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| ID | Type | Description | Link |
|---|---|---|---|
| R01HD055651 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | NIH |
| Baylor College of Medicine | OTHER |
| University of North Carolina | OTHER |
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This study is evaluating the impact of prenatal sequencing on the management of fetuses with ultrasound abnormalities. The hypothesis is that a significant subset of fetal abnormalities have a genetic cause that can be identified by sequencing and that prenatal knowledge of this information will improve prenatal care, reduce unnecessary diagnostic testing, reduce the cost of care, and improve the quality of life for both the child and the family.
Whole exome and whole genome sequencing (WGS) have expanded the ability to determine the genetic etiology of previously undiagnosed disorders. This study is a multicenter prospective cohort study to evaluate the emerging technology of sequencing for the management of fetuses with structural anomalies. The hypothesis is that a significant subset of fetal structural anomalies has a genetic etiology identifiable by sequencing and that prenatal knowledge of this information will improve perinatal care, reduce unnecessary diagnostic testing, reduce the cost of care, and improve quality of life for both the child and the family. The aims of this study are to investigate these multiple aspects of prenatal sequencing in a single study with an innovative integrated prospective design, which will permit a robust evaluation of the benefits and risks of delivering diagnostic and prognostic genetic testing results in a prenatal setting.
The study will determine, in a sequential population of pregnancies with selected fetal structural anomalies and a negative or non-causal chromosomal microarray (CMA), the frequency of pathogenic, likely pathogenic, and uncertain genomic variants identifiable by sequencing. To determine the impact of this information on clinical care, a control population of unsequenced pregnancies with similar structural anomalies will be prospectively recruited and the infants from both cohorts will be followed up to 1 year of age. This study component will evaluate differences in healthcare management and cost through discharge from hospital post-delivery, and perinatal and infant outcomes through 1 year of life. The educational, counseling and psychosocial impact of sequencing results during the prenatal period, in the nursery and through 1 year of life also will be evaluated. Since the analytical and clinical tools needed for the full translation of sequencing into care are still developing, optimization of bioinformatic tools to improve identification of pathogenic and likely pathogenic mutations associated with prenatal phenotypes of established disease genes will be investigated, as well as identification of new genes associated with presently undiagnosed fetal/neonatal phenotypes. This study will provide an in-depth evaluation of the prenatal diagnostic value of sequencing prior to its responsible introduction into practice and will provide independent data to guide its translation.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Prenatally Sequenced Group | 750 trios with fetal structural anomalies who receive prenatal sequencing from the study |
| |
| No Prenatal Sequencing (Unsequenced) Group | 350 trios with fetal structural anomalies who do not have prenatal sequencing |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Prenatal Genomic Sequencing | Diagnostic Test | Whole genome sequencing (which initially will be masked and reported as exome only) |
|
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants Who Had Reportable Variants | Reportable variants: defined as either Pathogenic / Likely pathogenic (P/LP) or variant of uncertain significance (VUS) identified by sequencing and deemed reportable by the Variant Adjudication Committee. | At end of study, approx 4 years |
| Healthcare Costs | Healthcare costs from time of diagnosis of anomaly to infant discharge between sequenced and unsequenced groups. | From time of diagnosis of anomaly to infant discharge |
| Measure | Description | Time Frame |
|---|---|---|
| Gestational Age at Delivery | Gestational age of newborn at delivery (in weeks) | At time of delivery |
| Neonatal Outcomes | Neonatal outcomes will be compared and outcomes will be measured by the number of newborns who experience: need for ventilator support, sepsis, need for pressor support, need for extracorporeal membrane oxygenation (ECMO), metabolic abnormalities (e.g., acidosis, elevated uric acid, hypo-/hyperglycemia), intraventricular hemorrhage, periventricular leukomalacia, encephalopathy, and seizure. |
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Inclusion Criteria:
Prenatal sequencing group
Fetus identified by ultrasound and/or MRI with at least one of the following:
Negative prenatal CMA (or those with CMA findings not related to the ultrasound finding)
Singleton or twin gestation
Gestational age less than 36 weeks, 0 days to allow for availability of sequencing results before delivery
Unsequenced Group
Fetus identified by ultrasound and/or MRI with at least one of the following:
Negative prenatal or postnatal CMA (or those with CMA findings not related to the ultrasound finding)
Declined prenatal sequencing
Singleton gestation
Exclusion Criteria:
Prenatal Sequencing Group
Unsequenced Group
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A total of 1,100 pregnancies with fetal structural anomalies and meeting eligibility criteria will be enrolled into the study. Of these, 750 will undergo prenatal genomic sequencing (prenatal sequencing group) and the remaining 350 pregnancies will not have any prenatal genomic sequencing (unsequenced prenatal group).
