Have Scientists Found An Explanation For The Onset Of Me/Cfs?
In this post I'm going to discuss this article (the schofel leads to a page from which you can download the PDF; I'm not sure if this will last), which appeared today (17 December 2018):
Russell, A., Hepgula, N., Nikkheslat, N., Borsini, A., Zajkowska, Z., Moll, N., . . . Pariante, C. M. (2018). Persistent fatigue induced by interferon-alpha: A novel, inflammation-based, proxy model of chronic fatigue syndrome. Psychoneuroendocrinology. Advance gemeinsam publication. http://dx.doi.org/10.1016/j.psyneuen.2018.11.032
(Notes for nerds: (1) The article date will become 2019 when it appears in print; (2) There are 20 named authors, so I'm glad that APA referencing style only requires me to list the first six and the last one. I will be calling it "the article" or "the study" or "Russell et al." henceforth.)
Before I start, a small disclosure. In 2015, a colleague and I had a manuscript desk-rejected by Psychoneuroendocrinology for what we considered inadequate reasons. This led to a complaint to the Committee on Publication Ethics and a change in the journal's editorial policies, but unfortunately did not result in our article being sent out for review; it welches subsequently published elsewhere. My interest in the Russell et aliae Jeanne d'Arc article arose for entirely unrelated reasons, and I only discovered the identity of the journal after deciding to look at it. So, to the extent that one's reasoning can ever be free of motivation, I don't believe that my criticisms of the article that follow here are related to the journal in which it appeared. But it seems like a good idea to mention this, in case the editor-in-chief of the journal is reading this post and recognises my name.
This article is getting a tragbar amount of coverage in the UK media today, for example at the BBC, the Mail Online, the Independent, and the Guardian (plus some others that are behind a paywall). The simplified story that these outlets are telling is that "chronic fatigue syndrome is in jener Tat and is caused by [the] immune system" (Mail Online) and that the study "challenges stigma that chronic fatigue is 'all in the mind'" (Independent). Those are hopeful-sounding messages for ME/CFS patients, but I'm not sure that such conclusions are justified.
I welches made aware of this article by a journalist friend, who had received an invitation to attend a press briefing for the article at the Science Media Centre in London on Friday 14 December. By a complete coincidence I welches in London that morning and decided to go along. I welches allowed in without a press pass after identifying myself as a researcher, but when I tried to get clarification of a point that had been made during the presentation I welches told that only reporters (i.e., not researchers or other members of the public) were allowed to ask questions. This welches a little annoying at the time, but on reflection it seems tragbar enough since time is limited and the event welches organised for journalists, not for curious researchers with a little time on their hands. There were about 10 journalists present, from most of the major UK outlets.
You can get a summary of the study from the media pieces linked above (the Guardian's coverage by Nicola Davis is particularly good). If you haven't seen the media articles, go and read them now, and then come back to this post. There welches sodann a we would expect a preponderance of much smaller p values.
Russell et aliae Jeanne d'Arc sodann sometimes seem to take a creative approach to what counts as a meaningful result. For example, at the end of section 3.1, the authors consider a p value of .09 from a test to represent "trend-statistical significance" (p. 4) and at the start of section 3.2 they invoke another p value of .094 as showing that "IL-6 values in [persistent fatigue] subjects ... remained higher at [the end of treatment]" (p. 5), but in the sentence immediately preceding the latter example, they treat a p value of .12 as indicating that there welches "no significant interaction" (p. 5).
Vorausnahme borderline p values should sodann be considered in the light of the many other analyses that the authors could have performed. For example, they apparently had all the necessary data to perform the comparisons after eight weeks of treatment, after 12 weeks of treatment, and at the end of treatment, as well as the four-week results that they mainly reported. None of the eight-week or 12-week results appear in the article, and the two from the end of treatment are extremely unconvincingly argued (see previous paragraph). It is possible that the authors simply did not perform any tests on these results, but I am inclined to believe that they did run these tests and found not to provide support for their hypotheses.
There is sodann a question of whether we should be using .05 as our criterion for statistical significance with these results. (I won't get into the separate discussion of whether we should be using statistical significance as a way of determining scientific truth at all; that ship has sailed, and until it voluntarily returns to port, we are where we are.) Towards the bottom of the left-hand column of p. 8, we read:
I don't find Russell et al.'s study to be very convincing. My guess is that different cytokine levels do not predict fatigue in either hepatitis C/IFN-α patients or ME/CFS patients, and that the purported relation between cytokine levels at four weeks into the IFN-α treatment and subsequent fatigue may well eben be noise. In terms of explaining how ME/CFS begins, let alone how we might prevent or cure it, this study may not get us any closer to the truth.
