Perinatal Precision Medicine

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Genetic Diseases, Genetic Syndrome, Mendelian Disorders

Intervention / Treatment
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* Genetic: Genomic sequencing and molecular diagnostic results, if any.


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Individual in whom one of the following criteria is met: Acutely ill inpatient of less than 4 months of age and within 96 hours of admission. 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. 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. 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: Neonatal infection or sepsis with normal response to therapy Isolated prematurity Isolated unconjugated hyperbilirubinemia Hypoxic Ischemic Encephalopathy with clear precipitating event Previously confirmed genetic diagnosis that explains their clinical condition (i.e. have a positive genetic test) Isolated Transient Neonatal Tachypnea Permission is unable to be obtained by a legal guardian or court-appointed representative within 96 hours of becoming eligible for enrollment. Non-viable neonates - newborns less than 28 days of life with a modified code status (only full code patients may be enrolled).

Ages Eligible for Study
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Maximum Age: 4 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The initial symptom-driven analysis will be conducted on the patient's (NICU infants) sample only (singleton analysis). Patients will be randomized to receive either whole genome sequencing or whole exome sequencing. If a diagnosis is not found promptly (within 24 hours) via singleton analysis, sequential analysis of 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. The study includes parental and physician questionnaires to understand perceptions regarding testing. There is no randomization of parents or physicians nor a requirement to respond to the questionnaires for the patient (NICU infant) to participate in the study. Enrollment: 213 patients (NICU infants)
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Whole Genome Sequencing<br>Genetic test that looks at all coding and non-coding areas of the genome | Genetic: Genomic sequencing and molecular diagnostic results, if any.<br>* Patients and their families will be randomized to either receive whole genome sequencing or whole exome sequencing.<br>|
| Other: Whole Exome Sequencing<br>Genetic test that looks at all coding areas of the genome | Genetic: Genomic sequencing and molecular diagnostic results, if any.<br>* Patients and their families will be randomized to either receive whole genome sequencing or whole exome sequencing.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subject's Main Provider's Perceived Clinical Utility of Genomic Sequencing | Perceived utility/benefit of sequencing based on Clinician Assessment questionnaire completed by patient's providers. Question: Was the test clinically useful? Response was measured on a 5-point Likert scale (very useful=5, useful=4, neutral=3, not very useful=2, not useful at all=1. | Within one week of the return of results | 
| Test Results Led to Change in Patient Management | Test results led to Change in clinical management (select all that apply): Surgical intervention added Surgical intervention removed Surgical intervention changed Medication added Medication removed Medication changed Diet changed New specialty service sought Prior specialty service no longer required New imaging sought Prior imaging cancelled New test ordered Prior testing cancelled Screening for additional comorbidities added Screening for additional comorbidities removed Palliative care initiated Palliative care withdrawn Other: (text box for written description) | Within 1 week of return of results | 
| Test Led to Changes in Management That Altered Patient Outcome | Primary physician perception of change in outcome | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diagnostic Proportion for Whole Genome Sequencing (WGS) and Whole Exome Sequencing (WES) | WGS and WES are two clinical diagnostic test modalities. Results of testing were placed in the electronic medical record. Results either provided a molecular diagnosis that explained the patient's condition or did not. The diagnostic proportion is the number of patients who received a molecular diagnosis by the test modality divided by the total number of patients who were tested by that modality. | Within approximately 30 days of enrollment | 
| Result Within 7 Days of Sample Receipt | Time to result. | Within 7 days of sample receipt | 
| Parental Perceived Usefulness of Test | Parental perception that test was useful | Within one week of the return of results and approximately one year after enrollment | 
| Parental Perception of Test Benefit for Their Infant | Parental perception that the test benefitted their infant | Within one week of the return of results and approximately one year after enrollment | 
| Parental Decisional Regret With Sequencing | Markers of harm in genetic diagnosis as evidenced by Brehaut's Decisional Regret scale. Scale 0-100. Higher scores indicate higher regret. | Within one week of the return of results and approximately one year after enrollment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neonate, Genomic Medicine, Rapid Precision Medicine, Rapid Whole Genome Sequencing, Diagnosis, Infant, Intensive care unit, clinical trial, Rapid Whole Exome Sequencing, Single locus disease, Ultra-rapid whole genome sequencing, Clinical Utility