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 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 problems 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 45 super-cited studies that Ioannidis focused on, 11 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 12 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.
Ioannidis initially thought the community might come out fighting. Instead, it seemed relieved, as if it had been guiltily waiting for someone to blow the whistle, and eager to hear more. David Gorski, a surgeon and researcher at Detroit’s Barbara Ann Karmanos Cancer Institute, noted in his prominent medical blog that when he presented Ioannidis’s paper on highly cited research at a professional meeting, “not a single one of my surgical colleagues was the least bit surprised or disturbed by its findings.” Ioannidis offers a theory for the relatively calm reception. “I think that people didn’t feel I was only trying to provoke them, because I showed that it was a community problem, instead of pointing fingers at individual examples of bad research,” he says. In a sense, he gave scientists an opportunity to cluck about the wrongness without having to acknowledge that they themselves succumb to it—it was something everyone else did.
To say that Ioannidis’s work has been embraced would be an understatement. His PLoS Medicine paper is the most downloaded in the journal’s history, and it’s not even Ioannidis’s most-cited work—that would be a paper he published in Nature Genetics on the problems with gene-link studies. Other researchers are eager to work with him: he has published papers with 1,328 different co-authors at 538 institutions in 43 countries, he says. Last year he received, by his estimate, invitations to speak at 1,000 conferences and institutions around the world, and he was accepting an average of about five invitations a month until a case last year of excessive-travel-induced vertigo led him to cut back. Even so, in the weeks before I visited him he had addressed an AIDS conference in San Francisco, the European Society for Clinical Investigation, Harvard’s School of Public Health, and the medical schools at Stanford and Tufts.
The irony of his having achieved this sort of success by accusing the medical-research community of chasing after success is not lost on him, and he notes that it ought to raise the question of whether he himself might be pumping up his findings. “If I did a study and the results showed that in fact there wasn’t really much bias in research, would I be willing to publish it?” he asks. “That would create a real psychological conflict for me.” But his bigger worry, he says, is that while his fellow researchers seem to be getting the message, he hasn’t necessarily forced anyone to do a better job. He fears he won’t in the end have done much to improve anyone’s health. “There may not be fierce objections to what I’m saying,” he explains. “But it’s difficult to change the way that everyday doctors, patients, and healthy people think and behave.”
As helter-skelter as the University of Ioannina Medical School campus looks, the hospital abutting it looks reassuringly stolid. Athina Tatsioni has offered to take me on a tour of the facility, but we make it only as far as the entrance when she is greeted—accosted, really—by a worried-looking older woman. Tatsioni, normally a bit reserved, is warm and animated with the woman, and the two have a brief but intense conversation before embracing and saying goodbye. Tatsioni explains to me that the woman and her husband were patients of hers years ago; now the husband has been admitted to the hospital with abdominal pains, and Tatsioni has promised she’ll stop by his room later to say hello. Recalling the appendicitis story, I prod a bit, and she confesses she plans to do her own exam. She needs to be circumspect, though, so she won’t appear to be second-guessing the other doctors.
Tatsioni doesn’t so much fear that someone will carve out the man’s healthy appendix. Rather, she’s concerned that, like many patients, he’ll end up with prescriptions for multiple drugs that will do little to help him, and may well harm him. “Usually what happens is that the doctor will ask for a suite of biochemical tests—liver fat, pancreas function, and so on,” she tells me. “The tests could turn up something, but they’re probably irrelevant. Just having a good talk with the patient and getting a close history is much more likely to tell me what’s wrong.” Of course, the doctors have all been trained to order these tests, she notes, and doing so is a lot quicker than a long bedside chat. They’re also trained to ply the patient with whatever drugs might help whack any errant test numbers back into line. What they’re not trained to do is to go back and look at the research papers that helped make these drugs the standard of care. “When you look the papers up, you often find the drugs didn’t even work better than a placebo. And no one tested how they worked in combination with the other drugs,” she says. “Just taking the patient off everything can improve their health right away.” But not only is checking out the research another time-consuming task, patients often don’t even like it when they’re taken off their drugs, she explains; they find their prescriptions reassuring.
Later, Ioannidis tells me he makes a point of having several clinicians on his team. “Researchers and physicians often don’t understand each other; they speak different languages,” he says. Knowing that some of his researchers are spending more than half their time seeing patients makes him feel the team is better positioned to bridge that gap; their experience informs the team’s research with firsthand knowledge, and helps the team shape its papers in a way more likely to hit home with physicians. It’s not that he envisions doctors making all their decisions based solely on solid evidence—there’s simply too much complexity in patient treatment to pin down every situation with a great study. “Doctors need to rely on instinct and judgment to make choices,” he says. “But these choices should be as informed as possible by the evidence. And if the evidence isn’t good, doctors should know that, too. And so should patients.”
In fact, the question of whether the problems with medical research should be broadcast to the public is a sticky one in the meta-research community. Already feeling that they’re fighting to keep patients from turning to alternative medical treatments such as homeopathy, or misdiagnosing themselves on the Internet, or simply neglecting medical treatment altogether, many researchers and physicians aren’t eager to provide even more reason to be skeptical of what doctors do—not to mention how public disenchantment with medicine could affect research funding. Ioannidis dismisses these concerns. “If we don’t tell the public about these problems, then we’re no better than nonscientists who falsely claim they can heal,” he says. “If the drugs don’t work and we’re not sure how to treat something, why should we claim differently? Some fear that there may be less funding because we stop claiming we can prove we have miraculous treatments. But if we can’t really provide those miracles, how long will we be able to fool the public anyway? The scientific enterprise is probably the most fantastic achievement in human history, but that doesn’t mean we have a right to overstate what we’re accomplishing.”
We could solve much of the wrongness problem, Ioannidis says, if the world simply stopped expecting scientists to be right. That’s because being wrong in science is fine, and even necessary—as long as scientists recognize that they blew it, report their mistake openly instead of disguising it as a success, and then move on to the next thing, until they come up with the very occasional genuine breakthrough. But as long as careers remain contingent on producing a stream of research that’s dressed up to seem more right than it is, scientists will keep delivering exactly that.
“Science is a noble endeavor, but it’s also a low-yield endeavor,” he says. “I’m not sure that more than a very small percentage of medical research is ever likely to lead to major improvements in clinical outcomes and quality of life. We should be very comfortable with that fact.”