Z S's List: Science

• 1960s,
• estrogen therapy evolved into a long-term remedy for the chronic ills of  aging
• American Heart Association
• mid-1990s
• recommended to older women as a means of warding off heart disease and osteoporosis
• beneficial effects of H.R.T
• 2001, 15 million women were filling H.R.T. prescriptions annually
• epidemiology
• to identify, the causes of the common chronic diseases that befall us
• In 1985
• Nurses’ Health Study
• Harvard Medical School
• women taking estrogen had only a third as many heart attacks as women who had never taken the drug
• protect them against osteoporosis and perhaps colorectal cancer, these benefits would be outweighed by increased risks of heart disease, stroke, blood clots, breast cancer and perhaps even dementia
• 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
• no matter how well designed and how many tens of thousands of subjects they might include
• The catch with observational studies
• they have a fundamental limitation
• they cannot inherently determine causation
• observational studies can only provide
• hypothesis-generating evidence
• circumstantial evidence
• No one questions the value of these epidemiologic studies when they’re used to identify the unexpected side effects of prescription drugs or to study the progression of diseases or their distribution between and within populations.
• antioxidants like vitamins E and C and beta carotene did not prevent heart diseas
• nor did eating copious fiber protect against colon cancer
• “Epidemiologic studies, like diagnostic tests, are probabilistic statements
• they allow both physicians and patients to “estimate the truth” so they can make informed decisions
• , double-blind trials, are typically considered the gold standard for establishing reliable knowledge
• clinical trials also have limitations beyond their exorbitant costs and the years
• They can rarely be used, for instance, to study suspected harmful effects
• Clinical trials
• invariably enroll subjects who are relatively healthy, who are motivated to volunteer and will show up regularly for treatments and checkups
• very good for showing that a drug does what the pharmaceutical company says it does
• but not very good for telling you how big the benefit really is and what are the harms in typical people
• they don’t enroll typical people
• While the tools of epidemiolog
• have proved effective over the centuries in establishing that a disease like cholera is caused by contaminated water
• it’s a much more complicated endeavor when those same tools are employed to elucidate the more subtle causes of chronic disease.
• even the success stories taught in epidemiology classes
• 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.
• Smoking and lung cancer is the emblematic success story of chronic-disease epidemiology. But lung cancer was a rare disease before cigarettes became widespread, and the association between smoking and lung cancer was striking: heavy smokers had 2,000 to 3,000 percent the risk of those who had never smoked. This made smoking a “turkey shoot,
• the problem is that people who faithfully engage in activities that are good for them — taking a drug as prescribed, for instance, or eating what they believe is a healthy diet — are fundamentally different from those who don’t
• Ideally, epidemiologists will carefully measure the wealth and education of their subjects and then use statistical methods to adjust for the effect of these influences — multiple regression analysis, for instance, as one such method is called — but, as Avorn says, it “doesn’t always work as well as we’d like it to.”
• The Bias of Compliance
• people who comply with their doctors’ orders when given a prescription are different and healthier than people who don’t
• those men who said they took more than 80 percent of the pills prescribed fared substantially better than those who didn’t. Only 15 percent of these faithful “adherers” died, compared with almost 25 percent of what the project researchers called “poor adherers.”
• but then the researchers looked at those men who faithfully took their placebos. And those men, too, seemed to benefit from adhering closely to their prescription: only 15 percent of them died compared with 28 percent who were less conscientious
• people who take their placebo regularly are just different than the others. The rest is a little speculative. Maybe they take better care of themselves in general. But this compliance effect is quite a big effect.”
• How Doctors Confound the Science
• prescriber effect
• reasons a physician will prescribe one medication to one patient and another or none at all to a different patient are complex
• explanation for why people who take cholesterol-lowering drugs called statins appear to have a greatly reduced risk of dementia and death
• medication itself is unlikely to be the primary cause in either case, says Avorn, because the observed associations are “so much larger than the effects that have been seen in randomized-clinical trials.”
• A physician is not going to take somebody either dying of metastatic cancer or in a persistent vegetative state or with end-stage neurologic disease and say, ‘Let’s get that cholesterol down, Mrs. Jones.’ The consequence of that, multiplied over tens of thousands of physicians, is that many people who end up on statins are a lot healthier than the people to whom these doctors do not give statins.
• associations perceived by the epidemiologic studies were due to healthy-user and prescriber effects and not H.R.T. itself. Women who took H.R.T. had less heart disease than women who didn’t, because women who took H.R.T. are different from women who didn’t take H.R.T. And maybe their physicians are also different. In this case, the trials got the right answer; the observational studies got the wrong answer.
• observational studies got the wrong answer, but only partly. Here, healthy-user and prescriber effects are viewed as minor issues; the question is whether observational studies can accurately determine if women were really taking H.R.T
• subjects of the Nurses’ Health Study were asked if they were taking H.R.T. every two years,
• If a nurse fills out her questionnaire a few months before she begins taking H.R.T., as Colditz explains, and she then has a heart attack, say, six months later, the Nurses’ study will classify that nurse as “not using” H.R.T. when she had the heart attack.
• If the compliance effect can explain why anyone faithfully following her doctor’s orders will be 50 percent less likely to die over the next few years than someone who’s not so inclined, then it’s certainly possible that what the Nurses’ Health Study and other observational studies did is observe a compliance effect and mistake it for a beneficial effect of H.R.T. itself.
• it would explain why the Nurses’ Health Study reported very similar seemingly beneficial effects for antioxidants, vitamins, low-dose aspirin and folic acid, and why these, too, were refuted by clinical trials. It’s not necessarily true, but it certainly could be.
• confidence can never be justified without a clinical trial, at least not when the associations being studied are so small.
• The reason clinicians test drugs with randomized trials is to establish whether the hoped-for benefits are real
• 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
• 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.

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