Katherine Callahan, a neonatologist and bioethicist, offers a poignant warning about the dangers of new diagnostic genomic tests. She begins with a scene that will be familiar to most clinicians, a family conference. The room is crowded. The parents are surrounded by geneticists and neonatologists, the best and the brightest practitioners of precision neonatology. Callahan’s hope is clear: “If we communicate clearly, they will understand. If they understand, this information will be important to them. They will take it with them and make good decisions.” When the father asks about the baby’s future, the doctors tell him that “no data exist to answer these questions.” The father is clearly frustrated. As they leave the meeting, he takes all the printed information that he was given about his baby’s diagnosis and prognosis and throws it in the trash.
“Discarding information is not easy,” Callahan writes. But then she remembers some events from her own family’s medical history. A generation earlier, her mother was diagnosed with toxoplasmosis early in her pregnancy. Testing pregnant women for toxoplasmosis was new. It was designed to inform parents about risks so that they could decide whether to continue the pregnancy. Callahan’s mother decided to terminate the pregnancy. Weeks later, a confirmatory test for toxo came back negative. The fetus would likely have been unaffected. “Her faith made the medical information seem impossible to ignore.” Callahan wonders what would have happened if, like the father of her patient, her mother had simply thrown the toxo test results in the trash.
She recalls how, a generation earlier, her physician grandfather had listened to doctors who predicted that a newborn with hydrocephalus would be severely impaired. The child was taken from the family and institutionalized, as was standard practice at the time. The child lived for many years in a group home. He was never a part of the family except in the ways that his long shadow often darkened the brows of Callahan’s grandparents. She recalls her grandmother as having “an inexplicable sadness.” She imagines how her parents and grandparents “received information from physicians and followed recommendations.” She wonders whether their decisions would have been different if the doctors were less cocksure of the value of their information.
Callahan and colleagues, in another study, showed that neonatologists’ clinical decisions are swayed by an unwarranted pessimism regarding outcomes for babies with genomic variants. Their results suggested that, among babies with identical clinical presentations, the finding of genomic variants made doctors more likely to recommend palliative care rather than potentially curative medical interventions. Their disturbing conclusion: “Our findings suggest that ambiguous genetic information may be more than unhelpful; it may be detrimental to clear and rational decision-making by physicians. Also troubling, diagnoses portending intellectual disability may be used to redirect care.”
These cautionary tales must be interpreted against the background of wildly optimistic assessments of the value of genomic testing. Kingsmore and Cole write that genome-based precision medicine “has considerable diagnostic and clinical utility and cost effectiveness in infants in ICUs.” Maron and colleagues believe that such testing should be “widely available” and that early genomic diagnosis “holds great promise for improving access to pharmacologic, biologic, and gene therapies.”
Even proponents of such testing acknowledge the sorts of concerns that trouble Callahan. As Maron et al note, their study “did not formally assess whether the differences in molecular diagnostic yield translated to improvements in clinical outcomes.” Kingsmore and Cole note that “knowledge of the underlying genetics…does not necessarily translate today into clinically actionable guidance for treatment or prognosis.” The note that “the unique physiologic and genomic characteristics of the newborn plus our incomplete understanding of encoded mechanisms of action, treatment guidance, and prognosis present bottlenecks to achieving the full potential of timely genetic diagnosis for reducing fetal and neonatal morbidity and mortality.”
There is a vast enterprise trying to develop precision neonatology. Pammi et al predict that genomics and AI will revolutionize perinatology by allowing better understanding of the causation of pre-eclampsia, premature labor, and preterm birth. They predict that such approaches will allow prevention of retinopathy, necrotizing enterocolitis, and sepsis. But there is a downside. Prognostication can become a self-fulfilling prophecy. We have seen how the assignment of a poor prognosis to babies with trisomy 13 or 18 leads to their preventable deaths. Similar self-fulfilling prophecies led many centers to forego life-sustaining treatment for babies born at the borderline of viability. Predictive genomics adds a new layer of complexity to the already daunting problems of prognostication. While we know that genetics is not destiny, the temptation to use genomics to predict the future is almost irresistible.
Still, the bandwagon rolls on. There have been dozens of studies showing that we can find genomic variants and that finding such variants can lead to changes in clinical management. As we read these studies, we should remember that not all changes in management are beneficial. Diagnostic findings led to changes in management for Dr. Callahan’s family members. Many families will be better off if, instead of changing management, they throw genomic results in the trash.