When worlds collide: Wakefield, ethics, & where I live

The News of the Day is that the British Medical Journal has called Andrew Wakefield’s notorious and notoriously retracted vaccine-MMR study “fraud.” That’s something a lot of people had already figured out, but with the imprimatur of BMJ, I guess this makes it official.

Ah, it takes me back, though. To the time I dined with Andrew Wakefield. To that day that the Lancet issued its full retraction of that horrific, fraudulent trash heap of a paper.  To that satisfying few hours of schadenfreude when the GMC handed down its decision to strip him of his license. To my various other Andy sightings about town. To the real horrors of what he wrought when he did what he did to those children in that study.

I’ve posted a lot about Wakefield on my personal blog, and some of the posts have focused on my anger at his bastardization of science and my musings on how people might feel when they falsify data. They’ve included mapping what the enormity of the alleged conspiracy against him would have to be and breaking down with tongue firmly in cheek his plea to make his book of apologia a bestseller. There was the post that I swore would be My Last Word on Wakefield (it wasn’t).

Finally, there is what I taught my son today. We’re studying science–Science–and we were discussing the qualities that make one a good scientist. Sure, there’s curiosity. Creativity. And…there’s honesty. For that and that alone, I close with my defense of ethics in science, why ethics matter, and why I think someone who perpetrates this level of harm to public health ought to be somewhere away from his comfortable, ultra-expensive home just a stone’s throw from where I live. Preferably a quiet place, perhaps with four bare walls, a place where he can ponder the damages he’s wrought.

NPR’s Asperger’s FAIL

NPR’s “All Things Considered” ran a piece today on the difficulties in defining “mental disorders.” Based on what is posted on their site regarding the piece, they essentially report the opinion of one man, Allen Frances, who has taken it upon himself to do two selfish things. The first is that he blames himself for what he calls the “Asperger’s epidemic.” The second is that he felt compelled to discuss some unfounded–or at least, unsupported–assumptions about Asperger’s diagnoses on NPR.

Frances, former chief of psychiatry at Duke University Medical Center, was the editor of the previous edition of the “mental disorders” bible, the Diagnostic and Statistical Manual of Mental Disorders. We’re coming up on the fifth version of this hefty tome. From my personal experience, by the time it comes out, research will be about five years ahead of much of what it contains. But never mind that. Frances’ issue with IV was that it contained Asperger’s as a diagnostic category (he has other issues not addressed in the NPR piece). He describes having acquiesced in its inclusion based on needs expressed by professionals who were seeing children with autism-like behaviors that weren’t as severe as the disorder known as autism.

Now he regrets that. Why? Because so many children are now being diagnosed with Asperger’s. As the parent of a child with autism, as the friend of many families with parents or children with autism, as the acquaintance of many grown people with autism–including Asperger’s–I can say that many of us would perceive that increase as a good thing. Why? Because that means more people with autism are able to recognize what makes them tick, and it helps them to know that yes, in a world where many of us feel like Temple Grandin’s aptly described “anthropologist on Mars,” there are a lot of other like-minded anthropologists out there.

That’s not Frances’ take. Based on a study done at the time IV was formulated, Asperger’s was “vanishingly rare.” That’s not too shocking given that for most professionals, it didn’t exist yet. The explanation that he offers for the increase in Asperger’s cases isn’t that there is now a diagnostic category for it, but that people–parents, presumably–seek the diagnosis so that their children can get services at school. This part is worth quoting from the piece:

“And so kids who previously might have been considered on the boundary, eccentric, socially shy, but bright and doing well in school would mainstream [into] regular classes,” Frances says. “Now if they get the diagnosis of Asperger’s disorder, [they] get into a special program where they may get $50,000 a year worth of educational services.”

The clear inference to draw from this is that there are hundreds of medical professionals out there deliberately stretching the diagnostic checklist for Asperger’s to cover children who are “doing well in school” and who are “socially shy” (what other kind of shy is there?). I have a few problems with this scenario.

First, if your child is doing well in school, you don’t get services. Services are for academic support. Period. There aren’t “special programs.” A child may have academic supports from almost nothing to a full-time aide in an integrated classroom to exclusion in a resource classroom. There is no one “special program.” That’s one reason they call those things INDIVIDUAL education plans. Regardless, if you’re doing well academically, you don’t get these supports. If you have speech or motor deficits, you receive appropriate therapies. But the deficits have to be there–they’re not something you just make up.

