Clinical Utility of Rapid Whole Genome Sequencing in Neonatal Patients Receiving Extracorporeal Membrane Oxygenation (ECMO)

doi:10.21203/rs.3.rs-4931447/v1

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Clinical Utility of Rapid Whole Genome Sequencing in Neonatal Patients Receiving Extracorporeal Membrane Oxygenation (ECMO)

https://doi.org/10.21203/rs.3.rs-4931447/v1

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Objective

The objective of this study is to describe the impact of rapid and ultra-rapid whole genome sequencing (rWGS/urWGS) on the care of neonatal intensive care (NICU) patients who require extracorporeal membrane oxygenation (ECMO).

Study Design

This is a retrospective cohort study at a single-center NICU in a tertiary children’s hospital. The study population includes NICU patients treated with ECMO from May 2017 to September 2023. Patients were evaluated for whether whole genome was completed, speed of testing (rapid vs ultra-rapid), diagnostic rate, and clinical utility.

Result

Twenty-six (72%) patients had rWGS/urWGS. A diagnosis associated with the patient’s phenotype was made in 12 patients (46%). A change in clinical management was made due to rWGS/urWGS in 10 patients (38%) including avoidance of imaging studies, decisions regarding goals of care, and screening studies.

Conclusion

This study demonstrates a high diagnostic rate and clinical utility of rWGS/urWGS for NICU patients requiring ECMO.

Health sciences/Health care/Diagnosis/Genetic testing

Biological sciences/Genetics/Clinical genetics/Genetic testing

The goal of precision medicine is to improve patient care and outcomes by identifying underlying genetic diagnoses and directing treatments (1–3). Genetic testing is especially important in the neonatal intensive care unit (NICU) due to the high infant mortality and morbidity that can be associated with genetic conditions (4). There is mounting evidence describing the benefits of rapid and ultra-rapid whole genome sequencing (rWGS/urWGS) in the NICU (3, 5, 6). rWGS/urWGS can have higher diagnostic yield at a reduced time compared to conventional genetic testing, provide actionable information influencing the clinical course of patients, and reduce inpatient health care costs (3, 7–9). While diagnostic and clinical utility of rWGS/urWGS in critically ill infants in the neonatal and pediatric intensive care units has been shown, we are still lacking clear guidelines for when patients benefit most.

Neonates that require extracorporeal membrane oxygenation (ECMO) have a high rate of morbidity and mortality (5). Historically, the most common neonatal diagnoses managed with ECMO in the extracorporeal life support organization (ELSO) registry have included congenital diaphragmatic hernia, meconium aspiration syndrome, and persistent pulmonary hypertension (10). Since 2000, the “Other” diagnostic category has been increasing with an average of 132 cases annually in the 2000s as compared to 76 annual runs in the 1990s (10). At the same time, there has been decreasing use of ECMO for the most common indications. This “Other” category comprises complex clinical conditions that may include genetic conditions. Early genetic diagnosis in this population could lead to targeted therapies, avoidance of invasive studies, and facilitate clinical decision making.

With the apparent benefits of rWGS/urWGS in the NICU, there is increasing interest in utilizing WGS amongst NICU ECMO providers. A national survey from 2022 of level IV NICU centers in the United States found that, if readily available, 63% of centers would consider implementing universal screening of ECMO patients with rapid whole exome or genome sequencing (11).

Studies have demonstrated both the impact of using rWGS/urWGS in the NICU and the clear interest in understanding the benefits of rWGS/urWGS when caring for ECMO patients. This study aims to demonstrate the clinical utility of rWGS/urWGS for NICU patients who require ECMO.

This was a retrospective cohort study at a single-center NICU in a tertiary children’s hospital. This study was approved by the institutional review board at the University of California San Diego. The study population included patients admitted to the NICU who required ECMO from May 2017 to September 2023, evaluating whether they underwent rWGS/urWGS with targeted phenotypic-driven analysis. Outcomes included diagnostic rate, defined as WGS detection of a pathogenic or likely pathogenic variant associated with the phenotype, and clinical utility, defined as a change in management based on test results. Patients were included if they were admitted to the NICU during the study period and required ECMO. rWGS/urWGS samples were obtained either before, during, or after ECMO runs. For those samples collected after ECMO runs, the decision was made prior to decannulation, and collection occurred in the period immediately after coming off ECMO. Exclusion criteria included patients who expired before rWGS/urWGS samples were collected.

The rWGS/urWGS were obtained through various avenues including both after consultation with the division of genetics/dysmorphology and as part of ongoing clinical trials of rWGS/urWGS in acutely ill infants and included GEMINI, NSIGHT2, and Project Baby Bear (12–14).

All rWGS/urWGS was performed by a single clinical diagnostic laboratory, Rady Children’s Institute for Genomic Medicine (RCIGM). The methods for each of these studies has previously been published in detail (12–14). Sequencing was performed as proband only or familial trio analysis. Compared to rWGS, urWGS has a faster turnaround time for prioritization of sequencing and analysis of the most critically ill infants. The current estimated turnaround time for a provisional positive report for urWGS through RCIGM is 3 days or less compared to 5 days or less for rWGS.

A genome-wide phenotype-driven analysis was performed on all patients. Variants related to phenotype were classified according to published guidelines (Richards et al, 2015). Pathogenic or likely pathogenic variants related to phenotype were counted towards the diagnostic rate. Secondary findings were not pursued or reported unless families consented to the disclosure of medically actionable incidental findings

Data on demographic factors, clinical features, other diagnostic testing, results of rWGS/urWGS, outcomes and changes in management was collected in a REDCap database and electronic spreadsheet and analyzed using Microsoft Excel version 16.66.1.

