Count-based size-correction analysis of maternal plasma DNA for improved noninvasive prenatal detection of fetal trisomies 13, 18, and 21.

PURPOSE

Our goal was to derive more sensitive and accurate Z-scores based on combined DNA count- and size-based algorithms to advance molecular diagnostics for noninvasive prenatal testing of fetal trisomies.

METHODS

We included 180 cases at high risk for fetal aneuploidy who underwent amniotic fluid cytogenetic analysis. We calculated their traditional count-based Z-scores, as well as their 100-, 130- and 150-, and 166-bp size-corrected Z-scores, and determined each Z-score's reliability based on its comparison to the cases' cytogenetic results.

RESULTS

We detected for trisomies 13, 18, or 21 among the 180 cases in our study by amniotic testing and DNA sequence analysis. None trisomies 13 was detected, while 1 case of trisomies 18 and 3 cases of trisomies 21 were found. The sensitivity, specificity, and accuracy of traditional count-based Z-scores were 75%, 98.86%, and 98.33%, respectively, while these rates increased to 80%, 99.43%, and 99.44% with a count-based 100- and 166-bp size correction. Moreover, the sensitivity, specificity, and accuracy of count-based Z-scores with 130- and 150-bp size corrections were 100%, and neither of these algorithms yielded false positive trisomies, unlike other evaluated size correction Z-scores.

CONCLUSIONS

Count-based Z-scores with 130- and 150-bp size corrections more robustly predict fetal trisomies than count-based methods alone or those combined with other size-correction cutoffs, such as 166 bp. These testing parameters may enhance the utility of DNA sequence-based methods for noninvasive prenatal detection of fetal trisomies.