The population selection flowchart is presented in Fig. 1. Since NHIS-EC was an administrative claim data, we could not apply formal diagnostic criteria of the International RLS Study Group [5 (link)] to identify patients with RLS. Instead, the presence of RLS was defined using the ICD-10 code G25.8. For diagnostic accuracy, patients with RLS were defined as those who had been diagnosed at least twice with this code (n = 5940). Meanwhile, RLS-free controls were defined as those who were never diagnosed with this code (n = 538,046). Among the 5940 patients with RLS, we excluded those diagnosed with dementia before the first diagnosis of RLS (n = 586) and the second diagnosis of RLS (n = 4). Considering the gradual onset of dementia, the minimal gap between the onset of RLS and any type of dementia was set at 2 years to minimize detection bias. Therefore, patients with RLS who were first diagnosed between 2012 and 2013 (n = 2361) or diagnosed with dementia within 2 years after RLS diagnosis (n = 329) were excluded. Additionally, patients with RLS in 2002, the first observation year of the NHIS-EC, were excluded due to the possibility that their first diagnosis was made before the observation period (n = 22). The patients were matched to controls in a maximum 1:4 ratio based on age, sex, and index date. Finally, 2501 patients with RLS and 9977 matched controls were included in the analysis.

Flowchart of study population selection

Abbreviations: NHIS-EC, National Health Insurance Service-Elderly Cohort; RLS, restless leg syndrome

All-cause dementia was defined as AD (ICD-10 F00 or G30), VaD (ICD-10 F01), and other types of dementia (ICD-10 F02, F03, F10.7, G23.1, G31.0, G31.1, G31.2, or G31.8). Dementia patients were defined as those diagnosed at least twice with the relevant ICD code(s) to minimize the possibility of over-classification of cases due to using ICD codes instead of formal diagnostic criteria. If patients had ICD codes of both AD and VaD, we classified these patients into VaD as a primary diagnosis following a previous study using the same database [27 (link)]. Among all-cause dementia cases (n = 874), 54.4% (n = 475) was AD, and 22.2% (n = 194) was VaD, which was consistent with the general epidemiology of dementia in South Korea [28 ]. Patients with other types of dementia were not analyzed separately because of heterogeneous disease entities and small sample sizes.
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