Should we all be on statins?

Well, probably not.

But a new review published earlier this month in the Cochrane Reviews looked at 14 different trials, with a total of 34,272 patients, in an attempt to answer this question, and came out with conflicting results. Scientific and medical experts looked at the review and have already reached diametrically opposed conclusions, reported in their blogs and in commentaries in several leading journals.

Everyone has heard of statins: they are a class of cholesterol-lowering drugs that offer clear benefits in people who already have suffered heart attacks or other serious cardiovascular problems. But what about the rest of us? If you have slightly elevated cholesterol, or even normal cholesterol, should you take statins? Drug companies would certainly like you too, and they have been pushing statins (such as Levacor, Zocor, Pravachol, Lipitor, and Crestor) for years in the U.S., through ad campaigns in print and on television. I wrote about a study of Crestor back in 2008, and I found serious problems with the study's design and conclusions.

First, what did this large-scale review find? All of the studies ran for at least a year, and all were randomized controlled trials, the most rigorous type of study. Overall risk of death was reduced by 17%, and the risk of a heart attack was reduced by 28%, which seem to be very positive results. None of the patients had previous history of cardiovascular disease, although most of the studies recruited patients with other risk factors such as high cholesterol, diabetes, or high blood pressure.

But - and this is a big but - the authors of the Cochrane review had big problems with the way these studies were run. They wrote in their conclusion that

"there was evidence of selective reporting of outcomes, failure to report adverse events and inclusion of people with cardiovascular disease. Only limited evidence showed that primary prevention with statins may be cost effective and improve patient quality of life. Caution should be taken in prescribing statins for primary prevention among people at low cardiovascular risk."

So the review authors were not convinced that people without previous heart disease should all go on statins, even though their own numbers showed a decreased risk. I think their skepticism is justified, because the benefits they observed were very small. This means that subtle biases such as including people who did have cardiovascular disease, could create the appearance of a benefit even if there wasn't one. And 9 of the 14 studies were funded by pharmaceutical companies, which hints at possible bias.

Writing in the journal BMJ, Susan Mayor highlighted the skeptical interpretation. She quoted one of the study's authors, Shah Ibrahim, who said "Absolute benefits were small, and evidence of selective reporting of outcomes makes the evidence less robust.”

Over at Science-Based Medicine, neurologist and skeptic Steven Novella has a more positive interpretation. He concluded that

"there is solid evidence that statins have a real benefit for primary prevention. This benefit is small, which is exactly what I would predict for a preventive measure in a low-risk population. The data also show that statins are safe. ... For interventions that prevent death – that lower mortality – I think even small benefits are worthwhile."

However, he goes on to say that "it is still unclear where to draw the line in terms of which patients should receive statins."

I would love to believe that statins will reduce everyone's risk of heart disease, but I couldn't ignore one statistic: the "number needed to treat." Based on the new study's findings, you'd have to treat 1000 low-risk patients for one year to prevent one death. To put that another way, if you are at low risk of heart disease, then there is a 99.9% probability that taking statins for a year will give you no benefit. Even so, given that statins have minimal side effects, you might think it's a reasonable preventative treatment, even with such a small benefit. The skeptic in me says that if there was even a tiny amount of bias in some of the trials, that apparent benefit might actually be zero.

On this question, we need more data from completely unbiased studies. In an editorial for the Cochrane Reviews, Carl Heneghan wrote that "Interventions targeting CVD risk reduction in low-risk population should be undertaken in the context of a randomised controlled trial; preventing scarce healthcare resources going to waste."

He's right. Statins might have a small benefit, but before we start prescribing them to tens of millions of people - and before I start taking them myself - I'd like to see unbiased studies conducted exclusively in low-risk populations.

Searching for the cause of chronic fatigue syndrome: XMRV turns out to be another blind alley

Chronic fatigue syndrome (CFS) causes severe fatigue that can last for months at a time. CFS is difficult to diagnose and even more difficult to treat, and its cause has long been a mystery. In 2009, in an apparent breakthrough, scientists reported that a virus found in mice, called XMRV, might be the long-sought cause of chronic fatigue. Their results were reported, with great fanfare, by Judy Mikovits and colleagues in the journal Science (Lombardi et al., Science 2009;326:585), with reports in respected outlets such as the New York Times making it seem that the answer had been found.

