Gardasil = Girls Gone Wild?

Stick to your guns, Governor Perry!

Four years ago, Texas governor Rick Perry raised a ruckus when he issued an executive order for all sixth-grade girls to undergo mandatory vaccination against the human papilloma virus, the cause of most cervical cancers and genital warts.  It was a strong and surprising move, especially coming from a politician who believes in teaching kids that cavemen coexisted with dinosaurs.  Critics from the right (and a few from the left) railed against the order, claiming it infringed upon parental rights and taught girls that premarital sex was O.K., despite the fact that the order gave parents the right to opt out of vaccination.  The order was overturned by the state legislature, and mandatory HPV vaccination never went through.  Now that he's running for the White House, Perry is apologizing for his earlier decision, stating, "I didn't do my research well enough."  Was he right then, or is he right now?  Well, Governor, how about if I do the research for you?

The landmark trial that got the HPV vaccine approved by the FDA was the "Females United  to Unilaterally Reduce Endo/Ectocervical Disease," Study, with the totally awesome acronym, "FUTURE II," bringing to mind a popular Disney attraction rather than genital warts.  ("Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions.")  Over 12,000 women ages 15 to 26 years were randomized to three doses of the HPV vaccine or placebo.  The vaccine was designed to protect against two HPV strains that cause 70% of cancers, and two other strains that cause the majority of genital warts.  The primary endpoint, which was carefully selected by Merck, maker of the vaccine, was the rate of cervical cancer or precancer caused by the two HPV cancer-causing strains in women who were not previously infected by these strains.  Got it?  Not the overall rate of all cervical cancer or precancer in all the women, but only a subgroup of cancers in a subpopulation.

The vaccine was extremely effective:  in women without prior infection, the vaccine prevented 98% of cancers and precancers caused by the two strains of virus, and almost 100% formed protective antibodies.  But what if you looked at the entire group of 12,000 women, and all forms of cervical cancers and precancers?  It turns out the efficacy was a disappointing 17%.

So why was the overall efficacy of the vaccine so low?  Two reasons:  First, the women who received the vaccine were still unprotected against the strains of HPV that cause the remaining 30% of cervical cancers.  Second, a good number of the women were already infected with the strains in the vaccine, rendering it useless.

So does that mean we shouldn't bother giving this expensive vaccine because of its low overall efficacy?  Actually, the results of the study strongly suggest that we should be giving the vaccine to girls before they become sexually active.  The CDC reported in 2006 that 70% of girls are sexually experienced by the time they are 19, and another study found that 27% of women aged 20-24 test positive for HPV.  If you follow the American Academy of Pediatrics' guidelines and give the vaccine to presumably uninfected 11- to 12-year-old girls, they should experience a 70% reduction in cervical neoplasms.  I suspect that pharmaceutical companies are probably working on adding more strains to the vaccine, to get the efficacy closer to 100%.

What about the argument that the vaccine will lead to a false sense of security, or an increase in early, sexually risky behavior?  Certainly, there are lot of misconceptions about the vaccine -- for example, that it protects against all cervical cancers, or that you can stop getting Pap smears.  The vaccine shouldn't be given without a fairly sophisticated discussion of the expected benefits.  Presumably, the discussion would be between the parent and the pediatrician, and then ideally, between the parent and the child.  I suspect that a big reason why some parents are reluctant to vaccinate their kids is that they want to avoid an uncomfortable conversation.

As for whether an STD vaccine would be, as one author put it, "a passport to promiscuity," there is very little data.  Four Scandinavian countries recently surveyed 65,000 women about their sexual behavior prior to the introduction of the HPV vaccine.   (Interviewing Swedish supermodels about their sexual proclivities: obviously the brainchild of some repressed male researcher!) They plan on re-surveying them after the vaccination campaign, to see whether it affects their behavior. ("Women's sexual behavior.  Population-based study among 65,000 women from four Nordic countries before introduction of human papillomavirus vaccination.")  HIV vaccine trials have not found an increase in sexually risky behavior among its participants, though many of them were high risk to begin with.  And one survey of adolescent girls found that only about 10% thought that getting the vaccine meant that they were old enough to start having sex.  ("Adolescents' beliefs about their parents' human papillomavirus vaccination decisions.") Frankly, I think most teenagers and young adults are more frightened at the prospect of pregnancy and HIV than they are of HPV, and I doubt the vaccine will do much to alter their behavior.

