Non-invasive prediction of fetal growth restriction by whole-genome promoter profiling of maternal plasma DNA: a nested case-control study

Objective: To predict fetal growth restriction (FGR) by whole-genome promoter profiling of maternal plasma.

Design: Nested case-control study.

Setting: Hospital-based.

Population or sample: 810 pregnancies: 162 FGR cases and 648 controls.

Methods: We identified gene promoters with a nucleosome footprint that differed between FGR cases and controls based on maternal plasma cell-free DNA (cfDNA) nucleosome profiling. Optimal classifiers were developed using support vector machine (SVM) and logistic regression (LR) models.

Main outcome measures: Genes with differential coverages in promoter regions through the low-coverage whole-genome sequencing data analysis among FGR cases and controls. Receiver operating characteristic (ROC) analysis (area under the curve [AUC], accuracy, sensitivity and specificity) was used to evaluate the performance of classifiers.

Results: Through the low-coverage whole-genome sequencing data analysis of FGR cases and controls, genes with significantly differential DNA coverage at promoter regions (-1000 to +1000 bp of transcription start sites) were identified. The non-invasive 'FGR classifier 1' (C_FGR 1) had the highest classification performance (AUC, 0.803; 95% CI 0.767-0.839; accuracy, 83.2%) was developed based on 14 genes with differential promoter coverage using a support vector machine.

Conclusions: A promising FGR prediction method was successfully developed for assessing the risk of FGR at an early gestational age based on maternal plasma cfDNA nucleosome profiling.

Tweetable abstract: A promising FGR prediction method was successfully developed, based on maternal plasma cfDNA nucleosome profiling.