The truth is that we aren’t that close to eliminating medical uncertainty and will never reach that ultimate goal because each one of us is different in ways that influence our health and how we respond to disease; there are few universal truths. The next chapter explains why we believe that not only is medical uncertainty real and inescapable, but that it is also necessary for each unique one of us to benefit most from the available evidence. That is why you want the help of the good doctor.
The William Osler Papers, “Father of Modern Medicine: The Johns Hopkins School of Medicine, 1889-1905,” U. S. National Library of Medicine: Profiles in Science.
Dr. Seuss, Happy Birthday to You (New York: Random House, 1959).
Recollection of a patient encounter, KB.
William Bennett Bean, ed., Sir William Osler: Aphorisms from His Bedside Teachings and Writings (New York: Henry Schulman, Inc., 1950).
J. Hinson, Jr., K. Brigham, and J. Daniell, “Catamenial Pneumothorax in Sisters,” Chest 80, no. 5 (1981): 634-635.
CHAPTER 2
Uncertainty Is Essential to Personal Health Care
A middle-aged woman who worked as a laboratory technician at a major university medical center developed high blood pressure because one of her kidneys was abnormal and had to be removed.6 When her physician employer went to visit her after surgery, he found her barely responsive even though there had been plenty of time for the anesthesia to wear off. She lay motionless in the bed breathing about five or six times a minute, did not respond at all even when her visitor shouted directly into her ear, and barely winced when he pinched the tendon at the back of her heel, a standard test for seeing whether a patient responds to pain. The doctor looked in her chart and discovered that the eighty-five-pound woman had been given an exorbitant dose of narcotic for her age and size. He paged the resident who was responsible for the service and asked why this petite woman had been given a man-size dose of drug. The resident responded. “That’s a standard post-op dose.”
“But,” the physician protested, “she’s not a standard woman!”
No doubt the resident was right; he had given a standard post-op dose of narcotic. But standard practice almost killed his patient. The possibility that the recommended dose might not fit the specific situation just didn’t cross this confident young doctor’s mind and so he failed to adapt the standard to the person he was treating. If that sounds like a lapse in common sense rather than a lack of knowledge, that was probably true in this case, but it raises a larger question. How does my doctor come to a conclusion about what I have and what to do about it?
The answer to that question has two parts: What are the facts (doctors call that evidence based medicine)? and How do the facts fit your specific situation (doctors call that personalized or precision medicine)?
WHERE DO MEDICAL FACTS COME FROM?
They come from accurately analyzed research done according to scrupulous scientific principles. A lot has been learned about human health and disease from such studies and in the twenty-first century, the learning curve is steeper than it has ever been. Doctors can rely confidently on a very large and expanding store of medical facts in their efforts to help us stay healthy or get well.
Most facts that are relevant to your health come from studies done on groups of people, often very large groups. Facts from those studies are based on statistics and they are never absolute. Depending on a host of things, including size of the study, what kind of people were studied, how carefully the study was designed, and whether there is more than one study that reached the same conclusions, your doctor’s confidence in the facts may vary. There is always some degree of uncertainty about the accuracy of the available information from studies with human participants; our species just isn’t that predictable.
There are a number of reasons to be less than absolutely sure about medical information that comes from studies in people. Even conclusions from carefully done research may not survive the trials of time and technology. Here are two examples.
In a series of detailed studies on human volunteers done with colleagues at the Rockefeller Institute in the early 1950s, Lewis Dahl concluded that a rice and fruit diet was effective treatment for high blood pressure because the diet was low in sodium.7 Dr. Dahl found that he could produce high blood pressure, with all of its complications, in rats by giving them big doses of salt. He gathered data from Eskimos, Marshall Islanders, North Americans, southern Japanese, and northern Japanese and produced a lovely graph showing a nearly perfect relationship between how much salt people ate and how many had high blood pressure. The Institute of Medicine, the U.S. Food and Drug Administration, and the U.S. Senate Select Committee on Nutrition and Human Needs were so convinced by Dr. Dahl’s studies that they issued an edict that we should all eat less salt if we want to be healthy and live a long and happy life—the less salt the better.
Then, an analysis of a large number of studies of the relationship between salt intake and health reported in the American Journal of Hypertension in April of 2014 concluded that, “Both low sodium intakes and high sodium intakes are associated with increased [emphasis added] mortality.”8 The final answer about how salt intake relates to health will require some more research in this area, but what Dr. Dahl and others established as a scientific fact that drove individual behavior, medical practice, and social policy for decades may have been an oversimplification.
And there is the notion that eating fat is bad for one’s heart and blood vessels. Ancel Keys, a brilliant and charismatic nutritionist, collected information about deaths from heart disease and diet in seven countries9 and published his results as a book in 1980.10 His work (and his effective advocacy) convinced the American Heart Association and the federal government to issue dietary guidelines based on his conclusion that eating fat was bad for the heart. Those events radically changed the American diet with enormous industrial, economic, and personal consequences. But an analysis of data from over half a million people from 76 different studies published in the Annals of Internal Medicine in 2014 concludes that “Current evidence does not clearly support cardiovascular guidelines that encourage high consumption of polyunsaturated fatty acids and low consumption of total saturated fats.”11 That’s scientific argot for eating fat doesn’t cause heart disease as far as we can tell from the available data. The medical “truth” may be different than what it was in 1980.
