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34 Results


Rapid Whole-Genome Sequencing and Clinical Management in the PICU: A Multicenter Cohort, 2016-2023

Rodriguez KM, Vaught J, Salz L, Foley J, Boulil Z, Van Dongen-Trimmer HM, Whalen D, Oluchukwu O, Liu KC, Burton J, Syngal P, Vargas-Shiraishi O, Kingsmore SF, Sanford Kobayashi E, Coufal NG.

Pediatr Crit Care Med. 2024 Apr 26. doi: 10.1097/PCC.0000000000003522. Online ahead of print. ABSTRACT OBJECTIVES: Analysis of the clinical utility of rapid whole-genome sequencing (rWGS) outside of the neonatal period is lacking. We describe the use of rWGS in PICU and cardiovascular ICU (CICU) patients across four institutions. DESIGN: Ambidirectional multisite cohort study. SETTING: Four tertiary children’s hospitals. PATIENTS: Children 0-18 years old in the PICU or CICU who underwent rWGS analysis, from May 2016 to June 2023. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 133 patients underwent clinical, phenotype-driven rWGS analysis, 36 prospectively. A molecular diagnosis was identified in 79 patients (59%). Median (interquartile range [IQR]) age was 6 months (IQR 1.2 mo-4.6 yr). Median time for return of preliminary results was 3 days (IQR 2-4). In 79 patients with a molecular diagnosis, there was a change in ICU management in 19 patients (24%); and some change in clinical management in 63 patients (80%). Nondiagnosis changed management in 5 of 54 patients (9%). The clinical specialty ordering rWGS did not affect diagnostic rate. Factors associated with greater odds ratio (OR [95% CI]; OR [95% CI]) of diagnosis included dysmorphic features (OR 10.9 [95% CI, 1.8-105]) and congenital heart disease (OR 4.2 [95% CI, 1.3-16.8]). Variables associated with greater odds of changes in management included obtaining a genetic diagnosis (OR 16.6 [95% CI, 5.5-62]) and a shorter time to genetic result (OR 0.8 [95% CI, 0.76-0.9]). Surveys of pediatric intensivists indicated that rWGS-enhanced clinical prognostication (p < 0.0001) and contributed to a decision to consult palliative care (p < 0.02). CONCLUSIONS: In this 2016-2023 multiple-PICU/CICU cohort, we have shown that timely genetic diagnosis is feasible across institutions. Application of rWGS had a 59% (95% CI, 51-67%) rate of diagnostic yield and was associated with changes in critical care management and long-term patient management. PMID:38668387 | DOI:10.1097/PCC.0000000000003522

April 26, 2024

Rapid genomic sequencing for genetic disease diagnosis and therapy in intensive care units: a review

Kingsmore SF, Nofsinger R, Ellsworth K.

NPJ Genom Med. 2024 Feb 27;9(1):17. doi: 10.1038/s41525-024-00404-0. ABSTRACT Single locus (Mendelian) diseases are a leading cause of childhood hospitalization, intensive care unit (ICU) admission, mortality, and healthcare cost. Rapid genome sequencing (RGS), ultra-rapid genome sequencing (URGS), and rapid exome sequencing (RES) are diagnostic tests for genetic diseases for ICU patients. In 44 studies of children in ICUs with diseases of unknown etiology, 37% received a genetic diagnosis, 26% had consequent changes in management, and net healthcare costs were reduced by $14,265 per child tested by URGS, RGS, or RES. URGS outperformed RGS and RES with faster time to diagnosis, and higher rate of diagnosis and clinical utility. Diagnostic and clinical outcomes will improve as methods evolve, costs decrease, and testing is implemented within precision medicine delivery systems attuned to ICU needs. URGS, RGS, and RES are currently performed in <5% of the ~200,000 children likely to benefit annually due to lack of payor coverage, inadequate reimbursement, hospital policies, hospitalist unfamiliarity, under-recognition of possible genetic diseases, and current formatting as tests rather than as a rapid precision medicine delivery system. The gap between actual and optimal outcomes in children in ICUs is currently increasing since expanded use of URGS, RGS, and RES lags growth in those likely to benefit through new therapies. There is sufficient evidence to conclude that URGS, RGS, or RES should be considered in all children with diseases of uncertain etiology at ICU admission. Minimally, diagnostic URGS, RGS, or RES should be ordered early during admissions of critically ill infants and children with suspected genetic diseases. PMID:38413639 | DOI:10.1038/s41525-024-00404-0