Of the 39 neonates who required ECMO during the study period, 3 were excluded from the study cohort. Two of these patients were excluded as they expired before the collection of rWGS/urWGS results. One patient was excluded as their WGS was not collected immediately after decannulation, but at a different time, as part of a clinical study. This patient’s WGS was not prioritized as a rWGS/urWGS, and it was not obtained with active clinical concerns or questions.

Characteristics of the cohort are listed in Table 1. Forty-two percent of the study population were of Hispanic/Latino descent (Table 1), consistent with the population of the greater San Diego area. There are similar sex and race/ethnicity demographics when comparing the full study cohort and the subset of patients who had rWGS/urWGS (Table 1). There were no documented cases of parental refusal in the 10 patients who required ECMO and did not have rWGS/urWGS sent.

Nineteen (73%) rWGS/urWGS were sent while on ECMO, 7 (27%) were sent before ECMO was initiated, and 1 (4%) was sent after decannulation. The median turnaround time to preliminary report for positive results was 4 days (range 2–14 days) for urWGS and 7 days (range 2–14 days) for rWGS (Table 2). Of the patients who had rWGS/urWGS, a primary variant associated with the patient’s phenotype was made in 12 patients (46%), no diagnosis was made in 13 patients (50%), and a variant of unknown significance was found in 1 of 26 patient (4%) (Table 3). One or more changes in clinical management were made due to rWGS/urWGS results in 10 patients (38%); including avoidance of tests or invasive procedures (2/10, 20%), dietary/medication changes (3/10, 30%), additional screening tests (3/10, 30%), sub-specialty consultation (3/10, 30%), and decisions regarding goals of care (2/10, 20%) (Table 4). One patient had clinical management changes based on a negative rWGS/urWGS result (Table 3,4).

Our study demonstrates that NICU patients requiring ECMO may benefit from rWGS/urWGS with results showing both a high diagnostic rate and clinical utility. The diagnostic rate of 46% in our study follows trends seen in previous studies assessing the use of WGS in cohorts of critically ill infants (3, 15). These previous studies, which have included cohorts with patients with neurodevelopmental disorders and patients critically ill in both the neonatal and pediatric intensive care units, have shown that rWGS/urWGS provides increased diagnosis at improved speed compared to standard genetic testing (3, 7, 15). Additionally, rWGS/urWGS has been shown to impact clinical management (3, 9, 16). The clinical impact resulting from rWGS/urWGS fits into six major categories – no change, dietary/medication changes, additional screening tests, avoidance of tests or invasive procedures, sub-specialty consultation, and decisions regarding goals of care (Table 4). One case, “Patient 12,” had a change in clinical management based on a negative rWGS/urWGS result. This patient had been prenatally diagnosed with lacrimo-auriculo‐dento‐digital (LADD) syndrome. Genomic testing was obtained to rule out other genetic disorders given the severity of the patient’s illness. The negative rWGS, aside from the already known LADD syndrome, resulted in the avoidance of a lung biopsy in this case.

There has been concern about the quality of samples used for genetic testing after blood transfusions (17). It has been shown that DNA from leukoreduced blood products is unlikely to interfere in genetic testing of immunocompetent patients, though there are few studies in the neonatal population (17). Given our population, 18 of the 26 rWGS/urWGS tests (69%) were obtained while on ECMO. Obtaining genetic testing while on ECMO did not appear to affect either the results or clinical utility of rWGS/urWGS in this cohort.

Limitations of the study include that at our institute ECMO is utilized to treat severe neonatal hyperammonemia due to increased availability compared to hemodialysis. Given the genetic basis of many of the conditions associated with inborn errors of metabolism disease, rWGS/urWGS are more likely to return positive results in this patient population. Though, of the four patients who were placed on ECMO for metabolic concerns and had rWGS/urWGS, two had no clinical change based on positive results as changes had already been made based on presumed diagnosis (Table 4). Additionally, assessing clinical utility, especially with negative results, was challenging retrospectively. We found that notes in the electronic health record appeared more likely to note positive rWGS/urWGS results when justifying clinical changes. Further prospective studies into the utility of rWGS/urWGS would better assess the impact of both positive and negative results. We also noted that rWGS and urWGS evolved during our study period as access to urWGS, which provides the fastest time to results, became more readily available.

With increasing access to rWGS/urWGS it is important to understand which patients and clinical scenarios would benefit most. Given the limitations associated with conducting randomized trials on this population, illness severity provides a practical guide, helping clinicians understand when rWGS/urWGS is indicated. Patients who require ECMO are some of the most critically ill patients in the NICU, and this study demonstrates they may be an ideal population for rWGS/urWGS given both the high diagnostic rate and results impacting clinical care. Prospective studies are needed to identify the clinical impact of a universal rWGS/urWGS screening program for neonatal ECMO patients.

Conflict of Interest:

The authors have documented no financial relationships to disclose or Conflicts of Interest (COIs) to resolve.

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Table 1 to 4 are available in the Supplementary Files section.

There is NO conflict of interest to disclose.

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Editorial decision: revise
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You are reading this latest preprint version

Clinical Utility of Rapid Whole Genome Sequencing in Neonatal Patients Receiving Extracorporeal Membrane Oxygenation (ECMO)

Status:

Version 1

Abstract

Objective

Study Design

Result

Conclusion

Introduction

Materials/Subjects and Methods

Results

Discussion

Declarations

Conflict of Interest:

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1