At home the kids current TV show of choice is How I Met Your Mother, supplanting Scrubs as the veg out show in the evening. Both shows are always on a cable channel somewhere and are often broadcast late at night. Late night commercials can be curious, and as I work on projects, I watch the shows and commercials out of the corner of my eye.

Law firms trolling for business seem common. If you or a family member has had a serious stroke, heart attack or death from Avandia, call now. The non-serious deaths? I suppose do not bother. One ad in particular caught my eye: anyone who developed ulcerative colitis or Crohn’s disease (collectively referred to inflammatory bowel disease, or IBD) after using Accutane, call now. Millions have been awarded.

My eye may have been caught because of my new progressive lenses, but I will admit to an interest in inflammatory bowel disease, having had ulcerative colitis for years until I took the steel cure. It also piqued my interest as these were three conditions among which I could not seen any connections. Accutane, ulcerative colitis, and Crohn’s. One of these is not like the other.

Accutane (its generic name is isotretinoin) is an anti-acne medication, released long after my puberty. The drug is chemically related to retinoic acid, a natural vitamin A derivative, and works in part by decreasing the production of sebum, not an issue with IBD.

Ulcerative colitis (UC) and Crohn’s have the same clinical presentation: lots of bloody diarrhea. Any resemblance stops there. Pathologically they are completely different diseases. Crohn’s can affect the entire GI tract, from the mouth to the rectum, and its hallmark is noncaseating granulomas. While considered an autoimmune disease, I have, for uncertain reasons, been drawn to the data that suggests the disease may be due to atypical mycobacteria. Wherever there are granulomas, some sort of infectious disease is often not far behind.

UC is limited to the colon, has a high risk of leading to colonic cancer, and its etiology is even more uncertain, perhaps also an autoimmune disease. The two illnesses have different rates of extraintestinal manifestations as well.  Besides the bloody diarrhea and abdominal pain, the two diseases have little in common except they can wax and wane for no damn good reason and when active are a compelling reason to know where every public toilet in the city is.

The Wikipedia pages for both diseases have nice ‘compare and contrast’ tables, and it is obvious the illnesses have little in common. UC and Crohn’s are as different as pulmonary tuberculosis and bronchiolitis obliterans with organizing pneumonia, so it would be most curious if an anti-acne medication could be cause either one, much less both.

Ulcerative colitis occurs in 35–100 people for every 100,000 in the United States, and Crohn’s in 6 to 7.1 per 100,000, and there have been over 13 million prescriptions given for Accutane, more if you add in the other brands of isotretinoin. So there are bound to be, by coincidence, some people who will get IBD around the time they get their Accutane. Like Guillain Barré and flu vaccine, the question is whether or not the risk is increased.

As one review pointed out:

Assuming 1) a background incidence of IBD in the US of approximately 45,000 cases per year, 2) the number of persons taking isotretinoin is approximately 400,000 per year, and 3) the total US population is approximately 306 million, the expected number of cases of IBD among isotretinoin users would be 59 cases per year (if there were no association between isotretinoin and IBD), or 0.01% of Accutane users. If more than 59 cases per year were observed in isotretinoin users, this would suggest a positive relationship between isotretinoin use and IBD. However FDA MedWatch reports include an average of only 14 cases per year.

There are a smattering of case reports on the pubmeds of people developing IBD around the time they started isotretinoin. A few cases of IBD waxed on the medication and waned when isotretinoin was stopped. Interesting, but given the variability of the disease, causality is suspect.

Is there a basic mechanism whereby isotretinoin would lead to IBD?

The mechanism by which (endogenous and exogenous) retinoids cause or exacerbate intestinal inflammation is not understood. Retinoic acid affects intestinal epithelial growth and is involved in cell repair and apoptosis. Retinoids also impair neutrophil chemotaxis, a mechanism involved in Crohn’s disease. The production of induced regulatory T cells (iTreg) and T helper 17 (Th17) cells is also controlled by retinoic acid — these also being involved in gut epithelial homeostasis.

But there is also basic science to suggest that retinoic acid has the potential to be protective for IBD.

