Genomic Sequencing for Childhood Risk and Newborn Illness

Study Overview
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Brief Summary
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The Genomic Sequencing for Childhood Risk and Newborn Illness (the BabySeq Project) is a research study exploring the use of genomic sequencing in newborns. The National Institutes of Health is funding this study. The investigators will enroll 240 healthy infants and their parents from the Brigham and Women's Hospital (BWH) Well Newborn Nursery and 240 sick infants and their parents at Boston Children's Hospital (BCH) or the BWH Neonatal Intensive Care Unit (NICU). A small blood sample will be collected from each infant and genome sequencing may be performed. Six weeks later, results are returned and explained. Over 12 months the investigators are studying the experiences of parents and pediatricians of infants who receive sequencing to help understand how best to use genomics in pediatric care.

Detailed Description
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The objective of this research protocol is to conduct a randomized clinical trial to assess the benefits and risks of adding the information from a genomic sequencing report to physician-mediated medical care of newborns during their pediatric years. The investigators will enroll 240 healthy infants and their parents from the Brigham and Women's Hospital (BWH) Well Newborn Nursery and 240 sick infants and their parents at Boston Children's Hospital (BCH) or the BWH Neonatal Intensive Care Unit (NICU). A small blood sample will be obtained from each enrolled infant. Samples will be collected from all infants enrolled, regardless of the arm to which they are assigned, in order to follow the same protocol for all subjects prior to randomization. Infants within each cohort will be randomized (1:1) to either standard-of-care (family history and standard newborn screening report) or to standard-of-care plus genomic sequencing. A study physician and genetic counselor will disclose the infant's randomization assignment and study results during an in-person consultation with each family. The study physician and genetic counselor will provide the consultation to families utilizing all available medical information. In the sequencing arm of the study, this will include the medical history, physical exam, family history, standard newborn screening (NBS) report and sequencing report(s). In the non-sequencing arm of the study, this will include the medical history, physical exam, family history and standard NBS report. Parents will be surveyed at four points over the 12 months after enrollment: baseline, immediately post-disclosure (approximately 6 weeks after enrollment), 3 months post-disclosure, and at 10 months post-disclosure.

Official Title
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Genomic Sequencing for Childhood Risk and Newborn Illness (The BabySeq Project)

Conditions
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Hereditary Disease, Genetic Predisposition to Disease

Intervention / Treatment
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* Genetic: Genomic sequencing
* Other: Family history report


