Accurate and robust genomic prediction of celiac disease using statistical learning

TL;DR

This study demonstrates that genome-wide SNP-based statistical learning models can accurately predict celiac disease, outperforming traditional HLA testing, and can be tailored for clinical risk stratification across diverse populations.

Contribution

The paper introduces a robust, genome-wide SNP-based predictive model for celiac disease using statistical learning, showing high accuracy and clinical utility beyond existing HLA testing methods.

Findings

High predictive accuracy with AUC 0.86-0.9 across cohorts

GRS explains 30-35% of disease variance

Potential for improved clinical risk stratification

Abstract

Practical application of genomic-based risk stratification to clinical diagnosis is appealing yet performance varies widely depending on the disease and genomic risk score (GRS) method. Celiac disease (CD), a common immune-mediated illness, is strongly genetically determined and requires specific HLA haplotypes. HLA testing can exclude diagnosis but has low specificity, providing little information suitable for clinical risk stratification. Using six European CD cohorts, we provide a proof-of-concept that statistical learning approaches which simultaneously model all SNPs can generate robust and highly accurate predictive models based on genome-wide SNP profiles. The high predictive capacity replicated both in cross-validation within each cohort (AUC of 0.87-0.89) and in independent replication across cohorts (AUC of 0.86-0.9), despite differences in ethnicity. The models explained 30-35% of disease variance and up to $\sim43\%$ of heritability. The GRS's utility was assessed in different clinically relevant settings. Comparable to HLA typing, the GRS can be used to identify individuals without CD with $\geq99.6\%$ negative predictive value however, unlike HLA typing, patients can also be stratified into categories of higher-risk for CD who would benefit from more invasive and costly definitive testing. The GRS is flexible and its performance can be adapted to the clinical situation by adjusting the threshold cut-off. Despite explaining a minority of disease heritability, our findings indicate a predictive GRS provides clinically relevant information to improve upon current diagnostic pathways for CD, and support further studies evaluating the clinical utility of this approach in CD and other complex diseases.