The Best American Science and Nature Writing 2011 (21 page)

He chose to publish one paper, fittingly, in the online journal
PLoS Medicine,
which is committed to running any methodologically sound article without regard to how "interesting" the results may be. In the paper, Ioannidis laid out a detailed mathematical proof that, assuming modest levels of researcher bias, typically imperfect research techniques, and the well-known tendency to focus on exciting rather than highly plausible theories, researchers will come up with wrong findings most of the time. Simply put, if you're attracted to ideas that have a good chance of being wrong, and if you're motivated to prove them right, and if you have a little wiggle room in how you assemble the evidence, you'll probably succeed in proving wrong theories right. His model predicted, in different fields of medical research, rates of wrongness roughly corresponding to the observed rates at which findings were later convincingly refuted: 80 percent of nonrandomized studies (by far the most common type) turn out to be wrong, as do 25 percent of supposedly gold-standard randomized trials, and as much as 10 percent of the platinum-standard large randomized trials. The article spelled out his belief that researchers were frequently manipulating data analyses, chasing career-advancing findings rather than good science, and even using the peer-review process—in which journals ask researchers to help decide which studies to publish—to suppress opposing views. "You can question some of the details of John's calculations, but it's hard to argue that the essential ideas aren't absolutely correct," says Doug Altaian, an Oxford University researcher who directs the Centre for Statistics in Medicine.

Still, Ioannidis anticipated that the community might shrug off his findings: sure, a lot of dubious research makes it into journals, but we researchers and physicians know to ignore it and focus on the good stuff, so what's the big deal? The other paper headed off that claim. He zoomed in on forty-nine of the most highly regarded research findings in medicine over the previous thirteen years, as judged by the science community's two standard measures: the papers had appeared in the journals most widely cited in research articles, and the forty-nine articles themselves were the most widely cited articles in these journals. These were articles that helped lead to the widespread popularity of treatments such as the use of hormone-replacement therapy for menopausal women, vitamin E to reduce the risk of heart disease, coronary stents to ward off heart attacks, and daily low-dose aspirin to control blood pressure and prevent heart attacks and strokes. Ioannidis was putting his contentions to the test not against run-of-the-mill research, or even merely well-accepted research, but against the absolute tip of the research pyramid. Of the forty-nine articles, forty-five claimed to have uncovered effective interventions. Thirty-four of these claims had been retested, and fourteen of these, or 41 percent, had been convincingly shown to be wrong or significantly exaggerated. If between a third and a half of the most acclaimed research in medicine was proving untrustworthy, the scope and impact of the problem were undeniable. That article was published in the
Journal of the American Medical Association.

 

Driving me back to campus in his smallish SUV—after insisting, as he apparently does with all his visitors, on showing me a nearby lake and the six monasteries situated on an islet within it—Ioannidis apologized profusely for running a yellow light, explaining with a laugh that he didn't trust the truck behind him to stop. Considering his willingness, even eagerness, to slap the face of the medical-research community, Ioannidis comes off as thoughtful, upbeat, and deeply civil. He's a careful listener, and his frequent grin and semi-apologetic chuckle can make the sharp prodding of his arguments seem almost good-natured. He is as quick, if not quicker, to question his own motives and competence as anyone else's. A neat and compact forty-five-year-old with a trim mustache, he presents as a sort of dashing nerd—Giancarlo Giannini with a bit of Mr. Bean.

The humility and graciousness seem to serve him well in getting across a message that is not easy to digest or, for that matter, believe: that even highly regarded researchers at prestigious institutions sometimes churn out attention-grabbing findings rather than findings likely to be right. But Ioannidis points out that obviously questionable findings cram the pages of top medical journals, not to mention the morning headlines. Consider, he says, the endless stream of results from nutritional studies in which researchers follow thousands of people for some number of years, tracking what they eat and what supplements they take, and how their health changes over the course of the study. "Then the researchers start asking, What did vitamin E do? What did vitamin C or D or A do? What changed with calorie intake, or protein or fat intake? What happened to cholesterol levels? Who got what type of cancer?" he says. "They run everything through the mill, one at a time, and they start finding associations, and eventually conclude that vitamin X lowers the risk of cancer Y, or this food helps with the risk of that disease." In a single week this fall, Google's news page offered these headlines: "More Omega-3 Fats Didn't Aid Heart Patients"; "Fruits, Vegetables Cut Cancer Risk for Smokers"; "Soy May Ease Sleep Problems in Older Women"; and dozens of similar stories.

When a five-year study of 10,000 people finds that those who take more vitamin X are less likely to get cancer Y, you'd think you have pretty good reason to take more vitamin X, and physicians routinely pass these recommendations on to patients. But these studies often sharply conflict with one another. Studies have gone back and forth on the cancer-preventing powers of vitamins A, D, and E; on the heart-health benefits of eating fat and carbs; and even on the question of whether being overweight is more likely to extend or shorten your life. How should we choose among these dueling high-profile nutritional findings? Ioannidis suggests a simple approach: ignore them all.

For starters, he explains, the odds are that in any large database of many nutritional and health factors, there will be a few apparent connections that are in fact merely flukes, not real health effects—it's a bit like combing through long, random strings of letters and claiming there's an important message in any words that happen to turn up. But even if a study managed to highlight a genuine health connection to some nutrient, you're unlikely to benefit much from taking more of it, because we consume thousands of nutrients that act together as a sort of network, and changing your intake of just one of them is bound to cause ripples throughout the network that are far too complex for these studies to detect and that may be as likely to harm you as help you. Even if changing that one factor does bring on the claimed improvement, there's still a good chance that it won't do you much good in the long run, because these studies rarely go on long enough to track the decades-long course of disease and ultimately death. Instead, they track easily measurable health "markers" such as cholesterol levels, blood pressure, and blood-sugar levels, and meta-experts have shown that changes in these markers often don't correlate as well with long-term health as we have been led to believe.

