Tuesday, September 13, 2016

After 11 years, you couldn't find a better study

"...for the purposes of popular discourse, it is not necessary for homeopaths to prove their case. It is merely necessary for them to create walls of obfuscation, and superficially plausible technical documents that support their case, in order to keep the dream alive in the imaginations of both the media and their defenders." 
--Ben Goldacre

If you remember my posting from the other day concerning the Banerji Protocol and homeopathy in general, one of my biggest sticking points is the Avogadro constant/number.  As I stated, "ignoring the Avogadro constant violates the principles of chemistry, pharmacology, and the laws of physics by diluting their starting remedies to nonexistence."

In a subsequent conversation, I delved a bit deeper concerning the "law of  infinitesimals" noting that Avogadro's number is not "just an arbitrary convention" as many proponents believe.
Harriet Hall of SBM counters an oft cited paper, Extreme homeopathic dilutions retain starting materials: A nanoparticulate perspective, concerning extreme or "ultramolecular dilutions" (as noted by some science writers) retaining measurable amounts of their original substance. According to Hall, This small study was not blinded, lacked a control group, and (as far as I know ATM) has never been replicated.
Even if nanoparticles are found in homeopathic remedies, the amount is too tiny to expect any effect on human physiology, and the remedies have not been shown to have any therapeutic effect.
Just on this issue alone - that homeopathic dilution is unlikely to have even a single molecule of original remedy in it other than contaminants carried over from the serial dilutions - is enough to discount the whole notion.  But there is an ethical issue to this point as well.
Let this sink in. Dr. Spence has just said that he thinks it’s acceptable to give something to patients and tell them that it will help them when it certainly will not. Homeopathic remedies are, after all, nothing more than water or whatever solvent is used to dilute the original remedy into nonexistence. (Sometimes ethanol is used.) Dr. Spence knows that. Dr. Spence agrees that that’s what homeopathy is. That’s why what I find even more disturbing is the level of contempt for the “worried well” that Dr. Spence’s post about homeopaths demonstrates. Oh, sure, he isn’t open about it. He disguises it quite well as compassion. But in reality what he is doing is saying, in essence, “I know homeopathy is quackery. I know there’s nothing to it. But homeopaths are such caring people and these worried well are so hard to deal with. Might as well give them water disguised as real medicine, all packed up into little sugar pills, tell them it will cure what ails them, and maybe things will be OK.” The subtext is, of course, that it will also get the “worried well” out of the doctor’s hair.
While much more can be said to this point, we will leave at that.  This "doctor" (among many others) has no problem selling water.  While the placebo effect may have its uses, selling it for profit is not one of them.
A second ethical issue, although not specifically related to the current conversation and one I have not explored beyond the work of Jim Humble and Kerri Rivera concerning MMS, clinical trials in Third World countries.
At the same time, homeopathy and homeopaths appall me. There are many reasons for this, not the least of which is how anyone claiming to have a rational or scientific viewpoint can fall so far as to twist science brutally to justify magic. Worse, homepaths [sic] and physicians sucked into belief into the sorcery that his homeopathy are driven by their belief to carry out unethical clinical trials in Third World countries, even on children. Meanwhile, time, resources, and precious cash are wasted chasing after pixie dust by our own government through the National Center for Complementary and Alternative Medicine (NCCAM). So while I laugh at the antics of homeopaths going on and on about the “memory of water” or quantum gyroscopic models” in order to justify homeopathy as anything more than an elaborate placebo, I’m crying a little inside as I watch.
As to "nanoparticles",

while I am sure it is a fascinating concept, it is a modern day notion to get around the bullshit of "water has memory", it doesn't fly. (Keep in mind, this is a conversation unto itself and may be explored at a later date as it also touches on the "science was wrong before" gambit.)
,,,the concept that homeopathy works through “nanoparticles.” Of course, like so many things that quacks appropriate for themselves, like quantum theory and epigenetics, nanoparticles are a real phenomenon with many therapeutic promises. Unfortunately, the versions of nanoparticles described by Bell are related to real nanoparticles as scientists currently understand them only by coincidence. So, as you will soon see, what we have here is an NIH-funded investigator (funded through NCCAM) teaming up with Mary Koithan to write a mass of pseudoscience defending homeopathy and proposing a mechanism by which it might work. Think on that a moment as I delve into the actual paper. In fact, even though this paper is open-source (which means that you can read the entire thing for yourself), I think I’ll nonetheless lay down the abstract, because it is truly a thing of quackademic beauty,,,
So lets get to the heart of the matter, if we ignore that there is no plausible manner for which homeopathy to work,,,

I'm not exactly sure why you feel this paper criticizing Shang is so ground breaking.  First Shang (2005) is published in the Lancet, a top-tier medical journal.  Second, had this paper really shown anything conclusive about Shang's review or about reviews on homeopathy, it would have been published directly in Lancet, but it wasn't. It was published in an obscure British journal, Homeopathy; impact factor of less than 1.  Third, as I mentioned in my initial response, the authors don't even see the difference between a homeopathic elixir and a vaccine.  [FYI::  I refer quite frequently to the "original" Rutten response to Shang as there is nothing written concerning the aforementioned title.  It seems to be a sort of summary of Rutten's prior work concerning Shang.]

