Current Practices for Genetic Testing in Neonatal Extracorporeal Membrane Oxygenation: Findings from a National survey

Abstract

Introduction: Comprehensive genetic testing with whole-exome (WES) or whole-genome (WGS) sequencing facilitates diagnosis, can optimize treatment, and may improve outcomes in critically ill neonates, including those requiring extracorporeal membrane oxygenation (ECMO) for respiratory failure. Our objective was to describe practice variation and barriers to the utilization of comprehensive genetic testing for neonates on ECMO.

Methods: We performed a cross-sectional survey of Level IV neonatal intensive care units in the United States across the Children’s Hospitals Neonatal Consortium (CHNC).

Results: Common indications for WES and WGS included concerning phenotype, severity of disease, unexpected postnatal clinical course, and inability to wean from ECMO support. Unexpected severity of disease on ECMO was the most common indication for rapid genetic testing. Cost of utilization was the primary barrier to testing. If rapid WES or WGS were readily available, 63% of centers would consider incorporating universal screening for neonates upon ECMO cannulation.

Conclusion: Despite variation in the use of WES and WGS, universal testing may offer earlier diagnosis and influence the treatment course among neonates on ECMO. Cost is the primary barrier to utilization and most centers would consider incorporating universal screening on ECMO if readily available.

Keywords

extracorporeal membrane oxygenation genetic testing genome sequencing exome sequencing

Introduction

Extracorporeal membrane oxygenation (ECMO) is a life-saving therapy offered to the most critically ill neonates with severe respiratory and/or cardiac failure refractory to maximal medical management.^1–5 Despite its success as a life-sustaining procedure, ECMO is invasive and costly, and carries a mortality of 10–40%.^1,4,6

Whole exome sequencing (WES) sequences all ∼20,000 protein-coding genes or exons, however these account for only ∼2% of the entire genome. Alternatively, whole genome sequencing (WGS) sequences the entire genome, both the protein-coding genes or exons, as well as the non-protein-coding genes, or introns, which may include important regulatory regions.

Historically, for neonates with respiratory failure or pulmonary hypertension of unclear etiology, invasive diagnostic testing such as a lung biopsy was pursued while on ECMO.⁷ However, lung biopsy is not without risk including air leak and bleeding. Recognition of underlying genetic defects, such as alveolar capillary dysplasia or surfactant protein deficiency disorders, has led to a shift from lung biopsy to genetic testing as the primary modality for diagnosis. Advances in technology have led to availability of increasingly sophisticated diagnostic tests. While more comprehensive genetic testing can allow a diagnosis to be made non-invasively, these tests have limitations. For example, chromosomal microarrays are only able to detect deletions and duplications while multigene panel testing only sequences a few genes of interest and does not have parental samples to interpret variants. Whole exome sequencing and WGS have the potential to provide rapid diagnosis, optimize treatments, and improve outcomes in critically ill neonates, including those requiring ECMO.^8–20 Information obtained through comprehensive genetic testing with WES and WGS may alter the course of ECMO through changes in initiation or management, or in some situations, discontinuation of ECMO.

Costs and turnaround time for comprehensive tests such as WES and WGS vary, with some centers waiting several weeks for results. With newer technology, select centers offer “ultra-rapid” protocols with a turnaround time of 1–3 days. Multiple studies have shown benefits of universal screening with rapid WGS in neonatal intensive care units (NICUs), including changes in management and improvements in diagnostic efficacy.^8-12 In 2021, Dimmock et al. found that 40% of infants received a diagnosis by rapid WGS and 32% of infants had a subsequent change in medical management. Rapid WGS also led to $2.2–2.9 million in cost savings.⁹ Similarly, in a large multi-center randomized controlled trial, infants with WGS performed in 15 days were twice as likely to have a change in medical management compared to infants who had WGS with a turnaround time of 60 days.¹⁰ While rapid WES and WGS are promising tools to aid in the management and prognostication of neonates on ECMO, little is known about their systematic use.³ Thus, we sought to evaluate the current practices, variation in, and barriers to the utilization of comprehensive genetic testing among neonatal ECMO patients in Level IV NICUs.

