Autism and MMR (More Measles Rubbish)
June 8th, 2009
A reader sent me a comment from a parent of an autistic child. This parent had been told that their child’s “measles titre” was “five times normal”, which was offered as an explanation of why this child had autism.
I assume that this information was provided by some form of “health care practitioner”, most likely of the “alternative” genre. The parent’s comments made it clear that they had also been told that this “elevated titre” was due to the MMR vaccine.
Let’s deconstruct that argument.
Measles Titres - what are they?:
The “old school” way of doing measles antibody titres is the plaque reduction neutralisation (PRN) test. This involves adding serial dilutions of the patient’s serum to a virus solution and then putting the mixture on a lawn of cells. The greatest dilution (titre) that still gives a specified reduction in plaques (areas of viral infection) on the cell culture is the “antibody titre”. Previously, this was reported as the dilution itself (e.g. 1:64), but now the trend is to reference the results to the international standard anti-measles serum and report it as milli-International Units per milliliter (mIU/ml).
An easier (not to mention cheaper and faster) method is to use an enzyme-linked immunosorbent assay (ELISA) to measure the anti-measles antibody. This is a test that can be done in almost any clinical lab and requires no finicky cell cultures. Although the test is usually set up to give results as “immune”, “not immune” and “equivocal”, it can be quantified by using dilutions of the standard serum to set up a calibration curve.
The PRN test has been shown to be more sensitive to low levels of antibody (Cohen 2008) and it is probably more accurate, but both tests are “good enough” to give the answer most clinicians want: “Is this person immune to measles?”
The “normal value” of anti-measles antibody:
The whole idea of an anti-measles antibody titre being “five times normal” is a little weird. You see, the report from the lab will give the titre (if it is quantified - often it is not) and then state the level at which immunity is assured. What value the lab uses depends on which level of certainty they have chosen.
Studies have shown that an antibody level (titre) of 120 mIU/ml is sufficient to prevent clinical illness. This is often used by labs as the “rock-bottom” level for immunity. At this level, the patient will show some laboratory signs of measles infection (e.g. rising antibody levels) and may be able to transmit the disease to others (for a brief period) but won’t generally feel ill or develop a rash. Generally.
Because there is some debate about whether people at 120 mIU/ml are truly protected from measles, most labs set their “immune” point somewhere between 200 and 300 mIU/ml. This gives some margin for error.
However, these are not “normal values” except in the sense that anything below these levels is abnormal (if you want to be protected from measles). There is no upper “normal value”.
Let me say that again:
There is no upper value of “normal” for measles titres.
Baird et al (2008) should be an interesting read for those clinicians telling parents that their autistic children’s anti-measles antibody titre is “five times normal”. Not only did Baird et al show that there is no relationship between measles antibody titre and autism, but their data show the extreme range of antibody titres in both the “normal” and “autistic” population.
Baird et al looked at 90 “neurotypical” children born between 1 July 1990 and 31 December 1991 (average age 12 yrs at the time of the study) as their control group. The measles titres they measured in this group ranged from 25 to 6,300 mIU/ml (geometric mean - 890 mIU/ml). Even using a “normal” value of 300 mIU/ml, the highest of these “neurotypical” children was “twenty-one times normal”.
The antibody titres of the autistic children in the Baird et al study were not statistically different from the “neurotypical” controls (geometric mean - 870 mIU/ml).
Just to show that this wasn’t a fluke, LeBaron et al (2007) looked at measles antibody levels in kindergerten children (4 - 6 years) and at middle school children (10 - 12 years) before and after their second MMR vaccination. They found that the kndergarten children had a geometric mean antibody level of 1559 mIU/ml (over “five times normal”). The middle school children had a geometric mean of 757 mIU/ml prior to their “booster” MMR and 1672 mIU/ml after the second MMR.
The significance of “elevated” serum anti-measles antibody titres:
None.
Why do practitioners get quantitative anti-measles antibody titres for autistic children?:
I have no way of knowing for certain. All plausible explanations involve a “belief” that measles vaccine - more specifically, the MMR vaccine - can cause autism. This is a “belief” that is not, currently, supported by any credible data (Dr. Wakefield’s work having passed into the category of “non-credible” some time past). From talking with parents in my area, I have discovered that it is still a common practice (among the “alternative” autism practitioners) to obtain (and even follow) anti-measles antibody levels.
