Spring is here, according to the calendar, although the fresh snow on the ground would seem to contradict that idea. At any rate, the Winter quarter is over, the tests have been graded and the final grades submitted to the Registrar and I finally have time to attend to my much-neglected ‘blog.

A lot has happened in the autism world since my last post. The VICP has agreed to pay damages to the family of a young girl whose mitochondrial dysfunction was possibly worsened by her reaction to vaccines. I say “possibly” because it is not at all clear what mitochondrial dysfunction she has, and so it is impossible to assess the biological plausibility of the claim.

This same restraint has not been shown by many in the vaccines-cause-autism camp, who are trumpeting this “victory” to the skies. They are apparently unaware that even if her autism were caused by the interaction of a mitochondrial dysfunction and vaccines, it is unlikely that a significant portion of autism is caused in this way. Again, not that I haven’t conceded that the vaccines were the “trigger” for this young girl’s autism – that has yet to be shown.

It has been fascinating (“appalling” might be a better word) to watch the many “autism advocates” rush to get on the new vaccines-and-mitochondrial-dysfunction-cause-autism bandwagon. I am reminded of a whale-watching trip I took, where most of the passengers kept rushing from starboard rail to port rail, following the cries of “There’s one!” ignoring the naturalist who was trying (largely in vain) to point out the real whales (instead of whitecaps and kelp).

In the midst of all the hoopla about mitochondria, two pieces of real research were published that should have a major impact on the way the followers of DAN! are treating their children.

Cass H, Gringras P, March J, McKendrick I, O’Hare AE, Owen L, Pollin C., Absence of urinary opioid peptides in children with Autism. Arch Dis Child. 2008 Mar 12 [Epub ahead of print]

In this study, Cass et al examined the urine of 65 boys with autism and 158 boys without autism (controls). They used HPLC (high-pressure liquid chromatography) to identify potential opioid peptides in the urine and then further examined these with MALDI-TOF MS (matrix-assisted laser desorbtion ionisation-time of flight mass spectroscopy).

Their results?

“There were no significant differences between the HPLC urinary profiles of the children affected by autism and the typically developing controls. In those cases where HPLC showed peaks in the locations at which opioid peptides might be expected to be found, MALDI-TOF established that these peaks did not, in fact, represent opioid peptides at all.”

This study confirms the finding of Hunter et al (Opioid peptides and dipeptidyl peptidase in autism. Dev Med Child Neurol. 2003 Feb;45(2):121-8.), whose study found that:

“Opioid peptides were not detected in either the urine of children with autism (10 children; nine males, one female; age range 2 years 6 months to 10 years 1 month) or their siblings (10 children; seven males, three females; age range 2 years 3 months to 12 years 7 months) using liquid chromatography-ultraviolet-mass spectrometric analysis (LC-UV-MS).”

Of course, the Cass et al study has more subjects and uses much more sophisticated, sensitive and accurate instrumentation, but it had the same findings. One wonders what it was that Dr. Reichelt was finding in the urine of autistic children. Whatever it was, it apparently wasn’t an opioid peptide.

For those who are new to controversies in autism, the “opioid peptide hypothesis” was the driving force behind the gluten- and casein-free (GFCF) diet.

It was postulated, by Karl Reichelt and others, that the proteins gluten (found in many grains, esp. wheat) and casein (found in milk, including human milk) were being broken down to shorter oligopeptides (proteins consisting of only a few amino acids) that were mimicking the endogenous opioid peptide (endorphins and enkephalins) in the brain.

It was further postulated that these “opioid peptides” were being absorbed through the “leaky gut” of autistic children (more on this later) and causing many or all of the symptoms of autism.

Now that it has been shown – twice – that there are no opioid peptides in the urine of autistic (or non-autistic) children (as there would be if they had been absorbed into the bloodstream), the primary hypothesis supporting the GFCF diet has been disproven. All that’s left is the rather pathetic argument “But it works!” – pathetic because the studies done to date (Knivsberg et al 2002, Sponheim 1991 and Elder et al 2006) have been mixed. Actually, only the study that included Karl Reichelt as an investigator (Knivsberg et al 2002) showed any improvement on the diet – the others showed no difference between the diet and control groups.

The other significant recent study looked at the other “leg” supporting the GFCF diet – the “leaky gut” hypothesis.

Robertson MA, Sigalet DL, Holst JJ, Meddings JB, Wood J, Sharkey KA. Intestinal Permeability and Glucagon-like peptide-2 in Children with Autism: A Controlled Pilot Study. J Autism Dev Disord. 2008 Feb 29 [Epub ahead of print]

This study looked at the intestinal permeability and glucagon-like peptide-2 (GLP-2) response to feeding, both of which have been claimed to be abnormal in autistic children. They used the lactulose:mannitol sugar permeability test for intestinal permeability.

This was a pilot study, with 14 autistic children and 15 controls (7 developmentally normal siblings of the autistic subjects and 8 unrelated developmentally normal children).

The results?

“Our study did not detect differences in these measures of gastrointestinal function in a group of children with autism.”

