California passes pro-vaccine bill, protects children

In a victory for children’s health, California passed a new law this week removing the “personal belief” exemption from the state’s vaccine requirements for children. Assuming that Governor Jerry Brown signs the bill this week–which no one is certain about–California will be transformed from a haven for anti-vaccine demagoguery to a state that protects children instead.

How this came to pass is a long tale, but the immediate impetus was the outbreak of measles in Disneyland in January–the worst outbreak in 20 years–which spread mostly through unvaccinated children. During that outbreak, we learned that in some areas of California, anti-vaccination hysteria had grown so widespread that more than half the children in some schools were unvaccinated.

And just three years ago, California had the worst whooping cough epidemic in 70 years, thanks to the anti-vaccine movement.

After the recent measles outbreak, California state Sen. Richard Pan, who is also a pediatrician, introduced SB 277 to remove personal and religious exemptions from vaccines in the state. In February, he and I were guests together on an episode of NPR's On Point with host Tom Ashbrook discussing this issue. Senator Pan spoke passionately and from direct experience about the need to protect children from disease. 

All states in the U.S. require children to be vaccinated in order to attend public schools, a policy that has been the foundation of our national effort to control infectious diseases. Under California’s current law, parents can opt out of vaccines for their children for almost any reason, simply by claiming a “personal belief” exemption. Anti-vaxxers have encouraged parents throughout the state to use this law to withhold vaccines from their children.

With this new bill, California moves back into the modern age. Without vaccinations, hundreds of thousands of children in the U.S. would get sick every year with measles, mumps, whooping cough, chicken pox, and other diseases. Thousands would die, and tens of thousands would be permanently injured. School-based vaccination policies have essentially eliminated these diseases from the U.S. in recent decades. I should add that SB 277 still allows medical exemptions, for those (rare) cases where a child has a legitimate medical reason (for example, because he/she is undergoing chemotherapy to treat cancer) to forego vaccination.

Ironically, vaccines’ very success has allowed anti-vaccine propaganda to spread. Vaccines have been so successful that most people don’t even remember the era when these diseases were a constant fear of childhood. Thus when anti-vaxxers spread (erroneous) claims that vaccines cause harm–most notoriously, that vaccines cause autism–new parents sometimes become convinced that the potential harm isn’t worth the benefit. Vaccines are safe, as the Institute of Medicine explained in a detailed report not long ago, and they are enormously beneficial.

Anti-vaxxers will continue to make extreme, and erroneous claims about vaccines. Just two months ago, the noted anti-vaxxer Robert F. Kennedy Jr. was in California campaigning against SB 277, calling vaccines a “holocaust” – perhaps the most extreme scaremongering I’ve seen on this issue. An anti-vax group called A Voice for Choice announced Thursday, after the vote, that they are “pulling out all the stops” and will try to challenge the new law in court.

Let’s hope that reason wins out–that Gov. Jerry Brown signs the bill and that California’s children are once again protected from vaccine-preventable diseases. We shouldn’t need another measles or whooping cough outbreak, or any more children dying of preventable diseases, to convince people once again that vaccines save lives.

Governor Scott Walker's attack on academic freedom in Wisconsin

Wisconsin Governor Scott Walker really doesn’t like professors. He seems to have a special grudge against the University of Wisconsin, against which he has launched a two-pronged attack this year.

It’s rare for a governor to attack the flagship university in his own state. Governors usually do just the opposite, promoting their universities to the rest of the world whenever the opportunity arises. 

What's more, Walker is currently campaigning for the Republican nomination for President. Presidential candidates usually try to make new friends and influence voters. It’s rare for a candidate to single out a large non-political group (other than foreign enemies of the United States, or other obvious bad guys) and systematically go after them.

Thus it’s surprising–startling, really–to observe how Scott Walker is waging a war on academic freedom in his home state of Wisconsin. Let's look at what he's doing, and then ask why.