If the antibody levels are HIGH (which, as I have shown above is nonsense), the parents are told that the child has a “persistent vaccine-strain measles infection” (without, I might add, ever doing any testing to show that it was a vaccine strain). In my area, the common “treatments” are intravenous immunoglobulin (puzzling, since it has only moderate levels of anti-measles antibody - the child’s level is, presumably, much higher than normal), valcyclovir (puzzling, since it is absolutely ineffective against measles virus) and/or chelation (again, no possible effect against the measles vaccine). The “treatments”, I have found, vary from region to region, practitioner to practitioner and - apparently - day to day.
If the anti-measles antibody levels are LOW, a few parents have been told that the measles virus is suppressing the immune system and that “treatment” is indicated. In the few instances I have come across, the only treatment consistently not used was intravenous immunoglobulin - the only treatment that might have worked, were the diagnosis correct (which I doubt).
Summary:
The anti-measles antibody titre is being used in a nonsensical way to convince parents that their autistic children have persistent measles infections. This is nonsensical for two reasons - first, there is no indication that high anti-measles antibody titres are even associated with autism. And, secondly, the claim that a child’s anti-measles antibody titre is “five times normal” (or even “fifty times normal”) is nonsensical on its face, as there is no upper “normal” limit.
Parents who are told by a doctor that their child’s anti-measles antibody titre is “five times normal” should thank the doctor, firmly grasp their child’s hand and walk briskly from the office. This doctor does not understand how the anti-measles antibody titre works and should not be trusted with your child’s health care.
Prometheus
References:
Baird G, Pickles A, Simonof E, et al. Measles vaccination and antibody response in autism spectrum disorders. Arch. Dis. Child. 2008 Oct;93(10):832-7.
Cohen BJ, Doblas D, Andrews N. Comparison of plaque reduction neutralisation test (PRNT) and measles virus-specific IgG ELISA for assessing immunogenicity of measles vaccination. Vaccine 2008 Nov 25;26(50):6392-7.
LeBaron CW, Beeler J, Sullivan BJ, et al. Persistence of measles antibodies after 2 doses of measles vaccine in a postelimination environment. Arch. Pediatr. Adolesc. Med. 2007 Mar;161(3):294-301.
Filed under: Autism Practitioners, Autism Science, Critical Thinking | 12 Comments »
The Chicago Tribune turns over some rocks
May 22nd, 2009
Almost everybody knows what happens when you turn over rocks in the garden - you find slugs, beetles and other slimy and creepy-crawly things underneath.
Well, the Chicago Tribune recently (21 and 22 May, 2009) came out with a two-day series of articles on what they found when they turned over some rocks in the “alternative” autism therapy world. What they found was beyond what I would have expected, and I’ve been critically analyzing “alternative” autism therapy for a fairly long time.
Here are the articles - I suggest you go read them yourselves. Be prepared to be disturbed:
“Miracle Drug” called Junk Science
Physician team’s crusade shows cracks
A Flawed Rationale for Treatment
Autism doctor: Troubling record trails doctor treating autism
Dr. Peter Rosi places blame on some parents for their babies’ deaths
I had to take a shower after reading these articles - I felt contaminated just reading the words of these…….people.
A few excerpts:
On the Geiers’ “Lupron Protocol”:
The blood tests the Geiers use as proof of excessive testosterone don’t show that at all, and other data they cite mean nothing, said Paul Kaplowitz, chief of endocrinology at Children’s National Medical Center in Washington, D.C., and an expert on precocious puberty. They also leave out test results that could help show whether the children are in early puberty, he added.
Looking at the tests, Kaplowitz said he asks himself: “Is Dr. Geier just misinformed and he hasn’t studied endocrinology, or is he trying to mislead?”
………………..
Mark Geier responded that these are “opinions by people who don’t know what they are talking about,” saying the pediatric endocrinologists interviewed by the Tribune don’t treat autistic children and have not tried the Lupron treatment. David Geier said prominent scientists support their work and gave as an example Baron-Cohen…
………………..
Simon Baron-Cohen, a professor of developmental psychopathology at the University of Cambridge in England and director of the Autism Research Center in Cambridge, said it is irresponsible to treat autistic children with Lupron.”The idea of using it with vulnerable children with autism, who do not have a life-threatening disease and pose no danger to anyone, without a careful trial to determine the unwanted side effects or indeed any benefits, fills me with horror,” he said.
Apparently, the Geiers don’t have the support of prominent scientists that they think they do.
