Better diagnosis of infections

This week I'm not posting an article here because I wrote a piece for BloombergView, the online magazine published by Bloomberg, the company founded by Michael Bloomberg. The article is titled "Make Way for Better Germ Tests." Check it out here.

NIH will spend $37 million to study discredited treatment that may harm patients

What do you do when you've spent $30 million to study a highly controversial, possibly harmful treatment, only to learn that it doesn't work?

If you're NIH's alternative medicine center, you double down. More than double, actually: NIH's NCCIH* just announced they will spend another $37 million to study chelation as a treatment for heart disease. Or to be more specific, Mount Sinai of Florida and Duke University issued a press release this past week proudly announcing that they'd won a $37 million grant to launch TACT2, the second Trial to Assess Chelation Therapy. TACT2 will be a followup study from TACT, which ended in 2012 after largely failing, as I'll explain below.

Chelation is a harsh chemical treatment, using a chemical called disodium EDTA, that is sometimes used to treat lead poisoning, because it can help to remove heavy metals from the blood. Some people think that this can somehow remove plaques from arteries, a sort of Roto-Rooter for your circulation, which in turn might improve cardiovascular health. This turns out to be wrong.

(Chelation is also promoted, tragically, as a treatment for autism. Anti-vax doctors who think that mercury causes autism have been pushing this for years. In 2014, the FDA issued a warning for parents to beware of this dangerous and ineffective therapy.)

Let's briefly review what TACT was, and some of its problems. There are far too many to list here, but I'll refer readers to a lengthy article published in 2008 by Dr. Kimball Atwood and colleagues for details. That article, which called for a halt to TACT, explained that:

  • a series of randomized trials in the 1990s found no evidence that chelation worked for coronary artery disease
  • most of the early advocates of chelation (in the 1960s) were also outspoken advocates for Laetrile and other ineffective therapies
  • at least 30 deaths have been report associated with EDTA, but the doctors pushing its continued usage deny that any deaths have occurred.
  • the scientific literature has shown that the underlying "heavy metals" hypothesis is implausible
  • the TACT study includes "nearly 100 co-investigators who, in our opinion, are unsuitable to care for human subjects or to report trial data ... several have been disciplined, for substandard practices, by state medical boards; several have been involved in insurance fraud; at least 3 are convicted felons."
  • "The researchers failed to inform the subjects that one risk of the treatment was death." (from The Chicago Tribune.)

Atwood and colleagues called for a halt to the TACT study, saying it was "pointless, dangerous, unethical, and wasteful."

The TACT study was indeed halted in 2008 for these and other ethical concerns, but it was quietly resumed about a year later. Then in 2012, the final results were reported. Although the results were almost entirely negative, the lead investigator, Gervasio Lamas, claimed that there was a benefit for a sliver of patients: people with diabetes who had a prior heart attack. That's the group he plans to focus on in the new TACT2 trial.

As Forbes writer Matt Herper explained in 2012, most doctors were highly skeptical of these results. Cardiologist Steve Nissen of the Cleveland Clinic said "It would be tragic if the result of this was a widespread use of chelation." Science blogger (and cancer doctor) Orac provided a detailed analysis of the results at the time, explaining why the study essentially failed to prove any benefit for chelation. Most of the results were not statistically significant, and the best the study could claim was very marginal significance for a small benefit, a result that could easily be explained by bias, which was rampant in this study.

TACT2 is being run by the same doctor, Gervasio Lamas, who recruited questionable practitioners into the first trial. There's no reason to think the second trial will be run any better. The new trial will subject 1,200 diabetic heart attack survivors to chelation therapy in an effort to prove that chelation helps prevent a second heart attack. Not only is this extremely unlikely to provide any benefit, it also exposes the patients to serious risks that Lamas and his colleagues don't seem to acknowledge, and probably won't tell the patients about.