Materials and methods

Data source

The Children’s Hospitals Neonatal Consortium (CHNC) is a multicenter collaborative of 41 Level IV NICUs in Children’s Hospitals in the United States and Canada dedicated to developing quality and research initiatives across participating institutions. Participating NICUs have > 400 annual admissions or > 25 NICU beds, and > 50% outborn neonates.²¹

Study design

Cross-sectional survey of practice for neonatal respiratory ECMO among 41 Level IV neonatal intensive care units across the CHNC from June to September 2021. The survey was created, and study data were collected using Research Electronic Data Capture (REDCap) hosted at the Children’s Hospital of Philadelphia (CHOP).

Survey development

The survey was developed by the study investigators who are members of the CHNC ECMO Focus Group, a collaborative group of neonatologists and pediatric surgeons from CHNC participating NICUs with interest and expertise in ECMO. Survey questions underwent several iterations for readability, clarity, and understandability based on feedback from members of the focus group. The final survey contained 19 questions (Supplemental Table 1).

Survey distribution

The survey was distributed to CHNC site sponsors by email via the organizational listserv in June 2021. The email contained a link to the online survey which collected data in REDCap. A survey reminder was sent twice between June and September 2021. Surveys were completed collaboratively between neonatologists and geneticists for accuracy.

Statistical analysis

Data analysis was conducted using descriptive statistics. Simple reporting of survey results are reflected in results. No secondary analysis was performed due to sample size.

Results

Survey results from 27/41 CHNC centers are summarized in Tables 1 to 3. All centers that completed the survey were high volume ECMO centers within the United States with >400 annual admissions or > 25 NICU beds, and >50% outborn neonates. Responses were curated from input of both neonatologists and genetic specialists for accuracy of site practice. As shown in Table 1, all centers currently utilize microarray testing, followed by WES (74%, N = 20) or WGS (30%, N = 8), in the evaluation of any critically ill neonate. Multigene panel testing is used by 48% (N = 13) of centers.

Table 1.

Survey responses - Likelihood of ordering genetic testing for critically ill neonates, neonates on ECMO with identified and unidentified causes of pulmonary hypertension.

	Critically ill neonates	Neonates on ECMO with pulmonary hypertension of unclear etiology	Neonates on ECMO with an identified cause of pulmonary hypertension
Genetic test	N (%)	N (%)	N (%)
Karyotype	9 (33)	4 (15)	6 (22)
Microarray	27 (100)	20 (74)	16 (59)
Single gene testing	5 (19)	3 (11)	0 (0)
Multigene panel testing	13 (48)	12 (44)	4 (15)
WES without copy number assessment	7 (26)	6 (22)	3 (11)
WES with copy number assessment	13 (48)	9 (33)	4 (15)
WGS without copy number assessment	1 (4)	1 (4)	0 (0)
WGS with copy number assessment	7 (26)	5 (19)	1 (4)
Pharmacogenomic testing	1 (4)	0 (0)	0 (0)
Diagnostic tissue biopsy	5 (19)	2 (7)	1 (4)
Autopsy	14 (52)	7 (26)	4 (15)
None	0 (0)	0 (0)	13 (48)

N: Center.

Table 2.

Utilization of comprehensive genetic testing (WES/WGS) for neonates on ECMO.

Comprehensive testing	N (%)
WES ± copy number assessment	16 (59)
WGS ± copy number assessment	5 (19)
Both	4 (15)
Unsure	2 (7)
Utilization of comprehensive testing (WES/WGS)
Screening for all	1 (4)
Screening for all non-CDH patients	2 (7)
Concern for inheritable condition based on family history	21 (78)
Phenotype on exam concerning for genetic disorder	25 (93)
Severity of disease inconsistent with primary ECMO indication	20 (74)
Inability to wean from ECMO support	19 (70)
Severe unexpected complications related to ECMO	20 (74)
Abnormal response to drug pharmacokinetics	0 (0)
Death on ECMO	8 (30)
Other	1 (4)
Timing of comprehensive testing (WES/WGS)
Prior to ECMO consideration	17 (63)
Upon cannulation	10 (37)
During ECMO without complication	10 (37)
Complications related to ECMO	8 (30)
Inability to wean from ECMO	19 (70)
Upon death/decannulation	11 (41)
Other	2 (7)
Utilization of rapid testing
All ECMO patients	4 (15)
All non-CDH ECMO patients	1 (4)
Only for patients with severity of disease inconsistent with primary ECMO indication	17 (63)
N/A	5 (19)
Priority of testing
Sequential: i.e. Microarray followed by WES or WGS	17 (63)
Comprehensive: Microarray and WES or WGS with copy number assessment	9 (33)
WES or WGS without copy number	1 (4)