Now, I fully expect people in the “alternative” autism therapy business (and their apologists) to “spin” this as a “kill the messenger” response or as the latest act of the “Big Pharma / AMA / Government Conspiracy to Hide the True Cause of Autism”. But this stuff is pretty hard to just “explain” away.
Let’s continue with the curious past (and dubious present) of one of the prominent “alternative” autism practitioners in the Chicagoland area - Dr. Mayer Eisenstein, head of “Home First Health Services”:
Eisenstein, who calls the American Academy of Pediatrics the “American Academy of Pharmaceuticals,” dismisses the many peer-reviewed studies that failed to find a link between autism and vaccines as “fake studies.”
Vaccine proponents won’t admit this because, he said, “Every doctor now essentially in this country has done something as heinous as the Nazis did, unknowingly.”
Where is the Hitler Zombie? Dr. Eisenstein is not coming across as a voice of reason so far. But let us continue…
Eisenstein’s practice has faced at least 19 malpractice cases in the last three decades, and two Homefirst doctors were involved in 15 of those cases — more than what’s typical. In 80 percent of the cases involving those two doctors, a jury either sided with the plaintiffs or the cases were settled, court records show.
OK, doctors get sued all the time. No big deal, right? Let’s read on…
For example, a case filed in 1986 alleged that a Homefirst doctor and midwife failed to diagnose that a mother and her newborn had incompatible blood types, which can lead to a potentially fatal condition if not caught by a routine blood test. The baby suffered kernicterus syndrome, athetoid cerebral palsy and hearing loss. The case was settled for $985,000 in a structured settlement, court records show.
The failure to diagnose incompatible blood types between a mother and newborn was also at issue in the case that netted the $30 million jury verdict. In that case, however, the baby, Na’eem Shahid, died.
A Homefirst doctor took a sample of blood from Na’eem’s umbilical cord that could have been used to diagnose the problem and could have led to prompt treatment, according to court testimony. But instead of dropping off the sample at the lab, the doctor said under oath, he was tired, went home and put the sample in his refrigerator, where it sat the whole weekend.
In an interview, Eisenstein blamed the parents for not taking the baby to the emergency room for a blood test. Na’eem’s parents testified that no one from Homefirst ever told them to go to the emergency room.
Remember that this is the doctor who claims that unvaccinated children do not get autism. To refresh our memories:
He proclaims that he’s seen “virtually no autism” in his patient pool of thousands of unvaccinated kids.
Well, if you don’t look, you don’t find.
Dr. Eisenstein also has strong views about telling the truth:
In his lectures at conferences, Eisenstein often describes a key lesson he learned in law school: falsus in uno, falsus in omnibus. Translated “false in one thing, false in everything,” this is a legal principle that if a witness lies about one thing, a jury can disregard anything that person says.
Yet Dr. Eisenstein has fallen tragically short of this standard:
In a different case, Eisenstein said under oath that he was a faculty member at the Hinsdale Hospital Family Practice Residency Program from 1992 to 2003. A hospital administrator testified that Eisenstein “never was” a faculty member. In a recent interview, Eisenstein said that while he wasn’t a faculty member there, he did teach students from that program and kept snapshots of them.
In that same case, Eisenstein also testified he knew little about the College of Health Sciences, where he and some of his doctors received their continuing medical education credits — a requirement for retaining privileges at some hospitals.
“I have no clue,” he said under oath when asked where the school was located.
The attorney questioning Eisenstein reminded the doctor that he could go to prison for lying under oath. He asked if Eisenstein had any connection to the college. “Not that I know of,” Eisenstein answered.
I won’t go into the sad and sordid case of Dr. Peter Rosi, one of Dr. Eisenstein’s associates at Home First - that story is too disturbing. Go read it yourself.
Despite all this, I fully expect to hear a chorus of defense from the “usual suspects”. They will defend the Geiers, Eisenstein and even Rosi because - frankly - they are all the “alternative” autism therapy supporters have. They’re willing to leap to the defense of the indefensible because the only other choice they have is to face the fact that “alternative” autism therapies are largely a bunch of baloney.
I’d love to be proven wrong, but I doubt I will be.
Prometheus
Filed under: Autism Practitioners, Autism Science, Autism Treatments | 9 Comments »
TVM for Autism
May 15th, 2009
A few weeks ago, a friend sent me a piece she had read on an autism “biomed” forum. In it, a parent was asking about using hydrochloric acid for “digestive problems” in her autistic child. Apparently, her “alternative” medicine provider had suggested it and this mom wanted to know where to find hydrochloric acid that wasn’t “contaminated”.