Of course, this is just a pilot study and will – I hope – lead to a larger study with great predictive power. Another recent study of 23 children with PDD (Kemperman et al 2008) also showed no abnormal intestinal permeability. This calls into question the one study (D’Euphemia et al 1996) that found altered intestinal permeability in 9 out of 20 autistic subjects (and 0 of 40 controls).

Now, I’m not naïve enough to think that either of these studies will have the slightest impact on the people who have their children on the GFCF diet. It wasn’t the data that convinced them to start the diet, so data won’t convince them to stop the diet. No, what I hope is that parents who are contemplating the GFCF diet will read these studies and think about it.

I also anticipate a number of impassioned stories about how the GFCF diet “recovered” their autistic child. I have no doubt that the people who write them are going to be very sincere, telling the “truth” as they see it. I also expect that I won’t be hearing from the parents who tried the GFCF diet and saw no results.

That’s the nature of things – the people who try it (whatever “it” might be) and experience improvement will attribute that improvement to whatever they tried. They will have become true believers and will be eager to share their discovery. The parents who try the GFCF diet and saw no improvement will not be nearly as eager to talk about their experiences. Especially given the hostility their story will generate among the “true believers”.

So, for those of you who still have open minds, the data has been laid before you. Enjoy!

For the rest of you – just pretend that I’m in the pay of “Big Pharma” or whatever fever-dream conspiracy is trying to suppress the “truth” about the GFCF diet. It will help with the cognitive dissonance.

Prometheus

One definition of insanity I’ve heard is:

Doing the same thing over and over and expecting different results.

Now, granted, this is not a comprehensive definition, since there are a lot of activities where different results actually do happen every time you repeat them. Slot machines and other “games of chance” come to mind although, in the long run, the result is always the same - you lose and the casino wins.

Still, no matter how many times you go to an empty well, you won’t get a drink.

Why do I bring this up?

Well, as Kathleen over at the Neurodiversity weblog has pointed out, some of the “premier” expert witnesses in the mercury-causes-autism camp have a pretty poor track record. Yet plaintiff’s lawyers are still hiring them - and, I assume, paying them.

For example, Dr. Mark Geier had his testimony thrown out of court twice in 2007 and, as the list below shows, this was just the tip of the iceberg.

For the following list, I am indebted to Kathleen at Neurodiversity weblog and an anonymous reader, WFJAG.

 Blackwell vs. Sigma Aldrich (2007):

“Dr. Geier is not qualified by his knowledge, skill, experience, training or education to render the opinions he proffers in this case… [T]his Court does not find that there exists a sufficient factual basis to support [Dr. Geier’s] proffered testimony…”

Redfoot vs. B.F. Ascher & Co. (2007):

“The… plaintiff has not met her burden of showing that Dr. Geier’s testimony is admissible. As an initial matter, the court notes that Dr. Geier is not qualified as a pediatrician, a neurologist, a toxicologist, or an epidemiologist, either by background or training. He is a medical doctor and a geneticist, but has no specialization in any of the relevant medical areas.”

“In particular, there is no evidence that Dr. Geier has either the training or the background to diagnose autism or to treat autism in any child. Simply having an “interest” in vaccines and the possible connection between thimerosal-containing vaccines and the development of neurodevelopmental disorders in children is not sufficient to qualify an individual as an expert in either pediatrics or neurology, or regarding the various forms of mercury and their neurotoxicity.”

“In addition, Dr. Geier’s testimony is not reliable. While his studies have been “peer reviewed,” in the sense that they have been published in scientific journals, they have been severely criticized by the IOM, the AAP, and others. In particular, both the AAP and the IOM have pointed out the problems inherent in studies that rely on the VAERS database.”

Doe vs. Ortho-Clinical Diagnostics (2006):

“However, even if the Court were to assume that general causation had been shown in this instance, the Court finds that Dr. Geier’s application of the differential diagnosis technique suffers from its own irregularities. First, the Court notes that Dr. Geier is not a pediatrician or a pediatric neurologist. In fact, testimony was presented to the Court that Dr. Geier was not even successful in sitting for his Medical Board examination in the specific field of pediatric genetics. (See Transcript, Vol. II of III, Document #121, at 65.) “

“Thus, there is a threshold question as to whether Dr. Geier is even qualified to perform a differential diagnosis so as to give a causation opinion with respect to the cause of a neurological disorder such as autism in a child such as Minor Child Doe. More troubling, however, is that Dr. Geier’s differential diagnosis failed to acknowledge the one conclusion that is generally accepted in the medical community with respect to the causation of autism, which is, that its cause is genetic, but that the exact genetic sequence of autism is unknown. “

And the hits just keep on coming…(again, beaucoup thanks to WFJAG for his/her digging).

Piscopo v. Sec’y, HHS, (2005):

The special master did not abuse his discretion in determining that Dr. Geier did not have the education, training or experience to proffer a reliable opinion on the cause of petitioner’s autoimmune disorder)

Militrano v. Lederle Laboratories, American Cyanamid Co., (2003):

Characterized Dr. Geier’s affidavit as “conclusory and scattershot” and “undermined by many of the materials submitted in support of it”

Thompson v. Sec’y, HHS (2003):

The special master found Dr. Geier unqualified to testify about infantile spasms and found his testimony filled with speculation.

