That personal touch.
Article Type: Letter to the editor
Subject: Genetic screening (Usage)
Life style (Health aspects)
Risk factors (Health) (Genetic aspects)
Authors: Caulffield, Timothy
Laberge, Anne-Marie
Evans, James P.
Lebel, Robert Roger
Menzel, Paul T.
Pub Date: 05/01/2011
Publication: Name: The Hastings Center Report Publisher: Hastings Center Audience: Academic; Professional Format: Magazine/Journal Subject: Biological sciences; Health Copyright: COPYRIGHT 2011 Hastings Center ISSN: 0093-0334
Issue: Date: May-June, 2011 Source Volume: 41 Source Issue: 3
Geographic: Geographic Scope: United States Geographic Code: 1USA United States
Accession Number: 268403507
Full Text: To the Editor: Last year I sent a vial of my spit to a prominent direct-to-consumer genetic testing company. The company's Web site promised that, in return, I would get genetic risk information that would allow me to "make lifestyle choices" and "make more informed decisions" about my health--in other words, personalize my health behaviors and medical care.

When the results arrived I found little that was helpful. There was lots of fun and interesting information. It was, after all, information about me--one of my absolute favorite topics. And the data were presented in a sophisticated and engaging manner that made them easy to understand. But was there any information that should or would nudge me toward adopting a unique and personalized preventive strategy? Not really.

Susan Gilbert's essay ("Personalized Cancer Care in an Age of Anxiety," Sept-Oct 2010) reminds us that even in the area of targeted cancer therapies, one of the most promising applications of genetic technologies, complex questions of utility and long-term benefit remain. But genetic information is supposed to help us do more than just treat disease. Indeed, it has long been suggested that the prevention of disease, not just personalized clinical treatment, will be one of the primary benefits of the "genetic revolution." Yet just as the use of genetic information in the clinical setting poses profound challenges--a theme of several of the essays in this volume--there are also tremendous limitations to the utility of this information as a tool for prevention.

Just a few weeks before writing this commentary, I received an update email from my testing company that contained some new genetic risk information. It turns out that I am at a slightly increased risk for colorectal cancer. The average lifetime risk for individuals of European ancestry is 5.6 out of 100, and my risk is 7.7 out of 100. Here is the lifestyle advice that accompanied the risk information I received: exercise, keep my weight down, drink only moderate amounts of alcohol, and eat fruits, vegetables, and whole grains.

Solid advice. But this is how we should live regardless of our genetic risk. And we all know (or should know) these simple, bedrock strategies to reduce the risk of common chronic diseases. The problem, of course, is that very few individuals live this way. Actually, to be more precise, almost nobody lives this way. A study exploring the eating habits of the American population published in the September 2010 issue of Journal of Nutrition found that "nearly the entire U.S. population consumes a diet that is not on par with [national] recommendations." In other words, no one in the United States is eating a healthy diet. Another study, published in 2010 in the American Journal of Preventive Medicine, found similarly depressing figures for exercise. Only 5 percent of Americans get any vigorous exercise. The most commonly reported moderate "exercise"? Food preparation.

These studies paint a grim picture--one that is supported by many other studies. And they remind us that from the perspective of public health, worrying about personalizing our preventive strategies based on genetic risk information borders on the absurd. When no one eats a healthy diet, few get sufficient exercise, over a third of the population is clinically obese, and many still smoke, we should not pay too much attention to tiny increases in genetic risk for common diseases. Let's start with the basics. Eat your broccoli, take the stairs, and don't worry about whether you have a 5.6 percent or 7.7 percent lifetime risk for a grave disease because either way, a sensible lifestyle is the healthy choice.

Timothy Caulfield

University of Alberta

To the Editor: Personalized medicine is not a new idea. Physicians already take into consideration a patient's personal situation (age, gender, weight, personal and family history, presence of risk factors, diet, and medications, for example) when selecting or adjusting a course of treatment. Screening tests have been used for decades to identify high-risk groups who could benefit from specific surveillance or different management. But the term "personalized medicine" suggests that the use of genetic information will identify the individual's own personal risk--not the subgroup he or she falls into, but his or her own individual risk--thereby allowing the physician to tailor management specifically to that individual. Unfortunately, it isn't as straightforward as it sounds. Phenotype is still important in personalized medicine.