NIH should pull the plug on this enormous ($37 million) and dangerous trial before it begins. If potential patients are informed correctly that there is a serious risk of harm with virtually no chance of benefit, then hopefully they will simply refuse to enroll. That would be the best outcome for everyone.

*In case you're wondering what NCCIH is, it's the new acronym for the former National Center for Complementary and Alternative Medicine, NCCAM. Last year it was renamed. The new name is the National Center for Crackpot and Implausible Hypotheses, Or maybe it's the National Center for Complementary and Integrative Medicine, you decide.

Is being a little bit obese unhealthy?

Everyone knows that being obese is very bad for your health. But how overweight do you have to be before you should worry? A new study covering millions of people attempts to answer this question.

The short answer: being a little bit fat isn't so bad, especially if you're already a senior citizen, but the fatter you are, the shorter your life expectancy. Let's dive into the details.

The new study, published in The Lancet, is a combined evaluation (a meta-analysis) of 239 studies that included over 10 million people from four continents: Asia, Australia, Europe and North America. All the studies followed their subjects for a long time, averaging nearly 14 years of observation. The authors (a large consortium called "The Global BMI Mortality Collaboration") wanted to exclude people who might have already been sick, so their study only looked at people who (a) had never smoked, and (b) who lived at least five years after the study began.

This left them with nearly 4 million people, of whom 385,879 died at some time during the course of the study. From this large data set, the researchers computed the risk of death as a function of body mass index (BMI).

[Aside: BMI is a simple function of your height and weight. For example, someone who stands 5'11" and weights 170 has a BMI of 23.7. A height of 5'6" and weight of 150 gets you a BMI of 24.2. You can calculate your own BMI using this calculator.]

The study divided people into six groups:

  • underweight, BMI 15–18.5
  • normal, BMI 18.5–24.9
  • overweight, BMI 25–29.9
  • obesity grade 1, BMI 30–34.9
  • obesity grade 2, BMI 35–39.9
  • obesity grade 3, BMI 40 or above

The main outcome that they studied was mortality (death) from any cause. Of course, one can argue that this is too simplistic, since if someone dies from, say, an auto accident, it probably wasn't due to their weight. But the results were consistent across all four continents, which argues that the study design was probably good. Here are the main findings for each group:
  • BMI 15–18.5: 47% increased risk of death
  • BMI 18.5–24.9: no increase (normal)
  • BMI 25–29.9: 11% increased risk of death
  • BMI 30–34.9: 44% increased risk of death
  • BMI 35–39.9: 92% increased risk of death
  • BMI 40 or above: 171% increased risk of death
Another way to describe these hazard ratios is this: with a BMI above 40, people are 2.71 times as likely to die during any particular time period as people with a normal BMI. 

If these numbers seem scary, keep in mind that this is relative risk, not absolute risk. So an 11% increase in risk might mean that your chance of dying increases from 1% to 1.11%; it certainly doesn't mean you have an 11% risk of dying. 

To put some real numbers on this risk, consider this comparison: out of 1,075,894 people with a near-optimal BMI between 22.5–25.0, 98,833 died during the course of the study, or 9.2%. (Remember that these data come from 239 different studies, and the average length of followup is 14 years. So fewer than 1% of this group died per year.) Compare this group to people with obesity grade 1, or BMI from 30–35. That group had 330,840 people, of whom 37,318 died, or 11.3%. After various adjustments, this translates into a 44% relative increase, but the actual mortality rate, per year, was about 0.66% versus 0.81% in the two groups.

One mildly positive note: if you're already 70 or older, having a BMI from 25–30 has almost no effect; in other words, it's okay to be a little plump when you're older.

A word of warning to men: the ill effects of obesity are much stronger in men than in women. The study breaks down those hazard ratios by sex, and in each range the risk is higher for men than for women. So for example, if you're a woman with a BMI of 30–35, your hazard ratio is 1.37 (37% higher risk of death), but for men it is 1.70 (70% increase). 

