Using deconditioned people as controls

I feel like as many trials as possible that compare ME/CFS to another group should include another deconditioned group, like sedentary depressed people.

For example, I believe Ron Davis's nanoneedle test included healthy people and people with depression, though I don't know if they were sedentary.

While, for example, Oxidative Stress is a shared characteristic of ME/CFS and Long COVID only looked at ME, LC, and healthy controls.

If running a trial and just comparing healthy vs. ME, it's easy to look at any differences and wonder if it's because the ME patients haven't exercised in so long. If pilot studies included a deconditioned group from the start, to show whether or not the effect is from deconditioning, it would help avoid wasting time and money on likely deadends in ME research.

I understand this would make studies more expensive, but it might be worth it in the long run.

So why not run every ME trial with ME patients, healthy controls, and deconditioned controls?

Edit: Though of course deconditioning isn't the only ME effect that could be causing different results. By my logic, you should also include a group that isn't sleeping well, a group that doesn't socialize much, etc. Ideally, you would find one group that matches the symptoms of ME as closely as possible, but does not experience PEM.

 

Absolutely agree @forestglip . It's perpetually convenient to dismiss ME bioresearch findings by claiming the results show the effects of deconditioning, not serious illness.

 

I pretty much consider studies comparing against healthy controls as worthless for ME research.

 

Well, I think it's important to include deconditioned and healthy. Because if it's just deconditioned vs. ME, then it's the opposite, and easy to say "it's because ME patients aren't actually sick."

 

couldnt agree more @forestglip its so obvious i cant understand why it isnt done. Healthy but active controls arent really an adequate control i dont think.

But how would you define 'deconditioned' ?
would it be sufficient to have sedentary controls - eg people who do sedentary jobs & take no regular exercise - but that would have to be specified i think - so what counts as 'sedentary', what counts as being deconditioned but healthy. It would need a specification/definition, otherwise what one study team considers 'deconditioned' might be totally different than others' which would be unhelpful

My brain is fried im sure theres a succinct/more articulate way of saying what i mean i'm not describing it well

 

I think maybe step count could be a good proxy. Although that would add some complexity in the recruitment process.

Maybe people diagnosed as severely depressed. Or maybe hospital patients on constant bedrest.

But even if it's not perfectly defined between different researchers, I think even an imperfect unhealthy control could add value. Just a good starting point to say, "look, the ME patient results are definitely not what we're seeing in healthy people, but not only that. The results are not what you should see if you were to assume they are unhealthy because they don't exercise."

Maybe "constant bed rest" is all that's needed for a basic definition. These people will have equal or less physical exertion than every ME patient. If the marker is the same with healthy people and people who do zero physical activity, it'd be surprising if deconditioning was the cause in people who do anything in between.

And it is important to make that distinction. Not just as an "I told you so" but also because doing virtually zero exercise is a significant thing to do to your body, and may well be the cause of lots of abnormal markers, so lets get that information as soon as possible to know what's a real lead and what's not.

 

completely agree

You'd be unlikely to find a cohort of healthy people on constant bedrest though. People on hospital bedrest are likely to be suffering from all sorts of stuff that could confound things. And surely bedrest would only be necessary if they were a control group for severe patients?

Not disagreeing/debating. just ruminating & thinking it through. Granted i not the person with expertise to do that but hey ho, just adding my thoughts

I wonder if simply "spend at least 'x' hours a day sitting or lying down, do not walk more than 'X' miles a day/wk & do no other exercise"

Just trying to think of a way to make it simple, easy and realistic in terms of recruitment, i guess it would depend on what we were needing from the controls - eg a blood sample is very different from an exercise challenge and then a blood test

 

I’m sure there must already exist some activity scoring questionnaire and people could be asked to fill it out and selected if they fit into the “sedentary” category.

 

I don't think whether they are healthy or not is important here if you also have a separate healthy control. The goal is to not only show that the marker shows different results from a healthy person, but that the level of exercise has nothing to do with the marker.

As an example, given a study that shows healthy, active people have a score of 1 on some blood marker. The group of people who have been laying in bed for months, maybe a mix of healthy and unhealthy, shows a score of 1.2. The ME patients return a score of 5.

One could then say pretty confidently that the marker separates ME patients from healthy people, and that lack of exercise, maybe the most important confounder for ME studies, isn't the reason for the marker.

In fact, choosing unhealthy sedentary people for the second group might even be better, because on top of the other two conclusions, you can say that the marker separates ME patients from people who are "generally unhealthy" or depressed or cancer patients, or whatever the group consists of.