So should the vaccine should be mandatory in girls?  I say yes, as long as parents have the option to decline.  Making it mandatory would remove its stigma as "the STD vaccine," and countries that have instituted school-based HPV vaccination programs have much higher rates of immunization that those that haven't.  Remember that this wouldn't be the first mandatory vaccine for a sexually transmitted disease; the hepatitis B vaccine is required for elementary school enrollment in most states. 

I do understand the argument that it shouldn't be as compulsory as, say, the measles vaccine, since your child can't catch HPV just by sitting next to an infected person in class.  But if we wait until girls are old enough to consent to the vaccine themselves, it may be too late.  I've seen too many 30-year-olds die agonizing deaths from cervical cancer to let my daughter suffer such a fate.  Even more women have to deal with the infertility resulting from treatment of their cancer or precancerous lesions.  We parents do all that we can to instill our own values into our children, but at a certain point, we have to accept that they will make their own decisions, good or bad.

So man up, Governor Perry!  Apologize for your apology, do the right thing, and become the public health advocate every presidential candidate should be.

Next week:  The HPV vaccine for boys

Is Homework Worth the Hassle?

Sarah's too cool for school, while JJ needs a lesson on how to wear

a backpack without attracting the attention of bullies.

I can't believe that summer is over and the kids are back to school.  Yep, back to the cold, hard grind of first and third grades.  All right, I'm exaggerating; aren't you allowed to do that in a blog?  But what I dread most about returning to school is forcing my son to do his homework, and to do it well.  (My 6-year-old daughter obviously reads and hews to the research showing that girls have a more positive attitude about homework.)  You wouldn't think that 10 measly worksheets a week could provoke such angst, but how could they possibly lure my son away from the siren call of the Wii?  Some of my friends send their kids to private schools that refuse to assign homework, and a couple of my more EBM-minded pals have even pointed out, "You know, there's no evidence that homework is effective."  Could that be true? 

The amount of research on homework is vast and generally crappy.  One literature search on the topic found over 4,000 papers, which I was planning to summarize for you, until I was fortunate enough to run across a 2006 systematic review on the subject ("Does homework improve academic achievement?").

The authors found only four trials that randomized either students or classrooms to homework vs. no homework.  All of the trials were small, and not one was published, which speaks to their quality.  Most used as their outcome measure a test of the specific subject material.  All four studies showed that students who were assigned homework performed better on the tests than those who did not.  For example, in one randomized trial of high school students who were studying Macbeth, those who got the homework were able to correctly identify that MacDuff was a Scottish nobleman and not a Simpsons beer company mascot.  ("Student and parental homework practices and the effect of English homework on student test scores.")  The reviewers tried to inject a note of optimism into their summary of the meager evidence, stating, "While each set of studies is flawed, in general the studies tend not to share the same flaws.”

Despite the lack of experimental data, there are multiple large observational studies looking at the effect of homework on academic achievement.  Many were based upon the National Education Longitudinal Study, which gathered achievement test scores, school grades and surveys filled out by tens of thousands of high school students, teachers and parents.  It turns out that in this age group, there is indeed a strong positive correlation between homework and test scores and grades.  And what was the optimal amount of homework for high school students?  One study found it to be 7 to 12 hours a week, or about 1-2 hours per night.  Spending over 20 hours a week (oh, the horror!) was no better than spending only 1-6 hours a week.  Of course, the most obvious flaw in these studies is that it is impossible prove causality.  Does homework lead to good test scores and grades, and by inference, improved learning?  Or do better teachers in upper-income schools, where there is more parental involvement, tend to assign more homework?

And what about elementary school students?  Here's where the evidence is at its shakiest.  This paper's meta-analysis of cross-sectional studies on students in grades K-6 found that there was no correlation between the amount of time spent on homework and academic achievement.  This latest review agrees with an analysis published 17 years prior that also showed no increasing benefit with increased amount of homework in this age group -- 15 minutes a week is as good as 15 hours.

So what are we left with?  I would have to agree with the authors' conclusion that more experimental research is needed, particularly in elementary school, though who would fund such a study, or whether teachers and parents would find it acceptable, is unclear.  Interestingly, in the past couple of decades, the average amount of homework assigned to the youngest age group, 6 to 8 years old, has doubled from 1 to 2 hours a week.  I know an extra hour isn't much.  But I suppose if I were a purist, I would demand that a randomized, controlled study be done comparing 2 hours a week of homework to 2 hours a week of Super Mario Brothers.  

Nintendo, are you listening?

Did I Nuke my Baby's Lungs?

 Did wireless make my Jojo wheeze?

