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.

Genetic analysis: my results and my reality

A few months ago, it was National DNA Day or something like that, and one of the genetics analysis companies had a sale on their analysis kits, offering a full panel of testing for only $100. Giddy with the excitement of saving almost $1000 on something I’d long been interested in doing, I signed on, ordering one kit each for my husband (a.k.a. “The Viking”) and me. Soon, we found ourselves spending a romantic evening spitting into vials and arguing about whether or not we’d shaken them long enough before packaging them.

The company promised results in six weeks, but they came much faster than that, in about three weeks. Much to my relief, I learned that neither of us carries markers for cystic fibrosis and that I lack either of the two main mutations related to breast cancer. Those basic findings out of the way, things then got more complex and more interesting.

How it works

First, a bit of background. These tests involve sequencing of specific regions to look for very small changes, a single nucleotide, in the DNA. If there is a study that has linked a specific mutation to a change in the average risk for a specific disorder or trait, then the company notes that. The more data there are supporting that link, the stronger the company indicates the finding is. Thus, four gold stars in their nomenclature means, “This is pretty well supported,” while three or fewer slate stars means, “There are some data for this but not a lot,” or “The findings so far are inconsistent.”

Vikings and Ireland

The Viking is a private person, so I can’t elaborate on his findings here except to say that (a) he is extraordinarily healthy in general and (b) what we thought was a German Y chromosome seems instead to be strictly Irish and associated with some Irish king known as Niall of the Nine Hostages. Why hostages and why nine, I do not know. But it did sort of rearrange our entire perception of his Y chromosome and those of our three sons to find this out. For the record, it matches exactly what we learned from participating in the National Geographic Genographic project. I’d ask the Viking if he were feeling a wee bit o’ the leprachaun, but given his somewhat daunting height and still Viking-ish overall demeanor (that would be thanks to his Scandinavian mother), I’m thinking he doesn’t. Lord of the Dance, he is not.

Markers that indicate an increased risk for me

I have an increased risk of…duh

Looking at the chart to the left (it’s clickable), you can see where I earned myself quite a few four gold stars, but the ones that seem most relevant are those with a 2x or greater increased risk: lupus, celiac disease, and glaucoma. The first two do not surprise me, given my family’s history of autoimmune disorders.

If you focus on a list like this too long, you can start to get a serious case of hypochondria, worrying that you’re gonna get all of these things thanks to those glaring golden stars. But to put it into context, for the lupus–for which my risk is 2.68 times higher than a regular gal’s–that still leaves me in the population in which 0.66 persons out of every 100 will develop this disorder. Compare that to the 0.25 out of every 100 in the regular-gal population, and it doesn’t strike me as that daunting.

Some of those other things on there? Well, let’s just say they’re close. My risk of thyroid cancer might be raised…but I no longer have a thyroid. Hypertension risk is increased–and I have stage 2 hypertension. Gallstones, gout, alcholism, asthma…based on family history, it’s no surprise to me to see some mixed or clear risk involved with these, although I have none of them. Does that mean that someone else with these increased risks will have related real-life findings? No. It only means that you’re at a bit more risk. It’s like riding a motorcycle vs. driving a car. The former carries more risk of a fatal wreck, but that doesn’t mean you’re absolutely gonna die on it if you ride it.

Disorders for which my risk is allegedly decreased

I have a decreased risk of...

None of my decreased risk findings are very eye catching in terms of actual drop in risk except for Type II diabetes (now where is my bag of sugar?). As I have been under evaluation for multiple sclerosis and have a family member with it, it’s interesting to see that my risk for it, based on existing studies and known polymorphisms, is decreased. And even though I know that much of this is largely speculative and based on little firm data, it’s still sort of comforting to see “decreased risk” and things like “melanoma” in the same group.

Don’t make my brown eyes blue!