Enrollment of pregnancies with an isolated nuchal translucency measurements ≥ 3.5 mm will be restricted to 5% within each group (sequenced and unsequenced) and isolated estimated fetal weight <5th %ile also will be restricted to 5% for each group (sequenced and unsequenced).
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| Name | Affiliation | Role |
|---|---|---|
| Ronald Wapner, MD | Columbia University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Columbia University Medical Center | New York | New York | 10032 | United States | ||
| University of North Carolina Chapel Hill |
In accordance with the NIH Genomic Data Sharing policy, sequencing data (including VCF files) and clinical data will be shared with other scientific investigators and through the controlled access dbGAP repository or comparable genomics commons, the Sequence Read Archive, and any NIH Birth Defects Commons that is established. A final dataset containing clinical and phenotypic data will be submitted to the NICHD data repository (DASH). In addition, new algorithms and allele frequency data will be shared with the newly developed Precision FDA platform as applicable.
After study completion.
Through dbGaP or other controlled access databases.
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Signed informed consent was obtained from the mother and the genetic father of the fetus prior to any study procedures for prospective enrollment. Enrollment of participants in the retrospective unsequenced prenatal group occurred under a waiver of consent. The "participants" in this record refer to the fetuses from which all study data was collected.
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| ID | Title | Description |
|---|---|---|
| FG000 | Prenatally Sequenced Group | Pregnancies with fetal structural anomalies will undergo prenatal genomic sequencing. |
| FG001 | No Prenatal Sequencing (Unsequenced) Group | Pregnancies will not have any prenatal genomic sequencing. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Prenatally Sequenced Group | Pregnancies with fetal structural anomalies will undergo prenatal genomic sequencing. |
| BG001 | No Prenatal Sequencing (Unsequenced) Group | Pregnancies will not have any prenatal genomic sequencing. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Gestational age at diagnosis |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Participants Who Had Reportable Variants | Reportable variants: defined as either Pathogenic / Likely pathogenic (P/LP) or variant of uncertain significance (VUS) identified by sequencing and deemed reportable by the Variant Adjudication Committee. | Only participants in the sequenced group were analyzed for this outcome. | Posted | Count of Participants | Participants | At end of study, approx 4 years |
|
|
Through study completion, an average of 12 months
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Prenatally Sequenced Group | Pregnancies with fetal structural anomalies will undergo prenatal genomic sequencing. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Jessica L Giordano, CGC | Columbia University | 516-521-5604 | jlg2197@cumc.columbia.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jan 14, 2019 | Oct 13, 2025 | Prot_SAP_000.pdf |
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| The George Washington University Biostatistics Center |
| OTHER |
| Oregon Health and Science University | OTHER |
| Children's Hospital Medical Center, Cincinnati | OTHER |
| The University of Texas Health Science Center, Houston | OTHER |
| Broad Institute of MIT and Harvard | OTHER |
| The Jackson Laboratory | OTHER |
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Remaining DNA from trios will be stored in a biorepository. Plasma from Streck tubes will be retained as well.