N: Center.

Table 3.

Reported barriers to testing and time to result for comprehensive genetic testing (WES/WGS) for neonates on ECMO.

Barriers to testing	N (%)
Cost of utilization	20 (74)
Complications from testing process	1 (4)
Disclosure of testing results	3 (11)
Lack of theoretical benefit	5 (19)
Facility policies	7 (26)
Other	4 (15)
Turnaround time for preliminary results of rapid testing
1–3 days	4 (15)
3–5 days	4 (15)
5–7 days	6 (22)
7–10 days	6 (22)
10–14 days	4 (15)
>2 weeks	3 (11)
Turnaround time for final results of rapid testing
1–3 days	0 (0)
3–5 days	2 (7)
5–7 days	2 (7)
7–10 days	5 (19)
10–14 days	9 (33)
>2 weeks	9 (33)

N: Center.

For neonates on ECMO specifically, WES and WGS were more likely to be utilized in neonates with pulmonary hypertension of unclear etiology, compared to those with a known etiology such as congenital diaphragmatic hernia (CDH). For neonates undergoing ECMO support with pulmonary hypertension of unclear etiology, 74% (N = 20) send chromosomal microarray, 44% (N = 12) send multigene panel testing such as an interstitial lung disease gene panel or a pulmonary hypertension gene panel, 56% (N = 15) send WES, and 22% (N = 6) send WGS. For neonates undergoing ECMO support with an identified cause of pulmonary hypertension, such as CDH, 59% (N = 16) send microarray, 15% (N = 4) send multigene panel testing, 26% (N = 7) send WES, and 4% (N = 1) send WGS. Autopsy was recommended for critically ill neonates in 52% of centers; in 26% of centers autopsy was recommended for neonates with pulmonary hypertension of unclear etiology and in 15% of centers for neonates with an identified cause of pulmonary hypertension. These results are summarized in Table 1.

As shown in Table 2, the most common indications for WES and WGS included concern for an inheritable condition based on family history (78%, N = 21), phenotype on exam concerning for a genetic disorder (93%, N = 25), severity of disease inconsistent with primary ECMO indication (74%, N = 20), inability to wean from ECMO support (70%, N = 19), and severe unexpected complications related to ECMO (74%, N = 20). While inability to wean from ECMO support was the most common indication for sending comprehensive testing, there are centers that send testing prior to and upon ECMO cannulation. For comprehensive genetic testing, 59% (N = 16) use WES and 19% (N = 5) use WGS. Genetic testing is most often done sequentially with microarray followed by WES or WGS if microarray returns non-diagnostic in 63% (N = 17) compared to comprehensive testing with WES or WGS that includes copy number evaluation as first line testing in 33% (N = 9). “Rapid” WES or WGS are most often offered for patients with severity of disease inconsistent with primary ECMO indication in 63% (N = 17). In 78% (N = 21), testing is recommended collaboratively between geneticists and neonatologists and in 74% (N = 20), results are disclosed collaboratively between geneticists and neonatologists. These results are shown in Table 2.

As shown in Table 3, the turnaround time for the results of rapid testing is highly variable. Preliminary results are most often available within 7 days and final results within 14 days. Cost of utilization is the primary barrier to testing in 74% (N = 20), but prolonged time to results may also represent a barrier to clinical utility. As shown in Figure 1, if cost were not an issue, most centers responded that they would be more likely to send WES and WGS in ECMO patients. Hospitals absorb the cost with institutional billing in 44% (N = 12) compared to insurance billing in 15% (N = 4). Twenty-six percent (N = 7) were unsure of how costs were paid. If rapid WES or WGS were readily available, 63% (N=17) would consider incorporating universal screening on ECMO patients upon cannulation.