On the relatively rare occasions when a study does go on long enough to track mortality, the findings frequently upend those of the shorter studies. (For example, though the vast majority of studies of overweight individuals link excess weight to ill health, the longest of them haven't convincingly shown that overweight people are likely to die sooner, and a few of them have seemingly demonstrated that moderately overweight people are likely to live
longer.
) And these probiems are aside from ubiquitous measurement errors (for example, people habitually misreport their diets in studies), routine misanalysis (researchers rely on complex software capable of juggling results in ways they don't always understand), and the less common, but serious, problem of outright fraud (which has been revealed, in confidential surveys, to be much more widespread than scientists like to acknowledge).

If a study somehow avoids every one of these problems and finds a real connection to long-term changes in health, you're still not guaranteed to benefit, because studies report average results that typically represent a vast range of individual outcomes. Should you be among the lucky minority that stands to benefit, don't expect a noticeable improvement in your health, because studies usually detect only modest effects that merely tend to whittle your chances of succumbing to a particular disease from small to somewhat smaller. "The odds that anything useful will survive from any of these studies are poor," says Ioannidis—dismissing in a breath a good chunk of the research into which we sink about $100 billion a year in the United States alone.

And so it goes for all medical studies, he says. Indeed, nutritional studies aren't the worst. Drug studies have the added corruptive force of financial conflict of interest. The exciting links between genes and various diseases and traits that are relentlessly hyped in the press for heralding miraculous around-the-corner treatments for everything from colon cancer to schizophrenia have in the past proved so vulnerable to error and distortion, Ioannidis has found, that in some cases you'd have done about as well by throwing darts at a chart of the genome. (These studies seem to have improved somewhat in recent years, but whether they will hold up or be useful in treatment are still open questions.) Vioxx, Zelnorm, and Baycol were among the widely prescribed drugs found to be safe and effective in large randomized controlled trials before the drugs were yanked from the market as unsafe or not so effective or both.

"Often the claims made by studies are so extravagant that you can immediately cross them out without needing to know much about the specific problems with the studies," Ioannidis says. But of course it's that very extravagance of claim (one large randomized controlled trial even proved that secret prayer by unknown parties can save the lives of heart-surgery patients, while another proved that secret prayer can harm them) that helps gets these findings into journals and then into our treatments and lifestyles, especially when the claim builds on impressive-sounding evidence. "Even when the evidence shows that a particular research idea is wrong, if you have thousands of scientists who have invested their careers in it, they'll continue to publish papers on it," he says. "It's like an epidemic, in the sense that they're infected with these wrong ideas, and they're spreading it to other researchers through journals."

 

Though scientists and science journalists are constantly talking up the value of the peer-review process, researchers admit among themselves that biased, erroneous, and even blatantly fraudulent studies easily slip through it.
Nature,
the grande dame of science journals, stated in a 2006 editorial, "Scientists understand that peer review per se provides only a minimal assurance of quality, and that the public conception of peer review as a stamp of authentication is far from the truth." What's more, the peer-review process often pressures researchers to shy away from striking out in genuinely new directions and instead to build on the findings of their colleagues (that is, their potential reviewers) in ways that only
seem
like breakthroughs—as with the exciting-sounding gene linkages (autism genes identified!) and nutritional findings (olive oil lowers blood pressure!) that are really just dubious and conflicting variations on a theme.

Most journal editors don't even claim to protect against the problems that plague these studies. University and government research overseers rarely step in to directly enforce research quality, and when they do, the science community goes ballistic over the outside interference. The ultimate protection against research error and bias is supposed to come from the way scientists constantly retest each other's results—except they don't. Only the most prominent findings are likely to be put to the test, because there's likely to be publication payoff in firming up the proof or contradicting it.

But even for medicine's most influential studies, the evidence sometimes remains surprisingly narrow. Of those forty-five super-cited studies that Ioannidis focused on, eleven had never been retested. Perhaps worse, Ioannidis found that even when a research error is outed, it typically persists for years or even decades. He looked at three prominent health studies from the 1980s and 1990s that were each later soundly refuted and discovered that researchers continued to cite the original results as correct more often than as flawed—in one case for at least twelve years after the results were discredited.

Doctors may notice that their patients don't seem to fare as well with certain treatments as the literature would lead them to expect, but the field is appropriately conditioned to subjugate such anecdotal evidence to study findings. Yet much, perhaps even most, of what doctors do has never been formally put to the test in credible studies, given that the need to do so became obvious to the field only in the 1990s, leaving it playing catch-up with a century or more of non-evidence-based medicine, and contributing to Ioannidis's shockingly high estimate of the degree to which medical knowledge is flawed. That we're not routinely made seriously ill by this shortfall, he argues, is due largely to the fact that most medical interventions and advice don't address life-and-death situations but rather aim to leave us marginally healthier or less unhealthy, so we usually neither gain nor risk all that much.

Medical research is not especially plagued with wrongness. Other meta-research experts have confirmed that similar issues distort research in all fields of science, from physics to economics (where the highly regarded economists J. Bradford DeLong and Kevin Lang once showed how a remarkably consistent paucity of strong evidence in published economics studies made it unlikely that
any
of them were right). And needless to say, things only get worse when it comes to the pop expertise that endlessly spews at us from diet, relationship, investment, and parenting gurus and pundits. But we expect more of scientists, and especially of medical scientists, given that we believe we are staking our lives on their results. The public hardly recognizes how bad a bet this is. The medical community itself might still be largely oblivious to the scope of the problem, if Ioannidis hadn't forced a confrontation when he published his studies in 2005.