Importance of accounting for timing of time‐varying exposures in association studies: Hydrochlorothiazide and non‐melanoma skin cancer

Abstract

PurposeHydrochlorothiazide (HCTZ), a widely prescribed antihypertensive drug with photosensitising properties, has been linked with non‐melanoma skin cancer (NMSC) risk. However, previous analyses did not fully explore if and how the impact of past HCTZ exposures accumulates with prolonged use and/or depends on time elapsed since exposures. Therefore, we used different models to more comprehensively assess how NMSC risk vary with HCTZ exposure, and explore how the results may depend on modeling strategies.MethodsWe used different parametric models with alternative time‐varying exposure metrics, and the flexible weighted cumulative exposure model (WCE) to estimate associations between HCTZ exposures and NMSC risk in a population‐based cohort of HCTZ users over 65 years old, in the province of Ontario, Canada.ResultsAmong 3844 HCTZ users, 273 developed NMSC during up to 8 years of follow‐up. In parametric models, based on all exposures, increased duration of past HCTZ use was associated with an increase of NMSC risk but cumulative dose showed no systematic association. Yet, WCE results suggested that only exposures taken 2.5–4 years in the past were associated with the current NMSC hazard. This finding led us to re‐define the parametric models, which also confirmed that any HCTZ dose taken outside this time‐window were not systematically associated with NMSC incidence.ConclusionsOur analyses illustrate how flexible modeling may yield new insights into complex temporal relationships between a time‐varying drug exposure and risks of adverse events. Duration and recency of antihypertensive agents exposures must be taken into account in evaluating risk and benefits.

Assessing cumulative effects of medication use: New insights and new challenges

“…9 By improving the model's fit to data, WCE analyses may help detect an association missed with simpler models, especially if drug exposure in different time intervals is associated with either increased or decreased current risks. 8,12,13 By revealing such complex cumulative effects, WCE results may also help understand the reasons for possibly contradictory results of some earlier studies. 13 Furthermore, WCE estimates help quantify how the risks vary depending on drug use patterns.…”

“…Equally salient is the fact that some real-world applications confirm specific practical advantages of flexible spline modeling. Indeed, for different drug-outcome associations, a variety of weight function shapes were estimated, including complex nonmonotone curves with bi-modal 11 and delayed 12 effects, as well as the inverted S-shaped curve suggesting risk increases for recently initiated exposures but decreases associated with long-term use. 13 Importantly, for all these complex functions substantive experts proposed potential explanations.…”

“…13 Importantly, for all these complex functions substantive experts proposed potential explanations. [11][12][13] Thus, flexible WCE modeling can help generate new hypotheses regarding the mechanisms underlying the observed cumulative effects of different drugs. Of course, ideally, further replication studies should help assess whether the conjectures suggested by WCE estimates are robust.…”