That aside, what I find telling is Rutten's "big pHARMA" gambit considering he ignores "big altie" in his criticism:

I mean, this is the Lex Rutten of the Association of Dutch Homeopathic Physicians?  Is it not?  If he wants to talk bias he needs to look at himself first.  As Paul Wilson notes, Shang allows for homeopathy becoming a tool in health care if warranted by science.  That IMO is not the stance of an individual shilling for "big pHARMA".
"We emphasise that our study, and the trials we examined, exclusively addressed the narrow question of whether homoeopathic remedies have specific effects. Context effects can influence the effects of interventions, and the relationship between patient and carer might be an important pathway mediating such effects. Practitioners of homoeopathy can form powerful alliances with their patients, because patients and carers commonly share strong beliefs about the treatment’s effectiveness, and other cultural beliefs, which might be both empowering and restorative. For some people, therefore, homoeopathy could be another tool that complements conventional medicine, whereas others might see it as purposeful and antiscientific deception of patients, which has no place in modern health care. Clearly, rather than doing further placebo-controlled trials of homoeopathy, future research efforts should focus on the nature of context effects and on the place of homoeopathy in health-care systems."
And, as Orac notes concerning the issue of bias in general,
,,,he [Rutten] is a member of a group of homeopaths who tried to introduce the concept of “plausibility bias,” in which scientists tend to be biased towards mechanisms that have at least a modicum of plausibility to them (very much unlike homeopathy). Of course, my response to Dr. Rutten and his colleagues is, “You say that as though it were a bad thing!” I promptly renamed “plausibility bias” as “reality bias,” which is far more accurate, given that homeopathy is far more akin to sympathetic magic than it is to science-based medicine.
In other words, "One of the things that distinguishes evidence-based medicine (EBM) and science-based medicine (SBM) is how the latter takes into account prior probability that a therapy is likely to work when considering clinical trials."
Basically, what Fisher is doing is a tried-and-not-so-true (albeit frequently effective) technique of obfuscation by arguing that, since EBM/SBM is not perfect that “alternatives” are needed and that SBM/EBM practitioners don’t practice what they preach. He even tries to turn the most potent criticism of homeopathy (namely its utter lack of plausibility) against SBM by claiming that plausibility is just a “bias”,,,The answer is not to lower the standard of evidence to be “fair” to magical thinking like homeopathy; the answer is to maintain a high standard of evidence and use it to decrease the use of non-EBM/SBM medicine,,,. [The Fisher paper being discussed.]
More on plausibility, and I will readily admit that I deny homeopathy on the limits set by the Avogadro constant. "They willfully reject the concept that extraordinary claims require extraordinary evidence, and homeopathy is nothing if not a highly extraordinary set of claims."  [An interesting bit about sympathetic magic as well.]
In other words, clinical evidence could make us question the rest of the “crossword puzzle” but only if it’s clinical evidence that is so extraordinary in result, quality, and quantity that it starts to rival the existing evidence from multiple disciplines that do not support homeopathy. No such evidence exists for homeopathy, and, in fact, the overall weight of the clinical evidence is consistent with homeopathy not working any more effectively than placebo. Indeed, Ruten et al wrongly relegate the question of how homeopathy could work to a secondary question, and here’s why: When, for a therapy to work the very laws of physics would have to be, as I say so often, not just wrong but spectacularly wrong, the question of how it could work is not secondary. This is in marked contrast to drugs (which inevitably work by either binding to a biological molecule or otherwise reacting somehow), in which case not knowing the exact mechanism is not as concerning. Even cases like the discovery that H. pylori causes duodenal ulcers is not a refutation of this principle with respect to homeopathy. After all, as implausible as the hypothesis that it was a particular bacterial species that was responsible for peptic ulcers in many cases, it did not require the violation of the laws of physics to imagine that a bacterial infection could somehow cause ulcers.
Steve Novella presents a good definition here,
A thorough basic and clinical science analysis of a medical claim can be summarized by the term “plausibility,” or “prior probability” if you want to put it into statistical terms. When we say a certain belief is plausible we mean it is consistent with what we know from the rest of science. In other words, because of the many weaknesses of clinical evidence, in order for a therapy to be generally accepted as part of SBM it should have a certain minimal supporting clinical evidence and overall scientific plausibility.
If we consider the SBM criteria above, we can summarize homeopathy by saying it has extreme implausibility and the clinical evidence shows lack of efficacy. It should not work, and it does not work. There is no legitimate controversy about this. The only think keeping homeopathy alive are delusional proponents and a public (including many regulators) who do not know what homeopathy truly is.
But prior, in the "introduction", Rutten is bitching about the 8 studies chosen.