First, back in January he proposed an enormous $300 million cut to the University of Wisconsin’s budget, at a time when other state universities are finally recovering from the recession. Now he’s proposing to get rid of academic tenure, not only threatening faculty jobs but also destroying academic freedom for professors at the University of Wisconsin.

Walker’s attack on tenure was just endorsed by a major committee in the state legislature, which voted 12-4 to eliminate tenure from state law. The Wisconsin faculty responded that this new policy, if implemented,

“will inflict lasting damage on a highly successful institution that was built and nurtured with major investments by Wisconsin taxpayers over a period of 167 years.... It would be difficult to overstate how destructive and unnecessary the [legislature's] proposed changes to tenure and shared governance are.”

Why is Governor Scott Walker (aided by his legislature) attacking his own state’s leading university? One could hypothesize that he harbors some resentment over the fact that he himself never graduated from college: he quit school in his senior year at Marquette University. Susan Milligan at US News argues that this disqualifies him as a candidate; perhaps this criticism bothers Walker. But plenty of people succeed in demanding careers without a diploma–just look at Bill Gates and Steve Jobs.

Perhaps the reason behind Walker’s dislike of academia is that he thinks that professors are too liberal. If true, this is deeply disturbing: it means he wants to stifle speech that he disagrees with. This kind of repression of scholarship is one of the most important reasons for tenure in the first place. One doesn’t have to look far–hello, Vladimir Putin?–to find examples of how powerful politicians can suppress speech, to the detriment of their societies. As UC Irvine’s Mark Levine wrote this week,

“none of academia’s core functions could occur without tenure and the assurance of academic freedom it enables.”

I wrote to Governor Walker's office to ask the question above, and also to ask if he thinks his actions will weaken the University of Wisconsin. His press secretary, Laurel Patrick, didn't answer directly, but responded that 

"the Governor’s original budget proposal removed all references to the UW from state statute in order to allow for the proposed authority to create its own policies.  This would allow the UW Board of Regents to address the issue of tenure going forward."

The leaders of a national university governing board association disagreed, pointing out that under Walker's proposed new policy,

"decisions about a tenured faculty member's service could be based less on performance and institutional finances and more on the political or personal views of board members."

I’ve observed the benefits of tenure directly many times, both at Johns Hopkins University and at my previous academic home, the University of Maryland. While at UMD, for example, I wrote several articles highly critical of the university president for his boneheaded decisions about the football coach. Many of my colleagues expressed similar views to me in private, but the untenured ones were unwillingly to speak openly. If we want scholars to speak truthfully, they need to be free of fears of retribution.

Governor Walker’s actions make even less sense when viewed from outside the state, where the University of Wisconsin is considered one of the nation's top public universities (currently ranked 13th among public schools). With his draconian budget cuts and his assault on the tenure system, Walker is sending a message that professors at Wisconsin should sit down and shut up. Some of them–those most able to move, which likely includes some of their best talent–might now be looking for greener pastures elsewhere. Come to think of it, we are recruiting for 50 new endowed professorships at Hopkins, thanks to Michael Bloomberg; perhaps I should be thanking Governor Walker.

It’s disturbing that Wisconsin's governor is using his power not only to weaken one of the state's biggest assets, but also to attack the free expression of ideas. I can't come up with any explanation for his actions that doesn't appear vindictive and short-sighted. This isn’t the kind of behavior I want in any politician, and certainly not in someone who wants to be the most powerful politician in the nation.

Massive genetic sharing effort shows power but also shows how little we know

Your genes are not your fate. 

Nonetheless, genes can tell us a lot about our risk for disease, and sometimes they can tell us how to lead healthier lives.

The landscape of the human genome is vast and mostly unexplored. There is far, far more that we don’t know than we do know. This is why it’s so important that as we test people for genetic mutations, we share information as much as possible. Genes have different effects on different people, and a mutation that is harmful in one group might be harmless in another. If we’re ever to fill in all the gaps in our knowledge, we have to pool our resources by sharing data.

