Rapid Precision Medicine

Am J Hum Genet. 2024 Dec 5;111(12):2643-2667. doi: 10.1016/j.ajhg.2024.10.020.

ABSTRACT

Large prospective clinical trials are underway or planned that examine the clinical utility and cost effectiveness of genome-based newborn screening (gNBS). One gNBS platform, BeginNGS, currently screens 53,575 variants for 412 severe childhood genetic diseases with 1,603 efficacious therapies. Retrospective evaluation of BeginNGS in 618,290 subjects suggests adequate sensitivity and positive predictive value (PPV) to proceed to prospective studies. To inform pivotal clinical trial design, we undertook a pilot clinical trial. We enrolled 120 infants in a regional neonatal intensive care unit (NICU) who were not under consideration for rapid diagnostic genome sequencing (RDGS). Each enrollee received BeginNGS and two index tests (California state NBS and RDGS). California NBS identified 4 of 4 true positive (TP) findings (TP rate 3.6%, sensitivity 100%) and 11 false positive (FP) findings (PPV 27%). RDGS identified 41 diagnostic findings in 36 neonates (diagnostic rate 30%). BeginNGS identified 5 of 6 on-target TP disorders (TP rate 4.2%, 95% confidence interval 1%-8%, sensitivity 83%) and no FPs (PPV 100%). Changes in management were anticipated following the return of 27 RDGS results in 25 enrollees (clinical utility [CU] 21%), 3 of 4 NBS TPs (CU 2.7%), and all BeginNGS TPs (CU 4.2%). The incidence of actionable genetic diseases in NICU infants not being considered for RDGS suggests (1) performance of RDGS in ∼20% of admissions misses many genetic diagnoses, (2) NICU enrollment in gNBS trials will greatly increase power to test endpoints, and (3) NICUs may be attractive for early implementation of consented BeginNGS screening.

PMID:39642868 | DOI:10.1016/j.ajhg.2024.10.020

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

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

NPJ Genom Med. 2024 Feb 26;9(1):15. doi: 10.1038/s41525-024-00396-x.

ABSTRACT

Early use of genome sequencing (GS) in the diagnostic odyssey can reduce suffering and improve care, but questions remain about which patient populations are most amenable to GS as a first-line diagnostic test. To address this, the Medical Genome Initiative conducted a literature review to identify appropriate clinical indications for GS. Studies published from January 2011 to August 2022 that reported on the diagnostic yield (DY) or clinical utility of GS were included. An exploratory meta-analysis using a random effects model evaluated DY based on cohort size and diagnosed cases per cohort. Seventy-one studies met inclusion criteria, comprising over 13,000 patients who received GS in one of the following settings: hospitalized pediatric patients, pediatric outpatients, adult outpatients, or mixed. GS was the first-line test in 38% (27/71). The unweighted mean DY of first-line GS was 45% (12-73%), 33% (6-86%) in cohorts with prior genetic testing, and 33% (9-60%) in exome-negative cohorts. Clinical utility was reported in 81% of first-line GS studies in hospitalized pediatric patients. Changes in management varied by cohort and underlying molecular diagnosis (24-100%). To develop evidence-informed points to consider, the quality of all 71 studies was assessed using modified American College of Radiology (ACR) criteria, with five core points to consider developed, including recommendations for use of GS in the N/PICU, in lieu of sequential testing and when disorders with substantial allelic heterogeneity are suspected. Future large and controlled studies in the pediatric and adult populations may support further refinement of these recommendations.

PMID:38409289 | DOI:10.1038/s41525-024-00396-x

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

Genet Med. 2023 Oct 20:101006. doi: 10.1016/j.gim.2023.101006. Online ahead of print.

ABSTRACT

PURPOSE: Copy number variants (CNVs) and other non-SNV/indel variant types contribute an important proportion of diagnoses in individuals with suspected genetic disease. This study describes the range of such variants detected by genome sequencing (GS).

METHODS: For a pediatric cohort of 1032 participants undergoing clinical GS, we characterize the CNVs and other non-SNV/indel variant types that were reported, including aneuploidies, mobile element insertions, and uniparental disomies, and we describe the bioinformatic pipeline used to detect these variants.

RESULTS: Together, these genetic alterations accounted for 15.8% of reported variants. Notably, 67.9% of these were deletions, 32.9% of which overlapped a single gene, and many deletions were reported together with a second variant in the same gene in cases of recessive disease. A retrospective medical record review in a subset of this cohort revealed that up to six additional genetic tests were ordered in 68% (26/38) of cases, some of which failed to report the CNVs/rare variants reported on GS.

CONCLUSION: GS detected a broad range of reported variant types, including CNVs ranging in size from 1 Kb to 46 Mb.

PMID:37869996 DOI:10.1016/j.gim.2023.101006