Perinatal Precision Medicine

Overview

This study will seek to determine if rapid genomic sequencing improves outcomes for acutely ill infants. The investigator will enroll up to 1,000 acutely ill infants in a prospective, randomized, blinded study to either rapid Whole Genome Sequencing (WGS) or rapid Whole Exome Sequencing (WES, which is 2% of the genome and ~4-fold less expensive). 213 infants were actually enrolled. Outcomes will be measured both by objective clinical measures and family perceptions (patient/family centered outcomes). Primary analysis of WGS or WES will be in infants alone. Secondary analysis, in infants who do not receive a diagnosis, will be of families – ideally trios (mother, father, and affected infant), which is ~2-fold more expensive. Trios will be analyzed within the same randomization arm (WGS or WES). This study is designed to quantify which acutely ill infants benefit from rapid genomic sequencing, by how much they benefit, how they benefit, which rapid genomic sequencing method is superior, and the cost effectiveness of such testing.

Full Title of Study: “Prenatal Precision Medicine (NSIGHT2): A Randomized, Blinded, Prospective Study of the Clinical Utility of Rapid Genomic Sequencing for Infants in the Acute-care Setting”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Diagnostic
    • Masking: Triple (Participant, Care Provider, Investigator)
  • Study Primary Completion Date: October 9, 2018

Detailed Description

Acutely ill infant inpatients who have an undiagnosed illness, and their families, will be eligible to participate in the study. The investigators will enroll up to 1,000 infants. Locally, the study population will be recruited from Rady Children's Hospital (RCH) inpatient population, primarily the neonatal intensive care unit (NICU), pediatric intensive care unit (PICU), and cardiovascular intensive care unit (CVICU), with a smaller population presenting to other hospital in-patient services. Recruitment will be targeted at the RCH main campus, but it may include referrals from satellite locations in the RCH network (particularly the RCH NICU network throughout San Diego County). All patients will continue to receive routine care as clinically indicated, including the state newborn screen and other genetic testing as determined by their treating providers. Half of the affected study participants will be randomized to receive rapid whole genome sequencing (WGS) and the other half will receive rapid whole exome sequencing (WES). Each arm will initially be analyzed using the patient's (proband's) sample only. If a proband-only analysis fails to yield a diagnosis, genomic data from the biological family members (typically parents), when available, will be used to supplement analysis (trio analysis). Occasionally, a second affected sibling may be available for family analysis. Not infrequently, the father is not available for study. Similarly, the investigators anticipate the need for targeted genetic analysis of biological parents, and possibly other family members, to confirm diagnostic results and/or provide additional information regarding inheritance. The investigators anticipate that in rare cases a newborn may be so ill that the team lacks equipoise that the child can wait for the estimated ten day turnaround time of our send-out exome testing. In these rare cases, the PI, or his delegate, will decide if the child is not eligible for randomization. These children will remain in the research study throughout the entirety of the study, but will receive in-house ultra-rapid whole genome sequencing by the Rady Children's Institute for Genomic Medicine (RCIGM, also called RadyPGSMI) laboratory in lieu of either a rapid genome or rapid exome (both anticipated to be 10 day turn-arounds). Enrollment will be sought within the first 96 hours following admission to RCH or an RCH network ICU or within 96 hours of meeting criteria for the study if the infant was not previously eligible. Patients and their family members who consent to participate will have their blood drawn and will be randomized to receive either rapid WGS or rapid WES. The initial symptom-driven analysis will be conducted on the patient's sample only (singleton analysis). If a diagnosis is not found promptly (within 24 hours) via a singleton analysis, the family (or any combination of parents and/or other family members) will be analyzed using the same technology that the patient was randomized to receive. Pathogenic and likely pathogenic variants (as determined by American College of Medical Genetics (ACMG) guidelines) that relate in part or in whole to the patient's current phenotype will be clinically confirmed and reported into the patients' medical record. Although the intention of the study is to return symptom-driven results to the medical record, the clinical report for confirmation of symptom-driven findings may include negative findings of testing. In the event that our analysis incidentally finds a pathogenic variant for which a treatment or intervention exists to improve morbidity and/or mortality, families may choose not to receive this additional information.

Interventions

  • Genetic: Genomic sequencing and molecular diagnostic results, if any.
    • Patients and their families will be randomized to either receive whole genome sequencing or whole exome sequencing.

Arms, Groups and Cohorts

  • Other: Whole Genome Sequencing
    • Genetic test that looks at all coding and non-coding areas of the genome
  • Other: Whole Exome Sequencing
    • Genetic test that looks at all coding areas of the genome

Clinical Trial Outcome Measures

Primary Measures

  • Subject’s main provider’s perceived clinical utility of genomic sequencing
    • Time Frame: Within one week of the return of results
    • Perceived utility/benefit of sequencing based on “Clinician Assessment” scale completed by patient’s providers.

