Hello. Thanks again for staying. My name's Catherine, or Katie Rodriguez, and I'm a third-year Pediatric Critical Care Fellow at the University of California San Diego Rady Children's Hospital. Today I'll be discussing the results of a multicenter cohort analysis of rapid whole genome sequencing and its impact in the Pediatric Intensive Care Unit. I have no disclosures. Genetic disorders are a significant contributor to morbidity and mortality in pediatric critical care. Rapid whole genome sequencing can now be completed in as little as two to three days. Over 30 studies since 2012 have shown that rapid whole genome sequencing is an effective method for diagnosing genetic diseases in infants in NICUs and improving outcomes by precision medicine. There remains a population of undiagnosed patients with rare genetic diseases who present critically ill to the PICU, and the application of RWGS in this setting is not yet fully understood. While individual disorders are rare, over 6,000 monogenic disorders have been described. Over 250 new monogenic disorders are discovered annually. The data in NICU populations with patients under four months reports a diagnostic rate ranging from 36 to 73 percent, and changes in management occurring in as high as 72 percent of diagnosed patients. PICU-PICU studies exist. In a single center study looking at 38 PICU patients, our group has reported a 45 percent diagnostic rate, with a 24 percent rate of changes in PICU management. This study aims to determine the clinical utility of rapid whole genome sequencing in the PICU, to assess the diagnostic rate of RWGS, and to evaluate clinical features of patients with a molecular diagnosis identified by sequencing. This is an ambidirectional cohort study conducted at three tertiary children's hospitals from May of 2016 to July of 2022. Patients were nominated by the care team when suspicion — when etiology of illness was unclear and prior suspicion of a genetic disorder was not required. Eighty children were eligible for inclusion. Rapid whole genome sequencing with targeted phenotype-driven analysis was performed. Data collection was retrospective prior to May 2021 at Site 1, and January 2022 at Site 3, followed by prospective enrollment. At Site 2, prospective enrollment began in December of 2021. Data collection for all sites was completed in July of 2022. Clinical diagnostic utility of RWGS was determined via multifaceted assessments, including medical record review, surveys of treating physicians, and surveys of patient families. Patient age ranged from zero through 17 years. Sixty-four percent of patients in this study were under one year of age at the time of admission, and 36 percent of patients were aged between one and 17 years. The average age was 2.8 years, and the median age was about three months. Fifty-six percent of patients sequenced were male, and 44 percent were female. The majority of patients sequenced were white and non-Hispanic. Fifty-two of the 80 genomes identified a causal genetic etiology, yielding a diagnostic rate of 65 percent. The molecular diagnosis was considered to completely describe the phenotypic presentation in 87 percent of the diagnosed cases. Average turnaround time for results was 10 days, with preliminary results returning as quickly as 36 hours. Genome sequencing could be ordered by physicians of any specialty. Fifty-five percent of genomes were ordered by intensivists, and 62 percent of those were diagnostic. Forty percent of genomes were ordered by geneticists. Seventy-five percent of those were diagnostic. Five percent of genomes were ordered by physicians of other subspecialties. We found high diagnostic utility among patients with primarily cardiac symptoms, such as congenital heart disease, sudden cardiac arrest, or suspected channelopathy, with 72 percent receiving a molecular diagnosis. Patients with suspected neurologic disease had a 50 percent rate of molecular diagnosis. Interestingly, 74 percent of patients with respiratory pathology received a molecular diagnosis. Eighty-seven percent of patients with renal failure requiring dialysis had diagnostic genomes. The remaining clinical course events were seen in patients with diagnostic genomes about two-thirds of the time. On average, all patients, regardless of genome result, had three events during their clinical course. Rapid whole genome sequencing molecular diagnosis was responsible for changes in management in 42 percent of the diagnosed patients. Thirty-eight percent of the changes occurred acutely, affecting management in the ICU. Sixty-two percent of the changes were subacute, affecting management throughout the remainder of the hospitalization and after discharge. Management changes made from diagnostic genomes resulted in results including medications either stopped or started, procedures avoided or performed, palliative care consultations, changes in code status, therapies initiated, and surveillance measures, including screening labs, imaging, or subspecialty follow-up. Some examples of these management changes included avoiding a renal biopsy, selecting appropriate antiarrhythmic therapy, and initiation of mitochondrial disease medications. Family screening was