Now, my friend sent this to me in the spirit of “Have you ever heard of such nonsense?” However, as I read it, I was pretty sure I had heard of this before, but in a very different context.
Going to my bookcases, I quickly found A Textbook of Practical Therapeutics by Hobart Amory Hare (MD, BSc), 5th Edition, published in 1895. On page 205, Dr. Hare writes the following:
In dyspepsia due to faulty gastric secretion, as in typhoid fever, and in gastric indigestion accompanied with fermentation, this acid is of service. In combination with compound tincture of cardamoms, it is of value in intestinal indigestion. (See Indigestion.)
The acid is best used in the form of the of the official dilute acid {Acidum Hydrochloricum Dilutum, U.S. and B.P.), dose 10 to 30 drops in water.
In the sick stomach and gastric distress following an alcoholic debauch, 20 drops of the dilute acid in water are often of service.
[Note: this book is also available on line.]
Amazingly, this appears to be identical to what the “alternative” practitioner was recommending over one hundred years later.
As I read through Dr. Hare’s text, I had frequent episodes of deja vu. Arnica, flax seed, cod liver oil, oxygen (but not hyperbaric oxygen - that came later), saunas (sweating out the “toxins”), colonic irrigation, even acupuncture - all of these “alternative” therapies were discussed at length in this book. And although Dr. Hare curiously omits mention of them, homeopathy was also very popular at the same time (having been invented by Hahnemann in 1796), and chiropractic had just been invented by D.D. Palmer at the time this book was published.
I gradually came to realize that many of the “alternative” therapies for autism - and much of “alternative” medicine in general - would be better described as “Traditional Victorian Medicine” (”TVM”, for these fast-paced times). It only seems appropriate to recognize the debt that current “alternative” practitioners owe to the far-sighted healers of that bygone era and acknowledge that so many of today’s “alternative” therapies were, in fact, “mainstream medicine” during the reign of Queen Victoria (1837 - 1901).
And besides, look what the word “traditional” has done for the marketing of “Traditional Chinese Medicine”.
The term “Traditional Victorian Medicine” becomes even more appropriate when you consider that medicine during Victoria’s reign was also largely based on the personal beliefs and “experience” of influential physicians - as is current “alternative” medicine. Neither the visonary healers of the Victorian Age nor the modern “alternative” practitioners are the slaves to “data” or “clinical trials” that “modern” physicians are.
Additionally, physicians in the Victorian Era spent much more time with their patients, since there was little else they could do. In these respects (and many more), current “alternative” providers are much more similar to physicians of Victoria’s era than they are to modern physicians.
As Dr. Hare’s text points out, physicians of his day rountinely observed patients recovering from serious illnesses with the help of the remedies contained therein. Even venesection (”bloodletting”, to the uninitiated) was known to be of great help in “extreme” cases, although Dr. Hare laments even then that younger physicians of his time were turning away from this invaluable treament and would come to regret that decision.
Just as the “Traditional Victorian Medicine” practitioners of today have their “testimonials”, Dr. Hare describes how people in the Victorian Era often got “better” after being treated with sandal-wood oil for their gonorrhea (p. 319) or lead acetate for dysentery (pp. 235 - 236). In this light, the anecdotes of autistic children today ”recovering” after (or in spite of) being treated with HBOT or chelation similarly vindicate the use of those therapies.
Remember, too, that when “Traditional Victorian Medicine” was originally practiced, people were much healthier than the sickly, toxin-loaded, pill-popping, latte-swilling populace of our age. Whereas today the life expectancy at birth in England is currently a mere 79 years, people back in the ”Golden Age” of “Traditional Victorian Medicine” could expect to live to the ripe old age of 47 years (in 1901).
It is only fitting that the “Brave Maverick Doctors” (BMD’s) treating autism with “alternative” therapies should acknowledge that they are following in the honored footsteps of Dr. John Watson in their practice of ”Traditional Victorian Medicine”. After all, the Victorian Era was a time of great heroes and these BMD’s are certainly considered heroes by many (thay are also, some might add, practicing “heroic medicine“).
So, all of you “Bave Maverick Doctors”, you “DAN!” practitioners, you “alternative”, “CAM” or “holistic” therapists, be proud of your roots - call it what it is:
Traditional Victorian Medicine
Something to think about, isn’t it?
