Starting With Curious

Match up the number on the left with the fact on the right:

1. 1400 A.  # of people demonstrated to suffer autism as a result of measles immunization
2. 2.6 million B.  # of annual deaths from measles in 1950
3. 0 C.  # of deaths per day from measles in 2014

(Correct answers: 1.C; 2.B, 3.A)

Despite the hysteria spread by several prominent but ill-informed celebrities, fueled at least in part by completely discredited “research,” vaccination remains one of the most important discoveries in the history of medicine, and along with sanitation one of the top advances in public health.  My first year of medical school we saw a movie celebrating the eradication of smallpox, which had been declared by the World Health Organization just a few years earlier in 1979 (the last naturally occurring case was in 1977).  It was moving to see this illness, which was responsible for up to half a billion deaths during the 20^th century alone, and the disfigurement of many survivors, wiped from the planet through scientific discovery and international collaboration.  I, of course, have never seen a case of smallpox.  But I have seen plenty of children suffer – and in some cases, die – from diseases that are now vaccine-preventable.  Measles, Hemophilus influenzae, meningococcemia, etc.  As inspiring as the triumph over smallpox was, it was equally disheartening to arrive in Philadelphia for my fellowship on the heels of one of the largest US measles outbreaks in the vaccine era, with over 1000 cases and 9 children dead.  The epidemic was traced to members of two sects who opposed vaccination on religious grounds.

Today, people are at least as likely to reject vaccines (either completely or selectively) for philosophical or personal reasons.  Although every state requires evidence of immunization for school entry, with exemptions for medical contraindications, 48 allow parents to refuse on religious grounds, and 20 (including Wisconsin) allow refusal on personal or philosophical grounds.  This is what is behind the current national measles outbreak.  Ironically, two of the poorest “Bible Belt” states – Mississippi and West Virginia – which do not permit religious exemption, have much higher immunizations rates than affluent communities like Orange County and Santa Barbara, California, where up to 40% or more of children are unimmunized.

Many politicians are framing this as an issue of individual choice.  Those who claim not to be antivaccine support education to convince parents to have their children immunized, but insist that it is a parent’s right to choose.  I’m not convinced by that argument.  We don’t allow parents to choose to abuse their children, and we don’t allow parents to refuse treatment for life-threatening conditions.  I don’t believe they should be allowed to withhold life-saving preventive measures either.  More importantly, though, this isn’t just about parents making decisions for their own children.  These decisions affect other children, too.  Most vaccines are incompletely effective in an individual.  Much of the protective effect is from what is called “herd immunity”: if enough individuals in a population are rendered non-susceptible to a disease, then the disease cannot perpetuate in that population and everyone is spared.  For measles, which is one of the most contagious diseases known, the level of vaccination required to achieve herd immunity is quite high.  Jenny McCarthy choosing not to immunize her kids put mine at risk.  (Well, not literally, since my kids are unlikely to ever be in the same population as hers, but you get the point.)

At some level, infectious diseases like smallpox, tuberculosis, and measles are the product of civilization.  They arise and thrive when people come together in societies.  Oliver Wendell Holmes said “Taxes are what we pay for civilization.”  So are vaccines.  Like taxes, they shouldn’t be optional.

Ask your doctor if MiracleCure™ is right for you!

We’ve all seen the ads for the latest pharmaceutical wonder.  Grimacing people, who presumably suffer from some sort of –itis or –osis, now able to play tennis or cuddle with grandchildren or sit in side-by-side outdoor bathtubs thanks to this amazing product.  There is then a rapid-fire list of potential side effects ranging from flatulence to hair loss to sudden death, followed by the concluding “Ask your doctor…”

How are you or your doctor supposed to know?

You need three basic pieces of information:

How well does it work?

How dangerous is it?

How much does it cost?

Some people who are given a medication will get better, and some won’t.  Similarly, some people will get better without any treatment, or with a different treatment.  If the number who improve with treatment is no bigger than the number who improve without, then the drug is useless and would be unlikely to be approved.  However, clinical trials may show that a drug is better than placebo or an alternative treatment, but the important question is how much better.  This can be summarized in a measure called the “number needed to treat (NNT).”  It quantifies how many people would need to be given a drug in order for one to be expected to benefit.  Let’s say MiracleCure is a new treatment for migraine.  In a clinical trial, 80% of subjects who received MiracleCure had a significant improvement in their headache.  That sounds really good.  But 75% of subjects who received WonderDrug™, a different migraine medication, also improved.  That difference was statistically significant, so it is a legitimate claim that MiracleCure is better than WonderDrug.  How much better?  You could say “a little,” but that is pretty subjective.   We can quantify it. The difference is 80%-75%, or 5%, which is 1 in 20.  Therefore, the NNT is 20, meaning 20 people would need to take MiracleCure instead of WonderDrug in order for one of them to see a benefit.

