Thursday, November 20, 2008
Race and the clinical exam
In the last several months it has become increasingly clear that I am guilty of racial profiling. Before you get too upset with me, consider the following behavior: if I see a patient considering pregnancy, and they appear to be Caucasian, I am far more likely to discuss screening for cystic fibrosis carrier status than sickle cell disease. Rarely do I ask the question formally: "With what racial group do you identify?" before I make this decision. Rarely do I discuss the decision process with my patients. I suspect that I am not alone.
What should the health care provider do in light of emerging understanding of race and ethnicity?
"Racial profiling" is reinforced by many national care guidelines, and is embedded in the training of health care providers from their first course in physical diagnosis. The conscious and sub-conscious binning of individuals by observed physical characteristics is one way to estimate an individual's personal probability of having certain diseases. Assessment of individuals through the lens of a population sub-group occurs at many junctures in the care delivery process, and rests on epidemiologic data demonstrating that disease prevalence varies among population groups.
The logic supporting such an approach is as follows: Particular sub-populations are at higher risk for certain conditions. Effectively distinguishing the sub-population to which an individual belongs helps to define that individual's probability of developing a given diagnosis. Accurate assignment of risk brings parsimony to the processes of prevention efforts, screening, differential diagnosis formulation, diagnostic workup and, potentially, therapeutic intervention. 
The binning of individuals by race and ethnicity is only one of a variety of discriminators health care providers routinely employ. The utility of binning individuals depends heavily on the quality of the determinants used to separate populations, and while age and gender are arguably fairly clear-cut, less controversial biological discriminators of disease risk, race and ethnicity are most certainly not.
The wealth of accumulating DNA sequence data from multiple individuals representing multiple population groups reveals that our understanding of human genetic variation is only rudimentary. Accompanying this realization is a growing acceptance that current definitions of race and ethnicity are poor proxies for estimating the genetic component of individual disease risk.
The bottom line is that the DNA of the U.S. population defines the cliche: We are a melting pot. Genetic variability is, in fact, greater between unrelated individuals than it is between racial and ethnic groups. Currently accepted racial and ethnic categories are a blur genetically, and drawing clinically useful boundaries for the purposes of assigning individuals to a group is quite difficult.
What effect does this have on clinical care? Fundamentally, it causes errors in assignment of risk because using self-defined race and ethnicity may over or under estimate actual risk. This can result in harms in a variety of ways, but most commonly as a consequence of providing too little (or too much) care.
How might the issue of assigning individual genetic risk in the setting of complex genetic ancestry be resolved? Options include eliminating the use of race and ethnicity as a consideration when deciding whether to offer genetic testing for disease risk or diagnostic purposes. The prototypical example of this approach can be found in the example of cystic fibrosis carrier screening, where the most recent guidelines suggest genetic screening should be offered in the prenatal setting to individuals of all races and ethnicities. Though in the case of cystic fibrosis screening this approach offers increased sensitivity, screening a larger population clearly results in increased costs.
Another approach would be to use genetic markers as a pre-test for the ancestry of regions of DNA harboring potential deleterious gene mutations of interest and then to base genetic testing on this ancestral determination. This could be practical when genetic tests are expensive and knowledge of the ancestral derivation of the DNA would determine the most cost-effective testing strategy. An example would be choosing between targeted mutation testing and full sequencing of the BRCA 1 and BRCA 2 genes in hereditary breast and ovarian cancer syndrome in an individual that might or might not be of Ashkenazi Jewish ancestry. However, such a genetic pre-test would amount to the morally tenuous use of genetic tests for racial and ethnic profiling.
Clearly neither of these approaches is fully satisfying. The best solution would be the advent of extremely low-cost full genome sequencing techniques that would reveal the entirety of an individual's genetic variation. This sequence information would allow an individual's care to be based on their own genetic variations rather than crude estimation of genetic risk. Of course this requires not only the availability of low-cost sequencing (which seems possible in the relatively near term) but an understanding of how the individual's genetic variants interact with each other and the environment to cause disease, a topic for more research and another column.
