Autism's false theories

The St. Petersburg (Florida) Times last week ran a feature story on the controversy surrounding autism and vaccines. I’ve written about this before and you can found many blogs and websites devoted entirely to autism - some good, some bad. The “controversy” is due to some people’s belief that autism is caused by the measles, mumps, and rubella (MMR) vaccine, which was first proposed in a 1998 article – later revealed to contain fraudulent data – by by Andrew Wakefield and colleagues. (10 of Wakefield’s 12 co-authors retracted their findings and repudiated the study.)

The St. Pete Times article does a better-than-average job at presenting the issue, although its title - “Debate rages over need for vaccines” – is very misleading, and I worry that the title alone will make some parents withhold vaccines from their children. But if you read the article, the reporter (Lisa Greene) does point out clearly that:

“Since then, the study [by Wakefield and colleagues] has been harshly criticized. Most of the researchers involved have retracted their results. In September, researchers who conducted a similar study said they found no link between measles virus and autism.”

Vaccines do not cause autism. After >20 studies, some of them quite large, there is no serious scientific debate over this question. But Greene makes an interesting point when she writes: “This is no longer principally a debate about science. The real question is whether Americans still believe in science — or at least, in the nation's scientists.”

That’s a good question. The anti-vaccine camp often uses conspiracy-theory arguments to make their case, as in “the government is hiding the truth” or “big pharma” doesn’t want us to know that vaccines are harmful. If you want to read some really extreme conspiracy-theory arguments, just look at what Robert F. Kennedy Jr. has been saying about thimerosal and vaccines. (And it worries me that his name is being floated for possible high-level positions in the Obama administration.) These arguments are indeed an effort to convince people (not just Americans, of course) not to believe scientists, but instead to believe, well, non-scientists, who make all sorts of other claims, ranging from the merely ignorant to the outright fraudulent. These frauds include people such as Mark and David Geier, who offer testosterone-reduction and chelation drugs to autistic children and claim that these treatments work, despite evidence that they don't - and that they might even cause serious harm.

Why do people prefer to trust quacks rather than science? Neurologist and skeptic Steven Novella has one explanation: “I know that when you are a parent of a sick child the gears of science may grind maddeningly slowly” and science hasn’t yet determined the cause, or a cure, for autism. So when someone comes along, perhaps someone with seemingly respectable credentials (but not always), and says he knows the answer, parents understandably want to believe it.

The St. Pete Times article includes a very interesting set of tables and charts (as a special supplement, not in the main article, alas) with real numbers showing the dramatic reductions over the years in the prevalence of measles and other diseases as vaccines were introduced. The press rarely does enough to point out what a major public health benefit vaccines represent, so kudos to SPT for their special report. As the Vaccine Ethics site at U. Penn says, “Vaccines are credited with having saved more lives than any medical treatment ever developed.”

Note: the title of this posting is a reference to Paul Offit’s outstanding new book, Autism’s False Prophets. I highly recommend it – Offit is a terrific writer who knows the science and the history of research on autism as well as anyone I've ever read.

Serious doubts about new study of statins and heart disease

The news this past week was filled with reports of a new study in the New England Journal of Medicine (NEJM), which reported a “dramatic risk reduction” in heart attack risk for men using Crestor, a statin drug made by AstraZeneca. This was all over the news, getting headlines on the Sunday (Nov 9) major TV networks and front page reports Monday in The New York Times, the Washington Post, and other major papers. What was striking about this study was that it claimed that people with normal cholesterol levels could get significant health benefits. If true, this new study implies that millions more people should start taking statins to protect themselves against heart attacks.

Wow. Should we all rush out and get some statins? Should we all buy AstraZeneca stock (which went up 20% on the news of this report)? Both?

Hold on a minute. This new finding is rife with problems, despite the breathless news reporting about it. Actually, there are two studies: one published in NEJM, and the second published in Circulation. I’ve read them both. Study 1, in NEJM, got most of the headlines. Study 2 reports on a new diagnostic test that looks at levels of C-reactive protein (CRP), a marker of inflammation. Study 2 found that use of a test called hsCRP – for high-sensitivity C-reactive protein – improved the predictions of cardiovascular risk in men. In other words, the study said, using this test would let you predict more accurately who’s going to have heart problems. Let’s go over the problems one by one. (This is a long blog post, so if you want to know the REAL problem with the study, scroll down to Problem 5 below.)

