Neonatologists' Attitudes About Diagnostic Whole-Genome Sequencing in the NICU Brett Knapp, Carole Decker and John D

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Neonatologists Attitudes About DiagnosticBrett Knapp, MHA, CCRP,a Carole Decker,Whole-Genome PhD, RN, CPHQ, FAHA,b John D. Lantos, MDa Sequencingabstract in the NICU

Using focus group methodology, we studied the attitudes of neonatologists regarding diagnostic rapid genome sequencing for newborns who were critically ill in a NICU. One focus group took place within the first year after whole-genome sequencing testing became available, and another focus group took place 3 years later. Focus groups were audiotaped, transcribed, and analyzed by using standard techniques of grounded theory. Different analysts coded them for themes. The analysts then discussed differences and agreed on major themes. Twelve doctors participated in the first focus group, and 9 doctors participated in the second; 62% were attending physicians, and the rest were fellows. There were 14 women and 7 men. We did not collect any other demographic information on participants. Surprisingly, we found few differences between the earlier focus group and the later one. Comments were categorized as falling into 4 domains: (1) uncertainty about the interpretation of results, (2) issues about parental consent and limits on their right to know genomic information, (3) different opinions about whether and how genomic results could be clinically useful, and (4) potential harms of genomic testing.

NIH

aChildren’s Mercy Hospital, Kansas City, Missouri; and bSaint Luke’s Mid America Heart Institute, Kansas City, Missouri Mr Knapp and Drs Decker and Lantos wrote, reviewed, and revised the manuscript and approved the final manuscript as submitted. This trial has been registered at www.clinicaltrials.gov (identifier NCT02422511). DOI: https://doi.org/10.1542/peds.2018-1099J Accepted for publication Jul 3, 2018 Address correspondence to John D. Lantos, MD, Children’s Mercy Bioethics Center, 2401 Gillham Rd, Kansas City, MO 64108. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2019 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: Funded by National Human Genome Research Institute grant U19HD077693 (subaward agreement 3282-S1-A2). Funded by the National Institutes of Health (NIH).