Retinoic acid, a form of vitamin A, has been shown to enhance barrier function by increasing expression of numerous tight junction proteins such as occludin, claudin-1, claudin-4, and zonula occludens-1. Furthermore, from the standpoint of immune function, retinoic acid has been shown to be capable of inhibiting pro-inflammatory interleukin-17-producing T helper cell (Th17) responses, while augmenting anti-inflammatory regulatory T cell induction. Such responses would be more likely to prevent the development of IBD, as opposed to trigger it.

So maybe there is a supporting mechanism, and maybe there isn’t. The putative mechanisms can go either way, although since there is perhaps less IBD than expected in patients on isotretinoin, the sparse data suggests a protective effect. Whether any of the basic science is clinically applicable is unknown and doesn’t really explain why it could be associated with two such widely divergent illnesses. Still, there may be unknown mechanisms that would be hinted at by epidemiology.

There really is a paucity of data with a grand total of about 49 references on Pubmed. One study found a relationship with UC, but not Crohn’s (which, given the etiology and pathology, perhaps makes more sense):

Isotretinoin use and the risk of inflammatory bowel disease: a case-control study.
OBJECTIVES:
Isotretinoin is commonly prescribed for the treatment of severe acne. Although cases of inflammatory bowel disease (IBD) have been reported in isotretinoin users, a causal association remains unproven.
METHODS:
We performed a case-control study using a large insurance claims database. Incident cases of IBD were identified and matched to three controls on the basis of age, gender, geographical region, health plan, and length of enrollment. Isotretinoin exposure was assessed in a 12-month period before case ascertainment. Conditional logistic regression was used to adjust for matching variables.
RESULTS:
The study population comprised 8,189 cases (3,664 Crohn’s disease (CD), 4,428 ulcerative colitis (UC), and 97 IBD unspecified) and 21,832 controls. A total of 60 subjects (24 cases and 36 controls) were exposed to isotretinoin. UC was strongly associated with previous isotretinoin exposure (odds ratio (OR) 4.36, 95% confidence interval (CI): 1.97, 9.66). However, there was no apparent association between isotretinoin and CD (OR 0.68, 95% CI: 0.28, 1.68). Increasing dose of isotretinoin was associated with elevated risk of UC (OR per 20 mg increase in dose: 1.50, 95% CI: 1.08, 2.09). Compared with non-users, the risk of UC was highest in those exposed to isotretinoin for more than 2 months (OR 5.63, 95% CI: 2.10, 15.03).
CONCLUSIONS:
UC but not CD is associated with previous isotretinoin exposure. Higher dose of isotretinoin seems to augment this risk. Although the absolute risk of developing UC after taking isotretinoin is likely quite small, clinicians prescribing isotretinoin as well as prospective patients should be aware of this possible association.

and another study found no relationship:

Isotretinoin is not associated with inflammatory bowel disease: a population-based case-control study.
OBJECTIVES:
There is anecdotal evidence that isotretinoin use is associated with development of colitis. We aimed at determining whether there is an association between isotretinoin use and development of inflammatory bowel disease (IBD).
METHODS:
The population-based University of Manitoba IBD Epidemiology Database and a control group matched by age, sex, and geographical residence were linked to the provincial prescription drug registry, a registry that was initiated in 1995. The number of users and duration of isotretinoin use were identified in both IBD cases and controls.
RESULTS:
We found that 1.2% of IBD cases used isotretinoin before IBD diagnosis, which was statistically similar to controls (1.1% users). This was also similar to the number of IBD patients who used isotretinoin after a diagnosis of IBD (1.1%). There was no difference between isotretinoin use before Crohn’s disease compared with its use before ulcerative colitis.
CONCLUSIONS:
Patients with IBD were no more likely to have used isotretinoin before diagnosis than were sex-, age-, and geography-matched controls. Although there may be anecdotes of isotretinoin causing acute colitis, our data suggest that isotretinoin is not likely to cause chronic IBD.

One for, one against. Crockett et. al. reviewed all the data, such as it is, and applied the nine Bradford Hill criteria to the data. The conclusions were underwhelming for causality

In conclusion, the only evidence to support a causal association between Accutane and IBD consists of isolated case reports. These reports support a possible temporal association between isotretinoin and the development of IBD, though such observations may have resulted from chance, confounding, bias, and misrepresentation of the natural history of IBD. A causal relationship remains biologically plausible, but beneficial effects of vitamin A derivatives on intestinal injury have been reported as well. None of the other commonly accepted causal criteria are met. The lack of evidence does not necessarily indicate lack of a causal connection.

