By David Tuller, DrPH
When I was a young gay man in the 1980s (I’m 67), a common term for sexual orientation was “sexual preference.” This phrase always struck me as weird. Preference? The urges I felt were not a “preference.” Preference clearly implies a choice—as in, I prefer to live in the city rather than the countryside. I was not given a choice about my sexual orientation. From my earliest awareness as a sexual being, I was attracted to men. Period. “Preference” had nothing to do with it.
(For me, that is. Others might have experienced their sexual orientation differently. Having said that, I want to add that were I given a choice now, I’d choose to be gay. Despite all the heartache and loss of the AIDS epidemic and the many other challenges of being a member of an often-despised minority, my life has been rich in experience, love, pleasure, and joy—all intermingled with the pain that is integral to being a sentient being.)
I mention this as a way of highlighting my initial reaction to the long-awaited and long-delayed publication of the US National Institutes of Health’s study of 17 ME/CFS patients, along with 21 healthy controls. The paper, titled “Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome,” was published in February in Nature Communications, a high-impact journal. It immediately triggered howls of protest.
One reason for concern was that the authors made sweeping claims for a paper based on such a small sample of patients, some of whom were too disabled to participate in every part of the study. (The study was originally supposed to include a much larger sample, but the coronavirus pandemic interrupted those plans.) Another was the controversial claim at its core–that the profound fatigue reported by patients is the result of a construct called “effort preference.” As noted in the third sentence of the abstract, “one defining feature of PI-ME/CFS was an alteration of effort preference, rather than physical or central fatigue.”
Members of the patient community have conducted extensive and robust analyses of the flaws of the “effort preference” construct. Jeannette Burmeister, a lawyer as well as a patient, posted a blockbuster four-part series about it on her blog, Thoughts About M.E. In an extensive thread, members of the Science for ME forum also whacked through the thicket of data shenanigans that led to the NIH’s conclusion. As of this posting, that thread includes almost 800 comments—many of them quite lengthy. (On the Health Rising forum, Cort Johnson offered a perspective that was more sympathetic to the research team.)
Last week on X (formerly Twitter), Burmeister reported that the NIH’s Agency Intramural Research Integrity Officer has begun assessing the complaints made about the study. Let’s hope this turns out to be an in-depth inquiry that figures out what exactly has gone on here. And let’s hope they clean up their EEfRT analysis and get rid of the “effort preference” mess. Unless that happens, it seems likely future research into ME/CFS and Long Covid will also adopt this approach.
Anybody who knows anything about the terrible history of ME (or CFS, or ME/CFS) should have realized the disastrous nature of suggesting the involvement of any sort of “preference.” Subsequent assurances from the NIH that “preference” refers to subconscious or unconscious or pre-conscious calculations by the brain and does not mean what it obviously means to the lay person—that is, a conscious choice–are pathetic, even if taken at face value.
It is hard to fathom how those leading this research team could be so out of touch and tone-deaf. We now have more than three decades of experience regarding the fallout of the decision by the US Centers for Disease Control and Prevention to name this devastating condition “chronic fatigue syndrome” in the 1988 study of the famous Lake Tahoe outbreak. Health officials seem to have learned nothing since then about the power of language to shape illness perceptions and negatively impact the lives of patients. That’s very troubling.
In response to the concerns, the NIH released a statement that sought to blunt the criticism. In describing the meaning of “effort preference,” the statement argued that “the term does not describe a psychological difference in people with ME/CFS and people without ME/CFS; it describes an actual abnormal finding in how the body’s neural system is supposed to function.”
Great! Explain that to everyone who will read the study and interpret the word “preference” in the normative sense, not in the convoluted and non-intuitive way that the NIH apparently thinks it should be taken. This includes clinicians who might be inclined to scold patients for “preferring” not to make an effort. For all we know, the study might already be generating this sort of result.
It is also unjustified for health officials to chastise patients for criticizing the study, as Avindra Nath, the senior and corresponding author, has done. During a public presentation of the findings, he said: “When you doubt our intentions and pick apart every single word, you also tear us apart. It causes pain and suffering on both sides and demoralizes us and shatters our goals.” Putting aside the issue of intentions, it is essential to “pick apart” words if they are, like “preference,” so poorly and ineptly chosen.