The news media has been trumpeting a study performed by Kaiser Permanente, reporting a strong link between exposure to magnetic fields during pregnancy and the development of childhood asthma.  ("Could microwaves be associated with children's asthma?")  So now pregnant women can't nuke their Irish coffee?  Seriously, we moms already have to give up a zillion things when we're preggers; do you really want to tell us hands off our cell phones and hairdryers?

The study did have its strengths.  ("Maternal exposure to magnetic fields during pregnancy in relation to the risk of asthma in offspring.") The researchers asked over 700 pregnant women in their first and second trimesters to wear a monitor to measure their exposure to magnetic fields for 24 hours.  They then followed their offspring for up to 13 years to see if they were diagnosed with asthma.  So the good things about the study were that they measured magnetic fields objectively, and the doctors diagnosing asthma were unaware of the level of exposure in the mothers.  The researchers also controlled for some, though not all, risk factors for asthma, such as smoking during pregnancy.  What they found was a clear dose-response relationship between magnetic field exposure and asthma in children.  Those in the top 10% of exposure level had children with an almost 50% chance of developing asthma.

Pretty convincing, huh?

Not so fast.  Why did the investigators study women in both their first and second trimesters, when lung development occurs primarily in the second trimester?  I'll tell you why first trimester women were enrolled: This research group has studied the effects of magnetic fields not only on asthma, but also on the rate of miscarriage and sperm quality (in men, of course).  In fact, all three of the studies they published have found a harmful association between magnetic fields and their outcome of interest.  So what does this mean?  That magnetic fields cause a wide array of harmful effects?  Or that lightning struck three times for this research group?  And why did this group choose asthma as an outcome to study anyway?  There are no other studies showing a link, nor have magnetic fields been shown to cause asthma in animals.

Here's what I think:  The investigators probably examined a number of outcomes, but they only reported the finding that was "statistically significant."  In studies, we say that a finding is "statistically significant" when there is a less than 5% chance that it was just a fluke, and therefore a greater than 95% chance that the result is "real."  But what if you are looking to see if magnetic fields are associated with two different outcomes, say asthma or low IQ?  Then you actually have a 10% chance that at least one of the outcomes will be associated in a "statistically significant" way with the exposure.  If you are looking for 20 different outcomes, the chances of finding a bogus, statistically significant result is up to 64%.  And here's the kicker -- as an investigator, you are not required to reveal how many hypotheses you tested.  All you have to do is publish the one result that comes back positive.  And forget publishing a negative result, unless it's to debunk someone else's positive result.  I doubt the Archives of Pediatrics and Adolescent Medicine would have as their lead article, "Maternal exposure to magnetic fields dudn't do nuttin'."

To be fair, I don't know how many hypotheses these researchers tested.  But when I asked the lead author of this study this question, this was his email response:  "This was the first prospective study of EMF [electromagnetic field] health effect.  For prospective studies, one can study multiple outcomes. But we are currently interested in conditions that have had....increase without any apparent explanation."  So all you women who are in the family way -- take this scary study, along with your microwaved Irish coffee, with a grain of salt!

The End of Chicken Pox?

Medical students are taught that chicken pox pox* are classically described as “dewdrops on a rose petal.”  How the textbook authors got from this:

to this:

is beyond me.  I suspect some dermatologist got a little carried away after taking a creative writing course.  Now, any Boomer mother would be able to diagnose chicken pox in her child without the use of a gardening manual.  But believe or not, there may soon come a generation of doctors who will be unable to diagnose chicken pox by sight alone – and that’s a good thing.  Why?  Because it means that the varicella vaccine is working.

Varicella zoster is the virus that causes chicken pox, and the vaccine has been given to kids in the U.S. since 1995.  The single-dose shot is about 85% effective in preventing chicken pox, and close to 100% effective in preventing severe cases (typically defined as a horrifying 500 or more skin lesions, or requiring hospitalization).  The journal Pediatrics recently published a report showing that the number of deaths due to varicella has dropped by almost 90%.  ("Near elimination of varicella deaths in the US after implementation of the vaccination program”)  In fact, the reduction in mortality exceeded that predicted by computer modeling when the vaccine first came out.

Now if you look at the vertical axis, you’ll see that the absolute number of deaths, even before the advent of the vaccine, has always extremely low.  Most kids who fall ill will do fine with a little chicken soup (or, in my family, chicken jook).  In EBM parlance, the number needed to vaccinate is 3 million kids in order to prevent one death.  But that’s not really why we get our kids vaccinated, is it?  It’s more to prevent the discomfort, inconvenience and lost productivity of a case of chicken pox.  Given that over 90% of today’s adults have been infected with chickenpox, and the 85% effectiveness of the vaccine, that’s a number needed to treat of about 2 to prevent human misery.  And that’s a pretty good number in my book.