February 27, 2024
RPM for NICU and PICUrWGSrWGS Efficacy

Multi-center implementation of rapid whole genome sequencing provides additional evidence of its utility in the pediatric inpatient setting

Thompson L, Larson A, Salz L, Veith R, Tsai JP, Jayakar A, Chapman R, Gupta A, Kingsmore SF, Dimmock D, Bedrick A, Galindo MK, Casas K, Mohamed M, Straight L, Khan MA, Salyakina D.

Front Pediatr. 2024 Feb 19;12:1349519. doi: 10.3389/fped.2024.1349519. eCollection 2024. ABSTRACT OBJECTIVE: Multi-center implementation of rapid whole genome sequencing with assessment of the clinical utility of rapid whole genome sequencing (rWGS), including positive, negative and uncertain results, in admitted infants with a suspected genetic disease. STUDY DESIGN: rWGS tests were ordered at eight hospitals between November 2017 and April 2020. Investigators completed a survey of demographic data, Human Phenotype Ontology (HPO) terms, test results and impacts of results on clinical care. RESULTS: A total of 188 patients, on general hospital floors and intensive care unit (ICU) settings, underwent rWGS testing. Racial and ethnic characteristics of the tested infants were broadly representative of births in the country at large. 35% of infants received a diagnostic result in a median of 6 days. The most common HPO terms for tested infants indicated an abnormality of the nervous system, followed by the cardiovascular system, the digestive system, the respiratory system and the head and neck. Providers indicated a major change in clinical management because of rWGS for 32% of infants tested overall and 70% of those with a diagnostic result. Also, 7% of infants with a negative rWGS result and 23% with a variant of unknown significance (VUS) had a major change in management due to testing. CONCLUSIONS: Our study demonstrates that the implementation of rWGS is feasible across diverse institutions, and provides additional evidence to support the clinical utility of rWGS in a demographically representative sample of admitted infants and includes assessment of the clinical impact of uncertain rWGS results in addition to both positive and negative results. PMID:38440187 | PMC:PMC10909823 | DOI:10.3389/fped.2024.1349519

February 19, 2024
RPM for NICU and PICUrWGSrWGS Efficacy


Report of two cases of Schaaf-Yang syndrome: Same genotype and different phenotype

Rodriguez AM, Schain K, Jayakar P, Wright MS, Chowdhury S, Salyakina D.

Clin Case Rep. 2023 Jul 30;11(8):e7753. doi: 10.1002/ccr3.7753. eCollection 2023 Aug. ABSTRACT We report two, genotypically identical but phenotypically distinct cases of Schaaf-Yang syndrome and propose the early use of Genome Sequencing in patients with nonspecific presentations to facilitate the early diagnosis of children with rare genetic diseases and improve overall health care outcomes. PMID:37529132 DOI:10.1002/ccr3.7753

July 30, 2023

Rapid Whole Genome Sequencing for Diagnosis of Single Locus Genetic Diseases in Critically Ill Children

Owen MJ, Batalov S, Ellsworth KA, Wright M, Breeding S, Hugh K, Kingsmore SF, Ding Y.