Secondary Measures

  • Diagnostic rates between WGS and WES
    • Time Frame: Within approximately 30 days of enrollment
    • Diagnostic rate of genome and exome based on rate of clinically confirmed diagnoses posted in medical record.
  • Comparing diagnostic rates between singleton and trio analysis
    • Time Frame: Within approximately 30 days of enrollment
    • Marginal increase in diagnostic yield above singleton analysis based on the number of clinically confirmed diagnoses posted in medical record following singleton and trio levels of analysis in cases when both biological parents are available.
  • Parental perceived benefits or harm of testing
    • Time Frame: Within one week of the return of results and approximately one year after enrollment
    • Perceived utility/benefits of sequencing based on Holm survey as assessed by parents/legal guardian of patient.
  • Parental satisfaction with sequencing
    • Time Frame: Within one week of the return of results and approximately one year after enrollment
    • Parental satisfaction with decision to pursue sequencing based on Brennan survey
  • Parental decisional regret with sequencing
    • Time Frame: Within one week of the return of results and approximately one year after enrollment
    • Markers of harm in genetic diagnosis as evidenced by Brehaut’s Decisional Regret scale.
  • Association of parental surveys with parent’s demographics
    • Time Frame: Within one week of the return of results and approximately one year after enrollment
    • Associations between parental opinions to clinical utility survey, satisfaction with sequencing survey, and decisional regret survey and the parent’s highest level of education, primary language spoken at home, and their trust in the heath care system.
  • Parental availability for trio analysis
    • Time Frame: Within three days of patient enrollment
    • Number of subjects in which both parents are available for trio analysis.

Participating in This Clinical Trial

Inclusion Criteria

Individual in whom one of the following criteria is met: 1. Acutely ill inpatient of less than 4 months of age and within 96 hours of admission. 2. Acutely ill inpatient of less than 4 months of age and within 96 hours of development of an abnormal response to standard therapy for an underlying condition. 3. Acutely ill inpatient of less than 4 months of age and within 96 hours of development of clinical feature or laboratory test value suggestive of a genetic condition. 4. Biological relative of an infant enrolled in this study. Exclusion Criteria:

Inpatients of greater than 4 months of age, or who do not meet any of the inclusion criteria, or with: 1. Neonatal infection or sepsis with normal response to therapy 2. Isolated prematurity 3. Isolated unconjugated hyperbilirubinemia 4. Hypoxic Ischemic Encephalopathy with clear precipitating event 5. Previously confirmed genetic diagnosis that explains their clinical condition (i.e. have a positive genetic test) 6. Isolated Transient Neonatal Tachypnea 7. Permission is unable to be obtained by a legal guardian or court-appointed representative within 96 hours of becoming eligible for enrollment. 8. Non-viable neonates – newborns less than 28 days of life with a modified code status (only full code patients may be enrolled).

Gender Eligibility: All

Minimum Age: N/A

Maximum Age: 4 Months

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Rady Pediatric Genomics & Systems Medicine Institute
  • Provider of Information About this Clinical Study
    • Principal Investigator: Stephen F. Kingsmore, President and CEO – Rady Pediatric Genomics & Systems Medicine Institute
  • Overall Official(s)
    • Stephen Kingsmore, MD, DSc, Principal Investigator, Rady Pediatric Genomics & Systems Medicine Institute

References

Milko LV, Chen F, Chan K, Brower AM, Agrawal PB, Beggs AH, Berg JS, Brenner SE, Holm IA, Koenig BA, Parad RB, Powell CM, Kingsmore SF. FDA oversight of NSIGHT genomic research: the need for an integrated systems approach to regulation. NPJ Genom Med. 2019 Dec 10;4:32. doi: 10.1038/s41525-019-0105-8. eCollection 2019. Review.

Citations Reporting on Results

Dimmock DP, Clark MM, Gaughran M, Cakici JA, Caylor SA, Clarke C, Feddock M, Chowdhury S, Salz L, Cheung C, Bird LM, Hobbs C, Wigby K, Farnaes L, Bloss CS, Kingsmore SF; RCIGM Investigators. An RCT of Rapid Genomic Sequencing among Seriously Ill Infants Results in High Clinical Utility, Changes in Management, and Low Perceived Harm. Am J Hum Genet. 2020 Nov 5;107(5):942-952. doi: 10.1016/j.ajhg.2020.10.003.

Cakici JA, Dimmock DP, Caylor SA, Gaughran M, Clarke C, Triplett C, Clark MM, Kingsmore SF, Bloss CS. A Prospective Study of Parental Perceptions of Rapid Whole-Genome and -Exome Sequencing among Seriously Ill Infants. Am J Hum Genet. 2020 Nov 5;107(5):953-962. doi: 10.1016/j.ajhg.2020.10.004.

Kingsmore SF, Cakici JA, Clark MM, Gaughran M, Feddock M, Batalov S, Bainbridge MN, Carroll J, Caylor SA, Clarke C, Ding Y, Ellsworth K, Farnaes L, Hildreth A, Hobbs C, James K, Kint CI, Lenberg J, Nahas S, Prince L, Reyes I, Salz L, Sanford E, Schols P, Sweeney N, Tokita M, Veeraraghavan N, Watkins K, Wigby K, Wong T, Chowdhury S, Wright MS, Dimmock D; RCIGM Investigators. A Randomized, Controlled Trial of the Analytic and Diagnostic Performance of Singleton and Trio, Rapid Genome and Exome Sequencing in Ill Infants. Am J Hum Genet. 2019 Oct 3;105(4):719-733. doi: 10.1016/j.ajhg.2019.08.009. Epub 2019 Sep 26.

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