Pediatric: Genetic Syndrome
Conditions
Brief summary
The Genomic Medicine for Ill Neonates and Infants (The GEMINI Study) is a research study aimed at comparing the clinical and economic utility of performing rapid whole genomic sequencing versus a targeted genomic sequencing panel on neonates and infants suspected of having a genetic disorder. This study is funded by the National Institutes of Health. This multicenter, prospective clinical trial will enroll 400 subjects at the Floating Hospital for Children at Tufts Medical Center (Boston, MA), Cincinnati Children's Hospital Medical Center (Cincinnati, OH), Mount Sinai Kravis Children's Hospital (New York, NY), North Carolina Children's Hospital (Chapel Hill, NC), Children's Hospital of Pittsburgh (Pittsburgh, PA), and Rady Children's Hospital (San Diego, CA).
Detailed description
This multicenter, prospective clinical trial will examine the diagnostic yield and clinical utility of NewbornDx, a targeted genomic sequencing panel for use in the neonate, and rapid whole genomic sequencing (rWGS) testing in high-risk infants with signs/symptoms consistent with a possible genetic disorder. Infants will undergo NewbornDx and rWGS (proband) testing. The biological parent(s), when available, will undergo NewbornDx testing at the same time as the infant. For rWGS,the infant will undergo testing first. If a specific diagnosis that is consistent with the phenotype is not made with rWGS proband analysis alone, the parent(s) will undergo rWGS. The study will also evaluate the cost effectiveness of each test as well as standard of care (SOC) testing. A retrospective chart review of infants with suspected genetic disorders will be done to understand 1-year cost and health outcomes that would have been incurred in the absence of the advanced testing. The resulting data from the trial will be used in the economic evaluation comparing NewbornDx, rWGS, and SOC over a 1-year period and used as basis to simulate the lifetime cost-effectiveness of these testing strategies. A web-based clinical reference database to provide references, clinical management guidelines, opportunities for clinical trial participation, and support groups for each condition will be developed with separate interfaces for the parent/guardian(s) and medical provider. The clinical reference database will be qualitatively assessed by a survey of medical providers.
Interventions
DIAGNOSTIC_TESTrapid whole genomic sequencing (rWGS)
rWGS and NewbornDx are genomic sequencing platforms
Sponsors
Rady Children's Hospital, San Diego
Children's Hospital Medical Center, Cincinnati
MOUNT SINAI HOSPITAL
University of North Carolina, Chapel Hill
University of Pittsburgh
Tufts Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
NONE
Intervention model description
Single Group - All participants underwent both rGS and NewbornDx.
Eligibility
Sex/Gender
ALL
Age
1 Days to 1 Years
Healthy volunteers
No
Inclusion criteria
* Documented informed consent from the parent/guardian * Signs/symptoms consistent with a possible genetic disorder * Admitted to a hospital participating in this study at the time of enrollment * Less than one year corrected gestational age
Exclusion criteria
* A known genetic diagnosis (e.g. prenatal testing) * Major congenital anomaly associated with a chromosomal anomaly detected on prenatal testing * Presence of documented congenital infection * Infants considered non-viable due to prematurity (\< 23 0/7 weeks GA)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time in Hours to a Positive Result by NewbornDx | 1-2 weeks | Duration of time (hours) to determine diagnosis by NewbornDx |
| The Number of Subjects With a Confirmed Genetic Disorder Detected by NewbornDx | 1-2 weeks | If NewbornDx diagnoses a genetic disorder |
| The Number of Subjects With a Confirmed Genetic Disorder Detected by rWGS | 1-2 weeks | If rWGS diagnoses a genetic disorder |
| Clinical Utility of Genomic Sequencing as Assessed by Changes in Clinical Care Management or Goals of Care | 1 week | The Clinician Assessment of Clinical Utility assessed by physician survey selecting the specific types of 35 possible management changes (i.e. surgical intervention implemented, medication changed, etc.) The intent was to examine any changes in care resulting from completing either genomic sequencing testing. |
| Time in Hours to a Positive Result by rWGS | 1-2 weeks | Duration of time (hours) to determine diagnosis by rWGS |
