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Editorial |
Department of Pathology, University of Utah, Salt Lake City, Utah
Address correspondence to the author at: Department of Pathology, Intermountain Medical Center, 5252 So. Intermountain Dr., P.O. Box 57970, Murray, UT 84157-0970, E-mail sterling.bennett{at}imail.org
"There’s nothing to winning, really," said Alfred Hitchcock. "That is, if you happen to be blessed with a keen eye, an agile mind, and no scruples whatsoever" (1). W.C. Fields put it a different way, "A thing worth having is a thing worth cheating for" (2).
Another Olympic year is here. Although neither of the aforementioned was referring specifically to the Olympic Games, one need not look far to find athletes, trainers, coaches, and sports executives who subscribe to a win-at-all-costs philosophy (3). As in the past, the idealism of this year’s Olympics will likely be diminished by disqualifications and revocations of medals for the use of prohibited substances and practices (4).
For more than a century, the modern Olympic Games have fueled a quest for excellence through a quadrennial pageant of athletics and nationalism, providing the world a transient common focus while turning the victorious into enduring heroes. Winning is no longer the domain of discipline, effort, desire, and innate ability—it also takes science. Scientifically driven improvements in training, facilities, equipment, and nutrition have such an impact on performance that world records now seem to have a shorter half-life than many RIA laboratory isotopes. Unfortunately, science is also the basis for doping and for activities designed to thwart its detection. Well might the Olympic motto "Citius, Altius, Fortius" (swifter, higher, stronger) apply to doping activists (5).
After a highly publicized doping scandal in cycling in the summer of 1998, the International Olympic Committee convened the World Conference on Doping in Sport. An outcome of this conference was the establishment of the World Anti-Doping Agency (WADA)1 in 1999, a foundation operated with the support and participation of the Olympic Movement, public authorities, governments, and other bodies fighting doping in athletics (6). WADA maintains the Prohibited List of banned substances, including specified anabolic agents, hormones, hormone antagonists, β-2 agonists, stimulants, narcotics, cannabinoids, glucocorticoids, alcohol, and β-blockers (4). Some substances are banned only during competition; others are banned at all times. The Prohibited List also includes banned methods such as blood doping, synthetic oxygen carriers, and gene doping. In addition, diuretics, masking agents, and other forms of specimen tampering are prohibited.
The front line of the antidoping movement is the laboratory. National antidoping agencies are required to use laboratories accredited by WADA in accordance with the International Standard for Laboratories regarding chain-of-custody procedures, quality assurance programs, proficiency testing, analytical methods, and ongoing research for test optimization (7). Most antidoping testing is aimed at the direct detection of banned substances using analytic methods that include gas chromatography, liquid chromatography, mass spectrometry, tandem mass spectrometry, isotope ratio mass spectrometry, isoelectric focusing, and immunoassays (8).
Despite the wide array of rigorous laboratory assays, some types of doping are difficult to detect by direct methods (8)(9). Recombinant human growth hormone (GH) is believed to be a widely used doping agent, favored by athletes for its perceived anabolic effects, lack of major side effects if well dosed, and most importantly, difficulty of detection due to its short half-life in blood, variable blood concentrations, and very low urine concentrations (9). In the late 1990s, the GH-2000 Study Group, supported in part by grants from the International Olympic Committee and the European Union, conducted studies on the effects of GH administration on the insulinlike growth factor (IGF) axis and markers of bone and collagen turnover, with the hope that GH doping would reveal itself in patterns of test results among the large number of biomarkers influenced by GH, providing the basis for an indirect method of GH doping detection (10)(11)(12)(13). Their studies identified statistically significant differences in the responses of several biomarkers to GH administration vs placebo, including some that persisted up to 8 weeks after withdrawal of GH. Although these results appeared promising, GH dosing in the studies was supraphysiological but not to the extremes reportedly used by some athletes, the studies were performed on healthy or conditioned adults but not elite athletes, and the ability to accurately discriminate between treatment and placebo groups degraded quickly after GH withdrawal. Ultimately, an international panel of endocrinologists concluded that the evidence did not support implementation of an indirect method for GH doping screening, so the focus shifted to development of direct methods for detecting GH doping (9).