Problem 1 (raise an eyebrow): Both studies were funded by AstraZeneca, the drug company that sells Crestor. Obviously, AstraZeneca must be pleased that the results suggest that millions more people – those currently considered at low risk for heart disease – should start taking Crestor. However, the funding was disclosed in the reports, and AstraZeneca did not interfere in the analysis, so the funding source does not invalidate the results – not at all. It just makes me a bit more skeptical.

Robert Bazell, a journalist at NBC, was much more credulous. He reported that the study was “squeaky clean.” Well, it’s awfully nice of Mr. Bazell to give his stamp of approval, but disclosure alone does not mean the study had no bias. We’ll get to that in a minute.

Problem 2 (raise the other eyebrow): Both studies also say that high levels of C-reactive protein (CRP) are linked to heart disease, even in men with normal cholesterol levels. The lead author of both studies was Paul Ridker. Paul Ridker owns the patent on the hsCRP test for CRP. Another consequence of these studies is that millions of people are now likely to get tested for CRP, using Ridker’s test. Clearly, Ridker has an interest in the results coming out the way they did. NBC’s Bazell gives him a pass: “As for Dr. Ridker, he says flat out that the financial interest in the test had no effect on the outcome. I certainly believe that. Dr. Ridker has spent most of career working on c-RP and this study validates all his work.”

So let me get this straight: because Ridker has spent his career working on CRP and this study validates his work, we shouldn’t question it? I don’t think so. What this meant to me was that the parties conducting and funding both studies had a very strong interest in the results coming out the way they did. That doesn't mean the results are wrong - again, it just makes me more skeptical. But that’s why we have placebo-controlled trials: to eliminate the effect of bias. So I read the papers, carefully, to see what the data actually said.

Problem 3: the Circulation study didn’t report separately on the effect of CRP and family history of heart disease. In this study, Ridker and colleagues looked at 10,724 men retrospectively (over a 10-year time period), and used a “traditional” model to predict the risk of heart disease. The traditional model had 5 variables: age, blood pressure, smoking status, total cholesterol, and HDL cholesterol. They then added two more variables to the model: (a) the hsCRP test and (b) family history of a heart attack before the age of 60. The report shows that the new, 7-variable model is somewhat more accurate. The study has several methodological problems that I won’t try to describe here, but the biggest problem is that the fail to report the separate effects of the two new variables. In other words, they report only that both variables should be used to measure risk, which means (of course) that patients should be getting the hsCRP test. But what if the entire effect of the study is due to the family history of heart disease? The study doesn’t say. We simply can't tell if the hsCRP test has added value or not. And the leader of this study - Ridker - has the patent on the hsCRP test.

Problem 4: the NEJM study actually reports a very small benefit. All the glowing press reports emphasized the “44% reduction in risk” in those taking Crestor, making it sound very dramatic, but they neglected to report the absolute risk. What I mean here is that if the risk is very, very small, then a relative reduction of 44% is not so significant. Here are the actual numbers: this was a large study, with 17,802 subjects, 8901 getting Crestor and 8901 getting a placebo. The placebo group suffered 251 “events” (one of five cardiac problems, including heart attack), and the Crestor group had 142 events.

This looks pretty significant – and statistically speaking, it is. But the clinical significance is different: you’d have to treat 95 people for 2 years with statins to prevent 1 heart attack. Is that worth it? And if we put millions of people on statins for the rest of their life, which might indeed prevent some heart attacks, will there be other consequences that we can’t yet foresee?
Having an NNT (number needed to treat) of 95 might not sound so bad, but that’s a very high number. An article in Business Week a few years ago pointed out that such high NNT numbers might just represent statistical noise. That article quoted Dr. Nortin M. Hadler, professor of medicine at the University of North Carolina, who said, "Anything over an NNT of 50 is worse than a lottery ticket; there may be no winners.” The article goes on to point out that “an estimated 10% to 15% of statin users suffer side effects, including muscle pain, cognitive impairments, and sexual dysfunction.” Furthermore, it is highly likely that lifestyle changes – getting more exercise, for example – will have a better NNT than 95. So rather than prescribing Crestor, perhaps physicians should explain the greater benefits – possibly much greater - that patients will have from changes in diet and exercise.

