Dataset Information

Feasibility of Ultra-Rapid Exome Sequencing in Critically Ill Infants and Children With Suspected Monogenic Conditions in the Australian Public Health Care System.

ABSTRACT:

Importance

Widespread adoption of rapid genomic testing in pediatric critical care requires robust clinical and laboratory pathways that provide equitable and consistent service across health care systems.

Objective

To prospectively evaluate the performance of a multicenter network for ultra-rapid genomic diagnosis in a public health care system.

Design, setting, and participants

Descriptive feasibility study of critically ill pediatric patients with suspected monogenic conditions treated at 12 Australian hospitals between March 2018 and February 2019, with data collected to May 2019. A formal implementation strategy emphasizing communication and feedback, standardized processes, coordination, distributed leadership, and collective learning was used to facilitate adoption.

Exposures

Ultra-rapid exome sequencing.

Main outcomes and measures

The primary outcome was time from sample receipt to ultra-rapid exome sequencing report. The secondary outcomes were the molecular diagnostic yield, the change in clinical management after the ultra-rapid exome sequencing report, the time from hospital admission to the laboratory report, and the proportion of laboratory reports returned prior to death or hospital discharge.

Results

The study population included 108 patients with a median age of 28 days (range, 0 days to 17 years); 34% were female; and 57% were from neonatal intensive care units, 33% were from pediatric intensive care units, and 9% were from other hospital wards. The mean time from sample receipt to ultra-rapid exome sequencing report was 3.3 days (95% CI, 3.2-3.5 days) and the median time was 3 days (range, 2-7 days). The mean time from hospital admission to ultra-rapid exome sequencing report was 17.5 days (95% CI, 14.6-21.1 days) and 93 reports (86%) were issued prior to death or hospital discharge. A molecular diagnosis was established in 55 patients (51%). Eleven diagnoses (20%) resulted from using the following approaches to augment standard exome sequencing analysis: mitochondrial genome sequencing analysis, exome sequencing-based copy number analysis, use of international databases to identify novel gene-disease associations, and additional phenotyping and RNA analysis. In 42 of 55 patients (76%) with a molecular diagnosis and 6 of 53 patients (11%) without a molecular diagnosis, the ultra-rapid exome sequencing result was considered as having influenced clinical management. Targeted treatments were initiated in 12 patients (11%), treatment was redirected toward palliative care in 14 patients (13%), and surveillance for specific complications was initiated in 19 patients (18%).

Conclusions and relevance

This study suggests feasibility of ultra-rapid genomic testing in critically ill pediatric patients with suspected monogenic conditions in the Australian public health care system. However, further research is needed to understand the clinical value of such testing, and the generalizability of the findings to other health care settings.

SUBMITTER: Australian Genomics Health Alliance Acute Care Flagship

PROVIDER: S-EPMC7312414 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Feasibility of Ultra-Rapid Exome Sequencing in Critically Ill Infants and Children With Suspected Monogenic Conditions in the Australian Public Health Care System.

Lunke Sebastian S Eggers Stefanie S Wilson Meredith M Patel Chirag C Barnett Christopher P CP Pinner Jason J Sandaradura Sarah A SA Buckley Michael F MF Krzesinski Emma I EI de Silva Michelle G MG Brett Gemma R GR Boggs Kirsten K Mowat David D Kirk Edwin P EP Adès Lesley C LC Akesson Lauren S LS Amor David J DJ Ayres Samantha S Baxendale Anne A Borrie Sarah S Bray Alessandra A Brown Natasha J NJ Chan Cheng Yee CY Chong Belinda B Cliffe Corrina C Delatycki Martin B MB Edwards Matthew M Elakis George G Fahey Michael C MC Fennell Andrew A Fowles Lindsay L Gallacher Lyndon L Higgins Megan M Howell Katherine B KB Hunt Lauren L Hunter Matthew F MF Jones Kristi J KJ King Sarah S Kumble Smitha S Lang Sarah S Le Moing Maelle M Ma Alan A Phelan Dean D Quinn Michael C J MCJ Richards Anna A Richmond Christopher M CM Riseley Jessica J Rodgers Jonathan J Sachdev Rani R Sadedin Simon S Schlapbach Luregn J LJ Smith Janine J Springer Amanda A Tan Natalie B NB Tan Tiong Y TY Temple Suzanna L SL Theda Christiane C Vasudevan Anand A White Susan M SM Yeung Alison A Zhu Ying Y Martyn Melissa M Best Stephanie S Roscioli Tony T Christodoulou John J Stark Zornitza Z

