Sun exposure and longevity: a blunder involving immortal time

Unfortunately we have to start this Editor’s Choice with an acknowledgment that we have fallen prey to a common, perennial problem; immortal time bias. To illustrate the concept we borrow an example from William Farr, as used by James Hanley and Bethany Foster in a full and entertaining exposition of the problem in this issue of the journal. Generals and bishops live longer than corporals and curates—but this is not necessarily because an elevated occupational status makes you live longer—it may simply be because you have to reach a certain age before it is possible to hold such positions. People become generals and bishops in middle age so their deaths arise after this point in time, whereas corporals and curates can die at any age above 20 or so. This difference in time during which an event can occur to one group but not the other produces a bias favouring longer life expectancy— immortal time bias. In the figure on the next page, the problem is evident at a glance (Figure 1). In the October issue of the International Journal of Epidemiology (IJE) last year, we published a paper by Peter Brøndum-Jacobsen and colleagues in which they examined the effects of sunlight exposure on mortality among the whole population of Denmark aged above 40 years, using linked data from national registries. They used non-melanoma skin cancer as a proxy for sun exposure, which is a clever idea but it should have been obvious that the findings were ‘too good to be true’—an apparent halving of all-cause mortality and reductions in myocardial infarction and hip fracture. The authors concluded: ‘Causal conclusions cannot be made from our data. A beneficial effect of sun exposure per se needs to be examined in other studies’. The Danish media picked up the story and it became front page news—‘Sunbathers live longer’. Although the authors never made this claim in their published paper, their interviews with the press did not appear to emphasize their non-causal conclusion. The Danish Cancer Association claims that this paper has undone all their good work in persuading Danes to keep out of the sun to avoid skin cancers. Commentators on the story identified a likely problem of immortal time bias. People in the ‘sun exposure’ group had to live long enough to be diagnosed with skin cancer but the comparison group only had to be over 40 years old—the design of the study had built in a potential bias in favour of longevity among those presumed to be more highly exposed to sunlight. Theis Lange and Neils Keiding, in a letter commenting on the paper, pose questions about how such highly improbable findings got through the editorial process at IJE. In response to this criticism, Brøndum-Jacobsen and colleagues argue that their paper used both cohort and case-control analyses, and that the latter should be free from immortal time bias as cases and controls were matched on age. They acknowledge that the case-control analyses—which showed much smaller survival advantage [odds ratio (OR): 0.97, 95% confidence interval (CI) 0.96 to 0.99; vs hazard ratio (HR): 0.52, 95% CI 0.52 to 0.53] —should have been included in their abstract. In addition, they conducted a revised Cox proportional hazards analysis stratified by 10-year, 5-year and 2-year age strata in an attempt to control for immortal time bias, and interpret these findings as similar to those in their original paper. However, they fail to stress that the effect sizes become increasingly attenuated as the age matching becomes more exact, suggesting that the apparent effect of sun exposure may indeed be produced by immortal time bias. Ironically, in parallel with the review and publication of this paper we had commissioned an ‘Education Corner’