There are many, many more details in the study, including a breakdown of how BMI is associated with four major causes of death (heart disease, cancer, respiratory disease, and stroke), and if you're interested in those, you should read the study

Of course, one can think of many caveats to these findings: people die from all sorts of illnesses, and many of them are not caused by being overweight. For any individual case, we might not be able to say whether someone's weight had anything to do with their illness. Nonetheless, this very large study shows clearly that the more obese you are, the greater your risk of dying. That's precisely what we would expect if obesity was causally linked to mortality.

So is it okay to be a little bit fat? The answer is probably yes: people with a BMI of 25 might view themselves as "a bit" fat, even though they are not overweight. But very high BMIs (and very low BMI, below 18.5) are definitely unhealthy. Unfortunately, no one has an easy answer to the problem of losing weight (despite what you might have heard from Dr. Oz), but if you do have a dangerously high BMI, reducing it will likely be good for your health.

Government regulation to the rescue: FDA halts the overuse of antibacterial soaps

Over the past two decades, anti-bacterial soaps have proliferated. It got to the point, a couple of years ago, where it was difficult to find any hand-washing products in some stores that were not labeled "antibacterial." All the way back in 2001, a study by Eli Perencevich and colleagues found that 76% of liquid soaps on the market contained some kind of antibacterial agent. It only got worse after that.

The primary active ingredients in most of these soaps are triclosan and triclocarban, chemical agents that do indeed kill bacteria. However, as Perencevich pointed out,
"No scientific data have been published to suggest that the use of antibacterial agents in household products prevents infection."
It didn't take long for triclosan to start showing up in freshwater streams and elsewhere in the environment. Triclosan has been detected in the water supply in the U.S., multiple countries in Europe, Canada, Australia, Japan, and Hong Kong. As use of antibacterial soaps proliferated, bacteria resistant to triclosan started to appear–an outcome that any biologist could have predicted, and that many did.

After many years, the FDA finally announced, in December 2013, that manufacturers needed to produce actual data showing that their products worked. They didn't, for the simple reason that antibacterial soaps don't work any better than plain old soap and water.

Finally, this past Friday, the FDA stepped in. They are banning 19 different chemicals, including triclosan. Their announcement states:
"Companies will no longer be able to market antibacterial washes with these ingredients because manufacturers did not demonstrate that the ingredients are both safe for long-term daily use and more effective than plain soap and water in preventing illness and the spread of certain infections."
This has been a very long time coming.

Antibacterial soaps are no more effective than simple hand-washing with regular soap, as Forbes contributor David DiSalvo explained last year. But people have been buying these products anyway, often not realizing that they might be hurting themselves and the environment. As Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research, explained in the FDA announcement:
“Consumers may think antibacterial washes are more effective at preventing the spread of germs, but we have no scientific evidence that they are any better than plain soap and water. In fact, some data suggests that antibacterial ingredients may do more harm than good over the long-term.”
Sometimes government regulation is the only effective way to fix a public health problem. Kudos to the FDA for stepping in to protect all of us from potentially deadly outbreaks of antibiotic resistant bacteria. Let's hope that other countries follow the U.S. example.

Clinical trials doctors claim they own patients' data, want others to pay for access

Image from "Honoring our promise: clinical trial data sharing"
at the NIH Director's blog.
Earlier this month, a consortium of 282 clinical trials doctors, in an article in the New England Journal of Medicine, threw down the gauntlet against the notion that they should share data. Under the misleading title “Towards fairness in data sharing,” these scientists, who label themselves The International Consortium of Investigators for Fairness in Trial Data Sharing, put forward the breathtakingly arrogant claim that doctors who collect data from patients should control it essentially forever.

I wonder what their patients would think if they knew.

