**1. Introduction**

Stroke is a major cause of death and disability [1–3]. In the United States, the annual incidence of stroke is approximately 795,000, of which approximately 610,000 are firstever stroke events, and 185,000 are recurrent stroke events [1]. In the European countries, there were 2.3 million new cases diagnosed with stroke and 20.4 million people living with stroke in 2017 [4]. Obesity is an important risk factor for cardiovascular disease (CVD) [5–9] and is reported to be associated with a greater incidence of stroke [10–12]. Conversely, underweight is also associated with a higher risk of several CVDs and adverse clinical outcomes [13–15]. However, the data on the risk of underweight with incident stroke are scarce. Moreover, stroke can be categorized into two types, ischemic stroke, and hemorrhagic stroke; additionally, the pathology of these two subtypes should be separately discussed. For example, several studies have shown that body mass index (BMI) could influence the risk of ischemic or hemorrhagic stroke differently [16,17]. However, the association of wide-range BMI (including both obesity and underweight) with incident ischemic or hemorrhagic stroke has not been fully elucidated [10–12,16,17]. Furthermore, the distribution of BMI is different between men and women; therefore, the relationship between BMI and the risk of stroke could differ by sex [10,12]. In this study, we sought to examine the relationship between BMI and incident ischemic or hemorrhagic stroke stratified by sex using a nationwide epidemiological database.

#### **2. Methods**

The data from the JMDC Claims Database are available for anyone who would purchase it from JMDC Inc. (JMDC Inc.; Tokyo, Japan), which is a healthcare venture company in Tokyo, Japan.

#### *2.1. Study Population*

We conducted this retrospective observational study using the JMDC Claims Database between January 2005 and April 2020 [18–23]. The JMDC Claims Database includes the health insurance claims data from more than 60 insurers. The majority of insured individuals enrolled in the JMDC Claims Database are employees of relatively large companies. The JMDC Claims Database includes the individuals' health check-up data, including demographics, prior medical history, medication status, and hospital claims recorded using the International Classification of Diseases, 10th Revision (ICD-10) coding. JMDC which is a healthcare venture company, collected the data on health check-up and clinical outcome such as diagnosis of stroke using ICD-10 code from insurer or medical institutes regularly, and assembled a database. We extracted 3,621,942 individuals with available health check-up data on BMI (12.5–60 kg/m2), blood pressure, and blood test results at health check-up from the JMDC Claims Database between January 2005 and April 2020. Subsequently, we excluded the individuals with a history of myocardial infarction, angina pectoris, stroke, heart failure, and atrial fibrillation or hemodialysis (n = 166,144), and those with missing data on medications for hypertension, diabetes mellitus, or dyslipidemia (n = 222,496), cigarette smoking (n = 15,404), alcohol consumption (n = 370,041), and physical inactivity (n = 107,079). Finally, 2,740,778 participants were included in this study (Figure 1).

**Figure 1.** Flowchart. We extracted 3,621,942 individuals with available health check-up data including physical examination and blood test from the JMDC Claims Database between January 2005 and April 2020. We excluded individuals with CVD history of myocardial infarction, angina pectoris, stroke, heart failure, and atrial fibrillation or hemodialysis (n = 166,144), and those having missing data on medications for hypertension, diabetes mellitus, or dyslipidemia (n = 222,496), cigarette smoking (n = 15,404), alcohol consumption (n = 370,041), and physical inactivity (n = 107,079). Finally, we included 2,740,778 participants in this study.

### *2.2. Ethics*

This study was conducted according to the ethical guidelines of our institution (approval by the Ethical Committee of The University of Tokyo: 2018–10862) and in accordance with the principles of the Declaration of Helsinki. The requirement for informed consent was waived because all the data from the JMDC Claims Database were de-identified.

#### *2.3. Category of Body Mass Index*

We categorized the study participants into four groups: underweight, normal weight, overweight, and obesity defined as BMI <18.5 kg/m2, 18.5–24.9 kg/m2, 25.0–29.9 kg/m2 and ≥30 kg/m2, respectively [14].

#### *2.4. Measurements and Definitions*

The data, including BMI, history of hypertension, diabetes mellitus, dyslipidemia, CVD, blood pressure, and fasting laboratory values were collected using standardized protocols at the health check-up. The information on cigarette smoking (current or non-current) and alcohol consumption (every day or not every day) were self-reported. Hypertension was defined as systolic blood pressure ≥ 140 mmHg, diastolic blood pressure ≥ 90 mmHg, or the use of blood pressure-lowering medications. Diabetes mellitus was defined as fasting glucose level ≥ 126 mg/dL or the use of glucose-lowering medications. Dyslipidemia was defined as low-density lipoprotein cholesterol level ≥ 140 mg/dL, high-density lipoprotein cholesterol level <40 mg/dL, triglyceride level ≥ 150 mg/dL, or the use of lipid-lowering medications. Physical inactivity was defined as not engaging in at least 30 min of exercise two or more times a week or not walking ≥ 1 h per day, as previously described [24].

#### *2.5. Outcomes*

The outcomes were collected between January 2005 and April 2020. The primary outcome was stroke (ICD-10: I630, I631, I632, I633, I634, I635, I636, I638, I639, I600, I601, I602, I603, I604, I605, I606, I607, I608, I609, I610, I611, I613, I614, I615, I616, I619, I629, and G459). We defined ischemic stroke as I630, I631, I632, I633, I634, I635, I636, I638, I639, and G459, and hemorrhagic stroke as I600, I601, I602, I603, I604, I605. I606, I607, I608, I609, I610, I611, I613, I614, I615, I616, I619, and I629.