All research is subject to legitimate criticism, no matter how much time and effort has gone into it. Complaining about the “pain and suffering” of researchers whose work is scrutinized closely is a form of emotional blackmail. To wield government authority in order to shame a long-abused patient community into shutting up is unwarranted—especially when it was the NIH, not patients, that selected a problematic term implying patients “prefer” to do less.
**********
The weird use of the EEfRT
The issues with “effort preference,” however, do not seem limited to the nomenclature. The construct emerged through the NIH’s use of something called the Effort-Expenditure for Rewards Task (EEfRT). This approach, which was designed to test motivation in depressive patients with anhedonia, was first described in a 2009 paper in PLoS One. The EEfRT is quite complicated, so I won’t go into it at length here. Suffice it to say that it involved requiring participants to choose between so-called “hard” and “easy” tasks in a series of button-pushing trials.
As the 2009 paper explained, “Successful completion of hard-task trials required the subject to make 100 button presses, using the non-dominant little finger within 21 seconds, while successful completion of easy-task trials required the subject to make 30 button presses, using the dominant index finger within 7 seconds.” The tasks involve varying amounts of small monetary rewards that participants might receive upon successful completion, as well as different probabilities for whether they would actually receive the designated reward for completing particular trials.
While the EEfRT has been adapted for use in subsequent studies, it is unclear why the NIH decided that a system designed with anhedonic depressives in mind would be applicable to and appropriate for ME/CFS. Given that Brian Walitt* [I originally misspelt this as Wallitt, here and in two other mentions], the lead author of the paper, has a long history of psychologizing complex chronic illnesses, perhaps the choice should not have been a surprise. Back when Walitt was tapped for this slot, many patients expressed dismay and noted his history of offensive statements regarding these conditions. Their concerns have been borne out.
This statement from the paper pretty much sums it up: “Effort preference is how much effort a person subjectively wants to exert.” And this one: “Together these findings suggest that effort preference, not fatigue, is the defining motor behavior of this illness.” And then there’s this statement from Walitt himself: “Rather than physical exhaustion or a lack of motivation, fatigue may arise from a mismatch between what someone thinks they can achieve and what their bodies perform.”
So the conclusion is that a patient’s subjective—and apparently inaccurate—feelings or thoughts about their capabilities, and nothing else, are the key drivers of ME/CFS. On its face, this assertion seems little different from the claims of the PACE authors that “unhelpful beliefs” about illness are a major cause of illness. Given Wallitt’s past claims, it is challenging to accept that these statements are just clumsy or inartful turns of phrase.
I’m not a statistician and can’t vet every argument made by Burmeister or commenters on the Science for ME forum. But their analyses have highlighted so many apparent departures from standard research practices in the conduct of the EEfRT and the presentation of the results that the validity and credibility of the study is now in question. Besides the fact that the EEfRT was designed for purposes completely unrelated to ME/CFS, Walitt and his colleagues seem to have ignored a central tenet: the tasks, even the “hard” ones, are supposed to be easy enough for everyone to complete without fatigue playing a role.
Here’s a key passage from the 2009 paper on “the effects of fatigue during the EEfRT”:
“An important requirement for the EEfRT is that it measure individual differences in motivation for rewards, rather than individual differences in ability or fatigue. The task was specifically designed to require a meaningful difference in effort between hard and easy-task choices while still being simple enough to ensure that all subjects were capable of completing either task, and that subjects would not reach a point of exhaustion.”
This was not apparently the case in the way the NIH applied the test. In fact, the data indicate that patients did have more problems completing the tasks than the healthy controls. That’s obviously a problem—and only one of many outlined in the critiques. Unfortunately, it seems that the EEfRT is likely to be used in studies of Long Covid as well. (I urge readers to review both Burmeister’s opus and the long thread on the Science for ME forum to assess the issues for themselves.)
**********
A related side note
In related news, Nath made the following statement during a podcast interview earlier this year: “The thing is that there’s so much overlap between that and long COVID, and the population affected by long COVID is so much larger, and the symptoms are so much more severe compared to ME/CFS, that we decided that what we should do is focus on long COVID.”
Really? On what basis did Nath decide that Long Covid symptoms “are so much more severe compared to ME/CFS”? Is he aware that the most severe patients could not even have dreamt of traveling to the NIH for two weeks to participate in his mammoth study? This assertion is mind-boggling—and a sign of serious problems in whatever is going on at the NIH complex in Bethesda, Maryland.
Agreed that the effort preference conclusions are not based in reality.
