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

Discussion in 'BioMedical ME/CFS Research' started by Sly Saint, Feb 3, 2020.

  1. Sly Saint

    Sly Saint Senior Member (Voting Rights)

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    https://www.preprints.org/manuscript/202002.0029/v1
     
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  2. John Mac

    John Mac Senior Member (Voting Rights)

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  3. alex3619

    alex3619 Senior Member (Voting Rights)

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    The real test will be specificity with respect to immune and mitochondrial disorders. However, though on the odds this test will fail like all the others, this is what we might see on what will be the eventual successful test. We have to wait for replication and further testing.
     
  4. borko2100

    borko2100 Established Member (Voting Rights)

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    Wow, if true, this is groundbreaking.
     
  5. Andy

    Andy Committee Member (& Outreach when energy allows)

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    A sensible note of caution from @Simon M
     
  6. Milo

    Milo Senior Member (Voting Rights)

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    Where are these authors from, and who are they affiliated with?
     
  7. Andy

    Andy Committee Member (& Outreach when energy allows)

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  8. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    It is worth remembering that a test with 100% sensitivity and specificity is useless, because it recognises a group that you have already recognised clinically.

    Tests are only useful if they indicate some underlying process that might be recognised better by the test than by clinical assessment. If the test is better it must have a specificity and sensitivity of less than 100% because at least some of the clinical assessments must be wrong (for there to be something better).
     
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  9. Londinium

    Londinium Senior Member (Voting Rights)

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    This line jumps out at me, unfortunately:

    This implies patient samples and control samples were not treated equally. If, say, patient samples traveled further before being frozen that might explain a high lymphocyte death rate upon being unfrozen, might it not?

    I hope that, upon coming out of pre-print, the peer review process will have necessitated the authors clarifying as to whether patient and HC samples were treated identically.
     
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  10. rvallee

    rvallee Senior Member (Voting Rights)

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    I'm not sure I understand the problem with that. Many diseases are diagnosed this way. It's not ideal but nothing ever is.
     
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  11. alex3619

    alex3619 Senior Member (Voting Rights)

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    One of my concerns is that ME might turn out to be some kind of spectrum disorder, and that we share hundreds of potential biomarkers but no biomarker is core to the disease.
     
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  12. Ryan31337

    Ryan31337 Senior Member (Voting Rights)

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    I thought it interesting that they made reference specifically to co-morbid POTS in the CCC-guided patient selection.

    Would seem to me like including those with POTS makes drawing any conclusions harder, given the many known diseases and issues that present with POTS beyond just CFS/ME. I doubt they were experts in POTS too and able to confidently exclude all of these.

    Even if they did, POTS research is showing secondary mito dysfunction in many of the patients, not all of which have a CFS/ME diagnosis...
     
  13. Hutan

    Hutan Moderator Staff Member

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    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.

    Screen Shot 2020-02-04 at 3.19.39 PM.png
    It sounds as though they have proved to their satisfaction that the length of time frozen doesn't affect lymphocyte viability upon thawing. But yes, as @Londinium said, there is the possibility that the samples from severe patients waited longer before being frozen. Still, I would have thought the majority of samples would have been from patients who could come in to the lab to give blood, just as the controls did. And the separation between CFS and controls is pretty good.

    It would be nice to have some confirmation from the researchers that time from collection to freezing isn't significantly different between groups.

    edited to add:
     
  14. Hutan

    Hutan Moderator Staff Member

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    Given this is a pre-print and maybe the authors are reading the thread:
    Page 8, this title looks like a typo, should be 'ME/CFS and control blood samples'
     
  15. Hutan

    Hutan Moderator Staff Member

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    So they looked at the ability of a score relating to 5 mitochondrial respiratory measures derived from the seahorse machine using lymphoblasts. Their conclusion was that this score worked about as well as the lymphocyte death related score.

    Screen Shot 2020-02-04 at 3.43.13 PM.png
    Again, pretty nice separation.

    So, not bad. Incidentally, another typo I think, 'regression' should be 'respirometry'.
     
  16. Hutan

    Hutan Moderator Staff Member

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    Same story with the third parameter - a measure of TORC1 activity - good separation of values between ME/CFS and controls, very similar values as a biomarker.
    So, when they combine the three:
    (another typo - ME/CFS and controls).

    Screen Shot 2020-02-04 at 4.05.51 PM.png
    And then they talk about the possibility of a 2-step test, with the seahorse analysis only being done if the lymphocyte death rate is bad.
    This was interesting in relation to JE's concern:
    So the test didn't pick up all of the people diagnosed with ME/CFS. The abstract only claims 'sensitivity and specificity approaching 100% in our sample'.

    And this was interesting given my earlier impression that they had only had a training set of data, although of course the numbers involved are small.
     
    Last edited: Feb 4, 2020
  17. Hutan

    Hutan Moderator Staff Member

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    Sorry to be going on a bit, but I feel a bit hopeful about this team's work. They have the best opening sentence in an ME/CFS paper that I have seen, I think.
    There is quite a bit in the discussion that is interesting.

    They say that it would be useful to compare the viability of frozen lymphocytes with other diseases.
    But they think the Step 2 Seahorse tests would differentiate ME/CFS from the rest.
    They note that lymphoblasts from Parkinson's patients look quite different to those of ME/CFS in these tests.

    They discuss why the ME/CFS thawed lymphocytes might be dying quicker. They say it could be due to the poorer mitochondrial function:
    They say that whatever the cell death pathway is, it may reflect the inability of the cells to respond normally to cell damage or stress (in this case freezing). They note that freezing causes damage, but also has been documented to affect PBMC expression of stress response genes.

    They noted this:
    I'm not sure what they have in mind. But they seem to be suggesting that there could be something pathological going on not directly related to the freezing. I wonder what the death rate is in ME/CFS lymphocytes that aren't frozen.

    Anyway, thanks to Daniel and the team for remaining interested in ME/CFS and their good work. And the funders, including the Mason Foundation which I have given a bit of a hard time previously for some of their funding choices.

    I look forward to replication of the work by this team and others. I note that the team in Otago have had some trouble getting consistent differences between people with ME/CFS and controls in the Seahorse studies; they thought they had some technical issues to sort out.
     
    Last edited: Feb 4, 2020
  18. borko2100

    borko2100 Established Member (Voting Rights)

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    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.
     
    Last edited: Feb 4, 2020
  19. Milo

    Milo Senior Member (Voting Rights)

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    The world of POTS is messy as well. Some of the internationally known POTS specialists do not believe in ME and believe those who have ME have primary POTS. Then their POTs patients are ‘tired’ too. Many if not all display several symptoms which overlaps with ME, without ever being diagnosed with ME.

    Other than Dr Rowe, POTS and ME specialists are not typically mingling and in my view, they should. They should be invited to ME conference and vice versa.

    To add to the complexity of just being diagnosed, first line physicians are not necessarily able to identify patients with POTs that come to their office. In my case, when i initially went in because i was feeling worse upright and slightly better reclining, i was deemed lazy and depressed and told i needed anti-depressants. I had to go 7 hours in a plane to a doctor who knew exactly what was wrong. And when i got back the doctor was still in disbelief, though willing to prescribe me atenolol which had been started in the US. It was another 8 years until she was willing to do a NASA lean test so I could be included in a study.
     
    Last edited: Feb 4, 2020
  20. butter.

    butter. Senior Member (Voting Rights)

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    This is just plain wrong. Your perfectly identified clinical diagnosis of me/cfs still makes you a psychiatric patient in 99% of all cases.
     
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