Problem 5: This one is the biggest problem of all. The patients in the NEJM study were randomly divided into two groups, treatment (Crestor) and placebo. Table 1 in the paper describes the groups according to a long list of features, and the groups are virtually indistinguishable for most of these – average age, blood pressure, LDL cholesterol levels, body mass index, etc. However, there are 3 critical variables where the two groups are not identical. Presumably this happened by chance, but when you have such a small effect as the one found in this study, small differences can have huge consequences. Let’s look at these 3 variables and at the number of patients in each group (Crestor vs. placebo) with these factors:

Numbers of subjects in Crestor vs. placebo groups

Treatment group:	Crestor	Placebo
Current smoker	1400	1420
Family history of premature CHD	997	1048
Metabolic syndrome	3652	3723

Notice that the Placebo number is higher in all 3 cases. There were 20 more smokers in the placebo group, 51 more people with a family history of CHD (coronary heart disease), and 71 more with metabolic syndrome. All 3 of these variables are risk factors for heart disease – in fact, 2 of them were used by Ridker in his Circulation paper as part of a test to predict risk!

Even if these differences are accidental, all 3 of them put the placebo group at higher risk of heart disease. We don’t know if these totals represent separate people (one person might be a smoker and have a family history of CHD), but if they were, we have as many as 142 more “at risk” people in the placebo group.

Remember, the total number of excess events in the placebo group was only 109 (252 events versus 141 in the placebo group). How many of those events occurred in people with the 3 “bad” variables above? It is entirely possible that these differences in the two study groups could dramatically reduce – even eliminate – the supposed benefit observed in the study.

So what does this all mean? Well, I am not convinced that Crestor has a clinically significant benefit for patients with normal cholesterol. My guess is that further studies, if done properly, will show that the benefit is smaller than that reported last week, and perhaps the benefit is nonexistent.

Finally, on a lighter note, I was pleased that one of my favorite “fake news” reporters, Stephen Colbert, wasn’t fooled at all – he made fun of the study on his show (The Colbert Report) on Wed 12 November. (Scott Hensley over at The Wall St. Journal blog has a nice post about this.) Colbert reported the study in his “Cheating Death with Dr. Stephen T. Colbert, D.F.A.”:

“This is a great breakthrough in the battle to find things to prescribe to people who don’t need them. True, the drug costs $100 a month, but that is a small price to pay to not have the heart attack that there’s no way of knowing if you would have had it.”

Colbert then showed a video clip of Stanford cardiologist Mark Hlatky. Hlatky was interviewed on PBS, where he said “we need to be cautious before we expand the numbers of patients so drastically.” Colbert responded: “sounds like someone hasn’t gotten enough free Crestor pens.”

I guess I haven’t gotten enough free Crestor pens either.

Johns Hopkins University offers quack medicine as "herbal consultations"

Well, it's sad to see, but one of the top medical research institutions in the world, Johns Hopkins University, is now offering - and advertising - a quack treatment for its students. This comes as part of its new "Integrative Medical Center", where "Integrative" is a code word for quackery. Oh, I'm sorry, that's not what JHU calls it: they say "integrative medicine refers to the practice of combining Western treatments such as pills and vaccinations with the traditional treatments of the East. It holds that curing a disease means treating the whole patient, not just the patient's illness."
Sorry, JHU, but there's only one kind of medicine: treatments that work. Using words such as "traditional," "integrative," and "alternative" is little more than marketing hype to disguise the fact that none of these treatments actually cure anything.

Having JHU endorse this nonsense is a big coup for proponents of these bogus treatments. But I should point out that many - I would venture to bet most - JHU medical researchers and physicians don't support this apparent endorsement by their institution. I was a professor at JHU myself not long ago, and I have many good friends and colleagues there who don't buy into quackery.

So just for entertainment, let's look at what JHU's own newsletter says about the new "herbal consultations":

"Allegra Hamman, CRNP, clinical herbalist and wellness consultant, will be administering the new services for the SHWC. Over the past three years, she has studied herbal medicine at the Tai Sophia Institute, where she received her master's degree in June. As part of her studies, Hamman spent a year and a half treating patients using herbal remedies."

