Sickle cell trait, exertion-related death and confounded estimates

Sickle cell trait (SCT) has historically been thought of as a benign condition. However, there has been increasing recognition that, in athletes, SCT is associated with an elevated risk for exertion-related death (ERD). With the hope to minimise future tragedies, Harmon et al sought to quantify the association of SCT and ERD. They looked at data compiled on nearly two million collegiate ‘athlete-years’ between 2004 and 2008. Since the risk associated with SCT was highest among Division 1 (D1) football players, the authors elected to focus on that group. Their highlighted conclusions, ‘Sickle cell trait associated with a RR of death of 37 times...’, are now being referenced in discussions regarding SCT testing. 4 Others may have concerns about generalising results from D1 athletes to all athletes or lack of discussion about the small number of deaths (from a statistical standpoint) and thus uncertainty surrounding the results. Our concern is that the conclusions based on combining data from all race/ethnicities are not meaningful because of confounding bias secondary to race/ethnicity. Among the D1 footballers, the researchers found 1 ERD in every 827 athlete-years in those who had SCT. Although the issue of race/ethnicity is an uncomfortable topic, given the known association of SCT and African-American race/ethnicity (referred to as ‘Black’ in the article), the researchers wisely analsed the data separately for ‘Black’ athletes and for ‘non-Black’ athletes. However, they subsequently combined the information from ‘all ethnicities’ and in their conclusions highlighted the relative risk (RR) of SCT from the combined data. Combining the data introduced confounding by race/ethnicity and biased the association of SCTwith ERD. Whether biological effect modification was also present cannot be evaluated because the small number of events makes any stratumspecific estimate unreliable. Table 1 highlights the pertinent numbers from the analysis. Among the Black D1 football players, SCT was associated with a 22-fold higher risk of ERD. However, among the non-Black players, only one ERD occurred, and that was in an athlete who did not have SCT. It is therefore impossible to conclude that SCT is a risk factor in the non-Black players. As seen in table 1 under the heading of ‘All Ethnicities’, when the numbers within all race/ethnicity strata are combined, it now appears that those with SCT are at a 37-fold higher risk. The reason to question the increase in RR from 22 (in the Black athletes) to 37 when adding athletes who are not at risk of ERD is because the results based on combining the data from all D1 footballer players are confounded by race/ethnicity.