What Rutten et al fail to understand, meta-analysis depends on the choice of trials used. That’s exactly the reason why the criteria for choosing trials to include in a meta-analysis are so important and need to be decided on before the study is done. If they aren’t, then investigators can cherry pick studies as they see fit. [Which is exactly what many criticism do.] That’s also exactly why the criteria need to be designed to include the highest quality studies possible.

So with Shang, only 8 papers out of 105 were used giving a total n=1923, pooling studies in order to get more statistically significant results than single studies.  Filtered out beforehand, studies of inadequate methodological quality and/or size, based on clearly stated criteria.
The paper found that for all the homeopathic trials, there was an effect beyond placebo. However, when the trials that were of low methodological quality and/or had sample sizes that were small were stripped out of the analysis, the remaining 8 trials showed no effect beyond placebo. On the other hand, when the same procedure was followed for the conventional medicine trials, the six remaining trials did show an effect beyond placebo.
This allows the authors to compare the results from all the studies with the results from the best studies. When you use only the best studies, there is no longer any benefit for homeopathy beyond placebo. In contrast, using the best studies of conventional treatments, there is an effect beyond placebo. Again, this is the whole point of the study, and criticising it on the basis that it seeks to use the best-quality studies seems somewhat misguided.
As Orac notes,
In other words, if a random effect meta-analysis is used, one can torture marginally significant odds ratios out of the data; if a meta-regression is used, one can’t even manage that! In other words, this study actually shows tht [sic] it doesn’t really matter too much which high quality studies are involved, other than that adding lower quality studies to higher quality studies starts to skew the results to seemingly positive values.

Exactly as one who knows anything about meta-analysis would predict.
As I stated above, and Orac strongly demonstrates, "[t]hat’s exactly the reason why the criteria for choosing trials to include in a meta-analysis are so important and need to be decided on before the study is done. If they aren’t, then investigators can cherry pick studies as they see fit."

More on the meta-analysis process used by Shang. http://hawk-handsaw.blogspot.com/2008/10/more-meta-analysis-delight.html Speaks to the original Shang paper and subsequent criticism, it does address some of the criticism of Rutten in the current paper at hand. http://hawk-handsaw.blogspot.com/2008/10/shang-study-remains-firmly-in-water.html

Orac speaks to the motivation behind the initial Rutten study.
One thing that’s very clear reading Lüdtke and Rutten is that this study was clearly done to try to refute or invalidate Shang et al. It’s so obvious. Indeed, no one reanalyzes the data from a study unless they think the original conclusions from it were wrong. No one. There’s no motivation otherwise. Otherwise, why bother to go through all the work necessary? Indeed, Lüdtke and Rutten show this right from the beginning:
Shang’s analysis has been criticized to be prone to selection bias, especially when the set of 21 high quality trials was reduced to those eight trials with large patient numbers. In a letter to the Lancet, Fisher et al. posed the question: ‘‘to what extend the meta-analysis results depend on how the threshold for ‘large’ studies was defined [3]. The present article addresses this question. We aim to investigate how Shang’s results would have changed if other thresholds had been applied. Moreover, we extend our analyses to other meaningful subsets of the 21 high quality trials to investigate other sources of heterogeneity, an approach that is generally recommended to be a valuable tool for meta-analyses.
Under "Provocation", Rutten mentions the 1997 Linde study but yet ignores the re-analysis of 1999 which concluded, "that because trials of higher methodological quality had smaller effect sizes, and that because a number of newly published high-quality trials showed negative results for homeopathy, their meta-analysis had over-estimated the effectiveness of homeopathy. Hence there is no reason to see to the discrepancy between" Shang (2005) and Linde (1997). [For further commentary on issues Wilson raises with Rutten's other work concerning the Shang study.]

While much of what I read concerned Rutten's original re-analysis (of which I haven't had time to digest), a third and final point with this paper I have issue with concerns the conclusion.

