Clinical pathway ‘turnaround time’,
In the PAGE study, an à priori protocol decision was made only to feedback information on pathologic variants after the end of the pregnancy27, whereas the Petroski study (indicated that the results of ES were not intended for use in clinical care) described that it took up to 8 weeks to obtain and interpret results28. Data from paediatric cohorts of critically ill neonates and infants have indicated that rapid ES testing and evaluation is possible (sometimes within 72 hours) and provide clinical benefit, improved decision making, aiding developmental and family emotional outcomes8,52,53,54. In prenatal diagnosis there is also a requirement for a relatively rapid TAT to aid informed parental decision making. Such TAT is affected and influenced by the whole pathway (including the potential need for cell culture to obtain fetal DNA, through the genetic variant bioinformatic filtering and clinical review panels assessment). Normand and colleagues indicated that prenatal TAT could be achieved on average within 14 days (range 7-38 days)32. A recent small retrospective study from the Netherlands indicated that prenatal ES aided parental decision making (including decisions on late termination of pregnancy) and aided prenatal / neonatal clinical pathways. Again, on average, TAT were within 21 days55. Certainly, parents (pre-testing) must be aware that test TAT can be of variable duration but that on average a result should be obtained within 28 days (Dr Dom McMullan personal communication, March 2020).
Cost effectiveness .
This will be affected by selection of phenotype, technical considerations such as DNA sequencing, variant interpretation, as well as the infrastructure for pre- and post-test counselling9. The use of ES in suspected monogenic disorders (in children) has been indicated to be increasingly cost-effective as the benefits of ES data reanalysis, cascade testing in first-degree relatives, and parental reproductive outcomes are incorporated into modelling56. Our own, rather conservative cost modelling used decision tree model populated using data from a prospective cohort of women undergoing invasive diagnostic testing. A comparison of four potential testing strategies (after screening for autosomal trisomies) were evaluated using CMA, ES, CMA followed by ES (”stepwise”) and CMA and ES combined. When ES was 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 compared to cases indicative of a single anomaly, is more cost-effective compared to using ES alone57. It is likely that these are conservative costs and different health care economies will need to evaluate their costs and make decisions as to whether it is possible to implement prenatal exome sequencing within their health care systems.