Now it turns out that, like many initially exciting reports, this one has a much more mundane explanation: contamination.

As happens all too often when a "surprising" discovery is announced, the result turns out to be an experimental error. Contamination is a common type of error in modern molecular genetics, because nothing is actually visible to the naked eye, and we have to rely on very sensitive methods (such as PCR) to detect what is present. In this case, the experimenters had a common mouse cell line in their lab (not unusual), and it turns out these mouse cells were contaminated with a virus called MLV, which looks a lot like XMRV.

The new study by Hue et al. from University College London (Retrovirology 2010, 7:111) is titled "Disease-associated XMRV sequences are consistent with laboratory contamination." The title pretty much tells the story, but here's a brief synopsis.

XMRV (Xenotropic murine leukaemia virus-related virus) is the virus in question - the one that Mikovits claimed is the cause of chronic fatigue syndrome. It's a retrovirus, and it is very similar to another mouse virus called MLV-X. It turns out the the PCR method for detecting XMRV uses short DNA sequences ("primers") that will also detect MLV-X. These primers were previously believed to be specific to XMRV, but they're not. Therefore, if you are looking for XMRV in a tissue sample, and the sample contains MLV-X, you'll think you found XMRV. But what: why would human patients have MLV-X? Perhaps MLV-X is a cause of chronic fatigue? Good question.

Well, it turns out that a common tumor cell line called 22Rv1 is infected with MLV-X. It also turns out that all the XMRV sequences from human patients are far more similar to the exact same strain of MLV-X that is in the mouse cell line. The tumor cell line was in the lab doing the experiments: ergo, it's contamination. Elementary, my dear Watson. Or, as Hue et al put it:

"We provide several independent lines of evidence that XMRV detected by sensitive PCR methods in patient samples is the likely result of PCR contamination with mouse DNA.... We propose that XMRV might not be a genuine human pathogen."

The initial Science paper by Mikovits and colleagues generated three published "Comments" in the journal, an unusually high number, which alone is enough to raise some red flags. The comments pointed out multiple methodological problems, including the possibility of contamination. In one of them, the authors (van der Meet et al) warned that

"Over the past few decades, we have witnessed a long series of papers claiming the discovery of the cause of CFS. None of these claims has been confirmed. Each time, this gives false hopes to large numbers of patients who seek a solution for their suffering. Shortcomings in the study by Lombardiet al. now raise concerns about the role of XMRV in the pathogenesis of CFS."

After the 2009 Science paper, several other studies looked at patients with chronic fatigue syndrome and failed to find anyone with XMRV (for example, this study from the CDC last summer). This was strikingly different from Mikovits' report that 67% of patients had XMRV. The latest report, by explaining where the false positive results came from, should put the final nail in the coffin for the XMRV hypothesis.

In retrospect, Science shouldn't have published the flawed study, and you could argue that peer review failed. On the other hand, the final resolution illustrates the self-correcting mechanism of science at its best. All of this is very reminiscent of the scientific response to Andrew Wakefield's notorious 1998 study claiming that autism was associated with the MMR vaccine: multiple followup studies, most of them conducted far more carefully, failed to reproduce the results. But in that case, bad scientists (Wakefield) aided by gullible journalists and non-scientists (Jenny McCarthy, Jay Gordon) have kept the story alive, causing continuing damage to children in the form of preventable illnesses and even deaths. Even after the story last week in the journal BMJ that explained Wakefield's outright fraud, he continues to push his discredited notions. (I love the title of the BMJ's editorial: "Wakefield's article linking MMR vaccine and autism was fraudulent.")

CFS has less visibility than autism, so I hope that scientific evidence will carry the day here. We still need to find the cause of chronic fatigue syndrome, and there's no telling right now where the answer lies.

"Recontrolling pertussis": a phrase we shouldn't have to hear

The word is going out that a lot of people need to get a pertussis booster shot Pertussis, more commonly known as whooping cough, is a bacterial infection that is very dangerous and sometimes fatal in young infants, whose immune systems are too immature to protect them. The only way to protect the very young is to make sure those around them -- parents, siblings, other relatives, and day care providers -- are vaccinated. Many adults were vaccinated as children, but the vaccine's protection wanes after about ten years, so they still need a booster shot if they are caring for children.