| Perception of the Clinical Utility of Genomic Sequencing | 1 week | The Clinician Assessment of Clinical Utility assessed by physician survey using units on a likert scale with 1 meaning not useful at all and 5 meaning very useful. The Clinician Assessment of clinical utility was done collectively as a whole for both modes of genomic sequencing. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| One Year Cost-effectiveness of Entire Cohort. | From enrollment to 1 year corrected gestational age | Total cost of hospitalization, post-discharge follow-up until infant's 1 year CGA (corrected gestational age). Cost effectiveness of the cohort was measured across both sequence groups as a single group. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Patients Receiving Genetic Testing in the Study The study included 400 probands, 388 mothers, and 316 fathers who participated
rapid whole genomic sequencing (rWGS): rWGS and NewbornDx are genomic sequencing platforms | 400 |
| Total | 400 |
Baseline characteristics
| Characteristic | Patients Receiving Genetic Testing in the Study |
|---|---|
| Age, Categorical <=18 years | 400 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Age, Continuous | 18 days |
| Diagnostic yield | 49 percentage |
| Ethnicity (NIH/OMB) Hispanic or Latino | 114 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 286 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 4 Participants |
| Race (NIH/OMB) Asian | 22 Participants |
| Race (NIH/OMB) Black or African American | 43 Participants |
| Race (NIH/OMB) More than one race | 63 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 7 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 53 Participants |
| Race (NIH/OMB) White | 208 Participants |
| Region of Enrollment United States | 400 participants |
| Sex: Female, Male Female | 169 Participants |
| Sex: Female, Male Male | 231 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 12 / 400 |
| other Total, other adverse events | 12 / 400 |
| serious Total, serious adverse events | 0 / 400 |
Outcome results
Primary
Clinical Utility of Genomic Sequencing as Assessed by Changes in Clinical Care Management or Goals of Care
The Clinician Assessment of Clinical Utility assessed by physician survey selecting the specific types of 35 possible management changes (i.e. surgical intervention implemented, medication changed, etc.) The intent was to examine any changes in care resulting from completing either genomic sequencing testing.
Time frame: 1 week
Population: Changes were determined via follow-up with the physician of record (intensivist or geneticist). Pre-specified in the protocol to assess and collect as a single group across both sequence tests.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| the Number of Subjects With a Confirmed Genetic Disorder by Newborn Dx | Clinical Utility of Genomic Sequencing as Assessed by Changes in Clinical Care Management or Goals of Care | Any changes in care | 76 Participants |
| the Number of Subjects With a Confirmed Genetic Disorder by Newborn Dx | Clinical Utility of Genomic Sequencing as Assessed by Changes in Clinical Care Management or Goals of Care | Medication | 44 Participants |
| the Number of Subjects With a Confirmed Genetic Disorder by Newborn Dx | Clinical Utility of Genomic Sequencing as Assessed by Changes in Clinical Care Management or Goals of Care | Surgery | 23 Participants |
| the Number of Subjects With a Confirmed Genetic Disorder by Newborn Dx | Clinical Utility of Genomic Sequencing as Assessed by Changes in Clinical Care Management or Goals of Care | Withdrawal of life-sustaining support | 12 Participants |
| the Number of Subjects With a Confirmed Genetic Disorder by Newborn Dx | Clinical Utility of Genomic Sequencing as Assessed by Changes in Clinical Care Management or Goals of Care | Diet | 7 Participants |
| the Number of Subjects With a Confirmed Genetic Disorder by Newborn Dx | Clinical Utility of Genomic Sequencing as Assessed by Changes in Clinical Care Management or Goals of Care | Change in goal of care from comfort to cure | 3 Participants |
| the Number of Subjects With a Confirmed Genetic Disorder by Newborn Dx | Clinical Utility of Genomic Sequencing as Assessed by Changes in Clinical Care Management or Goals of Care | No changes in care | 235 Participants |
Primary
Perception of the Clinical Utility of Genomic Sequencing
The Clinician Assessment of Clinical Utility assessed by physician survey using units on a likert scale with 1 meaning not useful at all and 5 meaning very useful. The Clinician Assessment of clinical utility was done collectively as a whole for both modes of genomic sequencing.
