Abstract
Oral clefts are common birth defects that have a major impact on the affected individual, their family and society. World-wide, the incidence of oral clefts is 1/700 live births, making them the most common craniofacial birth defects. The successful prediction of oral clefts may help identify sub-population at high risk, and promote new diagnostic and therapeutic strategies. Nevertheless, developing a clinically useful oral clefts risk prediction model remains a great challenge. Compelling evidences suggest the etiologies of oral clefts are highly heterogeneous, and the development of a risk prediction model with consideration of phenotypic heterogeneity may potentially improve the accuracy of a risk prediction model. In this study, we applied a previously developed statistical method to investigate the risk prediction on sub-phenotypes of oral clefts. Our results suggested subtypes of cleft lip (CL) and palate have similar genetic etiologies (AUC = 0.572) with subtypes of CL only (AUC = 0.589), while the subtypes of cleft palate only (CPO) have heterogeneous underlying mechanisms (AUCs for soft CPO and hard CPO are 0.617 and 0.623, respectively). This highlighted the potential that the hard and soft forms of CPO have their own mechanisms despite sharing some of the genetic risk factors. Comparing with conventional methods for risk prediction modeling, our method considers phenotypic heterogeneity of a disease, which potentially improves the accuracy for predicting each sub-phenotype of oral clefts.
Highlights
Oral clefts comprise a significant component of birth defects
We have identified 148 single nucleotide polymorphisms (SNPs) potentially associated with oral cleft, which were available in the dataset
Risk Prediction Modeling While prior studies have focused on building risk prediction models for either cleft lip (CL) with/without palate or cleft palate only (CPO), we extended the risk prediction analysis by explicitly considering all subphenotypes of oral clefts, defined by their clinical manifestations
Summary
Oral clefts comprise a significant component of birth defects. The birth prevalence of CL/P is about 1/700 with wide variability associated with geographic origin, whereas CPO affects 1/2500 births with less variability compared to CL/P (Mossey, 2003; Genisca et al, 2009; Beaty et al, 2011; Dixon et al, 2011). Oral clefts can be divided into non-syndromic and syndromic forms, where approximately 70% of CL/P and 50% of CPO are non-syndromic (Jones, 1988; Stoll et al, 2000; Calzolari et al, 2007; Genisca et al, 2009; Jugessur et al, 2009; Dixon et al, 2011). With the advent of genomic era, major breakthroughs have been made into identifying genetic variants predisposing to the syndromic oral
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