Great! The Tai Sophia Institute is a hotbed of quack treatments, including homoepathy, Qi Gong, and acupuncture. Their own website says their "values" include:

- Operate from an acknowledgement and declaration of Oneness.
- Use nature and the rhythms of the earth as a guide in teaching our students and one another.

This is New Age gobbledegook, not medicine. Gee, it's a good thing that Hopkins has a nurse who trained at Tai Sophia! I wonder how much they're paying for these valuable services.

By the way, the University of Pennsylvania Medical School started a joint master's degree program with Tai Sophia in 2005, but they came to their senses shortly thereafter and severed the relationship. Before they did, though, they were fiercely criticized by skeptics such as David Colquhoun:

"What on earth was the University of Pennsylvania thinking about when it associated itself with such pathetic twaddle [as Tai Sophia]? Is it that their senior people are so in the grip of the delusional age that they no longer care what's true and what isn't? Or did they just spot a good chance to make money from the gullible public?"

Too bad JHU didn't talk to UPenn before they went down this path. Here's more from nurse Hamman about her new herbal consulting practice: "From the point of view of the medical community, I function as a bridge," she said. "I can speak the language of herbs, and I can speak the language of medicine." The language of herbs? What? Is that supposed to mean something, or is it just more New Age nonsense?

She goes on: "Herbalists would say that there's an enormous written record: thousands of years of information about herbal medicines. Traditional use counts for a lot."

Actually, Ms. Hamman: no, it doesn't. What counts is scientific evidence that we can gather through proper studies. Some plant products do indeed have great benefit - take aspirin, for example - but before we can offer them as medicine, we need to show that they work. (Not to mention we need to understand how to identify the active ingredients and how to provide a controlled dose.)

The JHU Newsletter also published an Editorial on this article in which they expressed mild criticism of the move: "While a clinical herbalist may provide an alternative option that appeals to students who do not wish to undergo conventional treatments, the addition of a general practitioner rather than a specialist should be prioritized. Yet, if the University were to hire specialists, there are others who would better serve the needs of the student body, such as a gynecologist or dentist, whose availability should take precedence over the option of an alternative medicine practitioner."

The Editorial misses the main point entirely, though, when it endorses alternative medicine: "Alternative medicine has been proven to be a safe and effective form of treatment for some conditions, and the attractiveness of this more natural form of medicine has propelled it into the realm of mainstream Western medicine including at Hopkins's own Hospital and medical school." And they also say "we supported the Hospital in taking the progressive step of creating a branch for alternative medicine." Sorry, Newsletter editorial staff, but you're wrong. You've been sold by the marketing hype of quack practitioners. "Alternative" medicine has not been proven to be safe and effective for anything, and I challenge you to provide examples. There's only one kind of medicine - the kind that works - and we don't label it "alternative."

Surprisingly, the JHU Newsletter includes a skeptical comment from a student, junior Rick Carrick: "I think that Health and Wellness has some issues just servicing people with regular medicine," he said. "I think that they should focus on getting people the treatment they need normally before they focus on any sort of essentially fake medicine."

Bravo! At least some of the students are too smart to be fooled by this nonsense. Now if only JHU would listen to its own students - and doctors.

Patent dispute costs Robert Gallo the Nobel Prize

I've written before about how I'm opposed to patents, particularly software patents,
but also patents on biological discoveries. And pro-patent attornies and scientists have argued against me, here on this blog and elsewhere.

But this year's Nobel Prize in Medicine illustrates another peril of patenting, one that I'd never thought of: it can cost you the Nobel Prize.

How is that possible? The 2008 Nobel Prize in Medicine went to 3 scientists, Luc Montagnier and Francoise Barre-Sinoussi for their discovery of HIV, the virus that causes AIDS, and Harald zur Hausen for his discovery that human papilloma virus causes cervical cancer. Notably missing from the prize list was Robert Gallo, who many people believe deserves joint credit with Montagnier for discovering HIV. Montagnier himself commented, after learning that he was awarded the Nobel, that "it is certain that he [Gallo] deserved this as much as us two."

