A genome sequencing system for universal newborn screening, diagnosis, and precision medicine for severe genetic diseases.

Newborn screening (NBS) dramatically improves outcomes in severe childhood disorders by treatment before symptom onset. In many genetic diseases, however, outcomes remain poor because NBS has lagged behind drug development. Rapid whole-genome sequencing (rWGS) is attractive for comprehensive NBS because it concomitantly examines almost all genetic diseases and is gaining acceptance for genetic disease diagnosis in ill newborns. We describe prototypic methods for scalable, parentally consented, feedback-informed NBS and diagnosis of genetic diseases by rWGS and virtual, acute management guidance (NBS-rWGS). Using established criteria and the Delphi method, we reviewed 457 genetic diseases for NBS-rWGS, retaining 388 (85%) with effective treatments. Simulated NBS-rWGS in 454,707 UK Biobank subjects with 29,865 pathogenic or likely pathogenic variants associated with 388 disorders had a true negative rate (specificity) of 99.7% following root cause analysis. In 2,208 critically ill children with suspected genetic disorders and 2,168 of their parents, simulated NBS-rWGS for 388 disorders identified 104 (87%) of 119 diagnoses previously made by rWGS and 15 findings not previously reported (NBS-rWGS negative predictive value 99.6%, true positive rate [sensitivity] 88.8%). Retrospective NBS-rWGS diagnosed 15 children with disorders that had been undetected by conventional NBS. In 43 of the 104 children, had NBS-rWGS-based interventions been started on day of life 5, the Delphi consensus was that symptoms could have been avoided completely in seven critically ill children, mostly in 21, and partially in 13. We invite groups worldwide to refine these NBS-rWGS conditions and join us to prospectively examine clinical utility and cost effectiveness.

Project Baby Bear: Rapid precision care incorporating rWGS in 5 California children's hospitals demonstrates improved clinical outcomes and reduced costs of care.

Genetic disorders are a leading contributor to mortality in neonatal and pediatric intensive care units (ICUs). Rapid whole-genome sequencing (rWGS)-based rapid precision medicine (RPM) is an intervention that has demonstrated improved clinical outcomes and reduced costs of care. However, the feasibility of broad clinical deployment has not been established. The objective of this study was to implement RPM based on rWGS and evaluate the clinical and economic impact of this implementation as a first line diagnostic test in the California Medicaid (Medi-Cal) program. Project Baby Bear was a payor funded, prospective, real-world quality improvement project in the regional ICUs of five tertiary care children's hospitals. Participation was limited to acutely ill Medi-Cal beneficiaries who were admitted November 2018 to May 2020, were <1 year old and within one week of hospitalization, or had just developed an abnormal response to therapy. The whole cohort received RPM. There were two prespecified primary outcomes-changes in medical care reported by physicians and changes in the cost of care. The majority of infants were from underserved populations. Of 184 infants enrolled, 74 (40%) received a diagnosis by rWGS that explained their admission in a median time of 3 days. In 58 (32%) affected individuals, rWGS led to changes in medical care. Testing and precision medicine cost $1.7 million and led to $2.2-2.9 million cost savings. rWGS-based RPM had clinical utility and reduced net health care expenditures for infants in regional ICUs. rWGS should be considered early in ICU admission when the underlying etiology is unclear.

A Prospective Study of Parental Perceptions of Rapid Whole-Genome and -Exome Sequencing among Seriously Ill Infants.

Rapid diagnostic genomic sequencing recently became feasible for infants in intensive care units (ICUs). However, research regarding parents' perceived utility, adequacy of consent, and potential harms and benefits is lacking. Herein we report results of parental surveys of these domains from the second Newborn Sequencing in Genomic Medicine and Public Health (NSIGHT2) study, a randomized, controlled trial of rapid diagnostic genomic sequencing of infants in regional ICUs. More than 90% of parents reported feeling adequately informed to consent to diagnostic genomic sequencing. Despite only 23% (27) of 117 infants receiving genomic diagnoses, 97% (156) of 161 parents reported that testing was at least somewhat useful and 50.3% (88/161) reported no decisional regret (median 0, mean 10, range 0-100). Five of 117 families (4.3%) reported harm. Upon follow-up, one (1%) confirmed harm to child and parent related to negative results/no diagnosis, two (2%) reported stress or confusion, and two (2%) denied harm. In 81% (89) of 111 infants, families and clinicians agreed that genomic results were useful. Of the families for whom clinicians perceived harm from genomic testing, no parents reported harm. Positive tests/genomic diagnosis were more frequently perceived to be useful by parents, to benefit their infant, and to help manage potential symptoms (p < .05). In summary, the large majority of parents felt that first-tier, rapid, diagnostic genomic sequencing was beneficial for infants lacking etiologic diagnoses in ICUs. Most parents in this study perceived being adequately informed to consent, understood their child's results, and denied regret or harm from undergoing sequencing.

