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Stanford Community Symposium 2018: Phair, Metabolic traps, Tryptophan trap

Discussion in 'ME/CFS research news' started by NelliePledge, Sep 30, 2018.

  1. obeat

    obeat Senior Member (Voting Rights)

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    There seems to be another switch at the menopause with either improvement or deterioration occuring.
     
    Susan K, andypants, Kitty and 2 others like this.
  2. ScottTriGuy

    ScottTriGuy Senior Member (Voting Rights)

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    Fwiw, I suspect I'm not more sicker because of my HIV meds - but obviously have no proof, just anecdotal reports such as yours.
     
    andypants, Perrier, Annamaria and 3 others like this.
  3. Barry

    Barry Senior Member (Voting Rights)

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    And you clearly did not need anyone pushing CBT or GET at you to do so, I'm guessing.
     
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  4. Keela Too

    Keela Too Senior Member (Voting Rights)

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  5. Barry

    Barry Senior Member (Voting Rights)

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    Really good to read that, because I have always maintained that my wife is best evidence against the deconditioning theory. I'm totally convinced she always does more than would be needed to work past any deconditoning; in your case (glad you have improved by the way), that proves it very nicely. I would tentatively suggest that that little snippet of your ME history alone is very good anecdotal evidence against the deconditioning theory, and that it might be worth citing this as an illustration to NICE.
     
  6. Perrier

    Perrier Senior Member (Voting Rights)

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    Dear Keela, your improvement is really stunning, you know. Why did the doctor give you this drug? What was the thinking? Thank you.
     
  7. Mij

    Mij Senior Member (Voting Rights)

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    I've experienced several 'switches' in my 28yrs of ME without taking any meds. As long as we stay within our 'energy envelop" , and avoid PEM, I don't feel that some of us will worsen over time.

    BTW, my 'switches' occurred almost overnight.
     
    andypants and Kitty like this.
  8. Perrier

    Perrier Senior Member (Voting Rights)

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    Dear Mij
    Some folks don't have an energy envelope; they are bed bound, and becoming worse.
     
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  9. Mij

    Mij Senior Member (Voting Rights)

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    @Perrier yes I understand this. I'm sorry if I came across as insensitive.
     
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  10. Keela Too

    Keela Too Senior Member (Voting Rights)

    It’s all interesting. My initial onset had a period of viruses and failing but functioning health. Then a general anaesthetic triggered a dramatic drop.

    After that I had a year of ratcheting steeply downwards before I properly got the pacing concept, followed by a slower decline over another 3 years, which I still likened to ratcheting down, just slower. However, every slip on my part still involved losing some more ability, apparently permanently. It was a scary time, because by then I’d done enough reading to “know” what might happen on this trajectory. I felt powerless to stop the slow but relentless downward trend.

    The decision to take the ARV, was because I was in the right place at the right time to hear about it, and so after much contemplation we (joint decision with my husband, you understand) decided to try it privately. Beyond that I’m not commenting further on reaching the decision.

    It gave me a reprieve, and reset me back to probably about where I was just after the general anaesthetic. I remain eternally grateful for this second chance. . . . But am also aware that changes can happen spontaneously, and as such my anecdotal (n=1) experience may not mean much.
     
    Binkie4, rainy, NelliePledge and 9 others like this.
  11. Barry

    Barry Senior Member (Voting Rights)

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    8,385
    Interesting. My wife developed ME whilst recovering from a fairly minor op, but under general anaesthetic, and getting a horrible flu bug at virtually the same time. Her ME became evident by way of not seeming to recover from the operation; turned out her ME was cutting in as her op recovery was progressing OK. (Unless of course history shows ME to sometimes be a post-op-recovery failure mode). Can't help wondering if this could be the kind of perfect storm of trigger events @RDP speaks of regarding the metabolic trap. Either way, it would seem a potential perfect storm that very possibly triggered something.
     
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  12. Barry

    Barry Senior Member (Voting Rights)

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    I need to just clarify here. My wife was up and about and doing stuff within a day of getting out of hospital; no time for deconditioning. (Yes I know ... but YOU try telling her not to ;) ).
     
  13. RDP

    RDP Established Member (Voting Rights)

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    @Keela Too If you have those data on stepcounts vs. date in a spreadsheet or a text file, I would love to have a look. I'm always happiest when time is on the horizontal axis.
     