Time frame: 1 week
Population: Physicians of record rated the overall utility of the genomic-sequencing process, based on collective results from both platforms using a 5-point Likert Scale (1, \[not useful at all\], to 5 \[very useful\]). Pre-specified in the protocol to assess and collect as a single group across both sequence tests.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| the Number of Subjects With a Confirmed Genetic Disorder by Newborn Dx | Perception of the Clinical Utility of Genomic Sequencing | Very Useful | 150 Participants |
| the Number of Subjects With a Confirmed Genetic Disorder by Newborn Dx | Perception of the Clinical Utility of Genomic Sequencing | Useful | 152 Participants |
| the Number of Subjects With a Confirmed Genetic Disorder by Newborn Dx | Perception of the Clinical Utility of Genomic Sequencing | Neutral | 60 Participants |
| the Number of Subjects With a Confirmed Genetic Disorder by Newborn Dx | Perception of the Clinical Utility of Genomic Sequencing | Not very useful | 31 Participants |
| the Number of Subjects With a Confirmed Genetic Disorder by Newborn Dx | Perception of the Clinical Utility of Genomic Sequencing | Not useful at all | 5 Participants |
Primary
The Number of Subjects With a Confirmed Genetic Disorder Detected by NewbornDx
If NewbornDx diagnoses a genetic disorder
Time frame: 1-2 weeks
Population: Pre-specified in the protocol to assess and collect as a single group across both sequence tests.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| the Number of Subjects With a Confirmed Genetic Disorder by Newborn Dx | The Number of Subjects With a Confirmed Genetic Disorder Detected by NewbornDx | 109 Participants |
Primary
The Number of Subjects With a Confirmed Genetic Disorder Detected by rWGS
If rWGS diagnoses a genetic disorder
Time frame: 1-2 weeks
Population: Pre-specified in the protocol to assess and collect as a single group across both sequence tests.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| the Number of Subjects With a Confirmed Genetic Disorder by Newborn Dx | The Number of Subjects With a Confirmed Genetic Disorder Detected by rWGS | 195 Participants |
Primary
Time in Hours to a Positive Result by NewbornDx
Duration of time (hours) to determine diagnosis by NewbornDx
Time frame: 1-2 weeks
Population: Pre-specified in the protocol to assess and collect as a single group across both sequence tests.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| the Number of Subjects With a Confirmed Genetic Disorder by Newborn Dx | Time in Hours to a Positive Result by NewbornDx | 100.3 hours |
Primary
Time in Hours to a Positive Result by rWGS
Duration of time (hours) to determine diagnosis by rWGS
Time frame: 1-2 weeks
Population: Pre-specified in the protocol to assess and collect as a single group across both sequence tests.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| the Number of Subjects With a Confirmed Genetic Disorder by Newborn Dx | Time in Hours to a Positive Result by rWGS | 146.6 hours |
Secondary
One Year Cost-effectiveness of Entire Cohort.
Total cost of hospitalization, post-discharge follow-up until infant's 1 year CGA (corrected gestational age). Cost effectiveness of the cohort was measured across both sequence groups as a single group.
Time frame: From enrollment to 1 year corrected gestational age
Population: A decision model simulated and compared total costs of rWGS from enrollment through 1 year corrected gestational age (study period) for: 1) early rGS, and 2) early NewbornDx followed by later rGS for undiagnosed infants. Model inputs included GEMINI data and 2023 Medicare rates; the primary outcome was total costs over the study period. Pre-specified in the protocol to assess and collect as a single group across both sequence tests.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| the Number of Subjects With a Confirmed Genetic Disorder by Newborn Dx | One Year Cost-effectiveness of Entire Cohort. | 388,572 US dollars |