Participation Criteria
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Eligibility Criteria
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Newborns and Parents at Brigham and Women's Hospital (BWH) Well Newborn Nursery: Inclusion Criteria : Infants born at BWH and admitted to the Well Newborn Nursery At least one biological parent is physically available to have genetic counseling, donate DNA, and provide consent for testing the infant. If the second biological parent is known but not physically present, the second biological parent must be available to have genetic counseling by phone, return a signed consent form by mail, and donate DNA via a mailed saliva kit. If there is a rearing parent (an individual who is not biologically related to the infant, but who is dedicated to raising the child), that individual must also provide consent but will not be asked to submit a saliva sample. Mother (either rearing or biological) carried the pregnancy Exclusion Criteria: Parents are non-English speaking Parents are unwilling to have genomic reports placed in the medical record or sent to their primary care pediatrician Mother or father younger than 18 years of age Mother or father with impaired decisional capacity Age of infant is older than 30 days One of a multiple gestation Any infant in which clinical considerations preclude drawing 1.0 ml of blood Missing consent of either biological parent (if known) or rearing parent (if applicable) Sick Newborns and Parents at Boston Children's Hospital (BCH) or the BWH NICU: Inclusion Criteria: Infants admitted to BCH or the BWH NICU At least one biological parent is physically available to have genetic counseling, donate DNA, and provide consent for testing the infant. If the second biological parent is known but not physically present, the second biological parent must be available to have genetic counseling by phone, return a signed consent form by mail, and donate DNA via a mailed saliva kit. If there is a rearing parent (an individual who is not biologically related to the infant, but who is dedicated to raising the child), that individual must also provide consent but will not be asked to submit a saliva sample. Mother (either biological or rearing) carried the pregnancy Exclusion Criteria: Parents are non-English speaking Parents are unwilling to have genomic reports placed in the medical record or sent to their primary care pediatrician Mother or father younger than 18 years of age Mother or father with impaired decisional capacity Age of infant is older than 30 days One of a multiple gestation Any infant in which clinical considerations preclude drawing 1.0 ml of blood Hospital admission expected to be less than 72 hours Missing consent of either biological parent (if known) or rearing parent (if applicable) Previously performed exome/genome sequencing on patient
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: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Well Baby Family History Only<br>Parents of newborns in well-baby units receive an Annotated Family History Report only. Active Comparator: Standard of Care Only: Family History report only | Other: Family history report<br>* Participants from all arms of the study will have a family history taken by a study genetic counselor. Information collected through the family history will be summarized in a family history report that will be reviewed with all participants.<br>|
| Experimental: Well Baby Family History + Exome Sequencing<br>Parents of newborns in well-baby units receive a Genome Report and an Annotated Family History Report. Main Study Experimental: Genome Report and Family History report | Genetic: Genomic sequencing<br>* Both sick and healthy infants randomized to receive genomic sequencing will receive a 'Genomic Newborn Sequencing Report' (GNSR) which will include pathogenic or likely pathogenic variants identified in genes associated with childhood-onset disease.<br>Other: Family history report<br>* Participants from all arms of the study will have a family history taken by a study genetic counselor. Information collected through the family history will be summarized in a family history report that will be reviewed with all participants.<br>|
| Active Comparator: ICU Baby Family History Only<br>Parents of newborns in intensive care units receive an Annotated Family History Report only. Active Comparator: Standard of Care Only: Family History report only | Other: Family history report<br>* Participants from all arms of the study will have a family history taken by a study genetic counselor. Information collected through the family history will be summarized in a family history report that will be reviewed with all participants.<br>|
| Experimental: ICU Baby Family History + Exome Sequencing<br>Parents of newborns in intensive care units receive a Genome Report and an Annotated Family History Report. Main Study Experimental: Genome Report and Family History report | Genetic: Genomic sequencing<br>* Both sick and healthy infants randomized to receive genomic sequencing will receive a 'Genomic Newborn Sequencing Report' (GNSR) which will include pathogenic or likely pathogenic variants identified in genes associated with childhood-onset disease.<br>Other: Family history report<br>* Participants from all arms of the study will have a family history taken by a study genetic counselor. Information collected through the family history will be summarized in a family history report that will be reviewed with all participants.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Downstream Health Care Costs Attributable to BabySeq Project Disclosure: Days of Inpatient Care | Days spent in inpatient care from disclosure of randomization status / genomic sequencing results through 10 months post-disclosure. Services were identified through a combination of chart note review, medical record review and participant surveys. | From disclosure through 10 Months post-disclosure (approx. 15 months after baseline). | 