So time and technology can change the facts. And what we believe about health is influenced by a lot of other things—opinions of prominent public personalities, promiscuous advertising, personal beliefs, societal pressures—that are not reliable sources of accurate information. Then there are the quacks looking to make a buck at your expense, entrenched cultural attitudes, and ambiguities in the discovery process that add to the uncertainties. And there is always the money magnet tugging at honest and well-meaning professionals. If your doctor wants to practice evidence-based medicine (we hope so), she should have a firm grasp of what “evidence” she can be pretty sure about and when to respond to a “fact” as someone once wrote on the flyleaf of the Bible, “interesting if true.”12
HOW DO THE FACTS FIT YOU?
We are all members of the same species and so there is a storehouse of facts about humans that fits all of us. However, a lot of the critical evidence for these facts is based on statistics. A thinking doctor knows that statistics describe groups of people, not individuals. If she wants to practice personalized medicine (we hope so), she needs to figure out how the numbers describing what happens in a group of people relate to you. The statistics may not help her do that; in fact they can be misleading.
In his wonderful essay, “The Median Isn’t the Message,” the late Harvard paleontology professor Stephen Jay Gould makes this point.13 The median is one of the statisticians’ favorite numbers. It is a number in the middle of the group data; by definition, half the peo
ple score above the median and half below. While still a young man, Dr. Gould got the potentially devastating news that he had abdominal mesothelioma, described to him as a fatal disease with a median survival of five months. But he wasn’t ready to settle for a median fate and he knew a thing or two about statistics. He did an extensive search of the available information and discovered that while the median survival of people with abdominal mesothelioma was indeed five months and most of its victims died quickly, a few people with the disease lived much longer than the median, even years longer. After a careful look at the specifics of his own situation, Dr. Gould concluded that he was one of those lucky folks. He lived for another twenty years, eventually dying of something else. Statistical conclusions from even the most rigorously done population studies may be irrelevant to you and may lead you down a path to either despair or confidence with no good reason for either.
Rigorously done and carefully analyzed studies in groups of people with a given condition will always be essential “evidence” informing efforts to figure out what you have and what should be done about it. But the value of such evidence depends on both how well the studies were done and how relevant they are to your specific circumstance. The wise doctor pays careful attention to the numbers, but she is not mesmerized by them. Numbers are not indisputable and unique criteria for personal health related decisions. Evidence is absolutely necessary but not always sufficient. That’s why we need uncertain doctors.
RECONCILING EVIDENCE-BASED AND PERSONALIZED HEALTH CARE
You want a doctor who is comfortable with uncertainty because what she doesn’t know could save your life. How much liberty your doctor dare take in bending the evidence to suit your particular situation depends on what evidence there is and how sure your doctor is that it is true and relevant to you (that is, how much she doesn’t know). This relationship between relying on the evidence and taking into account the idiosyncratic you in arriving at a diagnosis and therapy can be illustrated by a simple graph. How much your doctor can justify modifying her approach to diagnosis and treatment because you don’t exactly fit the usual mold (flexibility) is directly related to what she doesn’t know, that is, how uncertain she is about the available evidence. If there were evidence that was 100 percent certain to be true for every human being (0 percent uncertainty), then there would be no need to massage the program to suit a specific person. It would truly be a one-size-fits-all solution. You wouldn’t even need a doctor in that case. You could just look it up on the internet.
Of course, in human biology there is no such animal, but for some situations there is excellent evidence in many different kinds of people so it is pretty clear what to do. The need for a personalized approach is not so great in that case; there is a good chance that any one of us will do well on the same evidence-based treatment. As the evidence becomes less certain, the need and the opportunity for fitting the intervention to the specific person being treated increases. Where there is no credible evidence (100 percent uncertainty), your doctor and you are on your own. In that situation, individual preferences, specific experiences, anecdotes, knowledgeable opinions, and personal priorities might help determine what to do and those decisions are unconstrained by “evidence.” It’s up to your doctor and you to do the best you can with whatever information you can get your hands on.
So one source of the good doctor’s uncertainty is whether a treatment that usually works in large groups of people will work for you. But that assumes that there is no doubt about what she is trying to treat, that she is sure about the diagnosis. What if the evidence for a specific diagnosis is not so clear? That is not an unusual situation. Arriving at a diagnosis is sometimes a journey rather than an event. The journey follows the pattern illustrated in the graph, progressing down the slope of decreasing uncertainty until finally arriving at the origin with an unequivocal diagnosis; therapy may be different at different points along the journey.
