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Sunday, 30 September 2018

Egregious - the Richard M. Fleming Story

An RCT paper claiming to show harmful effects of a low-carb diet passed briefly over the internet on the weekend before being shot down in flames.
The title is:

Long‐term health effects of the three major diets under self‐management with advice, yields high adherence and equal weight loss, but very different long‐term cardiovascular health effects as measured by myocardial perfusion imaging and specific markers of inflammatory coronary artery disease.
The paper is published in Clinical Cardiology [edit: not Preventive Cardiology], and is free to access.
https://onlinelibrary.wiley.com/doi/abs/10.1002/clc.23047

[update: the paper above has since been retracted. Its Pubpeer discussion is here
https://pubpeer.com/publications/AA81ABA153565C2A238B191DFE0FB6 ]
[Update: the paper has been quickly republished here, in what may well be a predatory journal https://biomedres.us/pdfs/BJSTR.MS.ID.002006.pdf
Retraction Watch story here: https://retractionwatch.com/2018/11/13/a-convicted-felon-writes-a-paper-on-hotly-debated-diets-what-could-go-wrong/ ]

Three of the authors work at Fleming's medical imaging company in California, one is a deceased psychologist from Iowa, another is a pediatric nutritionist from New York and one is a Kellogg's employee from Illinois.
How this group was able to run a 12-month diet trial in 120 subjects is something of a mystery.

The conclusions:

One‐year body mass changes did not differ by diet (P .999). Effect sizes (R, R2) were statistically significant for all indices. Coronary blood flow, R (CI 95%) = .48 to .69, improved with low‐to‐moderate‐fat and declined with lowered carbohydrate diets. Inflammatory factor Interleukin‐6 (R = .51 to .71) increased with lowered carbohydrate and decreased with low‐to‐moderate‐fat diets.
Conclusions
One‐year lowered‐carbohydrate diet significantly increases cardiovascular risks, while a low‐to‐moderate‐fat diet significantly reduces cardiovascular risk factors. Vegan diets were intermediate.

First I'll consider all the good reasons to reject this study, but after that I'll do something we should always do, even for the worst study - take it at face value.

1) Lead author Dr Richard M. Fleming is a self-confessed and convicted felony fraudster who has admitted falsifying data in another RCT.

Fleming admitted to knowingly executing and attempting to execute a scheme to defraud Medicare and Medicaid healthcare benefit programs in connection with the delivery of and payment for healthcare benefits, items, and services, namely by submitting payment claims for tomographic myocardial perfusion imaging studies that he did not actually perform. Fleming also pled guilty to one count of felony mail fraud in violation of 18 U.S.C. 1341 and 2 for conduct relating to money paid him to conduct a clinical study of a soy chip food product for the purpose of evaluating health benefits. As Fleming admitted during his guilty plea, he received approximately $35,000 for conducting a clinical trial, but he fabricated data for certain subjects.
https://www.federalregister.gov/documents/2018/09/28/2018-21210/richard-m-fleming-denial-of-hearing-final-debarment-order

2) Fleming obtained Robert Atkins' medical records by deception and shared them with Neal Barnard of the vegan activist group PCRM in 2004, another unethical behaviour and one demonstrating that Fleming has a long-standing animus against Atkins and his diet.

https://theskepticalcardiologist.com/2016/12/18/what-does-the-death-of-robert-atkins-tell-us-about-the-atkins-diet/

Now, vegans can do research into this exact question with a high standard of rigour, see Chris Gardner's studies - one can certainly dispute the interpretation of some results, but not the results themselves. And I have reviewed a vegan diet study favourably here (dealing with another Fleming paper in passing) - good results are good results; I don't doubt these diets can have also cardiovascular benefits over the short-to-medium term, but question their long-term effects on mental health, reproductive health, dental health, joint health etc.

3) The trial protocol number on the paper links to a study that was completed in 2002. This explains how a convicted felony fraudster was able to conduct a study. The protocol was posted in 2006, 4 years after the study concluded, which seems unusual on the Clinical Trials website.


https://clinicaltrials.gov/ct2/show/NCT00324545

4) The study has 35 citations - 15 of these are to Fleming's own papers. This self-spamming, which helps boost an author's citation rate, is frowned upon by reputable journals. One of these references has the word "quantum" in the title. Other references are to news articles and book chapters. The low carbohydrate diet references are more than 15 years old. Ref 16 is curious as an anonymous reviewer is given credit for the wording of a paragraph of interpretation, surely a run-of-the-mill interaction with a reviewer.

