Tag Archives: epidemiology

The Epidemic That Still Isn’t: Autism Rates and Case Definitions

A paper that came out yesterday in the American Journal of Psychiatry has generated a lot of press coverage of the “autism epidemic,” as it purportedly shows that one in every 38 South Korean children is autistic. That’s more than double the incidence previous epidemiological studies have found. I have no doubt that this result, completely devoid of its larger context, will now be picked up by all manner of woo-woo peddlers as indisputable proof of whatever nonsense they’re selling. What the paper really shows, though, is how slightly different interpretations of case definitions can produce radically different results.

First, let’s dispense with the most obvious flaw in much of the news coverage of autism: there is no “epidemic.” As numerous epidemiologists have found every time they’ve looked at this issue, the apparent rise in the rate of autism spectrum disorder (ASD) tracks perfectly with changes in the diagnostic and special education criteria for the disease. It’s not rising, just being identified more often.

One particularly telling point is that the supposed increase in ASD doesn’t age well. Autism appears in childhood, but many folks seem to forget that children grow up, and the disease doesn’t go away when they do. That means that if ASD rates are genuinely increasing, there should be more autistic kids than autistic adults. But as a paper last week in Archives of General Psychiatry showed, there aren’t.

A Reuters story on that paper explained the key finding nicely:

Researchers found nearly one percent of Britons older than 16 years have autism, a rate that is similar to that seen in children. Younger people were no more likely to be affected than older ones, however, which would have been expected if the condition were truly on the increase.

“It was surprising to all of us,” said Dr. Traolach Brugha, a psychiatrist at the University of Leicester, who worked on the study. “If this study is correct, it does put a big question mark over the autism epidemic.”

Not so much a question mark as a stake through the heart. Brugha’s team found that the adults with ASD were less likely to have been diagnosed previously than kids with it, pretty much proving that the rising rates are due to increased diagnosis and awareness. Nor is Brugha’s report the first in this genre. For example, Orac at Respectful Insolence has an excellent post about a 2006 study that essentially proved the same point using a different method.

So case rates aren’t rising. But are they really only 1%? That’s what Kim et al. wanted to determine in the new South Korean study. I encourage everyone to read the whole paper, which Am J Psych has made available for free. It’s an impressive piece of work.

First, the researchers identified a South Korean community that was demographically diverse, and set out to sample all 7- to 12-year-old kids in that region. There were 55,266 of them. Before I start my criticism of this study, I have to congratulate the authors on the dedication, organization, and plain hard work that they put in to tackle such a huge job. As I said, it’s an impressive paper.

Kim’s team broke their sample into two groups: those who received special education or other psychiatric help (the “high-probability group”), and those who were in the general school population. That ensured that their sample wouldn’t be skewed by accidentally pulling too many kids from special ed. Between the two groups, they found a whopping 2.64% prevalence for ASD, or about 1 in 38 kids. That’s the conclusion that’s been plastered all over the headlines, and the one that I predict will launch a thousand quacks.

As often happens, though, the Abstract giveth while the Results taketh away. Let’s start with the autism rates in the high-probability group, which were, unsurprisingly, very high:

In the high-probability group (those in the Disability Register, those in special education schools, and those in regular schools who had psychiatric or psychological service use) 97 of 114 children were confirmed to have autistic disorder (N=74) or other ASDs (N=23). The high- probability group contributes 0.18% for any ASD to the total population prevalence (autistic disorder=0.13% and other ASDs=0.05%; the ratio of autistic disorder to other ASDs was 2.6:1).

I’ll parse that. In ASD, the middle letter is critical: autism occurs on a spectrum. Contrary to popular belief, not everyone with ASD is Rain Man. In fact, the cases depicted in movies are generally the extreme end of the spectrum, people with the biggest problems. Milder cases extend from there all the way through (according to many researchers) Asperger Syndrome. There are no bright lines dividing these folks. Indeed, there’s no reason to believe that there’s even a clear boundary between “sick” and “well” here. Extremely autistic individuals clearly need help, but what about high-functioning folks with Asperger’s? At what point does one divide someone with very mild ASD from someone who’s just socially awkward? Like most psychiatric case definitions, it’s murky at the edge.

What Kim et al. found in the special ed group was a lot of ASD, with the majority of diagnoses in the “autistic” category rather than in milder categories. These are the sickest kids. Presumably that’s why they’ve been singled out for special help. So far, so good.