Methods Mol Biol. 2023;2621:217-239. doi: 10.1007/978-1-0716-2950-5_12. ABSTRACT Upon admission to intensive care units (ICU), the differential diagnosis of almost all infants with diseases of unclear etiology includes single locus genetic diseases. Rapid whole genome sequencing (rWGS), including sample preparation, short-read sequencing-by-synthesis, informatics pipelining, and semiautomated interpretation, can now identify nucleotide and structural variants associated with most genetic diseases with robust analytic and diagnostic performance in as little as 13.5 h. Early diagnosis of genetic diseases transforms medical and surgical management of infants in ICUs, minimizing both the duration of empiric treatment and the delay to start of specific treatment. Both positive and negative rWGS tests have clinical utility and can improve outcomes. Since first described 10 years ago, rWGS has evolved considerably. Here we describe our current methods for routine diagnostic testing for genetic diseases by rWGS in as little as 18 h. PMID:37041447 DOI:10.1007/978-1-0716-2950-5_12

April 12, 2023

Automated prioritization of sick newborns for whole genome sequencing using clinical natural language processing and machine learning

Peterson B, Hernandez EJ, Hobbs C, Malone Jenkins S, Moore B, Rosales E, Zoucha S, Sanford E, Bainbridge MN, Frise E, Oriol A, Brunelli L, Kingsmore SF, Yandell M.

Genome Med. 2023 Mar 16;15(1):18. doi: 10.1186/s13073-023-01166-7. ABSTRACT BACKGROUND: Rapidly and efficiently identifying critically ill infants for whole genome sequencing (WGS) is a costly and challenging task currently performed by scarce, highly trained experts and is a major bottleneck for application of WGS in the NICU. There is a dire need for automated means to prioritize patients for WGS. METHODS: Institutional databases of electronic health records (EHRs) are logical starting points for identifying patients with undiagnosed Mendelian diseases. We have developed automated means to prioritize patients for rapid and whole genome sequencing (rWGS and WGS) directly from clinical notes. Our approach combines a clinical natural language processing (CNLP) workflow with a machine learning-based prioritization tool named Mendelian Phenotype Search Engine (MPSE). RESULTS: MPSE accurately and robustly identified NICU patients selected for WGS by clinical experts from Rady Children’s Hospital in San Diego (AUC 0.86) and the University of Utah (AUC 0.85). In addition to effectively identifying patients for WGS, MPSE scores also strongly prioritize diagnostic cases over non-diagnostic cases, with projected diagnostic yields exceeding 50% throughout the first and second quartiles of score-ranked patients. CONCLUSIONS: Our results indicate that an automated pipeline for selecting acutely ill infants in neonatal intensive care units (NICU) for WGS can meet or exceed diagnostic yields obtained through current selection procedures, which require time-consuming manual review of clinical notes and histories by specialized personnel. PMID:36927505 DOI:10.1186/s13073-023-01166-7

March 16, 2023

Scalable, high quality, whole genome sequencing from archived, newborn, dried blood spots

Ding Y, Owen M, Le J, Batalov S, Chau K, Kwon YH, Van Der Kraan L, Bezares-Orin Z, Zhu Z, Veeraraghavan N, Nahas S, Bainbridge M, Gleeson J, Baer RJ, Bandoli G, Chambers C, Kingsmore SF. 

NPJ Genom Med. 2023 Feb 14;8(1):5. doi: 10.1038/s41525-023-00349-w. ABSTRACT Universal newborn screening (NBS) is a highly successful public health intervention. Archived dried bloodspots (DBS) collected for NBS represent a rich resource for population genomic studies. To fully harness this resource in such studies, DBS must yield high-quality genomic DNA (gDNA) for whole genome sequencing (WGS). In this pilot study, we hypothesized that gDNA of sufficient quality and quantity for WGS could be extracted from archived DBS up to 20 years old without PCR (Polymerase Chain Reaction) amplification. We describe simple methods for gDNA extraction and WGS library preparation from several types of DBS. We tested these methods in DBS from 25 individuals who had previously undergone diagnostic, clinical WGS and 29 randomly selected DBS cards collected for NBS from the California State Biobank. While gDNA from DBS had significantly less yield than from EDTA blood from the same individuals, it was of sufficient quality and quantity for WGS without PCR. All samples DBS yielded WGS that met quality control metrics for high-confidence variant calling. Twenty-eight variants of various types that had been reported clinically in 19 samples were recapitulated in WGS from DBS. There were no significant effects of age or paper type on WGS quality. Archived DBS appear to be a suitable sample type for WGS in population genomic studies. PMID:36788231 DOI:10.1038/s41525-023-00349-w

February 14, 2023
Newborn ScreeningRPM for NICU and PICUrWGS

25: A Multicenter Cohort Analysis of Rapid Genome Sequencing in the PICU

Rodriguez, Katherine; Kobayashi, Erica Sanford; VanDongen-Trimmer, Heather; Salz, Lisa; Foley, Jennifer; Whalen, Drewann; Oluchukwu, Okonkwo; Liu, Kuang Chuen; Burton, Jennifer; Syngal, Prachi; Kingsmore, Stephen; Coufal, Nicole.