Prometheus
Filed under: Autism Practitioners, Autism Treatments | 13 Comments »
More Hot Air about HBOT
April 5th, 2009
I’m being a “guest ‘blogger” over at Left Brain / Right Brain, where the article below is posted. Feel free to head on over there to post your comments.
A few weeks ago, BMC Pediatrics published an article that purports to show that Hyperbaric Oxygen Therapy (HBOT) can produce “…significant improvements in overall functioning, receptive language, social interaction, eye contact, and sensory/cognitive awareness..” in autistic children. This study (Rossignol et al, 2009) is billed as a “…multicenter, randomized, double-blind, controlled trial.”
It’s all that and much, much less.
Let’s start by looking at the six “centers” where this research was carried out.
The Centers
The International Child Development Research Center (ICRDC):
This imposing name is attached to a rather less imposing edifice. The ICRDC, brainchild Dr. Jeffrey Bradstreet, is located in a strip mall in Melbourne, Florida, where it not only carries out “cutting-edge research” but also sells a complete line of “supplements” and treats autistic children with a dizzying array of “alternative”, “biomedical” and “integrative” therapies, including HBOT.
Daniel Rossignol MD (Family Practice), Lanier Rossignol (Nurse Practitioner) and Scott Smith (Physician’s Assistant) were the authors from the ICDRC.
The Center for Autism Research and Education (CARE):
This “center” is located in Phoenix, Arizona and has - according to its website - a single practitioner, Cynthia Schneider, MD (OB/Gyn), who is also an author on this paper. One of the “integrative” therapies this “center” offers is HBOT.
One of the other authors, Sally Logerquist, is a PhD psychologist who - according to the paper - is also associated with CARE, but also appears to run social skills therapy groups for autistic children using the “Logerquist Excellent Attitude Program” (LEAP).
True Health Medical Center:
It’s rather difficult to find anything about this “center”, apart from the fact that it is located in Naperville, Illinois - in what appears to be an office complex. Anju Usman, MD (Family Practice) is the author associated with this location.
Neubrander Center:
Although not officially called a “center”, the office of James Neubrander, MD (Pathology) is apparently one of the “centers” of this study. His office is located in the Menlo Park Mall (near Macy’s) and offers - you guessed it! - HBOT as a treatment for autism.
Princess Anne Medical Associates:
A Family Practice medical group in Virginia Beach, Virginia, this “center” is the home of Eric Madren, MD (Family Practice). It’s not clear if this four-physician practice offers HBOT.
The Rimland Center for Integrative Medicine:
A small, one-physician “center” in Lynchburg, Virginia, this is practice location of author Elizabeth Mumper, MD (Pediatrics). Not surprisingly, this “center” sells HBOT services for autistic children.
So, of the six ”centers” involved in this study, five are single-physician operations. The remaining “center” has two physicians (three, if you count the naturopath).
I’m underwhelmed.
Well, what about the research itself? Maybe that’s better than the “facilities” might suggest. Let’s take a look.
The Subjects
This study initially enrolled 62 children (33 treatment; 29 control), but only 29 of the treatment group and 26 of the control group finished all 40 sessions. For reasons that pass my understanding, one treatment subject who only finished 9 sessions was included in the analysis. The authors stated that including this subject did not alter results, which begs the question: “Why did they include this subject if it made no difference?”
Outcome measures
The authors used the Aberrant Behavior Checklist (ABC), the Clinical Global Impression (CGI) scale and the Autism Treatment Evaluation Checklist (ATEC) as their outcome measures. All except the ATEC are widely accepted for use in autism treatment trials.
The ABC is a 58-question checklist of – surprise! – aberrant behaviors which are each given a score from “0” (not at all a problem) to “3” (severe problem). This test has been use – and validated – in a number of disorders, including autism. It gives a global score as well as five subscales: a total of six measures.
The CGI is a generic rating scale used in a variety of clinical trials. For each parameter (e.g. “overall functioning”, “sleep pattern”), the rater gives a score of between “1” (very much improved”) and “7” (very much worse). The authors had both the treating physician and the parents rate the subjects on overall improvement and eighteen discrete parameters: a total of 38 measures in all (19 by the physician and 19 by the parents).
