Benefits for children with suspected cancer from routine whole-genome sequencing

Clinical whole-genome sequencing (WGS) has been shown to deliver potential benefits to children with cancer and to alter treatment in high-risk patient groups. It remains unknown whether offering WGS to every child with suspected cancer can change patient management. We collected WGS variant calls and clinical and diagnostic information from 281 children (282 tumors) across two English units (n = 152 from a hematology center, n = 130 from a solid tumor center) where WGS had become a routine test. Our key finding was that variants uniquely attributable to WGS changed the management in ~7% (20 out of 282) of cases while providing additional disease-relevant findings, beyond standard-of-care molecular tests, in 108 instances for 83 (29%) cases. Furthermore, WGS faithfully reproduced every standard-of-care molecular test (n = 738) and revealed several previously unknown genomic features of childhood tumors. We show that WGS can be delivered as part of routine clinical care to children with suspected cancer and can change clinical management by delivering unexpected genomic insights. Our experience portrays WGS as a clinically impactful assay for routine practice, providing opportunities for assay consolidation and for delivery of molecularly informed patient care.</p

Benefits for children with suspected cancer from routine whole-genome sequencing.

Acknowledgements: We thank S. Wakeling (Alice’s Arc), J. Miles (East Genomics Laboratory Hub), A. Sosinsky (Genomics England), P. Moss (Genomics England), A. Maartens (science writer, Wellcome Sanger Institute), G. Collord (University College Hospitals, London) and T. Treger (Wellcome Sanger Institute) for the discussion regarding the paper. We thank the scientific, technical and administrative staff of the North Thames and East Genomic Laboratory Hubs for making WGS possible. We acknowledge funding from the Wellcome Trust (personal fellowship to S. Behjati, institutional grant to the Wellcome Sanger Institute; references 220540/Z/20/A and 223135/Z/21/Z), the Pessoa de Araujo family (personal fellowship to A.H.) and NIHR (academic clinical fellowship to S.M.L.). This research was supported by the NIHR GOSH Biomedical Research Centre and NIHR Cambridge Biomedical Research Centre (NIHR203312). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the paper. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. We are indebted to the children and families who participated in this study.Funder: NIHR Cambridge Biomedical Research Centre (NIHR203312)Funder: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Brazilian Federal Agency for the Support and Evaluation of Graduate Education); doi: https://doi.org/10.13039/501100002322Funder: The Pessoa de Araujo family - Personal Fellowship to Dr Angus HodderFunder: DH | National Institute for Health Research (NIHR); doi: https://doi.org/10.13039/501100000272Funder: NIHR GOSH Biomedical Research CentreClinical whole-genome sequencing (WGS) has been shown to deliver potential benefits to children with cancer and to alter treatment in high-risk patient groups. It remains unknown whether offering WGS to every child with suspected cancer can change patient management. We collected WGS variant calls and clinical and diagnostic information from 281 children (282 tumors) across two English units (n = 152 from a hematology center, n = 130 from a solid tumor center) where WGS had become a routine test. Our key finding was that variants uniquely attributable to WGS changed the management in ~7% (20 out of 282) of cases while providing additional disease-relevant findings, beyond standard-of-care molecular tests, in 108 instances for 83 (29%) cases. Furthermore, WGS faithfully reproduced every standard-of-care molecular test (n = 738) and revealed several previously unknown genomic features of childhood tumors. We show that WGS can be delivered as part of routine clinical care to children with suspected cancer and can change clinical management by delivering unexpected genomic insights. Our experience portrays WGS as a clinically impactful assay for routine practice, providing opportunities for assay consolidation and for delivery of molecularly informed patient care

Comparison of diagnoses of early-onset sepsis associated with use of Sepsis Risk Calculator versus NICE CG149: a prospective, population-wide cohort study in London, UK, 2020–2021

Objective We sought to compare the incidence of early-onset sepsis (EOS) in infants ≥34 weeks’ gestation identified &gt;24 hours after birth, in hospitals using the Kaiser Permanente Sepsis Risk Calculator (SRC) with hospitals using the National Institute for Health and Care Excellence (NICE) guidance.Design and setting Prospective observational population-wide cohort study involving all 26 hospitals with neonatal units colocated with maternity services across London (10 using SRC, 16 using NICE).Participants All live births ≥34 weeks’ gestation between September 2020 and August 2021.Outcome measures EOS was defined as isolation of a bacterial pathogen in the blood or cerebrospinal fluid (CSF) culture from birth to 7 days of age. We evaluated the incidence of EOS identified by culture obtained &gt;24 hours to 7 days after birth. We also evaluated the rate empiric antibiotics were commenced &gt;24 hours to 7 days after birth, for a duration of ≥5 days, with negative blood or CSF cultures.Results Of 99 683 live births, 42 952 (43%) were born in SRC hospitals and 56 731 (57%) in NICE hospitals. The overall incidence of EOS (&lt;72 hours) was 0.64/1000 live births. The incidence of EOS identified &gt;24 hours was 2.3/100 000 (n=1) for SRC vs 7.1/100 000 (n=4) for NICE (OR 0.5, 95% CI (0.1 to 2.7)). This corresponded to (1/20) 5% (SRC) vs (4/45) 8.9% (NICE) of EOS cases (χ=0.3, p=0.59). Empiric antibiotics were commenced &gt;24 hours to 7 days after birth in 4.4/1000 (n=187) for SRC vs 2.9/1000 (n=158) for NICE (OR 1.5, 95% CI (1.2 to 1.9)). 3111 (7%) infants received antibiotics in the first 24 hours in SRC hospitals vs 8428 (15%) in NICE hospitals.Conclusion There was no significant difference in the incidence of EOS identified &gt;24 hours after birth between SRC and NICE hospitals. SRC use was associated with 50% fewer infants receiving antibiotics in the first 24 hours of life