Haim v. Sec’y, HHS, (1993):

“Dr. Geier’s testimony is not reliable, or grounded in scientific methodology and procedure. His testimony is merely subjective belief and unsupported speculation.”

Marascalco v. Sec’y, HHS, (1993):

The special master described Dr. Geier’s testimony as intellectually dishonest.

Aldridge v. Sec’y, HHS, (1992):

The special master found Dr. Geier’s reliance on statement from two outdated medical textbooks which was not included in the current edition to be disingenuous. “Were Dr. Geier an attorney, he would fall below the ethical standards for representation.”

Ormechea v. Sec’y, HHS, (1992):

“Because Dr. Geier has made a profession of testifying in matters to which his professional background [obstetrics and genetics] is unrelated, his testimony is of limited value to the court.”

Pease v. American Cyanamid Co., (1992):

In granting summary judgment, trial judge noted inconsistencies in Dr. Geier’s opinion.

Jones v. Lederle Laboratories, American Cyanamid Co., (1992):

“[T]he court was unimpressed with the qualifications, veracity, and bona fides” of Dr. Geier.

Daly v. Sec’y, HHS, (1991):

“[T]his court is inclined not to allow Dr. Geier to testify before it on issues of Table injuries. Dr. Geier clearly lacks the expertise to evaluate the symptomatology of the Table injuries and render an opinion thereon.”

Graham v. Wyeth Laboratories, (1990):

Dr. Geier’s calculation error was of sufficient magnitude so as to warrant a new trial.

And these are just the ones we could find. I imagine that there are some further humiliations hidden in the 1993 - 2003 time period that appears blank in this list. Even if there aren’t, isn’t this enough?

So,the question I’ve posed to all the lawyers I know (not a long list) is this:

“Is it legal malpractice to use an ‘expert’ witness that has been disqualified so many times?”

Their answers were varied and most of them started with “don’t quote me on this”, so I won’t. The bottom line was that it might be useful to hire a repeatedly disqualified “expert” if there was a chance that it might lead to a favorable settlement out of court.

It also might be that there aren’t that many “experts” who will say the things that Dr. Geier does.

One explanation of this might be that Dr. Geier’s “expert opinions”  are not consistent with the data.

Or, it could be that he’s the victim of a massive government conspiracy (with or without reptilian alien shape-shifters).

And so the insanity continues.

Prometheus

[NOTE: an important addendum was added at the bottom on 13 January 2008]

A few days ago, Dr. DeSoto of DeSoto and Hitlan, put an FAQ (Frequently Asked Questions) section on her website. Among the “frequently asked questions” was this one:

“Can you or can you not support that mercury is ‘excreted’ into the hair?”

 In her response, she listed a number of studies that had used the word “excretion” when describing the elimination of mercury via hair and fur. This, I presume, was to support the “poor excretor” hypothesis put forth in the discredited Holmes et al study.

This has inspired me to write a series of infrequently asked questions.

These are questions that aren’t asked very often, but should be.

Q. I hear a lot about hair mercury levels and excretion. How does mercury get into hair?

A. I’m glad you asked. Hair is made up primarily of a protein called keratin. This protein includes a large amount of the sulfur-containing amino acid cysteine. Many of these cysteines are involved in disulfide bonds, which bind the individual keratin strands together and give hair its strength. These disulfide bonds are very “attractive” to mercury. Mercury has a great affinity for sulfur and binds to it avidly.

As the hair is actively growing in the hair follicle, mercury in the blood can diffuse into the tissues and bind to the growing hair shaft [ e.g. Zareba et al (2007) ]. This is a passive process that is driven by only the concentration of mercury in the blood and the affinity between mercury and the sulfur in cysteine. In fact, studies have show that even after the hair has been shed, it can still absorb mercury [e.g. Mckintosh and Pate (1982) ] .  

There is no evidence of active transport of mercury at the hair follicle and, thus, no way to impair “excretion” of mercury into the hair, except by reducing blood flow to the hair follicle.

Q. I hear a lot about excretion of mercury in hair. Is it an important way for humans to “excrete” mercury?

A. In a strictly physiological sense, mercury isn’t “excreted” in the hair, since there is nothing more happening than simple diffusion and chemical bonding - there is no active process. However, in a looser sense, mercury is “excreted” into the hair because it is removed from the body via that route.

As for its importance as a means of eliminating mercury, there has been a lot of confusion about this. Animal studies often show that a large fraction of retained mercury ends up in the pelt or hair [e.g. Thomas et al (1988)]. I emphasized the word “retained” because mercury stays in the hair essentially forever, and so remains with the body until the hairs are shed.

While the fraction of the retained mercury contained in hair goes up with time, it is because the total amount of mercury in the rest of the body is declining, leaving the hair with a relatively larger percentage of the remaining mercury [ e.g. Farris et al (1993) ].

Even in rats, the amount of mercury eliminated via hair (fur) is only about 10% of the total body burden.

This is all very interesting, but many of the people touting hair as a significant route of mercury elimination have overlooked one small detail:

Compared to other mammals, humans aren’t very hairy.