Doesn’t seem to be the kind of data that warrants millions to plaintiffs. To double check, I asked some drug company shills, er, I mean gastroenterologists, what they thought of the data. They were equally underwhelmed.

Dow Corning was in bankruptcy protection for years stemming from multibillion dollar lawsuits in the 1980’s and 90’s over the assertion that silicone breast implants lead to breast cancer and autoimmune diseases. Subsequently, after billions were spent and the company was bankrupt, it was then determined that silicone breast implants are associated with neither cancer nor autoimmune diseases. Oh. That’s different. Never mind.

Does isotretinoin lead to inflammatory bowel disease? Maybe. Maybe not. The facts to prove or disprove the association lean against, the odds are “Five to one against and rising…Anything you still can’t cope with is therefore your own problem.” It is hard to prove a negative, and money is being spent and awarded, independent of a reasonable set of confirming facts. Hopefully this will not be like the Dow cases, where “a tort system that allowed a few lawyers to extort billions of dollars using a dollop of junk science.” Although as is often the case with corporations, Dow Corning apparently did not act as the model of integrity. No one acts their best when there is money to be made.

As one reference on the topic noted

In most policy matters, scientific evidence is only one among a complex assortment of factors that interact to produce particular decisions.” A careful reading of the events, stakeholders, and outcomes in the silicone breast implant controversy reveals the social, economic, legal, political, and scientific factors involved “the practice of Federal regulation, the relationship between science and courts, the lack of consistently enforced professional standards in law, medicine and journalism.” A major lesson from this case also involves the role of the plaintiffs. The Houston lawyers’ relentless pressure with inconclusive medical facts on Dow Corning, along with their courtroom successes, demonstrates that “facts” alone are insufficient factors in determining truth.

He could have been writing about SCAMs in general: the facts, in quotes, are insufficient factors in determining truth indeed.

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Luis Fernando Verissimo, a Brazilian writer, once proposed “voodoopuncture”. Instead of going to the acupuncturist, you would be treated without leaving home. The voodoopuncturist would stick acupuncture needles in the voodoo dolls of you! I add that voodoopuncture could be outsourced to Haiti and/or China. It is a win-win-win situation!

– Leonardo Monasteri, Brazilian economist

As unbelievable as this might sound, “voodoopuncture” is no fiction at all.

The practice is called “Tong Ren healing,” and involves needling or hammering an acupuncture mannequin, as if it were a voodoo doll. The main Tong Ren “Master” in the US is an acupuncturist in the Boston area by the name of Tom Tam. He treats groups of terminally ill and debilitated patients in a deliverance ceremony that is noting but a revamped Taoist exorcism — only the clay or straw doll is replaced by a plastic mannequin:

Unfortunately, Tom Tam is not the only licensed healthcare provider who is treating patients with hocus pocus and crackpottery. There are over 30,000 other adepts of Traditional Chinese Medicine (TCM) in the US who practice medicine based on notions of health and disease that are rooted in paranormal and magical beliefs. Some of these practitioners take their delusions to the outer limits of absurdity: consider, for instance, “acutonics” and “colorpuncture” as described in these videos:

In anthropology of religion, the principles that underline the above practices are called “imitation” (e.g. using a doll to affect a person), and “correspondence” (e.g. using a sound to affect an object). They are the hallmarks of what is called “sympathetic magic,” meaning the belief that a person, or a thing, can be affected through something that represents it, or that has similar attributes.¹ The principle of magical correspondence in TCM is called wu xing (??) in Chinese, and is known as the Five Phases/Elements Theory in English. It can be summarized as follows:

1. Everything (including our organs) is ruled by one of 5 entities: Water (?), Wood (?), Fire (?), Earth (?), and Metal (?) — which are also the Chinese names for the planets Mercury, Jupiter, Mars, Saturn, and Venus.² For instance, the heart is ruled by Fire (Mars), the liver by Wood (Jupiter), etc.