Disease occurrence is influenced by phenotypic characteristics, even in the case of very strong monogenic risk factors for common diseases. For example, the probability that an individual with a family history of high cholesterol will develop cardiovascular disease is influenced by gender, family history, and a variety of environmental factors, like physical activity. This interindividual variability makes predicting occurrence of disease for genetic variants with weaker effects even more difficult.

Current technology makes it possible to test hundreds (if not millions) of genetic risk factors at a time. The models used to estimate individual risk from these data are still imperfect: we are still learning how genetic risk factors affect risk when combined. They may interact synergistically to increase the resulting risk estimate or cancel each other out. In many disease areas, our current understanding of such interactions is limited. With each additional genetic risk factor included in a risk estimation model, the number of potential interactions increases. The complexity of risk estimation modeling explains why tests based on different genetic risk factors might lead to different risk predictions. A promising approach is to study phenotypic markers as the functional reflections of known (and unknown) genetic risk factors, as well as interactions with environmental factors (diet or other drugs, for instance). Because phenotypic markers can act as proxies of both measurable and unmeasurable risk factors, their addition to risk estimation models could potentially improve their predictive value.

The result of a personalized genomic test is an estimate of the probability of developing disease. Although this risk can be anywhere between 0 and 100 percent, in the end it will most likely be expressed as a categorical result (low, moderate, or high risk). If personalized medicine is still based on risk categories, are risk categories based on genomic information more personal than risk groups based on a careful clinical (phenotypic) assessment by a physician? Is it genetic determinism to limit "personalized" medicine to medicine based on genetic profiles? Personal and family history, age, weight, and other phenotypic characteristics add context to an individual's genomic profile and should not be discounted. For example, a seventy-year-old who has a normal electrocardiogram and no history of heart disease but a genomic profile suggesting a high risk of heart disease will most likely be managed differently than a likewise asymptomatic forty-year-old with the same genomic profile and a strong family history of heart disease. For reasons like these, risk estimation models should include other personal characteristics.

In the meantime, personalized medicine gives physicians and patients access to what we hope to be valuable information about health risks. This information can be used to influence management and treatment decisions, yet still needs to be interpreted in the context of a careful clinical assessment.

Anne-Marie Laberge

University of Montreal

To the Editor: The ability to assay an individual's entire genome offers considerable promise as medicine seeks to extract utility from the last decade's breathtaking advances in genetics, as explored in the essay set in the September-October 2010 issue. However, as we seek to understand how best to apply emerging knowledge and technology to patient care, the all-too-messy context of clinical medicine must be kept firmly in mind.

By and large, the tools with which modern medicine can effectively intervene to heal or prevent disease are blunt. We treat (and prevent) cancer by removing the affected (or potentially affected) tissue--hardly an elegant approach. Likewise, pharmacologic treatments for cancer are toxic and rife with the potential for adverse events. Our most common (and certainly most practical) solution for avoiding the birth of a fetus affected by a genetic disorder is to eliminate the fetus itself. Even strong supporters of abortion rights (like me) must admit that such "prevention" is a blunt instrument.

When one employs a blunt instrument, indications for its use must be compelling and carry a reasonable degree of certainty given the high potential (by definition) for collateral harm. Thus, as we seek to use genetic information in medical care, we must focus on those areas in which its predictive power is high.

The day may come when we can fine-tune an individual's risk for a host of both common and rare diseases. But until we have equally subtle--and safe--interventions, such fine-tuning of risk is of little practical use. Speculation that genetic risk assessment for common diseases will prove clinically useful anytime soon is illusory. The high absolute risks that we are all at for heart disease and cancer mean that even those with a reduced relative risk stand a very high chance of dying from heart disease or cancer. Moreover, common diseases have many contributing etiologies. Thus, even when we can eventually delineate the entirety of an individual's genetic risk for such diseases, this will still only account for a minority of their risk.

