Investigating misclassification of type 1 diabetes in a population-based cohort of British Pakistanis and Bangladeshis using polygenic risk scores

Abstract

Correct classification of type 1 (T1D) and type 2 diabetes (T2D) is challenging due to overlapping clinical features and the increasingly early onset of T2D, particularly in South Asians. Polygenic risk scores (PRSs) for T1D and T2D have been shown to work relatively well in South Asians, despite being derived from largely European-ancestry samples. Here we used PRSs to investigate the rate of potential misclassification of diabetes amongst British Bangladeshis and Pakistanis. Using linked health records from the Genes & Health cohort (n = 38,344) we defined two reference groups meeting stringent diagnostic criteria: 31 T1D cases, 1842 T2D cases, and after excluding these, two further groups: 839 insulin-treated diabetic individuals with ambiguous features and 5174 non-diabetic controls. Combining these with 307 confirmed T1D cases and 307 controls from India, we calculated ancestry-corrected PRSs for T1D and T2D, with which we estimated the proportion of T1D cases within the ambiguous group at ~ 6%, dropping to ~ 4.5% within the subset who had T2D codes in their health records (and are thus most likely to have been misclassified). We saw no significant association between the T1D or T2D PRS and BMI at diagnosis, time to insulin, or the presence of T1D or T2D diagnostic codes amongst the T2D or ambiguous cases, suggesting that these clinical features are not particularly helpful for aiding diagnosis in ambiguous cases. Our results emphasise that robust identification of T1D cases and appropriate clinical care may require routine measurement of diabetes autoantibodies and C-peptide.

Fig. 1

Estimated prevalence of T1D in the G&H ambiguous group. Panel (A) includes all individuals in the ambiguous group (n = 839) and (B) excludes those individuals where only a T1D clinical code is present (n = 821). Points show mean estimates and horizontal lines indicate 95% confidence intervals. The dotted line indicates the median point estimate across all methods. The point type indicates the statistical method used for estimation. EMD: Earth Mover’s Distance; KDE: Kernel density estimation.

Fig. 2

Average PC-corrected T1D and T2D polygenic risk score (PRS) of subgroups in Genes and Health (G&H), with 95% confidence intervals. These have been standardised such that the controls have a mean of 0 and variance 1.

Fig. 3

Results from multiple linear regressions of the PC-corrected T1D or T2D PRSs on the indicated clinical variables within either the ambiguous or T2D cases from G&H. Points show the point estimates for the effect size and lines show the 95% confidence intervals. The estimates are split into two panels due to the difference in their scale. Note that the regression within the reference T2D group excluded ‘time to insulin’ and ‘having only a T1D code’ since these were not relevant because of how this group was defined.