And they didn’t. They nailed the eye color and other trait-related analysis, such as level of curl to the hair, earwax type, alcohol flush reaction, lactose intolerance (unlikely), and muscle performance (I am not nor have I ever been a sprinter). And even though I do not have red hair, they reported that I had a good chance of it, also true given family history. I am not resistant to malaria but allegedly resistant to norovirus. I wish someone had informed my genes of that in 2003 when I was stricken with a horrible case of it.

Ancestral homeland

Yep. They nailed this one. One hundred percent European mutt. Mitochondria similar to…Jesse James…part of a haplogroup that originated in the Near East about 45,000 years ago then traveled to Ethiopia and Egypt and from there, presumably, into Europe. It’s a pretty well traveled haplotype and happens to match exactly with the one identified by the National Geographic Genographic project. When it comes to haplotypes, we’re batting 1000.

In summary

Some of these findings are reliable, such as the absence of the standard breast cancer mutations or the presence of certain mutations related to autoimmune disorders, while other findings are iffy. The company duly notes their iffiness  in the reports, along with the associated citations, polymorphisms, and level of risk identified in each study. They don’t promise to tell you that your ancestors lived in a castle 400 years ago or hailed from Ghana. From this company, at any rate, the results are precise and precisely documented, and as I noted, pretty damned accurate. And they’re careful to be a clear as possible about what “increased risk” or “decreased risk” really means.

It’s fascinating to me that a little bit of my spit can be so informative, even down to my eye color, hair curl, and tendency to hypertension, and I’ve noted that just in the days since we received our results, they’ve continually updated as new data have come in. Would I be so excited had I paid $1100 for this instead of $200? As with any consideration of the changes in risk these analyses identified, that answer would require context. Am I a millionaire? Or just a poor science writer? Perhaps my genes will tell.

Think you're eating snapper? Think again

Grad students learn PCR, uncover fish fraud

It’s a great thing if you get your name published in the journal Nature, the pinnacle of publishing achievement for a biologist, while you’re still in school. Such was the fate of six graduate students participating in a course designed to teach them DNA extraction, amplification, and sequencing. They identified a real question to answer in the course of applying their techniques, and their results got them brief communication in Nature and national recognition. Not bad; I hope everyone also earned an “A.”

The group, led by professors Peter Marko and Amy Moran at the University of North Carolina-Chapel Hill, suspected that fish being sold as red snapper in markets in the U.S. were actually mislabeled, in violation of federal law. This kind of fraud is nothing new; marketers have in the past created “scallops” by cutting scalloped-shaped chunks from the wings of skates (part of the cartilaginous fish group), and have labeled the Patagonian toothfish as Chilean sea bass.

Protections can drive fraud

Such mislabeling has far-reaching implications, well beyond concerns about defrauding consumers of the fish they want. If fisheries and fish dealers are reporting their catches as red snapper or scallops or sea bass when they are, in fact, other marine species, then data on the abundance and distribution of all of these species will be misleading. Red snapper, Lutjanus campechanus, was placed under strict management in 1996, a move that gave incentive to the fishing industry and retailers to mislabel fish. Some experts suspect that many fish under heavy restriction end up with their names on a different species for market.

Who is responsible for the mislabeling? Fishermen pull in their catches and identify them on the boat or at the dock. The catch goes to a fish dealer, who is also responsible for reporting what species and how many of each species were caught. This report becomes the official number for the species. The dealer then sends the fish on to the retail market, where it is sold in stores and restaurants. Misidentification on the boat or dock is one reasonable possibility because some of the species identified in the North Carolina study frequent the same types of habitat, primarily offshore waters around coral reefs. These species, which include vermillion snapper and silk snapper, do look very much like red snapper, although there are some identifiable morphological differences.

One filet is just like the other?

So misidentification could be an honest mistake or purposeful change at the boat or dock, or it could be a willful relabeling at the restaurant or market. By the time a fish is processed, it consists essentially of a filet that is indistinguishable from that of other, similar fish. Hapless consumers end up paying twice as much for silk snapper, thinking they’re getting the pricier red snapper, instead.

