Sources of Unease About the Use of Genome Sequencing for Diagnosing Rare Diseases in Children

See related article, p 237There is a mystery surrounding the uptake of genome sequencing as a diagnostic tool in critical care pediatrics. Genome sequencing offers the promise of quicker and more precise diagnoses of rare diseases in children than is possible with other technologies.1Berg J.S. Agrawal P.B. Bailey Jr., D.B. Beggs A.H. Brenner S.E. Brower A.M. et al.Newborn sequencing in genomic medicine and public health.Pediatrics. 2017; 139: e20162252https://doi.org/10.1542/peds.2016-2252Crossref PubMed Scopus (113) Google Scholar This allows the possibility of innovative and personalized treatment for children with mysterious ailments.2Brittain H.K. Scott R. Thomas E. The rise of the genome and personalised medicine.Clin Med (Lond). 2017; 17: 545-551Crossref PubMed Scopus (37) Google Scholar Furthermore, some studies suggest that such testing, although expensive, actually saves money.3Li C. Vandersluis S. Holobowich C. Ungar W.J. Goh E.S. Boycott K.M. et al.Cost-effectiveness of genome-wide sequencing for unexplained developmental disabilities and multiple congenital anomalies.Genet Med. 2021; 23: 451-460Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar Fears that ambiguous results would lead to increased anxiety and depression among parents have been shown by careful study to be exaggerated.4Berrios C. Koertje C. Noel-MacDonnell J. Soden S. Lantos J. Parents of newborns in the NICU enrolled in genome sequencing research: hopeful, but not naive.Genet Med. 2020; 22: 416-422Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar Parents, for the most part, find the results of genome sequencing useful, even when they are not diagnostic. See related article, p 237 The mystery is that, despite these reported benefits of genome sequencing, clinicians still worry about the clinical utility and the psychological impact of genomic results on parents.5Knapp B. Decker C. Lantos J.D. Neonatologists' attitudes about diagnostic whole-genome sequencing in the NICU.Pediatrics. 2019; 143: S54-S57Crossref PubMed Scopus (11) Google Scholar Payors still seem reticent to cover the cost of genome sequencing testing.6Reuter C.M. Kohler J.N. Bonner D. Zastrow D. Fernandez L. Dries A. et al.Yield of whole exome sequencing in undiagnosed patients facing insurance coverage barriers to genetic testing.J Genet Couns. 2019; 28: 1107-1118Crossref PubMed Scopus (17) Google Scholar Bioethicists still worry that testing will cause harm without benefit and may foreclose a child's right to an open future.7Frankel L.A. Pereira S. McGuire A.L. Potential psychosocial risks of sequencing newborns.Pediatrics. 2016; 137: S24-S29Crossref PubMed Scopus (34) Google Scholar In this volume of The Journal, Franck et al had an opportunity to study the rollout of an innovative program to offer genome sequencing as a first-line test for babies admitted to intensive care units in 5 California hospitals.8Franck L.S. Kriz R.M. Rego S. Garman K. Hobbs C. Dimmock D. J Pediatr. 2021; 237: 237-243.e2Abstract Full Text Full Text PDF Scopus (8) Google Scholar,9Dimmock D. Caylor S. Waldman B. Benson W. Ashburner C. Carmichael J.L. et al.Project Baby Bear: rapid precision care incorporating rWGS in 5 California children's hospitals demonstrates improved clinical outcomes and reduced costs of care.Am J Human Genet. 2021; https://doi.org/10.1016/j.ajhg.2021.05.008Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar Their qualitative study was designed to understand the psychological and organizational factors that led to uptake of this technology. Franck et al showed that uptake depended on having a champion within each institution who believed that genome sequencing was important and devoted time and effort to convince others to use it. Uptake also depended on the education of front-line clinicians about the indications for such testing and the interpretation of results. Multidisciplinary teams of clinicians were needed to define and clarify the roles of each team member to provide seamless patient selection, result interpretation, and post-test counseling. Genome sequencing is unlike other tests; the most obvious difference is that, to interpret a baby's genomic results, the parents also have to be tested. These “trio” genomes allow more precise interpretation of variants found in the child.10Best S. Wou K. Vora N. Van der Veyver I.B. Wapner R. Chitty L.S. Promises, pitfalls and practicalities of prenatal whole exome sequencing.Prenat Diagn. 2018; 38: 10-19Crossref PubMed Scopus (154) Google Scholar The need for trio testing creates logistical, financial, and psychological complexities. There were some curiosities in the original study upon which the study of Franck et al is based. It was designed to test the hypothesis that genome sequencing is cost-effective and clinically useful in a population of critically ill babies even if clinicians do not suspect a genetic etiology in those babies. Thus, the enrollment criteria specified that there was no requirement for a baby to have a suspected genetic diagnosis to be enrolled. Instead, eligibility criteria include all “acutely ill inpatient Medi-Cal beneficiaries who were less than 1 year old…if they were either within 1 week of admission or within 1 week of development of an abnormal response to standard therapy for an underlying condition.” The rationale for this broad definition was clear: “Requiring a suspicion of a genetic disorder will miss half of all genetic conditions leading to neonatal intensive care unit or pediatric intensive care unit admission and delays in ordering testing.”9Dimmock D. Caylor S. Waldman B. Benson W. Ashburner C. Carmichael J.L. et al.Project Baby Bear: rapid precision care incorporating rWGS in 5 California children's hospitals demonstrates improved clinical outcomes and reduced costs of care.Am J Human Genet. 