6/04/2010

Sometimes a Urine Test is Full of Piss (or why a urine test for autism is not soon coming)

Yap, Angley, Veselkov, Holmes, Lindon, and Nicholson (2010) have ignited a lightning storm of interest with their theoretical urine test for autism that could prevent autism, at least according to study author Nicholson, speaking to Richard Alleyne of the Telegraph:

Professor Jeremy Nicholson, the author of the study, said: "Children with autism have very unusual gut microbes which we can test for before the full blown symptoms of the disease come through.
"If that is the case then it might become a preventable disease."

Yap et al. write that “Autism has been shown to have strong associations with various metabolic abnormalities, immunological function and gastrointestinal disturbances, although their mechanistic significance is unknown.5–8”

Let’s look at their sources for the idea that children with autism have intestinal issues that are causal for said autism, since this is outside mainstream scientific findings (Ibrahim et al., 2009; Buie et al., 2010), especially in light of Nicholson’s whole gut microbe bit.

(5) Kidd, P. M. Autism, an extreme challenge to integrative medicine. Part: 1: The knowledge base. Altern. Med. Rev. 2002, 7 (4), 292–316.

So, one source for this whole gut microbe difference is from a journal entitled Alternative Medicine Review. And Kidd (2002) has this to say about autism:

“Frequent vaccinations with live virus and toxic mercurial content (thimerosal) are a plausible etiologic factor.”  So, Yap  et al. used a dubious source with outdated information regarding a debunked thimerosal connection with autism? Really?

Moving on.

(6) Ashwood, P.; Anthony, A.; Pellicer, A. A.; Torrente, F.; Walker-Smith, J. A.; Wakefield, A. J. Intestinal lymphocyte populations in children with regressive autism: evidence for extensive mucosal immunopathology. J. Clin. Immunol. 2003, 23 (6), 504–17.

Okay, so in spite of all the controversy surrounding Walker-Smith and Wakefield, Yap et al. used a 2003 journal article by them for their gut theory?

Yeah, kinda lessens the legitimacy, doesn’t it?

Moving on:

(7) Chugani, D. C.; Sundram, B. S.; Behen, M.; Lee, M. L.; Moore, G. J. Evidence of altered energy metabolism in autistic children. Prog. Neuropsychopharmacol. Biol. Psychiatry 1999, 23 (4), 635–41.

1999?  And it’s a pilot, with 9 to 15 autistic children in it. Hardly definitive and has nothing to do with gut microbes whatsoever or with gastrointestinal issues or differences.

Let’s look at the last study Yap et al., and especially Nicholson, seem to be using to hang their hat on the gut differences theory.

(8) Levy, S. E.; Souders, M. C.; Ittenbach, R. F.; Giarelli, E.; Mulberg, A. E.; Pinto-Martin, J. A. Relationship of dietary intake to gastrointestinal symptoms in children with autistic spectrum disorders. Biol. Psychiatry 2007, 61 (4), 492–7.

Of all the sources, this perhaps is closest to being credible except for the fact that there are more recent, more exhaustive studies that discount there being more gastrointestinal issues in autistic individuals than the general population (Ibrahim et al., 2009; Buie etal., 2010). There’s a problem, though, even with this study in that it uses Wakefield’s retracted Lancet case series as one of its backbones.

In other words, Yap et al., despite the opportunity to be aware of the weakness of their sources, good mainstream science countering those sources, chose to use dubious sources as the backbone for their theory regarding “gut disturbances.”

Let’s say we ignore all the above and look at the actual science conducted by Yap et al. and contrast it to what Nicholson says in the Telegraph article.

Who did the researchers look at? Yap et al. report that they used  “34 controls, 28 siblings and 39 autistic urine samples.” The controls came from the Swiss Tropical Institute, and the autistic and siblings were from Australia. But the researchers assure readers that they made sure there was no difference: “To address bias deriving from geographical location, urine samples from the second group of controls were profiled together with the first group of controls. The two control data sets were shown to be statistically indistinguishable (data not shown).”

Okay, so this is an extremely small sample. It’s a new theory, so qualifies as a pilot investigation. Surely the researchers recognize that and don’t hype it past a “hey, isn’t this interesting?” kind of level, right? Wrong.