| Parents' Distress | Parents' Distress was assessed using validated scales measuring Anxiety and Depression, and a novel item assessing Blame with responses ranging from 1 to 5. Higher scores indicate more distress. Anxiety per the Edinburgh Postnatal Depression Scale anxiety subscale (baseline, post-disclosure, and 3 months; scores ranging from 0 to 9); Anxiety per the Generalized Anxiety Disorder Scale-7 (3 months and 10 months; scores ranging from 0 to 21); Depression per the Edinburgh Postnatal Depression Scale (baseline, post-disclosure, and 3 months; scores ranging from 0 to 30); Depression per the Patient Health Questionnaire-9 (3 months and 10 months; scores ranging from 0 to 30); Self-blame per a novel item (3 months and 10 months) | From baseline through 10 post-disclosure, with time points varying by measure. (Post-disclosure approx. 5 months after baseline; 3-months approx. 8 months after baseline; 10-months approx. 15 months after baseline) | 
| Parent-Child Relationship | Parent-Child Relationship was assessed using validated scales measuring parents' perceptions of parenting stress (General parenting stress per the Parenting Stress Index™, 4th Edition Short Form (10 months); scores range from 36 to 180), how vulnerable they perceive their child to be (Parents' perception of baby's vulnerability per the Vulnerable Baby Scale (baseline, postdisclosure, 3 months, 10 months); scores range from 4 to 20), and how they are bonding with their child (Parent-child bonding per the Mother-to-Infant Bonding Scale (baseline, postdisclosure, 3 months, 10 months); scores range from 0 to 24). Lower bonding scores indicate more problems with bonding. For other measures, higher scores indicate higher stress and perceptions of vulnerability. | From baseline through 10 post-disclosure, with time points varying by measure. (Post-disclosure approx. 5 months after baseline; 3-months approx. 8 months after baseline; 10-months approx. 15 months after baseline) | 
| Parents' Relationship | Parents' Relationship was assessed using validated and novel measures of marital satisfaction using the Relationship satisfaction per the Kansas Marital Satisfaction Scale (3 months; scores ranging from 3 to 15), relationship conflict per a novel item (all time points; scores ranging from 1 to 5), and partner blame per a novel item (3 months and 10 months; scores ranging from 1 to 5). Higher scores on Satisfaction indicates more Satisfaction. Higher scores on Conflict and Blame indicate higher conflict and blame. | From baseline through 10 post-disclosure, with time points varying by measure. Post-disclosure approx. 5 months after baseline; 3-months approx. 8 months after baseline; 10-months approx. 15 months after baseline. | 
| Downstream Health Care Utilization Attributable to BabySeq Project Disclosure: Number of Health Care Provider Visits | Per-patient counts for number of health care provider visits. Services were identified through a combination of chart note review, medical record review and participant surveys. | From disclosure through 10 Months post-disclosure (approx. 15 months after baseline) | 
| Downstream Health Care Utilization Attributable to BabySeq Project Disclosure: Number of Current Medications at 10 Months | Per-patient counts for number of current medications at 10 months. Services were identified through a combination of chart note review, medical record review and participant surveys. | From disclosure through 10 Months post-disclosure (approx. 15 months after baseline) | 
| Downstream Health Care Utilization Attributable to BabySeq Project Disclosure: Number of ER Visits | Per-patient counts number of ER visits. Services were identified through a combination of chart note review, medical record review and participant surveys. | From disclosure through 10 Months post-disclosure (approx. 15 months after baseline) | 
| Downstream Health Care Utilization Attributable to BabySeq Project Disclosure: Number of Outpatient Lab Tests | Per-patient counts for number of outpatient lab tests after results disclosure. Services were identified through a combination of chart note review, medical record review and participant surveys. | From disclosure through 10 Months post-disclosure (approx. 15 months after baseline) | 
| Downstream Health Care Utilization Attributable to BabySeq Project Disclosure | Per-patient means (SDs) for healthcare costs (in U.S. dollars) after disclosure of randomization status / genomic results from the BabySeq project. Services were identified through a combination of chart note review, medical record review and participant surveys. | From disclosure through 10 Months post-disclosure (approx. 15 months after baseline) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Perceived Utility Toward Genomic Sequencing | A novel survey item asked participants to rate the usefulness of whole genome sequencing results for managing health on a 1-10 scale at baseline and 3 months post-disclosure. Responses were on a 10-point scale anchored by not at all useful (1) to extremely useful (10). | From Baseline to 3 Months post-disclosure (approx. 8 months after baseline) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Genome Sequencing, Exome Sequencing, Newborn Screening, Childhood Onset Genetic Conditions