| Up to 28 days after birth |
| Number of Deaths | Neonatal/infant death at time of discharge and at 12 months of age. | From discharge to 12 months postpartum |
| NICU Stay Duration | Length of initial NICU stay and number of days spent in the hospital between initial discharge and 12 months of age. | From discharge to 12 months postpartum |
| Length in Centimeters | Infant length at 12 months of age. | 12 months postpartum |
| Weight in Kilograms | Infant weight at 12 months of age. | 12 months postpartum |
| Score on Development by Ages and Stages Questionnaire (ASQ-3) | Developmental outcomes defined by the following parameters: communication, gross motor, fine motor, problem solving and personal-social, at 12 months of age using ASQ-3. Lower scores are associated with developmental delay. For each developmental area, parents may answer YES=10, SOMETIMES=5, or NOT YET=0 by filling in a bubble for each item response. The full score range for each domain is 0 to 60. Cutoffs for each domain are: Communication 15.64, Gross Motor 21.49, Fine Motor 34.5, Problem Solving 27.32, Personal-Social 21.73 | 12 months postpartum |
| Anxiety by Self-report Questionnaire | Anxiety following result disclosure (or 8 weeks post enrollment for the unsequenced group), neonatal discharge and 12 months postpartum. The full score range is 0 to 21, where lower numbers represent lower anxiety (better outcome). | 2 weeks after disclosure of study sequencing results or 4 weeks after enrollment for the unsequenced group; 1 month after discharge from the hospital or end of the pregnancy if there was a fetal demise or pregnancy termination; 12-15 months postpartum |
| Depression by Self-report Questionnaire | Depression following result disclosure (or 8 weeks post enrollment for the unsequenced group), neonatal discharge and 12 months postpartum. The full score range is 0 to 24, where a lower score represents lower depression (better outcome). | 2 weeks after disclosure of study sequencing results or 4 weeks after enrollment for the unsequenced group; 1 month after discharge from the hospital or end of the pregnancy if there was a fetal demise or pregnancy termination; 12-15 months postpartum |
| Quality of Life by Self-report Questionnaire | Quality of life for the patient and family at 12 months postpartum. | Approximately 4.5 years |
| QALY, Measured in Cost Per Year | Incremental cost per Quality Adjusted Life Year (QALY). | Approximately 4.5 years |
| Total Number of Identified Phenotypes Associated With Disease- Sequenced Group ONLY | Phenotypic Expansion: Apparent prenatal phenotypic expansion from currently defined pediatric phenotypes. | 12 months postpartum |
| Number of Participants With VUS - Sequenced Group ONLY | Variants of uncertain significance (VUS) that have not yet been associated with this disease phenotype. This outcome was only intended to be measured in participants in the Sequenced arm, as outlined in the study protocol. Data for this outcome was not collected from any participant in the Unsequenced arm. | 12 months postpartum |
| Number of Participants With Variants Classified as GUS - Sequenced Group ONLY | VUS subclassified as compelling variants in novel genes that are not yet disease associated (genes of uncertain clinical significance; GUS). This outcome was only intended to be measured in participants in the Sequenced arm, as outlined in the study protocol. Data for this outcome was not collected from any participant in the Unsequenced arm. | 12 months postpartum |
| Digital WES - Comparison of Coding and Non-coding Results - Sequenced Group ONLY | Pathogenic, likely pathogenic and VUS variants identified by sequencing (coding and non-coding regions) compared with coding regions only (digital WES). | Approximately 4.5 years |
| Proband Only Versus Trio - Comparison of Results Between Trio and Proband Only - Sequenced Group ONLY | Pathogenic, likely pathogenic and VUS variants identified by analysis of a proband alone compared to a proband-parent trio. | Approximately 4.5 years |
| Change in Management (Healthcare) as Determined by NICU Physician and Record Review - Sequenced Group ONLY | Number of participants who had a change in management decisions attributable to genomic results, defined as changes to the patient's treatment plan or changes to the counseling of the patient/family regarding the immediate or long-term medical management. This outcome was only intended to be measured in participants in the Sequenced arm, as outlined in the study protocol. Data for this outcome was not collected from any participant in the Unsequenced arm. | From delivery until discharge or death (neonatal) |
