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Abstract
Background Systemic lupus erythematosus (SLE) has a female to male ratio of 9:1. While SLE is more prevalent in females, males with SLE may have increased disease severity and mortality. Mechanisms for these worse outcomes are not fully known. We assessed differences in comorbidities in males vs. females by performing the first electronic health record (EHR)-based phenome-wide association studies (PheWAS) in SLE to compare ICD-9 code-based phenotypes in males versus females. PheWAS are a systematic and efficient approach to identify novel clinical associations within subgroups of patients.
Materials and Methods We used our validated algorithm of ≥4 counts of the SLE ICD-9 code (710.0) and ANA positive >1:160 while excluding dermatomyositis and systemic sclerosis ICD-9 codes to identify SLE cases in a de-identified EHR called the Synthetic Derivative (SD). The SD contains over 2.5 million subjects with clinical data collected over several decades with approximate even distribution of predominantly Caucasian males and females. Our algorithm has a positive predictive value (PPV) of 89%, sensitivity of 86%, and an internally validated PPV of 94%. PheWAS were performed in males vs. females adjusting for covariates in a?logistic model and correcting for multiple testing using Bonferroni.
Results Using our validated algorithm, we identified 986 females and 111 males with SLE. Males and females with SLE were predominantly Caucasian (69% vs. 69%, p = 0.32) and had similar mean current age (52 ± 18 vs. 50 ± 17, p = 0.42), age at first use of a SLE ICD-9 code (43 ± 18 vs. 40 ± 17, p = 0.08), and years of follow-up in the EHR (8 ± 5 vs. 9 ± 5, p = 0.23). Adjusting for race/ethnicity and current age, males were more likely to have cardiovascular ICD-9 codes vs. females including atrial fibrillation odds ratio (OR) = 4.50 (95% CI: 2.32 – 8.72), p = 8.6 x 10−6, other chronic ischaemic heart disease OR = 4.40 (2.24 – 8.64), p = 1.7 × 10−5, atrial fibrillation and flutter OR = 4.08 (2.12 – 7.83), p = 2.4 × 10−5 (Figure 1).
Conclusion We report the first association of atrial fibrillation in males with SLE. While there is a 5-fold increased risk of cardiovascular disease overall in SLE, the risk of atrial fibrillation, specifically in males, has not been identified. These findings demonstrate the ability of PheWAS to uncover novel phenotype associations within subgroups of a disease.
PheWas of males vs. females with SLE. “The x axis represents phewas codes that are mapped to ICD-9 codes organized by organ system. The y axis represents the level of significance. Females are the reference group. The lower horizontal line represents the p< 0.05 significance threshold. The upper horizontal line represents the Bonferroni threshold. Three codes met the Bonferroni threshold and are indicated above with odds ration and 95% confidence intervals.