Racial and ethnic disparities in diagnostic efficacy of comprehensive genetic testing for sensorineural hearing loss

Abstract

Understanding racial and ethnic disparities in diagnostic rates of genetic testing is critical for health equity. We sought to understand the extent and cause of racial and ethnic disparities in diagnostic efficacy of comprehensive genetic testing (CGT) for sensorineural hearing loss (SNHL). We performed a retrospective cohort study at two tertiary children's hospitals on a diverse cohort of 240 consecutive pediatric patients (76% publicly insured, 82% non-White) with SNHL of unknown etiology who underwent CGT. Definite and possible genetic diagnoses were assigned for each patient, representing the likelihood of a genetic cause of hearing loss. Associations between diagnostic rates were examined. 3.8 ± 2.1 variants were detected per patient; this frequency did not vary between White/Asian and Hispanic/Black cohorts. Overall, 82% of variants were variants of uncertain significance (VUS). Compared with White and Asian subjects, variants identified among Hispanic and Black children were less likely to be classified as pathogenic/likely pathogenic (15% vs. 24%, p < 0.001), and Hispanic and Black children were less likely to have a definite genetic diagnosis (10% vs. 37%, p < 0.001). The adjusted odds ratio for definite genetic diagnosis in Black and Hispanic children compared with White and Asian children was 0.19. Expanding genetic diagnostic criteria to include predicted deleterious VUSs reduced these disparities between White/Asian and Hispanic/Black children, with comparable molecular diagnostic rates (41% vs. 38%, p = 0.72). However, in silico predictions are insufficiently valid for clinical use. Increased inclusion of underrepresented groups in genetic hearing-loss studies to clinically validate these variants is necessary to reduce racial and ethnic disparities in diagnostic efficacy of comprehensive genetic testing.

Fig. 1

Study population demographic and clinical characteristics. A. Blue shading and numbers reported in individual boxes indicate the number of patients with the paired criteria delineated by row and column. B. Categorical variables were reported as both a number and percentage. Descriptive analysis of continuous variables is reported as a mean and standard deviation for normally distributed variables

Fig. 2

Definite genetic diagnostic rate. A. Distribution of definite genetic diagnoses (Patient MD = 4) across race/ethnicity groups. Definite genetic diagnostic rate was compared by ANOVA between dichotomized race/ethnicity groups (White/Asian and Black/Hispanic). B. Distribution of definite genetic diagnosis across insurance, sex, racial-ethnic group, onset, severity, laterality, and inheritance characteristics. Coloring/shading is indicative of difference of diagnostic rate from the average diagnostic rate adjusted by row: orange indicates below the average diagnostic rate for patients with the characteristic defined by the row, white indicates a diagnostic rate average for patients with the characteristic defined by the row, and blue indicates higher diagnostic rate for patients with the characteristic defined by the row. Numbers in boxes indicate the number of patients who received a definite genetic diagnosis, defined as Patient MD of 4, with paired characteristics of the column and row

Fig. 3

Variant distribution. A. Mean number of variants identified per child across race/ethnicity groups with reported p-value of ANOVA for mean number of variants vs dichotomized race/ethnicity (White/Asian and Black/Hispanic). B. Known Variant rate. Left: Distribution of Known Variants across race/ethnicity groups. Known Variant rate was compared by ANOVA between dichotomized race/ethnicity groups (White/Asian and Black/Hispanic). Right: Distribution of Known Variants across characteristics is shown. Color scheme is as described in Fig 2. C. Predicted deleterious VUS rate. Left: Distribution of predicted deleterious VUSs (by PROVEAN prediction) across race/ethnicity groups. Deleterious VUS rate was compared by ANOVA between dichotomized race/ethnicity groups (White/Asian and Black/Hispanic). Right: Distribution of deleterious VUSs across characteristics is shown. Color scheme is as described in Fig 2

Fig. 4

Possible genetic diagnostic rate. A. Distribution of possible genetic diagnoses (Patient MD = 3) across race/ethnicity groups. Possible genetic diagnostic rate was compared by ANOVA between dichotomized race/ethnicity groups (White/Asian and Black/Hispanic). B. Distribution of possible genetic diagnosis across characteristics is shown. Color scheme is as described in Fig. 2