2. There is a sympathetic connection (or resonance) between things that are ruled by the same entity (or planet). For example, the heart is connected with the color red, the direction south, the summer season, a bitter taste, and the feeling of joy — because all of these are ruled by Fire (Mars).

3. All 5 entities are interconnected and act on each other. Disease is understood as a result of either the over-, or under-influence of one entity on another. For example, digestive disruptions can be attributed to “Wood overacting on Earth.”³

The concept map (pictogram) of wu xing is often drawn by placing the 5 entities in a circle, and then connecting them according to the lines of influence. The connecting lines create a “pentacle,” or a pentagram within a circle (Image 1).

Image 1. The pictogram of wu xing. Image Source: acupuncture.com

This pictogram, unbeknownst to most TCM practitioners, is nearly identical to a sigil (magical or religious symbol) found in the Old Religion of Northern Europe, also known as “Wicca” (from the Old English word wicca, meaning a male sorcerer). The only difference between the Chinese and the Wiccan pictograms is that Wicca uses Air instead of Wood, and Spirit instead of Metal. The assignment of attributes (color, sound, taste, etc.) to each entity also varies slightly (Image 2).

Image 2. The Five Elements of Wicca.

According to the historian Cornelia J. de Vogel, this sigil was commonly used by the druids in the context of spell casting, and protection against evil and malevolence.⁴ It was likewise used in ancient Greece among Pythagoreans in the context of the cult of Hygieia (?????, Salus in Latin), the Greek patron of well-being, sanitation, and the prevention of disease (Image 3). Notably, their brotherhood (an esoteric cult based on numerology) also believed in resonance between numbers, tastes, colors, sounds, and the classical elements.⁵

Image 3. Pythagorean pentagram in Three Books of Occult Philosophy (Libri Tres de Occulta Philosophia) by Heinrich Cornelius Agrippa (1486 – 1535). The word ????? (Hygieia) is inscribed on the outer circle.

In Christian Europe, some of these pagan beliefs and symbols were culturally assimilated. For instance, the pentacle became the symbol of the five wounds of Jesus Christ.⁶ But with the advent of science and modernity, magical thinking, its symbolism, and all the rituals that accompanied it were discredited as superstition and ignorance.

Paganism and magic, however, weren’t so easily done away with — and they experienced a renaissance with the American Counterculture of the 1960s. Vietnam-era demonstrations with large hippie contingents famously mixed politics with occultism, magic, and witchcraft. For example, at the mammoth antiwar protest near Washington DC, in October 1967, demonstrators performed a mock-exorcism to levitate the Pentagon and cast out its demons.⁷

The magical notions of occult resonance and interconnectedness now find their zealots in the growing Neo-pagan and New Age movements. These revamped notions provide the conceptual basis for energy or vibrational medicine, which includes not only colorpuncture and acutonics, but also herbalism, reiki, reflexology, crystal therapy, magnet therapy, aromatherapy, acupuncture, and many other methods to channel putative “energy fields.”

A 2006 publication reported that in 2004, the annual spending on various channeling methods and alternative healthcare in the US was about $10 to $14 billion. It also estimated the number of Americans involved with New Age activities to be around 12 million.⁸

The popularity of these unscientific ideas and practices in the last decades has had a terrible impact on the public health policy in the US. One consequence is the licensing of non-physician acupuncturists in over 40 states. As George Ulett wrote in 2003, “is a travesty that in this time of scientific evidence-based medicine, acupuncture treatments are given to unsuspecting US patients by some 20,000 acupuncturists, posing as primary care doctors.”⁹ Be noted that their number has now increased to over 30,000.

Another consequence is the attempt to mainstream TCM and energy medicine by means of lobbying and political pressure. This leads to national and regional healthcare policies that are not based on science and evidence, but on consumerism and financial interest. As Steven Novella writes in Politics and Science at the HHS, this tends to “contaminate” science, and change the rules so that a popular modality can get a free pass. Novella adds that “modalities that require political pressure to force them into our health care system are those that are not backed by good science.”

An example of politically-motivated healthcare policy is the Federal Acupuncture Coverage Act of 2011 (H.R.1328), which is sponsored by House Representatives Maurice Hinchey (D-NY), Judy Chu (D-CA). It intends to “… provide for coverage of qualified acupuncturist services under part B of the Medicare Program, and to amend title 5, United States Code, to provide for coverage of such services under the Federal Employees Health Benefits Program.”

