Supplementary Material for: Exome Sequencing for Prenatal Detection of Genetic Abnormalities in Fetal Ultrasound Anomalies: An Economic Evaluation

<b><i>Introduction:</i></b> In light of the prospective Prenatal Assessment of Genomes and Exomes (PAGE) study, this paper aimed to determine the additional costs of using exome sequencing (ES) alongside or in place of chromosomal microarray (CMA) in a fetus with an identified congenital anomaly. <b><i>Methods:</i></b> A decision tree was populated using data from a prospective cohort of women undergoing invasive diagnostic testing. Four testing strategies were evaluated: CMA, ES, CMA followed by ES (“stepwise”); CMA and ES combined. <b><i>Results:</i></b> When ES is priced at GBP 2,100 (EUR 2,407/USD 2,694), performing ES alone prenatally would cost a further GBP 31,410 (EUR 36,001/USD 40,289) per additional genetic diagnosis, whereas the stepwise would cost a further GBP 24,657 (EUR 28,261/USD 31,627) per additional genetic diagnosis. When ES is priced at GBP 966 (EUR 1,107/USD 1,239), performing ES alone prenatally would cost a further GBP 11,532 (EUR 13,217/USD 14,792) per additional genetic diagnosis, whereas the stepwise would cost a further additional GBP 11,639 (EUR 13,340/USD 14,929) per additional genetic diagnosis. The sub-group analysis suggests that performing stepwise on cases indicative of multiple anomalies at ultrasound scan (USS) compared to cases indicative of a single anomaly, is more cost-effective compared to using ES alone. <b><i>Discussion/Conclusion:</i></b> Performing ES alongside CMA is more cost-effective than ES alone, which can potentially lead to improvements in pregnancy management. The direct effects of test results on pregnancy outcomes were not examined; therefore, further research is recommended to examine changes on the projected incremental cost-effectiveness ratios.

**引言：** 鉴于前瞻性产前基因组与外显子组评估（Prenatal Assessment of Genomes and Exomes, PAGE）研究，本研究旨在明确针对已检出先天性异常的胎儿，联合使用外显子组测序（exome sequencing, ES）与染色体微阵列（chromosomal microarray, CMA），或以ES替代CMA开展检测时所产生的额外成本。
**研究方法：** 本研究纳入接受侵入性诊断检测的前瞻性队列女性数据构建决策树模型，共评估四种检测策略：染色体微阵列（CMA）、外显子组测序（ES）、先行CMA后行ES的"阶梯式"策略，以及CMA与ES联合检测策略。
**研究结果：** 当ES定价为2100英镑（2407欧元/2694美元）时，产前单独开展ES每新增1例遗传学诊断需额外花费31410英镑（36001欧元/40289美元），而阶梯式策略每新增1例遗传学诊断需额外花费24657英镑（28261欧元/31627美元）。当ES定价为966英镑（1107欧元/1239美元）时，产前单独开展ES每新增1例遗传学诊断需额外花费11532英镑（13217欧元/14792美元），而阶梯式策略每新增1例遗传学诊断需额外花费11639英镑（13340欧元/14929美元）。亚组分析显示，相较于产前单独使用ES，针对超声扫描（ultrasound scan, USS）提示存在多发异常的病例采用阶梯式检测策略更具成本效益。
**讨论与结论：** 联合使用ES与CMA相较于单独使用ES更具成本效益，或可优化妊娠管理流程。本研究未考察检测结果对妊娠结局的直接影响，因此建议开展进一步研究以明确预测增量成本效益比的变化情况。