5) The novel aspect of this paper may lie in the reference to that novel vegan touchstone, Neu5Gc. Pro-tip - if the vegan diet had a magic mechanism, you ought to know it already; some major low-carb mechanisms have been understood for generations. At this rate, if there is a magic mechanism for vegan health benefit, it will be discovered by a low-carb scientist.

We  now  know  that  these  food  choices  and  their  impact  are  at  least partially precipitated by the inflammatory effect of our diets based given our inability to convert Neu5Ac to Neu5Gc and our bodies immune response to the Neu5Gc present in animal protein. 

At this point, let's take the study at face value. the vegan diet avoided animal protein and Neu5Gc, the low carb diet probably included twice as much protein as the other diets (based on reference 6), but the low fat diet included more animal protein and Neu5Gc than the vegan diet.

One‐year lowered‐carbohydrate diet significantly increases cardiovascular risks, while a low‐to‐moderate‐fat diet significantly reduces cardiovascular risk factors. Vegan diets were intermediate.

So Fleming's own study, taken at face value, doesn't support the Neu5Gc hypothesis. In fact, it's unusual for the vegan diet to be inferior to the low-fat diet in any vegan study, and it's unusual for the low carb diet to be inferior to the low-fat diet in any low-carb study.

6) adherence to diets over 12 months was 100%. Of course, this is unheard of and entirely implausible; if honestly reported, it seems to show considerable gullibility or self-deception in the study team.


 That 100% of participants continued on their respective diet plans through a full year of dieting contrasts  sharply  with  much  of  diet  research  experience  with  drop outs  and  with  common experience with difficulties of dieting and remaining on diets. This success can be attributed to attention to well-established psychological principles of habit acquisition and extinction and of behaviour modification through Bandura [17] counseling.

Bandura's ethos seems sensible enough and appropriate for such a project, except perhaps when the people using it for counselling already believe that one approach is preferable to another.

7) the original report of the 2002 study (ref 6), if it is the same study, reports diet groups differently.





8) Implausible randomisation was the red flag that saw the PREDIMED study and many others retracted. Here randomisation of n=120 into 6 groups produced this result:


The  58  female  and  62  male  participants  were  randomly  assigned  to  equal  dietary  groups  by casting  a  die.  There  were  no  statistical  demographic  differences  between  group  assignments. There  were  no  statistically  significant  differences,  or  even  trends,  between  diet  groups  at  the initiation of the study. Since the groups were unequivocally randomized for all fifteen-baseline indices, statistical inference to the initial population, described by Table 1, is appropriate. 


9) Fleming et al state "A  four-month  post-intervention  analysis was obtained to determine post-intervention treatment, which has not previously been reported in the literature."

Post intervention status was in fact reported at 4 years by the Shai et al DIRECT study group.



10) the sponsor is listed as the Camelot Foundation. A search turned up this mention - Dr Fleming is the editor of a predatory journal, and the Camelot Foundation has little other existence online, it seems to be a 501(c)(3) legal tax-avoidance scheme within Fleming's own business.
https://www.omicsonline.org/editor-profile/richard-maximus-fleming/

11) Cardiovascular improvement by Fleming's medical imaging method correlates with improvement in the TG/HDL ratio. Taken at face value, although TG/HDL doesn't improve in Fleming's "low carb" arm, it does in most of the people reading this who have tried a low carb approach, so if Fleming's diagnostics are accurate this is not bad news. Interleukin 6 also improves during fasting but not a ketogenic diet in a 6-day study, but improves in a low carb diet vs a low fat diet in a 6 month study here (as there was at least one previous study in the literature that came to different conclusions from Fleming et al with regard to an outcome they highlighted, this should really have been cited).