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Genomic sequencing (GS) is a different opinions about whether powerful tool that is in need of ’ and how genomic results could be The study was conducted at a useful application. One area in clinically useful, and (4) potential Children s Mercy Hospital (CMH) which it is thought to have promise harms of genomic testing. in Kansas City, Missouri. CMH is Uncertainty About Interpretation is in the diagnosis of rare diseases a freestanding, 354-bed medical among infants in NICUs who are center. CMH provides comprehensive critically ill. After all, many infants ∼ primary and tertiary specialty care Clinicians were excited to have have congenital anomalies and/ to children from an 189-county access to the additional information or genomic syndromes that are ∼ region in Missouri and Kansas. The provided by WGS. They believed that rare and difficult to diagnose. NICU admits 1000 infants per year. this information could help them Approximately 7% of stillborn There are 23 attending physicians diagnose diseases and then treat infants and 0.5% of live-born infants 1 in neonatology and a fellowship their patients. However, there were have a chromosomal abnormality. program that has 9 fellows at a time several concerns about whether they Approximately 3.5% of all infants2 (3 per year). themselves truly understood the have a congenital malformation. genomic results and thus, whether Infants with genetic disorders are We invited all of the neonatologists they could effectively communicate at a high risk for mortality. Between and fellows to participate in two the findings to patients. Two 90-minute focus groups about their “ ’ 20% and 30% of all infant deaths3 representation comments were as ’ are due to genetic disorders. attitudes and beliefs regarding follows: We re going to find things ’ Congenital malformations, many whole-genome sequencing (WGS) in out that we re not sure what it means ’ with a genetic etiology, account for newborns. They were offered $100 to and we re going to suggest that it 4 ” “ 30% to 50% of postneonatal deaths. participate in the focus groups. One could mean something that it doesn t, Diagnosing these diseases earlier focus group took place within the at least until we know more. How could lead to effective treatment in first year after WGS testing became to interpret the stuff that nobody ’ some. Alternatively, it might end a available. The other took place 3 knows about including geneticists? diagnostic odyssey and lead to earlier years later. The focus groups were We re finding deletions and changes ” redirection of care toward palliation conducted by trained qualitative that have never been reported before. rather than life prolongation. researchers. The discussions So what do you do with that? were audiotaped, transcribed, and analyzed by using standard The clinicians were worried that GS may be more efficient than other techniques of grounded theory. neither they nor the geneticists forms of diagnostic testing. GS allows Different analysts coded them for would be able to interpret many doctors to test for not just 1 or a “ themes. The analysts then discussed findings and that parents would be dozen genetic variants but every differences and agreed on major even more confused: If I know what variation in the entire genome. GS ’ themes. that information means, I can share testing should be more accurate and RESULTS it. But if I don t know what it means, cost-effective and should generate I cannot just share it, throwing ’ results quicker than testing 1 gene names and numbers at them, ” at a time. The primary disadvantage because it s going to confuse Twelve doctors participated in the of GS is that it inevitably generates a them and confuse me. lot of ambiguous information that is first focus group, and 9 doctors Clinicians felt overwhelmed by difficult to interpret. participated in the second; 62% were “ ’ attending physicians, and the rest the sheer volume of information We wanted to understand how were fellows. There were 14 women presented to them. One said, It s almost like we have the capability to neonatologists thought about the and 7 men. We did not collect any other demographic information on get more information than we know trade-offs between the potential participants. Surprisingly, we found what to do with, than we know how advantages and disadvantages of this ” few differences between the earlier to interpret, than we know what it new technology. We were fortunate focus group and the later one. means. to be at a center that was at the cutting edge of diagnostic GS. Thus, Comments were categorized A related issue was whether the “ ’ we were able to study neonatologists as falling into 4 domains: (1) results were useful for either ’ near the time when GS first became uncertainty about the interpretation diagnosis or prognosis: We don t available as a clinical test. We then of results, (2) issues about parental want to be sounding like we re ’ ’ ’ studied them again 3 years later to consent and limits on their right predicting the future. Because we see if their views had changed. to know genomic information, (3) don t know. I don t think there s Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 143, number s1, January 2019 55 ’ ” ” a way for us to know. We might be but we don t need to get their to eight weeks to come back and I ’ predicting, we might give them the permission. wanted to know something quickly. ” Potential Harms numbers, but there s no way for us “ to know. One made an analogy to mandated newborn metabolic screening: Look “ Although the potential benefits of Some results seemed more definitive at the newborn screen. You send the WGS are immense, there also exists than others: If the results are newborn screen without consent. ” the potential for harms. One of the positive, I think it is okay to make a And sometimes it comes with ” biggest concerns, voiced by several decision based on that. information that could change clinicians, was the potential for the Usefulnesstheir life. of the Results “ Physicians clearly struggle with information to be misused by outside interpreting results from WGS. parties. One said, It has the potential They worry that their own lack of of really being abused by third Physicians had different views about parties like insurance companies knowledge may reflect widespread ” lack of knowledge about the meaning whether GS results were clinically when these kids turn twenty and try of genomic results. They worry that useful in the sense of making a to get insurance. positive difference in the clinical care the lack of knowledge may lead to “ One clinician was concerned that if of a particular infant. Skeptics noted difficulty in explaining results to testing led to decisions to withdraw the following: I have not personally parents and to parental frustration. life-sustaining treatment, then Parental Consent made any big decisions based on the “ it could be abused to advance test results because the results came a eugenic agenda: It gets very back and the patient was already ” “ ’ concerning, if this test can be used to The doctors in these focus groups improving. It took three or four days ’ ’ decide who deserves to live and who were offering GS as part of a to come back. I said okay, we ll do ” doesn t. If that becomes ending their prospective randomized trial of the [GS] but it s not going to change my life, then that becomes eugenics. You efficacy of such testing compared management. ” can get to very weird things, very with standard genomic testing. Thus, Despite this skepticism about the scary things. the consent process for GS was part value of diagnostic testing, many of the consent process for a research Another potential harm was the risk physicians thought that GS results “ study. It may have been more of receiving undesired information: could be useful in other ways. The detailed and rigorous than a typical You might learn something that most frequent response was that the consent for diagnostic testing in the really may never create disease but test led to a diagnosis that was more NICU. The doctors nevertheless had “ creates a risk for disease, breast definitive, which helped both doctors concerns about whether consent was cancer, that sort of thing, and has a and parents make choices: It has … necessary and whether parents could lot of implications forty years later. been really useful in a couple of kids. be adequately informed. Clinicians For a newborn, you kind of wonder We actually made a diagnosis that ” “ noted that parents had to consent for ” some families may not want to know kind of led to a decision that we felt genetic testing to be in the research that. There are implications of was right for the patient. finding things that you may not want study but did not have to consent ” for routine genetic testing, such as a Clinicians used the test results not to know. And how do you handle microarray or a karyotype. Clinicians only to make a diagnosis but also to that? were unsure whether detailed formulate a treatment plan and as “ One doctor cited a case in which test consent ought to be required. One a tool to talk to parents. One said, results led to marital disharmony said that consent was essential and ’ “ If we can give the family some because 1 parent blamed the other that parents alone should decide “ definitive information about some of for the child s illness: A few families whether testing was appropriate or those situations then it helps us and felt like genetic testing would not: We allow parents to make these helps them charge a course of what ’ ” contribute to assigning blame to one decisions. Our job is to make sure ” they think is best for their baby, and parent or the other. Not that we do parents are best informed, and then ” their baby s life. that but that the family would or the they make the decision. All thought that the faster the results extended family would. “ “ Others thought that the decision were returned, the more useful the CONCLUSIONS belonged to the doctors: Do you test could be. One said, Two times order genetic testing without talking I have done it when the babies were to the parents? I think the answer is very, very sick so the tests that I Physician responses to the yes. We should inform the parents needed to know about were six introduction of rapid GS as a clinical Downloaded from www.aappublications.org/news by guest on October 1, 2021 56 KNAPP et al test clustered around 4 main themes: that are on the newborn8 metabolic that may result from testing? The interpretation of results, parental screening panel. clinical use of GS means that clinicians consent, usefulness of the test, and WGS with rapid return of results outside of the field of genomics will potential harms. Many of these raises the stakes regarding all of these have to grapple with these issues responses sound similar to concerns issues. The key questions raised by more than ever. that have been raised about5,6 previous these focus groups are the following: ABBREVIATIONS genetic testing modalities. ‍ What sort of parental consent is Concern about the meaning of test appropriate before allowing a child ’ results dogged some of the earliest to undergo GS? How can physicians CMH: Children s Mercy Hospital attempts to screen children for 7 be better educated to understand and GS: genomic sequencing sickle cell disease. They continue to communicate results? And how can WGS: whole-genome sequencing be a concern regarding many tests we minimize the psychosocial harms

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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Downloaded from www.aappublications.org/news by guest on October 1, 2021 Neonatologists' Attitudes About Diagnostic Whole-Genome Sequencing in the NICU Brett Knapp, Carole Decker and John D. Lantos Pediatrics 2019;143;S54 DOI: 10.1542/peds.2018-1099J

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