The general population data get more problematic:

For 104 children with ASDs in the general-population sample, among the 172 assessed, the crude prevalence for any ASD was similar to that in the high-probability group (0.19%). However, the ratio of autistic disorder to other ASDs was reversed, with prevalences of 0.05% and 0.14%, respectively (ratio, 1:2.6) (Table 2). Other differences between the high-probability and general-population groups included the ratio of boys to girls, which was 5.1:1 in the high-probability group and 2.5:1 in the general-population sample (p=0.037) (Table 2). Mean performance IQ for individuals with any ASD was 75 (SD=28) in the high-probability group and 98 (SD=19) in the general-population sample (p<0.001)

Now we’re seeing a majority who are on the mild end of the spectrum. How mild? In some cases, quite. The surveys the researchers used to assess ASD, while standard in the field, suffer from the usual drawbacks of any psychiatric survey tool. Does your child have only a few friends? Prefer playing alone? Is he or she easily overwhelmed by extraneous stimuli? There’s lots of wiggle room on questions like these, and the closer you look the more likely you are to start pathologizing mere eccentricity.

Finally, there’s an extrapolation problem. As the numbers in the paragraphs above indicate, the researchers didn’t manage to get detailed diagnostic information on all 55,266 kids in the district. A lot of parents responded to the initial questionnaire, but many didn’t. Of the ones who did, many declined subsequent followups. By the time we get to the most detailed tests, the investigators are down to hundreds rather than thousands of data points. Nonetheless, they extrapolate from this self-selected group to the entire population. If we assume that parents who had some concerns about their children were more likely to follow up with the study – a reasonable assumption – then the extrapolation fails.

I’m not saying the results are completely bogus. The researchers are aware of their tools’ limitations, and they take efforts to control for some of them. Still, we have to ask whether a child who’s enrolled in regular school programs, hasn’t been identified as sick by any of his or her teachers, and seems to be progressing just fine in life needs to be given a diagnosis. Maybe there are a lot of children who aren’t truly “normal,” but who are acting the part well enough to pass. On some level, doesn’t that describe us all?

Brugha, T., McManus, S., Bankart, J., Scott, F., Purdon, S., Smith, J., Bebbington, P., Jenkins, R., & Meltzer, H. (2011). Epidemiology of Autism Spectrum Disorders in Adults in the Community in England Archives of General Psychiatry, 68 (5), 459-465 DOI: 10.1001/archgenpsychiatry.2011.38

Kim, Y., Leventhal, B., Koh, Y., Fombonne, E., Laska, E., Lim, E., Cheon, K., Kim, S., Kim, Y., Lee, H., Song, D., & Grinker, R. (2011). Prevalence of Autism Spectrum Disorders in a Total Population Sample American Journal of Psychiatry DOI: 10.1176/appi.ajp.2011.10101532

Anecdotes, Data, Case Reports, and Sex

Last week, I blogged briefly about a report of an unusual cluster of Zika virus infections. Like a lot of scientists, I got a good chuckle out of Martin Enserink’s reporting on the story for Science, and figured that if people wanted the full analysis they could read the freely available primary report.

In the ensuing days, the popular media picked up the story and might have taken it a little too seriously, as my friend and fellow TWiV host Vincent Racaniello explains over at Virology Blog. Vincent’s objection echoes the sentiments I’m hearing from other scientists as well: the news coverage sounds as if this proves that Zika virus is sexually transmitted, a claim the paper doesn’t quite back up.

It’s a valid complaint, but it misses some important points. While it’s true that anecdote is not data, there is nonetheless an established and legitimate tradition for this sort of publication in the scientific literature. It’s called a case report, and it’s the basis of much of modern medicine. Consider this publication from 1982. Not much to it, really, just a note about some odd diseases in a cohort of homosexual men in California. These patients could have some common risk factor for an unknown immune disorder, or it could just be a really bizarre coincidence. By itself, the report proves nothing, only that these cases might deserve a closer look. When researchers did look closer, they found AIDS.

I’m not saying Zika virus has that kind of potential, only that we shouldn’t dismiss case reports as “anecdotes.” The difference is that while an anecdote is a purely personal story, a peer-reviewed case report is a medically and scientifically rigorous analysis of such a story. Foy et al. were right to report their experiences, which do strongly suggest that Zika virus could be transmitted sexually. Of course there are other possibilities. The point of a case report isn’t to prove etiology beyond all doubt, it’s to redefine the limits of the possible. Previously, we didn’t know this might happen. Now we should try to see if it really does.

As for the press coverage, I’m not convinced it’s been so horrible either. Consider the story on Fox News, a source not normally known for its evidence-based reporting. While the headline is certainly sensational and definitive-sounding, the story itself quotes the original paper accurately:

According to Foy’s study, the circumstantial evidence for [Zika virus] sexual transmission is strong. “Patients 1 and 3 reported having vaginal sexual intercourse in the days after patient 1 returned home but before the onset of his clinical illness,” he wrote. Foy said there are hints in other literature that sexually transmitted mosquito-borne viruses are possible. Boars who were infected with Japanese encephalitis shed the virus in their semen, and when female pigs were artificially inseminated with the boars’ semen they also became infected.