An RCT of Rapid Genomic Sequencing among Seriously Ill Infants Results in High Clinical Utility, Changes in Management, and Low Perceived Harm.

The second Newborn Sequencing in Genomic Medicine and Public Health (NSIGHT2) study was a randomized, controlled trial of rapid whole-genome sequencing (rWGS) or rapid whole-exome sequencing (rWES) in infants with diseases of unknown etiology in intensive care units (ICUs). Gravely ill infants were not randomized and received ultra-rapid whole-genome sequencing (urWGS). Herein we report results of clinician surveys of the clinical utility of rapid genomic sequencing (RGS). The primary end-point-clinician perception that RGS was useful- was met for 154 (77%) of 201 infants. Both positive and negative tests were rated as having clinical utility (42 of 45 [93%] and 112 of 156 [72%], respectively). Physicians reported that RGS changed clinical management in 57 (28%) infants, particularly in those receiving urWGS (p = 0.0001) and positive tests (p < 0.00001). Outcomes of 32 (15%) infants were perceived to be changed by RGS. Positive tests changed outcomes more frequently than negative tests (p < 0.00001). In logistic regression models, the likelihood that RGS was perceived as useful increased 6.7-fold when associated with changes in management (95% CI 1.8-43.3). Changes in management were 10.1-fold more likely when results were positive (95% CI 4.7-22.4) and turnaround time was shorter (odds ratio 0.92, 95% CI 0.85-0.99). RGS seldom led to clinician-perceived confusion or distress among families (6 of 207 [3%]). In summary, clinicians perceived high clinical utility and low likelihood of harm with first-tier RGS of infants in ICUs with diseases of unknown etiology. RGS was perceived as beneficial irrespective of whether results were positive or negative.

A Randomized, Controlled Trial of the Analytic and Diagnostic Performance of Singleton and Trio, Rapid Genome and Exome Sequencing in Ill Infants.

The second Newborn Sequencing in Genomic Medicine and Public Health study was a randomized, controlled trial of the effectiveness of rapid whole-genome or -exome sequencing (rWGS or rWES, respectively) in seriously ill infants with diseases of unknown etiology. Here we report comparisons of analytic and diagnostic performance. Of 1,248 ill inpatient infants, 578 (46%) had diseases of unknown etiology. 213 infants (37% of those eligible) were enrolled within 96 h of admission. 24 infants (11%) were very ill and received ultra-rapid whole-genome sequencing (urWGS). The remaining infants were randomized, 95 to rWES and 94 to rWGS. The analytic performance of rWGS was superior to rWES, including variants likely to affect protein function, and ClinVar pathogenic/likely pathogenic variants (p < 0.0001). The diagnostic performance of rWGS and rWES were similar (18 diagnoses in 94 infants [19%] versus 19 diagnoses in 95 infants [20%], respectively), as was time to result (median 11.0 versus 11.2 days, respectively). However, the proportion diagnosed by urWGS (11 of 24 [46%]) was higher than rWES/rWGS (p = 0.004) and time to result was less (median 4.6 days, p < 0.0001). The incremental diagnostic yield of reflexing to trio after negative proband analysis was 0.7% (1 of 147). In conclusion, rapid genomic sequencing can be performed as a first-tier diagnostic test in inpatient infants. urWGS had the shortest time to result, which was important in unstable infants, and those in whom a genetic diagnosis was likely to impact immediate management. Further comparison of urWGS and rWES is warranted because genomic technologies and knowledge of variant pathogenicity are evolving rapidly.

Assessing Diversity in Newborn Genomic Sequencing Research Recruitment: Race/Ethnicity and Primary Spoken Language Variation in Eligibility, Enrollment, and Reasons for Declining.