The ATEC was developed by Bernie Rimland and Stephen Edelson and has not been validated. In fact, it has only been used in two published studies – one by Rossignol et al. The ATEC has 25 questions on which the evaluator rates the subject on either a three-point (not true, somewhat true, very true) or four-point (not a problem, minor problem, moderate problem, serious problem) scale. It provides a total score and four subscales: a total of five measures.
In all, each subject had a total of 49 evaluation measures (change in ABC and ATEC scores and the CGI scores), of which 45 are independent. The importance of this will become apparent in the section on statistical analysis.
Analysis
As I mentioned above, the decision to include one treatment subject who only completed nine sessions was curious. Why they included this subject and not any of the other three treatment subjects and three control subjects who also failed to complete the entire course of the study is concerning. The smart thing – and the proper response – would have been to drop this subject from analysis.
The authors’ method of analyzing the CGI scales was also curious. Rather than simply using the scores as they were provided, they took the scores and subtracted them from four (the “no change” score). There are a few problems with this.
For starters, the scores are not linear – the difference between “much improved” and “very much improved” is not necessarily the same as between “no change” and “minimally improved”. Nor is the difference between “no change” and “much improved” twice the difference between “much improved” and “very much improved”. For that reason, these types of numerical scores are often referred to as “pseudo-numbers”.
This may seem like nit-picking, but it is a serious concern. Imagine, if you will, that the numbers were replaced by colors. Is the difference between green and orange twice the difference between orange and red? If half of a population of birds are blue and the other half are yellow, is the “average” bird green? The simple fact is that it is not appropriate to treat these “scores” as though they were real numbers, to be added, subtracted and averaged.
Secondly, it appears that the authors used parametric statistics for their analysis of the CGI scores. This is a problem since - as I indicated above - it is nonsensical to do math on pseudo-numbers. I don’t have the raw numbers, so it isn’t possible for me to calculate the absolute impact of this mistake for all of the CGI subclasses, but I can figure out the raw numbers for one group, so let’s look at that one.
It took a little work, but the authors gave enough clues to tease out the raw numbers in the physician ”overall functioning” CGI score. The treatment group had an “average” of 2.87 and the control group’s “average” was 3.62; using the unaltered data, a t-test [Note: not an appropriate use of the t-test] gives p-value of 0.0006, not far from what the authors report. When a more appropriate statistical test [Mann-Whitney U-test] is used, the p-value is 0.002, very different from the reported 0.0008. While this is still less than the threshold p-value of 0.05, see below for a discussion of multiple comparisons.
All of these statistical analysss of the CGI scores ignore the fact that these are pseudo-numbers and need to be treated as discrete groups rather than as actual numbers. In truth, even the ABC and ATEC scores should have been treated this way, as well, although it is fairly common practice to treat such multi-factor scores as real numbers. A Chi-square test or Fisher Exact test would be the ideal test, but the problem with that is that the treatment group has one score of “1″ (very much improved) and the control group doesn’t. Likewise, the control group has two subjects with a score of “5″ (minimally worse) and the treatment group has none. This prevents a Chi-square or Fisher test from comparing each score independently.
One solution is presented by the authors themselves, although they apparently didn’t use it. In their discussion of the CGI, the authors said:
“Children who received a score of ‘very much improved’ or ‘much improved’ on the physician CGI overall functioning score were considered to be ‘good responders’ to treatment.”
If we “bin” the scores into “good responders” and “others”, we find that there were 9 (out of 30 - 30%) “good responders” in the treatment group compared to 2 (out of 26 - 8%) in the control group. Unfortunately, this is not a statistically significant difference (p = 0.08) in the (Yates) Chi-square test and barely reached significance (p = 0.05, but see below) in the Fisher Exact test.
An even bigger problem in the statistical analysis was the failure to correct for multiple comparisons. This problem was brought up by one of the reviewers, and the authors responded by eliminating a table. They did not make the appropriate corrections.
The reason that multiple comparisons are a problem is that the analysis for statistical significance is based on probability. If the probability (the p-value) that the differences between the two groups (treatment and control) is due to random chance is equal to or less than 5%, that difference is considered to be “statistically significant” and accepted as real. That means that there is still a 5% (or less – look to the p-value) chance that the difference is due to chance and not real.
If multiple comparisons are made on the same group of subjects, the probability that one (or more) of them will be “statistically significant” by chance starts to climb. If 14 comparisons are made, the chance of an erroneous “statistical significance” is over 50%. If 46 independent comparisons are made – as in this study – the chance of erroneous “statistical significance” is over 90%.
