NEJM says open access is unnecessary. Right.

Surprise: the New England Journal of Medicine thinks open access is a bad idea. Open access is the model of scientific publishing in which all results are freely available for anyone, anywhere, to read.

This week NEJM published an editorial by one of their correspondents,  Charlotte Haug, that purports to present an objective look at open access publishing, and finds that the "experiment" has failed, and that free access to scientific publications hasn't delivered on its promises.

What is NEJM worried about? Their expensive, exclusive model of publishing–where everyone has to pay high subscription fees, or else pay exhorbitant fees for each article they read–is threatened by scientists who want all science to be free. Pesky scientists!

NEJM is especially worried about "Plan S", a proposal in Europe to require that all scientists whose work is funded by the public be required to publish their results in open-access venues. Plan S is due to take effect very soon, in 2020 for 11 research funders in Europe.

The NEJM article is a clever but deeply flawed effort to prove that open access isn't working. It's full of fallacies and straw men, so much so that it's hard to know where to begin. Since they're not playing fair, though, I won't either: I'll cherry-pick three of Haug's arguments and explain why she's wrong about each one.

But first, to set the stage, let's remind everyone of what we're talking about. Scientific papers are written by scientists (like me), who are largely funded to do their work by governments, non-profit organizations, and occasionally by commercial companies. The writing is done by the scientists themselves, who submit papers to journals for peer review. The peer reviewing is also done by scientists (again, like me) who do this work for free. The journals pay nothing for all this work.

In other words, we do all the work for free, using funding provided by the public, and the journals then take that work and sell it for a very tidy profit. (Richard Smith estimates that NEJM itself has an income of $100 million with a 30% profit.) The vast majority of scientific and medical journals are owned by five for-profit corporations, as the NEJM points out:

"The five largest publishing houses (SAGE, Elsevier, Springer Nature, Wiley-Blackwell, and Taylor & Francis) continue to grow, with high profit margins."

For the past two decades, scientists have spoken out more and more over the outrageous practices of for-profit publishers, whose subscription fees and profits have grown while the costs of distribution have plummeted. Virtually everyone gets scientific papers online now. Why sign over copyright when we can distribute our work so cheaply now? The open access movement was founded to provide an alternative: open access journals allow everyone to read all the content for free, and the authors retain their copyrights.

Now let's look at the NEJM article. Haug starts by pretending to agree that open access is a good thing, writing:

"The idea — that the results of research should be available to be read, discuss, and examine... — has few, if any, opponents in either the scientific community or the public."

Reading this, you might think that Haug (and NEJM, by extension) are fans of open access. They are not.

Haug then proceeds (she thinks) to dismantle the arguments in favor of open access. First, she states that publishing costs have not dropped, but have increased. As evidence, she asserts that "Electronic production and maintenance of high-quality content are at least as expensive as print production and maintenance." This claim is, frankly, nonsense, but since Haug doesn't cite any evidence to back it up, there's nothing really to refute. It's obviously much cheaper to post a PDF on a website than to print thousands of hardcopies and physically ship them to libraries around the world. If costs are going up (and again, Haug cites no evidence), that could be simply because publishers are paying themselves higher salaries (NEJM reported compensation of  $703,324 for its chief editor in 2017), or hiring large staffs, or renting luxurious offices–who knows? Haug doesn't explain.

In any case, the costs of publishing at NEJM, a closed-access, subscription-based journal, have little to do with whether or not scientific and medical research should be freely available.

Her next argument against open access is that the most highly-cited journals are subscription-based, like (ahem) NEJM. My response: so what? Everyone within academia knows that it takes a very long time to establish a reputation as a "top" journal, and young scientists will always want to publish in those journals, regardless of how expensive they are. This has given closed-access journals like NEJM (and Nature, Science, JAMA, and Cell, to name a few more) tremendous power, which they have wielded to fight against open access at every opportunity. This editorial represents another example of that fight. The fact that many scientists still want to publish in these journals doesn't mean they should keep the results locked behind a paywall.

Setting aside this tiny number of "prestige" journals, open access papers do get cited more, as was demonstrated by this study from 2016. The evidence shows that open access does lead to higher impact: papers that are freely available are read more and cited more.

Finally, let's turn to Haug's coup de grace, which she wields near the end of her piece, as a sort of "proof" that open access is really unnecessary. Here she argues that NEJM is already open, mostly:

"About 98% of the research published in the Journal since 2000 is free and open to the public. Research of immediate importance to global health is made freely accessible upon publication; other research articles become freely accessible after 6 months."

First, let's acknowledge that merely by pointing this out, Haug is admitting that the main arguments for open access are legitimate; i.e., that it's a huge benefit to society to make research freely available. I'm going to agree with her here.

What Haug doesn't mention here is that there is one reason (and only one, I would argue) that NEJM makes all of its articles freely available after some time has passed: the NIH requires it. This dates back to 2009, when Congress passed a law, after intense pressure from citizens who were demanding access to the research results that they'd paid for, requiring all NIH-funded results to be deposited in a free, public repository (now called PubMed Central) within 12 months of publication.