Beginning in 2004, a direct immunoassay method for detecting recombinant GH, based on the suppression of endogenous isoforms by the recombinant isoform, has been used during the Olympic Games and some other major events. Although this test represents an improvement over no testing, it has yet to identify any positive cases (14). The test is severely limited by a 24- to 36-h window of detectability after GH injection and by an inadequate supply of reagents to support frequent out-of-competition testing (9)(15). Consequently, GH doping in the off-season can easily go undetected. Furthermore, the direct assay is not designed to detect efforts to stimulate overproduction of endogenous GH by amino supplements such as arginine, ornithine, lysine, and tryptophan (9). Thus, an indirect method for detecting GH doping remains desirable.
In this issue of Clinical Chemistry, Nguyen and colleagues have resurrected the hunt for an accurate indirect method for GH doping detection using 6 IGF axis and collagen markers (16). The principal aim was to determine the within-subject variances of the markers relative to the between-subject variances in elite athletes, without respect to exercise, training, food intake, or time of day; that is, conditions under which specimens for doping control would be collected. Applying Bayesian methods to these statistics, the authors calculated confidence intervals for individual measurements to assess whether the values were "probably" within the limits expected in the nondoping population of elite athletes. Compared with earlier studies, the study by Nguyen and colleagues makes two important contributions. First, it provides reference values for 6 markers in elite athletes, forming a much more credible basis for assessment than values from other populations. Second, it introduces a technique for generating a probability of doping rather than a simple yes/no answer. By its nature, an indirect method is inferential, consisting of the assessment of the likelihood of a set of assumptions based on a set of observations. So it seems fitting that the result of an indirect method would be a probability or a confidence interval rather than a mere categorical answer.
Nevertheless, the study raised more questions than it answered. Is long-term within-subject variation larger than the short-term variation reported in the article? If so, how are the probability calculations affected? How should decision limits be selected for a probabilistic screening protocol? What level of confidence is required? Are the wide confidence intervals evident in the article capable of detecting GH doping? Can single-sample screening be used or will a multisample protocol be required? Can an indirect method be developed that is sufficiently reliable to be the basis for sanctions? Is the best role for an indirect method the identification of "high-risk" athletes who then become subject to more intensive scrutiny? Can the validity of an indirect method be established without a controlled trial (and what elite athlete would openly subject himself or herself to a prohibited substance to participate in the trial)? These and related questions form the basis for an extension of Nguyen et al.’s work.
Clearly, much remains to be done before a robust indirect method for GH doping becomes reality, but the pursuit is worthy, not only for GH but for doping control in general. Although direct methods will undoubtedly continue to be the mainstay of doping detection, there is a place for indirect methods. Because every legitimate medical advancement, drug, and piece of knowledge has the potential for abuse, because designer drugs can be manufactured and distributed easily, and because these abuses can be implemented much more quickly than specific assays can be developed and validated, indirect monitoring using biomarkers may be the only way to get ahead of the curve by, if nothing else, raising suspicion of doping to form the basis for more intensive monitoring of selected athletes (8).
Oscar Wilde commented, "One should always play fairly when one has the winning cards" (17). But as long as winners are recipients of praise and lucrative endorsements, it seems highly likely that some athletes without the "winning cards" will succumb to the temptation to cheat. Advancements in the laboratory sciences—a little here and a little there—will continue to help preserve the honor of clean athletes and the Olympic ideal of fair play (5).
Acknowledgments
Grant/Funding Support: None declared.
Financial Disclosures: None declared.
Footnotes
1 Nonstandard abbreviations: WADA, World Anti-Doping Agency; GH, human growth hormone; IGF, insulinlike growth factor. 
References
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