    Binkie4, Joh, andypants and 7 others like this.
  14. RDP

    RDP Established Member (Voting Rights)

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    @Chris Ponting I've struggled with the statistical aspects of this, and I'll follow up on your suggestions. It has always seemed odd to me that the appropriate statistical test depends on how you came upon the observation you want to test for significance. As I've said elsewhere, I'm a classical (maybe dated) Popperian hypothesis tester. Like many biologists coming to ME/CFS, I started with the theory that the problem must be mitochondrial, but I also had this conviction based on the existence of outbreaks/epidemics/clusters that any predisposing mutation MUST be common, otherwise epidemics would be inexplicable. Just as I was beginning in ME/CFS, Ron Davis presented me with access to his Big Data study on severely ill ME/CFS patients. This was my very first opportunity to look at any sequencing data in the context of a real project, but the ready accessibility of genome browsers gave me hope that I could become sufficiently expert to test my own ideas. So I searched all the genes coding for proteins in all the complexes in the mitochondrial ETC. That's 70+ genes. You'll be aghast that I did all that by hand, displaying my 20 genomes for one gene at a time and looking for shared common (hopefully missense) mutations among the 20 severely ill patients. Took weeks, but I was a free-agent and I was learning new stuff. Bottom line, perhaps not surprising, there are no common shared missense mutations in the genes coding for components of the mitochondrial ETC. Still thinking it had to be energy metabolism, I turned to other aspects of central energy metabolism. I soon came to the kynurenine pathway because it's one of the sources of NAD+. There are no common damaging mutations in TDO2 or IDO1, but you can imagine what it felt like to type IDO2 into the IGV search bar and have multiple mutations line up for many of the 20 patients. The rest of the story is in the paper. The search of the entire dataset for common damaging mutations in enzymes or transporters came two years later when a student came to me who had those skills in abundance. IDO2 was the 82nd gene I looked at in this way. Does that mean my burden of multiple testing is 82 instead of 20,000? Moreover, with 74 patients, none of the 4 damaging SNPs in IDO2 is statistically more common in the patients than in healthy controls. My risk of false positives is high and it keeps me awake, but the IDO metabolic trap hypothesis is compelling on enough other grounds that, to me at least, it remains worth testing at the level of metabolic fluxes in CFS cells. So, as I've said before, your GWAS of the UK Biobank self-diagnosed patients failing to reach genome-wide significance seems to me correct. It's because we are focused on common mutations that we have the unusual situation of four different keys all capable of unlocking the same lock. Only in a case like this would it make sense to ask how many patients have zero damaging mutations, and how does that number compare to what is expected based on the population allele frequencies?

    I will follow up on your ideas, and I'm sure I'll learn a lot. Thanks for sharing your thoughts. Rob
     
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  15. Keela Too

    Keela Too Senior Member (Voting Rights)

    I’m just on the iPad just now, but I’ll fire up the computer later and send you some stuff in a PM.

    PS... Edited to add, @RDP I just watched your video at the top of this thread. :) Really that trap idea seems to make so much sense! I wonder can there be multiple traps? Given my n=1 observation that I seem to have climbed from one relatively steady state to another, but am not yet actually healthy.
     
    Last edited: Aug 9, 2019
  16. Robert 1973

    Robert 1973 Senior Member (Voting Rights)

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    Location:
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    If the original testing which identified damaging IDO2 mutations as a potentially predisposing factor was only done on the 20 severely affected patients, I assume that the remaining 46 samples were tested after the IDO2 hypothesis was generated. Does this not mean that, from a statistical point of view, the 46 should be treated separately from the original 20, without the need to adjust for multiple testing in the 46?

    [edited for clarity]
     
    Last edited: Aug 9, 2019
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  17. RDP

    RDP Established Member (Voting Rights)

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    EDIT: @Chris Ponting Reading your post for maybe the fifth time, I infer that the burden of multiple testing does not devolve from how many tests I DID, but rather how many tests I could have done. Is that inference correct?
     
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  18. RDP

    RDP Established Member (Voting Rights)

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    This is a great idea. I'm on it.
     
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  19. Andy

    Andy Committee Member

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    21,814
    Location:
    Hampshire, UK
    Just wanted to highlight that, if you need to source samples for any replication test, then there is the UK ME/CFS Biobank, https://cureme.lshtm.ac.uk/researchers/ as a potential resource. As they are able to visit donors at home they have samples from severe patients, and they have experience in shipping samples internationally.
     
  20. RDP

    RDP Established Member (Voting Rights)

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    @Andy That too is a great idea. Thanks!
     
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