Second, if your child is doing well in school, parents and schools and medical professionals don’t generally go looking for a label to slap on the child. Parents seek help because their child has a problem or problems. The gold standard for calling something a disorder is if it interferes regularly with the general processes of daily life. Doing well in school but being “shy” doesn’t meet that standard. With autism, with Asperger’s, we’re talking about debilitating, meltdown-inducing, terror-filling anxiety. There is a difference.

Third, I don’t have a clue where he got the monetary value from, and NPR provides no balance for that statement. It’s just sitting there, making any family with a child receiving any services look like a faking money suck. Nice.

The piece as presented on the NPR Website provides nothing in the way of confirmation from objective sources. No studies indicating overdiagnosis. No input from experts in autism confirming what Frances says. His off-the-cuff commentary, his self blame, his stirring the pot all just sit there, unchallenged. Even the apparent effort at “balance” at the end of the story is almost a non-sequitur, part of a story with no real core. It’s as though they can’t make up their minds about whether the piece is about difficulties of diagnosis in general, the blurred lines between disorder and merely discombobulated, or that Asperger’s in particular is an overdiagnosed condition.

They don’t even provide Frances’ qualifications to speak to autism in particular. Not all doctors are oncologists, and not all psychiatrists have a deep understanding of developmental disorders.

All in all, a shoddy presentation that is already making its way around the Twitterverse, with parents once again feeling as though they have to defend their child’s diagnosis of a developmental difference that often goes unseen. Here’s the deal: The diagnostic criteria are clear, and a child who’s merely eccentric and doing well in school does not fit those criteria. If there is some modicum of overdiagnosis, it’s certainly not because of parents overseeking a label so they can have their child be stigmatized at school by receiving services. Look to the diagnosticians to blame. Or, in the complete absence of any evidence from Frances himself or NPR, do what Frances asks and blame him. Given his focus on his regrets over IV, he clearly seems to have something to expiate. And so does NPR. I’ll turn to D.H. Lawrence and say that thing is…a pettiness.

Autism, SHANK, and busy highways

Two autism studies in the news. I’ve summarized them at the Thinking Person’s Guide to Autism here. Let’s just say that the headlines, stories, and news releases have hyped yet again. Indeed, the title of this post should’ve been: “Headlines hype, news releases overpromise again in autism research.”

The worst offender is easily, “Proximity to freeways increases autism risk, study finds.” Um, no. The study found that autism rates are higher among people living within 309 meters of freeways. That in no way means that living close to a freeway increases autism risk. It’s a common, basic overinterpretation of correlation and epidemiological conclusions, but it’s really starting to get old. You can read more about the fuzzy definition of “freeway” and “major road” here.

Mitochondrial dysfunction and autism

Beautiful pic of mitochondria

Mitochondria are the powerhouses of the cell, the biology teachers will tell you. These organelles also happen to be likely former bacteria that once were independently living cells, capable of dividing on their own to make new mitochondria. Indeed, they continue to divide by a kind of binary fission as our cells divide, ensuring that a double dose is available for partitioning into the two new cells that result from cell division.

To achieve these feats, mitochondria have their own DNA, their own proteins, and their own protein-making machinery. That means that they also have the potential to undergo genetic mutations that affect the sequence of the proteins their genes encode. Because most of the proteins in mitochondria are mission critical and must function exactly right, the persistence of such mutations is relatively rare. But they do happen, causing disease. One question that has arisen in the study of the causes of autism is whether or not such changes might underlie at least a portion of the cases of this developmental difference.

The high-profile Hannah Poling case

Certainly lending a high profile to this question was the case of Hannah Poling, whose mitochondrial disorder appeared to be linked to her autism symptoms and may have interacted with a bolus of vaccine doses she received, followed by a high fever. Fevers can tax our cellular powerhouses, and if mitochondrial function is already compromised, the high temperatures and extra burden may result in chronic negative outcomes.

Poling’s case brought to the forefront the question of whether or not people with autism might have mitochondrial dysfunction at greater rates. A recent study in the Journal of the American Medical Association (which steadfastly keeps its articles unavailable behind a paywall) has sought to address that question by measuring markers of mitochondrial dysfunction in children with autism and comparing these endpoints with outcomes in children without autism.

