Jonathan Edwards
"Gibberish"
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Excuse me for being very thick here but can I just clarify by talking about my own case. For me beta- blockers and naltrexone are good symptomatic treatments, each controls one of my ME symptoms (POTS and sleep respectively) quite well.
So using this composite measure in a trial of naltrexone as an overall ME treatment I would (1) rate my overall improvement as say 10% because it acheives good control of one of my top five symptoms (2) my TTT shows no change (3) an my actometer data shows I'm a little bit more active because I am less groggy in the mornings but still have to pace carefully to avoid PEM
SO Naltrexone comes out as an ineffective treatment for my ME although it is good for a single symptom control. Which would be a true reflection in my case.
But if you tested beta blockers as an ME treatment I would (1) rate my improvement as 20-50% because controlling OI allows me to be much more active, up to my PEM limit (2) my TTT would be normalish (3) my actometer would confirm (1)
So beta blockers are a moderately effective treatment for my ME which is also true. So for the subgroup that has OI this test would be good.
Hypothetically a really good treatment (like rituximab) affects a number of my symptoms, including PEM,OI, sleep which would lead to a higher overall improvement rating still supported by 2 TTT & 3 actometer
Is that what we are saying? Sorry again to be so thick
Not thick at all, this is very relevant. There is no one answer to what measures to use and that needs to be kept in mind because people forget it. A trial of paracetamol (Tylenol) for pain in RA should not use ACR grading, just a pain scale. In fact the swollen and tender joint score part of ACR was invented for the ibuprofen trial, which reduces acute inflammation but not the chronic disease process. It may not be entirely suitable for testing more modern drugs like TNF inhibitors or rituximab. The tenderness is probably not very helpful but it was the thing that change most for ibuprofen maybe.
I think part of the idea of mixing different sorts of measure is to gain confidence that 'the treatment is having an underlying effect of the sort we hypothesised'. So we want evidence that the person says they feel better because their physiology has changed in a way we might have predicted.
There is an important false argument here, however, shown by the anti-IL-6 case. If we know treatment X tends to increase Y (some cellular or physiological measure) then measuring Y is no help as evidence that X is causing improvement via Y. You need to measure some Z that you thin kis on the way between Y and feeling better. So measuring NK cell function after ampligen is not helpful if we know that ampligen increases NK function. To increase confidence that patients are better because of this one would need to measure something that we think links NK function to feeling well in the context of ME but not in someone without ME. The main advantage of measuring NK function would in fact be to show that it might not correlate and that ampligen might be working some other way.
It all gets a bit complicated here!