Scientific publishers fought furiously against this policy. I know, because I was there, and I talked to many people involved in the fight at the time. The open-access advocates (mostly patient groups) wanted articles to be made freely available immediately, and they worked out a compromise where the journals could have 6 months of exclusivity. At the last minute, the NIH Director at the time, Elias Zerhouni, extended this to 12 months, for reasons that remain shrouded in secrecy, but thankfully, the public (and science) won the main battle. For NEJM to turn around now and boast that they are releasing articles after an embargo period, without mentioning this requirement, is hypocritical, to say the least. Believe me, if the NIH requirement disappeared (and publishers are still lobbying to get rid of it!), NEJM would happily go back to keeping all access restricted to subscribers.

The battle is far from over. Open access advocates still want to see research released immediately, not after a 6-month or 12-month embargo, and that's precisely what the European Plan S will do.

With Plan S looming, I've no doubt we'll see more arguments against open access in the coming months, but scientists have at least one ace up our sleeves: we're the ones who do all the work. We do the experiments, we write the papers, and we review the papers. Without us, the journals would cease to exist. The journals will have no choice but to go along with plan S, because without the scientists, they'll have nothing to publish. Let's hope the U.S. will follow suit in the very near future. It's long past time to change the archaic, closed-access policies that have kept medical and scientific results–results that were funded by the public–locked behind the paywalls of for-profit publishers.

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.

A DNA Sequencing Breakthrough for Pregnant Women

DNA sequencing has made its way to the clinic in a dramatic new way: detecting chromosomal defects very early in pregnancy.  We've known for 25 years that traces of fetal DNA can be detected in a pregnant women's blood. But these traces are very small, and until now, we just didn't have the technology to detect an extra copy of a chromosome, where the DNA itself is otherwise normal.

Last week, in a study published in The New England Journal of Medicine, Diana Bianchi and colleagues showed how DNA sequencing can detect an extra copy of a chromosome with remarkable accuracy. This report heralds a new era in prenatal DNA testing.

First, some background: three copies of chromosome 21 causes Down syndrome, a genetic disease that causes intellectual disability and growth delays. Down syndrome is also called trisomy 21, where trisomy = 3 copies of a chromosome instead of the normal 2 copies. Much less common is Edwards syndrome, caused by three copies of chromosome 18. Edwards syndrome, or trisomy 18, has much more severe effects, with the vast majority of pregnancies not making it full term. Having an extra copy of any other chromosome almost always causes an early miscarriage. For many reasons, prospective parents want to know if a fetus carries any of these abnormalities.

The accuracy of the new test is remarkable. Out of 1914 young, healthy pregnant women, there were just 8 pregnancies where the fetus had an extra chromosome, and the test detected all 8. What was most impressive was its low false positive rate: in total, the new DNA-based test had just 9 false positives (for either chromosome 21 or chromosome 18 trisomy).  By contrast, the conventional screening test, which also identified all 8 true cases, produced 80 false positives, nearly 9 times as many as DNA sequencing.

Why does this matter? In most cases, women with a positive result on one of these tests will opt for amniocentesis ("amnio"), an invasive procedure where a doctor inserts a long needle directly into the womb and collects a sample of amniotic fluid. Amnio almost always gives a definitive answer about Down syndrome. With the conventional method, its false positive rate is so high that even with a positive test, over 95% of amnios will be negative, versus 55% with the new DNA sequencing test. Or to put it another way, as Bianci et al. wrote:

"if all women with positive results had .. decided to undergo an invasive procedure, there would have been a relative reduction of 89% in the number of diagnostic invasive procedures."

89% fewer invasive procedures is a huge reduction, not only in costs but in stress for the parents and risk to the baby (because amnio carries a small risk of miscarriage).

With DNA sequencing getting faster and cheaper every year, it might be surprising that we are only now seeing it used to detect trisomy. The difficulty with detecting an extra copy of a chromosome is that the DNA sequence itself is normal. If you sequence the genome, you won't find any mutations that indicate that the fetus has an extra chromosome copy. This is where the remarkable efficiency of next-generation sequencing comes in.

In a matter of hours, modern sequencing machines can sample millions of small fragments of DNA. We can use computational analysis to determine which fragments come from the fetus, and how many came from each chromosome. If any chromosome has three copies, we'll see a 50% increase in DNA from that chromosome. The power of sequencing lies in large numbers: because we can sequence many fragments from each chromosome, a 50% increase is easy to detect.

The method that Bianchi used to detect trisomy was published in 2011 by Amy Sehnert and colleagues from 2011, some of whom are contributors to the new NEJM study. [Side note: they use a software program called Bowtie, developed by my former student Ben Langmead, to do the analysis.] The method is likely to get even better over time, further reducing the false positive rate.

The American College of Obstetricians and Gynecologists has already recommended DNA testing for pregnant women at high risk of fetal aneuploidy (an extra chromosome). To be precise, they recommend that high-risk pregnant women be offered fetal DNA testing as an option, after they get genetic counseling. This new study, which was conducted in a low-risk population, shows that the benefits of prenatal DNA testing should offered to all women.