On 25 and 26 May of this year I wrote two posts about an acupuncture trial that, in my view, was dodgy. To refresh your memory, here is the relevant part of the 2nd post:
This new study was designed as a randomized, sham-controlled trial of acupuncture for persistent allergic rhinitis in adults investigated possible modulation of mucosal immune responses. A total of 151 individuals were randomized into real and sham acupuncture groups (who received twice-weekly treatments for 8 weeks) and a no acupuncture group. Various cytokines, neurotrophins, proinflammatory neuropeptides, and immunoglobulins were measured in saliva or plasma from baseline to 4-week follow-up.
Statistically significant reduction in allergen specific IgE for house dust mite was seen only in the real acupuncture group. A mean (SE) statistically significant down-regulation was also seen in pro-inflammatory neuropeptide substance P (SP) 18 to 24 hours after the first treatment. No significant changes were seen in the other neuropeptides, neurotrophins, or cytokines tested. Nasal obstruction, nasal itch, sneezing, runny nose, eye itch, and unrefreshed sleep improved significantly in the real acupuncture group (post-nasal drip and sinus pain did not) and continued to improve up to 4-week follow-up.
The authors concluded that acupuncture modulated mucosal immune response in the upper airway in adults with persistent allergic rhinitis. This modulation appears to be associated with down-regulation of allergen specific IgE for house dust mite, which this study is the first to report. Improvements in nasal itch, eye itch, and sneezing after acupuncture are suggestive of down-regulation of transient receptor potential vanilloid 1.
…the trial itself raises a number of questions:
- Which was the primary outcome measure of this trial?
- What was the power of the study, and how was it calculated?
- For which outcome measures was the power calculated?
- How were the subjective endpoints quantified?
- Were validated instruments used for the subjective endpoints?
- What type of sham was used?
- Are the reported results the findings of comparisons between verum and sham, or verum and no acupuncture, or intra-group changes in the verum group?
- What other treatments did each group of patients receive?
- Does anyone really think that this trial shows that “acupuncture is a safe, effective and cost-effective treatment for allergic rhinitis”?
In the comments section, the author wrote: “after you have read the full text and answered most of your questions for yourself, it might then be a more appropriate time to engage in any meaningful discussion, if that is in fact your intent”, and I asked him to send me his paper. As he does not seem to have the intention to do so, I will answer the questions myself and encourage everyone to have a close look at the full paper [which I can supply on request].
- The myriad of lab tests were defined as primary outcome measures.
- Two sentences are offered, but they do not allow me to reconstruct how this was done.
- No details are provided.
- Most were quantified with a 3 point scale.
- Mostly not.
- Needle insertion at non-acupoints.
- The results are a mixture of inter- and intra-group differences.
- Patients were allowed to use conventional treatments and the frequency of this use was reported in patient diaries.
- I don’t think so.
So, here is my interpretation of this study:
- It lacked power for many outcome measures, certainly the clinical ones.
- There were hardly any differences between the real and the sham acupuncture group.
- Most of the relevant results were based on intra-group changes, rather than comparing sham with real acupuncture, a fact, which is obfuscated in the abstract.
- In a controlled trial fluctuations within one group must never be interpreted as caused by the treatment.
- There were dozens of tests for statistical significance, and there seems to be no correction for multiple testing.
- Thus the few significant results that emerged when comparing sham with real acupuncture might easily be false positives.
- Patient-blinding seems questionable.
- McDonald as the only therapist of the study might be suspected to have influenced his patients through verbal and non-verbal communications.
I am sure there are many more flaws, particularly in the stats, and I leave it to others to identify them. The ones I found are, however, already serious enough, in my view, to call for a withdrawal of this paper. Essentially, the authors seem to have presented a study with largely negative findings as a trial with positive results showing that acupuncture is an effective therapy for allergic rhinitis. Subsequently, McDonald went on social media to inflate his findings even more. One might easily ask: is this scientific misconduct or just poor science?
END OF QUOTE
This and the previous post created lots of discussion and comments. However, the question whether the study in question amounted to scientific misconduct was never satisfactorily resolved. Therefore, I decided to write to the editor of ‘Ann Allergy Asthma Immunol‘ where the trial had been published. He answered by saying I would need to file an official complaint for him to address the issue. On 13 June, I therefore sent him the following email:
Thank you for your letter of 3/6/2016 suggesting I make a formal complaint about the paper entitled ‘EFFECT OF ACUPUNCTURE ON HOUSE DUST MITE…’ [ Ann Allergy Asthma Immunol 2016] by McDonald et al. I herewith wish to file such a complaint.
The article in question reports an RCT of acupuncture for persistent allergic rhinitis. It followed a parallel group design with 3 groups receiving the following interventions:
3. No treatment
There was a plethora of outcome measures and time points on which they were measured. A broad range of parameters was defined as primary endpoints.
The conclusion reached by the authors essentially was that acupuncture affected several outcome measures in a positive sense, thus supporting the notion that acupuncture is efficacious [“Symptoms and quality of life improved significantly and were still continuing to improve 4 weeks after treatment ceased.”] This conclusion, however, is misleading and needs correcting.
The main reasons for this are as follows:
· Despite the fact that the authors did many dozens of statistical tests for significance, they did not correct for this multiplicity of tests. Consequently, some or most of the significant results are likely to be false positive.
· Many of the positive results of this paper were not obtained by comparing one group to another but by doing before/after comparisons within one group. This approach defies the principle of a controlled clinical trial. For doing intra-group comparisons, we obviously do not need any control group at all. The findings from intra-group comparisons are prominently reported in the paper, for instance in the abstract, giving the impression that they originate from inter-group comparisons. One has to read the paper very carefully to find that, when inter-group comparisons were conducted, their results did NOT confirm the findings from the reported intra-group comparisons. As this is the case for most of the symptomatic endpoints, the impression given is seriously misleading and needs urgent correction.
On the whole, the article is a masterpiece of obfuscation and misrepresentation of the actual data. I urge you to consider the harm than can be done by such a misleading publication. In my view, the best way to address this problem is to withdraw the article.
I look forward to your decision.
END OF QUOTE
I had to send several reminders but my most recent one prompted the following response dated 7/11/ 2016:
- Our editorial team recognizes that this is not the best clinical trial we have published in the Annals of Allergy, Asthma and Immunology. However, neither is is the worst. As in most published research studies, there are always things that could have been done better to make it a stronger paper. Never-the-less, the criticism falls fall short of any sort of remedy that would include withdrawal of the manuscript.
- Regarding your accusation that the multiple positive endpoint resulted in the authors making specific therapeutic claims, our assessment is that no specific therapeutic claim was made but rather the authors maintained that the data support the value of acupuncture in improving symptoms and quality of life in patients with AR. We do not believe there was overreach in those statements.
- The authors’ stated intent was to show immune changes associated with clinical markers of improvement in the active acupuncture group compared to controls. The authors maintain (and our editors agree) that their data assessments were primarily based upon three statistical tests not “dozens” (as stated in your original letter of complaint). The power analysis and sample size calculations were presented to us and deemed adequate , making the probability of a type I error quite low.
- The authors acknowledge in their paper that there could be limitations to their data interpretation based upon potential disparities between intra- and intergroup comparisons. The editors felt their transparency was adequately disclosed.