Critical Care Medicine 51(1):p 13, January 2023. Genetic disorders contribute significantly to morbidity and mortality in pediatric critical care. Diagnostic rapid whole genome sequencing (rWGS) has dramatically impacted care in neonatal intensive care units (ICU). There remains a population of undiagnosed patients with rare genetic diseases who present critically ill to the pediatric ICU (PICU) and the application of rWGS in this setting is not yet fully described. This study evaluated the clinical utility of rWGS in the PICU. DOI: 10.1097/01.ccm.0000905976.97417.e4

January 31, 2023
RPM for NICU and PICUrWGSrWGS Efficacy

Breaking Barriers to Rapid Whole Genome Sequencing in Pediatrics: Michigan’s Project Baby Deer

Bupp CP, Ames EG, Arenchild MK, Caylor S, Dimmock DP, Fakhoury JD, Karna P, Lehman A, Meghea CI, Misra V, Nolan DA, O’Shea J, Sharangpani A, Franck LS, Scheurer-Monaghan A.

Children. 2023; 10(1):106.

The integration of precision medicine in the care of hospitalized children is ever evolving. However, access to new genomic diagnostics such as rapid whole genome sequencing (rWGS) is hindered by barriers in implementation. Michigan’s Project Baby Deer (PBD) is a multi-center collaborative effort that sought to break down barriers to access by offering rWGS to critically ill neonatal and pediatric inpatients in Michigan. The clinical champion team used a standardized approach with inclusion and exclusion criteria, shared learning, and quality improvement evaluation of the project’s impact on the clinical outcomes and economics of inpatient rWGS. Hospitals, including those without on-site geneticists or genetic counselors, noted positive clinical impacts, accelerating time to definitive treatment for project patients. Between 95–214 hospital days were avoided, net savings of $4155 per patient, and family experience of care was improved. The project spurred policy advancement when Michigan became the first state in the United States to have a Medicaid policy with carve-out payment to hospitals for rWGS testing. This state project demonstrates how front-line clinician champions can directly improve access to new technology for pediatric patients and serves as a roadmap for expanding clinical implementation of evidence-based precision medicine technologies.

January 4, 2023
RPM for NICU and PICUrWGSrWGS Efficacy


Rapid genome sequencing identifies novel variants in complement factor I

Rodriguez KM, Vaught J, Dilley M, Ellsworth K, Heinen A, Abud EM, Zhang Y, Smith RJH, Sheets R, Geng B, Hoffman HM, Worthen HM, Dimmock D, Coufal NG.

Cold Spring Harb Mol Case Stud. 2022 Dec 28;8(7):a006239. doi: 10.1101/mcs.a006239. Print 2022 Dec. ABSTRACT Complement factor I deficiency (CFID; OMIM #610984) is a rare immunodeficiency caused by deficiencies in the serine protease complement factor I (CFI). CFID is characterized by predisposition to severe pneumococcal infection, often in infancy. We report a previously healthy adolescent male who presented with respiratory failure secondary to pneumococcal pneumonia and severe systemic inflammatory response. Rapid genome sequencing (rGS) identified compound heterozygous variants in CFI in the proband, with a novel maternally inherited likely pathogenic variant, a single nucleotide deletion resulting in premature stop (c.1646del; p.Asn549ThrfsTer25) and a paternally inherited novel likely pathogenic deletion (Chr 4:110685580-110692197del). PMID:36577522 DOI:10.1101/mcs.a006239

December 28, 2022

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