That’s right. Compared to, for instance, mice, rats or even macaques, humans have a trivial amount of hair.

Especially infant humans.

Even at the very elevated levels of hair mercury reported in the anomalous Holmes et al study (3.63 ppm), the amount of mercury “excreted” in infant hair is miniscule. Even assuming a relatively bushy 10 grams of hair, this would only be 36.3 micrograms of mercury removed from the body. And remember, the average infant takes months to grow this much hair.

So, although mercury is found in the hair and - as a result of hair shedding - is lost from the body in the hair, hair is not an important route of elimination for mercury in humans.

Q. So, hair isn’t an important route of mercury “excretion” - isn’t it a marker for poor excretion in the rest of the body?

A. As mentioned above, mercury gets into hair by diffusing out of the blood and into the hair. Since the hair grows fairly slowly (about a centimeter a month), and because of the cysteine in hair, the concentration of mercury in the hair is much higher than in the blood - even with steady mercury intake.

However, this process is completely passive. It requires nothing more than the physical property of diffusion and the chemical affinity of mercury for sulfur, none of which is determined by the physiology of the hair grower. The two determining factors seem to be blood flow to the hair follicle and the amount of mercury in the blood [ e.g. Mottet, Body, Wilkins and Burbacher (1987) ]. Even transplanting human hair follicles into a different species (nude mice) didn’t change the hair:blood ratio significantly, so this seems to be something intrinsic to the hair and not dependent on the rest of the body.

A number of studies have shown that there are individual differences in the ratio of hair to blood mercury, including large differences between species. However, nobody has shown that there is anything resembling an active excretion pathway for mercury in hair follicles that could be impaired by genetic mutation, “toxic exposure” or other other mechanism. There have also not been any studies showing that reduced hair mercury is associated with “impaired excretion” of mercury by other routes.

Nor is there any physiological reason to suspect that there would be an association.

 Q. But Holmes et al showed that autistic children had lower hair mercury than they should have, based on their mercury exposure - why isn’t that “proof” enough?

A. Holmes et al didn’t actually measure mercury intake; they couldn’t, since the hair samples were years old by the time they analyzed them. What they did was to collect a lot of historical information - about vaccines, dental amalgams (fillings), fish consumption, etc. from the parents (mothers, primarily) of the autistic and control children.

They then used the hair mercury levels of the control (non-autistic) group to develop a formula which would use some of the historical information to generate “predicted” hair mercury levels that matched well with the actual hair mercury levels of the control group.

They then used this formula to calculate the “predicted” hair mercury levels for the children in the autistic group. As it turned out, the actual hair mercury levels in the autistic group were lower than the formula predicted. Their conclusion from this was that the autistic children were less able to excrete mercury than the non-autistic controls.

However, a later study - the NHANES study of hair mercury in children and women of childbearing age - showed that children ages 1 - 5 years (838 of them were studied) had much less mercury in their hair than the Holmes et al study found in their control. In fact, the Holmes et al controls had a mean hair mercury level that was more than fifteen times the NHANES mean level (it was about five times the 95th percentile value of the NHANES study results).

If the Holmes et al controls had anomalously high hair mercury levels, then the formula that they developed to predict hair mercury levels would “predict” anomalously high levels. That would go a long way toward explaining their results, without having to invoke an undocumented “poor excretion” hypothesis.

As it turns out, the autistic subjects in the Holmes et al study also had hair mercury levels that were above the mean levels found in 1 - 5 year-olds by the NHANES study, at about the 90th percentile.

 Although there have been a lot of discussion about what may have caused the Holmes et al control data to be so far from a much larger and better study, the bottom line is that the Holmes et al data are probably garbage. Unless and until somebody repeats the Holmes et al study and gets the same results, they are of no value.

Q. Why are some people continuing to argue that autistic children are “poor excretors” of mercury?

A. I don’t know. It’s probably a matter of inertia. People have heard the “poor excretor” story over and over, but don’t know much about the physiology of hair. It’s easier to repeat what they’ve heard than to actually stop and think, “How would that work?”

In addition, the hypothesis that mercury causes autism hasn’t been supported by the data. As a result, people who “believe” in the hypothesis are looking for something - no matter how weak - to support their belief system.

Q. Isn’t it possible that autistic children are “poor excretors” of mercury?

A. Absolutely. It’s possible, but there aren’t any data to support that hypothesis yet. It is also possible - although intuitively absurd - that mercury protects children from autism, if one believes the data from Holmes et al.

If some data are found that support the “poor excretor” hypothesis, then I’m all ears. But it will have to be something a lot more direct that simple hair mercury measurements. The researchers will have to be able to show that mercury elimination - in total, via all routes - is significantly lower in autistic children than in non-autistic children.

In short, it’s possible, just very unlikely, given the current data.

I’m always open to new data.

Prometheus

ADDENDUM!

Do’C and Interverbal sent me a reference they found on Dr. DeSoto’s “FAQ” section that is highly relevant to this topic. They’re working on a joint ‘blog article on DeSoto’s “FAQ” and sent this to me in advance of their post because it seemed so timely. I completely missed it when I read her FAQ, so I’m indebted to these two fine bloggers.