Figure 1.

Removing cost of utilization, ECMO site likelihood to order comprehensive genetic testing (WES/WGS) versus diagnostic biopsy or autopsy.

Discussion

Postnatal genetic testing utilization varies widely among ECMO centers. While all centers currently send microarray testing in the evaluation of critically ill neonates, use of comprehensive genetic testing is variable. Despite these variations, most centers would consider sending WES or WGS on neonatal ECMO patients if the cost of testing was not prohibitive.

Not surprisingly, WES and WGS were more likely to be sent in neonates on ECMO with pulmonary hypertension of unclear etiology compared to those with an identified cause of pulmonary hypertension, such as CDH. Similarly, rapid WES or WGS were offered most often for patients with severity of disease inconsistent with primary ECMO indication. In neonates with pulmonary hypertension of unclear etiology or unexpected severity of disease, a genetic diagnosis may explain the need for ECMO and guide decisions about the remainder of the ECMO course.

Multigene panel testing, often done as an interstitial lung disease panel or surfactant dysfunction panel, is sent by 48% of centers for critically ill neonates compared to 44% of centers for neonates with pulmonary hypertension of unclear etiology and only 15% of centers for pulmonary hypertension with an identified cause. Similar to WES and WGS, these panels are often considered when neonates are not responding to ECMO as expected. Despite containing fewer genes, many of these panels cannot be performed on a rapid basis like WES and WGS and take at least 4 weeks to result. These panels also do not incorporate parental samples making variants of uncertain significance more difficult to interpret.

Cost of utilization was the primary testing barrier identified, with WGS most likely to be incorporated if cost was not a barrier. However, multiple studies have demonstrated the cost effectiveness of WES and WGS in critically ill neonates.^9,16,20 Whole exome sequencing and WGS costs are also expected to decrease precipitously over the next few decades.²² Comprehensive genetic testing has the potential to be particularly cost effective in neonates on ECMO as a better understanding of the underlying genetic etiology may improve prognostication and allow for more thoughtful discussions with families about continuing or limiting care as soon as a few days into an ECMO course. Genetic testing a priori may also limit ECMO utilization if the therapy has no potential benefit.

Historically, the turnaround time of the results of WES and WGS was a significant barrier to their use as a screening tool. This barrier remains for many centers where results may not be available for 1–2 weeks. Rapid diagnosis, especially in cases where results may be available in 1–3 days, may reduce the need for invasive diagnostic testing such as a lung biopsy while on ECMO. At most centers, testing is done sequentially with microarray followed by WES or WGS if microarray is non-diagnostic. However, this is likely to change in the future as most laboratories now offer WES and WGS with copy number analysis, making way for WES, and more likely WGS, to become first line tests. Universal screening with WES or WGS would also be more cost effective than sequential testing by reducing the number of tests sent for each neonate, decreasing time to result of testing, and theoretically reducing duration of treatment and/or duration of hospitalization. Additional barriers included obtaining testing approval, completing a comprehensive consent, specifically having the support of geneticists, and obtaining parental samples. Parental samples are important as testing sent as a trio with a sample from the neonate, as well as from both parents, is the most informative for interpretation.

Given that the majority of centers would consider incorporating universal screening with rapid WES or WGS for neonates upon ECMO cannulation if readily available, these are likely to become standard of care for neonates on ECMO. While genetic testing would ideally be sent at or before cannulation, it can be sent at any time during an ECMO course as testing is performed on white blood cells. This is contrary to common misconceptions that genetic testing cannot be sent after blood transfusions or initiation of ECMO.

This survey also found low use of autopsy for neonates on ECMO, which is consistent with a recent CHNC study that found low utilization and high variability in the use of autopsy for neonates in level IV NICUs.²³ Universal WES and WGS may provide a less invasive diagnosis for many of these neonates and provide closure and recurrence risk information for families.