 

A recruitment ad for couch potatoes? I'm wondering whether there are TV or gaming addicts who do as little physical activity as moderate PWME. Controls for serious ME would be a different group. Controls for mild ME would probably be easiest to find.

One difficulty is comparing activities. "10 minutes of housework" may be quite different between an energetic person and a PWME who is achy and lethargic. Maybe heart rate monitoring (total time at different rates, and maximums) would be the most consistent measure.

 

Questionnaires are too unreliable. If a dozen researchers did the same basic study based on individually-created questionnaires, you might get a dozen completely different--and even contradictory--findings. It's all on how you word and present the questionnaires.

 

I mean the point is to get generally deconditioned people right? Do we need such high precision. If we can find one questionnaire that accurately predicts sedenterism and make that the standard (ie. each study doesn’t make up a new questionnaire) it might be a little less precise than counting steps and heart rate, but it will save a **lot** of money and time compared to having each possible control wear a fitbit or equivalent for a month or so.

 

I think that could provide some value if the questionnaire was thouroughly studied to not have many shortcomings.

But I think hospitalized bedrest patients might be best. It's easy to find plenty of them - just look up "hospital" in the phone book. Maybe ask the nearest attending which patients have barely left their bed in at least 3-6 months. Again, I don't think they need to be exactly the same activity level as the ME patients, just at least as deconditioned. The ME participants' level just needs to be between the healthy controls and deconditioned controls.

Though they should probably have been sedentary for at least as long as the ME patients as well. And it might be harder to find hospital patients who have been in the hospital for, say, over 6 months, or ME patients who have been sick for less than 6 months.

If there are enough patients, this should at least be doable for studies that only draw blood looking for markers. If you're trialling a drug or other intervention, it might be more challenging to do, since these hospitalized people will probably be severely sick and don't need random other drugs added to their cocktails.

 

Do clinical trials usually have Healthy controls? I am not well versed in medicine at all but I was under the impression it was usually a Placebo group and a Drug group for drugs.

 

You're right, I was writing too fast and wasn't thinking. So yes, when researchers are just looking at a new potential biomarker, like the nanoneedle test, it shouldn't be too hard to pop into the hospital and get some blood from patients, who probably already have a line set up in their arm.

I think Ron Davis used depressed people as a second control for the nanoneedle, though whether they were as sedentary as ME patients, I don't know.

I would not be surprised if it turned out we were just finding lots of biomarkers of deconditioning, unless and until we prove otherwise.

 

i definetly understand. I think that’s why the MS comparison is often good too.

I wonder if elderly people who are “unhealthy” (and deconditioned) because of age but not disease would be a possible help.

 

I don't know too much about the history of MS. What's the comparison to this?

Elderly people is a good thought.

On a somewhat related note, why in the world is every study not severe bedbound ME patients?? At least those that only require a blood draw.

Presumably, any biomarker will be more pronounced in a severe patient. And when you're dealing with small samples, which we usually are in pilot studies, we want as much of an effect as possible so that it doesn't get lost in the noise of a small sample, leading to a possibly promising path being dropped because the effect wasn't significant, or some other biomarker the researchers weren't actively looking for might fly under the radar. We want as big of an advantage as possible and severe ME gives us that.

Yes, it might require more resources to access these patients. Maybe doing mobile blood draws. But this cost should easily be outweighed by the risk of missing real biomarkers.

Especially with large organizations, like NIH. Spend some of that billion dollars to access severe patients, even if the sample size is smaller.

It's like I'm doing a scavenger hunt, and I have a mild ME patient at my side, whispering clues to me, half of which I can barely hear over the wind. While the severe ME patient would have been happy to come along and scream the clues instead.

I don't think elderly people would work as a control for severe patients though, as most elderly people at least walk or roll a little bit at least.

Though I did just think of another possibility for a deconditioned control. Those with severe muscular dystrophy, who require an electric wheelchair, and are carried in and out of the chair/bed/bath by a caregiver.

 

Totally agree!
It might just be hard to find the sweetspot between of someone bedbound but that can also tolerate a nurse present for blood draws and filling questionnaires.

As a bedbound person, the idea of someone new in my room who might make noise is terrifying (all noise makes me crash — I haven’t heard a human voice in months). And that is not to mention the possible consequences of a blood draw, I find some don’t do anything while some lead to crashes.

 

Wow, I forget sometimes how bad it can get, but I can see how a simple blood draw can turn into something terrible. Hopefully some possible ways to do so can be found, like non-traumatic/painful blood draw techniques, having a caregiver do all question answering, or at least find the most severe patients who can handle it.