However, our ability to robustly query an individual's genome holds near-term promise in a different way--one that derives its power from a public health stance rather than that of the individual clinical encounter. If an individual's risk for a disease is high enough, then our blunt instruments can be effective. A case in point is the identification of a deleterious mutation in BRCA1 or BRCA2. Such mutations confer a high enough probability of disease that risk-reducing surgery or enhanced (but imperfect) surveillance are logical strategies. Likewise, the identification of those at very high risk for lethal cardiac dysrhythmias are at sufficient peril to benefit from our decidedly imperfect strategies for preventing adverse events (such as drugs and implantable automatic defibrillators). Doing the arithmetic reveals that roughly 1 percent of the population carries highly penetrant genetic lesions for which we currently have effective preventive strategies.

Thus, the true promise of personalized medicine may be realized only when it is implemented in a public health context. Such an approach isn't too different from the way we currently practice medicine, which is a far more incremental endeavor than we often care to recognize. For example, many patients taking cholesterol lowering medication would be shocked to learn that one needs to treat more than one hundred individuals with a statin to prevent a single death over a five-year span. This is not to say that such treatment isn't worthwhile. Indeed, by taking a public health approach to medical care, we save many lives.

The way to reap the fruits of genomic medicine in the near term may be by taking a population approach and recognizing that while most of us have little to gain from "personalized medicine," a few of us--now identifiable with the tools of modern genomics--have much to gain.

James P. Evans

University of North Carolina

at Chapel Hill

To the Editor: The essay set on personalized medicine in the September-October 2010 issue was well conceived, timely, and useful. It will find a place in our medical school's personalized medicine course. My attention was drawn especially to the excellent piece by Ronni Sandroff ("Direct-to-Consumer Genetic Tests and the Right to Know"). She provides a succinct but focused discussion of some of the most important problems with this recent laboratory marketing trend. But she also provides a superb object lesson by presenting herself as an example of the practical implications of increased awareness of the diagnostic and predictive opportunities in the genome era.

The clinical problem: parental origin of a Factor V Leiden mutation discovered in her daughter. Of course, Sandroff cannot offer us all the details of conversations surrounding this discovery. However, I would like to pose a few questions. It is not my intent to pry into things private, but to offer what for clinical geneticists and genetics counselors would have been a standard approach to the problem.

Is "you've lived with it this long" an adequate summary of her physician's response to the request for testing? Was nothing more trenchant said, or does this display the physician's actual subtlety of knowledge on this subject?

Was any discussion offered about the practical use of the information in absence of any (as yet) thrombotic events? Was there a discussion about greater care in management of known environmental factors such as smoking, hormone replacement, strategies for lengthy automobile or airplane rides, and prophylaxis in the event of major surgery? Was she encouraged to discuss, face-to-face, feelings of guilt that might attend discovery of such a mutation? Was a meaningful family history taken to explore likely sources of the mutation?

Was anything said about the other five genetic causes of thrombophilia? Does she know that it is not rare for a person with one of these factors to also have a second factor? Was her daughter tested for the others?

Once Sandroff was found not to be the source of the mutation, was a meaningful effort made to warn her ex-husband that he may be facing a serious health risk? What about his siblings and extended family?

Sandroff cites the dubious ethics of offering expensive vitamin supplements to people who have been found to "need" them for management of purported genetic risk factors. I offer another. Some direct-to-consumer labs offer phone interviews with genetic counselors. These counselors' job security may be at risk if, after their discussion, a client opts not to go forward with these unvalidated tests. This may constitute a conflict of interest.

Board-certified genetic counselors and clinical geneticists, in private practice or at an academic center, would not fill out paperwork for testing until the above questions had been explored. Sandroff has raised herself as an example of the dangers of a little bit of knowledge, thus making herself an advertisement for consulting with an unencumbered professional geneticist when thinking about genetic tests.