I still think too many people are reacting over a researchers opinion from seeing both of these illnesses first hand. Are they not allowed to an opinion in which they are justifying to the host why they are focusing on one over the other?
For example if you watch the ME NIH meeting from last May, there is no doubt the amount of professional respect shown for all.
Nath isn’t perfect, but he does have a point that picking apart these words from their original context is just as problematic.
Besides the point, the take away from that study holds ground with what is being found in long COVID. The NIH advisory meeting last June and a pathobiology meeting last September goes to show the research is still valid although it has numerous flaws such as effort preference and even Walter is trying to defend it which seems like a losing game in the long run.
Concur, and well said.
I still think there’s a physical mechanism (a physical problem) in the bodies of people with {PEM PESE PENE} which leads to bad consequences if energy is consumed in excess of some ceiling — which can’t exist if the basic theory underlying medical practice and research today is correct and complete, and can’t be measured — and that the more aware patients learn to keep their energy consumption under this ceiling. This learning is no more “preference” than a diabetic keeping their carb consumption below the level at which their blood sugar stays under control.
The patients who don’t learn to limit energy use soon enough, or are in situations where they have to use the energy anyhow to survive, are the ones who end up bedbound unmoving in dark silent rooms.
My conjecture remains that {PEM PESE PENE} is caused by bodywide progressive destruction or blocking of the channels through which oxygen enters each cell; that this destruction or blocking can only occur when the oxygen storage site at the entrance to a channel is empty (it’s normally occupied by an oxygen molecule, so exertion must have occurred); that the number of such channels on a cell sets a peak rate at which oxygen can enter that cell (think millisecond by millisecond); that other than certain performance athletes most of us would feel just fine if 80% or 90% of a normal person’s oxygen into cell peak rate were gone.
The “energy use ceiling” felt in {PEM PESE PENE} would then occur when the cells are asking for peak oxygen intake well above the rate their un-destroyed channels permit.
If zero channels were left, the cell would survive on diffused oxygen, but any use of energy would be by anaerobic metabolism, even though plenty of oxygen was there in adjacent blood vessels. That’s the bedbound unmoving patient in the dark silent room.
Those channels are proteins called myoglobin (muscle) and neuroglobin (certain neurons). Not the situation where an athlete overtrained, the cell wall broke, and whole myoglobin got into the blood. Not the situation where the globin is used entirely inside the cell. The situation where the myoglobin or neuroglobin is folded and pierces the cell wall, with the globin end capturing and storing oxygen off passing hemoglobin, and the channel bringing the stored oxygen into the cell on demand.
I speak blasphemy, of course. But that’s a discussion for another day.
I think the ME/CFS patient community has enough data to strongly suspect that participating in additional ME/CFS intramural research at the NIH that is controlled by either Brian Wallitt or to a lesser degree Avindra Nath may not be in the best interests of ME/CFS patients. Mr Wallitt seems to have an agenda that involves framing the illness in ways that hurt our prospects and our reputations. If the resources devoted to intramural research come at the expense of funding extramural research by less problematic researchers we might be better off if the NIH put less resources into intramural ME/CFS research. In any case letting the NIH be the source of authoritative opinions about ME/CFS for the medical community is very dangerous and likely contrary to our interests.
Nath and Wailtt should be made to listen to the coroner for two weeks from 22nd July 2024, where a young person suffered – as so many have and are still doing so. Explain how their paper would stop the abuse they will hear on a system built on the PACE trial.
I consider this paper from NIH and the PACE trial; part funded by DWP as giving misinformation or disinformation, and that I believe is a crime now? This needs to be taken seriously and I hope the enquiry will be robust and without bias and better than the one on the PACE trial. However I doubt they will clearly see the obvious and what many others point out.
Accountability for every death from ME and Ling Covid should now be seen as preventable and each one to be given the respect of an full enquiry including the attitude with wich they were treated.
>“When you doubt our intentions and pick apart every single word, you also tear us apart. It causes pain and suffering on both sides and demoralizes us and shatters our goals.”
Like they’ve done to every patient who has turned up to their doctors for decades complaining of fatigue and illness after trying to do normal tasks?
“everyone gets tired” “well you must be deconditioned” “nothing is wrong”
The patients goal is help. The result of the doctors actions is that the patient no longer trusts them or bothers. The patient IS shattered and suffers a lot. And the patient doesn’t get paid for it, they lose pay and life experiences.
Researchers should be held to a standard, and are paid. They shouldn’t be using phrases that make it worse on already suffering patients.