Besides once again alluding to "big pHARMA", Rutten believes that real science supports his contention that homeopathy works.  No it doesn't.
So-called “alternative” therapies, mostly derived from ancient healing traditions and superstitions, have a strong appeal for people who feel left behind by the explosive growth of scientific knowledge. Paradoxically, however, their nostalgia for a time when things seemed simpler and more natural is mixed with respect for the power of modern science (Toumey 1996). They want to believe that “natural” healing practices can be explained by science. Purveyors of alternative medicine have, therefore, been quick to invoke the language and symbols of science. Not surprisingly, the mechanisms proposed to account for the alleged efficacy of such methods as touch therapy, psychic healing, and homeopathy involve serious misrepresentations of modern physics.
Second, he is ignoring the true scientific nature of homeopathy with statements like this, "There are indications that the succussion induces some physical information that remains despite the dilution."  This goes to a point concerning magical thinking, the impartating of the homeopath's "intention" on to the elixir; the idea that the mind is special, “above” the natural world of matter.  The whole water has memory bullshit (and the faux science used to bypass that objection) is bunkum.  The need to sound all science-y is just that as Goldacre notes above.

Like religious apologia, eliminate the creation narrative the whole house of cards falls; the authority of the Bible becomes nothing.  In homeopathy, eliminate the efficacy of dilutions, homeopathy fails.  What you are left with is numerous attempts to validate a failed 19th century premise with 21st century woo.

In Hahnemann's original works, as explained and understood by others, he suggested the essence of a substance,
,,,So Hahnemann insisted that a “vital force” was present both in the human body and in the medications. He recognized that his successive dilutions ("potentizations”) of the allegedly active substance in water inevitably reduced the amount of the original substance to none; but the water carried the essence of the active substance, with which it had been in contact; and that essence worked on the vital force of the patient. Moreover, the power of the medication-its “potency” or “dynamization,” terms borrowed from Schelling-was increased by grating or pulverizing the original material and by shaking the solution ("succussion”).
Just as Hahnemann's work has been available since the early to mid 1800s so too has Avogadro's.  As Park notes,  "[m]odern day followers of Hahnemann, however, are perfectly aware of Avogadro’s number. Nevertheless, they regularly exceed the dilution limit — often to an astonishing extent."

Homeopathy as a practice, quietly went about its business until the mid to late 1980s when Jacques Benveniste (Nature Vol. 333, No. 6176, pp. 816-818, 30th June, 1988) asserted that homeopathic remedies work by altering the structure of water, allowing the water to retain a "memory" of the structure of the homeopathic substance that has been diluted out of existence .

As Parks again notes, a subsequent editorial "encouraged other scientists to repeat the Benveniste experiments."  BUT, "the existence of this one paper published in a respected journal has been widely trumpeted by the homeopathic community as proof that homeopathy has a legitimate scientific basis."

Lionel Milgrom, like Dana Ullman, is your typical homeopathic apologist,
So, Milgrom spectacularly fails to refute the central charge levelled at homeopathy.  His use of reviews that are cherry-picked, written by advocacy groups and exist outside of the peer-reviewed medical literature is deeply flawed.  The major meta-analyses of the literature provide no justification for using homeopathy in clinical practise.

The cherry-picking continues as the essay ventures into the area of what passes for basic homeopathic science.  He cites the discredited Nature paper on basophil degranulation.  (Davenas et al., 1988) and an alleged replication* by Belon et al (2004).

In typical cherry-picking style he omits a failed attempt at replication published in Nature during 1993 (Hirst et al., 1993).  He also neglects to mention another failed replication by Guggisberg et al (2005),,,
As you can see, Rutten ignores all this.  With homeopathy and its inherent  complications, I wish I could have added more to this specific criticism.  The notion of "water memory" or "structured water" is awash in the pseudo world of justification and the apologia is immense as evidenced above.  Two hundred years of apologia, and there is nothing to show.  Nothing as a consumer I would remotely wish to add as treatment.

On a final note, one criticism that has been leveled at Shang - the trials deemed to be large and of higher quality were not identified, and that the reporting of the meta-analysis was inadequate - does carry some weight.  The reporting in the original paper was not good enough. However, the authors recognized the problem, and rectified it by identifying the trials in a reply to published criticisms that appeared in the Lancet.
So, is it possible to find which eight trials of homeopathy were finally selected?  Yes.  In fact one poster did provide an answer to this question.  He noted that “…The 8 homeopathy trials and 6 conventional trials that were considered to be large, high quality trials are identified by the authors in their reply to comments on the original article. See Lancet 366 (2005); p. 2083. The list of included trials can be found as an appendix to the online version of the original article, see Lancet 366 (2005); 726-732.”

Where did this idea come from?  Well, Shang et al. did omit these details from their original paper.  This was picked up by many apologists, including correspondents to the Lancet: Fisher et al., Linde  and Jonas, Walach et al., and Dantas.  Shang et al. then provided the information, as noted above, in the same issue of the Lancet as the critical letters.

But, as we have seen, the complete story has been missed by some homeopathic apologists.  It would seem that they only read the critical correspondence, or quotations from it.  This ‘secrecy’ myth has now passed into homeopathic folklore.
P.S. I do find it odd that after 11 years you couldn't find a better study that "affirms" homeopathy.

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