Let’s just replay Nicholson’s quote again:

Professor Jeremy Nicholson, the author of the study, said: "Children with autism have very unusual gut microbes which we can test for before the full blown symptoms of the disease come through.
"If that is the case then it might become a preventable disease."

There is no indication of how these study participants were selected, there’s no mention of differences in diet that would contribute to differences.

In addition, Nicholson with his five pound urine test to diagnose autism as early as six months and thereby prevent it goes much farther than the study itself does. And Alleyne certainly goes well beyond it:
Eventually the link between the learning difficulties and the gut microbes could be established and that could lead to "probiotic" treatments or cures.”

There is an abundance of evidence that gastrointestinal issues are not causative or correlated with autism (Ibrahim et al., Buie et al.). 

There is no reason despite 34 autistic children (whose selection criteria is not visible) having different urine results to believe what Nicholson is asserting in his interview with Alleyne. Yap et al. didn’t call for using the urine test to diagnose early, but noted that further, larger studies needed to be done. Certainly, relying on sound scientific data for one’s theories is important and it is not clear, based on the four studies the authors rely on for their assumption of a gastrointestinal link with autism, that they are on solid ground.

Nicholson, at least as presented by Alleyne, did not speak as a circumspect scientist with preliminary data from a small sample, would or should.

Alleyne, as a member of the media, went too far in asserting “The latest breakthrough shows that it is possible to distinguish between autistic and non-autistic children by looking at the by-products of gut bacteria and the body's digestive processes in the children's urine.” No, that’s not what this study showed. It showed that the three groups were different, but it didn’t show why and it didn’t rule out sample selection bias.

References:

(Buie et al., 2010). Buie, Timothy, Campbell, Daniel B., Fuchs, George J., III, Furuta, Glenn T., Levy, Joseph, VandeWater, Judy, Whitaker, Agnes H., Atkins, Dan, Bauman, Margaret L., Beaudet, Arthur L., Carr, Edward G., Gershon, Michael D., Hyman, Susan L., Jirapinyo, Pipop, Jyonouchi, Harumi, Kooros, Koorosh, Kushak, Rafail, Levitt, Pat, Levy, Susan E., Lewis, Jeffery D., Murray, Katherine F., Natowicz, Marvin R., Sabra, Aderbal, Wershil, Barry K., Weston, Sharon C., Zeltzer, Lonnie, Winter, Harland. Evaluation, Diagnosis, and Treatment of Gastrointestinal Disorders in Individuals With ASDs: A Consensus Report Pediatrics 2010 125: S1-S18

(Ibrahim et al., 2009) Samar H. Ibrahim, Robert G. Voigt, Slavica K. Katusic, Amy L. Weaver, and William J. Barbaresi Incidence of Gastrointestinal Symptoms in Children With Autism: A Population-Based Study Pediatrics, Aug 2009; 124: 680 - 686

(Yap et al., 2010). Ivan K. S. Yap, Manya Angley, Kirill A. Veselkov, Elaine Holmes, John C. Lindon and Jeremy K. Nicholson  Urinary Metabolic Phenotyping Differentiates Children with Autism from Their Unaffected Siblings and Age-Matched Controls J. Proteome Res., 2010, 9 (6), pp 2996–3004 Publication Date (Web): March 25, 2010 (Article) DOI: 10.1021/pr901188e

An excellent breakdown of the study is here. Some of the limitations are noted:

"The research has several limitations:
  • The researchers point out that, as it is not possible to tell whether these differences indicate a cause or consequence of the disease, further research is needed in a larger group of children over time.
  • Different statistical analyses had different results, some showing differences in certain chemical levels in autistic children, while others did not.
  • The researchers did not assess the medications the children with autism were taking for their condition or the diet they were following. Both would affect the chemicals they found in the children’s urine samples." 
Kinda makes Nicholson going out there all gung-ho on his study look even more suspect, doesn't it?

7 comments:

Life as the mother of 4 said...

You cited some of Tim Buie's research so I thought you might be interested in what he has to say about treating GI issues and having behaviors that were attributed to autism disappear or lessen. This is something he has lectured on frequently. On a personal note, he is a fabulous doctor. He is my son's pediatric gastroenterologist.