By itself, the NNT is a step in the right direction, but it’s incomplete to answer the question if it’s right for you.  If MiracleCure were not only better, but also cheaper and safer, than WonderDrug, the answer would be obvious.  But that is rarely the case.  New medications are usually more costly, and sometimes have different side effects.  For now, let’s just stick with the cost issue.  (Risks and side effects can be summarized by a similar number called the number needed to harm, perhaps the topic for a future column.)  Let’s say the newer, more expensive MiracleCure costs $500 per dose, while WonderDrug is $250.  Most people taking either one will get better; we’ve already determined that 20 people would have to take MiracleCure instead of WonderDrug for one of them to benefit.  In other words, 20 people would need to take a drug that costs $250 more, for a total cost difference of 20 times 250, or $5000.  That is the cost needed to treat.

Now, this actually is not quite so straightforward.  Your cost isn’t really $5000.  If you choose MiracleCure over WonderDrug, your cost will be $250 (the difference in price between them).  It’s essentially a $250 bet on a 1 in 20 chance of a benefit.  That can be hard to evaluate in the abstract.  Thinking of it as an overall expected cost of $5000 to achieve the benefit is a more concrete way to put it all together.

Then you can decide.  Is it worth $5000 for that extra shot at making your headache go away?  It may depend on how bad the headaches are, or exactly what symptoms you tend to get.  It may depend on the consequences: if the headache comes on the day before you are scheduled to deliver a major presentation, you may want to pay the extra money for the small additional chance that you’d be able to give the talk, whereas if you have nothing high stakes planned the next day, maybe you’ll take a chance on the slightly less effective drug.

The point is, it’s your decision.  The question shouldn’t be “Ask your doctor if MiracleCure is right for you,” but rather,  “Ask your doctor to help you decide if MiracleCure is right for you.”  And if you are going to make an informed decision, you now know the basic data to request.

The mention of funding for additional research in “precision medicine” attracted applause from both sides of the aisle in a State of the Union address that was notably thin in bipartisan appeal.  But it was hard for me to bring my hands together over the concept.  When I hear about the promise of the “genetic revolution,” I think of Carly (not her real name).  I took care of Carly, an 8 year old with sickle cell disease, a few years ago when she came to the emergency department with a massive stroke.

In medical school, in 1983, a professor told us with great authority that within 15 years, sickle cell disease would be an historical relic.  Because it was known to be caused by a single mutation coding for a single amino acid in the hemoglobin molecule, it was an obvious target for the emerging field of gene therapy – it would be the simplest genetic disease to cure.  If that professor had been correct, Carly wouldn’t have sickle cell disease, much less a crippling stroke.  I think everyone knows that sickle cell disease is still very much with us.  Carly’s family certainly does.

Now, I know “precision medicine” isn’t about gene therapy.  As described by the White House, the initiative is designed to “provide clinicians with new tools, knowledge, and therapies to select which treatments will work best for which patients.”  The concept is appealing.  Therapies have different effects on people depending on their genetics.  Rather than a “one size fits all” approach, drugs can be targeted to people whose genetics suggest they would be more likely to benefit, and dosages can be adjusted according to genetic differences in metabolism.

But as Mayo clinic anesthesiologist and physiologist Michael Joyner points out in a recent New York Times op-ed, it’s never quite as simple as it seems.  First, most diseases, and certainly the most common ones, turn out to be genetically very complex.  In sickle cell disease, 100% of the risk is associated with a single gene mutation.  For most conditions studied so far – diabetes, heart disease, autism – multiple genes account for at most a few percent of the variability.  Environment and behavior remain far stronger risk factors.  And of course there is an interplay between genes, environment, and behavior that increases the complexity further.