recommended 54 percent of the time. Of the changes occurring in the ICU setting, 56 percent were medication-related and 44 percent were procedure-related. Families were sent to treating providers regarding the clinical utility of RWGS. Physicians felt RWGS led to a direct change in management 39 percent of the time. Forty-six percent felt that obtaining the genome helped to make a positive impact on their relationship with the patient's family, and 66 percent felt that the genome results enhanced their understanding of the patient's prognosis. I would like to briefly discuss two cases. The first case is of a 14-year-old girl who presented in ventricular fibrillation cardiac arrest. Her initial echocardiogram revealed a new onset dilated cardiomyopathy with a left ventricular ejection fraction of 3 percent. At the time, it was unclear if the etiology of her heart failure was infectious or genetic. A diagnostic genome resulted within 48 hours with a pathogenic variant of the LMNA gene. Due to this variant, she was promptly listed for a heart transplant despite the incomplete infectious workup. She received a heart one week after admission. The second case is of a 2-year-old boy who presented in respiratory distress. He was found to have a necrotizing complex pneumonia. His genome resulted in eight days with a homozygous ATM gene variant suggesting a diagnosis of ataxia telangiectasia. The patient lacked classic physical exam findings of AT and the diagnosis had not been previously considered. Due to this timely diagnosis, the patient was referred to immunology, instructed to avoid cancer-causing radiation exposure, and enrolled in developmental services. In conclusion, we found that molecular diagnosis of genetic disorders in the PICU population frequently results in important changes in management. These changes often occur in the critical care setting, making rapid case identification and testing imperative. Diagnostic rates are highest in patients with cardiac, neurologic, and respiratory disease processes. Intensivists have similar ability as geneticists to identify patients who would benefit from RWGS. Providers feel that RWGS enhances prognostication and improves their relationship with patient families. Increasing availability of RWGS can significantly impact patient care and assist families in making difficult decisions during times of critical illness. Fortunately, insurance coverage and testing access are beginning to show improvement. Medicaid policies now exist for ICU patients aged less than one year in Oregon, California, Michigan, Maryland, and Louisiana. Minnesota is the first state to have a Medicaid coverage plan for the entire pediatric population in ICUs. Moving forward, we are continuing to enroll in this prospective multicenter study. We have recently added a fourth site to the study, and we continue to incorporate both provider and family surveys to better assess the impact rapid whole genome sequencing has on patient care. Thank you for your time. I'd like to thank my collaborators at the Rady Children's Institute for Genomic Medicine, Children's Hospital of Illinois, and Cedars-Sinai. I could not have accomplished this without this amazing group of physicians, genetic counselors, research nurses, and nurse practitioners, especially my PI, Dr. Kufal. I would also like to thank all of the physicians who took part in submitting the many surveys and the patients and their families for being part of this project. I'll take any questions. Thank you. Absolutely. I think that that's a, you know, a very important question because we do have, we, especially in RADIs, we've kind of opted in the ICU setting to go straight for whole genome sequencing as opposed to panels just because of the availability to get things back in real time. And we have had good success with reimbursement from insurance, and that's one of our main objectives is to continue to encourage that. Absolutely, actually, in our initial single center paper, we've done a secondary Adelphi analysis looking at the cost-effectiveness, and that particular paper was skewed because a patient was diagnosed with like a lifetime need of factor for like a coagulopathy where they were continuously need, and that was a very expensive ad, but, and that was kind of weighed in terms of cost years, life years, but I think generally the cost of each genome has been going down and becoming more affordable, and then also when we look at, like most of these patients are on, many of them are on ECMO, CRT, like the cost of the ICU stay, and if this maybe leads to a withdrawal of life-sustaining support or some sort of redirection, then you can kind of say that maybe we've saved many days of that, and I think the intangibles of a negative genome, which I've really struggled to kind of capture in this presentation, but just the, which obviously people who are concerned about the bottom line maybe don't really think about, but just having the family feel confident that they've done all the testing possible and that there is nothing else to do has been really important. Thank you.

Pediatric Critical Care Fellow

rapid whole genome sequencing

Pediatric Intensive Care Unit

clinical utility

diagnostic rate