Study specifics: “Full-syndrome autism”

The autistic group in the study had what the researchers called “full syndrome autism,” which I take to mean intense symptoms of autism. They used the Autism Diagnostic Inventory-Revised

(ADI-R) and the Autism Diagnostic Observation Schedule (ADOS) to confirm this diagnosis and to ensure as uniform a population among their autistic group as possible. Ultimately, the study included 10 children in this group, recruited consecutively in the clinic based on their fulfillment of the selection criteria. This study was essentially case control, meaning that the control group consisted of 10 non-autistic children, selected to match as closely as possible the demographic characteristics of the autistic group.

The authors report that while only one child among the 10 who were autistic fulfilled the definitive criteria for a mitochondrial respiratory chain disorder, the children with autism were more likely to have indicators of mitochondrial dysfunction.

A problem with pyruvate dehydrogenase (break out your Krebs notes, folks)

Specifically, six out of ten showed lowered levels of activity for one parameter, while eight out of ten showed higher levels than controls for another metabolic endpoint, and two of ten showed higher levels than controls of a third metabolic endpoint. Overall, the results indicated low activity of a mitochondria-specific enzyme, pyruvate dehydrogenase, which is involved in one of the first steps of carbohydrate metabolism that takes place in the mitochondria. Reduced activity of an enzyme anywhere in this process will result in changes in the enzyme’s own products and products further down the pathway and throw off mitochondrial function. Further, half of the autistic group exhibited higher levels of DNA replication, an indicator of cellular stress, more frequently than controls and also had more deletions in their DNA than controls. Statistical analysis suggested that all of these differences were significant.

What does it mean for autism?

Do these findings mean that all or most people with autism have mitochondrial dysfunction? No. The study results do not support that conclusion. Further, the authors themselves list six limitations of the study. These include the possibility that some findings of statistical significance could be in error because of sample size or confounders within the sample and that there were changes in some of the endpoints in the autistic group in both directions. In other words, some autistic children had much higher values than controls, while some had lower values, muddying the meaning of the statistics. The authors note that a study like this one does not allow anyone to draw conclusions about a cause-and-effect association between autism and mitochondria, and they urge caution with regard to generalizing the findings to a larger population.

If there is an association, questions arise from that conclusion. Does mitochondrial dysfunction underlie autism, producing autistic-like symptoms, as some argued in the Hannah Poling case? Or, do autistic manifestations such as anxiety or high stress or some other autism-related factor influence the mitochondria?

Chickens, eggs, MRI, mitochondria, autism

As interesting as both of these recent autism-related studies are, we still have the “Which came first” question to deal with. Did autism cause the brain or mitochondrial differences, or did the brain or mitochondrial differences trigger the autism? Right now, these chicken-and-egg questions may not matter as much as the findings do for helping to identify autism more specifically and addressing some of its negative aspects. Regardless of your stance on neurodiversity or vaccine or acceptance or cure or the in-betweens where most of us fall, it would be difficult to argue that a mitochondrial dysfunction shouldn’t be identified and ameliorated or that an awareness of brain structure differences won’t lead to useful information about what drives autism behaviors.

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Note: More lay-accessible versions of this post and the previous post are available at BlogHer.

MRI, brain differences, and autism

MRI: Sagittal view of the brain. Photo courtesy of Wikipedia commons.

You may have read the news reports blaring the finding of an “autism test” that could lead to early and definitive diagnosis of autism. The new evaluation, which has proved worthy of its own name, the Lange-Lainhart test, uses magnetic resonance imaging (MRI) techniques to image brain areas to detect changes associated with autism.

I’ve been unable to find the complete paper, reported to have been published in Autism Research on Nov. 29; the journal has only papers through October available on its Website as of this writing. According to reports, however, the authors state that the new test was 94% accurate in identifying who was autistic and who wasn’t among 60 males tested. The participants in the study were ages  8 to 26; 30 were diagnosed with what the researchers call “high-functioning autism,” and 30 were typically developing.

The imaging technique the authors used involves tracing water diffusion along axons, the long connectors that link neurons to other neurons or tissues. This diffusion tensor imaging process yields an image that can highlight variations in the patterns of these connective pathways in different areas of the brain. This study focused on six brain areas associated with language, social, and emotional functioning, all of which are traditionally considered to be problematic among people with autism.

In the brains of non-autistic participants, the flow patterns were organized in a typical way that indicated connectivity among the brain regions. In the participants diagnosed with high-functioning autism, the flow was disorganized in a pattern common to the autistic group, indicating less connectivity and interaction and thus less exchange of information in the network. The researchers repeated the test on another, smaller set of participants, 12 with autism and 7 without, and produced similar results.