Both LFD and LCD led to similar reductions in body weight, while beneficial effects on glycaemic control were observed in the LCD group only. After 6 months, the levels of IL-1Ra and IL-6 were significantly lower in the LCD group than in the LFD group, 978 (664–1385) versus 1216 (974–1822) pg/mL and 2.15 (1.65–4.27) versus 3.39 (2.25–4.79) pg/mL, both P < 0.05.

Taken at face value, Fleming's possibly fraudulent paper predicts cardiovascular benefit from a low carb diet if people get different results from the ones he claims to have produced, which is usually the case in other studies and in real life...


The question is, how did this paper pass peer review with all the red flags above? [edit]



Credit to @MacroFour and Ivor Cummins @FatEmperor for the links regarding Dr Fleming's colourful past.


9 comments:

George Henderson said...

Curiouser and Curiouser - Dr Fleming studied anti-matter for one year, and seems to have acted the part of James Woods acting the part of Max in Sergio Leone's Once Upon a Time in America.
https://www.imdb.com/name/nm6222842/

valerie said...

The abstract also has this gem:
"One‐year body mass changes did not differ by diet (P>.999)."

How can you possibly get P >.999?
Are we supposed to believe that all three groups had precisely the same weight loss after one year?

George Henderson said...

Wow.

I also call this implausible - the best TG/HDL ratio he reports is 2.4.
At this ratio, not great for this kind of study, small dense LDL will predominate, it's less likely that conditions for regression of CAD are present.

Bruce Wilson said...

How did the paper pass peer review? Perhaps Fleming owns the journal.

On a more serious note, you should be careful before accusing somone of fraud.

George Henderson said...

Hi Bruce,

thanks, but the FBI have provided the claim, and I am not accusing this paper of being fraudulent but of being poorly presented and reviewed, so that 1) the methods are not clear, 2) the citations are all over the place rather than addressing the unusual findings, and thus does not explain how another researcher would need to proceed to replicate the results.
The metabolic results are more explicable if the low carb arms were not particularly adherent, but are inexplicable in terms of the literature if adherence was 100% as stated and this was any normal low carb diet advice.
The date of the study, description of location and some other methods should have been supplied. Dr Fleming has contacted me but not contradicted any claim, only stressed the value of his work and the difficulty of running and publishing a private trial in general, as well as the hostile attitude of the soy industry, FDA, AHA etc (he didn't mention the FBI). I can sympathise with this - I'd just like to understand what we're seeing better, I just can't have 100% confidence in 100% adherence and convergence in a randomised trial without knowing a lot more. Dr Fleming also tells me that word and reference count explain some omissions, again I sympathise and know what he means, but I ask you, does it look like these were used wisely?
Reviewers...

Unknown said...

Is the method of measuring cardiovascular risk (perfusion imaging) a validated method of predicting cardiovascular risk? Or is it another well intentioned surrogate? He sounds like an interesting chap bet his talks are well presented.

George Henderson said...

One of his points is that it avoids dangerous imaging radiation. A criticism I've seen of it is, that it's not measuring CVD - no-one in this study was diagnosed with it, for example - but flow-mediated dilation, which is a situational adjustment of blood vessels. FMD is reduced in atherosclerosis, but can be limited without athero being present, and the higher nitrate content of various diets, different electrolytes, etc. could be enough to explain the differences.
I do think it likely that Fleming has good ideas about the causes of inflammation, at least in the context of the usual diet (e.g. I had an inflammatory reaction to beef, but not lamb, before I went keto, but have no such reaction to it now). I am willing to believe that this knowledge indeed benefits his patients. But wishful thinking in the way some things are being reported cannot be ruled out - no-one else has reported metabolic results anything like this from a low-carb diet, especially one with weight loss, and what that diet actually was like is going begging.

Unknown said...

Thanks for the response George. Love your work on here and on twitter. As someone with high cholesterol (LMHR) getting an idea of the total picture of health rather than one lipid metric has helped. I did consider getting a CAC but I don't fit the criteria really (too young), been trying to find other total health metrics to make sure I'm not going down a wrong path, which is why I was asking about that test.

keep at it.
John (UK)

Regret said...

Out of curiosity, are you able to find information on "The Camelot Foundation?" The limited online information that I can locate appears to show the organization went dormant sometime in the early 2000s, but I may be looking in the wrong places.