Even as the National Institutes of Health (NIH) intramural study on myalgic encephalomyelitis (ME) was getting underway in 2016, people with the disease were already concerned about its design, lack of urgency, and potential bias. Brian Vastag, one of the 17 participants who dedicated weeks of his time and risked worsening of his condition to take part in the study, traveled across the country to the main NIH campus in Bethesda, Maryland. Vastag was joined by his partner, the late Beth Mazur, who he says gave input about the study’s design to the lead clinical investigator, Brian Walitt.
“I was patient number four,” Vastag said, “By the time I got there, we could kind of tell, the pace that they were going at, that the study was going to take forever.” Mazur, the co-founder of the advocacy group #MEAction, predicted the small study would take five years to complete. “That’s not acceptable,” Vastag remembers her telling Walitt. Due to delays from the Covid-19 pandemic, it ended up taking eight years.
After the study’s findings were published last month in the journal Nature Communications, some patient-advocates and experts in the ME community say their worst fears about this $8 million, eight-year research project were realized. In interviews with The Sick Times, advocates and experts shared concerns about which patients were included in the research, the tests used to evaluate those patients, and a potential underlying bias among the scientists that may have informed the paper’s conclusions.
The Sick Times reached out to the NIH for comment but did not hear back by the time of publication.
These criticisms contradict mainstream media coverage of the study, which has presented it as a landmark paper. Articles in outlets such as the New York Times and STAT highlight that the NIH found many biological irregularities between people with ME and healthy volunteers, such as issues in the immune and nervous systems. Indeed, some “very bright, very hardworking” researchers contributed to the study, leading to detailed findings about how ME impacts different parts of the body, said Jaime Seltzer, director of scientific and medical outreach at #MEAction.
However, for Seltzer, like other members of the ME community, these findings are overshadowed by concern that the NIH paper interprets its data in a way that suggests the disease is psychosomatic, or all emerging from patients’ heads. The study reads like “an argument between the biological and psychosomatic schools” of ME research, Seltzer said. Both she and Vastag compared it to Frankenstein’s monster, an attempt to merge two different interpretations of the research results.
In identifying the “psychosomatic” argument, the study’s critics point to a lack of focus on post-exertional malaise, a core symptom of ME. Critics also highlight the NIH’s use of “effort preference,” a construct describing motivation in psychiatric conditions that has not previously been used for ME. Some ME experts and advocates suggest that Brian Walitt, the study’s first author, could be a potential source of the psychosomatic interpretation due to his prior research and commentary.
Doctors who disbelieve patients may use this study to back up their arguments, some advocates warn. Some have gone as far as calling for the study to be corrected or even fully retracted. Todd Davenport, a researcher and physical therapist at the University of the Pacific who specializes in ME, is one of those calling for the study to be retracted. The paper features “erroneous conclusions” that, to him, represent misconduct and should not have passed peer review, Davenport told The Sick Times.
“This recent study fits into a long-standing pattern of the NIH marginalizing and psychologizing ME/CFS,” said public health researcher and patient-advocate Elise Racine in an email. To move forward, she would like to see the NIH “acknowledge the flaws and limitations” of this research, conduct larger studies that better represent people with ME, and significantly increase its budget for this disease.
“As the Covid-19 pandemic gives rise to a growing wave of individuals living with energy-limiting illnesses, the time for action is now,” Racine said.
Unrepresentative sample of patients
One of the study’s greatest flaws, according to ME experts and advocates, was that the NIH chose to study a small group of patients who are not representative of most people with ME. The agency tested just 17 out of over 200 patients whom researchers reviewed as potential candidates, a tiny sample for a very complex disease.
In selecting patients, the NIH excluded people with more severe forms of ME. To participate in the study, patients had to travel to D.C. for extensive testing — a difficult prospect for people with severe symptoms. Dr. Lucinda Bateman and Dr. Brayden Yellman at the Bateman Horne Center flagged this issue in a statement, writing that the study “fell short by not including enough patients who are moderately to severely ill.”
Another issue with the patient selection was that the NIH team disqualified patients diagnosed with other chronic diseases in addition to ME, Seltzer said. This process led the study to focus on unusual patients, because “the vast majority of people with ME” also have other chronic illnesses, she said. Four of the 17 participants recovered between the initial study testing and publication, which further struck Seltzer as unrepresentative.
In a webpage responding to questions about the study, the NIH explains that the sample size was so small in part because the team had to end its in-person testing in early 2020 due to the start of the Covid-19 pandemic. It also explains that the team wanted to observe people who had only ME and were sick for a shorter period to examine underlying biological issues.