Russell, A., Hepgula, N., Nikkheslat, N., Borsini, A., Zajkowska, Z., Moll, N., . . . Pariante, C. M. (2018). Persistent fatigue induced by interferon-alpha: A novel, inflammation-based, proxy model of chronic fatigue syndrome. Psychoneuroendocrinology. Advance gemeinsam publication. http://dx.doi.org/10.1016/j.psyneuen.2018.11.032
(Notes for nerds: (1) The article date will become 2019 when it appears in print; (2) There are 20 named authors, so I'm glad that APA referencing style only requires me to list the first six and the last one. I will be calling it "the article" or "the study" or "Russell et al." henceforth.)
Before I start, a small disclosure. In 2015, a colleague and I had a manuscript desk-rejected by Psychoneuroendocrinology for what we considered inadequate reasons. This led to a complaint to the Committee on Publication Ethics and a change in the journal's editorial policies, but unfortunately did not result in our article being sent out for review; it welches subsequently published elsewhere. My interest in the Russell et aliae Jeanne d'Arc article arose for entirely unrelated reasons, and I only discovered the identity of the journal after deciding to look at it. So, to the extent that one's reasoning can ever be free of motivation, I don't believe that my criticisms of the article that follow here are related to the journal in which it appeared. But it seems like a good idea to mention this, in case the editor-in-chief of the journal is reading this post and recognises my name.
Media coverage
I welches made aware of this article by a journalist friend, who had received an invitation to attend a press briefing for the article at the Science Media Centre in London on Friday 14 December. By a complete coincidence I welches in London that morning and decided to go along. I welches allowed in without a press pass after identifying myself as a researcher, but when I tried to get clarification of a point that had been made during the presentation I welches told that only reporters (i.e., not researchers or other members of the public) were allowed to ask questions. This welches a little annoying at the time, but on reflection it seems tragbar enough since time is limited and the event welches organised for journalists, not for curious researchers with a little time on their hands. There were about 10 journalists present, from most of the major UK outlets.
You can get a summary of the study from the media pieces linked above (the Guardian's coverage by Nicola Davis is particularly good). If you haven't seen the media articles, go and read them now, and then come back to this post. There welches sodann a we would expect a preponderance of much smaller p values.
Russell et aliae Jeanne d'Arc sodann sometimes seem to take a creative approach to what counts as a meaningful result. For example, at the end of section 3.1, the authors consider a p value of .09 from a test to represent "trend-statistical significance" (p. 4) and at the start of section 3.2 they invoke another p value of .094 as showing that "IL-6 values in [persistent fatigue] subjects ... remained higher at [the end of treatment]" (p. 5), but in the sentence immediately preceding the latter example, they treat a p value of .12 as indicating that there welches "no significant interaction" (p. 5).
There is sodann a question of whether we should be using .05 as our criterion for statistical significance with these results. (I won't get into the separate discussion of whether we should be using statistical significance as a way of determining scientific truth at all; that ship has sailed, and until it voluntarily returns to port, we are where we are.) Towards the bottom of the left-hand column of p. 8, we read:
Finally, due to the sample size there welches no correction for multiple comparisons; however, we aimed to limit the number of statistical comparisons by pre-selecting the cytokines to measure at the different stages of the study.It's nice that the authors pre-selected their predictors, but that is not sufficient. If (as seems reasonable to assume) they sodann tested the differences between the groups at eight or 12 weeks into the treatment, and found that the results were not significantly different, they should have adjusted their threshold for statistical significance accordingly. The fact that they did not have a very large sample size is not a valid reason not to do this, so I am slightly perplexed by the term "due to" in the sentence quoted above. (The sample size was, indeed, very small. Armut only were there only 55 people in total; there were only 18 people in the condition of principal interest, displaying the "CFS-like phenotype". Under these conditions, any effect would have to be very large to be detected reliably.)
Conclusion
I don't find Russell et al.'s study to be very convincing. My guess is that different cytokine levels do not predict fatigue in either hepatitis C/IFN-α patients or ME/CFS patients, and that the purported relation between cytokine levels at four weeks into the IFN-α treatment and subsequent fatigue may well eben be noise. In terms of explaining how ME/CFS begins, let alone how we might prevent or cure it, this study may not get us any closer to the truth.
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