PURPOSE: Diagnostic genomic research has the potential to directly benefit participants. This study sought to identify barriers to equitable enrollment of acutely ill newborns into a diagnostic genomic sequencing research study. METHODS: We reviewed the 16-month recruitment process of a diagnostic genomic research study enrolling newborns admitted to the neonatal intensive care unit at a regional pediatric hospital that primarily serves English- and Spanish-speaking families. Differences in eligibility, enrollment, and reasons for not enrolling were examined as functions of race/ethnicity and primary spoken language. FINDINGS: Of the 1248 newborns admitted to the neonatal intensive care unit, 46% (n = 580) were eligible, and 17% (n = 213) were enrolled. Of the 16 languages represented among the newborns' families, 4 (25%) had translated consent documents. Speaking a language other than English or Spanish increased a newborn's likelihood of being ineligible by 5.9 times (P < 0.001) after controlling for race/ethnicity. The main reason for ineligibility was documented as the clinical team declined having their patient recruited (41% [51 of 125]). This reason significantly affected families who spoke languages other than English or Spanish and was able to be remediated with training of the research staff. Stress (20% [18 of 90]) and the study intervention(s) (20% [18 of 90]) were the main reasons given for not enrolling. IMPLICATIONS: This analysis of eligibility, enrollment, and reasons for not enrolling in a diagnostic genomic research study found that recruitment generally did not differ as a function of a newborn's race/ethnicity. However, differences were observed depending on the parent's primary spoken language. Regular monitoring and training can improve equitable enrollment into diagnostic genomic research. There are also opportunities at the federal level to improve access to those with limited English proficiency and thus decrease disparities in representation in research participation.

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

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.

Rapid whole genome sequencing impacts care and resource utilization in infants with congenital heart disease.

Congenital heart disease (CHD) is the most common congenital anomaly and a major cause of infant morbidity and mortality. While morbidity and mortality are highest in infants with underlying genetic conditions, molecular diagnoses are ascertained in only ~20% of cases using widely adopted genetic tests. Furthermore, cost of care for children and adults with CHD has increased dramatically. Rapid whole genome sequencing (rWGS) of newborns in intensive care units with suspected genetic diseases has been associated with increased rate of diagnosis and a net reduction in cost of care. In this study, we explored whether the clinical utility of rWGS extends to critically ill infants with structural CHD through a retrospective review of rWGS study data obtained from inpatient infants < 1 year with structural CHD at a regional children's hospital. rWGS diagnosed genetic disease in 46% of the enrolled infants. Moreover, genetic disease was identified five times more frequently with rWGS than microarray ± gene panel testing in 21 of these infants (rWGS diagnosed 43% versus 10% with microarray ± gene panels, p = 0.02). Molecular diagnoses ranged from syndromes affecting multiple organ systems to disorders limited to the cardiovascular system. The average daily hospital spending was lower in the time period post blood collection for rWGS compared to prior (p = 0.003) and further decreased after rWGS results (p = 0.000). The cost was not prohibitive to rWGS implementation in the care of this cohort of infants. rWGS provided timely actionable information that impacted care and there was evidence of decreased hospital spending around rWGS implementation.

Diagnosis of genetic diseases in seriously ill children by rapid whole-genome sequencing and automated phenotyping and interpretation.

By informing timely targeted treatments, rapid whole-genome sequencing can improve the outcomes of seriously ill children with genetic diseases, particularly infants in neonatal and pediatric intensive care units (ICUs). The need for highly qualified professionals to decipher results, however, precludes widespread implementation. We describe a platform for population-scale, provisional diagnosis of genetic diseases with automated phenotyping and interpretation. Genome sequencing was expedited by bead-based genome library preparation directly from blood samples and sequencing of paired 100-nt reads in 15.5 hours. Clinical natural language processing (CNLP) automatically extracted children's deep phenomes from electronic health records with 80% precision and 93% recall. In 101 children with 105 genetic diseases, a mean of 4.3 CNLP-extracted phenotypic features matched the expected phenotypic features of those diseases, compared with a match of 0.9 phenotypic features used in manual interpretation. We automated provisional diagnosis by combining the ranking of the similarity of a patient's CNLP phenome with respect to the expected phenotypic features of all genetic diseases, together with the ranking of the pathogenicity of all of the patient's genomic variants. Automated, retrospective diagnoses concurred well with expert manual interpretation (97% recall and 99% precision in 95 children with 97 genetic diseases). Prospectively, our platform correctly diagnosed three of seven seriously ill ICU infants (100% precision and recall) with a mean time saving of 22:19 hours. In each case, the diagnosis affected treatment. Genome sequencing with automated phenotyping and interpretation in a median of 20:10 hours may increase adoption in ICUs and, thereby, timely implementation of precise treatments.