These findings imply that autistic brains may operate like a set of computer hardware components that cannot communicate very well with each other while still functioning perfectly well separately. There may be camera that captures a visual image without trouble or a microphone that captures a voice clearly, but the system lacks the network necessary to integrate the two inputs into a unified perception.

The news reports I’ve read on the study make a big deal out the prospect that this imaging breakthrough could lead to earlier diagnosis of autism, something that most experts believe is key to ameliorating some of its negative manifestations. But experts also urge the standard cautious optimism, and rightfully so.

For one thing, the participants in this study were ages 8 to 26, not within the time frame for early diagnosis of autism, and all of them were male. The study findings can’t tell us whether their brains present with these differences as a result of developing with autism, or whether they have autism because their brains are built this way. Before there can be talk of “early diagnosis” and linking these changes to manifestations of autism, we’d need studies showing these differences in much younger children. Further, given the frequent findings of differences between males and females on the spectrum, investigations involving autistic girls and women are necessary.

This study is not the first to use imaging to identify distinctions between autistic and non-autistic people. Other studies have also done so, finding pattern variations in the neuronal tracts of children with autism compared to children without it, in critical areas relevant to the clinical symptoms of autism.

While I find these results intriguing, I note one thing that no one seems to have commented on. In the reports I’ve read about this study, the researchers observe that currently, the only way to diagnose autism is based on a symptom checklist, questionnaires, screenings, and so on—any autism parents reading this will know that drill—and the ultimate call relies on the expertise of the medical professional conducting the evaluations. The implication of these comments is that we need some better, more unequivocal, less-subjective methods of identifying autistic people.

Yet, presumably the autistic boys and men they used for this study were diagnosed using just such subjective evaluation, and their autism diagnoses appear to have been confirmed in 94% of cases by similarities of MRI findings. In my mind, this outcome suggests that the process of subjective evaluation seems to be working pretty well. Of course, we’re a visual species and like our decisions to be given literally in black and white. Such MRI results may fulfill a need that has less to do with correct outcomes than it does with a dose of visual confirmation–and satisfaction.

A drug for Fragile X syndrome?

Hopeful news but not peer-reviewed

A new report describes success in a very small trial with a new drug that targets behavioral signs of Fragile X syndrome. This syndrome, which affects about one in every five thousand children, mostly boys, usually involves some form of intellectual disability along with a suite of typical physical characteristics, including large jaws and ears and elongated faces. It is the most common known heritable cause of intellectual disability and has also been associated with autism.

Novartis has been working on an experimental drug targeting some of the behavioral manifestations of Fragile X and has just reported, via interview, positive results from a small trial. Because the results are not public and have not been peer reviewed, the nature of the improvements is unknown, as is the nature of the drug itself. All that is known is that a parameter in the treatment group improved in some, but not all, participants with Fragile X. Also, the drug targets reduction of the synaptic noise that people with Fragile X experience. This reduction in neural background noise, it is thought, may pave the way for more typical neurological development.

Why is the X fragile?

The X chromosome consists of many many genes. Some of these sequences may contain repeats of the same three nucleotides, or letters of the DNA alphabet. For example, a gene section might have 50 repeats of the sequence C-A-G. These trinucleotide repeats, as they are known, are associated with a few well-known disease states when they occur in larger numbers. At a certain low number of repeats, they may have no effect, but when the number of repeats increases, a phenomenon known as trinucleotide expansion, the result can be disease. Huntington’s disease is one well-known disorder associated with trinucleotide expansion, and the general rule is that the more repeats there are, the more severe and/or the earlier the onset of the disorder.

On the X chromosome, where these repeats achieve sufficient numbers to result in Fragile X syndrome, the X chromosome itself looks like it’s literally at a breaking point. This visual fragility is what gave the disorder its name when this chromosome characteristic was discovered in 1969. A parent who carries an X chromosome with relatively few repeats does not have Fragile X, but the gene is in a state known as a premutation. Thanks to various rearrangements and events during cell division, this premutation can expand even in a single generation to sufficient numbers of repeats to cause the disorder in an offspring.

Because the relevant gene is on the X chromosome, Fragile X is an X-linked disorder. It’s more prevalent among males than among females because males receive only one X chromosome. Without the second X chromosome backup that females have, males are stuck with whatever genes–and mutations–are present on the single X chromosome they receive.