But the DNA sequencing the North Carolina group performed not only turned up species closely related and very similar to red snapper, but also uncovered some sequences that have no identity with those of known species in gene databanks. In other words, fish of unknown identity are being caught, sold, and eaten as red snapper before we even have a chance to document what they are, their habitats, or their numbers.

Mislabeling is rampant

The grad students and professors also found that some of the fish being marketed as Atlantic red snapper were, in a few cases, from the other side of the planet, including the crimson snapper, which occurs in the Indo-West Pacific. All told, they found that 77% of the fish samples from stores in the eastern and midwestern U.S. were mislabeled as red snapper.

One way to prevent such mislabeling is to require identification of the country of origin of fish sold at market. The USDA has instituted such a program, although confusion will likely persist about fish caught in international waters. And the mislabeling isn’t only a U.S. phenomenon.

In the meantime, how do you know you’re getting red snapper? Some fish ecologists recommend avoiding it entirely because it still suffers from overfishing; however, one way to know your fish is to ask for it with the skin on, or completely intact. If you’ve got a smart phone, you can just look up the image and compare. Alternatively, you could just order the salad.

Identical twins grow less identical

DNA sequence is just a starting point

Identical twins are identical only in that their DNA is the same. In what might be an argument against cloning yourself or a pet hoping to get an identical reproduction, scientists have found that having an identical genetic code does not translate into being exactly alike. We have long known that identical twins do not always share the same health fate, for example. One twin can have schizophrenia while another twin may never develop it. Or one twin might develop cancer or diabetes, while the other remains disease-free, even though there can be a strong genetic component to all of these disorders.

So a burning question in the field of genetics and disease has been identifying the difference between a twin who gets a disease and one who does not. A strong candidate mechanism has been the process of genomic modification in which molecules attached to the DNA can silence a gene or turn it on. Typically, methyl groups attached to DNA will make the code unavailable, and acetyl groups attached to the histone proteins that support DNA will ensure that the code is used.

Chemical tags modify DNA sequences

This process of genomic regulation is involved in some interesting aspects of biology. For example, methylation is the hallmark of genomic imprinting, in which each set of genes we inherit from our parents comes with its own special pattern of methylation. The way some genetic disorders manifest can be traced to genomic imprinting. In Prader-Willi syndrome, a person inherits a paternal mutant allele and manifests characteristic symptoms of the disorder, which include obesity and intellectual disability. But people who inherit the same mutant allele from the mothers will instead have Angelman’s syndrome, in which they are small and gracile, have a characteristic elfin face, and also have intellectual disability. Modification from methyl or acetyl groups, also called epigenetic modification, plays a role in dosage compensation for the X chromosome. Women, who have two X chromosomes, shut most of one down through methylation to produce an X chromosome gene dosage like that of men, who have a single X.

Twinning: Nature’s clones

Identical twins have identical DNA because they arise from a single fertilized egg. The egg divides mitotically into two identical cells, and then each cell, for reasons we don’t understand well, resets the developmental process to the beginning and develops as a new individual. The process of twinning carries interesting implications for bioethics, cloning discussions, and questions about when life begins, but it also has helped us tease apart the influences of genetics and environment. A recent study examining life history differences and differences in epigenetic modification in 80 pairs of twins ranging in age from 3 to 74 has revealed some fascinating results that have implications for our understanding of nature vs. nurture and our investigations into the role of epigenesis in development of disease.

You are what you do to yourself

The older the twins were, the more differences researchers found in methylation or acetylation of their DNA and histones. For twins raised apart, these differences were even more extreme. Researchers also concluded that environmental influences, such as smoking, diet, and lifestyle, may have contributed to the differences in the twins’ epigenetic modifications. The three-year-old twins were almost identical in their methylation patterns, but for twins older than 28 years, the patterns were significantly different for 60 percent of the pairs.

These results have major implications for our understanding of disease. For example, we can use this knowledge to identify genes that are differently methylated in people with and without a disorder and use that as a lead in identifying the genes involved in that disease state. We also may be able to pinpoint which environmental triggers result in differential methylation and find ways to avoid this mechanism of disease.