JAMA 20200601 24

<h4>Importance</h4>Widespread adoption of rapid genomic testing in pediatric critical care requires robust clinical and laboratory pathways that provide equitable and consistent service across health care systems.<h4>Objective</h4>To prospectively evaluate the performance of a multicenter network for ultra-rapid genomic diagnosis in a public health care system.<h4>Design, setting, and participants</h4>Descriptive feasibility study of critically ill pediatric patients with suspected monogenic con ...[more]

PMID: 32573669

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Project description:BackgroundRare diseases are complex disorders with huge variability in clinical manifestations. Decreasing cost of next-generation sequencing (NGS) tests in recent years made it affordable. We witnessed the diagnostic yield and clinical use of different NGS strategies on a myriad of monogenic disorders in a pediatric setting.MethodsNext-generation sequencing tests are performed for 98 unrelated Chinese patients within their first year of life, who were admitted to Xin Hua Hospital, affiliated with Shanghai Jiao Tong University School of Medicine, during a 2-year period.ResultsClinical indications for NGS tests included a range of medical concerns. The mean age was 4.4 ± 4.2 months of age for infants undergoing targeting specific (known) disease-causing genes (TRS) analysis, and 4.4 ± 4.3 months of age for whole-exome sequencing (WES) (p > 0.05). A molecular diagnosis is done in 72 infants (73.47%), which finds a relatively high yield with phenotypes of metabolism/homeostasis abnormality (HP: 0001939) (odds ratio, 1.83; 95% CI, 0.56-6.04; p = 0.32) and a significantly low yield with atypical symptoms (without a definite HPO term) (odds ratio, 0.08; 95% CI, 0.01-0.73; p = 0.03). TRS analysis provides molecular yields higher than WES (p = 0.01). Ninety-eight different mutations are discovered in 72 patients. Twenty-seven of them have not been reported previously. Nearly half (43.06%, 31/72) of the patients are found to carry 11 common disorders, mostly being inborn errors of metabolism (IEM) and neurogenetic disorders and all of them are observed through TRS analysis. Eight positive cases are identified through WES, and all of them are sporadic, of highly variable phenotypes and severity. There are 26 patients with negative findings in this study.ConclusionThis study provides evidence that NGS can yield high success rates in a tertiary pediatric setting, but suggests that the scope of known Mendelian conditions may be considerably broader than currently recognized.

Project description:Genetic disorders are a frequent cause of hospitalization, morbidity and mortality in pediatric patients, especially in the neonatal or pediatric intensive care unit (NICU/PICU). In recent years, rapid genome-wide sequencing (exome or whole genome sequencing) has been applied in the NICU/PICU. However, mtDNA sequencing is not routinely available in rapid genetic diagnosis programs, which may fail to diagnose mtDNA mutation-associated diseases. Herein, we explored the clinical utility of rapid exome sequencing combined with mtDNA sequencing in critically ill pediatric patients with suspected genetic disorders. Rapid clinical exome sequencing (CES) was performed as a first-tier test in 40 critically ill pediatric patients (aged from 6 days to 15 years) with suspected genetic conditions. Blood samples were also collected from the parents for trio analysis. Twenty-six patients presented with neuromuscular abnormalities or other systemic abnormalities, suggestive of suspected mitochondrial diseases or the necessity for a differential diagnosis of other diseases, underwent rapid mtDNA sequencing concurrently. A diagnosis was made in 18 patients (45.0%, 18/40); three cases with de novo autosomal dominant variants, ten cases with homozygous or compound heterozygous variants, three cases with hemizygous variants inherited from mother, three cases with heterozygous variants inherited from either parent, and one case with a mtDNA mutation. The 18 patients were diagnosed with metabolic (n = 7), immunodeficiency (n = 4), cardiovascular (n = 2), neuromuscular (n = 2) disorders, and others. Genetic testing reports were generated with a median time of 5 days (range, 3-9 days). Thirteen patients that were diagnosed had an available medical treatment and resulted in a positive outcome. We propose that rapid exome sequencing combined with mitochondrial DNA sequencing should be available to patients with suspected mitochondrial diseases or undefined clinical features necessary for making a differential diagnosis of other diseases.