I searched online for a lecture and this came up. I don't know when this was filmed. But I've heard him passionately discuss the unjustness of how children with disabilities are often not treated for GI issues when if they were typically developing they would be.

Fair Autism Media

KWombles said...

Thank you; I'm actually very familiar with Buie's work.

I've never argued that gastrointestinal issues don't impact behavior, and it's absolutely reprehensible that any child with medical issues would not receive appropriate interventions. Personally, my three children have never received lesser treatment nor had their illnesses brushed off because of being on the spectrum. On the same note, though, I have had medical issues brushed off over my lifetime. Disability isn't required to not be taken seriously by medical professionals. All that's required is an asshat of a medical professional.

Of course, if an autistic child has accompanying intestinal distress, behaviors will be more severe. As someone who has lived most my life with gastrointestinal issues, I can well attest to the difficulty it places on one's ability to focus and attend. It can also make one significantly short-tempered to always be in distress.

There is no question that a number of autistic children present with gastrointestinal issues. There's also little question that some of the restricted diets can play a role in increasing those gastrointestinal issues. However, there's also absolutely no known, sound connection between autism and a "leaky gut" and Wakefield's autistic enterocolitis is on an equivalence with Morgellon's.

kathleen said...

Yes-another study that is just pissing in the wind. What do G I issues have to do with peeing in a cup? None of my four have GI issues..three are on the spectrum...what could their pee possibly show-besides that they were able to pee in a cup?

David said...

A possible issue here is how long it takes for papers to get through the system for publication: 3 months is GOOD time. Hence, it's all to easy for a source to become outdated or be wholly falsified in just the time it takes to go from submission to acceptance.

KWombles said...

Certainly, there is no way the authors knew at the time of the study that Wakefield would have three studies retracted. I didn't argue that. I argued that there was every reason to know at the time that their sources were dubious at best. The literature they chose reflected their bias in favor of what they almost certainly had to know was not accepted by the mainstream scientists researching autism.

It'd be like using Blaxill, Deth, the Geiers, or Haley's work: immediately apparent to anyone informed in autistic research what angle one was approaching their own research from.

Life as the mother of 4 said...

I'm glad your kids haven't suffered. Unfortunately, Will did. I felt very guilty once I learned that he'd suffered from abdominal pain for a year. One of my friends is still trying to find the source of her son's pain episodes. It's so hard to figure things out when you are dealing with non-verbal or verbally challenged kids. Many doctors get so intimidated by the idea of a disability that they freak out.

KWombles said...

My children haven't suffered in the sense that they have never had their health issues dismissed because of their ASD. That isn't the same as not having had health issues, though.

Yes, dealing with nonverbal children can make assessing their pain tremendously difficult. It isn't much easier (having dealt with both) with a verbal autistic child who has difficulties in expressing his or her sensory experiences and finding a way to put his or her sensations into a meaningful descriptor. Having children who are hypersensitive to pain and feel a scratch keenly, intensely, and who react to it more forcefully than a serious injury requires a bit of improvisation on my part.

As to guilt over suffering, I watched my son experience a stroke at the age of 9; we're coming up on the 12th anniversary of it. His expression at the time was that he had a headache; that was what he used to communicate he didn't want to do something. So, the evening of his stroke, when he complained of a headache, I didn't take it seriously initially. By the time we got him to the hospital he was paralyzed on the right side and couldn't speak.

My point: as parents we all have a plethora of events, decisions, misses that we can add up to weigh us down with guilt. The why-didn't-Is are non-ending if we let them be.

That's no way to live, though. We do the best we can as we go along. Sometimes, the best isn't enough. But if we did the best we could, then choosing to carry guilt instead of acceptance is a choice we make. And it weighs us down, impairs our ability to give our best now. It serves no purpose.

This study is a preliminary study founded on dubious sources with what appears to be a poorly selected sample. It doesn't help autistic children now, whether they have gastrointestinal issues or not. It likely will not help them in the future, either.

As to medical professionals brushing off our children's health issues: it's my job to advocate for my children. It's my job. If a health professional brushes off my concerns, I state my case to the professional. If that doesn't fix it, I go to a different physician. Period. I don't assume I'm better informed than the health professional, that I have the answers, but I make sure I know what questions to ask.