Flexible Modeling of the Association Between Cumulative Exposure to Low-Dose Ionizing Radiation From Cardiac Procedures and Risk of Cancer in Adults With Congenital Heart Disease

Abstract

Adults with congenital heart disease are increasingly being exposed to low-dose ionizing radiation (LDIR) from cardiac procedures. In a recent study, Cohen et al. (Circulation. 2018;137(13):1334-1345) reported an association between increased LDIR exposure and cancer incidence but did not explore temporal relationships. Yet, the impact of past exposures probably accumulates over years, and its strength may depend on the amount of time elapsed since exposure. Furthermore, LDIR procedures performed shortly before a cancer diagnosis may have been ordered because of early symptoms of cancer, raising concerns about reversal causality bias. To address these challenges, we combined flexible modeling of cumulative exposures with competing-risks methodology to estimate separate associations of time-varying LDIR exposure with cancer incidence and all-cause mortality. Among 24,833 patients from the Quebec Congenital Heart Disease Database, 602 had incident cancer and 500 died during a follow-up period of up to 15 years (1995-2010). Initial results suggested a strong association of cancer incidence with very recent LDIR exposures, likely reflecting reverse causality bias. When exposure was lagged by 2 years, an increased cumulative LDIR dose from the previous 2-6 years was associated with increased cancer incidence, with a stronger association for women. These results illustrate the importance of accurate modeling of temporal relationships between time-varying exposures and health outcomes.

Keywords: cancer epidemiology; competing risks; splines; time-varying exposure.

Figure 1.

Estimated weight functions (dotted-dashed lines) and pointwise 95% bootstrap confidence intervals (shaded areas) for associations between the logarithms of past doses of low-dose ionizing radiation exposure and cancer incidence (A) and all-cause mortality (B) among persons with congenital heart disease (2-year-lagged analysis), Quebec, Canada, 1995–2010.

Figure 2.

Estimated weight functions (dotted-dashed lines) and pointwise 95% bootstrap confidence intervals (shaded areas) for associations between the logarithms of past doses of low-dose ionizing radiation exposure and cancer incidence (left panels) and all-cause mortality (right panels) for men (A and B) and women (C and D) with congenital heart disease (2-year-lagged analysis), Quebec, Canada, 1995–2010.

Figure 3.

Adjusted hazard ratios from the final model (2-year-lagged analysis of associations between the logarithms of past doses of low-dose ionizing radiation (LDIR) exposure and cancer incidence) for selected hypothetical patterns of LDIR received at 2 different times in the past 9 years, relative to patients with no LDIR procedures in the past 9 years, among men (A) and women (B) with congenital heart disease, 1995–2010.