What's new here? First, there's a new report from an expert advisory panel to the Centers for Disease Control. The CDC panel is urging doctors to vaccinate everyone who might be in contact with young children, even if they can't remember when or if they had the pertussis vaccine. A report in the Journal of the American Medical Association this past week quotes pertussis expert Michael Brady, M.D., who chairs the American Academy of Pediatrics committee on infectious diseases, who says the new recommendations are needed as part of our efforts at "recontrolling pertussis."

What does Dr. Brady mean when he says "recontrolling"? Well, whooping cough is not under control right now. In California, a serious epidemic continues. (See my previous post about it here.) The CDC reports over 7,800 cases of pertussis throughout California, including the deaths of 10 infants. These infants were too young to be vaccinated, and their deaths are a tragedy that could have been prevented. The last time we saw this many cases of whooping cough in California was 63 years ago, in 1947.

Meanwhile, Michigan continues to have its own pertussis outbreak, with 1,092 cases this year, and 902 cases last year. And the pertussis epidemic has spread to Ohio, where two counties collectively report 910 cases this year, the largest number in 25 years.

In infants and very young children, pertussis causes violent, spasmodic coughing that repeats over and over. The cough is so strong that babies cannot breath properly, and after multiple coughs they will breathe in sharply with a classic "whooping" sound, which gives the disease its name. Pertussis is far more dangerous in infants than in adults: from 2000-2004, 92% of the pertussis deaths in the U.S. were in children less than one year old.

Whooping cough used to be under control. The number of nationwide cases was dropping for years, and although the disease didn't disappear, we were getting to the point where most people didn't know anyone who'd had it. The question is, why did we lose control? Is a new strain of pertussis to blame? Or is it our own behavior?

Unfortunately, the answer seems to be that these outbreaks are spreading as a result of falling vaccine rates, for which we can thank the anti-vaccine movement, which has been very effective at getting their message out through mainsteam media, including the Larry King show, Oprah, and The Huffington Post. One of the main groups in this movement is the mis-named National Vaccine Information Center, which really should be called the Vaccine Misinformation Center. Their pertussis web page contains a section titled "Can pertussis vaccine cause brain damage and death?" The mere act of asking this question is part of their anti-vaccine strategy. And rather than answering "no," the website goes on for several paragraphs, selectively quoting from studies that looked at vaccine risks - which are very small, but not zero - while ignoring the much greater risks of the disease itself. NVIC's website concludes by claiming (without citation) that

"Most pediatric neurologists acknowledge that vaccination, including use of vaccines for smallpox, rabies, influenza, mumps, measles, tetanus, polio and pertussis, can and does occasionally cause neurological complications that can lead to permanent brain dysfunction."

Scare tactics indeed. Not only is NVIC trying to scare parents away from the pertussis vaccine, but they take the opportunity to warn against many other vaccines. NVIC claims on its website that it "does not promote the use of vaccines and does not advise against the use of vaccines," but that, to put it bluntly, is a lie. Their primary mission is anti-vaccine advocacy, as illustrated by their current advertising campaign that claims we are "over-vaccinating" children and injecting them with harmful toxins.

So we can thank NVIC and other anti-vaccine groups, such as Generation Rescue (which claims, among many other mistaken notions, that the pertussis vaccine causes autism), for the re-emergence of whooping cough.

In contrast, here's what the CDC says about the pertussis vaccine:

"Results from clinical trials showed that these vaccines are very safe for infants and children....The most common adverse events reported have been tenderness and redness where the shot was given, headache, diarrhea, and fussiness."

Unlike NVIC, the CDC gives details and citations to the scientific literature. The CDC also maintains a separate page listing all possible side effects from a long list of vaccines.

The current vaccine against whooping cough is called DTaP or TDaP (short for " tetanus toxoid, reduced diphtheria toxoid and acellular pertussis", and the evidence shows that it is very safe. The vaccine does not contain any whole cell, not even killed bacteria, meaning that it is impossible for the vaccine to cause even a mild case of any of the diseases that it protects against.