This is the second salvo from NEJM this year. Back in January, the editors of NEJM published an opinion piece that used the derogatory phrase “research parasites” to describe scientists who want to re-analyze data from other scientists’ experiments. This caused an outcry, with many scientists pointing out serious flaws in the editors’ arguments. As I wrote at the time,   
“Drazen and Longo [the NEJM editors] are saying, essentially, that only the people who originally collect a data set can truly understand it, and anyone else who wants to take a look is a parasite.”
Keeping scientific data locked away is a recipe for bad science. In the absence of data sharing, flawed results may go unchallenged for years. If someone has distorted or misinterpreted data, we need someone else–someone not invested in proving the same result–to take a second look. This is how science corrects itself.

Even so, at least Drazen and Longo endorsed some data sharing. The authors of this new article (P.J. Devereaux, Gordon Guyatt, Hertzel Gerstein, Stuart Connolly, and Salim Yusuf, all from Ontario’s McMaster University) and their consortium are vehemently opposed to sharing their data with anyone, ever.

Let’s go through their arguments. First, they point out that it takes years of work to set up and run a clinical trial. Absolutely right–no argument there. But then they explain why they conduct these trials:
“A key motivation for investigators to conduct RCTs is the ability to publish not only the primary trial report, but also major secondary articles based on the trial data. The original investigators almost always intend to undertake additional analyses of the data and explore new hypotheses.”
Oh really? This is why they run clinical trials, in order to publish papers? Somehow I doubt that is what they tell the patients as they are asking for informed consent. Not “we want to figure out what is making you sick” or “we want to find a cure”, but “we want to publish a paper, or maybe several papers!” I’m sure that patients would be lining up around the block to join these studies.

Don’t get me wrong: of course the scientists want to publish their findings, and of course they would like to mine the data for more papers, year after year. That’s what some investigators do now. In this world, doctors running clinical trials would never share data. Why would they, when things are working so well for their careers?

But they seem to have forgotten THE motivation for clinical trials: curing disease. I am honestly dumbfounded that Devereaux and his colleagues don’t mention the words “disease” or “illness” in their article, not even once. Instead they focus on “risks” of sharing data, by which they mean the risk that someone else will make a discovery that they didn’t think of, versus the “benefits,” which in their world means either confirming the original study or possibly testing a new hypothesis. They seem oblivious to the notion that re-analyzing the data to contradict the original claims might actually be a benefit to the rest of the world.

Appalling. Did they feel this way when they first went into medical research? Probably not, but somewhere in the competitive struggle to succeed as researchers, they lost their way.

It gets worse. Devereaux and his consortium go on to lay out what they might be willing to consider:
  • Exclusive use of the data for a minimum of 2 years after the first publication
  • Another 6 months of exclusivity for every year the trial lasted, up to 5 years of exclusivity
  • Anyone who wants the data should pay the original investigators “for their efforts and investments in the trial.”
This last point is the most outrageous of all. Hello? Investigators in clinical trials are already paid for their efforts (though the patients are not), often totaling millions of dollars, and often from taxpayers’ money. Now they want to be paid again by each scientist who wants to look at the data?

These guys need to get over it. The reason we fund clinical trials is to cure disease, not to allow Devereaux and company to publish papers. Publication is the means by which we communicate results, but it’s not the reason that anyone pays for the experiments.

Interestingly, in the same issue of NEJM, U.S. Senator Elizabeth Warren writes about data sharing, expressing quite the opposite view from Devereaux and company. I won’t attempt to summarize her points here, but instead let me quote from one of the public comments published in response to the anti-data-sharing doctors:
“ `This is not working. I just hope that my death will not be in vain and someone learns from it so that others don't have to go through this’ was what my husband said when it became clear that the new drug combination was not working fast enough for us…. My husband died now more than 4 years ago. I have watched his and others' lives been plotted on curves at conferences like ASCO or EMSO and it is deeply upsetting that there are more than 280 researchers who are more concerned about their own careers than the lives of the patients on whom those careers are built. Claiming rights to data paid for with the lives of others has nothing to do with fairness.” Bettina Ryll, M.D., Ph.D., Melanoma Patient Network Europe
I couldn’t say it any better than that. The International Consortium of Investigators for Fairness in Trial Data Sharing–as the 282 investigators called themselves–should be ashamed.