| Parental Support Needs by Self-report Questionnaire - Sequenced Group ONLY | Assessment of educational/counseling and social support needs of the mother and father. The full score range is 12 to 60, where a higher score represents a higher satisfaction with the experience (better outcome). | At sequencing completion, approximately 4.5 years |
| Parental Understanding by Self-report Questionnaire - Sequenced Group ONLY | Accuracy of parental understanding of genetic test results. The parental responses to the question "How well do you understand your prenatal genetic test results?" will be collected. All possible responses are: "Not at all", "A little bit", "Moderately", "Quite a bit", and "Extremely" | At sequencing completion, approximately 4.5 years |
| Number of Participants Who Had a Change in the Sequencing Result - Sequenced Group ONLY | Reinterpretations of sequencing results that lead to a change in classification of sequencing variants. This outcome was only intended to be measured in participants in the Sequenced arm, as outlined in the study protocol. Data for this outcome was not collected from any participant in the Unsequenced arm. | From sequencing completion to data analysis period, up to 4.5 years |
| Turnaround Time - Sequenced Group ONLY | Turnaround time of sequencing components and how it changes over time. This outcome was only intended to be measured in participants in the Sequenced arm, as outlined in the study protocol. Data for this outcome was not collected from any participant in the Unsequenced arm. | Time from sequencing initiation until study site result, up to 38 days |
| Chapel Hill |
| North Carolina |
| 27514 |
| United States |
| Children's Hospital, Cincinnati Medical Center | Cincinnati | Ohio | 45229 | United States |
| Baylor College of Medicine | Houston | Texas | 77030 | United States |
| UT Health Houston | Houston | Texas | 77030 | United States |
| BG002 | Total | Total of all reporting groups |
| Median |
| Inter-Quartile Range |
| weeks |
|
| Sex: Female, Male | Sex/gender was not collected from any fetus | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Of the 346 enrolled in the unsequenced comparison cohort, 150 were enrolled prospectively and 196 were retrospectively enrolled. Paternal race/ethnicity was not collected from the retrospective cohort. Paternal race/ethnicity was not collected from one participant in the sequenced arm. | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Anomaly systems involved | Count of Participants | Participants |
|
| Type of anomaly | Count of Participants | Participants |
|
| Participants |
|
|
| Primary | Healthcare Costs | Healthcare costs from time of diagnosis of anomaly to infant discharge between sequenced and unsequenced groups. | Posted | Mean | Standard Deviation | US dollars | From time of diagnosis of anomaly to infant discharge |
|
|
|
| Secondary | Gestational Age at Delivery | Gestational age of newborn at delivery (in weeks) | Posted | Median | Inter-Quartile Range | weeks | At time of delivery |
|
|
|
| Secondary | Neonatal Outcomes | Neonatal outcomes will be compared and outcomes will be measured by the number of newborns who experience: need for ventilator support, sepsis, need for pressor support, need for extracorporeal membrane oxygenation (ECMO), metabolic abnormalities (e.g., acidosis, elevated uric acid, hypo-/hyperglycemia), intraventricular hemorrhage, periventricular leukomalacia, encephalopathy, and seizure. | Posted | Count of Participants | Participants | Up to 28 days after birth |
|
|
|
| Secondary | Number of Deaths | Neonatal/infant death at time of discharge and at 12 months of age. | Posted | Number | deaths | From discharge to 12 months postpartum |
|
|
|
| Secondary | NICU Stay Duration | Length of initial NICU stay and number of days spent in the hospital between initial discharge and 12 months of age. | Posted | Median | Inter-Quartile Range | days | From discharge to 12 months postpartum |
|
|
|
| Secondary | Length in Centimeters | Infant length at 12 months of age. | Data was collected from participants who had a follow-up visit at 12 months postpartum. | Posted | Mean | Standard Deviation | cm | 12 months postpartum |
|
