Hearing Loss, Hereditary Disease, Metabolism, Inborn Errors
Conditions
Brief summary
The NC NEXUS research study is exploring the utility of next generation sequencing in newborn screening and parental decision making. The National Institutes of Health (NICHD and NHGRI) are co-funding this study under a single U-19.
Detailed description
The investigators will enroll and perform whole exome sequencing on two cohorts of patients. One cohort will consist of two hundred newborns with no known conditions whose parents will be recruited during the mother's pregnancy. The second cohort will include two hundred infants and children up to the age of five years with diagnosed conditions including conditions detected through standard newborn screening such as phenylketonuria and other inborn errors of metabolism, hearing loss and other rare conditions that may fit criteria for newborn screening in the future. Parents will be introduced to the study by their clinician or a study recruiter. Those who agree to enroll in Phase I will review an online decision guide and be offered a study visit conducted by a genetic counselor to obtain informed consent for genomic sequencing of their child. Parents consenting to have their child's genome sequenced will be seen after the child's birth or at a convenient pre-arranged time and duplicate saliva samples will be collected from the children and one sample will be sent to the BioSpecimen Processing (BSP) Facility and to Dr. Jonathan Berg's laboratory for sequencing and the other sent to the Molecular Genetics Laboratory (MGL) for DNA extraction and storage until needed for clinical confirmation. Results will be returned for diagnostic (in the Diagnosed cohort) and medically actionable disorders of childhood (both cohorts). Two-thirds of parents who consent to sequencing will be randomly assigned to be eligible to request additional findings and use a supplement of the online decision aid. All results will be reported to parents by trained genetic professionals (genetic counselors and clinical geneticists)
Interventions
GENETICWell infant, whole exome sequencing
Whole exome sequencing will be performed in children with diagnosed conditions. Investigators will analyze results that are associated with their condition.
GENETICDiagnosed, whole exome sequencing
In addition to returning results of conditions associated with a child's phenotype, investigators will also analyze genes that are associated with conditions that have childhood onset and are medically actionable.
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Human Genome Research Institute (NHGRI)
RTI International
University of North Carolina, Chapel Hill
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Hours to 5 Years
Healthy volunteers
Yes
Inclusion criteria
* Uncomplicated pregnancy and healthy newborn
Exclusion criteria
* Abnormalities such as major malformation or chromosomal disorder detected prenatally or significant complications during pregnancy or at the time of delivery.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Parental Choices Following Decision Aid | average of 3-6 months | Analysis of parents' decisions after they complete an on-line decision aid to see if they wish to participate in the study. Options will be yes, no, or undecided. |
| Number of Participants Identified With Genetic Conditions Through Whole Exome Sequencing | approximately 3-6 months after DNA sample obtained | Investigators analyzed next generation sequencing (NGS) results in the diagnosed cohort to determine the ability of whole exome sequencing to detect pathogenic variants in genes related to phenotype determined by standard newborn screening (NBS). The category of genes analyzed is termed the Next Generation Sequencing/Newborn Screening (NGS/NBS) category. Healthy newborns with no known genetic conditions also had the NGS/NBS category of genes analyzed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Parental Reaction Scores | Time 3 - 2 weeks after results visit and Time 4 - 3 months after results visit | Test-related distress is assessed with an adapted version of the Multidimensional Impact of Cancer Risk Assessment (MICRA). It asks participants to report how often in the past week they have experienced worries and distress related to their child's genomic sequencing procedure and test results, and the social and familial consequences of sequencing and the test results. Possible responses are provided on the following scale: 0=Never, 1=Rarely, 3=Sometimes, and 5=Often. Because it refers to respondents' experience of their child's sequencing and the test results they received, it is administered only in assessments that occurred after sequencing at Time 3 (2 weeks after results visit and Time 4 (3 months after results visit). Comparisons are made between couples who could chose to receive additional information about their child's genome and a control group who were not eligible to receive additional information. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Well Infant, Whole Exome Sequencing Healthy infants and their parents enrolled in the study prenatally will participate. After the infant is born saliva sample will be collected for DNA extraction and whole exome sequencing will be done. Investigators will analyze genes that are associated with conditions that have childhood onset and are medically actionable. | 61 |
| Diagnosed, Whole Exome Sequencing Infants and children with diagnosed conditions whose parents enroll in the study and consent to having their child sequenced will have saliva samples obtained and whole exome sequencing will be done on extracted DNA. In addition to returning results of conditions associated with the child's phenotype, investigators will also analyze genes that are associated with conditions that have childhood onset and are medically actionable. | 45 |
| Total | 106 |
Baseline characteristics
| Characteristic | Well Infant, Whole Exome Sequencing | Diagnosed, Whole Exome Sequencing | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 61 Participants | 45 Participants | 106 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants | 2 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 51 Participants | 42 Participants | 93 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 4 Participants | 9 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants | 3 Participants | 12 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) White | 44 Participants | 37 Participants | 81 Participants |
| Region of Enrollment United States | 61 Participants | 45 Participants | 106 Participants |
| Sex: Female, Male Female | 29 Participants | 28 Participants | 57 Participants |
| Sex: Female, Male Male | 32 Participants | 17 Participants | 49 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 61 | 0 / 45 |
| other Total, other adverse events | 0 / 61 | 2 / 45 |
| serious Total, serious adverse events | 0 / 61 | 0 / 45 |
Outcome results
Primary
Number of Participants Identified With Genetic Conditions Through Whole Exome Sequencing
Investigators analyzed next generation sequencing (NGS) results in the diagnosed cohort to determine the ability of whole exome sequencing to detect pathogenic variants in genes related to phenotype determined by standard newborn screening (NBS). The category of genes analyzed is termed the Next Generation Sequencing/Newborn Screening (NGS/NBS) category. Healthy newborns with no known genetic conditions also had the NGS/NBS category of genes analyzed.
Time frame: approximately 3-6 months after DNA sample obtained
Population: By definition, there were no well infants in the Diagnosed, whole exome sequencing Arm category.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Well Infant, Whole Exome Sequencing | Number of Participants Identified With Genetic Conditions Through Whole Exome Sequencing | All participants | Hearing Loss | 0 Participants |
| Well Infant, Whole Exome Sequencing | Number of Participants Identified With Genetic Conditions Through Whole Exome Sequencing | Positive NGS/NBS result | Metabolic Disorder | 0 Participants |
| Well Infant, Whole Exome Sequencing | Number of Participants Identified With Genetic Conditions Through Whole Exome Sequencing | Positive NGS/NBS result | Well infant | 1 Participants |
| Well Infant, Whole Exome Sequencing | Number of Participants Identified With Genetic Conditions Through Whole Exome Sequencing | Negative NGS/NBS results | Well infant | 60 Participants |
| Well Infant, Whole Exome Sequencing | Number of Participants Identified With Genetic Conditions Through Whole Exome Sequencing | All participants | Metabolic Disorder | 0 Participants |
| Well Infant, Whole Exome Sequencing | Number of Participants Identified With Genetic Conditions Through Whole Exome Sequencing | Negative NGS/NBS results | Hearing Loss | 0 Participants |
| Well Infant, Whole Exome Sequencing | Number of Participants Identified With Genetic Conditions Through Whole Exome Sequencing | Positive NGS/NBS result | Hearing Loss | 0 Participants |
| Well Infant, Whole Exome Sequencing | Number of Participants Identified With Genetic Conditions Through Whole Exome Sequencing | Negative NGS/NBS results | Metabolic Disorder | 0 Participants |