This is the goal of ClinGen, a new project described in this week’s New England Journal of Medicine. ClinGen relies on a public database called ClinVar, where researchers, clinical labs, clinicians, and patients can deposit information about genetic variants and their effect on disease. 

What makes this effort so complex is that many disease-causing mutations are quite rare. If two patients share the same disease and the same genetic mutation, and if we’ve never seen that mutation before, can we claim that the mutation cause the disease? Not really: we might have to wait until we’ve seen many more patients before we can have any confidence in the cause-and-effect relationship. This is why sharing data is so important: more data means more power to discriminate between real effects and coincidences.

ClinGen has already shown us that our knowledge has flaws: perhaps 17% of the disease associations that clinicians have reported might be incorrect. More precisely, the NEJM paper reports that out of more than 118,000 mutations that have a clinical affect, almost 13,000 were reported by more than one lab. Of those, 17% were interpreted inconsistently, with some labs calling mutations "pathogenic" while other labs calling them benign.

I disagree with the headline of an AP report headlined “flaws in gene testing,” which reported that 

“The first report from a big public-private project to improve genetic testing reveals it is not as rock solid as many people believe.”

This is a straw man argument: experts in the field don't think genetic testing is “rock solid”, and the 17% rate of disagreement in disease-mutation association is not that surprising. What's more, these conflicts don’t always represent flaws, but rather holes in our knowledge that we just haven’t filled yet. 

Disagreements over the effects of a genetic mutation represent opportunities to clarify and improve our genetic knowledge base. And as the ClinGen authors emphasize, it’s only by sharing our findings that we can discover and correct these flaws. This is why clinicians, scientists, and labs need to adopt a culture of sharing results, as the ClinGen project has emphasized (see their “Wall of Fame” of labs and institutions that have shared data).

All of us have mutations in our DNA; geneticists estimate that each of us carries perhaps 30 new mutations that even our own parents don’t share. The vast majority of these, fortunately, are harmless. Even mutations that do affect our health usually only have a small influence, changing our risk for disease but not actually causing it.

I'd be remiss if I didn't point out that sometimes, your genes are your fate. If you have certain mutations in the CFTR gene, you will have cystic fibrosis, and some mutations in the HTT gene will inevitably cause Huntington’s disease. 

As geneticist Luke Jostins cogently wrote, identical twins usually don’t die from the same thing. So even though genes may influence our fate, we still have control over it. Knowing your genetic risks can be valuable, but we have a lot more to learn about how our genes influence our health.

Do hyaluronic acid injections help knee pain? Don't waste your money.

As spring turns into summer, we spend more time outdoors, exercising, gardening, or just walking around. And for many people, more exercise means knee pain. Count me among the afflicted.

Several people, including my orthopedic specialist, have suggested that I try injections of hyaluronic acid to treat my knee pain. Many people swear by it, and even though I looked into this two years ago (and rejected it as ineffective), I thought I would look again. Perhaps the evidence had changed.

It hadn't.

Superficially, these injections sound reasonable. Hyaluronic acid is already inside your knee and helps to lubricate and cushion the joint. Adding more lubricant seems like a good idea; after all, it works for cars, bicycles, door hinges, or any other creaky joint.

But not for knees. Just recently, Anne Rutjes, Peter Jüni and their colleagues published a very large review of the evidence on knee injections. They looked at 89 trials involving over 12,000 adults and found that in the trials that were properly controlled (blinded), hyaluronic acid injections had either no effect or a “clinically irrelevant effect”; that is, too small a difference to matter to the patient. (They also found five unpublished trials that showed no effect at all; this is a good example of the so-called “file drawer effect”, where studies that don’t have the desired outcome are stashed away in a drawer and never published.)

Rutjes and colleagues also pointed out that there’s a real risk of harm when you inject something deep into the knee joint. To quote their summary for patients (published along with the article),

“Viscosupplementation [injection of hyaluronic acid] may provide little if no pain relief or function improvement in patients with knee osteoarthritis. It also seems to increase the risk for adverse events."

