Screening Student Athletes for Sickle Cell Trait — A Social and Clinical Experiment — NEJM

Screening Student Athletes for Sickle Cell Trait — A Social and Clinical Experiment
Vence L. Bonham, J.D., George J. Dover, M.D., and Lawrence C. Brody, Ph.D.

N Engl J Med 2010; 363:997-999September 9, 2010

On April 13, 2010, the legislative council for Division I of the National Collegiate Athletic Association (NCAA) approved mandatory testing for sickle cell carrier status (sickle cell trait) for all student athletes participating in Division I sports. Students are to begin being tested for the first season during which they are eligible to compete, and the new rule takes effect this academic year (2010–2011).1 NCAA data for the 2008–2009 academic year suggest that the requirement will ultimately affect more than 166,900 student athletes.

The NCAA program is the most extensive and high-profile sickle cell screening program instituted in the past 30 years. Like its predecessors, it is controversial and full of potential pitfalls, and there remain unanswered questions about its implementation and implications. But it provides an opportunity to evaluate the implementation of a genetic-based, personalized risk-prevention program. Given the program's extensive scope, the data needed to answer important questions about such programs could be obtained in short order.

The screening program resulted from the settlement of a lawsuit brought by the family of Dale Lloyd II against the NCAA and Rice University. Lloyd was a 19-year-old freshman at Rice when he died after a football practice in 2006. His death was attributed to acute exertional rhabdomyolysis associated with sickle cell trait. Lloyd's family took legal action in the hope of preventing other deaths.2

A 1995 review of nontraumatic sports-related deaths of high school and college athletes over a 10-year period included seven deaths attributed to exertional rhabdomyolysis associated with sickle cell trait.3 In the past decade, a number of deaths of college football players have been linked to sickle cell trait, including some deaths in athletes who were aware of their carrier status. In 2007, the National Athletic Trainers' Association and the College of American Pathologists recommended that colleges and universities consider screening athletes for sickle cell carrier status in an effort to save lives.

Sickle cell anemia was the first disease to be understood at the genetic level, but it remains a serious chronic disease for which early intervention is recommended. Newborns throughout the United States are screened for sickle cell anemia. But sickle cell carriers — who have inherited one S allele of β-globin and one normal allele — do not have overt sickle cell disease. Unless the trait is brought to light by a family history of sickle cell anemia or a carrier-screening program, most carriers and their families remain unaware of their status. There are an estimated 100 million carriers of hemoglobin S worldwide; in the United States, the more than 2 million carriers include roughly 8% of blacks, 0.5% of Hispanics, and 0.2% of whites. Thus, nearly all NCAA colleges and universities fielding multiple Division I teams will have students who test positive, and the screening program could identify 400 to 500 carriers each year.

Carriers are generally asymptomatic and have a normal life span but appear to be at increased risk for splenic infarction, renal medullary carcinoma, and exertional rhabdomyolysis, all of which are rare. Evidence suggests that the risk of exercise-related sudden death is 10 to 30 times higher among sickle cell carriers than it is among noncarriers. This risk is associated with a combination of conditions that are likely to be present in some college sports: heat exposure, dehydration, and intense physical activity.

In the 1970s, mass screening programs for sickle cell trait were established with the aim of benefiting individual health and assisting carriers in making informed reproductive decisions. Unfortunately, state government agencies, advocacy groups, and community-based organizations established these voluntary screening programs without appropriate foresight or provisions for education and counseling — and often caused confusion by disseminating misinformation regarding the difference between a diagnosis of sickle cell anemia and the presence of sickle cell trait.4 These programs were thought to do more harm than good5 and have since been abandoned or heavily modified.

Although the NCAA program differs in scope and purpose from earlier programs, it shares the potential for unintended consequences. Will the NCAA assist student athletes and their parents in making informed decisions regarding testing and in understanding the implications of the test results? Will the first-line test, hemoglobin solubility, be followed by a second test to eliminate false positives? What role will primary care providers play in screening and counseling? How will knowledge of their carrier status affect student athletes and their families? How will the athletic program and the institution protect the privacy of athletes who test positive? Surveillance and research aimed at understanding the program's effects on universities, athletes, and families will need to be conducted if inadvertent harm is to be avoided.

The experience of the U.S. armed forces provides an instructive example: a military screening program for sickle cell trait initially led to discrimination against carriers, who were banned from performing certain duties; when research revealed that the risks associated with carrier status could be eliminated with appropriate hydration and modification of training, the service restrictions were dropped. Key questions for the NCAA are whether equivalent interventions can reduce risk in student athletes with sickle cell trait and whether changing the practice and culture of college athletics by instituting prevention measures for everyone would be more beneficial than targeted interventions.

The NCAA's implementation of mandatory testing also raises questions unique to student athletes. For instance, are there special implications for the testing of minors? Can such tests be voluntary in the context of athletic scholarships? Are athletes in NCAA Divisions II and III at less risk, and if not, why are they exempt from testing? Will the athletic program and the university treat carriers differently from noncarriers? Will the screening program lead to stigmatization? Alter a student athlete's self-image? Affect his or her employability in professional sports?

The NCAA program is not a product of new knowledge or technology. The genetic and molecular underpinnings of sickle cell anemia have been understood for more than half a century, and clinical tests for carrier status have been commercially available since the early 1970s. But there is now great interest in genetic-based risk profiling and personalized medicine. Although the NCAA program shares some elements with these new approaches to care, it differs from them in many ways: the screening takes place outside the physician–patient relationship, the “patient” is undergoing testing because his or her genetic makeup may produce an adverse reaction in circumstances related to a chosen avocation, and the possible corrective “intervention” — modification of practice and training regimens — could require a shift in the culture of sports.

The screening program may also open the door to additional testing. Inherited cardiac arrhythmia and cardiomyopathy syndromes have been implicated as the most common nontraumatic cause of deaths among athletes.3 Because the genetics of arrhythmias are considerably more complex than the genetics of hemoglobinopathies, current tests for affected individuals are technically challenging to perform and interpret. Should the NCAA add tests when advances in DNA sequencing eliminate these technical hurdles? What criteria would be used in evaluating tests and expanding the program?

Although the NCAA program may be an enlightened first step toward ensuring the health and well-being of student athletes, it could easily become subject to some of the perils that troubled earlier programs. The fact the students can avoid the testing if they prove they have already been tested or sign a waiver releasing their university and the NCAA from liability suggests that it is designed primarily as a defensive legal measure. Perhaps it is best viewed as an experiment — one with possible ramifications for other associations, other screening programs, and sickle cell carriers worldwide. If it is indeed an experiment, the related data should be collected and analyzed rigorously, objectively, and transparently so that the costs and benefits of testing can be evaluated.

The opinions expressed in this article are those of the authors and do not necessarily reflect those of the National Human Genome Research Institute, the National Institutes of Health, or the Department of Health and Human Services.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Source Information
From the Social and Behavioral Research Branch (V.L.B.) and the Genome Technology Branch (L.C.B.), National Human Genome Research Institute, Bethesda, MD; and the Department of Pediatrics, Johns Hopkins University, Baltimore (G.J.D.).
Screening Student Athletes for Sickle Cell Trait — A Social and Clinical Experiment — NEJM