|
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| Secondary | Weight in Kilograms | Infant weight at 12 months of age. | Data was collected from participants who had a follow-up visit at 12 months postpartum. | Posted | Mean | Standard Deviation | kg | 12 months postpartum |
|
|
|
| Secondary | Score on Development by Ages and Stages Questionnaire (ASQ-3) | Developmental outcomes defined by the following parameters: communication, gross motor, fine motor, problem solving and personal-social, at 12 months of age using ASQ-3. Lower scores are associated with developmental delay. For each developmental area, parents may answer YES=10, SOMETIMES=5, or NOT YET=0 by filling in a bubble for each item response. The full score range for each domain is 0 to 60. Cutoffs for each domain are: Communication 15.64, Gross Motor 21.49, Fine Motor 34.5, Problem Solving 27.32, Personal-Social 21.73 | Only includes participants who completed the follow-up questionnaire | Posted | Median | Inter-Quartile Range | score on a scale | 12 months postpartum |
|
|
|
| Secondary | Anxiety by Self-report Questionnaire | Anxiety following result disclosure (or 8 weeks post enrollment for the unsequenced group), neonatal discharge and 12 months postpartum. The full score range is 0 to 21, where lower numbers represent lower anxiety (better outcome). | Only includes participants who completed the questionnaire | Posted | Median | Full Range | score on a scale | 2 weeks after disclosure of study sequencing results or 4 weeks after enrollment for the unsequenced group; 1 month after discharge from the hospital or end of the pregnancy if there was a fetal demise or pregnancy termination; 12-15 months postpartum |
|
|
|
| Secondary | Depression by Self-report Questionnaire | Depression following result disclosure (or 8 weeks post enrollment for the unsequenced group), neonatal discharge and 12 months postpartum. The full score range is 0 to 24, where a lower score represents lower depression (better outcome). | Only includes participants who completed the questionnaire | Posted | Median | Full Range | score on a scale | 2 weeks after disclosure of study sequencing results or 4 weeks after enrollment for the unsequenced group; 1 month after discharge from the hospital or end of the pregnancy if there was a fetal demise or pregnancy termination; 12-15 months postpartum |
|
|
|
| Secondary | Quality of Life by Self-report Questionnaire | Quality of life for the patient and family at 12 months postpartum. | Not Posted | Jul 2026 | Approximately 4.5 years | Participants |
| Secondary | QALY, Measured in Cost Per Year | Incremental cost per Quality Adjusted Life Year (QALY). | Not Posted | Jul 2026 | Approximately 4.5 years | Participants |
| Secondary | Total Number of Identified Phenotypes Associated With Disease- Sequenced Group ONLY | Phenotypic Expansion: Apparent prenatal phenotypic expansion from currently defined pediatric phenotypes. | This outcome was only intended to be measured in participants in the Sequenced arm, as outlined in the study protocol. Data for this outcome was not collected from any participant in the Unsequenced arm. | Posted | Number | phenotypes | 12 months postpartum |
|
|
|
| Secondary | Number of Participants With VUS - Sequenced Group ONLY | Variants of uncertain significance (VUS) that have not yet been associated with this disease phenotype. This outcome was only intended to be measured in participants in the Sequenced arm, as outlined in the study protocol. Data for this outcome was not collected from any participant in the Unsequenced arm. | Posted | Count of Participants | Participants | 12 months postpartum |
|
|
|
| Secondary | Number of Participants With Variants Classified as GUS - Sequenced Group ONLY | VUS subclassified as compelling variants in novel genes that are not yet disease associated (genes of uncertain clinical significance; GUS). This outcome was only intended to be measured in participants in the Sequenced arm, as outlined in the study protocol. Data for this outcome was not collected from any participant in the Unsequenced arm. | Posted | Count of Participants | Participants | 12 months postpartum |
|
|
|
| Secondary | Digital WES - Comparison of Coding and Non-coding Results - Sequenced Group ONLY | Pathogenic, likely pathogenic and VUS variants identified by sequencing (coding and non-coding regions) compared with coding regions only (digital WES). | Not Posted | Jul 2026 | Approximately 4.5 years | Participants |