Here is an example. About every six weeks over sixteen months a forty-four-year-old man had three or four days of fever, aching in his arms and legs, and drenching sweats at night.14 Between those episodes he felt fine. His general physician could find nothing wrong on a physical exam and a battery of lab tests was normal. When he reappeared five months later with more frequent episodes, he was referred for a second opinion. Infectious disease experts noted that he now had pain in his leg and shoulder joints, but again physical and extensive lab examinations were all normal. With nothing specific to go on, his doctors thought he might have some obscure infection or an autoimmune disease. Someone suggested the possibility of an immune system related disorder called Still’s disease. After seven more months, the patient was sent to an academic rheumatology unit where nothing specific was discovered. However, the working diagnosis was Still’s disease and he was treated initially with a non-steroidal anti-inflammatory agent (NSAID). When he didn’t improve, he was given a corticosteroid and methotrexate, potent medicines for immune related disorders like Still’s disease. In spite of the potent medicines, the patient gradually developed obvious arthritis in his joints and some abnormal non-specific lab tests. Finally, almost six years after his initial vague complaints caused him to seek help from his general doctor, the patient developed frequent watery diarrhea and rapid weight loss. At that point, a biopsy of his small intestine revealed the classical findings of a rare disease of the intestine first described by George Whipple in 1907 and subsequently shown to be due to an infection with an unusual bacterium. Whipple’s disease is often associated with arthritis but diarrhea and weight loss are the essential clues to the diagnosis.
So for six years, this unfortunate patient endured a long and difficult journey down the path toward less and less uncertainty through several possible diagnoses and several unsuccessful therapies, to finally arrive at a clear diagnosis. Now how about therapy?
Treatment of Whipple’s disease involves a year course of antibiotics, but which antibiotics? Therapy of rare diseases is fraught with uncertainty. There are too few cases of Whipple’s disease to do careful trials of different antibiotics, so a regimen has to be designed based on less than stellar evidence. How to go about that?
Here’s what a thinking doctor would do. She would sit down with the patient and review the efficacy, side effects, and complications of the various regimens that have been used. How many patients have a good initial response? What is the relapse rate? What is the cost to the patient? How many pills must be taken and how often? Does the patient have any allergies? Has he taken antibiotics in the past and if so were there any complications or unpleasant side effects? Taking all of those things into account, she and the patient would design an individual-specific treatment regimen based on the best evidence available, given the inherent level of uncertainty. She would closely monitor whether the patient’s response to this carefully designed regimen was positive, negative, or equivocal. Depending on his response, she would move him up or down the uncertainty-flexibility curve shown in the figure and that would determine his continuing therapy. Toeing that fine line that relates the evidence to a specific person demands the skill of an experienced professional. That’s why it matters so much who you choose for your doctor.
WON’T A COMPLETE ANALYSIS OF YOUR GENOME ELIMINATE UNCERTAINTY?
Some knowledgeable people would go even further and ask: With the complete analysis of my genome in hand, why will I need a doctor at all? And there are some impressive anecdotes that tempt us to think that perhaps we should be hunting for a good geneticist or a more powerful computer to take over responsibility for our health care instead of looking for the right doctor.
Writing in the New York Times, Gina Kolata introduces one of those impressive anecdotes in the person of Dr. Lukas Wartman.15 Dr. Wartman got interested in leukemia as a medical student. He was gearing up for a career doing research in that area when, during his last year of med school, ironically, he developed the disease himself. Chemotherapy suppressed his cancer for
a while and when it recurred, a bone marrow transplant seemed effective for a bit. By then he was an assistant professor on the faculty of Washington University in Saint Louis, an amiable colleague of the excellent scientists at that institution. His leukemia came back yet again. Survival after two recurrences of his kind of leukemia is so rare that there are no statistics. There was no known treatment for his disease at that point and his health was rapidly heading south.
Dr. Wartman’s genetics colleagues decided that they were not going to lose their associate without a serious fight. For the first time ever, they mapped out the entire complement of genes and measured their activity in Dr. Wartman’s leukemic cells and in his normal cells and compared the two results. “Eureka!” Archimedes would have shouted. They found a gene that was going gangbusters and its product was a stimulator of the leukemic cells. What’s more (eureka! again), there was a drug that was known to switch off that gene, although it had only been used to treat kidney cancer. Dr. Wartman took the drug and, for all practical purposes, got well (the appropriately cautious cancer doctors would say that he went into remission). He also had another bone marrow transplant in case his cancer developed resistance to the drug. Dr. Wartman remained in remission at least for several months, remains apparently well three or so years after the precise treatment of his cancer.
Hoping that experiences like Dr. Wartman’s can be scaled up, the National Cancer Institute has begun enrolling thousands of patients with intractable cancers from 2,400 clinics scattered across the country. Their cancers’ genomes will be analyzed and they will be given anti-cancer drugs that the genetics predict might be effective. This is an entirely new way to match therapy to the essential nature of the disease (the institute has named the study the MATCH trial).16 And, no doubt, this is just the beginning. The technology is irresistible. It is virtually certain that genetics will change how we think about and how we treat some cancers.
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