Two seismic events in the past three years have caused the ground to shift in neonatal genetics. After a lifetime of our thinking about pattern recognition, family histories and highly focused testing with poor sensitivity, next-generation techniques of whole exome and genome sequencing are suddenly not only technically feasible away from the research lab, but also seemingly quite inexpensive. The potential for enormous diagnostic and prognostic impact in the NICU is substantial, and some of the futurists among us are even whispering about universal genomic screening of newborns to supplement or replace current newborn screen approaches. In that context, the newest of a handful of commentaries dealing with the bigger picture is welcome: Wilkinson D, Barnett C, Savulescu J, Newson A. Genomic intensive care: should we perform genome testing in critically ill newborns? Arch Dis Child Fetal Neonatal Ed March 2016 Vol 101 No 2
The authors present a balanced, case-based discussion of the potential consequences of genomic testing. They outline its potential uses: treatment modification to improve biological outcome, treatment limitation to improve end-of-life transition for fatal conditions, and anticipation or information in cases in between. Essentially, the argument is that widespread genomic screening and testing is imminent (from direct-to-consumer sources if not the formal medical establishment), and that we need to decide the circumstances in which to implement.
The paper argues (appropriately) that there should not be a presumption against testing, but I’d argue that we actually have the opposite. We’ve not done a very good job in neonatology of holding back on testing. We operate under a diagnostic imperative: when we can test, we do, because information seems like an undeniable good. Consider cranial ultrasound screening for prognosis, which is undertaken almost universally and repeatedly in preterm infants without evidence that it changes outcomes, and without particularly good predictive validity. There are certainly babies in whom the risk is elevated and the test characteristics better, but a screening, rather than diagnostic, approach has had a firm hold for twenty years.
Why might we want to resist the diagnostic imperative? First, tests that have poor test characteristics tend to lead to a diagnostic cascade, with the potential for eventual adverse biological consequences of either the tests themselves or of the resulting interventions. Next generation sequencing, with its enormous amount of uncertain but potentially actionable information in a single report, is as stark an example as we have seen of this phenomenon. Second, the costs of testing are often far greater than the cost of the test itself. In part this is a consequence of that same diagnostic cascade, but it is also from the a second, therapeutic cascade. In the case of genomic testing, for example, the intensive personnel involvement for interpretation, consultation and counseling is likely to swamp the famously $500 genome. Finally, and most importantly, prognostic (or even diagnostic) information may simply not be wanted by parents. We’ve only started to ask families about this regarding neuroimaging; for the multiple prognostic findings in a screened genome, the preference issues multiply exponentially.
Although the article frames the discussion as ‘ethics,’ most of the arguments are thus actually not in a moral sphere but rather a practical, societal one (and therefore of additional interest to us in here). The management of false positives, incidental findings, costs, uncertainty, and actionability are all technical to some degree, in that they can be measured, judged against other tests, and optimized before introduction. So why not defer until we’ve measured and considered, just a bit? This is exactly what is underway in the NSIGHT Consortium, a multi-site initiative of the National Human Genome Research Institute, which will study both NICU babies and healthy term infants. The investigators will “explore, in a limited but deliberate manner, the implications, challenges and opportunities associated with the possible use of genomic sequence information in the newborn period.” Critically, the program includes analysis of the ethical, legal and social implications. Dr. Dmitry Dukhovny, a health services researcher and neonatologist at OHSU, will co-lead an examination of economic outcomes.
To their credit, the authors call for “revision of models of informed consent” prior to introduction of NGS. We should take care that we have accurate, empirical information to present during that process, before we launch into it.
Delivering Newborn Care 