This recent study fits into a long-standing pattern of the NIH marginalizing and psychologizing ME/CFS.
elise racine
Conversely, some patient-advocates say the small group of participants should have been selected with more rigorous criteria. To take part in testing, the patients needed to meet at least one of three commonly-used definitions of ME/CFS and demonstrate post-exertional malaise (or worse symptoms after exertion, a key symptom of the disease). The NIH should have used a framework called the International Consensus Criteria, published in 2011, that is stricter about screening patients for dysfunction after exertion, said advocate Colleen Steckel, who has also written about the study on her Substack.
To Steckel, any study that does not use these criteria may have been based on people who don’t actually have ME, but rather have similar symptoms from a different underlying issue. “Imagine you had lung cancer,” she said, “and they told you they were going to select people with a chronic cough, and you were going to be expected to have those results apply to you with lung cancer.”
While ME advocates and researchers disagree about how the NIH should have selected patients for such an in-depth study, they agree that the 17 patients chosen are a small, not necessarily representative sample of a complicated disease.
“The selection criteria biased the whole study, and therefore all of its conclusions are potentially suspect,” Seltzer said.
Controversial testing choices
With the small number of patients who participated in the study, the NIH researchers made errors in the tests they used and how they interpreted results, experts and advocates say. The research team performed a wide variety of tests with the purported intent of “doing mechanistic work to get to the bottom of ME,” but the study “fell far short” of that goal, Davenport said.
For Davenport and other outside researchers, one significant issue is the study’s failure to use a two-day cardiopulmonary expertise test, or CPET. In this test, patients exercise while scientists measure how well their hearts and other bodily systems are working. To measure ME, doing this test two days in a row is important because patients demonstrate post-exertional malaise on the second day, Davenport said.
On their FAQ page, the NIH explains that they avoided a two-day CPET to “reduce stress and other harmful effects” for participants; instead, the study used a single-day test to induce post-exertional malaise, which researchers then measured through other tests, the agency claims. While the impulse to avoid making symptoms worse is understandable, this testing choice means that the study is out of line with established ME research practices, Davenport said. The researchers also failed to measure problems in how people with ME produce energy — a hallmark of the disease — he said.
Another common criticism of the study is the NIH’s use of a construct called “effort preference,” which they assessed with a test developed to evaluate how people with psychiatric conditions make decisions. In this test, people press buttons in a game to simulate choosing between an “easy task” and a “hard task.”
The effort preference test has never been used for ME before and is designed for mental disorders rather than chronic diseases, writer and ME advocate Mary Dimmock said. In fact, in the original paper describing this test, its authors note that the test is not set up to measure “differences in ability or fatigue.” Yet the NIH added this test to its study in order to measure fatigue, according to its FAQ page.
In the study, the patients opted for “easier tasks” than people included as healthy controls, but the two groups performed similarly on the test by other measurements. The NIH researchers interpreted this result as a demonstration of patients choosing to pace to avoid expending energy. However, outside commenters like Dimmock and Davenport say this is an incorrect interpretation: they suggest participants with ME instead had a harder time completing the test due to less physical capacity to press buttons.
“The selection of this outcome measure suggests the mindframe of the study team, of conflating post-exertional disablement with a psychological or psychiatric disorder,” Davenport said. Users on the “Science for ME” forum are organizing to call for a formal correction to this part of the study.
The NIH additionally made errors in its examination of the autonomic nervous system by failing to include some tests that could have demonstrated dysfunction, said Lauren Stiles, a neurology professor at Stony Brook University and director of Dysautonomia International, which advocates for people with autonomic nervous system disorders. The researchers suggested that ME is a “central nervous system problem,” or driven by the brain and spinal cord, without fully assessing other parts of the nervous system, she said — an error that she views as indicative of other flaws in the tests used.
“It’s very convenient to attribute [symptoms] to a functional deficit in the brain,” as this study does, “when you haven’t looked at the entire structural system,” Stiles said.
Furthermore, in analyzing the results from their testing, the NIH recruited healthy volunteers to serve as controls in the study, rather than people who are not physically active for other reasons, as is typical for ME research, Davenport said. This comparison is important because people with ME may otherwise appear to be suffering from “deconditioning,” a process in which the body changes due to a lack of physical activity, he said.
It’s very convenient to attribute [symptoms] to a functional deficit in the brain… when you haven’t looked at the entire structural system.
lauren stiles
Biased researcher in charge?
Many of these concerns with the study were clear years ago: as far back as the research’s initial setup in 2016, people with ME pushed back on not only the study’s design, but also on its first author and clinical investigator, Brian Walitt. They cited his past research, opinion pieces, and interviews, which they said demonstrated bias against ME and related diseases and conditions.
