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.