Yet another example is the current pressure put on the US Department of Health and Human Services by Judy Chu (a Representative for a district with a heavy concentration of acupuncturists and apothecaries) to make TCM and acupuncture part of the “Essential Health Benefits.” These benefits are a set of federally-mandated services under the Patient Protection and Affordable Care Act (PPACA).

This comes at a time when California State Senator Leeland Yee is trying to expand the scope of acupuncturists’ practice in his state to include the performance of “Chinese traumatology” — whatever that means.

If Maurice Hinchey, Judy Chu, Leeland Yee, and the TCM syndicate get their way, then revamped exorcism and sorcery will further infest the American healthcare system.

And if they don’t, I can already imagine voodoopuncturists in their cubicals in China, just like Leonardo Monasteri predicted: “…tap, tap, tap, can you feel me now?”

REFERENCES:

1. Frazer JG (Author), Fraser R (Editor). The Golden Bough: A Study in Magic and Religion: A New Abridgement from the Second and Third Editions. Oxford University Press, USA; Abridged edition. 1998.
2. Walters D. Chinese Astrology. Aquarian Press. 1987.
3. Maciocia G. The Foundations of Chinese Medicine: A Comprehensive Text for Acupuncturists and Herbalists. Churchill Livingstone. 1989.
4. de Vogel CJ. Pythagoras and Early Pythagoreanism. Assen: Van Gorcum; 1966.
5. Burkert W. Lore and Science in Ancient Pythagoreanism. Cambridge, MA: Harvard University Press; 1972.
6. Ferguson G. Signs and Symbols in Christian Art. New York: Oxford University Press, 1959.
7. Paglia C. Cults and Cosmic Consciousness: Religious Vision in the American 1960s, Arion, Winter 2003.
8. Pike SM. New Age and Neopagan Religions in America. Columbia University Press. 2006.
9. Ulett GA. Acupuncture: archaic or biologic? Am J Public Health. 2003;93(7):1037; author reply 1037-1038.

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Daryl Bem is a respected psychology researcher who decided to try his hand at parapsychology. Last year he published a series of studies in which he claimed evidence for precognition — for test subjects being influenced in their choices by future events. The studies were published in a peer-reviewed psychology journal, the Journal of Personality and Social Psychology. This created somewhat of a controversy, and was deemed by some to be a failure of peer-review.

While the study designs were clever (he simply reversed the direction of some standard psychology experiments, putting the influencing factor after the effect it was supposed to have), and the studies looked fine on paper, the research raised many red flags — particularly in Bem’s conclusions.

The episode has created the opportunity to debate some important aspects of the scientific literature. Eric-Jan Wagenmakers and others questioned the p-value approach to statistical analysis, arguing that it tends to over-call a positive result. They argue for a Bayesian analysis, and in their re-analysis of the Bem data they found the evidence for psi to be “weak to non-existent.” This is essentially the same approach to the data that we support as science-based medicine, and the Bem study is a good example of why. If the standard techniques are finding evidence for the impossible, then it is more likely that the techniques are flawed rather than the entire body of physical science is wrong.

Now another debate has been spawned by the same Bem research — that involving the role and value of exact replication. There have already been several attempts to replicate Bem’s research, with negative results: Galak and Nelson, Hadlaczky, and Circee, for example. Others, such as psychologist Richard Wiseman, have also replicated Bem’s research with negative results, but are running into trouble getting their studies published — and this is the crux of the new debate.

According to Wiseman, (as reported by The Psychologist, and discussed by Ben Goldacre) the Journal of Personality and Social Psychology turned down Wiseman’s submission on the grounds that they don’t publish replications, only “theory-advancing research.” In other words — strict replications are not of sufficient scientific value and interest to warrant space in their journal. Meanwhile other journals are reluctant to publish the replication because they feel the study should go in the journal that published the original research, which makes sense.

This episode illustrates potential problems with the  scientific literature. We often advocate at SBM that individual studies can never be that reliable — rather, we need to look at the pattern of research in the entire literature. That means, however, understanding how the scientific literature operates and how that may create spurious artifactual patterns.