The CDC advisory on the pertussis vaccine is not part of a conspiracy to "over-vaccinate" the public, or to pad the profits of Big Pharma. (By the way, to pre-empt some of the commenters: I am not paid a single penny by any pharmaceutical company, nor am I paid by Forbes.) The advisory is a necessary step to "recontrol" whooping cough, a disease that we should not have let back into our communities. I fear that if we keep listening to the anti-vaccine activists, pertussis will be just the first in a series of diseases that will return to plague us, causing needless suffering and anguish.

Short and sweet: the strawberry genome

Happy holidays to everyone, and here's a very short seasonal post: the strawberry genome is here! Kevin Folta from the University of Florida led the effort to put the paper together for the journal Nature Genetics, and he has a nice behind-the-scenes summary on his blog here. One tasty tidbit is that the initial proposal for funding failed because the peach and apple genomes had stronger support - but strawberry beat them both (neither of those genomes is yet complete). It's the first plant to be assembled entirely from next-generation sequences, thanks in large part to the efforts of assembly guru Art Delcher.

And the genome really is "short and sweet", weighing in at just 240 million bases of DNA. (See the paper here.) That's pretty small, for a plant. The apple tree genome is over ten times larger, and the pine tree is 100 times larger. But strawberries are sweeter.

Non-GMO foods: nonsense

I was at a local organic food market recently buying lunch, and I noticed that my avocado-and-hummus sandwich proclaimed that it contained "non-GMO" ingredients (GMO = "genetically modified organism).

Now, I happen to like organic groceries. The ones near me tend to have better produce and fish, two of the main ingredients in my diet. But organic markets are a hotbed of bogus, even laughable health claims, and I often have to suppress my urge to complain to the store's management. (I once wrote to Whole Foods, but they never responded.)

Here in the U.S., most of our food supply is filled with so-called GMO foods, but in Europe the situation is dramatically different. For some reasons, our otherwise well-educated European friends are terrified of GMO foods. They don't seem to realize that we've been modifying the genes in our foods for centuries, and it's generally been a good thing. The latest biotechnology merely allows us to modify plants (and animals too, though none are yet on the market) much more quickly, and more intelligently. Today we can alter just a few genes to produce a more-desirable plant, rather than doing it by trial-and-error over many generations.

In fact, the "GMO" foods of the past likely had hundreds of unknown gene modifications.Farmers selected plants for seed because they looked and tasted good, without having any idea of what was really different about them.

Let's take a look at corn. The corn we eat today, organic or not, looks nothing like the "real" corn (or maize) from centuries ago. The earliest corn cobs discovered by archaeologists were tiny, with only a few kernels. This picture shows a primitive form of corn, called teosinte, compared to modern corn:

The history of corn is a history of genetic modifications made by earlier humans who didn't even know what a gene was. Today's GMO food is simply a continuation of that history.

That hasn't stopped opponents of GMO foods from sounding the alarm. Even the World Health Organization makes some errors on its website, where it discusses three main "issues of concern for human health":

1. Allergenicity. Not a problem. The WHO says "No allergic effects have been found relative to GM foods currently on the market."
2. Gene transfer. The WHO gets this one wrong. They write that "gene transfer from GM foods to cells of the body or to bacteria in the gastrointestinal tract would cause concern if the transferred genetic material adversely affects human health." Gene transfer is a topic that I've studied in some detail, and published papers on. The WHO says that the likelihood of a gene transfer event is "low," but in fact it is vanishingly small - so small, in fact, that not a single gene transfer event has ever happened. In the history of our species, and of all mammals, going back tens of millions of years, not a single gene from something we've eaten has been transferred into the human genome or, as far as we can tell, into bacteria within our guts.
3. Outcrossing. This is "the movement of genes from GM plants into conventional crops," and this really can happen - they're the same species, so they can interbreed. But it's only a concern if GM plants are harmful, which they're not.

The bottom line is, you're far more likely to be harmed by being hit on the head by a corn cob than by some kind of deviant GMO corn gene.