The history of the discovery of HIV has been documented in great detail elsewhere - including a 1993 movie, "And the Band Played On," that I highly recommend. But briefly: in the early 1980s, both Montagnier and Gallo were racing to discover the cause of AIDS. Montagnier is now widely acknowledged as having found it first, although Gallo announced his discovery soon after. The two viruses identified by the scientists were later determined to be the same, but Gallo was, for a while, credited with independently finding the virus. [The Nobel committee, in announcing the prize, said that there was "no dispute" that the French duo had discovered HIV first.] It was only much later - in 1991 - that independent NIH scientists determined that Gallo had, in fact, grown the French strain of HIV, which he had obtained from Montagnier and which had contaminated some of his own samples.

Gallo is, however, given credit for proving that HIV is indeed the causative agent of AIDS. The Nobel committee's press release acknowledges this: "several groups contributed to the definitive demonstration of HIV as the cause of acquired human immunodeficiency syndrome (AIDS)." Although their press release never mentions Gallo by name, many scientists thought (and still think) that this contribution by Gallo, along with his other groundbreaking AIDS work, would justify him jointly receiving the Nobel.

Now for the patent story: both Gallo and Montagnier filed for patents on a blood test for the AIDS virus. This spawned a huge controversy, in part because Gallo applied first, and also because Gallo's claim excluded Montagnier. The Pasteur Institute (Montagnier's employer at the time) sued the U.S. government in 1985 in an effort to share in the patent royalties. After two years of fighting, the U.S. and France agreed to share royalties on the patents, and in March 1987 President Ronald Reagan and Prime Minister Jacques Chirac held a joint press conference to announce that Montagnier and Gallo had independently identified the AIDS virus.

It was only after this press conference that scientists discovered that Gallo's virus was actually the same as Montagnier's, and that both must have come from the same patient.

Why did the Nobel committee snub Bob Gallo? Of course, they won't admit that they did any such thing. Gallo and Montagnier themselves have long since repaired their relationship, as indicated by Montagnier's generous comments quoted above. But the patent dispute caused deep and lingering resentment among a much broader community, resentment towards Gallo personally and towards the U.S. and its patent system. As was later revealed in an investigation by the U.S. Congress:

"Just minutes before the press conference, HHS submitted applications for U.S. patents on an HIV antibody blood test and a method of producing the virus. These patent applications contained the seeds of the French/American dispute; they contained fundamental assertions that could not be substantiated. Chief among these was the assertion that, "... we are the original, first and joint inventors ... of the subject matter which is claimed and for which a patent is sought ...." The real inventors of the HIV blood test were the IP [Institute Pasteur] scientists, who had developed and begun to use their blood test the previous Summer (1983). Dr. Gallo knew about the IP blood test. In fact, as early as September 1983, Dr. Gallo and his colleagues actually sent LTCB AIDS patients' samples to Paris to be assayed with the IP blood test.

Dr. Gallo and his colleagues did not disclose to PTO their knowledge and use of the IP blood test, nor did they disclose the IP scientists' considerable body of scientific work on their virus and blood test."

Not surprisingly, the patent application infuriated the Institute Pasteur scientists. NIH didn't behave well either - their response was to defend Gallo's claim uncritically. If Gallo - whose work was all publicly funded by his employer, the NIH - simply hadn't filed for a patent, who knows how things would have turned out?

So here's my advice to scientists with a hot discovery: publish it, and share it freely with the world. Don't apply for a patent on the hope that you will get lucky and cash in - you probably won't. And you never know what kinds of backlash a patent application may cause. You might just cost yourself a Nobel Prize.

Obama for President

In case it isn't obvious, I might as well make it explicity: I support Barack Obama for President. In the scientific community, support for Obama is very strong, so I'm joining with my colleagues on this one. Recently, a group of 63 Nobel Laureates announced their endorsement of Obama, in an open letter you can find here. (Of course I don't consider myself a part of this group - by "colleagues" I mean the broad scientific community.)

It's a short letter, but I'll quote just one sentence: "we support the measures he plans to take – through new initiatives in education and training, expanded research funding, an unbiased process for obtaining scientific advice, and an appropriate balance of basic and applied research – to meet the nation's and the world's most urgent needs." Francis Collins, formerly the Director of NHGRI, also endorsed Obama recently, and although he focused primarily on positive aspects of Obama's plans, he also wrote: "As I have examined the positions taken by the current Presidential candidates on these critical issues, I regret to say that I have found little comfort in Sen. John McCain's plan."