Another “straightforward” example provides further caution.  Metabolism of many drugs is affected by a genetic variants in the cytochrome p450 complex.  The presence of certain alleles alters drug metabolism in predictable ways.  Knowing a patient’s cytochrome p450 alleles should allow a clinician to adjust drug dosages without the need for trial and error – giving more to people known to metabolize more readily, or less to those who are slow metabolizers –  potentially maximizing benefit while avoiding toxicity.  Warfarin (Coumadin®), an anticoagulant commonly prescribed to prevent blood clots in patients with a variety of heart and other conditions, is one of the drugs metabolized in this way.  Moreover, it has a narrow therapeutic index, meaning there is a relatively small zone of appropriate dosages: too little is ineffective, too much is dangerous.    The usual way to find the sweet spot is to start with a given dose and monitor blood tests to check clotting, making frequent adjustments until the desired effect  if achieved.  This can take many weeks, during which time the patient is at risk for either blood clots or excessive bleeding if the dose is too low or too high.  And people can vary in the necessary dosage by a factor of almost 20, in large part due to known variants in the p450 genes.  So when these variants were identified, it was appealing to think that prescribing based on knowing a patient’s p450 genotype would be safer and more effective.  There was a lot of hype about the coming “pharmacogenetic revolution,” and in 2010, the FDA actually changed the labeling on warfarin to recommend that  physicians choose the dose based on p450 genotype.

They appear to have jumped the gun.  A recent study, a meta-analysis of 9 clinical trials comparing genotype-based dosing of warfarin with standard “trial and error,” found no advantage to the “precision” approach in terms of any laboratory or clinical outcomes.

No doubt as our understanding of disease improves, we will be able to target treatments more effectively.  Some things we consider a single condition will turn out to be a cluster of many different conditions, based at least on part on genetic differences, each with a different optimal treatment.  Cancer chemotherapy is already a step in this direction.  But we shouldn’t get overly distracted by this latest shiny object.  The more we learn about the human genome, the more we realize that external factors – environment and behavior – remain the primary determinants of disease and the keys to prevention.  The single biggest advance in the 40+ year “war on cancer” has not come from the lab; it was the reduction in smoking.

Diet, exercise, and other behavioral and environmental factors aren’t very sexy, and they are not the stuff on which academic careers are built, but in the end they are what will make us healthier.  We can’t let the allure of precision medicine threaten support for these mundane but proven strategies.  Gene therapy sounded pretty cool, but it didn’t help Carly.

One of the worst episodes of the original Star Trek series was one called “Spock’s Brain.”  I can’t recall all the details (although – nerd alert – I undoubtedly had the entire script committed to memory at one point in my life).  But it involved a technologically backward planet where the males and females lived separate lives: the men (called “morg”) lived on the surface in a sort of late Ice Age existence, while the women (“imorg”) lived in a comfortable underground city, though the whole place apparently ran on autopilot, since both morg and imorg had the intelligence level of 8 year olds. (When asked the whereabouts of Spock’s brain – don’t even ask why – one of the imorg, confused, replied, “Brain and brain! What is brain?”)

Many of the episodes from the 1960s had a hidden – or sometimes quite blatant – moral message, but I could never figure out what it might have been in this episode.  Given how bad it was, maybe there wasn’t one.  But a couple of recent articles shed some light on a possible allegory.

One study examined the ability of randomly created groups of 2-5 members to perform a set of tasks.  Success was only minimally correlated with several hypothesized factors, such as average or maximal IQ, or group cohesion.  The three factors most strongly predictive of success were equal distribution of speaking turns, average social sensitivity of the group, and the proportion of women. (Most of this last effect was mediated by the greater social sensitivity of women, but there was an independent contribution from femaleness itself.)

Other work examines gender differences in decision making.  In low-stress situations, men and women approach decisions similarly, gathering information and weighing risks and benefits, and their average overall risk appetite is the same.  But a series of studies demonstrates that under conditions of stress (physical stress, anxiety), decision-making strategies diverge.  Men tend to take larger risks for larger potential gains, while women tend to go for surer but smaller rewards.  Moreover, when asked to evaluate their strategies, men were less likely to recognize their riskier approaches as actually riskier.

Now, I don’t mean to suggest that men are a bunch of insensitive adrenaline junkies.  And the data don’t say one style is better or worse.  But teams with a diversity of approaches will likely outperform one with a single-minded risk-averse or risk-taking strategy, and this is also borne out by evidence.  A review of 2400 large global companies showed that those with at least one woman on their board outperformed those with all-male boards by 26%.  (You might argue that we also need to see how a large global company with an all-female board would compare.  Sigh.)

Working in pediatrics, and specifically at children’s hospitals, for my entire career, I take this sort of balanced approach to work groups for granted.  But too many organizations are like that planet where the morg live above ground, the imorg below, and both suffer as a result.  Brain seems to require both.