Epidemiology

Sunday, Jul 31, 2011

By the mid-1990s, the American Heart Association, the American College of Physicians and the American College of Obstetricians and Gynecologists had all concluded that the beneficial effects of hormone-replacement therapy were sufficiently well established that it could be recommended to older women as a means of warding off heart disease and osteoporosis. By 2001, 15 million women were filling H.R.T. prescriptions annually; perhaps 5 million were older women, taking the drug solely with the expectation that it would allow them to lead a longer and healthier life. A year later, the tide would turn. In the summer of 2002, estrogen therapy was exposed as a hazard to health rather than a benefit, and its story became what Jerry Avorn, a Harvard epidemiologist, has called the “estrogen debacle” and a “case study waiting to be written” on the elusive search for truth in medicine...

In the case of H.R.T., as with most issues of diet, lifestyle and disease, the hypotheses begin their transformation into public-health recommendations only after they’ve received the requisite support from a field of research known as epidemiology. This science evolved over the last 250 years to make sense of epidemics — hence the name — and infectious diseases. Since the 1950s, it has been used to identify, or at least to try to identify, the causes of the common chronic diseases that befall us, particularly heart disease and cancer. In the process, the perception of what epidemiologic research can legitimately accomplish — by the public, the press and perhaps by many epidemiologists themselves — may have run far ahead of the reality. The case of hormone-replacement therapy for post-menopausal women is just one of the cautionary tales in the annals of epidemiology. It’s a particularly glaring example of the difficulties of trying to establish reliable knowledge in any scientific field with research tools that themselves may be unreliable... the question of how many women may have died prematurely or suffered strokes or breast cancer because they were taking a pill that their physicians had prescribed to protect them against heart disease lingers unanswered. A reasonable estimate would be tens of thousands... between 2002 and 2004, breast cancer incidence in the United States dropped by 12 percent, an effect that may have been caused by the coincident decline in the use of H.R.T. (And it may not have been. The coincident reduction in breast cancer incidence and H.R.T. use is only an association.)...

At the center of the H.R.T. story is the science of epidemiology itself and, in particular, a kind of study known as a prospective or cohort study, of which the Nurses’ Health Study is among the most renowned. In these studies, the investigators monitor disease rates and lifestyle factors (diet, physical activity, prescription drug use, exposure to pollutants, etc.) in or between large populations (the 122,000 nurses of the Nurses’ study, for example). They then try to infer conclusions — i.e., hypotheses — about what caused the disease variations observed. Because these studies can generate an enormous number of speculations about the causes or prevention of chronic diseases, they provide the fodder for much of the health news that appears in the media — from the potential benefits of fish oil, fruits and vegetables to the supposed dangers of sedentary lives, trans fats and electromagnetic fields. Because these studies often provide the only available evidence outside the laboratory on critical issues of our well-being, they have come to play a significant role in generating public-health recommendations as well.

The dangerous game being played here, as David Sackett, a retired Oxford University epidemiologist, has observed, is in the presumption of preventive medicine. The goal of the endeavor is to tell those of us who are otherwise in fine health how to remain healthy longer. But this advice comes with the expectation that any prescription given — whether diet or drug or a change in lifestyle — will indeed prevent disease rather than be the agent of our disability or untimely death. With that presumption, how unambiguous does the evidence have to be before any advice is offered?

The catch with observational studies like the Nurses’ Health Study, no matter how well designed and how many tens of thousands of subjects they might include, is that they have a fundamental limitation. They can distinguish associations between two events — that women who take H.R.T. have less heart disease, for instance, than women who don’t. But they cannot inherently determine causation — the conclusion that one event causes the other; that H.R.T. protects against heart disease. As a result, observational studies can only provide what researchers call hypothesis-generating evidence — what a defense attorney would call circumstantial evidence.

Testing these hypotheses in any definitive way requires a randomized-controlled trial — an experiment, not an observational study — and these clinical trials typically provide the flop to the flip-flop rhythm of medical wisdom. Until August 1998, the faith that H.R.T. prevented heart disease was based primarily on observational evidence, from the Nurses’ Health Study most prominently. Since then, the conventional wisdom has been based on clinical trials — first HERS, which tested H.R.T. against a placebo in 2,700 women with heart disease, and then the Women’s Health Initiative, which tested the therapy against a placebo in 16,500 healthy women. When the Women’s Health Initiative concluded in 2002 that H.R.T. caused far more harm than good, the lesson to be learned, wrote Sackett in The Canadian Medical Association Journal, was about the “disastrous inadequacy of lesser evidence” for shaping medical and public-health policy. The contentious wisdom circa mid-2007 — that estrogen benefits women who begin taking it around the time of menopause but not women who begin substantially later — is an attempt to reconcile the discordance between the observational studies and the experimental ones. And it may be right. It may not. The only way to tell for sure would be to do yet another randomized trial, one that now focused exclusively on women given H.R.T. when they begin their menopause...

These studies have also been invaluable for identifying predictors of disease — risk factors — and this information can then guide physicians in weighing the risks and benefits of putting a particular patient on a particular drug. The studies have repeatedly confirmed that high blood pressure is associated with an increased risk of heart disease and that obesity is associated with an increased risk of most of our common chronic diseases, but they have not told us what it is that raises blood pressure or causes obesity. Indeed, if you ask the more skeptical epidemiologists in the field what diet and lifestyle factors have been convincingly established as causes of common chronic diseases based on observational studies without clinical trials, you’ll get a very short list: smoking as a cause of lung cancer and cardiovascular disease, sun exposure for skin cancer, sexual activity to spread the papilloma virus that causes cervical cancer and perhaps alcohol for a few different cancers as well.

Richard Peto, professor of medical statistics and epidemiology at Oxford University, phrases the nature of the conflict this way: “Epidemiology is so beautiful and provides such an important perspective on human life and death, but an incredible amount of rubbish is published,” by which he means the results of observational studies that appear daily in the news media and often become the basis of public-health recommendations about what we should or should not do to promote our continued good health...

While the tools of epidemiology — comparisons of populations with and without a disease — have proved effective over the centuries in establishing that a disease like cholera is caused by contaminated water, as the British physician John Snow demonstrated in the 1850s, it’s a much more complicated endeavor when those same tools are employed to elucidate the more subtle causes of chronic disease.

And even the success stories taught in epidemiology classes to demonstrate the historical richness and potential of the field — that pellagra, a disease that can lead to dementia and death, is caused by a nutrient-deficient diet, for instance, as Joseph Goldberger demonstrated in the 1910s — are only known to be successes because the initial hypotheses were subjected to rigorous tests and happened to survive them. Goldberger tested the competing hypothesis, which posited that the disease was caused by an infectious agent, by holding what he called “filth parties,” injecting himself and seven volunteers, his wife among them, with the blood of pellagra victims. They remained healthy, thus doing a compelling, if somewhat revolting, job of refuting the alternative hypothesis...

All of this suggests that the best advice is to keep in mind the law of unintended consequences. The reason clinicians test drugs with randomized trials is to establish whether the hoped-for benefits are real and, if so, whether there are unforeseen side effects that may outweigh the benefits. If the implication of an epidemiologist’s study is that some drug or diet will bring us improved prosperity and health, then wonder about the unforeseen consequences. In these cases, it’s never a bad idea to remain skeptical until somebody spends the time and the money to do a randomized trial and, contrary to much of the history of the endeavor to date, fails to refute it.

Do We Really Know What Makes Us Healthy?, Gary Taubes, The New York Times Magazine, September 16, 2007, http://gemini.econ.umd.edu/jrust/econ623/files/econ623/16epidemiology-t.html.