Project description:OBJECTIVES:Sepsis is associated with high early and total in-hospital mortality. Despite recent revisions in the diagnostic criteria for sepsis that sought to improve predictive validity for mortality, it remains difficult to identify patients at greatest risk of death. We compared the utility of nine biomarkers to predict mortality in subjects with clinically suspected bacterial sepsis. DESIGN:Cohort study. SETTING:The medical and surgical ICUs at an academic medical center. SUBJECTS:We enrolled 139 subjects who met two or more systemic inflammatory response syndrome (systemic inflammatory response syndrome) criteria and received new broad-spectrum antibacterial therapy. INTERVENTIONS:We assayed nine biomarkers (?-2 macroglobulin, C-reactive protein, ferritin, fibrinogen, haptoglobin, procalcitonin, serum amyloid A, serum amyloid P, and tissue plasminogen activator) at onset of suspected sepsis and 24, 48, and 72 hours thereafter. We compared biomarkers between groups based on both 14-day and total in-hospital mortality and evaluated the predictive validity of single and paired biomarkers via area under the receiver operating characteristic curve. MEASUREMENTS AND MAIN RESULTS:Fourteen-day mortality was 12.9%, and total in-hospital mortality was 29.5%. Serum amyloid P was significantly lower (4/4 timepoints) and tissue plasminogen activator significantly higher (3/4 timepoints) in the 14-day mortality group, and the same pattern held for total in-hospital mortality (Wilcoxon p ? 0.046 for all timepoints). Serum amyloid P and tissue plasminogen activator demonstrated the best individual predictive performance for mortality, and combinations of biomarkers including serum amyloid P and tissue plasminogen activator achieved greater predictive performance (area under the receiver operating characteristic curve > 0.76 for 14-d and 0.74 for total mortality). CONCLUSIONS:Combined biomarkers predict risk for 14-day and total mortality among subjects with suspected sepsis. Serum amyloid P and tissue plasminogen activator demonstrated the best discriminatory ability in this cohort.

Project description:ImportanceOptimal use of whole-exome sequencing (WES) in the pediatric setting requires an understanding of who should be considered for testing and when it should be performed to maximize clinical utility and cost-effectiveness.ObjectivesTo investigate the impact of WES in sequencing-naive children suspected of having a monogenic disorder and evaluate its cost-effectiveness if WES had been available at different time points in their diagnostic trajectory.Design, setting, and participantsThis prospective study was part of the Melbourne Genomics Health Alliance demonstration project. At the ambulatory outpatient clinics of the Victorian Clinical Genetics Services at the Royal Children's Hospital, Melbourne, Australia, children older than 2 years suspected of having a monogenic disorder were prospectively recruited from May 1 through November 30, 2015, by clinical geneticists after referral from general and subspecialist pediatricians. All children had nondiagnostic microarrays and no prior single-gene or panel sequencing.ExposuresAll children underwent singleton WES with targeted phenotype-driven analysis.Main outcomes and measuresThe study examined the clinical utility of a molecular diagnosis and the cost-effectiveness of alternative diagnostic trajectories, depending on timing of WES.ResultsOf 61 children originally assessed, 44 (21 [48%] male and 23 [52%] female) aged 2 to 18 years (mean age at initial presentation, 28 months; range, 0-121 months) were recruited, and a diagnosis was achieved in 23 (52%) by singleton WES. The diagnoses were unexpected in 8 of 23 (35%), and clinical management was altered in 6 of 23 (26%). The mean duration of the diagnostic odyssey was 6 years, with each child having a mean of 19 tests and 4 clinical genetics and 4 nongenetics specialist consultations, and 26 (59%) underwent a procedure while under general anesthetic for diagnostic purposes. Economic analyses of the diagnostic trajectory identified that WES performed at initial tertiary presentation resulted in an incremental cost savings of A$9020 (US$6838) per additional diagnosis (95% CI, A$4304-A$15 404 [US$3263-US$11 678]) compared with the standard diagnostic pathway. Even if WES were performed at the first genetics appointment, there would be an incremental cost savings of A$5461 (US$4140) (95% CI, A$1433-A$10 557 [US$1086- US$8004]) per additional diagnosis compared with the standard diagnostic pathway.Conclusions and relevanceSingleton WES in children with suspected monogenic conditions has high diagnostic yield, and cost-effectiveness is maximized by early application in the diagnostic pathway. Pediatricians should consider early referral of children with undiagnosed syndromes to clinical geneticists.

Dataset Information

Feasibility of Ultra-Rapid Exome Sequencing in Critically Ill Infants and Children With Suspected Monogenic Conditions in the Australian Public Health Care System.

Importance

Objective

Design, setting, and participants

Exposures

Main outcomes and measures

Results

Conclusions and relevance

Publications

Feasibility of Ultra-Rapid Exome Sequencing in Critically Ill Infants and Children With Suspected Monogenic Conditions in the Australian Public Health Care System.

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