| Secondary | Proband Only Versus Trio - Comparison of Results Between Trio and Proband Only - Sequenced Group ONLY | Pathogenic, likely pathogenic and VUS variants identified by analysis of a proband alone compared to a proband-parent trio. | Not Posted | Jul 2026 | Approximately 4.5 years | Participants |
| Secondary | Change in Management (Healthcare) as Determined by NICU Physician and Record Review - Sequenced Group ONLY | Number of participants who had a change in management decisions attributable to genomic results, defined as changes to the patient's treatment plan or changes to the counseling of the patient/family regarding the immediate or long-term medical management. This outcome was only intended to be measured in participants in the Sequenced arm, as outlined in the study protocol. Data for this outcome was not collected from any participant in the Unsequenced arm. | Posted | Count of Participants | Participants | From delivery until discharge or death (neonatal) |
|
|
|
| Secondary | Parental Support Needs by Self-report Questionnaire - Sequenced Group ONLY | Assessment of educational/counseling and social support needs of the mother and father. The full score range is 12 to 60, where a higher score represents a higher satisfaction with the experience (better outcome). | Only includes participants in the sequenced group who completed the questionnaire | Posted | Median | Full Range | score on a scale | At sequencing completion, approximately 4.5 years |
|
|
|
| Secondary | Parental Understanding by Self-report Questionnaire - Sequenced Group ONLY | Accuracy of parental understanding of genetic test results. The parental responses to the question "How well do you understand your prenatal genetic test results?" will be collected. All possible responses are: "Not at all", "A little bit", "Moderately", "Quite a bit", and "Extremely" | Only includes participants in the sequenced group who completed the questionnaire | Posted | Number | parental responses | At sequencing completion, approximately 4.5 years |
|
|
|
| Secondary | Number of Participants Who Had a Change in the Sequencing Result - Sequenced Group ONLY | Reinterpretations of sequencing results that lead to a change in classification of sequencing variants. This outcome was only intended to be measured in participants in the Sequenced arm, as outlined in the study protocol. Data for this outcome was not collected from any participant in the Unsequenced arm. | Posted | Count of Participants | Participants | From sequencing completion to data analysis period, up to 4.5 years |
|
|
|
| Secondary | Turnaround Time - Sequenced Group ONLY | Turnaround time of sequencing components and how it changes over time. This outcome was only intended to be measured in participants in the Sequenced arm, as outlined in the study protocol. Data for this outcome was not collected from any participant in the Unsequenced arm. | Posted | Mean | Standard Deviation | days | Time from sequencing initiation until study site result, up to 38 days |
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|
| 75 |
| 751 |
| 0 |
| 751 |
| 0 |
| 751 |
| EG001 | No Prenatal Sequencing (Unsequenced) Group | Pregnancies will not have any prenatal genomic sequencing. | 37 | 346 | 0 | 346 | 0 | 346 |
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| Hispanic |
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| Other |
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| Hispanic |
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| Other |
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| Pressor support |
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| Sepsis |
|
| Metabolic abnormalities |
|
| Intraventricular hemorrhage |
|
| Periventricular leukomalacia |
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| Encephalopathy |
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| Seizure |
|
| Fine motor |
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| Problem solving |
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| Personal-social |
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| 1 month after discharge from the hospital or end of the pregnancy |
|
|
| 12-15 months postpartum |
|
|
| 1 month after discharge from the hospital or end of the pregnancy |
|
|
| 12-15 months postpartum |
|
|
| Moderately |
|
| Quite a bit |
|
| Extremely |
|