For this reason, it is standard procedure to apply a correction for multiple comparisons. The most well-known (and simplest) of these is the Bonferroni Correction, which changes the threshold for statistical significance by dividing it by the number of comparisons. In the case of this study, the threshold (normally p less than or equal to 0.05 or 5%) is reduced to 0.001.
Applying the appropriate correction for multiple comparisons changes the results of this study significantly. Only the physician CGI scores for overall functioning and receptive language reach significance – and these numbers are already suspicious because they were improperly handled to begin with. In fact, as I have shown above, the CGI overall functioning p-value wouldn’t reach significance. It is possible that - if the proper statistical tests were used - that the CGI score for receptive language would also not reach significance.
Another curious thing. The authors asked the parents after the study whether they thought their child was in the treatment or the control group. Rather than say that the parent’s guesses were no better than random (i.e. 50%), the authors stated:
“…there was no significant difference between the two groups in the ability of the parents to correctly guess the group assignment of their child.”
As I said, this was a curious way to put it. As I read this, all it says is that each group of parent were equally able to guess which group their child was assigned to. That could be a 50% accuracy (which would be equal to chance), but a 90% or 99% accuracy would also fit that description.
Now, this could simply be an clumsy phrasing by the authors, or it could be a way to make it sound like their blinding was successful when it actually was not.
Summary
This study may have collected some useful data, but its analysis of that data rendered it useless. The CGI scores – where the only statistically significant result was (possibly) seen – were improperly manipulated and the wrong statistical analysis was used.
The other issue is that there is no discussion of why HBOT is thought to be superior to providing the same partial pressure of oxygen at room pressure. This study used 24% oxygen at 1.3 atm, which gives the same partial pressure of oxygen as 31% at sea level. This concentration of oxygen can be easily attained with an oxygen mask or simple oxygen tent – both of which are vastly less expensive than HBOT.
If the authors are arguing that the mild pressure of their inflatable HBOT chambers contributes to the treatment effect, they need to look at the literature on cell membrane compressibility. For those who want to do the calculations at home, the bulk modulus of water (the major component of cells) is 21,700 atm. This means that a 0.3 atm increase in pressure will reduce the cell volume by 0.0014%. The bulk modulus of the lipid bilayer in cell membranes is around 30,000 atm. This means that an increase of 0.3 atm pressure causes a 0.0010% reduction in membrane volume. These are well below the threshold for any clinical effects.
Real pressure effects on the central nervous system are seen at pressures over 19 atm. These effects are:
dizziness
nausea
vomiting
postural and intention tremors
fatigue and somnolence
myoclonic jerking
stomach cramps
decrease intellectual and psychomotor performance
poor sleep with nightmares
increased slow wave and decreased fast wave activity in EEG
None of these effects could be construed as “improvements”, even in autism.
So, this study fails to answer the following questions about HBOT and autism:
[1] Does HBOT improve any feature of autism?
[2] If so, is HBOT any better than supplemental oxygen (which is much cheaper)?
The only real effect of this study was to give a cover of legitimacy to practitioners who are already using HBOT to “treat” autism.
Prometheus
Filed under: Autism Practitioners, Autism Science, Autism Treatments | Comments Off
This can’t be for real…
March 11th, 2009
But it is.
Sometimes, I read about new “treatments” for autism that seem too wacky to be real. Unfortunately, most of the time they are all too real. What I am talking about today is the use of nicotine patches to “treat” autism.
No, I’m not kidding.
The history of this latest therapeutic misadventure in autism begins with a presentation on 17 November 2008 at the Society for Neuroscience meeting in Washington, D.C. by Dr. Rene Anand, an associate professor of Pharmacology at Ohio State University’s College of Medicine.
Dr. Anand’s presentation was about neurexin-1, a gene that has been implicated in nicotine addiction, schizophrenia and autism. In his research (not yet published), Dr. Anand has apparently found that one of the products of the neurexin-1 gene (neurexin-1 beta) is responsible for directing a specific type of acetylcholine receptor (nicotinic receptors) to the synapse.
Since abnormalities in acetylcholine receptors have been noted in autism (see here and here) and the neurexin-1 gene has also been implicated in autism, this seems like an promising line of inquiry into the etiology of autism. When asked, Dr. Anand was quoted as saying:
“If we were to use drugs that mimic the actions of nicotine at an early time in human brain development, would we begin to help those and other circuits develop properly and thus significantly mitigate the deficits in autism? This is a novel way of thinking about how we might be able to use drugs to approach autism treatment.”
