title: Accurate and robust genomic prediction of celiac disease using statistical learning.
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 cohorts, we provide a proof-of-concept that statistical learning approaches which simultaneously model all SNPs can generate robust and highly accurate predictive models of CD 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 ∼43% 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 ≥99.6% negative predictive value however, unlike HLA typing, fine-scale stratification of individuals into categories of higher-risk for CD can identify those that 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 genomic risk score 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.
authors.affiliation: Medical Systems Biology, Department of Pathology and Department of Microbiology & Immunology, The University of Melbourne, Parkville, Victoria, Australia ; NICTA Victoria Research Lab, Department of Computing and Information Systems, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Gad
authors.initials: G
authors.lastname: Abraham
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia ; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia ; Department of Gastroenterology, The Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Tye-Din
authors.affiliation: Medical Systems Biology, Department of Pathology and Department of Microbiology & Immunology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Oneil G
authors.initials: OG
authors.lastname: Bhalala
authors.affiliation: NICTA Victoria Research Lab, Department of Computing and Information Systems, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Adam
authors.initials: A
authors.lastname: Kowalczyk
authors.affiliation: NICTA Victoria Research Lab, Department of Computing and Information Systems, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Justin
authors.initials: J
authors.lastname: Zobel
authors.affiliation: Medical Systems Biology, Department of Pathology and Department of Microbiology & Immunology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Inouye
mesh_terms: D000483:Alleles; D001699:Biometry; D002446:Celiac Disease / Q000235:genetics* / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D023281:Genomics; D006680:HLA Antigens / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D012306:Risk
chemical_list: D006680:HLA Antigens