Effects of Age on the Association between Down Syndrome and Common Disease Conditions

Importance Age based screening and prevention guidelines in healthcare are developed largely in populations without Down syndrome (DS). If disease risk among individuals with DS differs significantly relative to typically developing (TD) individuals of similar ages, standard guidelines may overlook critical windows of care. Objective To determine the age specific risk of ten common conditions in individuals with DS compared to a matched TD cohort to evaluate the presence of risk modification by age. Design Retrospective longitudinal cohort study. Setting Midwest healthcare system. Participants 4,912 individuals with DS and 37,924 TD controls, with clinical encounters between January 2005 and May 2025. Total person years (PYs) were 25,896 and 149,078 respectively. Exposure DS status Main Outcomes and Measures Incidence of acute sinusitis, anxiety, asthma, depression, gastroesophageal reflux disorder, nervous system disorders, respiratory failure, thyroid gland disorders, vasomotor/allergic rhinitis, and vitamin D deficiency. Incidence rate ratios (IRR) trajectories were analyzed using generalized additive mixed models. Wald tests assessed the presence of age modification. Results In our DS cohort (median age 24, 48% female), we found evidence of age-related risk modification in 6 of 10 conditions examined. The relative incidence of anxiety was significantly lower among individuals with DS in early childhood (at age 5, IRR 0.23, 95%CI 0.19, 0.29), compared to TD controls of the same age. However, risk in the DS cohort increased with age approaching equal levels with controls around ages 65. Similar trends were observed for depression. The association between DS and gastroesophageal disease was largely null except between ages 1 to 8, where the incidence among DS cohort was elevated (5 to 7 cases per 1000 PYs) compared to controls (2 to 3 cases per 1000 PYs). The association between DS and respiratory failure was statistically insignificant until age 53 to 70, where incidence among individuals with DS rose sharply (13 to 30 cases per 1000 PYs), while for TD counterparts it remained constant at 8-9 cases per 1000 PYs. Lastly, risk of vitamin D deficiency fluctuated with a peak at age 20 (IRR 2.34, 95%CI 2.02, 2.72). Conclusions and Relevance These findings demonstrate age effect modification among individuals with DS across a variety of disease conditions and highlight the importance of population-specific care guidelines.