In one paper from 2015, Walitt claimed chronic fatigue syndrome and fibromyalgia were “somatoform” (i.e. psychological) illnesses. Similarly, in a 2013 opinion piece on fibromyalgia, Walitt wrote that “psychological issues are clear” and referred to patient advocates who objected to that perspective as “societal forces” seeking to interfere with research.
The group MEadvocacy compiled a petition letter with over 700 signatures in February 2016, demanding that then-NIH director Francis Collins “immediately cancel” the intramural study. They wrote: “If NIH follows through with this study as is it will propagate, aggravate, and add immeasurable harm to… ME patients.” The group also sent a follow-up letter, writing, “The choice of Dr. Brian Walitt as lead clinical investigator is an outrage… certainly the NIH had knowledge of Dr. Walitt’s beliefs yet, chose to put him in charge.”
In an NIH call with advocates in March 2016, ME patient advocate Wilhelmina Jenkins also asked about Walitt’s bias. Walitt responded by saying that ME is a “biological disorder” and said if ME/CFS is all in your head, “it’s only because your head is part of your body.” The response was criticized by many people with ME and did not ease their concern about his bias in the study.
“Putting Walitt in charge of this study despite his glaring bias against ME patients is just one item on a long list evidencing an atrocious track record on the part of the federal health agencies, including NIH, when it comes to ME,” attorney, writer, and ME patient advocate Jeannette Burmeister wrote to The Sick Times.
Burmeister hypothesized that some of the most harmful parts of the study, including the notion of “effort preference,” likely came from Walitt himself. “When you compare the psych language historically used by Walitt with the language of the paper or his quotes in the NIH press release and media interviews, it tracks 100%.”
Vastag, who took part in the study as a participant, agreed that the language likely came from Walitt and said that the ME community was right to be worried about him leading the study. This psychological perspective contradicts the paper’s biological findings, Vastag said.
Vastag had originally hoped the study would help rebuild trust between the patient community and the NIH, he said. But after seeing patients’ reactions to it, he doesn’t think that happened either.
What’s next for the NIH on ME?
Stephen Smith, who tracks clinical trials on the Twitter/X account “Post-Viral Trial News,” said the eight-year intramural ME study shows a severe lack of urgency about understanding and finding cures for the disease. He’d like to see the NIH start clinical trials as soon as possible; other advocates are skeptical that the agency will ever provide meaningful ME results.
The NIH team suggested that a type of cancer drug called immune checkpoint inhibitors might be a viable target for ME. Smith said he’s spoken with scientists interested in pursuing these in potential research, but that many scientists are writing off the NIH because of how slow they are to support promising research.
Seltzer also expressed interest in trials of immune checkpoint inhibitors, while Stiles suggested that other researchers may follow up on the NIH’s neurological and immune system findings. To make these findings “meaningful to the millions of people diagnosed with ME/CFS,” the results need to be replicated in larger, more representative groups of patients, she said.
“ME has been underfunded,” Smith said, “But even when they spend the money, they don’t spend it well.” Researchers and advocates have similarly criticized RECOVER, the NIH’s large-scale Long Covid study that has spent much of its initial $1.15 billion in funding on observational research.
Because of the NIH’s track record with ME, Sam Nolen, an engineer with ME, doesn’t want to see any further ME research from the NIH, he said. The intramural study was “a conscious and malicious effort to harm ME/CFS patients by delegitimizing their disability,” he said. “I put my hope for progress in privately commissioned research and in patient-led enterprises. The ideal outcome for me would be a Congressional decision that the NIH has shown such corruption in its attention to ME/CFS that, in the future, all its funds for that disease should be appropriated by an independent research collaborative.”
Burmeister worries that the same kind of psychological labels like “effort preference” highlighted in the intramural ME study could appear in future studies, since Walitt is the principal investigator for ongoing intramural studies in Long Covid and Gulf War Illness at the NIH.“Chances are that NIH will build on their false effort-preference claim,” she warned.
In the conclusion of a 2021 review paper anticipating “post-Covid-19 syndromes,” Walitt and co-author Elizabeth Bartrum wrote that they expect the “most common” post-Covid disease will feature a “persistent mix of somatic and psychiatric complaints in the absence of a clearly observable cause.”
Editor’s note, March 19, 4:19 PM ET: This story has been updated to clarify Brian Walitt’s role in the study.
Betsy Ladyzhets and Miles Griffis collaborated on reporting and writing this story. We thank veteran ME journalists Julie Rehmeyer and David Tuller for taking time to read over a draft and provide feedback.
All articles by The Sick Times are available for other outlets to republish free of charge. We request that you credit us and link back to our website.
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