“Is he aware that the most severe patients could not even have dreamt of traveling to the NIH for two weeks to participate in his mammoth study?”
I would add that patients like me, who are profoundly impaired but considered to have “moderate” ME/CFS since we are still able to infrequently leave our homes, could also never have participated in this study.
And yes, Nath’s comments do feel like emotional blackmail. “If you ME/CFS patients aren’t sufficiently complementary about and grateful for our work, we will stop researching your illness and speak publicly about how you all are a pain in the ass.”
Where are the doctors that push ME patients to fight their fatigue and try harder?
I’ll tell you where they are not — they’re not feeding someone bite by bite because they can’t raise their arm, or hiding in their bedroom to tear off a piece of aluminum foil.
If only the consequence for callous, irresponsible characterization of ME that you describe here were for those researchers to – just for one day – experience the neuro-inflammation these patients endure daily. Only one day would be a mercy.
Feels like Wallitt snuck in ‘Effort preference’ as a last ditch attempt to do damage to ME/CFS. I read it and instantly knew it’s him intentionally stirring, because he just can’t let go of his debunked personal opinions
As for ‘effort preference’ …Whitney Dafoe more accurately describes it as ‘Harm Avoidance’. Because if we actually had a preference option that doesn’t worsen us later (which we don’t), we’d choose to do a massive amount of things. Unfortunately we are punished with physical harm for it.
Even if the effort tests aren’t appearing to cause harm. Like the lever tapping sounds innocuous enough. The neurons of ME patients poop out much faster than healthy controls do. That will be another reason why ME patients may ‘appear’ to be ‘preferring’ to reduce or stop the amount of effort. When neurones are depleted in energy, they try to conserve it. And in turn will be likely by not being able to reward the patient for the effort. So one would expect preference to utilise effort would reduce.
It’s much like the unrelated ‘willpower testing’ in healthy people. It turned out that ‘willpower’ was directly related to blood sugar levels. When subjects hadn’t eaten, their neurones didn’t have enough energy to function optimally, so pooped out much earlier, causing the subject to give up earlier in the willpower tests compared to when they were allowed a glucose drink. Similar will be what’s happening in the ‘Effort Preference’, simply not enough fuel being converted to energy by the neurones themselves.
The fact that this test is even in an ME/CFS study shows the utter ignorance, and arrogance of those who insisted it be in the study.
As for Nath, even though I like him personally and he has a kind soul, he would have to be one of the more ridged scientists I’ve had to correspond with. He’s like talking to a brick wall. He has little ability to question or speculate outside of the data. even with a massive abundance of anecdotal information. For example it comes to a point when an observant and prudent researcher suspects that there’s enough correlation to investigate if there is actual causation. Unfortunately Nath sadly lacks that ability. It’s like his brain is purely running on AI algorithms using previously collected data by others.
That said, he is good at bringing together the later stages of well collected evidence in already well researched areas. Unfortunately ME/CFS research isn’t previously well researched. But I wouldn’t give up on him yet, as he is thorough in the discipline of science. In time as the data grows he’ll be a great asset for ME/CFS..
“Successful completion of hard-task trials required the subject to make 100 button presses, using the non-dominant little finger within 21 seconds, while successful completion of easy-task trials required the subject to make 30 button presses, using the dominant index finger within 7 seconds.”
This is incredible! I can’t even imagine being able to move my fingers so fast! EVER!
If these feats are what the average person is able to do, then this explains why I struggled so hard to learn to play guitar but never got anywhere! :/ How many people can even move their non-dominant middle finger on its own without a lot of practice?
I’m much more handicapped than I had thought. 🙁
I would like to share the fact that there is 1 area not being tested and that is that those with M.E./CFS/Fibro have all had issues with atp production, which indicates a mitochondrial imbalance! I recently took a new test from a specific company that is a Heartrate Variability Test. In the test, on one day I made 42 energy and spent 62. The second test showed I made 24 energy and used 48. A normal human creates 300-350 units of energy per day. THIS is where Dr.’s can find quick useful info for their patients that ultimately proves they literally are not producing enough mitochondrial energy to function or provide “effort” or work. I have waited 34 years for any test proving I am exhausted when I wake, and exhausyed when I go to sleep. Sometimes, I cannot even produce enough energy to even sleep well. The Chiropractor/N.D. revealed that info to me. So please tell patients and Dr.’s to get their patients this test.