What should the health care provider do in light of emerging understanding of race and ethnicity? First, re-examine your own preconceptions regarding race and ethnicity, and how you use them in your practice. You may find that you are doing your patients a disservice. Second, take an appropriate family history, including the ancestral origins of the patient's grandparents. Third, if you use an individual's self-identified race/ethnicity in medical decision making, particularly with regard to genetic testing, recognize that the information provided you is less reflective of genetic variation than previously thought.
Patients should understand that we have much to learn about genetic variation, and that our current methods for selecting individuals for genetic tests as well as test interpretation are far from perfect. Finally, if you are an educator, examine how you teach your students and trainees to think about approaching the evaluation of patients. Make sure that they understand what genomics is revealing about how genetic variation in individuals and in populations relate to one another. With a firm grounding and the current pace of genomic discoveries, they will likely be the generation that resolves the controversies surrounding the use of race and ethnicity in health care.
W. Gregory Feero, MD, PhD, a family physician with a doctorate in human genetics, is senior adviser for genomic medicine in the Office of the Director at the NIH's National Human Genome Research Institute. His column runs every issue in ACP Internist.
Labels: genetics, genomics, Practical Genomics
posted by W. Gregory Feero, MD, PhD at
3:03 PM
2 Comments
Thursday, August 14, 2008
Genomics making warfarin easier to manage
Warfarin is a very challenging drug to prescribe and manage. Not only is the therapeutic window narrow, but achieving the correct dose and maintaining a stable international normalized ratio (INR) for patients can be problematic. Any reasonably cost- and time-effective improvement in warfarin management would be welcomed by most clinicians.
Over the last several years new genetic tests for variants in the CYP2C9 and VKORC1 genes have been developed that predict a substantial component of warfarin metabolism. Many scientists and academic health care providers feel that prospective use of these tests may save lives and health care resources. To date, several small studies comparing the use of genetic testing to standard of care have produced mixed results. There may be evidence for reduced use of blood draws for INRs and office visits, but no large trial has demonstrated a mortality benefit. The FDA has altered warfarin's labeling to reflect this new information.A number of companies and health care systems already have geared up to offer warfarin pharmacogenetic tests with a rapid turn-around time. The National Heart, Lung and Blood Institute of the National Institutes of Health started a major trial of warfarin pharmacogenetic testing through the University of Pennsylvania, which should greatly enhance our understanding of the clinical utility of such tests.
Interestingly, the Centers for Medicare and Medicaid Services opened a National Coverage Analysis (NCA) of the topic. The public comment for this NCA runs until Sept. 3. For some in the personalized medicine community, this NCA is viewed as a critical test case of personalized medicine predicated on genomic information. Perhaps this overstates the situation. It probably is best viewed as an opportunity for a much-needed dialogue between supporters of personalized medicine and evidence-based medicine.
Will the nation's largest health care payer accept the current evidence supporting the use of warfarin pharmacogenetic testing in routine care? A recent review using the Rapid ACCE format by McClain et al. raised serious concerns regarding gaps in the current evidence base. However, this is a rapidly moving field and more data are now available.
In a time of rapid advances in genetics and genomics and spiraling health care costs, any significant "evidentiary gap" will be increasingly problematic for promising and potentially very significant improvements in standard of care. Substantial resources should be directed at re-tooling our research and health care delivery systems to rapidly and responsibly generate the types of effectiveness data needed to separate the wheat from the chaff in genomics, and more broadly, all emerging health care technologies.W. Gregory Feero, MD, PhD, a family physician with a doctorate in human genetics, is senior adviser for genomic medicine in the Office of the Director at the NIH's National Human Genome Research Institute. His column runs every issue in ACP Internist
Labels: genetics, genomics, Practical Genomics
posted by W. Gregory Feero, MD, PhD at
9:14 AM
2 Comments
Thursday, July 10, 2008
The long arm of your chromosomes and the law
A great debate is raging in the wider genetics community that is directly relevant to day-to-day internal medicine. In the last three years, the advent of genome-wide association studies has facilitated the discovery of more than 180 markers for risk of a growing list of common chronic diseases, including cancers, diabetes, coronary heart disease and Alzheimer's. In the last six to nine months, a number of companies have moved to make these markers directly available to consumers in the form of genome-wide scans that can be obtained over the Internet for between $1,000 and $2,500, and several are seeking to lower that price point drastically.