If you don’t believe Rutjes, perhaps you’ll believe the American Academy of Orthopaedic Surgeons (AAOS), who reviewed a large body of evidence and wrote: 

“We cannot recommend using hyaluronic acid for patients with symptomatic osteoarthritis of the knee. Strength of recommendation: Strong.”

After looking at numerous studies, the AAOS concluded that there was no clinically meaningful benefit from these injections. This document is their official recommendation for physicians.

I was disturbed, though, to find that the AAOS information for patients directly contradicts their own recommendations to clinicians, and suggests that knee injections might work. On their patient-oriented web page, they offer the wishy-washy comment that “hyaluronic acid does seem to have anti-inflammatory and pain-relieving properties … [that] may last for several months,” though “not all patients will have relief of pain.”

What the heck? Are they orthopedists trying to hide the truth from their patients? Why would they do that?

I checked to see if the AAOS patient information was merely out of date, but no, it was reviewed in 2014, and the clinical recommendations appeared in 2013. I have to assume that the authors of the patient information page are not the same doctors who established the official recommendations for clinicians–but it seems unlikely that they are ignorant of their own organizations official guidelines. So why don’t they warn patients that hyaluronic acid injections don’t work? Is it because hyaluronic acid treatments are a significant money-maker for some orthopedists? 

I can hear the response from some doctors already: "In my experience," they say, "this works for some patients." Sorry, but one doctor's experience (or "clinical judgment", as some call it) doesn't trump science. That's why we do experiments, to determine whether or not our subjective impression is correct. In this case, the science is clear.

Incidentally, the Mayo Clinic also fails on this topic. Their site states that hyaluronic acid 

“can be injected into your knee to improve mobility and ease pain. Relief may last as long as six months to a year.” 

They cite no evidence to back this up. Patients looking at either the Mayo site or the AAOS site will be misled into thinking that these injections might be worth a try.

WebMD does a much better job, writing that 

“one study published in Rheumatology found that hyaluronan was no better at reducing joint pain than a placebo injection of salt water. An analysis of seven different studies published in the Journal of Family Practice did not recommend the treatment, since the benefits–if it had any at all–were so slight.”

Note that unlike the Mayo Clinic page,  the WebMD page mentions specific studies and names the journals.

So what does work for knee pain? Physical therapy and exercise to strengthen the muscles around the knee is still the best course, according to the AAOS's clinical guide. Weight loss also helps, by reducing the load on the knee. The only medical intervention that helps is an NSAID pain reliever such as ibuprofen. (See my 2013 article for other treatments that don’t work, including acupuncture (not even close) and glucosamine-condroitin supplements).

As for me, I bought a knee brace even though the AAOS says it doesn’t help. But it feels like it’s helping, and it was cheap. And my knee is definitely feeling better. Why not take advantage of a placebo effect once in a while?

MMR vaccine (still) doesn't cause autism, new study finds

Nope.

We’re still spending vast amounts of time and money trying to counter the ill effects of a discredited, retracted paper from 1998 that claimed to find a link between the MMR (measles, mumps, and rubella) vaccine and autism. Even after the The Lancet retracted the study, and even after the British Medical Council revoked the medical license of its lead author, Andrew Wakefield, many people continue to withhold vaccines from their children because of a fear that somehow, despite all the evidence to the contrary, vaccines might cause autism. Vaccines, I hasten to add, have saved millions of lives and are probably the greatest medical advance of the past two centuries.

Now another study has appeared to add more weight to the evidence about the safely of the MMR vaccine. The new study by Anjali Jain and colleagues, just published in the Journal of the American Medical Association, looked at a huge number of children–95,727–for evidence of any link between autism and the MMR vaccine.

The results were not surprising, to those who have been following the science. To quote the conclusions directly: 

“Receipt of the MMR vaccine was not associated with increased risk of ASD [autism spectrum disorder], regardless of whether older siblings had ASD. These findings indicate no harmful association between MMR vaccine receipt and ASD even among children already at higher risk for ASD.”