Indeed, the circumstantial evidence is strong. Now someone should try to get some less circumstantial evidence.

Meanwhile, science just got a big shot of free publicity. Adventurous expeditions. Sex. Deadly diseases. Sex. New scientific discoveries. And did I mention sex? Kids, does that sound like the kind of career you’d like to pursue? I thought so.

Scientists should certainly maintain their skepticism when talking to the press, and the press could certainly use a bit more skepticism of its own with reports like this, but let’s pick our battles. From what I’ve seen, the mainstream media coverage of this story has focused mainly on the novelty of the virus and, of course, the sex. It sells, you know. I suspect that six months from now, the general public will remember only a vague outline of this report, if anything. What effect would that have? For starters, it might make people think twice about having unprotected sex. They might also get some general idea that even obscure, exotic diseases can travel rapidly and unpredictably. Those seem like good take-home lessons to me.

ResearchBlogging.org

Foy, B. (2011). Probable Non–Vector-borne Transmission of Zika Virus, Colorado, USA Emerging Infectious Diseases DOI: 10.3201/eid1705.101939

Gee, Your Carcinogens Smell Terrific

I did a little bit of amateur epidemiology last week, and now a professional has found some evidence supporting my theory.

My wife had a persistent cough for weeks, which she’d attributed to seasonal allergies. Then her car needed to go to the shop, so I was driving it for a couple of days while she took mine. I developed a cough. When I went back to driving my car, my cough resolved. I suggested throwing out the air freshener she’d had in her car, and when we did that, her cough went away, too. Googling the problem revealed that it’s impossible to find out exactly what’s in an air freshener, so I became leery of the whole product category.

A typical air freshener, but what's in it? Image courtesy bradleygee.

A typical air freshener, but what's in it? Image courtesy bradleygee.

Now a paper by Anne Steinemann and her colleagues at the University of Washington suggests my leeriness is well-founded. As a press release accompanying the publication explains:

A study led by the University of Washington discovered that 25 commonly used scented products emit an average of 17 chemicals each. Of the 133 different chemicals detected, nearly a quarter are classified as toxic or hazardous under at least one federal law. Only one emitted compound was listed on a product label, and only two were publicly disclosed anywhere. The article is published online today in the journal Environmental Impact Assessment Review.

“We analyzed best-selling products, and about half of them made some claim about being green, organic or natural,” said lead author Anne Steinemann, a UW professor of civil and environmental engineering and of public affairs. “Surprisingly, the green products’ emissions of hazardous chemicals were not significantly different from the other products.”

The team previously found that about 38% of Americans they sampled reported some sort of adverse response when exposed to scented products. I’m starting to think there should be a law requiring manufacturers to disclose the ingredients of these things. Apparently, I’m not alone.

XMRV: Cause or Bystander?

Xenotropic murine leukemia virus-related virus (XMRV), previously best known for showing how an awkward name can turn into an awesome abbreviation, has now become the hot new pathogen for virologists to hunt. As mentioned in numerous media outlets, some researchers have found that XMRV shows up in prostate cancer more frequently than it does in healthy prostate tissue. That finding led to rampant speculation about this retrovirus’s potential to generate tumors.

More recently, another group found that XMRV infection correlates with chronic fatigue syndrome, a very different – and rather poorly characterized – condition. Could this virus be the secret cause of all of our mysterious ills?

I think not. First of all, neither finding has been reproduced yet, and in fact the prostate cancer result might have been a fluke; scientists in Germany just released a report where they analyzed hundreds of prostate tumor samples for XMRV, and came up empty-handed:

589 prostate tumor samples were genotyped by real-time PCR with regard to the RNaseL mutation. DNA and RNA samples from these patients were screened for the presence of XMRV-specific gag sequences using a highly sensitive nested PCR and RT-PCR approach. Furthermore, 146 sera samples from prostate tumor patients were tested for XMRV Gag and Env antibodies using a newly developed ELISA assay. In agreement with earlier data, 12.9% (76 samples) were shown to be of the QQ genotype. However, XMRV specific sequences were detected at neither the DNA nor the RNA level. Consistent with this result, none of the sera analyzed from prostate cancer patients contained XMRV-specific antibodies.

Translation: at least in this rather large sample of German patients, it ain’t there. Germans still get prostate cancer, but they don’t have XMRV.

At the moment, my favorite hypothesis is that XMRV is just a bystander, showing up in patients whose immune systems have been strained by some other condition. Maybe the virus exacerbates diseases that have already started by other mechanisms, or maybe it’s just a symptom, and doesn’t cause any pathology at all on its own. The German-versus-American skew in the prostate cancer samples might reflect different background rates of infection by XMRV on different continents. The virus appears to have originated in mice, so it could even be caused by differences in local rodent populations.