The widespread availability of rapid and “ultra-rapid” WES and WGS brings up several ethical questions. In the era of rapid genetic diagnosis, there may be neonates for whom ECMO is or is not offered based on a coexisting genetic diagnosis, which may not fit the traditional criteria of reversibility. This is further complicated by the expanded use of genetic testing, which has led to increased diagnostic rates in patients with milder phenotypes who may not have received a molecular diagnosis previously and may impact who is offered ECMO. This broadening of the phenotypic spectrum for many conditions complicates the decision of who is a candidate for ECMO. There may also be diagnoses where there is not enough evidence to support or refute the utility of ECMO. There are also many interstitital lung diseases that may be diagnosed with genetic testing including alveolar capillary dysplasia and various surfactant deficiencies wherein the approach may have to be individualized. For example, a relevant diagnosis may redirect the ECMO course from expected recovery to a potential bridge to lung transplant, or may exclude patients who have a lethal diagnosis and are not transplant candidates. Thus, it is important that ECMO providers collaborate with geneticists in the interpretation of genetic testing and counseling of families.

The strengths of this study include that it is the largest, and to our knowledge, the only, description of genetic testing practices during neonatal ECMO utilization. Our survey incorporated responses from multiple children’s hospitals with a good response rate of 66%. Limitations include a survey design which may introduce bias by individual respondents. The survey only included large referral-based level IV NICUs, almost all of whom are affiliated with robust academic centers and pediatric subspecialists. Given this, our findings may not be as applicable to other non-academic based NICUs that provide neonatal ECMO, but may have limited geneticist support to offer and interpret complex test results, which may contribute to disparities in care. While this survey found that most centers would consider incorporating universal screening with WES or WGS for neonates on ECMO for respiratory failure, future work will still be needed to demonstrate benefit of widespread comprehensive genetic testing for neonatal ECMO patients.

Conclusions

WES and WGS are emerging as the first line diagnostic tests for critically ill neonates. Despite variation in the use of WES and WGS, rapid testing may offer earlier diagnosis, be useful for prognostication, and influence treatment course among neonates on ECMO. Cost is the primary barrier to utilization and most centers would consider incorporating universal screening with WES or WGS for neonates on ECMO if the testing was economical and ultra rapid testing was readily available. Additional barriers include lack of access to rapid testing with prolonged turnaround time of results.

Supplemental Material

Supplemental Material - Current practices for genetic testing in neonatal extracorporeal membrane oxygenation: Findings from a National survey

Supplemental Material for Current practices for genetic testing in neonatal extracorporeal membrane oxygenation: Findings from a National survey by KT Wild, Franscesca Miquel-Verges, Natalie E Rintoul, Robert DiGeronimo, Sarah Keene, Shannon E Hamrick, Burhan Mahmood, Rakesh Rao, Nicholas R Carr, on behalf of the Children’s Hospitals Neonatal Consortium (CHNC) in Perfusion

Footnotes

Acknowledgements

Beverly Brozanski, Jacquelyn Evans, Theresa Grover, Karna Murthy, Michael Padula, Eugenia Pallotto, Anthony Piazza, Kristina Reber and Billie Short and ex-officio David Durand, Francine Dykes, Jeanette Asselin), are executive members of the Children’s Hospitals Neonatal Consortium, Inc., who developed and manage the CHND (). For more information, please contact: exec@thechnc.org.

We are indebted to the following CHNC participating institutions that serve the infants and their families; these institutions (and their site sponsors) also have invested in and continue to participate in the Children’s Hospital’s Neonatal Database (CHND):