The WHO concludes that GM foods "are not likely to present risks for human health." Of course, not all GMO foods are good. I'm not a fan of engineering crops to be more tolerant of pesticides, for example: this type of GMO food benefits big agricultural firms rather than the consumer. And it is theoretically possible to insert harmful genes into plants, but agricultural firms wouldn't have any reason to do that.

So the next time you see the non-GMO claim in your grocery, ask yourself whether the ingredients could really be completely unmodified from their "natural" state. I doubt it.

My sandwich was really good, by the way.

At the movies: popcorn and anti-vaccine fearmongering

The anti-vaccinationists have launched a new campaign this holiday season to spread cheer – oops, I mean fear – to moviegoers everywhere. Yes, the folks at SafeMinds and Age of Autism have produced an advertisement that they are trying to place in AMC theaters across the country. In fact, they almost succeeded, but quick action by skeptical science bloggers at SkepChick, Respectful Insolence, and their readerships convinced AMC to cancel the ad – for now.

The ad that SafeMinds is trying to run is intended to scare people away from getting their flu vaccine, just as flu season is beginning. The vaccine this year will protect you against both the new “swine” flu, called H1N1, and the previous flu strain, H3N2. Early data from the CDC makes it clear that both strains are still around, with H3N2 showing up somewhat more frequently so far this fall. The vaccine not only protects you, but also your family, your colleagues, and the many other people you might come into contact with each day while at work, shopping, or elsewhere.

Why try to scare people? Well, the people behind SafeMinds and Age of Autism believe that the preservative thimerosal, which is used in some but not all flu vaccines, causes autism. This theory has been thoroughly investigated over the past 10 years, and just as thoroughly discredited. In fact, it never had any positive evidence to support it in the first place, but it has been promoted aggressively by a journalist, David Kirby, who made his fortune off a book based on the thimerosal-autism hypothesis. (I’m not providing a link – Kirby has already made far too much money off this bogus claim, and I don’t want to give him the web traffic.)

Thimerosal was introduced into vaccines in the 1930s, and it is a very effective means to prevent the growth of bacteria without affecting the potency of the vaccine itself. In over 60 years and hundreds of millions of doses, it has proven to be quite benign. Nonetheless, it contains a form of mercury called ethylmercury, which anti-vaccinationists claim causes autism and other neurological disorders.

The claim that thimerosal causes autism was the central question of a large, multi-year Autism Omnibus trial, which ruled definitively last year that thimerosal does not cause autism. I wrote about that ruling at some length back in March, and I won’t repeat it here, except to quote again from the Special Master’s decision:

“The numerous medical studies concerning the issue of whether thimerosal causes autism, performed by medical scientists worldwide, have come down strongly against the petitioners’ contentions. Considering all of the evidence, I find that the petitioners have failed to demonstrate that thimerosal-containing vaccines can contribute to the causation of autism.”

The anti-vax crowd will not give up, unfortunately. Rather than spending their time and effort trying to find the true causes of autism, they continue to repeat claims that have already been shown false. For example, the SafeMinds website lists 5 “key points” that are just flat-out wrong. Here are the first two:

1. “The autism epidemic that began in the late 1980’s is likely due primarily to toxins adversely affecting fetus and infants during development.” Wrong, in at least two ways. First, there is no autism “epidemic.” The best evidence today indicates that the rising rates of autism are due to a combination of factors, primarily (a) rising rates of diagnosis due to increased awareness among physicians and patients and (b) a dramatically broader medical definition of autism that was introduced in the early 1990s.
2. “Mercury is likely a major contributor to this toxin-induced autism, whether the source of the mercury is from vaccines or environmental mercury exposure.” Wrong again. This is the claim that was so thoroughly refuted in the lengthy Autism Omnibus trial, with hundreds of pages of testimony from dozens of experts, and epidemiological data from literally hundreds of thousands of people.

But data doesn’t seem to have any effect on the anti-vax zealots at Age of Autism and SafeMinds.

Because AMC refused to run their ad, Age of Autism is telling its readers to stay away from AMC theaters this holiday season. I hope they do! Why? Because these unvaccinated individuals are a genuine threat to public health. Movie theaters, and the malls in which they are located, are an ideal place for infectious diseases to spread. Without vaccines, countless thousands of people would fall ill every holiday season after mingling with other shoppers, and some would likely die. My message to the unvaccinated crowd at SafeMinds is: stay away from the rest of us.