2021; https://doi.org/10.1016/j.ajhg.2021.05.008Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar However, fidelity to this protocol was abysmal. Over the study period, there were 4300 babies younger than 1 year of age admitted to an intensive care unit (ICU). Of those, only 190 (4%) were deemed eligible for the study. There is no detail about the reasons for excluding the other 96% of the babies. Thus, this study, like most studies of genome sequencing, was marred by questions about patient selection and thus about the generalizability of the results. Given the exclusion of most patients in the ICU, it is hard to know whether genome sequencing as a first-line diagnostic test would be useful in the general population of patients in the ICU. A more important issue with this study, as with most studies of genome sequencing, is that there is no gold-standard test against which to measure the rate of false-positive or false-negative results. Thus, when researchers report that genome sequencing led to a “molecular diagnosis,” we do not know whether the molecular diagnosis is truly the cause of a baby's problems. We do know that many babies with genomic variants that are classified as “clearly pathogenic” remain asymptomatic.11Lantos J.D. The false negative phenotype.Pediatrics. 2019; 143: S33-S36Crossref PubMed Scopus (3) Google Scholar There are many reasons why even a plausible genotype–phenotype association may not truly reflect causation. Adams et al analyzed this problem and concluded, “Although the technical sensitivity and technical specificity of sequencing (whether a genetic variant is truly present or not) can be measured relatively easily, there has so far been no effort to determine the clinical sensitivity or clinical specificity (whether the condition is truly present or not) of sequencing in the general population. Thus, it is completely unknown how genomic screening will fare in terms of predictive value.”12Adams M.C. Evans J.P. Henderson G.E. Berg J.S. The promise and peril of genomic screening in the general population.Genet Med. 2016; 18: 593-599Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar They warn that our limited ability to interpret the pathogenicity of rare genomic variation could result in great harm. The only rigorous scientific solution to this problem is to identify a population of patients with a certain genomic variant and follow them carefully to see how many, eventually, develop the symptoms that the molecular diagnosis predicts. Such studies are almost impossibly expensive to do for rare variants because the rarer the variant, the larger the study would need to be to enroll enough infants to generate meaningful follow-up data.13Waltz M. Meagher K.M. Henderson G.E. Goddard K.A. Muessig K. Berg J.S. et al.Assessing the implications of positive genomic screening results.Per Med. 2020; 17: 101-109Crossref PubMed Scopus (5) Google Scholar There is a cautionary tale about false-positive genome sequencing results in the story of newborn screening. New York State initiated newborn screening for Krabbe disease in 2005.14Duffner P.K. Caggana M. Orsini J.J. Wenger D.A. Patterson M.C. Crosley C.J. et al.Newborn screening for Krabbe disease: the New York State model.Pediatr Neurol. 2009; 40 (discussion 253-5): 245-252Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar Over the next decade, they screened more than 2 million children. Of those, 14 children had both low enzyme levels and a genetic variant classified as “clearly pathogenic” for Krabbe disease. Pediatric neurologists followed these children carefully. Over 10 years, only 5 of 14 of those children developed symptoms of Krabbe disease.15Wasserstein M.P. Andriola M. Arnold G. Aron A. Duffner P. Erbe R.W. et al.Clinical outcomes of children with abnormal newborn screening results for Krabbe disease in New York State.Genet Med. 2016; 18: 1235-1243Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar An additional 37 children thought to be at moderate risk after a molecular diagnosis also remained asymptomatic. The molecular diagnosis thus had a false-positive rate between 70% and 90%. To know this, however, required testing 2 million children at a cost of hundreds of millions of dollars. We do not know, and will never know, the rate of false positives for most other molecular diagnoses, including the ones reported in this study. The problem of false-positive tests has important implications for estimates of the cost-effectiveness of genome sequencing. The study by Franck et al asserts that genome sequencing is not only cost-effective (ie, has benefits that are considered worth the cost) but that it is actually cost-saving. That is, they claim that, by implementing genome sequencing, the cost of care was $2-3 million dollars less than it would have been in the absence of such testing. Many treatments are cost-effective. Very few actually save money.16Frakt A. Cost-savings vs. cost-effectiveness and preventative care. The Incidental Economist. A health services research blog.https://theincidentaleconomist.com/wordpress/cost-savings-vs-cost-effectiveness-and-preventative-care/Date: 10/11/2011Date accessed: June 17, 2021Google Scholar Thus, it is important to look at the methodology that led to these estimates of cost saving, which can be found in a supplemental appendix to the parent study upon which this study is based. Most cost-savings were attributed to cases in which genome sequencing led parents and clinicians to opt for comfort care. That occurred in 11 of the 29 cases (38%) in which cost-savings were reported. But would all these babies have died? We will never know. Some might have survived without sequelae. Others may have survived with disabilities. Such an approach risks conflating judgments about medical futility with judgments about quality of life with disabilities.17Deem M.J. Whole-genome sequencing and disability in the NICU: exploring practical and ethical challenges.Pediatrics. 