I’ve put it into an IAQ of its own:

Q. Are there any studies that show what would happen to hair mercury in the presence of true impaired mercury excretion?

A. Yes.

Gundacker et al (2007): “Glutathione-S-transferase polymorphism, metallothionein expression, and mercury levels among students in Austria.”

In this study, the authors looked at 222 Austrian students for the presence of deletion polymorphisms of two glutathione-S-transferase genes (GSTT1 and GSTM1) and the resulting hair and blood mercury levels and gene expression of two metallothionein subgroups (MT1 and MT3).

To put a bit simpler, they looked at the effect of deletion mutations of genes critical for mercury “detoxification” on hair and blood mercury levels, as well as the effect on the gene expression of two types of metallothionein (also important for mercury “detoxification”). People who lack a functional copy of the GSTT1 and/or GSTM1 gene(s) are much less able to excrete mercury. They are - in fact - “poor excretors”. They have what some in the mercury sub-group of autism advocacy refer to as “mercury efflux disorder”.

So, here we finally have the “poor excretors” that Holmes et al thought they had. These are people who actually have an impairment of their ability to excrete mercury.

I won’t keep you in suspense any longer. The mean blood mercury was 1.73 mcg/L (min = 0.11, max 7.79, N=222) and the mean hair mercury was 449 ng/g (min = 3, max = 3691, N=174 - 18 subjects didn’t provide enough hair for analysis).

Mean hair mercury by genetic group was as follows:

GSTT1 +/+ and GSTM1 +/+ (no gene deletions; “normal”): 244 ng/g

GSTT1 -/- or GSTM1 -/- (deletion in one - but not both - gene): 413 ng/g

GSTT1 -/- and GSTM1 -/- (deletions in both genes): 624 ng/g

These differences were statistically signficant (p = 0.017) by the Kruskal-Wallis test.

That’s right, folks. The “poor excretors” had elevated hair mercury. And Dr. DeSoto cited the study that showed it in her own “FAQ”. If that’s not hoisting yourself on your own petard, I don’t know what is.

So much for Holmes et al; so much for DeSoto and Hitlan. Impaired mercury excretion or “mercury efflux disorder” leads to increased hair mercury, not decreased hair mercury.

I wonder if anybody has sent this article to SafeMinds.

A big tip of the hat to Do’C and Interverbal.

Prometheus

Back from a relaxing holiday, I’ve decided to tackle a topic that I’ve been mulling over for months. 

For many years, I have pondered the paradox that the people who know the least about a subject are often disproportionately confident in their mastery of it.

For example, in the mercury-causes-autism movement, many of the people who are the most disdainful of those who disagee with their received knowledge have little or no discernible education, training or experience in science, let alone biology or medicine. These people have degrees in business, art or - in the case of one self-proclaimed expert - Google.

As I was pondering this paradox, a friend sent me a copy of an old (1999) article by Kruger and Dunning:

“Unskilled and Unaware of It: How Difficulties in Recognizing One’s Own Incompetence Lead to Inflated Self-Assessments”

In this paper, Kruger and Dunning, using Cornell undergraduates as subjects (OK, not exactly normal volunteers), examined how well a person’s performance in a variety of intellectual skills was reflected in their self-assessment of their own abilities. Using an exhaustive set of tests, they showed that the students’ prediction of their performance was unrelated to their actual ability.

Now, Kruger and Dunning felt that their data showed an inverse relationship between perception and ability - and that may be. Subsequent studies (e.g. Kreuger and Mueller (2002), Burson et al (2006), and Moore and Small (2007) ) suggest that the real issue is that everybody thinks that they are “above average” and have difficulty comparing their abilities to those of others. In the absence of actual face-to-face comparison, they assume that their abilities are equal to or better than most people.

Finally - a glimmer of illumination!

You see, it had always puzzled me that a person with, say, an MBA and a “Google PhD” (or, at least, a “Google MS”) would have the temerity to accuse me of arrogance when I disagreed with them on a matter that is within my “sphere of special competence”. I would have felt utterly foolish arguing with them about accerated depreciation or global marketing based on my “Wikipedia MBA”, so I was dumbfounded that they were so confident at the same time that they were so clearly wrong.

Let me get past any false modesty here: I may not be the top in my field, but I know far more about biology, physiology and genetics than the average - or even above average - person. Even if they have an MBA. That isn’t to say that somewhere among the 6.6 billion people on Earth there isn’t somebody with an MBA who knows more about biology than I do. However, I feel confident saying that there aren’t many people with no science background (apart from their MBA) that do.

So, who’s the more arrogant; the person with a deep background in biology who states that the current data doesn’t support a connection between autism and mercury or the person with no background in science (apart from Google-based “research”) who insists that there is?

How about somebody with no background in science who presumes to lecture experienced medical researchers about the “limitations” and “flaws” of their study? I have here a modest example:

[from New England Journal of Medicine, 358(1), p 93-94, 3 Jan 2008]

(paragraph breaks inserted in Ms. Bernard’s letter to enhance readability)

Early Thimerosal Exposure and Neuropsychological Outcomes

To the Editor: Thompson et al. (Sept. 27 issue) [1] report the results of a study investigating the neuropsychological outcomes of early exposure to thimerosal.