Polio vaccine-related polio

Polio virus bits in vaccine rarely join forces with other viruses, become infectious

[Note: some of the links in this piece are to New England Journal of Medicine papers. NEJM does not make its content freely available, so unfortunately, unless you have academic or other access, you'd have to pay per view to read the information. I fervently support a world in which scientific data and information are freely available, but...money is money.]

Worldwide, billions of polio vaccine doses have been administered, stopping a disease scourge that before the vaccine killed people–mostly children–by the thousands in a horrible, suffocating death (see “A brief history of polio and its effects,” below). The polio vaccination campaign has been enormously successful, coming close to the edge of eradicating wild-type polio.

But, as with any huge success, there have been clear negatives. In a few countries–15, to be exact–there have been 14 outbreaks of polio that researchers have traced to the vaccines themselves.  The total number of such cases as of 2009 was 383. The viral pieces in the vaccine–designed to attract an immune response without causing disease–occasionally recombine with other viruses to form an active version of the pathogen. Some kinds of viruses–flu viruses come to mind–can be notoriously tricky and agile that way.

Existing vaccine can prevent vaccine-related polio

Odd as it sounds, the existing vaccines can help prevent the spread of this vaccine-related form of polio. The recombined vaccine-related version tends to break out in populations that are underimmunized against the wild virus, as happened in Nigeria. Nigeria suspended its polio vaccination program in 2003 because rumors began to circulate that the vaccine was an anti-Muslim tactic intended to cause infertility. In 2009, the country experienced an outbreak of vaccine-derived virus, with at least 278 children affected. Experts have found that the existing vaccine can act against either the wild virus or the vaccine-derived form, both of which have equally severe effects. In other words, vaccinated children won’t get either.

Goal is eradication of virus and need for vaccine

Having come so close to total eradication before wild-type-associated cases plateaued between 1000 and 2000 annually in the 21st century, global health officials hold out the hope for two primary goals. They hope to eradicate wild-type polio transmission through a complete vaccination program, which, in turn, will keep vaccine-derived forms from spreading. Once that goal is achieved, they will have reached the final target: no more need for a polio vaccine.

As Dr. Bruce Aylward, Director of the Global Polio Eradication Initiative at WHO, noted: “These new findings suggest that if (vaccine-derived polio viruses) are allowed to circulate for a long enough time, eventually they can regain a similar capacity to spread and paralyse as wild polioviruses. This means that they should be subject to the same outbreak response measures as wild polioviruses. These results also underscore the need to eventually stop all (oral polio vaccine) use in routine immunization programmes after wild polioviruses have been eradicated, to ensure that all children are protected from all possible risks of polio in future.”

If that sounds nutty, it’s been done. Until the early 1970s, the smallpox vaccination was considered a routine vaccination. But smallpox was eradicated, and most people born after the early ’70s have never had to have the vaccine.

A brief history of polio and its effects

I bring you the following history of polio, paraphrased from information I received from a physician friend of mine who works in critical care:

The original polio virus outbreaks occurred before the modern intensive care unit had been invented and before mechanical ventilators were widely available. In 1947-1948, the polio epidemic raged through Europe and the United States, with many thousands of patients dying a horrible death due to respiratory paralysis. Slow asphyxiation is one of the worst ways to die, which is precisely why they simulate suffocation in torture methods such as water boarding. The sensation is unendurable.

In the early twentieth-century polio epidemics, they put breathing tubes down the throats of patients who were asphyxiating due to the respiratory paralysis caused by the polio virus. Because ventilators were unavailable, armies of medical students provided the mechanical respiratory assist to the patients by hand-squeezing a bag which was connected to the breathing tube, over and over and over, 16 times a minute, 24 hours each day, which drove air in and out of the patients’ lungs.  Eventually the iron lung was developed and became widely implemented to manage polio outbreaks. The iron lung subsequently gave way to the modern ventilator, which is another story.

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