| Well Infant, Whole Exome Sequencing | Number of Participants Identified With Genetic Conditions Through Whole Exome Sequencing | All participants | Well infant | 61 Participants |
| Diagnosed, Whole Exome Sequencing | Number of Participants Identified With Genetic Conditions Through Whole Exome Sequencing | Negative NGS/NBS results | Metabolic Disorder | 2 Participants |
| Diagnosed, Whole Exome Sequencing | Number of Participants Identified With Genetic Conditions Through Whole Exome Sequencing | All participants | Well infant | 0 Participants |
| Diagnosed, Whole Exome Sequencing | Number of Participants Identified With Genetic Conditions Through Whole Exome Sequencing | All participants | Hearing Loss | 28 Participants |
| Diagnosed, Whole Exome Sequencing | Number of Participants Identified With Genetic Conditions Through Whole Exome Sequencing | All participants | Metabolic Disorder | 17 Participants |
| Diagnosed, Whole Exome Sequencing | Number of Participants Identified With Genetic Conditions Through Whole Exome Sequencing | Positive NGS/NBS result | Well infant | 0 Participants |
| Diagnosed, Whole Exome Sequencing | Number of Participants Identified With Genetic Conditions Through Whole Exome Sequencing | Positive NGS/NBS result | Hearing Loss | 5 Participants |
| Diagnosed, Whole Exome Sequencing | Number of Participants Identified With Genetic Conditions Through Whole Exome Sequencing | Positive NGS/NBS result | Metabolic Disorder | 15 Participants |
| Diagnosed, Whole Exome Sequencing | Number of Participants Identified With Genetic Conditions Through Whole Exome Sequencing | Negative NGS/NBS results | Well infant | 0 Participants |
| Diagnosed, Whole Exome Sequencing | Number of Participants Identified With Genetic Conditions Through Whole Exome Sequencing | Negative NGS/NBS results | Hearing Loss | 23 Participants |
Primary
Parental Choices Following Decision Aid
Analysis of parents' decisions after they complete an on-line decision aid to see if they wish to participate in the study. Options will be yes, no, or undecided.
Time frame: average of 3-6 months
Population: Those parents initially approached received an email link to the 1st Decision Aid. However, they were not considered enrolled unless they came for an in-person consent visit and elected to have their child's genome sequenced.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Well Infant, Whole Exome Sequencing | Parental Choices Following Decision Aid | Said yes or undecided after decision aid | 120 Participants |
| Well Infant, Whole Exome Sequencing | Parental Choices Following Decision Aid | Did not want child sequenced | 25 Participants |
| Diagnosed, Whole Exome Sequencing | Parental Choices Following Decision Aid | Said yes or undecided after decision aid | 57 Participants |
| Diagnosed, Whole Exome Sequencing | Parental Choices Following Decision Aid | Did not want child sequenced | 2 Participants |
Secondary
Parental Reaction Scores
Test-related distress is assessed with an adapted version of the Multidimensional Impact of Cancer Risk Assessment (MICRA). It asks participants to report how often in the past week they have experienced worries and distress related to their child's genomic sequencing procedure and test results, and the social and familial consequences of sequencing and the test results. Possible responses are provided on the following scale: 0=Never, 1=Rarely, 3=Sometimes, and 5=Often. Because it refers to respondents' experience of their child's sequencing and the test results they received, it is administered only in assessments that occurred after sequencing at Time 3 (2 weeks after results visit and Time 4 (3 months after results visit). Comparisons are made between couples who could chose to receive additional information about their child's genome and a control group who were not eligible to receive additional information.
Time frame: Time 3 - 2 weeks after results visit and Time 4 - 3 months after results visit
Population: Total number completing T3 and T4 MICRA scales
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Well Infant, Whole Exome Sequencing | Parental Reaction Scores | T4 | 2.5 score on a scale | Standard Deviation 2.5 |
| Well Infant, Whole Exome Sequencing | Parental Reaction Scores | T3 | 2.3 score on a scale | Standard Deviation 2.4 |
| Diagnosed, Whole Exome Sequencing | Parental Reaction Scores | T3 | 1.7 score on a scale | Standard Deviation 1.5 |
| Diagnosed, Whole Exome Sequencing | Parental Reaction Scores | T4 | 1.5 score on a scale | Standard Deviation 0.4 |
Comparison: T3p-value: 0.168linear mixed effect model
Comparison: T4p-value: 0.026linear mixed effect model