As a dissenting member of the panel of external consultants for this study, I object to the authors’ conclusion that there is no causal association between thimerosal and children’s brain function. The sample comprised children who were least likely to exhibit neuropsychological impairments. Specifically, children with congenital problems, those from multiple births, those of low birth weight, and those not living with their biological mother were excluded.

The sample was skewed toward higher socioeconomic status and maternal education — factors that are associated with lower rates of neurobehavioral problems and higher intervention rates and that were not measured. The sampling frame included only children enrolled from birth in the health maintenance organization (HMO) and still enrolled after 7 to 10 years, excluding children in higher-mobility families, who tend to have lower academic and behavioral function.[2] Children with neurobehavioral problems may have been less likely to remain with the HMO. Only 30% of families selected for recruitment participated, a low rate for scientific research.

Among the families selected for recruitment, 26% refused to participate. Another 28% “could not be located,” which included families that did not respond to multiple recruitment attempts (internal documentation from the study contractor, Abt Associates) — another form of refusal.

Sallie Bernard, B.A.
SafeMinds
Aspen, CO 81611
sbernard@safeminds.org

[1] Thompson WW, Price C, Goodson B, et al. Early thimerosal exposure and neuropsychological outcomes at 7 to 10 years. N Engl J Med 2007;357:1281-92.

[2] Rumberger RW. Student mobility and academic achievement. In: Child & adolescent development. MentalHelp.net. January 23, 2003. (Accessed December 12, 2007, at http://mentalhelp.net/poc/view_doc.php?type=doc&id=2084&cn=28.)

The measured reply from the authors:

Bernard raises several points that we wish to address. First, children with low birth weight or serious congenital conditions or conditions developing in infancy that are known to be associated with an increased probability of neurodevelopmental problems were excluded from the study. It would have been difficult to distinguish the possible added influence of thimerosal exposure on neuropsychological deficits among such children. To do so, a larger study with a different design would be required.

Second, our sample was probably skewed toward higher socioeconomic status because participating families were members of HMOs in which coverage was provided by employers. In the study population, thimerosal exposure was associated with both maternal education and maternal IQ. We therefore controlled for socioeconomic factors, maternal education, and maternal IQ in the statistical analyses.

Third, our study was less likely to include highly mobile families because the participants had to have been enrolled in the same HMO during the first year of life and during the time of testing 7 to 10 years later. These criteria ensured that we had all immunization records during the first year of life, as well as access to the participants’ medical records during the time of testing. This enhanced the internal validity of our study but makes the results less generalizable to highly mobile families.

Finally, the 30% participation rate may have resulted in some unmeasured biases. Participation in the study required a substantial time commitment from mothers and their children. Although the 30% participation rate was relatively low, it was higher than we estimated when we planned the study. More discussion regarding participation and other issues can be found in the study technical reports, available on the Web site of the Centers for Disease Control and Prevention.[1,2]

William W. Thompson, Ph.D.
Centers for Disease Control and Prevention
Atlanta, GA 30333
wct2@cdc.gov

Cris Price, Sc.M.
Abt Associates
Bethesda, MD 20814

Frank DeStefano, M.D., M.P.H.
RTI International
Atlanta, GA 30341

[1] Price C, Goodson B, Stewart G. Infant environmental exposure to thimerosal and neuropsychological outcomes at ages 7 to 10 years. Technical report. Vol. I. Bethesda, MD: Abt, 2007.

[2] Idem. Infant environmental exposure to thimerosal and neuropsychological outcomes at ages 7 to 10 years. Technical report. Vol. II. Bethesda, MD: Abt, 2007.

Ms. Bernard’s inclusion in the “panel of external consultants” was - whether she realized it or not - an attempt to forclose this sort of argument from the mercury-causes-autism advocates. Having been part of the decision-making process, Ms. Bernard’s argument that the study was flawed falls, at least in part, on her own head.

Of course, the researchers didn’t do their study in exactly the manner that Ms. Bernard would have wanted - that would have led to results that were more noise than signal. The cynical part of me wonders if that isn’t what Ms. Bernard wanted.

I don’t want to leave the impression that I am singling out Ms. Bernard as a particularly egregious example of the “arrogance of ignorance” - she is no more than average in this regard. There are people in the mercury-causes-autism movement who are far more arrogant than she. I picked her because her NEJM response is so recent.

So, what can be done to combat the “arrogance of ignorance”? The papers I listed at the beginning of this post give some suggestions. Although not universally seen, education seems to help in a number of situations. Once people learn more about a subject, they begin to develop a grasp of how much they do not know. This should feel familiar to some people reading this ‘blog - myself included: the more you learn about a subject, the more you realize that you don’t know.

[Corollary: If you think you have a complete grasp of a subject, you are probably wrong.]

However, one of the problems that we deal with - especially in autism-related subjects - is the propaganda disseminated by many of the so-called autism advocates. In addition to the vast amounts of speculative, conjectural and often incorrect information these groups put out, they also promote the idea that “mainstream” science and medicine are uninformed, biased, corrupt or even conspiring to hide “the truth”.