And I encourage everyone else to get your flu shot, get your kids vaccinated, and then go see a movie at an AMC theater. Meanwhile, you can also tell them at this link that you appreciate their taking a stand against misinformation and for the benefit of public health.

Oscillo – what? Homeopathic flu “cures” and dead ducks

Oscillococcinum sounds like medicine. And if you saw this package in a store next to all the other cold and flu remedies, you might be tempted to give it a try. It looks just like a box of anthistamines or other real medicines. With flu season coming soon, you might want to look at this box more closely before you buy it.

You can buy oscillococinum at Walgreen’s, Target, Amazon.com, and many other places. At Walgreen’s, one of the largest pharmacy chains in the U.S., it’s listed under “Cough and Cold” where it sells for $9.99 (a savings of $4.50!) for 6 doses.

It sounds like medicine, but it’s not. The front of the box says (in small print) that it’s “homeopathic medicine,” which isn’t medicine at all. In fact, it’s nothing more than a sugar pill, which is why the product can advertise that it has “no side effects” and “no drug interactions.”

But in much larger print, the package says “Flu-like Symptoms”, followed by a list of symptoms: “Feeling run-down, hadaches, body aches, chills, fever.” Anyone might be fooled into thinking this product is supposed to treat these conditions. If you go to the manufacturer’s (Boiron) website, they make the explicit claim that it “Temporarily relieves flu-like symptoms such as feeling run down, headache, body aches, chills and fever.” The Walgreen’s website says the same thing.

What’s in Oscillococcinum, and how can its producer get away with these claims?

Oscillo contains “Anas barbariae hepatis et cordis extractum 200CK.” Don’t be fooled by the Latin – it just means extract from the heart and liver of a duck. Yes, they kill ducks to make this stuff. The manufacturer then dilutes it to 200C, which in homeopath-speak means that 1 gram of extract is diluted to one part in 10⁴⁰⁰. Yes, that’s 10 raised to the power 400. Wow! The entire known universe has far fewer than 10⁴⁰⁰ molecules. If you filled the entire solar system with water, and mixed in one molecule of duck liver, it would be much more concentrated than this stuff. Oscillo is so diluted that there is essentially zero chance that even a single molecule of the original extract is in the product. The package does say that sugar is added to the pills, and that’s all they are: sugar pills.

The idea that infinitely diluted substances can cure disease is a type of magical thinking, and it’s at the heart of homeopathy, whose proponents believe that the more dilute something is, the more powerful its effects. This bit of nonsense goes against basic principles of chemistry and physics, but no matter: homeopaths continue to insist on it.

And I shouldn’t forget to mention that there’s not a whit of evidence that extracts made from the heart and liver of a duck can cure the flu. Nope, not a chance.

The French-based manufacturer, Boiron, and the U.S. stores selling Oscillo can get away with this because it’s not a drug at all – it’s a supplement. Supplements are basically unregulated in the U.S., thanks to laws passed decades ago, some of them specifically designed to protect homeopaths. As long as you don’t claim that your product can treat a specific illness, you can sell it.

The box itself doesn’t say that Oscillococcinum cures the flu, but the product’s manufacturers have been making this claim on their website. Some of them have stepped over the line: the FDA sent a warning letter to one homeopathic marketer this past summer telling them that Oscillo “has not been approved or otherwise authorized by FDA for use in the diagnosis, mitigation, prevention, treatment , or cure of the H1N1 Flu Virus” and requesting that they “immediately cease marketing unapproved or unauthorized products for the diagnosis, mitigation, prevention, treatment, or cure of the H1N1 Flu Virus.”

Unfortunately, the FDA only steps in when the claims get particularly outrageous, or when (as here) they involve a high-profile disease such as avian flu. The purveyors of Oscillo can simply modify their packaging (and websites) slightly and go right ahead misleading the public.

So if you want to waste $10 on 6 sugar pills, go ahead. But at least try find a product that doesn’t require dead ducks.

Further reading: see Orac’s recent post on this same topic here.