data to help work out what is going on.

 

Nothing is easy for severe, bedbound patients.

 

Yes, Ron Davis understands that better than anyone.

 

It feels like they dont want ME to be a real disease.

 

Or it could be that they've been doing formal research on this, but are not saying anything about results not submitted as a part of their paper. Taking that cautious approach with public statements probably would be best. I'd hope work like this has been going on, but we've seen how researchers can become prematurely confident in their own findings and fail to do the sort of double checking that others see as important. Fingers crossed that this sort of work has been/is being done.

 

Wessely is probably trying to say, without actually saying it, that the observed effect is due to deconditioning.

 

I'd have thought that even just having sedentary healthy controls and a single disease control group (e.g. MS) would have been hugely informative. There seems to be something about this that I'm not getting!

 

Article in ScienceAlert with comments from Ron Davis, Simon Wessely, Andrew Lloyd and Robert Naviaux : A Chronic Fatigue Blood Test Looks Increasingly Promising, But It's Still Early Days

ScienceAlert reaches a huge audience. They have 9 million followers on FB.

 

TBH I don't care about the psych lobby at this point - I care about having good science done to get us a valid test and I think that the objection that the test might simply be showing something to do with deconditioning seems entirely valid, regardless of who is bringing it up. For our own sakes, I think we need that comparison to be made.

 

I've just skimmed the paper, and find it extremely interesting, and not just for ME/CFS. They are running a provocative test at the cellular level, rather than attempting to wreck the entire patient, as in some tests I've had. Using osmotic stress tallies with widespread experience that patients have serious problems with dehydration or electrolyte imbalances. These are physiological stressors which should not be confused with psychological stress.

Aside: with some training in mechanics of continuous media I was taken aback that medical people generally assumed "stress" was psychological. We were used to distinguishing stress and strain in things like piano wire, which has minimal psychology.

Operating at the cellular level also allows you to deal with localized problems, as in tissues deprived of oxygenated blood by abnormalities in circulation. Nothing in biology requires the effect to cover the entire body.

I doubt that this will clearly distinguish patients according to clinical judgment, because we already know that judgment is subject to real difficulty. It takes a considerable effort to make clinical judgment produce anything like a uniform cohort. This is not a defect in the research, but in clinical evaluation in the absence of biomarkers.

Requiring a biomarker to match clinical assessments, when different schools of thought have trouble agreeing, is a recipe for stagnation. I would also point to severe problems in distinguishing a known serious illness like periodic paralysis in the absence of laboratory tests. Most such patients go decades without a correct diagnosis. That rare illness also depends on problems with electrolytes and ATP production, so it might be detected by this, though I would expect the machine learning algorithms to need different training.

As a separate example of the problem with matching clinical judgment, one not depending on osmotic stress AFAIK, I will also mention the clinical difficulty of diagnosing anti-NMDA receptor encephalitis without detailed laboratory tests. In that case, there is little question "something is wrong", but demanding that testing should support the whole range of clinical descriptions would be ridiculous. The illness can look like all kinds of strange things.

Added: waiting for the biopsychosocial group to understand support-vector machine learning could take a while.

 

Agreed, but it's all relative and in terms of getting healthy but sedentary controls and patients from other disease groups, especially if blood has been biobanked, it ought to be fairly easy.

 

I've only read the paper once, but it seems this test currently requires very custom one-off research equipment, and the test itself takes 3 hours to run, never mind all the before and after prep. So it's a slow, researcher intensive process.

The 40 samples tested in the paper had to be tested within 5 hours of collection. This really limits what you can do from an experimental point of view.

The paper describes some of the the handling challenges / experiments

So immediate liquid nitrogen freezing and storage is a possibility. But at present it seems they can only test one sample at a time. I believe access to biobank freezers requires special procedures. You can only open the freezers so many times before the samples degrade with the temperature changes. My take is that taking one sample out of a freezer at a time logistically is very difficult. Also those biobank samples will have had to be immediately processed and frozen in a consistent manner.

Anyone on here know more about biobank collection, handling per the supplemental instructions, and liquid nitrogen freezing and retrieval? Would the London biobank samples be usable for example?

 

Karl Morten touched on blood handling issues and quick degradation in his NZ talk. I believe this was in relation to his work to try and validate the Myhill et al ATP profile test
Transcript : https://www.s4me.info/threads/dr-ka...-his-research-december-2018.7287/#post-130458

 

Of course Henrik had to have a say...

What exact tools is he referring to? Psychobabble ones?

https://twitter.com/user/status/1123252190301310977


https://twitter.com/user/status/1123253763639214081


https://twitter.com/user/status/1123245423534202885

 

Good questions @Jonathan Edwards . I would love to learn more about the structure, how many sensors, when to capture a reading from a sensor.... could other structure geometries work better.

I posted this yesterday in case you missed it.

This previous paper talks more about the nanoneedle measurement

ETA : Link to full text of 2013 paper for anyone wanting to understand the technical details of the sensor more.
http://sci-hub.se/10.1002/bit.25171

 

This

 

"What" is a lot easier to answer than "why".

They produced "simplified blood" of each patient made up of PBMCs resuspended in plasma, 200 cells per microlitre.

A sample of this was added to the Nanoneedle chip and they then measured in impedance. Impedance is defined as the ratio of applied voltage to the induced current (if that helps).

Each chip has 4000 Nanoneedles, I think, and they used a sample frequency of five times a second for approximately three hours.

Once they had a study baseline measure they increased plasma sodium chloride concentration to 200 mmol per litre, to apply osmotic stress/increase energy demand.

Here are the diagrams from the paper showing the Nanoneedle design, and the captions:

​

(B ) Circuit model of a sensor−solution interface, where Zm-s is media−sensor surface interactions, Zc-c is cell−cell interactions, Zc-s is cell−sensor surface adhesion, Zc is a cell impedance (membrane capacitance Cm, and cytoplasm conductivity of the cells, σcp), and Rs is resistance of the solution. (E and F) SEM images of a nanoelectronic sensor tips, (E) top view

The "why?" Is more complex.

The paper states that "the array directly measures the impedance modulation results from cellular and/or molecular interactions". However, they don't offer any direct evidence of that, though more later on what they think is going on.

Interestingly, they weren't initially trying to develop a diagnostic test. Instead they were trying to set up a cellular model of post exertional malaise, using a high salt environment to ramp up ATP consumption and presumably lead to its depletion. Salt stress had been used to do that in other biological systems.

However the differences between patients and controls were so dramatic that they switched to investigating the Nanoneedle system as a diagnostic test.

They say the exact mechanisms behind the differences remains unclear and is they have a programme of work to try to narrow things down. They suggested several possibilities, including changes involving the endoplasmic reticulum and plasma membrane, and even increased cytokine production in response to the salt stress.

One possibility was change in size/shape in response to the osmotic pressure, but live microscopy at several critical stages in the experiment revealed no visible differences between patient and control cells.


Does that help? I don't understand the details of the different types of impedance measured.