Development of reference ranges in elite athletes for markers of altered erythropoiesis

Our previous research developed two statistical models that are useful indicators of current (ON-model) or recently discontinued (OFF-model) recombinant human erythropoietin (rHuEPO) use by athletes. The component variables of the ON-model are hematocrit (Hct), reticulocyte hematocrit (RetHct), serum erythropoietin (EPO), percent macrocytes (%Macro), and soluble transferrin receptor (sTfr), whilst the OFF-model uses only the first three variables. Genetics and training modalities of elite athletes may conceivably produce unusual values for blood parameters related to erythropoiesis. The aims of this study were to develop reference ranges in elite athletes for key hematologic parameters as well as ON- and OFF-models scores, and to evaluate the effect of ethnicity, gender, residence at moderate altitude (approximately 2000 m) and within-individual variation on the variables and model scores.

Over a period of three weeks, 413 female and 739 male elite athletes from 12 countries visited laboratories to provide three blood samples for analysis of blood parameters sensitive to erythropoiesis. For each parameter and for the ON- and OFF-model scores, we used mixed modeling to establish the range within which we could be 95% certain that the value for a randomly chosen athlete would fall, taking into account various random effects (variation within and between subjects and laboratories) and fixed effects (means for different levels of ethnicity, age, sport, altitude of residency). We performed similar analyses for changes in the ON- and OFF-model scores between the three visits.

Most fixed effects were accompanied by clear-cut, small to moderate differences in several parameters. However, residency at moderate altitude was accompanied by a much higher hematocrit than residency nearer sea level, with the mean (and 95% confidence limits) for the difference being 2.3 (0.9 to 3.7) and 1.8 (0.1 to 3.5) units for males and females, respectively. Males at altitude also demonstrated a moderately higher ON-model score. Otherwise the influence of these effects was small for ON-, OFF- and changes in model scores.

Assessment of an athlete's blood parameters and ON- and OFF-model scores may need adjustment for training modalities and other characteristics of the subject. Changes in model scores (together with monitoring of urine samples for the presence of rHuEPO) provide a promising approach to detection of rHuEPO abuse, because they are less sensitive to subject characteristics and less variable than raw model scores.