Someone needs to tell Michael Phelps to stop bruising himself

It happens every four years. No, not the Olympics, though of course that happens too. I'm talking about new wackadoodle performance enhancement fads. In the 2008 and 2012 Olympics, it was magic tape, which we saw plastered across the arms and legs of many swimmers. This year it's "cupping," a crude technique that leaves nasty red or purple welts all over your body. Michael Phelps, one of the best male swimmers in Olympic history, featured these lovely welts in photos this week, and you can catch a glimpse of him getting the treatment in the UnderArmour "Rule Yourself" ad featuring Phelps (which is otherwise an excellent ad).

Phelps isn't the only one. Former Olympic swimmer Natalie Coughlin and gymnast Alex Naddour have displayed the distinctive circular welts too.

The New York Times, USA Today, and People all ran articles yesterday explaining what those nasty red bruises were all over Phelps' torso and shoulders. USA Today reported, unquestioningly, that athletes use cupping "to relieve tension in their muscles." The NY Times (from which we might expect a bit more skepticism) reported blithely that "Physiologically, cupping is thought to draw blood to the affected area, reducing soreness and speeding healing of overworked muscles." People used the same argument, and then added this bit of illogic:
"given that Phelps took home his 23rd Olympic medal last night, it's tough to argue."
No, it's not. Cupping is ridiculous. There's no scientific or medical evidence that it provides any benefit. The NY Times did express a bit of doubt (though not much), summarizing two small experiments that showed that cupping worked no better than placebo. But the Times couldn't help itself, and went back to quoting anecdotal evidence from true believers.

Rather than review the evidence here, I refer you to a thorough takedown of cupping written last month by Orac, a well-known science blogger who is also a surgeon:
"Among the silliest of alternative medicine therapies is something called cupping.... The suction from cupping breaks capillaries, which is why not infrequently there are bruises left in the shape of the cups afterward."
As Orac points out, repeated cupping in the same spot can destroy your skin and lead to dangerous infections. Another physician, Dr. Harriett Hall, in an article for Slate in 2012, made similar points.

I'm not sure who told Michael Phelps that cupping would help him swim faster, but I am sure that it's terrible advice–definitely not helpful and maybe harmful.

I know athletes are notoriously superstitious, and they get some psychological benefits from the various rituals they use to prepare for competition. There's no harm in believing that magic tape, or a lucky shirt, or always stepping onto the field with your left foot first–or whatever–will help you win. But Michael Phelps and his fellow Olympians should run as fast as possible from unproven treatments (and make no mistake, cupping is one of these) that can only cause them harm.

Did a biotech CEO successfully reverse her own aging process? Maybe not.

Elizabeth Parrish, CEO of BioViva.
Humans have been searching for the fountain of youth for millenia, dating back to ancient times. No one has found it yet, so I was very skeptical when I saw the recent announcement from BioViva, a biotech company, of what they called the first successful gene therapy against human aging:
"Elizabeth Parrish, CEO of Bioviva USA Inc., has become the first human being to be successfully rejuvenated by gene therapy, after her own company's experimental therapies reversed 20 years of normal telomere shortening."
That's quite a dramatic claim. If true, this would be a historic breakthrough: no one has ever reversed aging before. While human life expectancy has doubled over the past 150 years, virtually all of this progress has been from preventing early deaths, thanks to the developments of antibiotics, vaccines, and public health advances such as clean water.
Human life expectancy has doubled since the 1840's.
Figure source: Natl Institute on Aging.
Most claims about anti-aging therapies are easily dismissed as pseudoscience, nonsense, or scams. Not this one, though. BioViva has two experimental therapies, both based on legitimate science, and both with at least a chance of working. Neither has yet been proven to work in humans, but both are plausible.

According to BioViva and to interviews with its CEO, Elizabeth Parrish, Parrish received two therapies last year, one to protect against the loss of muscle mass, and one to lengthen her telomeres. The recent announcement claims that the telomere-lengthening therapy is already working, so I looked a bit deeper to understand what might be going on.