2015; 137: e20153731IGoogle Scholar Imagine that all babies in New York state who had a molecular diagnosis of Krabbe disease had life support withdrawn. That would certainly have resulted in cost savings; however, it would also have led to the deaths of many babies who, as it turned out, had apparently false-positive tests and no serious underlying disease. Unfortunately, in the report by Dimmock et al of these diagnoses and decisions to opt for comfort care, very little information is given about the actual genomic diagnosis. Instead, case descriptions are brief summaries. Some examples including the following: Site 1, case 19 was critically ill with fetal akinesia of unknown etiology. Rapid whole-genome sequencing (rWGS) revealed a diagnosis of a likely pathogenic variant known for its poor prognosis. Family decided to transition to comfort care. Site 3, case 3 presented with a skeletal dysplasia, inguinal hernia, and pulmonary hypoplasia. A gene panel and rWGS were ordered at about the same time; the gene panel results were returned 2 weeks after rWGS with the same diagnosis of a fatal genetic disorder. With the conclusive rWGS report in hand, the family opted for comfort care. Site 3, case 23 had hypotonia at admission. There was a family history of facioscapulohumeral muscular dystrophy. Following a decline in respiratory status requiring continuous ventilator support, rWGS delivered a diagnosis. After many family meetings, the parents decided to transition the baby to comfort care. Site 4, case 4 presented with respiratory failure, presumed hypoxic–ischemic encephalopathy at birth and received therapeutic hypothermia. Subsequently, magnetic resonance imaging of the head and cervical spine was normal. The postcooling electroencephalography background was normal. The child had poor muscle bulk, severe hypotonia since birth with no respiratory effort, small chin, smooth philtrum, and long fingers. rWGS identified a diagnosis that explained the symptoms. Given the baby's poor prognosis, the family made an informed decision to opt for comfort care. In each of these cases, a molecular diagnosis led to a decision to withdraw life support. However, as reported, it is impossible to evaluate whether the diagnoses would have justified such a decision or whether the diagnoses could have been made with genomic results. As noted previously, even if reported, and even if accurately classified as clearly pathogenic (as were the Krabbe variants in New York State,) we do not know the predictive value of such testing. There may be good reasons for clinicians to be uneasy about the clinical use of genome sequencing.18Johnston J. Lantos J.D. Goldenberg A. Chen F. Parens E. Koenig B.A. members of the NSIGHT Ethics and Policy Advisory Board. Sequencing newborns: a call for nuanced use of genomic technologies.Hastings Cent Rep. 2018; 48: S2-S6Crossref PubMed Scopus (36) Google Scholar In the end, there are 2 very different stories to tell about such unease. The one reported in this paper is that clinician unease is the result of misperceptions of cost, lack of education, and inertia.8Franck L.S. Kriz R.M. Rego S. Garman K. Hobbs C. Dimmock D. J Pediatr. 2021; 237: 237-243.e2Abstract Full Text Full Text PDF Scopus (8) Google Scholar For these, a champion who educates clinicians about the facts can overcome these remediable defects in knowledge and enthusiasm. However, it is also possible that clinicians are skeptical because the claims of efficacy and cost-effectiveness are exaggerated in published studies. They may worry, appropriately, that the data, so far, are inconclusive at best and misleading at worst. It may be that clinicians understand that the correlation between molecular diagnoses and clinical reality is inevitably imperfect and that they are appropriately wary of adding ambiguity and uncertainty to their diagnostic approach, their prognostic estimates, and their clinical recommendations to families of complex patients. Implementing Rapid Whole-Genome Sequencing in Critical Care: A Qualitative Study of Facilitators and Barriers to New Technology AdoptionThe Journal of PediatricsVol. 237PreviewTo characterize the views of members of the multi-disciplinary team regarding the implementation of rapid whole-genome sequencing (rWGS) as a first-tier test for critically ill children in diverse children's hospital settings. Full-Text PDF Open AccessRapid whole-genome sequencing in critically Ill children: shifting from unease to evidence, education, and equitable implementationThe Journal of PediatricsVol. 238PreviewIn his editorial, Lantos incorrectly claimed poor protocol adherence because many eligible patients were not enrolled.1 Project Baby Bear was a quality improvement project implementing rapid whole-genome sequencing (rWGS) in infants receiving Medicaid assistance in 5 California hospitals.2 Funding allowed enrollment of 184 infants. Physicians selected patients among those eligible until resources were depleted. Full-Text PDF