1. Alfred I. duPont Hospital for Children, Wilmington, DE (Kevin Sullivan)

2. All Children’s Hospital Johns Hopkins Medicine, St. Petersburg, FL (Victor McKay)

3. American Family Hospital, Madison, WI (Jamie Limjoco, Lori Haack)

4. Advent Health for Children, Orlando, FL (Narenda Dereddy, Raj Wadhawan)

5. Ann & Robert H. Lurie Children’s Hospital of Chicago; Chicago, IL (Karna Murthy, Gustave Falciglia)

6. Arkansas Children’s Hospital, Little Rock, AR (Becky Rogers)

7. Boston Children’s Hospital, Boston, MA (Anne Hansen)

8. Brenner Children’s Hospital, Winston-Salem, NC (Cherrie Welch)

9. Cincinnati Children’s Hospital; Cincinnati, OH (Beth Haberman)

10. Children’s Healthcare of Atlanta at Egleston; Atlanta, GA (Anthony Piazza)

11. Children’s Healthcare of Atlanta at Scottish Rite; Atlanta, GA (Gregory Sysyn)

12. Children’s Hospital and Medical Center, Omaha, NE (Nicole Birge)

13. Children’s Hospital Colorado, Aurora, CO (Theresa Grover)

14. Children’s Hospital of Orange County; Orange, CA (Michel Mikhael, Irfan Ahmad)

15. Children’s Hospital of Philadelphia; Philadelphia, PA (Michael Padula, David Munson)

16. Children’s Hospital of Pittsburgh of UPMC; Pittsburgh, PA (Toby Yanowitz)

17. Children’s Hospital of Wisconsin, Milwaukee, WI (Michael Uhing, Ankur Datta)

18. Children’s Medical Center; Dallas, TX (Rashmin Savani, Luc Brion)

19. Children’s Mercy Hospitals and Clinics, Kansas City, MO (Julie Weiner)

20. Children’s National Medical Center, Washington, DC (Billie Short, Lamia Soghier)

21. Children’s of Alabama, Birmingham, AL (Carl Coghill, Allison Black)

22. Children’s Hospital of Los Angeles, Los Angeles, CA (Rachel Chapman)

23. Children’s Hospital of Michigan, Detroit, MI (Girija Natarajan)

24. Connecticut Children’s Medical Center, Hartford, CT (AnneMarie Golioto)

25. Cook Children’s Medical Center, Fort Worth, TX (Jonathan Nedrelow, Annie Chi, Yvette Johnson)

26. Dell Children’s Hospital, Austin, TX (Ashley Lucke, Molly Pont)

27. Hospital for Sick Children, Toronto, Ontario, Canada (Kyong-Soon Lee)

28. Le Bonheur Children’s Hospital, Memphis, TN (Mark Weems)

29. Levine Children’s Hospital, Charlotte, NC (Eugenia Pallotto)

30. Nationwide Children’s Hospital, Columbus, OH (Thomas Bartman)

31. Nemours Children’s Hospital, Orlando, FL (Aaron Weiss)

32. Oklahoma Children’s Hospital, Oklahoma City, OK (Trent Tibble)

33. Primary Children’s Hospital, Salt Lake City, UT (Con Yee Ling, Shrena Patel)

34. Rady Children’s Hospital, San Diego, CA (Mark Speziale, Brian Lane, Laurel Moyer)

35. Riley Children’s Hospital, Indianapolis, IN (Rebecca Rose)

36. Seattle Children’s Hospital, Seattle, WA (Elizabeth Jacobsen-Misbe, Robert DiGeronimo)

37. Stead Family Children’s Hospital, Iowa City, IA (Julie Lindower)

38. St Christopher’s Hospital for Children, Philadelphia, PA (Vilmaris Quinones)

39. St. Louis Children’s Hospital, St. Louis, MO (Beverly Brozanski, Rakesh Rao)

40. Texas Children’s Hospital, Houston; Houston, TX (Kristina Reber, Lakshmi Khatakam)

41. UCSF Benioff Children’s Hospital Oakland; Oakland, CA (Priscilla Joe)

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

This manuscript is original research, has not been previously published and has not been submitted for publication elsewhere while under consideration.

Author Note

Data and references can be made available upon request.

ORCID iDs

KT Wild

Rakesh Rao

Nicholas R Carr

Supplemental Material

Supplemental material for this article is available online.

References

Extracorporal life support organization (ELSO) ECLS registry report: international summary, January 2020. 2020.

Paden

Conrad

Rycus

, et al. Extracorporeal life support organization registry report 2012. ASAIO J 2013; 59(3): 202–210.