That should settle it, right? But then, dozens of previous studies should have already settled this question. Unfortunately, due to the ongoing activism of anti-vaccine groups such as Age of Autism, (who already attacked this new study) and to conspiracy theorists such as Robert F. Kennedy Jr. (whom I wrote about last summer, and who was campaigning against vaccines in Vermont just last week), misguided claims that vaccines cause autism or neurological problems persist.

Here are the numbers from the new study. The authors compared vaccinated children to unvaccinated children, using a huge database of medical claims that included at least 5 years of followup. (This was an "observational" study, by necessity–it would be unethical to withhold vaccines from children on purpose.) The relative risk for autism in children who had 2 doses of the MMR vaccine (the recommended amount) compared to unvaccinated children was 0.74. In other words, a child was somewhat less likely to be diagnosed with autism if he or she were vaccinated. 

Even more surprising was the relative risk among children who had an older sibling with autism: in this smaller group, children with 2 doses of MMR were just 44% as likely to be diagnosed with autism as unvaccinated children. This statistically significant finding indicates, unexpectedly, that vaccines might actually protect children from autism.

The authors were quick to note that there are other good reasons for this apparent protective effect of vaccines: in particular, if parents of autistic children withheld vaccines from their younger children, this could explain the effect. Why? Because we know that autism has a genetic component, and that if one child has autism, his younger sibling is more likely (because they share many genes) to have autism as well. Jain and colleagues explained that if these parents withheld vaccines–because of fears spread by the anti-vaccine movement–then their children could contribute to the apparently lower rate of autism in children who were vaccinated. The authors couldn’t rule out a protective effect of vaccines, but scientifically it seems unlikely, and they wisely offered an alternative explanation.

So: once again we have a large, carefully conducted study showing that the MMR vaccine does not cause autism, and even finding evidence that vaccinated children have lower rates of autism. Let's hope this study helps to end the anti-vax movement, so that we can soon stop spending time and money trying to refute their long-discredited hypotheses and instead focus on trying to understand the true cause.

DNA testing offers a far better way to detect Down syndrome

The results of a new study offer very good news for expectant parents: a remarkably accurate prenatal genetic test for Down syndrome that requires only a blood sample from the mother.

Expectant parents have a lot to deal with. What can a mom-to-be eat, drink, or do to ensure the health of the baby? There is plenty of advice out there, both good and bad, but one area that has advanced rapidly in recent years is prenatal genetic testing. We now have tests that can identify a small but growing number of genetic disorders early in pregnancy.

Until recently, the only way to test the genetic makeup of a fetus was through amniocentesis ("amnio"), an invasive procedure in which a doctor inserts a long needly directly into the womb and collects a sample of amniotic fluid. This test is not only uncomfortable, but it also carries a small risk of miscarriage. Fortunately, it may soon become completely unnecessary, thanks in part to advances in DNA sequencing.

It turns out that small amounts of fetal DNA are circulating in the mother's blood from a very early point in pregnancy, just 10 weeks along. New technology allows us to take a simple blood sample from the mother and use that to examine the baby's DNA to look for trisomy–the presence of 3 copies of a chromosome rather than two. The new study primarily looked at trisomy 21, which causes Down syndrome, but it also looked at the ability of DNA screening to detect other trisomies.*

The new study by Mary Norton and colleagues, by far the largest of its kind to date, involved almost 19,000 women at 35 locations in 6 different countries, all of whom were undergoing routine prenatal screening. The study compared the standard blood test, the "triple screen", to a new cell-free DNA sequencing (cfDNA) test from Ariosa Diagnostics (recently acquired by Roche). I wrote about a similar study involving 1914 patients last year, which used the same kind of DNA testing. The new study is ten times larger, and the results are even better. All of the participants had both standard screening and DNA testing.