The companies qualify that all test results provided to the consumer are preliminary in nature and that their products represent information, rather than medical advice. However, after looking at these companies' Web sites, one could conclude that the companies--implicitly or explicitly--suggest to consumers that they might use the results to improve their health. There is no direct evidence that providing patients with genetic risk information from genome-wide association studies improves health outcomes, though, importantly, this is very likely to change in the next few years.Yet, there are reports--many provided by the testing companies themselves--that patients are bringing their results to health care providers with the expectation that some form of action be taken to mitigate their newly discovered disease risk. However, beyond selected anecdotes, we know little about what providers are doing with the information patients bringing them.
Though direct to consumer (DTC) testing for traditional genetic conditions (think hereditary breast cancer and ovarian cancer syndrome) has been around for a number of years, the sophistication, scale and potential reach of this new crop of offerings has raised the interest of both state and federal regulatory bodies. Not unexpectedly, these companies have also been subject to intense criticism from the scientific and medical communities. The central theme of those voicing concerns is that the health care implications of this embryonic realm of genetic testing is unknown at this time and that potential harms could result from either over-, under- or misinterpretation of test results.
In the last few months, the intensity of the debate has ratcheted up. The state of California sent cease-and-desist letters to 13 concerns offering DTC genetic services to California residents. The letter stipulated, among other things, that the companies need to offer their tests through Medicare approved, CLIA certified labs and that a licensed physician needs to be involved in ordering the test. At the federal level, there is ongoing Congressional scrutiny of the topic, evidenced by a June 12, 2008 roundtable held by Senator Gordon Smith of the U.S. Senate Special Committee on Aging. On July 7 and 8 a committee that advises the U.S. Secretary of the Department of Health and Human Services on issues surrounding genetics/genomics examined this issue in some depth. From these proceedings it is clear that there are widely divergent opinions on the topic of DTC availability of genome-wide scans.
Interestingly, this scrutiny has brought an unexpected windfall to those of us in primary care. Individuals from the most technology-driven reaches of medicine are discussing the need for increased research on determinants of health behaviors and a re-evaluation of how our current system values preventive interventions.
The core questions confronting DTC genetic testing are not new to medicine, nor even genetics/genomics: first, when is a new technology ready for clinical use; and second, how much regulation is appropriate to ensure its safe and effective application while fostering innovation and minimizing risk of disparities?
One side of this debate argues strongly that consumers should be empowered with every bit of information about their health possible, and that to deny them direct access to their genetic makeup through overly strict regulation is old-fashioned and paternalistic. The other side argues that this type of genome-wide scanning is still a research tool. Consequently, offering it DTC at this point in time in a loosely regulated manner may substantially mislead the public and health care providers, incurring costs both in terms of morbidity and scarce health care resources.
Both sides have valid points. The American Medical Association and the American College of Medical Genetics have taken note of the new DTC movement and have developed official positions critical of DTC genetic testing. It is unclear what effect these statements will have on the entities offering this type of testing. What is clear is that much hinges on consumer demand and opinion--and to some extent the ability to shape that demand rests in the hands of health care providers like you. The best two pieces of wisdom at this juncture? First, patients should consider involving their health care provider prior to undergoing any DTC genetic test. Second, patients should hold off for now on getting a genome-wide scan for health care purposes. At present we know far too little about how to use this information to promise or imply benefit.W. Gregory Feero, MD, PhD, a family physician with a doctorate in human genetics, is senior adviser for genomic medicine in the Office of the Director at the NIH's National Human Genome Research Institute. His column runs every issue in ACP Internist
Labels: genetics, genomics, Practical Genomics
posted by W. Gregory Feero, MD, PhD at
11:02 AM
0 Comments
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