To test that hypothesis, we should look for XMRV in other immunocompromised populations in the US. If the bystander hypothesis is right, we should find it in most if not all of them. Check samples from transplant patients, HIV patients, anyone on steroids, anyone with clinical depression, or really any handy group of sick people. My guess is that we’ll soon see XMRV cropping up in lots of interesting places.

Green Mice, Hantavirus, and The “20/80 Rule”

An old epidemiological rule of thumb says that for any given contagious disease, 20% of the population will be responsible for 80% of the disease spread. The numbers are certainly not exact, it’s just a way of stating a commonly observed phenomenon: a small number of individuals is disproportionately contagious. The real question in controlling an outbreak is figuring out who those individuals are.

For hantavirus, a potentially deadly pathogen whose reservoir host is wild deer mice, the key 20% may be the oldest and largest mice:

University of Utah researchers dusted wild deer mice with fluorescent pink, blue, green, yellow and orange talcum powders to show which rodents most often fought or mated with others and thus were most likely to spread deadly hantavirus. The study identified bigger, older mice as the culprits.

“If mice were in contact with a powdered mouse, you’d see the colored bite mark on their ear or tail, or color on their genitals,” says Denise Dearing, a University of Utah professor of biology and senior author of the study published online Jan. 7 in the British journal Proceedings of the Royal Society B.

“You knew when they got lucky,” adds Christy Clay, who ran the study as part of her University of Utah Ph.D. thesis under Dearing’s supervision.

Fluorescently dyed green mouse released into the wild; image courtesy University of Utah.

Hiking boots: $100. Backpack: $200. Trail map: $5. Stumbling upon a pair of cute, fuzzy, fluorescently dyed mice going at it in the desert: priceless.

Disease Mapping

Through my new gig on the podcast This Week in Virology, I found out about an amazingly slick new mapping application. Pop over to Healthmap, and you can see a global overview of disease outbreaks and epidemics. The map draws its data from multiple sources, including the World Health Organization and ProMED, and automatically plots the location of each reported outbreak. This is a huge boon to folks like me, who need to stay on top of health news without being swamped by information overload.

Of course, such a web site could be highly cyberchondrogenic if not used carefully. You’ve been warned.

As If Foreclosure Weren’t Bad Enough

In the summer of 2007, the incidence of West Nile virus cases in Bakersfield, CA shot up 276%. Simultaneously, the rate of home foreclosures in the area went up 300%. The two numbers are very similar, but obviously that’s just a coincidence – viruses don’t track real estate trends. Or do they?

Reporting in the November issue of Emerging Infectious Diseases, a team of researchers reveals a surprising consequence of the mushrooming foreclosure crisis:

Adjustable rate mortgages and the downturn in the California housing market caused a 300% increase in notices of delinquency in Bakersfield, Kern County. This led to large numbers of neglected swimming pools, which were associated with a 276% increase in the number of human West Nile virus cases during the summer of 2007.

The abandoned pools, which are clearly identifiable in aerial photos because they’re green with algae instead of light blue, become ideal mosquito breeding ponds. Pools are extremely popular backyard accessories in that part of the country, so the widespread foreclosures boosted the local mosquito population dramatically, with a corresponding increase in WNV infections. I’d predict that other pool-friendly areas with foreclosure epidemics, such as South Florida, will see similar vector increases.

By the way, I learned about this fascinating finding on This Week in Virology, a podcast my former thesis advisor just launched. Check it out.

Still Pulling for Poor Countries’ Vaccines

The G7 nations are apparently setting up another effort to entice drug companies to work on unprofitable diseases:

The UK and other leading industrialised nations are setting up a £750m ($1.5bn) fund to speed up the development of new vaccines for use in poorer countries.

The plan is to subsidise the future purchase of vaccines in the hope this will galvanise drug firms into action.

A vaccine for pneumococcal disease is the first target.

A jab already exists, but developing countries need a tailored version which firms have been slow to invest in as there is no guaranteed market.

This is an example of a “pull” incentive, guaranteeing a market for the putative vaccine by committing rich countries to buy a certain amount once it’s developed. This contrasts with “push” efforts, which fund the research up front. The idea of “pull” systems is that drug companies will invest their own money in development if they perceive that there’s going to be a market for the final product. By guaranteeing an artificial market in the future, we can reap the benefits of corporate research without having to put taxpayers’ cash on the table until the products are ready.

It’s a neat idea, and drug company executives publicly laud it. Privately, however, they consistently admit that their own company probably won’t do it. Developing a new vaccine can take a decade or more, and there’s a tremendous risk that politicians yet to be elected will balk at honoring the expensive promises of their predecessors. Also, the governments involved have to be willing to pay the companies a suitable profit margin beyond their basic development costs, which would inevitably become a political lightning rod.

On the other hand, as the ongoing problems with “push” efforts like the Bioshield project show, there’s clearly a need for some alternative. It’s just not clear that pulling will be any more successful.