For example, I recently wrote about the so-called “decline effect” — a tendency for effect sizes to shrink or “decline” as research on a phenomenon progresses. In fact, this was first observed in the psi research, as the effect is very dramatic there — so far, all psi effects have declined to non-existence. The decline effect is likely a result of artifacts in the literature. Journals are more inclined to publish dramatic positive studies (“theory-advancing research”), and are less interested in boring replications, or in initially negative research. A journal is unlikely to put out a press release that says, “We had this idea, and it turned out to be wrong, so never-mind.” Also, as research techniques and questions are honed, research results are likely to become closer to actual effect sizes, which means the effect of researcher bias will be diminished.

If the literature itself is biased toward positive studies, and dramatic studies, then this would further tend to exaggerate apparent phenomena — whether it is the effectiveness of a new drug or the existence of anomalous cognition. If journals are reluctant to publish replications, that might “hide the decline” (to borrow an inflammatory phrase) — meaning that perhaps there is even more of a decline effect if we consider unpublished negative replications. In medicine this would be critical to know — are we basing some treatments on a spurious signal in the noise of research.

There have already been proposals to create a registry of studies, before they are even conducted (specifically for human research), so that the totality of evidence will be transparent and known — not just the headline-grabbing positive studies, or the ones that meet the desires of the researchers or those funding the research. This proposal is primarily to deal with the issue of publication bias — the tendency not to publish negative studies.

Wiseman now makes the same call for a registry of trials before they even begin to avoid the bias of not publishing replications. In fact, he has taken it upon himself to create a registry of attempted replications of Bem’s research.

While this may be a specific fix for replications for Bem’s psi research — the bigger issues remain. Goldacre argues that there are systemic problems with how information filters down to professionals and the public. Reporting is highly biased toward dramatic positive studies, while retractions, corrections, and failed replications are quiet voices lost in the wilderness of information.

Most readers will already understand the critical value of replication to the process of science. Individual studies are plagued by flaws and biases. Most preliminary studies turn out to be wrong in the long run. We can really only arrive at a confident conclusion when a research paradigm produces reliable results in different labs with different researchers. Replication allows for biases and systematic errors to average out. Only if a phenomenon is real should it reliably replicate.

Further — the excuse by journals that they don’t have the space now seems quaint and obsolete, in the age of digital publishing. The scientific publishing industry needs a bit of an overhaul, to fully adapt to the possibilities of the digital age and to use this as an opportunity to fix some endemic problems. For example, journals can publish just abstracts of certain papers with the full articles available only online. Journals can use the extra space made available by online publishing (whether online only or partially in print) to make dedicated room for negative studies and for exact replications (replications that also expand the research are easier to publish). Databases and reviews of such studies can also make it as easy to find and access negative studies and replications as it is the more dramatic studies that tend to grab headlines.

Conclusion

The scientific endeavor is now a victim of its own success, in that research is producing a tsunami of information. The modern challenge is to sort through this information in a systematic way so that we can find the real patterns in the evidence and reach reliable conclusions on specific questions. The present system has not fully adapted to this volume of information, and there remain obsolete practices that produce spurious apparent patterns in the research. These fake patterns of evidence tend to be biased toward the false positive — falsely concluding that there is an effect when there really isn’t — or at least in exaggerating effects.

These artifactual problems with the literature as a whole combine with the statistical flaws in relying on the p-value, which tends to over-call positive results as well. This problem can be fixed by moving to a more Bayesian approach (considering prior probability).

All of this is happening at a time when prior probability (scientific plausibility) is being given less attention than it should, in that highly implausible notions are being seriously entertained in the peer-reviewed literature. Bem’s psi research is an excellent example, but we deal with many other examples frequently at SBM, such as homeopathy and acupuncture. Current statistical methods and publication biases are not equipped to deal with the results of research into highly implausible claims. The result is an excess of false-positive studies in the literature — a residue that is then used to justify still more research into highly implausible ideas. These ideas can never quite reach the critical mass of evidence to be generally accepted as real, but they do generate enough noise to confuse the public and regulators, and to create an endless treadmill of still more research.

The bright spot is that highly implausible research has helped to highlight some of these flaws in the literature. Now all we have to do is fix them.

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