What did they find? First, the number of mothers who had both standard and cfDNA testing was 15,841. (For technical reasons, some of the 19,000 participants didn't get both tests.) Out of all pregnancies, there were a total of 38 fetuses with trisomy 21. Standard screening detected 30 out of 38, while cfDNA detected all 38. Much more impressive–startling, really–was the difference in false positives. The standard screen had 854 false positives, while cfDNA testing only had 9. This is nearly 100 times better.

Or to put it another way: among all the mothers, standard screening reported 884 "positive" results, of which only 30 were correct. Thus if you were a mom who got the standard screen, and you had a positive result, there was only a 3.4% chance that your baby would have Down syndrome. Nearly all of these mothers would probably elect amniocentesis to confirm, and go through the anxiety as well as risk of miscarriage that amnio entails.

The cfDNA test reported only 47 positive results, of which 38 were correct. Thus there was an 81% chance (38/47) that the baby will a positive result would have Down syndrome.

Although the numbers were smaller, cfDNA testing was also far more accurate for detecting trisomy 13 and 18, rarer conditions that cause health problems so severe that most infants die before reaching their first birthday.

With a false positive rate nearly 100 times lower than the standard blood test (9 versus 854 false positives), the superiority of DNA testing for prenatal screening is clear. Let's hope that we can soon replace the older blood tests and spare parents-to-be the anxiety and unnecessary follow-up testing caused by thousands of false positive results under the current standard of care.

*For those who want to understand the technical details, this paper by Sparks et al. (2012) explains the sequencing and statistical methods.

How disruptive are MOOCs? Hopkins launches new genomic data science series.

If you could visit a college classroom a hundred years from now, would you expect it to look just like one of today's classrooms?

I suspect not.

Yet if you walked into almost any college classroom today, you’d see a scene right out of the 19th century: students sitting in a classroom listening to a professor talk. Perhaps the professor is using a laptop to project slides, rather than writing on a chalkboard, but other signs of the 21st century can be hard to find. 

Of course the content today is different, particularly in the sciences–no one even knew what DNA was 200 years ago–but the way we teach has barely changed in the past two centuries.

Well, it’s changing now. The advent of massive, online open courses (MOOCs) is making high-quality content available to millions of people for the first time, and much of it is free. These online courses, even in their infancy, have generated a huge response, revealing the hunger out there for learning. 

Professors too are discovering something: how rewarding it is to reach thousands of students rather than just a handful. And capturing lectures on video allows us to mix and match material, updating just the parts that need changing and re-using the good stuff with relatively little effort. 

Hopkins joined the MOOC revolution last year, with a Data Science series of courses led by Brian Caffo, Jeff Leek, and Roger Peng. This June we’re launching a new specialization on genomic data science, that five of my colleagues and I are teaching. Coursera announced our 6-course specialization just a few days ago; Jeff Leek and Roger Peng produced a teaser video that you can watch here:

The specialization will cover statistics, Python programming, the Bioconductor and Galaxy environments, and more, all designed as a gentle introduction to genomic data science for students, postdocs, or even established scientists who want to start learning the tools behind genomics and “precision medicine.” 

Most of the videos are “in the can” and we’re doing the post-production now, creating the quizzes and projects that go along with the classes. Students can sign up now, but they'll have many chances to take the series. Once it launches, the classes will run every month, forever. (Okay, maybe not forever, but for a while.)

One of the first questions people ask me about MOOCs is, how can you offer all this content for free? Isn’t this a threat to the traditional university model?

You bet it is. But it’s happening, whether universities like it or not. As with other disruptive technologies, MOOCs are likely to change dramatically over the next few years, but they aren’t going away.

We're just learning how to deliver knowledge through MOOCs and we’ll get better at it. Right now MOOCs exist in a separate world from universities, but that’s likely to change. Maybe the experiment will fail, and MOOCs will fade away. Maybe that classroom in the year 2115 will look just like my classroom today. I’m betting it won't.