What is the autism link?

Fragile X underlies a small percentage of diagnosed cases of autism, between 2 and 6%. Because of the usual genetic complexity underlying autism, Fragile X is also the most common known single-gene cause of autism.

These prematurely reported results have also yielded some speculation that a drug that is effective in reducing background noise and improving behaviors for people with Fragile X might do the same for autistic people, even if their autism isn’t related to Fragile X. With nothing in the way of peer-reviewed findings to consider and results available only via interview, such hopes remain in the purely speculative realm.

For your consideration

Males are born with a single X chromosome. Females have two. The X chromosome has hundreds of genes on it. How is it that women can walk around with a double dose of these genes, or conversely, men can be healthy with a half dose?

Trinucleotide expansion occurs when a trinucleotide repeat sequence expands in numbers of repeats, potentially evolving from a premutation to a full-blown disruption of a gene. What are some possible mechanisms by which this expansion might occur?

In the article related to this report, there is reference to “synaptic noise” and to the idea that a drug might reduce this noise and allow more space for typical development. What do you think “synaptic noise” is, physiologically, and how might a drug target this noise?

Autism and oxytocin: facilitating social interaction?

Oxytocin: Hormonal bliss

Oxytocin is a peptide hormone the brain produces in the posterior pituitary. It appears to play many roles in our lives, starting with birth, when it manifests one of the few examples of positive feedback during labor: The more you make, the more you make, until the uterus, the most powerful muscle in the body, contracts sufficiently and frequently enough to push a baby out of an area through which you’d think no baby could fit. In fact, in many childbirths, a synthetic form of oxytocin is used to facilitate labor. Following the birth experience, oxytocin works further magic by facilitating the mother-child bond.

Oxytocin doesn’t stop there, however. It also appears to function in facilitating trust among adults. One study found that a whiff of the hormone caused study participants to be more likely to continue in their trusting behavior, even if the target of their trust had betrayed them.

Social deficits characterize autism

Autism is a term that describes a broad spectrum of developmental manifestations that can include problems with verbal communication, social interaction, and motor skills. Some research has indicated that people with autism may have comparatively low levels of oxytocin, which has led to the hypothesis that boosting these levels might facilitate a greater social understanding for them.

Oxytocin boosts social skills?

A recent study from France published in the Proceedings of the National Academy of Sciences appears to bear out this idea. Caveats include the fact that while it was a controlled clinical trial, the study involved only 13 autistic people who had been diagnosed either with high-functioning autism (HFA) or Asperger’s (and 13 age-matched non-autistic participants). The low number of participants and the mix of diagnoses (there is controversy about the overlap or equivalency of HFA vs. Asperger’s) mean that these findings qualify as suggestive only. In addition, the authors in their paper offer some assumptions about autism that do not necessarily apply or apply in equal measure among all autistic people.

With those caveats in mind, the study findings remain intriguing. The autistic participants exhibited a greater awareness of social dynamics after exposure to oxytocin, in addition to also having higher measured levels of the hormone in their blood. Oxytocin, like most hormones, does not persist for long, and these effects would be expected to be only transient.

Is it direct improvement of social function or diminished social anxiety?

Among the assumptions the paper authors make about autism, one is that autistic people do not engage in eye contact and that this indicates a lack of social engagement. Another assumption is that the autistic participants were unable to understand the social dynamics without oxytocin because of a social incapacity.

Other studies, however, suggest a relationship between increased oxytocin and reduced social anxiety. Social anxiety can be a paramount manifestation in autism, and social phobias in general translate into an apparent inability to socialize. So the question that remains is, Did the oxytocin in this study somehow directly affect social capacity in these participants, or did it lower their social anxiety sufficiently enough that they could more comfortably engage in social interpretation?

Ideas for questions

The brain releases oxytocin from the posterior pituitary. Can you identify the feedback pathway that causes this release? What other hormone or hormones does the posterior pituitary release? What about the anterior pituitary?

Oxytocin is involved in parent-child bonding. Were you aware that this “natural” bond has a hormone underlying it? Do you think that this applies only in human parent-child bonding? Research this question and explain why or why not.

One problem autistic people sometimes encounter is being too trusting because they do not recognize when someone is cheating them. Given findings in other studies that oxytocin facilitates trust in people even when they have experienced betrayal, how do you think these results might affect any effort to apply oxytocin therapeutically in autism?

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