Robert Roger Lebel

SUNY Upstate Medical University

To the Editor: In "Personalized Medicine's Ragged Edge" (Sept-Oct 2010), Leonard Fleck correctly argues that genetic tests that refine the prognosis of a therapy for individual patients will not simplify or reduce dilemmas about resource allocation. Personalized medicine will provide no "thick, bright line separating minimal ... from maximal responders." He cites a Food and Drug Administration panel's recommendation to revoke approval for the use of Avastin for breast cancer, which costs roughly $100,000 per year for an apparent median life extension of only six weeks. The ragged edge, Fleck notes, is that for some genotype subgroups, Avastin's added benefit may be nearly two years: "Should the drug retain approval only for the small percentage of patients who are likely to benefit the most?"

Yes, genetically refined prognoses will confront us with difficult challenges about allocation and reimbursement, but these challenges should not be placed at the feet of the FDA. Because we in the United States are so loath to acknowledge--much less endorse--any explicit prioritizing of care, we fall into the trap of ceding such allocation decisions to the FDA. We don't have anything like the United Kingdom's National Institute of Clinical Effectiveness. Even Medicare's new advisory panel on comparative effectiveness research from the 2010 reform legislation was rendered practically toothless, and normally Medicare just covers any drug the FDA approves. To be sure, the logic of the FDA requirement to show effectiveness, not just safety, is sound: desperate patients would otherwise be exploited to buy all sorts of worthless stuff. That does not, however, make allocation the FDA's proper job. Its task is not to determine what ought to be included in a basic minimum of care to which people should have universal access. Drugs should be safe and somewhat effective to be marketed to anyone--rich or poor, insured or not, within or beyond the basic minimum, in fat plans or lean.

To be sure, the FDA properly faces a version of Fleck's "ragged edge" problem when it is confronted with evidence that a therapy is effective for certain genetic subgroups but not effective more generally, but the problem then is not difficult: approve the therapy for the effective subgroup and deny it for more general, ineffective use. That's not, however, the kind of FDA decision that Fleck cites.

Fleck's choice of FDA example is hardly surprising. In the context of a country like the United States, where all the other major health policy players seem to run as fast as they can away from prioritizing, the FDA gets pulled into being the allocator of last resort.

Paul T. Menzel

Pacific Lutheran University

Leonard M. Fleck replies:

Let me begin by thanking Paul Menzel for his thoughtful comments. I actually agree entirely with him. That is, I am not advocating that the FDA should have responsibility for addressing the "ragged edge" issue with regard to these expensive cancer drugs (or other comparable drugs for other conditions).

In rereading my essay, I found a couple of sentences that might suggest my support for that role for the FDA. But my view is that we need a broad, transparent, rational process of democratic deliberation to address these "ragged edge" issues. This is rationing, and it is inescapable. The minimal requirements for a fair rationing process are that it be visible and that rationing decisions be self-imposed. A broad public deliberative process will meet those conditions.

In the present hyperpartisan political climate, such a deliberative process might seem impossibly utopian. However, a deliberative process skillfully facilitated outside the media glare will diminish substantially the partisan rhetoric and move deliberators toward cooperative problem-solving. (The interested reader should see my essay in Wrestling with Behavioral Genetics [Johns Hopkins, 2005]). I see these deliberative groups spread across the entire United States. Their work ultimately needs to be brought to a legitimated conclusion through a NICE-like entity. I do not have the FDA as such in mind, in part because their advisory committees are comprised entirely of experts. I think I would prefer a national committee comprised of representatives from deliberative groups across the nation, with all manner of FDA-like expertise available to that deliberative body. However, the focus of the deliberations at all levels needs to be on the justice issues and other relevant values questions, which the medical and scientific issues are secondary to. If the deliberative process were expert-dominated, there would be no need for deliberative groups outside the FDA. Likewise, an expert-dominated decision would hardly represent an authentic form of self-imposed rationing. Both moral and political legitimacy would be lost in those circumstances.
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