Social Determinants of Health and Neurocognitive Functioning in Sickle Cell Disease
Authors: Heitzer Andrew M , Longoria Jennifer , Okhomina Victoria I , Porter Jerlym S. , Estepp Jeremie H. , Davis Robert L , Kang Guolian , Hankins Jane S 
Published: November 2021

Abstract
Sickle cell disease (SCD) is associated with significant neurocognitive risk due to a combination of disease and environmental factors. Neurological complications, including overt stroke, silent cerebral infarctions, and chronic insufficiencies in oxygen and/or glucose delivery to the brain contribute to neurocognitive decline. Environmentally, patients with SCD experience greater rates of poverty and fewer protective socioeconomic factors when compared with the Black population in the United States. Both personalized (e.g. familial education and occupation) and community measures of socioeconomic status uniquely contribute to neurocognitive outcomes. However, no studies have examined the specific community-level factors that contribute to neurocognitive performance. The primary objective of this study was to investigate associations between familial and community-level social determinants with cognitive and academic outcomes in a large prospectively recruited sample of patients with SCD ranging from childhood to young adulthood.
We included 103 patients with SCD (51% HbSS/HbSβ 0-thalassemia). The mean age of participants was 12.86 (SD=4.04) years. Familial socioeconomic status was measured using the Barratt Simplified Measure of Social Status (BSMSS), a composite of parent education and occupation status. Community-level (based on census block) socioeconomic variables included: poverty rate, unemployment rate, percentage of individuals with a bachelor's degree, and access to food nutrition services. Following informed consent, patients completed gold-standard neurocognitive measures supervised by a psychologist, assessing intellectual (Wechsler Abbreviated Scale of Intelligence - Second Edition) and academic functioning (Woodcock Johnson Tests of Achievement - Third Edition). Multivariate linear regression was used to examine associations between community and familial level socioeconomic status with cognitive/academic outcomes after adjusting for age, sickle genotype, and hydroxyurea exposure. Stepwise linear regression was used to identify the independent factors associated with cognitive/academic outcomes. The False discovery rate (FDR) developed by Benjamini and Hochberg was used to control for multiple testing and FDR-adjusted p-values (pFDR) &lt;0.05 were considered statistically significant. Otherwise, p-values &lt;0.05 were considered significant.
Patients with SCD lived in communities with high rates of poverty (26.57%) and unemployment (13.58%) and low rates of college education (13.26%). In multivariate analyses adjusting for age, sickle genotype, and hydroxyurea exposure, IQ was associated with the BSMSS (estimate = 0.31, standard error [SE] = 0.10, p=0.003) at pFDR&lt;0.05 but measures of basic reading and math were not (all pFDR&gt;0.05).
In contrast, reduced intellectual functioning was associated with increased poverty rates (Estimate=-0.29, SE=0.09, p=0.003), increased unemployment rates (estimate=-0.43, SE=0.18, p=0.018), increased access to food nutrition services (Estimate=-0.21, SE=0.09, p=0.015), and decreased percentage of individuals with a bachelor's degree (Estimate=0.33, SE=0.10, p=0.003) at pFDR&lt;0.05. Measures of basic reading and math were not associated with any of the community-level variables. Stepwise linear regression analysis showed that the BSMSS (Estimate=0.22, SE=0.11, p=0.04) and poverty rates (Estimate=-0.18, SE=0.09, p=0.049) are independently associated with full scale IQ after adjusting for age, sickle genotype and hydroxyurea exposure. Overall, community and familial socioeconomic factors accounted for greater variance in intellectual functioning than age, genotype, and hydroxyurea treatment exposure (see Figure 1).
Social determinants at the community-level contribute to intellectual development in patients with SCD independent of familial socioeconomic status. Surprisingly, academic performance was not associated with community-level social determinants. Evaluation of community-level social determinants may provide insights into potential targets for neurodevelopmental interventions.
Figure 1 Figure 1.

Disclosures
Estepp: Global Blood Therapeutics: Consultancy, Research Funding. Hankins: Bluebird Bio: Consultancy; UpToDate: Consultancy; Global Blood Therapeutics: Consultancy; Vindico Medical Education: Consultancy.