Morrison

Kirsch

. Pushing the ECMO envelope for children with genetic conditions. Pediatr Crit Care Med 2017; 18(9): 896–897.

Paden

Rycus

Thiagarajan

, et al. Update and outcomes in extracorporeal life support. Semin Perinatol 2014; 38(2): 65–70.

Wild

Rintoul

Kattan

, et al. Extracorporeal life support organization (ELSO): guidelines for neonatal respiratory failure. ASAIO J 2020; 66(5): 463–470.

Ijsselstijn

van Heijst

. Long-term outcome of children treated with neonatal extracorporeal membrane oxygenation: increasing problems with increasing age. Semin Perinatol 2014; 38(2): 114–121.

Inwald

Brown

Gensini

, et al. Open lung biopsy in neonatal and paediatric patients referred for extracorporeal membrane oxygenation (Ecmo). Thorax 2004; 59(4): 328–333.

Dimmock

Clark

Gaughran

, et al. An RCT of rapid genomic sequencing among seriously ill infants results in high clinical utility, changes in management, and low perceived harm. Am J Hum Genet 2020; 107(5): 942–952.

Dimmock

Caylor

Waldman

, 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 Hum Genet 2021; 108(7): 1231–1238.

10.

The NICUSeq Study Group Krantz

Medne

, et al. Effect of whole-genome sequencing on the clinical management of acutely ill infants with suspected genetic disease: a randomized clinical trial. JAMA Pediatr . Published online September 27, 2021.

11.

Meng

Pammi

Saronwala

, et al. Use of exome sequencing for infants in intensive care units: ascertainment of severe single-gene disorders and effect on medical management. JAMA Pediatr 2017; 171(12): e173438.

12.

Kingsmore

Cakici

Clark

, et al. A randomized, controlled trial of the analytic and diagnostic performance of singleton and trio, rapid genome and exome sequencing in ill infants. Am J Hum Genet 2019; 105(4): 719–733.

13.

Elliott

du Souich

Lehman

, et al. RAPIDOMICS: rapid genome-wide sequencing in a neonatal intensive care unit-successes and challenges. Eur J Med Genet 2019; 178(8): 1207–1218.

14.

Bell

. Ethical implications of rapid whole-genome sequencing in neonates. Neonatal Netw 2018; 37(1): 42–44.

15.

Smith

du Souich

Dragojlovic

, et al. Genetic counseling considerations with rapid genome-wide sequencing in a neonatal intensive care unit. J Genet Couns 2019; 28(2): 263–272.

16.

Farnaes

Hildreth

Sweeney

, et al. Rapid whole-genome sequencing decreases infant morbidity and cost of hospitalization. NPJ Genom Med 2018; 3: 10.

17.

Duyzend

. Non-diagnostic results from rapid exome sequencing can change clinical management in the critical care setting. J Pediatr 2020; 226: 1–4.

18.

Kingsmore

. Is rapid exome sequencing standard of care in the neonatal and pediatric intensive care units? J Pediatr 2020.

19.

Brunelli

Mao

Jenkins

, et al. A rapid gene sequencing panel strategy to facilitate precision neonatal medicine. Am J Med Genet A 2017; 173(7): 1979–1982.

20.

Stark

Schofield

Martyn

, et al. Does genomic sequencing early in the diagnostic trajectory make a difference? A follow-up study of clinical outcomes and cost-effectiveness. Genet Med 2019; 21(1): 173–180. DOI: 10.1038/s41436-018-0006-8

21.

Murthy

Dykes

Padula

, et al. The Children’s Hospitals Neonatal database: an overview of patient complexity, outcomes and variation in care. J Perinatol 2014; 34(8): 582–586.

22.

Denny

Collins

. Precision medicine in 2030-seven ways to transform healthcare. Cell 2021; 184(6): 1415–1419. DOI: 10.1016/j.cell.2021.01.015

23.

Datta

Niehaus

Weiner

, et al. Inter-center variation in autopsy practices among regional neonatal intensive care units (Nicus). J Perinatol 2021; 41(12): 2820–2825.

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