These accusations make it nearly impossible for people who “buy in” to ever recognize incorrect information. Since, as they are told, anyone who disagrees is either ”stuck in old, fixed dogma” or “part of the conspiracy of silence”, there is no way for the “believers” to discover their errors.

As a result, a group of parents and other supporters are convinced that they know more about biology, physiology, genetics and medicine than the people who really do know the most about those subjects. This upside-down situation is perpetuated by a small group of scientists (who should know better) and doctors (who also should know better, but usually don’t) who support both the erroneous perception of competence and the assumption that dissenting opinions are not just wrong, but immoral.

For reference, the way real scientists deal with disagreement is not by accusing each other of corruption, conspiracy or incompetence (although that sometimes happens, it is not respected and is generally ignored). The way real scientists rebut a hypotheses is by generating more data (not more press conferences). When you see a “scientist” resorting to rebuttal-by-press-conference (as was prominent in the Cold Fusion debacle), you know that you’re not seeing science.

In an interesting parallel, many of the cold fusion “believers” also claim that “the government” (in collusion with “Big Energy”, of course) is trying to “suppress” cold fusion. They also love to claim that physicists who aren’t convinced that cold fusion exists do so, not because of the general lack of data supporting cold fusion, but because they are “stuck in old, fixed dogma” or are part of the “conspiracy of silence”.

Sound familiar?

Ignorance is nothing to be ashamed of - we are all ignorant in many areas.

On the other hand, ignorance is nothing to be arrogant about, either.

Prometheus

Two articles have been making the rounds on autism “biomed” ‘blogs and lists recently:

 DeSoto and Hitlan, “Blood levels of mercury are related to diagnosis of autism: a reanalysis of an important data set.”

 and

Curran et al, “Behaviors associated with fever in children with autism spectrum disorders.”

The first of these has been dealt with by other bloggers, but it keeps rearing its ugly head, so, with a degree of reluctance, I will try to deal with it in my own inimitable (if pedantic) manner.

 The second article, when I read it, struck me as sort of a “so what?” study. Then I found out that there is a whole sub-culture in the “autism community” that believes some autistic children have been “cured” by a high fever. While this may have originated as a “grass-roots” anecdote, it probably got a big boost from a story by Dan Olmsted, ex-UPI Senior Editor for autism and now stringer for an “biomed”-advocacy ‘blog. My, how the mighty have fallen.

DeSoto and Hitlan:

The origins of this article is a study by Ip et al (June 2004) on hair and blood mercury levels in autistic children compared to non-autistic controls. In this study, the authors found no significant difference between the autistic and non-autistic groups’ hair and blood mercury levels.

 Now, this was only “an important data set” to a small group of “researchers” - those who are trying desperately to show that mercury causes autism. More specifically, it is critically important to those who are trying to resuscitate the stillborne hypothesis that autistic children can’t excrete mercury.

 This unsupported claim was first made by Holmes et al, in their article of August 2003. Not only did they fail to give a single piece of data to support this outlandish assertion, their entire data set was called into question when, in August 2004, the NHANES study on hair mercury (in 838 children) showed that the Holmes et al control subjects had over sixteen times the hair mercury levels of the children in the NHANES study. The autistic group had hair mercury levels that were over twice the NHANES mean.

Well, for anyone with a brain, that was pretty much “Game Over!” for the Holmes et al study. No matter what caused the huge discrepancy in their analysis, none of their data can be trusted. And even if we allow them to wiggle out of the control discrepancy, the autistic group still had more hair mercury than the NHANES mean, so “poor excretion” doesn’t apply.

In April of 2007, Kern et al tried another go at the “poor excretor” hypothesis. What they came up with a lack of significance for mercury. They tried to put a brave face on it by showing a “statistically significant” correlation between arsenic, cadmium and lead and autism, which they asserted was just as good as showing it for mercury, since they’re all “sulfhydryl-reactive metals”.

This was all well and good, except that their section on statistical analysis doesn’t mention any correction for multiple comparisons (e.g. the Bonferroni correction), so “significant” may be a relative term.  At any rate, Kern et al failed to show any statistically significant difference in hair mercury levels between the autistic and control groups, so they didn’t support the assertion (I refuse to call it an hypothesis) of “poor excretion” made in Holmes et al.

Now the husband and wife team of DeSoto and Hitlan are trying to show how an “important data set” that also failed to show a statistically significant difference between the hair (and blood) mercury levels in autistic and non-autistic children was “flawed” and inappropriately analysed.

In a nutshell, DeSoto and Hitlan (D&H) argue that a one-tailed test should have been used because Ip et al knew which direction the difference between autistic and non-autistic groups would be (i.e. that the autistic group would have a higher blood mercury and a lower hair mercury) based (presumably) on the appallingly bad Holmes et al study.

 In reality, it appears that D&H are making some unsupported assumptions of their own, by using a test that would show higher “significance” if the difference were in the direction they assume. Given, however, that Ip et al really didn’t know beforehand (or at least, didn’t assume) the direction of the difference, the two-tailed test they used was very appropriate.

