Research square · 2026
Phenome-wide association study of uterine fibroid subtypes reveals symptoms of fibroid severity and subtype-specific comorbidities.
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Edwards Digna Velez, Kim Jeewoo, Jasper Elizabeth, Jones Sarah, Edwards Todd, Hellwege Jacklyn
Аннотация
BACKGROUND: Uterine leiomyomata (or fibroids) are common benign tumors of the uterus. Fibroids are classified into subtypes by location: submucosal, intramural, subserosal. Although the symptomology and comorbidities associated with fibroids have been extensively assessed, there is less knowledge regarding factors associated with fibroid subtypes. We tested the associations between fibroid subtypes and a broad range of clinical diagnoses to characterize their shared and unique comorbidity profiles.
METHODS: Using billing codes and clinical note text from the Vanderbilt University Medical Center's electronic health record (EHR) system, we identified individuals with three common fibroid subtypes (cases/controls): submucosal (2,445/28,746), intramural (4,877/20,315), subserosal (3,472/24,447). Using multivariate logistic regression, we performed a phenome-wide association study (PheWAS) for each subtype with over 1,800 constructed clinical diagnoses (phecodes) as predictors.
RESULTS: We identified 149 significant phecode associations with submucosal fibroids, 218 with intramural fibroids, and 178 with subserosal fibroids. The most significant submucosal fibroid associations were "disorders of menstruation" (odds ratio [OR][95% Confidence Interval] = 5.35[4.79-5.97]) and "iron deficiency anemia secondary to blood loss (chronic)" (OR = 5.20[4.53-5.97]). The most significant association with intramural fibroids was also "disorders of menstruation" (OR = 4.68[4.31-5.08]). The most significant association in the subserosal analysis was with "other benign neoplasm of connective and other soft tissue" (OR = 5.35[4.74-6.04]). We performed sensitivity analyses to narrow down subtype-specific associations. From these, only submucosal fibroids had multiple anemia-, irregular menstruation-, and dysmenorrhea-related phecodes remain significant, and only submucosal and intramural fibroids remained significantly associated with infertility.
CONCLUSIONS: We identified multiple factors that were more strongly or uniquely associated with having a specific fibroid subtype. We demonstrated a greater severity of fibroid symptoms in individuals with a subtype-level fibroid diagnosis.
METHODS: Using billing codes and clinical note text from the Vanderbilt University Medical Center's electronic health record (EHR) system, we identified individuals with three common fibroid subtypes (cases/controls): submucosal (2,445/28,746), intramural (4,877/20,315), subserosal (3,472/24,447). Using multivariate logistic regression, we performed a phenome-wide association study (PheWAS) for each subtype with over 1,800 constructed clinical diagnoses (phecodes) as predictors.
RESULTS: We identified 149 significant phecode associations with submucosal fibroids, 218 with intramural fibroids, and 178 with subserosal fibroids. The most significant submucosal fibroid associations were "disorders of menstruation" (odds ratio [OR][95% Confidence Interval] = 5.35[4.79-5.97]) and "iron deficiency anemia secondary to blood loss (chronic)" (OR = 5.20[4.53-5.97]). The most significant association with intramural fibroids was also "disorders of menstruation" (OR = 4.68[4.31-5.08]). The most significant association in the subserosal analysis was with "other benign neoplasm of connective and other soft tissue" (OR = 5.35[4.74-6.04]). We performed sensitivity analyses to narrow down subtype-specific associations. From these, only submucosal fibroids had multiple anemia-, irregular menstruation-, and dysmenorrhea-related phecodes remain significant, and only submucosal and intramural fibroids remained significantly associated with infertility.
CONCLUSIONS: We identified multiple factors that were more strongly or uniquely associated with having a specific fibroid subtype. We demonstrated a greater severity of fibroid symptoms in individuals with a subtype-level fibroid diagnosis.