Phenotype-guided post-triage of combined screening–positive pregnancies using an interpretable decision-tree model

The first-trimester combined screening test (CST) increases aneuploidy risk but results in a substantial false-positive burden, with most CST-positive pregnancies ultimately being euploid. Optimizing decision-making within this already risk-enriched population remains a major clinical challenge. This retrospective observational study evaluated a phenotype-guided post-triage (PGT) model applied exclusively to CST-positive pregnancies using the use of routinely collected maternal, biochemical, and ultrasound markers. An interpretable classification and regression tree (CART) model was developed to distinguish true-positive aneuploid pregnancies from false-positive euploid pregnancies. The dataset was split into training, validation, and independent test cohorts, and model performance was assessed in the test cohort. A prespecified positive predictive value–priority operating point was selected to minimize false-positive classification while maintaining acceptable aneuploidy detection. Among the 5,015 CST-positive pregnancies, the aneuploidy prevalence was 4.0% in the test cohort. The PGT model demonstrated strong discrimination comparable to baseline CST risk (area under the receiver operating characteristic curve of 0.93 for both), indicating unchanged global discrimination despite post-triage refinement. At the conventional CST cutoff of 1:300, 52% of euploid pregnancies were classified as screen-positive; application of the PGT model reduced false-positive classification to 3%. A false-positive reduction was observed across guideline-defined CST risk bands, and all aneuploid pregnancies misclassified as negative were detectable by cell-free DNA testing. Phenotype-guided post-triage substantially reduces false-positive classification among CST-positive pregnancies without altering global discrimination, supporting a decision-focused evaluation paradigm for postscreening tools and more efficient use of downstream prenatal testing.