So far, so good. It certainly sounds like an intriguing area for future research. But how did the “biomedical” community of practitioners respond to this information?
Well, Dr. Jeff Bradstreet, noted DAN! physician, has jumped on this news and is currently treating autistic children with nicotine patches (see here, esp. the last three slides). I’m sure he’s not the only one, but he’s been kind enough to put his……”practices” on the web for all to see.
And if Dr. Bradstreet is treating autistic children with the nicotine patch, there are sure to be several other “alternative” practitioners who are following his lead.
It is truly frightening to watch how a bit of speculative musing was “morphed” in a few short months into a full-blown “biomedical” treatment for autism. Without even a single piece of data supporting the use of nicotine in autism, “alternative” practitioners are slapping nicotine patches on autistic children across the country (and possibly all over the world).
In his usual fashion, Dr. Bradstreet has marshalled a number of tangentially relevant studies to support - after the fact - his decision to promote this “treatment”. He cites the Potter and Newhouse (2008) study that showed the nicotine patch improved cognitive performance in young adults (18 - 22 years old) with ADHD [Note: ADHD is not the same as autism].
He also cites (but apprently does not comprehend) the Sacco et al (2004) review of nicotinic receptor mechanisms and cognitive function (if he had understood it, he would have seen that it didn’t support the use of nicotine in autism - it doesn’t even mention autism).
Likewise, he makes liberal use of the graphics in the de Jonge and Ulloa (2007) article about the anti-inflammatory actions of the α-7 acetylcholine receptor without showing that autism is caused by neuroinflammation (although he seems fixated on that concept, the data supporting it is weak at best). His presentation also wanders into vagal nerve stimulation, which is a frightening window onto what he may be considering in the future.
I’d like to emphasise that I’m not picking on Dr. Bradstreet. He, at least, has made an attempt (largely negated by his use of scientific studies to “prove” what he already “believes”) to understand the science behind what he proposes to do to autistic children. Others haven’t even gone that far - they simply mimic what “everyone else is doing”.
But enough about Dr. Bradstreet and the parrot practitioners. What is the actual likelihood of the nicotine patch helping an autistic child? Let’s go back to Dr. Anand’s statement for a moment:
“If we were to use drugs that mimic the actions of nicotine at an early time in human brain development, would we begin to help those and other circuits develop properly and thus significantly mitigate the deficits in autism?”
“…at an early time in brain development…” does not mean six years old. Dr. Anand was probably speaking about intrauterine development. In fact, Dr. Anand doesn’t have any idea if this would work or not - he’s just speculating. Read the sentence again if you disagree with me.
In addition, the studies looking at acetylcholine receptor abnormalities in autism have shown problems with expression of the genes for the receptors themselves, not with neurexin-1-related proteins. In fact, even the study linking neurexin-1 disruption to autism found:
“A scan of the NRXN1 coding sequence in a cohort of ASD subjects, relative to non-ASD controls, revealed that amino acid alterations in neurexin 1 are not present at high frequency in ASD.”
These facts together suggest that treating autistic children with nicotine patches is not likely to help them at all.
And what are the risks of treating young children with nicotine?
Well, for starters, nicotine is an addictive drug. Parents who recoil at the thought of giving their children Ritalin (methylphenidate) because it is addictive should contemplate this fact carefully.
Secondly, nicotine withdrawal causes anxiety, irritability and aggressive behaviors. Will this lead parents to believe that the nicotine patch is “working” because their children are so much worse when they don’t get their “fix”? I suspect it will.
Thirdly, we don’t have a lot of information about how nicotine affects childhood development, largely because few children - prior to now - have become addicted to nicotine before their early teens. Once again, parents of autistic children are queing up to have their kids turned into guinea pigs.
The chance of benefits is extremely low and the risk of bad outcomes is significant (nearly a certainty, given what we know about nicotine in adults). In addition, the symptoms of withdrawal in nicotine-addicted autistic people are likely to be misinterpreted by parents (and many “alternative” practitioners) as signs that the nicotine patch “works” to treat autism.
We should ”just say no” to giving nicotine to autistic children. Not just because nicotine is an addictive drug, but also because it’s a poorly thought-out idea with no data to support it.
Prometheus
Filed under: Autism Practitioners, Autism Treatments | 30 Comments »