First a bit of background: telomeres are special DNA sequences that act as "caps" on both ends of every chromosome, providing a kind of protection for your genes. Each time a cell divides, its telomeres get a little bit shorter, and eventually they get too short and the cell dies. Telomeres therefore act as a kind of molecular clock that tells a cell how old it is. Our cells also have a special enzyme called telomerase that rebuilds telomeres. Cells with lots of telomerase can live much longer, and those without it die more quickly. Discovering how this all worked was a tremendous scientific achievement, for which Elizabeth Blackburn, Carol Greider, and Jack Szostak received the 2009 Nobel Prize.

Scientists have been speculating for years that telomerase might somehow hold the key to aging. BioViva's gene therapy delivers telomerase to the blood with the help of weakened viruses called adeno-associated viruses (AAVs), which they modified to carry the telomerase gene. The virus infects human cells and releases its payload into them, where the "transgene" produces extra telomerase.

This may sound very nice, but it's really, really complicated in practice. Gene therapy can have unexpected negative effects, and no human trials have yet shown that anyone can deliver telomerase effectively to human cells. However, studies in mice have shown some remarkable results: in 2012, a group of scientists at the Spanish National Cancer Centre used AAV to deliver telomerase to mice, and found that it "had remarkable beneficial effects on health and fitness" and that
"telomerase-treated mice, both at 1-year and 2-years of age, had an increase in median lifespan of 24 and 13%, respectively."
This exciting scientific result, and a few others like it, are what led BioViva and Elizabeth Parrish to try the same therapy in humans.

But did it work? Well, this is where things get a bit fuzzy. BioViva claims it did, based on their measurements of the length of telomeres in Parrish's white blood cells in September 2015, before therapy started, and again in March 2016. They claim that her telomeres got longer, from 6.71 kilobases (a kilobase is 1000 DNA letters) to 7.33 kilobases. This increase corresponds to about 20 years of aging: in other words, Parrish's white blood cells "have become biologically younger," as the company reported.

Setting aside the problem that we cannot really conclude anything from an experiment involving only one person, we can still ask: did Parrish's telomeres really get longer? As much as I want to believe BioViva's claim, there are several rather serious problems here. First, the company itself reported that Parrish's telomeres were unusually short for her age before the experiment began. Does this mean that the measurements were simply a bit off, and the second measurements were closer to the true number? Second, as UCLA's Prof. Rita Effros explained in an interview at,
"The overarching problem is that peripheral blood contains a mixture of many different cell types with disparate telomere lengths.... Thus, a simple change in the proportion of different cell types within the peripheral blood could easily explain the data."
In other words, it's possible that Parrish's telomeres did not get any longer. Despite the apparently precise numbers, BioViva has not provided any details showing that these measurements are accurate and reproducible (and they didn't respond to my request for these details). Their claim might be much more convincing if they made multiple measurements, both before and after treatment, and if these measurements showed that Parrish's telomere lengths really did increase.

There are a number of red flags about BioViva itself. Parrish herself is not a scientist, though she is an eloquent spokesperson for her company's therapies. More concerning is their Chief Medical Officer, Jason Williams, who previously ran "a dubious stem cell clinic," Precision StemCell (now located in Mexico) that offers stem cell therapies to patients with ALS (Lou Gehrig's disease), for which there is no evidence that they work. Personally, I would not trust Dr. Williams with my medical care.

The bottom line is that we simply don't know if BioViva's treatment worked on Elizabeth Parrish. They need to produce more data, on more patients, to construct even a mildly convincing scientific argument. Getting more patients may be very difficult, though: Parrish bypassed FDA regulations by traveling outside the U.S. (to Colombia) to conduct this experiment on herself.

Telomerase treatment to reverse aging is very promising, and it might really work, someday. I sincerely hope it will.  For now, though, BioViva's announcement leaves me very skeptical.