One last observation:  Since 2006, pediatricians now give a second, booster dose of varicella vaccine.  The number of breakthrough infections with the 2-dose vaccine is even lower than with the 1-dose.  So if, in the future, your doctor fails to diagnose chicken pox in your child without ordering a blood test, don’t be too hard on him!

(*Sorry, I know that sounds like “woodchuck chuck.”)

Son of a Gun!

Cops and Robbers.  Cowboys and Indians.  Or, to be au courant, Cowboys and Aliens.

Would you let your kids play with toy guns?  If your answer is “yes,” you’re in the minority.  A 2009 survey conducted in pediatricians’ offices of over 800 parents found that 67% would “never” allow their child to play with a toy gun. (“Community norms on toy guns”)  I personally find this hard to believe, as most of my son’s friends have toy weapons, but maybe he runs with sociopaths.  More likely, the parents in this study were trying to curry favor with their doctors, just as I tell my kids’ dentist that they “rarely” eat candy and “always” brush their teeth.

At the same time, I do know parents who have a zero tolerance weapons policy, to the point that they spell out the word “G-U-N” in front of little Rambo.  Their concern, of course, is that playing with toy weapons might make them more aggressive kids, which might result in their becoming more aggressive adults.  But is there any data to substantiate this concern?

Before you read any further, here’s my full disclosure:  We hosted a Nerf gun birthday party for our 8-year-old son and 20 of his buddies, complete with a stadium rock soundtrack and American Gladiator code names: 

Based on this uncontrolled, observational study (and when I say “uncontrolled,” I really mean “out of control”), toy gun play led to increased levels of aggression and decreased levels of cooperation, with the birthday boy entering full sulk mode as every kid jockeyed for control of his Vulcan EBF-25 machine gun.  (Yes, you can buy machine guns for kids.) 

Before you scoff at my unscientific report, let me assure you that the quality of the “war toy” literature is little better, and the quantity scant, especially compared to the vast number of studies on violent video games and T.V. shows.  In one typical study, preschoolers were watched through a one-way mirror playing with their usual toys, new airplanes, or new guns.  (“Effects of toy guns and airplanes on children’s antisocial free play behavior”)  Two observers counted the number of instances of “physical, antisocial behavior,” such as hitting, kicking, shoving, or grabbing objects away from others.  “Thematic aggression,” e.g., pretending to kill someone with a gun, was not counted as antisocial behavior, though some would object to this exclusion.  Here were their results:

Guns clearly led to higher rates of antisocial behaviors, though airplanes were not far behind.  The main flaw in this and similar studies is, of course, that the observers were not blinded to the intervention – they obviously knew when the children were exposed to guns vs. airplanes – and you could see how it would be easy to find aggression when you want to find aggression, especially if you have a postdoctoral thesis riding on the results.

To get past the subjective nature of this research, investigators at Knox College came up with an ingenious way of measuring the effects of gunplay on aggression.  (“Guns, testosterone and aggression")  In this study, male college students were divided into two groups:  those who were allowed to play with (though not shoot) a pellet gun, and those who were allowed to play with the game Mouse Trap.  Testosterone levels in saliva samples were measured before and after the play sessions, as testosterone levels have been shown to correlate with aggressive behavior.  You probably won’t be surprised to hear that testosterone levels increased after exposure to the gun, but not the game.  Here’s where it gets interesting:  After the play session, investigators asked the students to add as much hot sauce as they wanted to a cup of water, which they were told would be given to another, anonymous subject to drink.  Hot sauce administration has been validated in other studies as a marker for physical aggression; it’s sort of a sadistic twist to the infamous Milgram’s fake shock experiments.  Turns out that the guys who played with the gun added three times as much hot sauce to the water as those who played with little mousie.  “Interestingly,” the authors deadpanned, “several subjects were disappointed when told that the sample of hot sauce and water they had prepared would not actually be given to the next subject.”

Whether this research applies at all to girls, or even prepubescent boys, is a big question mark.  And while there seems to be a short-term link between gunplay and aggression, there are absolutely no studies, not even retrospective ones, that examine whether adult antisocial  behavior might be linked to playing with weapons as children.  I guess we parents are left with performing what doctors call “N of 1” experiments – seeing how our own particular child responds to weapon play.  So I say let them play Cowboys and Aliens! But if their playdates end up being more Pulp Fiction than science fiction….well, maybe it’s time to pack the six-shooter away.