1.1 Data source
The Taiwan National Health Insurance (NHI) program is a singlepayer system instituted on March 1, 1995, which, according to the Bureau of the National Health Insurance (BHNI), covers approximately 99% of the 23.74 million citizens of Taiwan. The BNHI has authorized the National Health Research Institutes (NHRI) to create the National Health Insurance Research Database (NHIRD) for medical research; this database contains administrative and health claims data collected through the NHI program. In this study, we used the Longitudinal Health Insurance Database 2010 (LHID2010), which is a subset of the NHIRD comprising patient data from 1996 to 2013. The LHID2010 comprises data on 1,000,000 beneficiaries randomly sampled from the original NHIRD.
1.2. Sampled patients
Patients who was diagnosed with thalassemia (ICD-9-CM code 282.4) and born between 1997 and 2010 were included in our study cohort. We excluded patients with a history of transfusion (ICD-9-CM code: 990 or treatment code 990) or a history of partial or total splenectomy (ICD-9 treatment code 70001B, 70003B, and 70006B), immunodeficiency (ICD-9-CM: 279), iron deficiency and other deficiency anemias (ICD-9-CM: 280 ~ 281), myelodysplastic syndrome (ICD-9-CM: 238.7), primary or secondary hemochromatosis (ICD-9-CM: 275.0), and hematological malignancies (ICD-9-CM: 200 ~ 208 ), or for whom age or sex information at the baseline was missing.
One thalassemia patient was matched with four control patients without thalassemia (1:4 matching) according to year of birth, sex, and the propensity score model based on comorbidities. The comorbidities included were atopic dermatitis (ICD-9-CM code 691.xx), allergic rhinitis (ICD-9-CM code 477.xx), and enteroviral infections including enteroviral infection (ICD-9-CM code: 008.67); meningitis due to enterovirus, coxsackievirus, and echovirus (ICD-9-CM code: 047, 047.0, and 047.1); other enterovirus diseases of central nervous system (ICD-9-CM code: 048); specific diseases related to coxsackievirus (ICD-9-CM code: 074, 074.1, 074.2, 074.20, 074.21, 074.23 and 074.8); herpangina (ICD-9-CM code: 074.0); hand-foot-and-mouth disease (ICD-9-CM code: 074.3); and echovirus and coxsackievirus infection (ICD-9-CM code 079.1 and 079.2). The propensity score was calculated using the Statistical Analysis System 9.4 program (SAS Institute, Cary, North Carolina, USA).
1.3. Outcome and comorbidities
The patients in both the thalassemia and non-thalassemia cohorts were followed up until they were diagnosed with asthma (ICD-9-CM: 493.xx); or death; or the end of 2013. The index date was defined as the date of the first visit for asthma. To improve data accuracy, the selection criteria of thalassemia, atopic dermatitis, allergic rhinitis and enteroviral infections required all cases ICD-9 code to be diagnosed once at hospitalization or at least thrice in the outpatient department in one year. Enteroviral infections were identified according to diagnoses in the claims records data before the index date while atopic dermatitis and allergic rhinitis were enrolled no matter they were diagnosed before or after the diagnosis of asthma.
1.4. Statistical analysis
The distributions of categorical demographics and clinical characteristics between the thalassemia and non-thalassemia cohorts were compared using the chi-square test. The incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were estimated using Poisson regression. Univariate and multivariate Cox proportional hazard regression models were used to estimate the hazard ratios (HRs) and 95% CIs for asthma. All statistical analyses were performed using SAS software, Version 9.3 (SAS Institute, Cary, NC, USA). A P value < 0.05 in 2-tailed tests was considered statistically significant.