There are many non-scientific reasons to support a candidate, but this is a science-focused blog, so I'll stick with these. On scientific issues, Obama has a far better agenda than McCain.

Debate reveals who will help science funding

The final presidential debate between Obama and McCain had at least one telling moment for U.S.-based scientists who depend on grants for their research. After McCain repeated his promise to immediately freeze all federal funding, Obama pointed out (a bit later) that if you impose a freeze, you can't do new research to discover new cures. They were talking about special-needs children, but the broader implication was clear to me, and it was nice to see Obama point it out.

Yes, I realize I'm speaking as a member of an interest group on this (but who isn't a member of some interest group or other?), but science funding can't just be frozen. A budget freeze is an unthinking administrative step, and it's the coward's way out - it's a way to avoid favoring any one program over any other. Obama pointed out, correctly, that the smarter path is to set priorities and cut some programs, but not others. Admittedly he didn't make it so clear what he would cut either, but at least he said he would pick winners and losers rather than freeze everything. Whenever I hear "across the board freeze" (or "cut"), I know that someone was too chicken to make some tough decisions.

Most people outside academic science don't realize that a "freeze" has real consequences for biomedical and scientific research. New programs cannot get started unless there is new money. Most large scientific programs have multi-year funding, so you can't just cut those off to start new ones. And the costs of doing science increase like everything else, so if you freeze funding, the amount of scientific research steadily declines.

McCain made one other anti-science comment - for the second time in a debate - though many people don't realize it. This is his annoying gripe about the "$3 million overhead projector." It makes a good sound bite, but no one is paying $3 million for an overhead project - that's absurd. The money was for the Adler planetarium in Chicago, a very popular exhibit with children and adults alike. They need a new Zeiss Mark VI star projector to replace their 40-year-old one, and they are trying to raise money for it. Phil Plait (the Bad Astronomer) blogged about this in detail the first time McCain raised it.

So in the last debate, when it came to Science issues, the score in my book was Obama 2, McCain 0.

new members for Vioxx Hall of Shame

Back in May, I created a list of medical researchers who had been paid by Merck to conduct studies of Vioxx (rofecoxib), and who had helped Merck "prove" that Vioxx was safe. It later turned out, as many of us now know, that Vioxx substantially increased the risk of heart attacks in some patients. Unfortunately, this risk wasn't known to the public until multiple patients had died.

What made their behavior particularly egregious was that, in many cases, the doctors hadn't even written the articles - the articles had been written by Merck employees or contractors, and the doctors' names had been added only when the article was submitted for publication. This violates multiple ethical standards for research and scholarship.

Well, my list wasn't complete, and I learned recently of a few additional names that should be added. Chief among them is Marvin Konstam, a Tufts University professor who is also an advisor to the National Heart, Lung, and Blood Institute (NHLBI) at NIH. In addition to his Merck-supported articles on Vioxx (see the list below), he recently wrote an article in support of medical devices produced by a heart device company that he works for. He recently switched his affiliation from NIH to Tufts after he was named in the JAMA article about ghost writing as one of many researchers who allowed his name to be attached to articles that he didn't write.
So here are some additions to the

Vioxx Wall of Shame (Addendum)

Martin Konstam, M.D., Tufts University School of Medicine, Boston
Matthew R. Weir, M.D., University of Maryland Hospital, Baltimore
These two researchers are the first two authors on

"Cardiovascular thrombotic events in controlled, clinical trials of rofecoxib."

Circulation. 2001 Nov 6;104(19):2280-8. They also jointly authored a review paper called "Current perspective on the cardiovascular effects of coxibs," Cleve Clin J Med. 2002;69 Suppl 1:SI47-52.

More recently, Konstam was a co-author of another Vioxx study (Bresalier et al., N Engl J Med. 2005 Mar 17;352(11):1092-102) that reported - somewhat to Dr. Konstam's credit - an increased risk of heart attack associated with Vioxx.

I should add that the original JAMA article included a much longer list than my Wall of Shame. Dr. Konstam's name only came to my attention because of the new controversy, reported in the Boston Globe and elsewhere, over his conflict of interest involving a medical device company.