 In fact, the analysis by D&H appears to be nothing more than post hoc statistical fiddling to get the desired answer.

Some of the other fiddling was to remove outliers - always a tricky proposition and one that need to be very well justified. Their stated assumption is that these values disproportionately skew the results, which is rather a poor reason for removing them. An even  better argument could be given for removing the values as the lower end of the scale, since these are at the lower end of detection and cannot be distinguished from zero.

Here’s the original (as corrected by Ip in November 2007) Ip et al data:

 As you can see there are two values - one in the autistic group and one in the non-autistic group - that are clearly not grouping with the others. This data gives a one-tailed p-value of 0.028 and two-tailed p-value of 0.057 for the blood values and p-values of 0.40 and 0.80 for the one- and two-tailed t-test on the hair data.

So, if you think that Ip et al should have known which way the difference would go, the results are signficant for blood and not hair. If, on the other hand, you think they should have gone into their study with an open mind - since there is no a priori reason they should have known that the difference would go a certain direction - then the results are not significant.

But what about those outliers? Here’s what is looks like when I remove these ”outlying” data points in each group.

This gives a one-tailed p-value of 0.0089 and a two-tailed value of 0.018 for the blood values and 0.14 and 0.29 (one- and two-tailed) for the hair values. That would give a significant difference for blood and not hair, no matter how many tails you use.

So, D&H have deomonstrated that by removing the “outliers”, the blood mercury levels in autistic subjects is higher than that of the control subjects, while their hair mercury is indistinguishable.

One possible explanation of this could be that autistic children excrete less mercury than their non-autistic peers….except that nobody has ever shown - in any mammal (let alone primate) - that mercury is excreted by the hair. In all studies performed to date, the hair mercury is a constant fraction of the blood mercury [note: some animal studies have shown precisely the individual variation in that fraction that the Ip et al data show].

So, unless D&H (or Holmes et al, Kern et al, or Whoever et al) have shown that hair mercury level says anything about mercury excretion (by the organs that really excrete mercury - the kidneys and liver), then all they’ve shown is that - in this group of children, the autistic group had a higher blood mercury.

D&H also do not address the numerous other studies that have failed to find a connection between mercury and autism, which is probably why they refer to the Ip at al study as “an important data set”. If they can “turn” Ip et al - so they must think - the wall of data refuting the mercury-causes-autism dead-as-a-doornail hypothesis will crumble.

Except that it won’t. No other study refuting the mercury-causes-autism undead-parrot hypothesis is critically dependant in the Ip et al study. They all stand on their own merits - unlike the myriad “poor excretor” studies that live or die by the finding that hair mercury is an indicator of mercury excretion.

It’s also curious that no matter how D&H twist the data, the hair mercury levels remain essentially the same in the two groups. Curious. Yet D&H insist that their re-analysis supports the Holmes et al conclusions, which were based on autistic children having significantly lower hair mercury than their non-autistic peers.

It’s also curious that the mean hair mercury values in the Ip et al study (and, by extension, the DeSoto and Hitlan article) is about nine times the hair mercury levels found in the NHANES study.

Maybe the Ip et al study says more about living in Hong Kong than it does about autism.

And maybe - just maybe - the Ip et al data set is only “important” if it can be “turned” to support an physiologically un-supportable hypothesis.

Curran et al:

The Curran et al study is an interesting one. As I mentioned above, unless you know the background - the persistent stories of how fever has “cured” autism - it comes across as a “so what” study.

However, this is not how the media - and the “biomed”-advocacy ‘bloggers - have presented it.

To hear it on the radio, television and ‘blogosphere, Curran et al have shown that fever “cures” autism. Unfortunately, this isn’t what their published study says:
“We documented behavior change among children with autism spectrum disorders during fever. The data suggest that these changes might not be solely the byproduct of general effects of sickness on behavior; however, more research is needed to prove conclusively fever- specific effects and elucidate their underlying biological mechanisms (possibly involving immunologic and neurobiological pathways, intracellular signaling, and synaptic plasticity).”

Looking at the data shows exactly how far from reality many of the reports have been.

Curran et al examined the Aberrant Behavior Checklist (ABC - a parent checklist) subscale scores of autistic children during, 1 - 3 days after, and one week after a febrile illness (greater than or equal to 38 degrees C) and compared them to autistic children without fever.

What they found was interesting, but not a “cure” for autism.

The “lethargy” subscale went up during fever and gradually returned to baseline at one week after the fever had passed (no surprise here).

The “irritability” subscale went down slightly but then rose and remained higher than baseline throughout the duration of the testing.

The “hyperactivity”, “stereotypy” and “inappropriate speech” subscales went down during the fever and gradually returned to baseline by one week after the fever.

Bottom line: all subscales were back to baseline - except for “irritability”, which remained slightly elevated - by one week after the fever.

Not exactly a “cure”.

Of course, I expect that the “biomed” advocates will shortly be trotting out recommendations to induce hyperthermia in autistic children in order to effect a “cure”. Doubtless the “IR sauna” manufacturers will be claiming that this study validates their product.

Oh, if only it were that simple.

Prometheus