Measurement error case series models with application to infection-cardiovascular risk in older patients on dialysis

Infection and cardiovascular disease are leading causes of hospitalization and death in older patients on dialysis. Our recent work found an increase in the relative incidence of cardiovascular outcomes during the ~30 days after infection-related hospitalizations using the case series model, which adjusts for measured and unmeasured baseline confounders. However, a major challenge in modeling/assessing the infection-cardiovascular risk hypothesis is that the exact time of infection, or more generally "exposure," onsets cannot be ascertained based on hospitalization data. Only imprecise markers of the timing of infection onsets are available. Although there is a large literature on measurement error in the predictors in regression modeling, to date, there is no work on measurement error on the timing of a time-varying exposure to our knowledge. Thus, we propose a new method, theme asurement error case series (MECS) models, to account for measurement error in time-varying exposure onsets. We characterized the general nature of bias resulting from estimation that ignores measurement error and proposed a bias-corrected estimation for the MECS models. We examined in detail the accuracy of the proposed method to estimate the relative incidence of cardiovascular events. Hospitalization data from the United States Renal Data System, which captures nearly all (>99%) patients with end-stage renal disease in the United States over time, are used to illustrate the proposed method. The results suggest that the estimate of the relative incidence of cardiovascular events during the 30 days after infections, a period where acute effects of infection on vascular endothelium may be most pronounced, is substantially attenuated in the presence of infection onset measurement error.