Winter Potpourri
December 10th, 2007
Two articles have been making the rounds on autism “biomed” ‘blogs and lists recently:
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
Filed under: Autism Science, Autism Treatments, Critical Thinking | 20 Comments »
Piddling Diagnostic Tests for Austism
December 5th, 2007
Every once in a while, I get one of those “Aha!” moments.
I got one a few days ago from the most unlikely source.
I was answering a rather snarky e-mail from a reader who is a firm believer in Google inerrancy and wanted to ask me (not really - she wanted to tell me) how her autistic son’s urine tests could have gone from showing Clostridia and “yeast” to being “clean” if it wasn’t due to the treatments he had received.
Her son had gone to a DAN! doctor (who shall remain nameless) and had been put on the “usual suspects”: GFCF (gluten-free/casein-free) diet, “supplements”, chelation, “pro-biotics”….you know the drill.
As the result of this ‘blog, I get a lot of hostile “questions” from various Google PhD’s and Yahooligans (like on the game show Jeopardy, the “answer” is often phrased as a question), so I like to make sure of my facts before I put pen to paper (or, more accurately, bits to memory).
So, as part of my usual prep to answer this technical question (it was “technically” a question), I did a literature search on the two “organic acids” that a certain diagnostic lab (which shall also remain nameless) found in her son’s urine and had assured her were “diagnostic of Clostridia or yeast overgrowth.”
I’ll admit that I was curious (and not just a little skeptical) about how these two compounds (DHPPA and hippuric acid) could be “diagnostic” of both a single bacterial genus and a eukaryote (”yeast” - presumably Candida spp.) and not also be “diagnostic” of a whole host of other bacteria and fungi.
What I found was a surprise.
DHPPA (dihydroxyphenylproprionic acid) is used as a marker for the amount of bran (found in whole grains) in a person’s diet (see: Koskela et al 2007, “Quantification of Alkylresorcinol Metabolites in Urine by HPLC with Coulometric Electrode Array Detection”). It is a normal metabolic product of alkylresorcinols, which are quite prevalent in grains.
I also suspect that the “new” compound that this lab is looking for [ 3-(3-hydroxyphenyl)-3-hydroxypropionic acid - HPHPA] as a “diagnostic” marker for “dysbiosis” will also be found to be a normal metabolic product - if anybody else ever finds it (no luck on searches of MedLine and Web of Science).
In fact, the HPHPA “story” sounds suspiciously like that of IAG (indolyl-3-acryolylglycine), which was initally thought to be a specific marker for autism (in a single lab) and was later found to be present in the urine of all children (by a different researcher) in that nobody else seems to have found it - or at least published about it.
So, it looks as though DHPPA (and probably HPHPA) is a marker for whole-grain consumption. Now it all starts to make sense.
Here is a possible scenario:
[1] Parents have child tested for ”organic acids” and find DHPPA (or HPHPA). They are told that the child has “intestinal dysbiosis” due to an overgrowth of Clostridia and/or “yeast”.
[2] Parents are given instructions to give various antibiotics, probiotics, prebiotics (I’m not making this up) and are advised to put child on gluten-free (and casein-free) diet, which eliminates most grains that are high in alkylresorcinols.
[3] With consumption of alkylresorcinols reduced, child’s urinary DHPPA (and probably HPHPA) decreases.
[4] Parents are told that the “treatment” has cleared up the child’s “dysbiosis”.
[5] Laboratory and physician collect fees from parents (actually, this probably happened before [1]) and bask in the glow of their appreciation.
But how about the other “marker” for dysbiosis: hippuric acid?
Hippuric Acid is a metabolite seen in the urine of most humans. It is especially elevated in people who are exposed to toluene and it is used to medically monitor the exposure of workers who use this solvent.
It is also is the metabolic product of benzoic acid (sodium benzoate - look on the food labels for this one) and all sorts of flavonoids, such as those found in tea, citrus, soy products and chocolate.
Although there aren’t too many autistic children drinking tea, I’ll bet that a few of them are eating soy products, citrus fruit and fruit juices and maybe even a bit of chocolate, now and then.
And, when you think about it, some of the dietary interventions (e.g. the Feingold diet) would also reduce the intake of phenolic compounds and flavonoids.
Voila! The “dysbiosis” is cured!
Another thing that showed up in this study was 3-(3-hydroxyphenyl)propioic acid, a metabolic product of flavonoids found in citrus. It is only a single hydroxy group away from the HPHPA that a certain mail-order laboratory is claiming to be “diagnostic” of Clostridia and “yeast”.
In the end, do DHPPA/HPHPA and hippuric acid in the urine mean anything?
Absolutely!
DHPPA is an indicator of bran intake, and can be used to quantify the amount of bran in a person’s diet.
Hippuric acid is an indicator of the amount of dietary flavonoids and phenolic compounds.
HPHPA is a marker for citrus-derived flavonoids.
But none of them appear to be specific for Clostridia, “yeast” or any other organism.
So, it looks as though the parents paying for these tests are just pissing their money away.
Prometheus
Filed under: Autism Science, Autism Treatments | 15 Comments »